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681

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NATIONAL

HEART, BLOOD VESSEL, LUNG, AND BLOOD

PROGRAM

FIRST ANNUAL REPORT OF THE

DIRECTOR OF THE

NATIONAL HEART AND LUNG INSTITUTE

^ 00 D

FEBRUARY 13, 1974

U.S. DEPARTMENT OF HEALTH. EDUCATION, AND WELFARE

Public Health Service

National Institutes ol Health

N.itinn.ii Heart and Lung Institute

FIRST JWNUAL REPORT OF THE

DIRECTOR OF THE

NATIONAL HEART AND LUNG INSTITUTE

SUBMITTED TO
THE PRESIDENT OF THE UNITED STATES

FOR TRANSMITTAL TO

THE CONGRESS OF THE UNITED STATES

IN ACCORDANCE WITH PUBLIC LAW 92-423

FEBRUARY 13, 1974

U.S. DEPARTMENT OF HEALTH. EDUCATION. AND WELFARE

PUBLIC HEALTH SERVICE

NATIONAL INSTITUTES OF HEALTH

NATIONAL HEART AND LUNG INSTITUTE

6¥l

DEPARTMENT OF HEALTH, EDUCATION. AND WELFARE

PUBLIC HEALTH SERVICE

NATIONAL INSTITUTES OF HEALTH

BETHESDA, MARYLAND 20014

NATIONAL HEART AND LUNG INSTITUTE

February 13, 1974

The President
The White House
Washington, D. C.

Dear Mr. President:

I am pleased to submit to you for transmittal to Congress the first
annual report on the National Heart, Blood Vessel, Lung, and Blood
Program. It highlights the activities, progress, and accomplishments
of the Program during the past calendar year and updates the Program
Plan completed in May 1973. This report is prepared in response to
Section 413(b) of the National Heart, Blood Vessel, Lung, and Blood
Act of 1972 (Public Law 92-423, 86 STAT 679).

The National Heart, Blood Vessel, Lung, and Blood Program is gaining
momentum and interest. Contributing to its implementation, planning,
and evaluation are thousands of scientists, physicians, and other
health professionals across the United States; the National Heart and
Lung Institute and its Advisory Council; other bureaus, institutes,
and divisions of the National Institutes of Health; Federal agencies
and departments both within and without the Department of Health,
Education, and Welfare; and voluntary organizations and interested
and committed citizens .

The Program gives special emphasis to prevention of heart attacks,
the greatest killer in our nation; high blood pressure education, since
millions of our citizens do not know that they have it and that it can
be treated; expansion of the attack on lung diseases, a heretofore
neglected area; and the development of a national blood policy, a
critical national need. Also, the previous emphasis on the control
of sickle cell disease will be continued.

We strongly agree with you that "Keeping People Healthy" is one of our
nation's most important goals for the 1970' s, and appreciate your pledge
to give "increased attention to the fight against diseases of the heart,
blood vessels, and lung which account for more than half of the deaths
in this country."

Respectfully,

Theodore Cooper, M. D.
Director

CONTENTS

Page

I. INTRODUCTION 1

II. HIGHLIGHTS OF THE NATIONAL PROGRAM 7

Highlights: Heart and Blood Vessel Diseases 11

Highlights: Lung Diseases 15

Highlights: Blood Diseases and Blood Resources 17

III. STATUS OF PROGRAM AND UPDATED FIVE-YEAR PLAN 19

Research 21

Heart and Blood Vessel Diseases 23

Lung Diseases 51

Blood Diseases and Blood Resources 75

Prevention, Control, and Education 97

Heart and Blood Vessel Diseases 99

Lung Diseases 105

Blood Diseases and Blood Resources 110

IV. PROGRAM COORDINATION 117

National Collaboration 1 19

Heart and Blood Vessel Diseases 120

Lung Diseases 1 24

Blood Diseases and Blood Resources 126

International Collaboration 1 28

V. MANPOWER DEVELOPMENT 131

Heart and Blood Vessel Diseases 132

Lung Diseases 133

Blood Diseases and Blood Resources 134

VI. IMPLEMENTATION OF OTHER PROVISIONS OF THE ACT 135

National Research and Demonstration Centers 135

Construction 136

Mechanisms of Support 137

Administrative Changes 138

Program Review and Evaluation 139

VII. RESOURCE ALLOCATION PLAN 141

Fiscal Summary and Projections 142

NHLI Staff Allocation Plan 148

APPENDIX A - National Heart, Blood Vessel, Lung, and
Blood Act of 1972

APPENDIX B - Definition of Major Problem Areas

I. INTRODUCTION

The United States, despite its high state of technology, lags behind many other
Western nations in the health of its citizens. In fact, it ranks 24th in the
world with respect to life expectancy for men. The high mortality from heart
and blood vessel diseases is the major contributing factor to this shortened
life expectancy.

The quality and composition of our environment are important to the maintenance
of health — the air we breathe, the water we drink, the food we eat. We can live
only a few minutes without oxygen, a few days without water, and a few weeks
without food. Many of the diseases addressed by the National Program on Heart,
Blood Vessel, Lung, and Blood Diseases are known to be related to the quality
of our environment. The impact of these diseases, as compared to that of other
diseases, is summarized in Table 1.

Table 1. Ranking of Diseases According to Health Impact, United States, 1971

DISEASE

DAYS OF BED
DISABILITY

HOSPITAL
DISCHARGES

HOSPITAL
DAYS

RANK

DAYS"

RANK

NUMBER"

RANK

DAYS"

Influenza & pneumonia
Upper respiratory

1
2

206.241
164.840'

1.311

3.444

"Heart disease

93.137

1.390

17.921

Arthritis
Mental disorders
Fracture! & dislocation?
Malignant neoplasms (Cancerl
Impairments ot back & spine

6
7
8

57.639
41.965
35.626
32.374
31.895

12
5
3
6

217

695

1.249

646

9
3
2

3.837
16.273
17,097

7.785

" 'Hypertensive without heart involvement

"Bronchitis

"Asthma

"Cerebrovascular disease

II
12

27,476
27.388
25.997
24.762

314
264

2,780
5.128

Paralysis

Diabetes

Impairments of lower extremities

Ulcer

14
15
16

24.062
23.739
20.986
17.669

10
8

280
492

10
6

3.498

5,245

" "Emphysema

13.124

Hernia

Gall madder

Absence ol extremities

Impairments of upper extremities

18
19
20
21

11.948
11.892
7.347
5.491

728
530

8
5

4.836
6.922

OtU not #»i>iabkr SOURCE Unpublished Oil* Irom <ht Ninon*! Oni.i for Ht.lth Statistics
In thousands
*' AcSdlMMU by National Program

Through the mandate provided by the National Heart, Blood Vessel, Lung, and Blood
Act of 1972, the nation's scientific and medical resources are beginning to be
mobilized in a national collaboration of Federal, non-Federal, and private organi-
zations, as well as citizens at large.

The initial Program Plan,* dated May 1, 1973, which was forwarded to the President
and Congress, presented a broad program strategy for achieving improved health.
This strategy is:

" . . .to marshall national resources for promoting and restoring
health, and for preventing and treating disease more effectively
by:

• Initiating an ordered sequence of coordinated
program activities ranging from the acquisition
of new knowledge to demonstration and control
programs in the health care setting of the
community

• Providing adequate program evaluation before the
application of existing knowledge to health care
delivery systems

• Evaluating the impact of implemented programs on
the health of the American people."

Within the broad strategy outlined above and in compliance with the National
Heart, Blood Vessel, Lung, and Blood Act of 1972, a multifaceted National Pro-
gram has taken shape. The scope of the evolving program ranges from fundamental
studies of molecules inside single cells within the human system to studies of
effects of pharmacological agents, to development and evaluation of new types of
therapy involving advanced bioengineering concepts. It also includes studies of
patient attitudes, behavioral studies, and investigations dealing with man's
ability to cope with underwater and space environments, reaching into future
vistas of mankind.

In implementing this broad strategy, a number of basic factors having impact on
all program components for the future, as well as the present were considered

*The National Heart, Blood Vessel, Lung, and Blood Program was presented in five
volumes; DHEW Publication Numbers are shown below:

Volume I. National Heart and Lung Institute Summary (NIH 73-515)
Volume II. Report of the National Heart and Lung Advisory Council

(NIH 73-516)
Volume III. Report of the Panel Chairmen (NIH 73-517)
Volume IV. Panel Reports (NIH 73-518 - 73-521)
Volume V. Program Analysis (NIH 73-522 - 73-524)

and dealt with initially. During the past eight months since the Plan was ini-
tiated, six major strategic actions have been taken by the National Heart and
Lung Institute:

1. Reorganization of the Institute's programs.

2. Promotion of collaborative efforts.

3. Creation of an Office of Prevention, Control, and Education.

4. Development of guidelines for national centers.

5. Analysis and evaluation of actions in the initial Plan.

6. Review and assessment of goals, progress, and future
challenges.

These actions are outlined briefly below:

REORGANIZATION

NHLI activities have broadened considerably under the National
Program. To meet these new responsibilities, the Institute has
reorganized its entire program into divisions corresponding to
the major heart, lung, and blood disease areas. This development
is discussed in greater detail in Chapter VI.

collaboration To most effectively utilize all of our national resources to combat
heart, blood vessel, lung, and blood diseases, the NHLI has initi-
ated and fostered collaborative programs involving many sectors of
society. This activity has been promoted through the Interagency
Technical Committee as well as other mechanisms, as elaborated in
Chapter IV.

PREVENTION.
CONTROL. AND
EDUCATION

To implement a special provision of the National Heart, Blood
Vessel, Lung, and Blood Act, the NHLI has created an Office of Pre-
vention, Control, and Education. This office is responsible for
disseminating health information and for public education activi-
ties. It is also responsible for the prevention and control programs
as outlined in Chapter III.

NATIONAL
CENTERS

To expedite the further development of the National Program
throughout the country, explicit criteria and guidelines for the
establishment of national research and demonstration centers have
been developed and released for use by potential applicants. This
action is described further in Chapter VI.

ANALYSIS
OF ACTIONS
IN INITIAL
PLAN

During the past year, the NHLI has made a careful study of the
material upon which the Actions in the initial Plan were based.
As a result, a revised program structure of 22 elements (10 for
heart and blood vessel diseases, 8 for lung diseases, and 4 for
blood diseases and blood resources) was developed as illustrated
in Table 2. This revised program structure is used in this report,
in lieu of the 17-element structure of the initial Plan, to describe
progress, update the Plan, and allocate proposed fiscal resources.
Also, as a part of this study, each Action of the initial Plan has
been examined for its relative importance to the total program.
This report reflects several minor shifts in emphasis resulting
from this analysis.

REVIEW AND
ASSESSMENT
OF GOALS.
PROGRESS.
CHALLENGES

Finally, with respect to the item above, a thorough review and
assessment of Program Goals, Recent Progress, and Future Challenges
have been carried out in each program area. The results of this
assessment are reflected mainly in Chapter III. Actions of the
initial Plan have been updated and some additional items have been
included in the updated Plan.

Table 2. National Heart, Blood Vessel, Lung, and Blood Program Structure

HEART AND BLOOD VESSEL DISEASES

Arteriosclerosis

Hypertension

Cerebrovascular Disease

Coronary Heart Disease

Peripheral Vascular Diseases

Arrhythmias

Heart Failure and Shock

Congenital and Rheumatic Heart Diseases

Cardiomyopathy and Infections of the Heart

10.

Circulatory Assistance

LUNG DISEASES

Structure and Function of the Lung

Pediatric Pulmonary Diseases

Emphysema and Chronic Bronchitis

Fibrotic and Immunologic Lung Diseases

Respiratory Failure

Pulmonary Vascular Diseases

Inhalation Diseases

Respiratory Assistance

BLOOD DISEASES AND 8L00D RESOURCES

Bleeding and Clotting Disorders

Sickle Cell Disease and Related Disorders of the Red Blood Cell

Biomaterials

Blood Resources

This report on the National Program is the first annual report on the activities,
progress, and accomplishments in the Program and is the first update of the 5-Year
National Plan. It supersedes Volume I of the original Plan. In addition to shed-
ding more light on the six strategic actions described above, the report covers
the following topics:

Chapter II. Highlights of the National Program

Chapter III. Status of Program and Updated Five-Year Plan

Chapter IV. Program Coordination

Chapter V. Manpower Development

Chapter VI. Implementation of Other Provisions of the Act

Chapter VII. Resource Allocation Plan.

The National Heart, Blood Vessel, Lung, and Blood Act of 1972 is reproduced in
Appendix A. Definitions, full descriptions, and the mortality and morbidity
impact of major problem areas have been reprinted from the National Heart and
Lung Institute Summary (May 1, 1973) of the National Program and are presented
in Appendix B with definitions of new problem areas added at the end.

Insofar as possible, the report is presented in nontechnical language in order
to communicate with interested laymen who may be unfamiliar with medical termi-
nology. Where such terminology is unavoidable, effort has been made to provide
clarification in the text of the report. Reference to the definitions and dis-
cussions of major heart, blood vessel, lung, and blood problem areas contained
in Appendix B will also be helpful to the lay reader in understanding the con-
cepts discussed in this report.

II. HIGHLIGHTS OF THE NATIONAL PROGRAM

Collectively, heart, blood vessel, lung, and blood diseases cause more deaths
than all other diseases in the United States combined. They have a devastating
effect on the health of our citizens as well as on the nation's economy. More
than 30 million Americans suffer from these diseases. Their impact in terms of
national economic loss has been estimated at more than $40 billion a year. These
figures, while impressive in terms of identifying the problem, fail to convey the
seriousness of the social impact of these diseases — the dimensions of suffering,
grief, disability, stress and hardship, and the effects these diseases have on the
patient and the patient's family.

Why do these diseases overwhelm our current health care system, and is there hope
for a solution to the problem? The principal reason why they overwhelm our health
care system is that we lack the necessary understanding to deal with them effec-
tively. This understanding can be obtained through research. A second reason is
that the results of medical research are sometimes not applied to the health care
system as expeditiously as they might be. Thus, further medical research and the
application of the knowledge gained through research offer substantial hope of
reducing the devastating effects of heart, blood vessel, lung, and blood diseases
in the future. Accordingly, the National Heart, Blood Vessel, Lung, and Blood
Program focuses primarily on two types of efforts: (1) Research Programs, and
(2) Prevention, Control, and Education Programs to bridge the gap between research
findings and clinical application. Currently, the expenditures for research on
these problems represent less than one percent of the total costs for these dis-
eases. For instance, in the case of heart and blood vessel diseases, the estimated
annual cost to the economy is more than $30 billion, while the total Federal expen-
diture for research in this area in FY 72 was about $200 million.* Yet, medical
research is the wisest investment that the nation can make to insure further prog-
ress in the attack against heart, blood vessel, lung, and blood diseases. Thus,
the common interest of everyone in our society dictates a high priority for the
further development of the comprehensive National Heart, Blood Vessel, Lung, and
Blood Program.

*Volume I, National Heart and Lung Institute Summary, May 1973, p. 17

A conceptual strategy for the National Program Plan was presented nearly one
year ago in the National Heart and Lung Institute Summary, referred to earlier.
This initial strategy provided the first approximation of the direction the
program would take, its underlying principles, and its method of implementation.
The strategy was not complete in concept or in operational detail — nor was it
intended to be at this early stage. Each year as we gain more experience and
knowledge in the planning, implementation, and evaluation of a major national
program for biomedical research, the conceptual and operational aspects of the
program will become clearer and more precise. In the initial program strategy,
three underlying principles were outlined as summarized below:

• The long-range goal must be to improve the health of the
American people.

• Programs for achieving this goal must be based on an
orderly progression of sequenced activities from acqui-
sition of fundamental knowledge to the application of
existing knowledge.

• Evaluation of the use of knowledge — both before its appli-
cation in health care delivery and after to determine its
impact on the health of the American people — will be the
key to meeting national health goals.

The major planning problem addressed during this past year has been how to trans-
late abstract goals and principles, conceived at a policy-making level, into
meaningful program activities involving thousands of individuals. In formulating
an attack on this problem, we have reexamined the above principles and found them
still viable. We have extended these principles conceptually into a more complete
strategy. And we have begun to implement this strategy operationally. The
updated program strategy, outlined below, gives increased attention to the impor-
tance of the social and physical aspects of our human environment and their rela-
tionship to health and disease. The operational steps taken to implement this
strategy are described in Chapters III, IV, V, and VI of this report, and the
estimated resources to put the plan into effect are presented in Chapter VII.

In seeking solutions to the pressing health problems of heart, blood vessel, lung,
and blood diseases, we are giving special recognition to the social and physical
aspects of the human environment and their role in the development of these dis-
eases. Also, the importance of the context of the total human environment to the
success of the National Program is being considered in the planning, implementa-
tion, evaluation, and coordination of the Program.

Our modern technological society offers many choices of life style both for every-
day working life and for the increasingly available leisure time. We live in an
age characterized by specialization of labor, sophisticated machinery, complex
systems of organization, and mass production. In communicating with the public
and the health professions, the Program emphasizes how the choice of life style
and physical environment, by individuals as well as communities, in fact may imply
a choice of future health or disease of the heart and the lungs. Current and
future program plans stress how disease might be prevented before the onset of

catastrophic illness which may be beyond the reach even of modern medical tech-
nology. Currently, the National Program gives special emphasis to five program
areas described in detail in Chapter III and highlighted below:

• Prevention of heart attacks — the greatest killer in
our nation

• High blood pressure education — millions of our citizens
do not know that they have high blood pressure, that it
may lead to serious complications such as stroke and
death, and that treatment is available

• Expansion of the attack on lung diseases — a heretofore
neglected area

• Development of a national blood policy — a critical
national need

• Methods of controlling sickle cell disease.

Social change, brought about by the increasing use of rapid communication and
transportation systems, has radically altered leisure and work activities,
resulting in new health problems which fall within the scope of the National
Heart, Blood Vessel, Lung, and Blood Program.

Changing attitudes are directing our attention to long-neglected disease prob-
lems particularly prevalent in certain population groups. Sickle cell disease,
one of these problems, is receiving special emphasis in the National Program.
Such programs, in addition to the need for medical expertise, require a high
degree of knowledge about the special needs and desires of these patients. The
great expense of providing available medical treatment, such as Factor VIII for
patients with hemophilia, creates drastic social changes for the family of the
victim. It may, in fact, condemn the family to life-long poverty. Social change
is causing increasing numbers of elderly citizens, many of whom have cardiovas-
cular or respiratory problems, to be without the aid of or proximity to their
families in times of need.

Socioeconomic factors play a role in the development of many diseases. While
poverty is associated with increased infant, maternal, and overall mortality,
the general affluence in the United States is thought to be associated with the
high mortality rate from coronary heart disease and heart attacks.

Social isolation is a problem in many parts of the United States, both in urban
and rural areas. This often prevents the National Program from reaching those
people who need it most. The Institute is paying particular attention to devel-
oping lines of communication with community health resources and developing edu-
cation and demonstration programs to alert the medical profession and the public
to new methods of disease control and treatment in the local community. Speci-
fically, the Institute is developing cooperative programs with Federal and non-
Federal health agencies for the purpose of controlling, and in the long-term
preventing, heart, blood vessel, lung, and blood diseases. One example is the
National High Blood Pressure Education Program, discussed in Chapter III under
Prevention, Control, and Education.

Social mobility, particularly geographic mobility, creates problems which limit
the timing of National Program efforts. An average of 18 percent of the total
U. S. population- moves annually. This places restrictions on the length of time
available for follow-up of patients participating in clinical studies to deter-
mine the benefits of new treatments, such as the modification of diet in the
therapy of heart disease. It further poses managerial problems in carrying out
well-controlled studies in large free-living populations. The Institute is care-
ful to take these factors into consideration in its planning of long-range clin-
ical trials, such as the Multiple Risk Factor Intervention Trial discussed in the
section on Arteriosclerosis in Chapter III.

Our American culture and the quality of life in the United States appear impor-
tant in increasing a person's susceptibility to heart and lung disease. For
instance, in Denmark, Norway, and Sweden, the death rate from coronary heart dis-
ease for men under the age of 55 is less than half that for the same age group in
the United States. In Japan it is one-sixth that in our country. These interna-
tional statistics indicate that the high death rates from coronary heart disease
in the United States are neither necessary nor inevitable. Research has identi-
fied a number of factors which appear important in increasing a person's suscepti-
bility to heart and lung disease. Programs are being developed to modify these
factors without disrupting our way of life. Specifically, the National Program
emphasizes research, control, and education efforts on how heart and vascular
disease might be prevented through changes in life style, and how such changes
can be most effectively implemented. Good health is everyone's major source of
wealth and happiness. The American public is generally not aware of the extent
to which the individual can contribute to maintenance of good health and preven-
tion of disease. Programs are underway to explore, develop, and evaluate the
most effective means of motivating the public as a whole to take voluntary action
which may be helpful in promoting personal health, preventing disease, and assur-
ing prompt treatment of disease before a crisis situation develops.

Urbanization and life stresses in general are being studied to determine how these
factors affect the development of disease. Behavioral studies have indicated that
certain types of individuals are more prone than others to develop heart and lung
disease under conditions of similar stress. Periods of mental and environmental
stress may thus be associated with an increased incidence of disease. However,
the exact nature of these associations remains to be defined.

In the case of lung diseases, the social habit of cigarette smoking is believed
to be a prime factor in the etiology or exacerbation of both chronic bronchitis
and emphysema — two chronic obstructive lung diseases which are on the increase
in the United States. Smoking also contributes to environmental lung diseases
and hypersensitivity lung diseases. Up to 20 percent of smokers have chronic
obstructive lung disease, and almost all afflicted patients are smokers. Thus,
one of the major goals of the National Program in the field of lung diseases is
to modify the smoking habits of persons at risk of developing lung diseases and
to extend successful anti-smoking programs to the general population. The Pro-
gram also addresses the problem of pollution brought on by the technological
revolution in the United States. This is a well-recognized problem in lung dis-
ease, and one which may be regulated by society. The choice is ours.

In developing and evaluating highly sophisticated therapeutic modalities such as
artificial circulatory assistance, the National Program has given a prominent
place to nonmedical aspects of the human environment. Examples are public atti-
tudes and social, ethical, legal, and other factors important in assessing the
public impact and in ensuring the acceptance of the new treatment when it is
introduced in practice. Behavioral scientists, ethicists, lawyers, economists,
educational experts, and interested laymen are cooperating in the Program to
identify nonmedical issues that may help or hinder this and other research, pre-
vention, and treatment programs.

The human environment also plays an important role in the National Program
efforts to deal with the difficult problem of national blood resources. This
entire program depends upon the willingness of human beings to donate blood
for use by other human beings. High quality blood and blood products are essen-
tial to effectively treat many diseases as well as to save the lives of injured
individuals. To be able to supply sufficient quantities of any given blood
product on a moment's notice requires many steps, from recruiting the donor
to collecting the blood, separating it into its components, detecting and elimi-
nating disease-causing agents, matching the components for compatibility with the
recipient's blood, and administering the blood or blood component to the patient
in a safe manner. In the United States, many different organizations are respon-
sible for these operations. A major problem with the present system is the lack
of uniform quality control of blood donations. The NHLI, in cooperation with a
number of Federal and non-Federal agencies, is striving for an all-volunteer
blood system.

A comprehensive account of recent progress and future challenges for all program
areas addressed by the National Program is presented in Chapter III of this report.
Since Chapter III is rather technical in content, the use of medical terminology
is unavoidable. To provide the lay reader with an overview of prominent program
developments, highlights of recent progress and future challenges are presented
below in lay language for each of heart and blood vessel diseases, lung diseases,
and blood diseases and blood resources.

HIGHLIGHTS: HEART AND BLOOD VESSEL DISEASES

Highlights of recent progress and future challenges in research, prevention,
control, and education programs include:

Prevention of There are approximately 1,250,000 heart attacks in America each
Heart Attacks year. The five major and well-established risk factors for coro-
-Identification nary artery disease and heart attacks are: age, male sex, high
0< R|S,< levels of blood lipids, high blood pressure, and cigarette smok-
3Ct0rs ing. The latter three can be modified, and for two of these we

know that a decrease in the factor results in reduced risk. Cessa-
tion of cigarette smoking will decrease the enhanced risk of heart

attacks among smokers. Reduction of moderate or severe hyper-
tension reduces devastating complications such as stroke, heart
failure, and kidney failure.

Prevention of
Heart Attacks
-Modification

of Risk

Factors

The Institute has implemented three large-scale clinical trials
to evaluate the cardiovascular effects of risk factor modifica-
tion. Within this decade, we should know the impact of lowering
the levels of blood lipids on heart attacks and the impact of
controlling high blood pressure on heart attacks, as well as
the impact of controlling simultaneously the three major
risk factors: high levels of blood lipids, high blood pres-
sure, and cigarette smoking.

Prevention of
Heart Attacks
-Determination
of Blood Lipids

Accurate and precise determination of blood lipids is essential
for effective and efficient risk factor detection and management.
Review of operating conditions in United States laboratories
reveals a wide and unacceptable variation in the accuracy and pre-
cision of blood lipid (cholesterol and triglyceride) measurements.
Quick-kit methods are totally unacceptable. Many of the large
automated laboratories are employing techniques that yield values
10 to 40 percent too high. Over the last two years the NHXI has
evaluated available technology and developed with industry a rapid,
inexpensive, accurate, and precise method for determining choles-
terol and triglyceride levels.

Prevention of Current studies demonstrate that chronic and asymptomatic dis-
Heart Attacks orders such as arteriosclerosis (hardening of the arteries) and
-Behavioral high blood pressure are not easily brought and held under con-
Studies trol. Health attitudes and lack of motivation often lead to

failures in compliance with changes in life style or with diets
and drugs in attempting to change risk factors. Evidence from
smoking clinics and from diabetics or hypertensives under treat-
ment indicates that these behavioral elements rather than our
understanding of risk factors may prove to be the limiting fac-
tors in our ability to prevent coronary heart disease.

Prevention of
Heart Attacks
-Role of

Public

Education

Public education is of primary importance in the prevention of
coronary heart disease. Major steps have been taken to educate
the general public regarding the cai'ses and prevention of coro-
nary heart disease. An example is the Seattle Heart Watch which
includes a series of television programs produced with the Uni-
versity of Washington. Among topics covered in the series are
dietary alteration, exercise programs, signs of impending heart
attack, and whom to contact concerning an attack.

Heart Attacks Epidemiological studies have established strong positive associa-
-TheRoleof tions with high levels of blood lipids (cholesterol) and with age
Blood Lipids relative to the incidence of heart attacks. A recent study with
a special X-ray technique has emphasized these associations in
terms of the pathological changes in the coronary arteries.

Heart Attacks A previously undefined syndrome of potentially major clinical
-A New Sudden importance has been described. This new syndrome has been called
Cardiac Death the Primary Ventricular Fibrillation Syndrome or Instantaneous
Syndrome Death Syndrome. Clinically, those patients fortunate enough to
be resuscitated following sudden collapse exhibit disturbance of
heart rhythm, absence of recent or evolving myocardial infarction
(death of heart muscle) , presence of chronic coronary heart disease,
and a very high incidence of sudden death (30 percent per year)
subsequent to resuscitation. The recognition of this sudden death
syndrome presents an opportunity to prevent premature deaths from
coronary artery disease by preventing or controlling the distur-
bance in heart rhythm.

Heart Attacks
-Therapy to
Reduce Heart
Muscle
Damage

Recent investigations have shown that the patient's prognosis is
directly related to the amount of dead heart muscle resulting from
a heart attack. Pharmaceutical agents, oxygen therapy, and mechan-
ical circulatory assistance are promising new therapies for limit-
ing the amount of heart muscle damage from heart attacks.

High Blood

Pressure
-National
Education
Program

Drug therapy to control high blood pressure reduces the incidence
of strokes and heart failure among persons with moderate or severe
hypertension. However, only about 12 percent of hypertensives in
the United States are currently receiving adequate treatment. The
National High Blood Pressure Education Program, initiated in 1972,
is an interagency Federal/non-Federal cooperative effort designed
to bring individuals with moderate and severe hypertension under
effective treatment. Sustained effective blood pressure management
in such persons is expected to result in a reduction of disability
and death by as much as 40 percent when compared with expected rates
for untreated hypertensives.

Prevention of
Heart and
Blood Vessel
Disease

-The Framingham
Heart Study

A 22-year follow-up has been completed on 5,209 participants in the
Framingham study. Analysis of the data reveals that: (1) High blood
pressure is the major cause of congestive heart failure, with eleva-
tions of systolic pressure ("upper" blood pressure reading) playing
as great a role as diastolic pressure ("lower" blood pressure reading)

(2) Cigarette smoking is a major contributor to intermittent claudi-
cation (severe cramps and pain in the muscles of the legs on walking
due to insufficient blood supply) and acts independently of high
blood pressure, high levels of blood lipids, or diabetic status;

(3) Obesity is a risk factor in coronary heart disease, stroke, and
congestive heart failure, independent of other risk factors; and (4)
The quantitative influence of several risk factors acting simultane-
ously has been analyzed and the results published for use by clini-
cians in the prevention of heart disease.

Understanding Arteriosclerosis is responsible for about 85 percent of the deaths
Arteriosclerosis from heart and blood vessel diseases. Recent progress has been
made in the understanding of arteriosclerosis. Certain prelim-
inary studies of smooth muscle cells that make up the bulk of
atherosclerotic plaques suggest the possibility that each plaque
consists mainly of one colony of cells that have all arisen from
a single cell of the artery wall that is ancestral for the par-
ticular plaque. While this work remains to be confirmed, it
raises fundamental issues in the pathogenesis of atherosclerosis.

Studies of
the Blood
Vessel Wall

While elaborating and extending methods of culturing cells derived
from human blood vessels, investigators are studying their proper-
ties to develop ways to use these cells in artificial blood vessels.
The method has now been carried beyond seven generations of cells
in culture as pure colonies that maintain all the basic morpholog-
ical and metabolic properties of the lining of the vessels. These
methods offer hope for enhancing our ability to construct artificial
blood vessels compatible with the blood.

Using

Computers
to Detect
Irregularities
in the Blood
Vessel Wall

Utilizing contrast angiograms (a special X-ray technique) together
with computerized analysis of the images produced, it has been pos-
sible to obtain sensitive and highly reproducible diagnosis of
changes in the blood vessel wall resulting from disease. This
technique can facilitate early detection of cardiovascular disease.

Noninvasive Instrumentation is probably the most important single constraint
Instrumentation to the effective prevention of clinical complications of arterio-
sclerosis. Convenient, preferably noninvasive, specific, and
sensitive instrumentation for the diagnosis and monitoring of
atherosclerotic plaques is needed. This would allow studies of
the relationship of risk factor levels to actual development of
arteriosclerosis in the individual patient and provide a precise
statement of what the total identified risk factors mean for that
individual. Of most importance, such instrumentation could moni-
tor the development of arteriosclerosis and measure the therapeutic
effect of changing one or more of the risk factors. The ability to
safely determine the results of a therapy or life style change on
the development of arteriosclerosis, without having to wait for a
crisis event such as heart attack or death, would also enormously
decrease the rigorous demands and costs of clinical trials.

Mechanical
Circulatory
Assistance

Mechanical circulatory assistance with intra-aortic balloon coun-
terpulsation was introduced into clinical studies about a decade
ago. Its exact role and effect in patients with acute heart attack
had to be determined. Studies showed that this form of mechanical
left heart assist could temporarily reverse shock even when refrac-
tory to all forms of medical therapy. This assistance permits
further diagnostic studies and possible surgical therapy in patients
who would otherwise be unable to withstand these procedures.

However, the overall impact of this form of therapy remained to
be determined, especially in relation to the morbidity and mor-
tality in those patients less critically ill. Recent studies in
patients have now shown a definite reduction of infarct size asso-
ciated with the use of mechanical left heart assist.

Implantable
Heart Assist
Device

A totally implantable left heart assist device may have a signif-
icant future in terms of acute and chronic cardiac insufficiency.
In recent experiments, a device has performed successfully in
calves. In several acute implantations, excellent results were
obtained in terms of the amount of blood put out by the heart,
heart rates, and blood pressure. These implantations have demon-
strated functionally the potential of these devices for individuals
requiring left ventricular assist.

HIGHLIGHTS: LUNG DISEASES

Highlights of recent progress and future challenges in research, prevention,
trol, and education programs include:

con-

Pediatric
Lung Disease
-Detection
Before Birth

Hyaline membrane disease (HMD) is a disorder of newborn babies
characterized by the immaturity of the lung. It usually occurs
in premature infants, starts within hours of birth, and frequently
leads to death within a few days. Without special treatment, over
50 percent of babies with this disease will die. If death from
this disease could be eliminated, the infant mortality rate in
this country might be reduced to a level comparable to the best
in the world. Current therapy is available for treatment of
hyaline membrane disease. However, delay in diagnosis contrib-
utes greatly to its high morbidity and mortality. A major diag-
nostic breakthrough has occurred which allows detection of
hyaline membrane disease before birth. This technique, which
involves sampling amniotic fluid, promises to result in exciting
new therapeutic and preventive measures.

Pediatric Hyaline membrane disease is characterized by collapse of the

Lung Disease oxygen-exchanging portions of the lung resulting in extreme dif-
fer* Therapy ficulty in breathing and in death, as noted above. The course
of HMD is relatively rapid, and survival is usually determined
within a matter of days to 1 to 2 weeks. Therapeutic efforts
have focused on methods of maintaining the airways open and
allowing adequate oxygenation of the blood. Until recently, the
usual therapy for HMD consisted of artificial ventilation and
other intensive care usually available in large hospital centers.
Unfortunately, this was not sufficient. Many infants still died

from this disease. The therapeutic breakthrough that long has
eluded investigators may now have been achieved. A provocatively
simple technique, albeit one that requires scrupulously attentive
patient care, has resulted in a survival rate of up to 90 percent
in some studies. This therapy is continuous positive airway pres-
sure (CPAP) and is used in conjunction with artificial ventilation.

Asthma
-Diagnosis in
the Asymptomatic
Child

Asthma, which affects more than 8 million Americans, could be pre-
vented or treated while still reversible if it were diagnosed suf-
ficiently early. A diagnostic test has been developed recently
and is currently undergoing evaluation. This test involves expos-
ing patients to a substance called methacholine. It may allow
physicians to predict, perhaps years before symptoms develop,
whether an individual is a potential victim of asthma. This poten-
tially important diagnostic tool should permit already available
therapeutic and preventive measures to be initiated early.

Chronic Obstructive Chronic bronchitis and emphysema are the major chronic obstructive
Lung Disease pulmonary diseases (COPD) . A new, and potentially more sensitive,

-Early Detection method has been developed for early detection of changes in lung

function and structure which appear to be the first sign of chronic
obstructive pulmonary disease. This method (measurement of closing
volume) is now being used on selected populations to determine its
usefulness as a mass screening test.

Chronic Obstructive Emphysema is the fastest growing cause of death in the United
Lung Disease States. There are many different kinds of emphysema, none of
-Risk Factors which is well understood. Cigarette smoking has long been rec-
ognized as a major risk factor for emphysema, but attempts to
identify other causes and risk factors have frequently ended in
failure. New lines of research have been opened up by the recent
discovery of a genetic basis for one type of emphysema. Other
risk factors may soon be found as well.

Understanding It has been recognized that the lung is an organ with several
Lung Disease functions which may be as complex as the liver. The structure
of the lung is also very complex as it is made up of as many as
40 different cell types. Technology is now at hand to relate
structure and function at the cellular level by using cell cul-
ture techniques. As this information develops, it should be
possible to begin investigations into the molecular basis of lung
disease — an essential step toward effective prevention and treat-
ment.

Artificial Lung
To Treat
Respiratory
Failure

It has been estimated that at least 150,000 adult patients a year
suffer from respiratory failure. Despite the availability of
intensive care units, the lung function of these patients on occa-
sion continues to deteriorate. Approximately 40 percent of these
patients die. Therefore, patients with potentially reversible
lung disorders still die because of a need for short-term respir-
atory augmentation. An artificial lung has been developed and
tested that oxygenates the blood external to the body. This
device can provide long-term (days) support without serious blood
damage. In recent years, clinical studies have shown that these
membrane oxygenators can be used successfully to provide partial
respiratory support for patients with acute respiratory failure.

HIGHLIGHTS: BLOOD DISEASES AND BLOOD RESOURCES

Highlights of recent progress and future challenges in research, prevention,
control, and education programs include:

Dissolving
Blood Clots
in the Lung

A clinical trial has been completed of an enzyme capable of dis-
solving blood clots in the lung. Results indicate that the enzyme
streptokinase (a relatively inexpensive and available preparation)
dissolves blood clots in the lung just as effectively as the more
widely publicized urokinase (another enzyme preparation) , which
is quite difficult to obtain. These results are important to the
development of more readily available treatment of thromboembolic
diseases.

A New Technique
to Measure
Abnormal
Tendency of
Blood to Clot

A hypercoagulable state in which the blood is more likely to clot
than normally contributes to a variety of diseases including devel-
opment of arteriosclerosis and heart attacks. Methods to ade-
quately measure or characterize this state have been lacking. A
method of sufficient sensitivity and specificity has now been devel-
oped which will make possible earlier initiation of appropriate
therapy.

Sickle Cell

Disease
-Prevention
of Sickle
Cell Crisis

While clinical trials to evaluate urea as an anti-sickling agent
have shown that it is not effective in the treatment of the sickle
crisis, evaluation of other anti-sickling agents continues. Pre-
liminary studies with sodium cyanate are quite promising.

A Cooperative Study Group composed of researchers and clinicians
has been formed to collaborate and work together to answer research
and clinical questions in sickle cell disease. This group will
form the nidus for a larger group which will address itself to
hemolytic diseases in general.

Five sickle cell disease centers and eleven screening and educa-
tion clinics have been added to continue research and demonstra-
tion efforts (bringing the total to 15 centers and 26 clinics) .

Hemophilia
-Improved
Treatment

A procedure has been developed which will improve production of
Factor VIII, which is used to stop bleeding in hemophiliac patients.
This procedure will enable blood banks and laboratories throughout
the country to obtain more potent and more uniform Factor VIII from
donor blood. Use of this procedure will improve hemophilia therapy
and also permit more efficient use of donated blood and plasma.

Hepatitis
-Transmission
through
Blood
Transfusion

Two large studies on the epidemiology of hepatitis B infection
are nearing completion, including one in New York City of blood
donors found to be carriers of hepatitis antigen. Newer, more
sensitive detection systems for hepatitis B are being developed
and compared. A study of the efficacy of hepatitis B immune
globulin in the treatment or prevention of hepatitis B infection
has shown that this agent is not effective in the treatment of
acute fulminant type B viral hepatitis.

Preventing the
Rejection of
Transplanted
Organs

Investigators are pursuing means of preventing the sensitization
of the transplant patient by lowering or attempting to eliminate
histocompatibility-antigens (HL-A) in transfused blood. Platelet
(one of the formed elements in blood) studies are in progress to
determine the indications for HL-A typing in platelet transfusions.
Studies of _in vitro methods for removing HL-A from blood will be
completed this year to be followed by clinical trials on renal
dialysis patients.

Development of
Artificial Materials
Which Will Not
Harm Blood

Important progress has been made in developing techniques to impart
blood compatibility to materials for artificial organs in contact
with blood. As one example, a class of "springy" polypropylene
has been synthesized with unique tissue-like physical properties
for potential prosthetic applications. The technology now exists
to graft blood compatible materials, such as hydrogels, to the
polypropylene surface and thus greatly increase its potential for
biologic use.

Safe Materials A method has been developed and evaluated which accurately detects
for Blood Bags the amount of plasticizer DEHP (di-2-ethylhexylphthalate) , a sub-
stance leached out of blood bags during blood storage. It should
now be possible to assess more readily the clinical significance
of the presence of DEHP in tissues and body fluids of transfused
patients.

III. STATUS OF PROGRAM AND UPDATED FIVE-YEAR PLAN

STATUS OF PROGRAM AND UPDATED FIVE-YEAR PLAN

The current status of the National Heart and Lung Institute Program and the
Program Plan over the next five years are presented together in this chapter.
The overall goals of the National Program are to: promote health, prevent
disease, treat disease, and restore health. To advance toward these goals the
Institute, through the National Heart, Blood Vessel, Lung, and Blood Program,
is focusing primarily on two types of program efforts:

• Research, and

• Prevention, Control, and Education.

The Research programs deal largely with the development of new knowledge and the
testing and evaluation of existing knowledge. The Prevention, Control, and Edu-
cation programs deal with the application and dissemination of knowledge already
developed and evaluated through research, but not yet effectively applied toward
the prevention, control, and treatment of disease. These Prevention, Control, and
Education programs are an essential link between biomedical research and health
care. Their purpose is not to deliver health services but rather to improve and
expedite the transmission of fundamental research advances to the public and to
medical practitioners and thereby help to promote the health of our citizens.

For clarity and emphasis, Research programs and Prevention, Control, and Educa-
tion programs are discussed separately in this chapter. The Institute gives
special emphasis to the need for ensuring that the results of research are uti-
lized for the prevention and control of disease; hence, where appropriate in this
chapter, Research programs are cross-referenced with Prevention, Control, and Edu-
cation programs.

In 1972, the Institute initiated an intensive planning effort in response to the
National Heart, Blood Vessel, Lung, and Blood Act. This planning effort involved
the participation of four advisory Panels and their Task Groups drawn from univer-
sities, medical schools, hospitals, and other institutions throughout the United
States. Advice and recommendations were also sought from the National Heart and

Lung Advisory Council, the Interagency Technical Committee on Heart, Blood
Vessel, Lung, and Blood Diseases and Blood Resources, and representatives of
non-Federal and voluntary organizations with related programs. Ongoing program
efforts as well as means for expanding successful past research efforts were
also considered.

The purpose of this planning effort was to formulate a National Program for
heart, blood vessel, lung, and blood diseases and blood resource problems. The
initial Program Plan developed during this planning effort was published in May
1973. Since that time, the Institute has carefully reviewed and assessed the
projects and activities of the National Program. The program structure devel-
oped initially has been revised (see Table 2, Chapter I). This revised struc-
ture includes 10 program areas for Heart and Blood Vessel Diseases, 8 for Lung
Diseases, and 4 for Blood Diseases and Blood Resources. The current status and
updated 5-year Plan for all of these program areas are presented in this chapter
in the Research section and the Prevention, Control, and Education section.

For each program area, the goals, actions, and schedules for implementation, as
set forth initially, have been reviewed and updated. Recent progress and future
challenges for each program area have been identified. The results of this review
are presented here in detail for each program area. Program Goals are correlated
with Recent Progress and Future Challenges, and specific Actions and Schedules for
implementation of these Actions are set forth. This comprehensive discussion of
the National Program should provide the basis for continued monitoring, annual
review, and updating of the 5-year Program Plan.

RESEARCH

Programs of research are fundamental to the National Heart, Blood Vessel, Lung,
and Blood Program. Future developments in the prevention, treatment, and control
of disease are dependent upon basic knowledge of the life processes, how and why
these change with disease, and how such changes might be controlled or reversed.
For instance, we cannot prevent heart attacks until we know more about the mech-
anisms of arteriosclerosis, how those mechanisms may be accelerated by risk fac-
tors, and how the process of arteriosclerosis might be arrested or reversed. Also
through research, the knowledge necessary for promoting and restoring health will
be developed. Only when we fully understand, for instance, the normal and abnor-
mal functioning of the lung will we be able to promote conditions conducive to
good health.

The Institute supports a broad range of fundamental and clinical research in order
to develop this essential information base for achieving the overall goals of the
National Program. By strongly supporting research, the first and basic step in
the sequence from acquisition of fundamental knowledge through testing and evalua-
tion to application of that knowledge, the Institute can provide for the orderly
progression of activities as conceived in the program strategy cited earlier.

In this section, research programs are discussed separately for Heart and Blood
Vessel Diseases, Lung Diseases, and Blood Diseases and Blood Resources. Although
discussed separately, these diseases are linked one to the other. As stated by
the Panel Chairmen during the planning effort, "Disordered biological functions
seldom involve a single area. As examples, pulmonary embolism begins with throm-
bosis and involves the lung and its circulation as well as the heart. Effective
delivery of oxygen to the tissue depends on the lung, the heart, the amount,
type, and functional states of the hemoglobin, and the peripheral circulation."
Research efforts in one program area will impact on research efforts in other
program areas. The activities in Coronary Heart Disease will have an impact on
the program areas of Arrhythmias and Heart Failure and Shock. The recent progress
and future challenges in research and the scheduled Actions in Cerebrovascular
Disease are closely related to those for Arteriosclerosis and Hypertension.
Research advances in understanding Thromboembolic Disorders will be important
in clarifying the role of these disorders in precipitating heart attacks and
their relationship to the development of Arteriosclerosis. Developments through
research on blood compatible prostheses will have an impact on many techniques
and devices developed for heart, blood vessel, and lung diseases. Research on
the Structure and Function of the Lung will be important in decreasing the mor-
tality and morbidity resulting from Emphysema and Chronic Bronchitis. Thus,
the research programs in all areas are closely related. Appropriately, cross-
references among the program areas are provided in this Research section to
elucidate some of the complexities of research.

In FY 75, the highest priority program areas in research are: Arteriosclerosis,
Hypertension, Coronary Heart Disease, Structure and Function of the Lung, Emphysema
and Chronic Bronchitis, Bleeding and Clotting Disorders, Sickle Cell Disease, and
Blood Resources. These programs are selected as high priority because research
advances in these areas are expected to have the greatest impact on developing our
information base on heart, blood vessel, lung, and blood diseases; on preventing
and controlling these diseases; and on promoting and restoring the health of our
citizens.

HEART AND BLOOD VESSEL DISEASES

The Legislative Act charges the Institute to conduct research programs to
investigate the epidemiology and etiology of heart and blood vessel diseases,
and to study the basic biological mechanisms and processes involved in normal
and abnormal phenomena. An impressive array of opportunities and needs can be
pursued in the heart and blood vessel (cardiovascular) disease area at this
time. The approaches that appear most promising, most efficient, and are most
needed to develop new knowledge about heart and blood vessel diseases are sum-
marized here.

Cardiovascular disease is by far our number one health problem in the United
States. In 1971, an estimated 1,022,000 Americans died from heart and blood
vessel diseases, i.e., more than 53 percent of deaths from all causes. Of
these deaths, heart attack was responsible for 676,000, and stroke for 208,000.
Currently, an estimated 27,710,000 Americans have some major form of heart and
blood vessel disease; 22,340,000 have hypertension; 3,870,000, coronary heart
disease; 1,700,000, rheumatic heart disease; and 1,650,000, stroke.

The Institute planning effort relied heavily on the Heart and Blood Vessel Diseases
Panel and Task group participants, representing many universities, medical schools,
hospitals, and other institutions throughout the United States. Advice and recom-
mendations were also sought from the National Heart and Lung Advisory Council, the
Interagency Technical Committee on Heart, Blood Vessel, Lung, and Blood Diseases
and Blood Resources, and representatives of non-Federal and voluntary organizations
with related programs. The National Program in Heart and Blood Vessel Diseases,
developed with participation from the above groups, was outlined in the National
Heart and Lung Institute Summary (Volume I) of the National Heart, Blood Vessel,
Lung, and Blood Program which was published on May 1, 1973.

The updated National Program, presented here, represents an assessment and orderly
expansion of NHLI activities in the cardiovascular area in response to the mandate
of the National Heart, Blood Vessel, Lung, and Blood Act. The updated heart and
blood vessel research programs of the National Heart and Lung Institute deal with
ten program areas:

1. Arteriosclerosis

2. Hypertension

3. Cerebrovascular Disease

4. Coronary Heart Disease

5. Peripheral Vascular Diseases

6. Arrhythmias

7. Heart Failure and Shock

8. Congenital and Rheumatic Heart Diseases

9. Cardiomyopathy and Infections of the Heart
10. Circulatory Assistance.

The first nine program areas were identified separately in 1973. The tenth program
area, Circulatory Assistance, was included initially under the section on Heart
Failure and Shock, and is presented separately for emphasis in this updated Plan.

Following its review and evaluation of program activities, the Institute has modi-
fied some Actions and has increased the total number of research Actions in heart
and blood vessel diseases from 28 in the initial Plan to 45 in the updated Plan.
Most of this increase occurs in the program areas of Arteriosclerosis and Coronary
Heart Disease. These additional Actions will be important in expanding the Insti-
tute's efforts to prevent heart attacks, the greatest single cause of death in the
United States.

1. ARTERIOSCLEROSIS

PROGRAM
GOALS

Arteriosclerosis is by far the most common serious disease affect-
ing man in Western society. It is responsible for about 85 percent
of the deaths from heart and blood vessel diseases in the United
States. It is a slow, progressive disease that sets the stage for
heart attacks, heart failure, and strokes. To understand the ori-
gins and control of arteriosclerosis is the primary objective of
the National Program in heart and blood vessel diseases.

Recent research has developed a significant amount of new knowledge
about the causes and development of arteriosclerosis. Significant
positive statistical associations have been demonstrated between
arteriosclerotic disease and high blood lipids, high blood pressure,
heavy consumption of cigarettes, physical inactivity, personality
type, and other factors. However, we do not yet completely under-
stand the causal relationship of these variables to arteriosclerosis.
Current studies on molecular and tissue interactions promise to help
explain the development of arteriosclerosis and offer opportunities
for its prevention.

Obviously, preventing the events leading to atherosclerotic plaque
formation in the arteries would be better and far less costly than
attempting to treat the resultant vascular disease and its sequelae.
The Institute has many leads to prevention and better understanding
of arteriosclerosis, some of which come from research on metabolism,
normal and abnormal structure and function of the arteries, and
genetic and environmental factors which influence atherogenesis .
The NHLI concurs with the priority recommendations of the Heart and
Blood Vessel Diseases Panel, which was convened for developing the
initial plan, to "define more completely the pathogenesis of athero-
sclerosis" and "to conduct controlled clinical trials." Accordingly,
the National Program gives high priority to continued emphasis on
these activities.

Our overall goal in arteriosclerosis is to obtain a
better understanding of its basic process and to
improve the prevention, diagnosis, and treatment of
the process and its sequelae.

RECENT
PROGRESS

Strong efforts to find solutions to the problem of arteriosclerosis
are being made in fundamental research, nutritional studies, and
clinical investigations. As a result of these efforts, the Insti-
tute can report significant progress in adding new knowledge and
techniques to help in our attack against arteriosclerosis. Exam-
ples of these many detailed advances are given below.

Fundamental Research. The processes leading to the development of
atherosclerosis are closely related to altered permeability of
the walls of the arteries. Lipids are deposited in the wall more
rapidly than they are removed. Experiments in living animals and
isolated human blood vessels indicate that patterns of increased
permeability which permit greater fat deposition are virtually
identical to patterns of early atherosclerosis. The arterial wall
is made more permeable by various hemodynamic factors such as con-
strictions, increased blood flow, and increased blood pressure, as
well as by endothelial injury.

Studies on the transport of lipids to and from the arterial wall
have been extended by the development of better techniques of iso-
topically tagging lipid and protein components of plasma lipopro-
teins to permit analyses of the mechanism of transport of these
molecules into the arterial wall, either as units or in parts.
Methods of determining alterations in "chemical barrier" and wall
ultrastructure have been developed. Examination of the transport
of lipid molecules away from the arterial wall once they have been
deposited indicates this to be a complex and slow process.

The process of lipolysis (decomposition of lipids) is central to
the utilization of fats by the body, whether ingested in the diet
or made in the tissues, and is a major determinant of blood lipid
concentrations . The part played by various enzymes in the arterial
wall during this process is being explored. The arterial wall con-
tains enzymes such as alkaline lipase (lipoprotein lipase) and acid
hydrolases capable of breaking down the lipids entering the wall
from the blood. Lipoprotein lipase has been the subject of inten-
sive study almost continuously since its discovery at the NHLI
20 years ago. Scientists have now shown that there are at least
two different lipases that can be liberated into blood to hasten
lipid removal. One enzyme, coming from the liver, is believed to
play a role in degrading lipid remnants, possibly for entry into
the liver. The other acts primarily to degrade larger lipid parti-
cles, chylomicrons and very low density lipoproteins. Lipoprotein
lipase is selectively absent in one human mutation (familial Type I
hyperlipoproteinemia) leading to abnormal levels of lipid in the
blood of these individuals. Other tissue enzymes capable of decom-
posing lipids have also been intensively studied this past year.
New compounds have been found which may be involved in arterio-
sclerotic plaque formation. The previous observations on the rapid
and reversible effect of insulin on lipids have been further advanced
and it is now possible to study more directly the nature of the
effects of insulin and adrenal hormones in the handling of fats by
the body.

Hyperlipidemia (high blood lipids) is one of the major conditions
associated with premature atherosclerosis, particularly coronary
artery disease, and is one of the first rank problems facing American
physicians, especially those engaged in preventive medicine. The
NHLI has been a leader in promulgating new systems of classification
and identification of causes and treatment of hyperlipidemia.

The Institute's extramural Lipid Research Clinic Program had its
birthplace within the NHLI Intramural Research Division. The prev-
alence of and mechanisms behind the human forms of hyperlipidemia
are now being studied at the 12 extramural Lipid Research Clinics
(LRC's). The 12 clinics are collaborating on a protocol for central
processing and evaluation of the heart, coronary, and major vessels
in post-mortem examinations on LRC patients. The central pooling
and processing of all pathologic material in the LRC Central Pathol-
ogy Laboratory at the NHLI will allow us to gather useful clinical
pathologic correlations regarding human hyperlipidemias .

In several of the Institute's Specialized Centers of Research in
Arteriosclerosis, improvements are now being made in invasive and
noninvasive diagnostic methods for the recognition of atherosclero-
tic plaques in the blood vessels. Other fundamental studies involve
the development and use of nonhuman primate models for studies on
the development, progression, and regression of the atherosclerotic
process.

Nutrition. Nutritional factors are believed to play an important role
in the development of arteriosclerosis, and studies are in progress
to clarify the role of these factors. The Multiple Risk Factor Inter-
vention Trial, currently being implemented, has a strong nutritional
component with the objective of reducing elevated serum cholesterol
by adherence to a lipid-lowering diet, and in certain cases, weight
control and correction of obesity. In addition, reduced intake of
total carbohydrate and alcohol will be advised for men with elevated
triglycerides who fail to respond to the basic diet.

A detailed nutritional questionnaire and 1-day diet recall are
included in the Lipid Research Clinics' prevalence studies, and a
central computerized data system has been created to evaluate the
role of diet in hyperlipidemia and the association of diet with the
incidence of vascular disease. The relationship of nutritional fac-
tors to lipid metabolism and development of atherosclerosis is being
studied by many scientists, primarily in the Institute's Specialized
Centers of Research in Arteriosclerosis.

Clinical Investigations. The clinical investigations within the program on
arteriosclerosis are varied, complex, and broad in scope. The recent
progress highlighted here only refers to some of the major efforts
underway and does not, by far, reflect the total Institute effort.
The Lipid Research Clinics are initiating an in-depth study of the
relatives of patients found to have primary hyperlipoproteinemia
during the prevalence studies. The clinics are also finalizing a
protocol to evaluate the feasibility of using placental cord blood
for the early diagnosis of hyperlipidemia. A central clinical chem-
istry laboratory has been selected for the network of clinics collab-
orating in the Lipid Research Clinics Primary Prevention Trial,
designed to test whether or not lipid lowering can prevent or delay
the onset of manifest vascular disease. Recruitment of patients for
this important clinical trial has begun.

The planning and organizational phases for another primary preven-
tion trial, the Multiple Risk Factor Intervention Trial, have just
been completed. Twenty clinics, a coordinating center, and a cen-
tral EKG and chemistry laboratory for the trial have been selected.

Two extensive studies of patients with the most common form of
hypercholesterolemia (hyperbetalipoproteinemia. Type II hyperlipo-
proteinemia) were completed in 1973 by the NHLI's Intramural Research
laboratories . One study involved analysis of over 200 children born
of parents with a form of familial hypercholesterolemia, which prob-
ably affects about 1 in 200 Americans . The genetic data indicated
a clear-cut mode of inheritance determined by a single gene and mani-
fested early in childhood; information about the clinical manifesta-
tions and potential for diagnosis at birth was also developed. In
a companion analysis, the cardiovascular risks of this hypercho-
lesterolemia in over 1,000 relatives of affected patients were exam-
ined. This was the most extensive such analysis ever undertaken of
this genetic defect. This study provides striking evidence of the
premature atherosclerotic risk of patients affected with this disorder.

In-depth genetic investigation of risk factors is being encouraged
in the Specialized Centers of Research in Arteriosclerosis. A study
is in progress to characterize with regard to cardiovascular risk
factors the familial and genetic associations of offspring of 1,644
spouse sets who were part of the original Framingham cohort. More
than 2,200 offspring have undergone evaluation to date in this study.
The NHLI Twin Study has now collected data on more than 600 sets of
identical twins aged 25 to 55, and preliminary results indicate major
genetic determinants of the observed variability in height, weight,
blood pressure, and serum cholesterol. Offspring study of the pro-
positi of the Honolulu cohort of the Honolulu-Hiroshima-San Francisco
Heart Disease Study has also begun.

The Coronary Drug Project, a secondary prevention clinical trial of
lipid-altering drugs has reached an average follow-up of 58 months
in a population of 8,400 men aged 30 to 64 who have had one or more
myocardial infarctions prior to entry into the study. This trial
has already uncovered unfavorable features of two drugs, i.e.,
estrogen and dextro thyroxine, and is scheduled to terminate in 18
months .

future All aspects of the study and treatment of arteriosclerosis would be
challenges greatly advanced if we had diagnostic instruments for detecting

small changes in atherosclerotic plaques. The present state of tech-
nological development suggests that this is possible. Current
approaches include highly sophisticated techniques such as ultrasonic
methods, X-ray densitometry, and computer-assisted enhancement of
complex image signals. These techniques are not yet adequate but
indicate a feasible and promising technical area where rapid and
successful progress can be expected.

Many needed studies of chronic arterial disease cannot be conducted
in man and require the development of suitable animal models of human
disease, particularly nonhuman primate models with chronic experimen-
tal arteriosclerosis and chronic experimental hypertension. These
models would allow us to study the development and regression of
atherosclerotic plaques, local biochemical and cellular changes in
advanced plaques, and treatment of advanced plaques. Animals with
spontaneous metabolic disease such as hyperbetalipoproteinemia (ele-
vated blood lipids) or diabetes need to be bred to create resource
colonies for studies of the relationship of these disorders to arte-
riosclerosis.

Recent studies have shown genetic influence on the metabolism of
lipoproteins, on the excretion of sterols, and on the atherogenetic
reaction of the arterial wall. This research, presently incomplete
and in need of both confirmation and detailed investigation, will be
fundamental to the identification of patients at high risk of arte-
riosclerosis as well as to the development of rational treatment.

A strong, general research program is needed in the pathogenesis of
arteriosclerosis with emphasis on studies of lipoproteins and their
interaction with the vessel wall. Recent progress in cellular
research, enzyme studies, and collagen and mucopolysaccharide chemis-
try now allows sophisticated investigation of the tissue in the
artery wall and its role in plaque formation. In addition, current
population studies such as those in the Institute's Lipid Research
Clinics and Specialized Centers of Research in Arteriosclerosis
have identified a need for new and sophisticated investigations to
clarify the role of nutrition in the development and treatment of
arteriosclerosis.

Several clinical trials are currently underway to evaluate ways of
preventing coronary heart disease. These efforts are aimed at inves-
tigating the potential benefits derived from controlling the risk
factors of high blood lipids, high blood pressure, and smoking.
Potentially useful drugs and surgical approaches are under study.
Such important trials of potential preventive measures have both
theoretical and practical value.

Arteriosclerosis takes years to become clinically evident. In the
interval, the individual may appear to be in good health. Often
the first evidence is catastrophic illness such as heart attack or
stroke. Therefore, if we are to reach the patient before it is too
late, efforts must be made to reach the patient in the community
with the latest information through programs in health education,
public motivation, and compliance with preventive or therapeutic
regimens. (See section on Prevention, Control, and Education.)

actions The Institute plans to:

1. Emphasize pathogenetic studies within existing research programs,
centers of research, and lipid research clinics.

2. Stimulate development of sensitive, specific, invasive and non-
invasive, convenient, and safe diagnostic techniques for use in
determining arteriosclerotic changes in blood vessels.

3. Evaluate current techniques for diagnosis of hyperlipoprotein-
emia and other risk factors and encourage the development of
better ones.

4. Establish colonies of suitable animal models with particular
reference to nonhuman primates with arteriosclerotic or hyper-
tensive disease for use in research on arteriosclerosis, hyper-
tension, and cerebral vascular disease. Animal research will
also be encouraged in genetics related to arteriosclerosis.

5. Expand current population studies in the Institute's Lipid
Research Clinics, Specialized Centers of Research in Arterio-
sclerosis, and clinical applications and prevention programs to
include in-depth genetic studies.

6. Encourage experts in psychology, sociology, and behavioral
research to investigate the problems associated with health
education and attitudes, motivation, and compliance as these
relate to the prevention of arteriosclerosis, hypertension, or
stroke and to the therapy and rehabilitation of patients with
these diseases. (See section on Prevention, Control, and Educa-
tion. )

7. Implement a Multiple Risk Factor Intervention Trial to determine
whether, for men at above average risk of death from coronary
heart disease (because of elevated serum cholesterol, elevated
diastolic blood pressure, and cigarette smoking) , a special inter-
vention program will result in a significant reduction in mortal-
ity from coronary heart disease.

8. Continue an intervention study in high-risk subjects to test the
effectiveness of lowering the concentration of lipids by selected
means to reduce cardiovascular mortality and morbidity.

9. Provide for acquisition, analysis, and storage of data on the
prevalence of different types of hyperlipoproteinemia, particu-
larly in young age groups, with special emphasis on their rela-
tionship to diet and premature atherosclerosis.

10. Promote further clinical, laboratory, and epidemiologic studies
of personal attributes and life styles such as nutrition, exer-
cise, obesity, cigarette smoking, behavior, biochemical and
hormonal patterns, and response to psychosocial stress and their
relationship to the development of arteriosclerosis, coronary
heart disease, stroke, and hypertension, particularly with respect
to the onset of arteriosclerosis in the young and in women.

11. Expand current population studies and develop new epidemiologic
studies of the role of environmental factors such as trace sub-
stances, water hardness, climate, geography, and occupational
exposures in the pathogenesis of arteriosclerosis.

12. Implement the US-USSR cooperative study to define the prevalence
of different types of hyperlipoproteinemia, their relationship
to environmental factors, especially nutrition, as well as many
broadly defined cardiovascular risk factors.

schedule The costs of clinical trials now in progress will plateau in FY 75.
Present programs related to the prevalence of lipid abnormalities
and hypertension among children and young and middle-aged adults will
be completed between FY 76 and FY 78. Program action will be contin-
ued or initiated in pathogenesis, instrumentation, epidemiology,
genetics, nutrition, animal models, and behavioral studies.

2. HYPERTENSION

program High blood pressure is a leading cause of disease and death in the
G0ALS United States, particularly among the black population. It is a

major risk factor in coronary heart disease. One of every six adults
has some elevation of blood pressure. High blood pressure can be
controlled, and we know that such control results in a reduced inci-
dence of stroke and heart failure, kidney failure, and perhaps also
a reduced incidence of heart attacks.

In more than 90 percent of the cases, the cause of the hypertension
is unknown, and although the condition can be treated, it cannot be
cured or prevented. Because of the large numbers of people affected
by hypertension and its serious nature, it would be especially desir-
able to be able to prevent it; to accomplish this, increased emphasis
is needed in fundamental research.

• The long-range goal in hypertension is to prevent it;
the short-range goal is to optimize the utilization
of effective treatment which currently exists.

recent Research related to high blood pressure is a major effort within
progress the Institute's program on heart and blood vessel diseases. The
regulation of normal blood pressure is dependent upon striking a
balance between a number of vasodilator and vasoconstrictor systems.
Therefore, studies have been undertaken in each of these systems to
identify their roles in hypertensive disease and also to define the
interrelationships between them.

Kallikreins are enzymes which control the production of certain sub-
stances, kinins, which are potent endogenous vasodilators (agents
that dilate blood vessels) . Normal volunteers excrete on the aver-
age twice as much kallikrein in the urine as patients with essential
hypertension. These patients appear to have reduced basal activity
of the kallikrein-kinin system and also reduced responsiveness to
physiologic stimuli.

The renin-angiotensin-aldosterone system is vasoconstrictor. During
the past year radioimmunoassay procedures have been developed which
are easier, quicker to perform, and very specific, sensitive, and
reproducible. Normal levels of plasma renin activity (PRA) have been
established and it has been shown that urinary and plasma kallikrein
levels can be dissociated from PRA. It has also been demonstrated
that a centrally acting antihypertensive drug, alphamethyldopa, is
capable of lowering PRA.

The prostaglandins (PG) are endogenous unsaturated fatty acids with
potent effects on blood vessels. A radioimmunoassay has been devel-
oped which makes it possible to measure very small amounts of these
substances in the plasma or urine.

Catecholamines and the adrenergic nervous system have profound
effects on blood pressure and renal function. Studies show that
acute infusions or chronic administration of salt to normal humans
cause an increase in a urinary substance, dopamine; a decrease in
another substance, norepinephrine; and a decrease in a blood enzyme,
dopamine (3-hydroxylase. This enzyme plays a key role in the mainte-
nance of the salt and water balance of the body.

Blood pressure, like most physiologic variables, is a periodic func-
tion. Studies on the classification, causes, and/or the treatment
of hypertension are in progress, including a detailed study of the
rhythm for blood pressure and the characterization of the circadian
component. The ultimate objective is to define an optimal treatment
for each patient with special reference to the abnormalities of con-
trolling factors shown by that patient.

In the past year, unusual success has been achieved in the develop-
ment of assays needed to carry out the complex biochemical studies
needed for the investigation of factors relative to hypertension.
Specialized laboratories are working on various assays of angiotensins,
aldosterone, and prostaglandins to determine more fully the role of
each in the pathogenesis and etiology of hypertension. In 1973,
clinical tests were started of an agent which blocks the conversion

of Angiotensin I to Angiotensin II. Since Angiotensin I is inac-
tive on blood vessels while Angiotensin II is an effective constric-
tor, it will be possible to measure the effect on blood pressure when
one effector is eliminated. If this test proves to be as useful as
anticipated, more laboratories will be encouraged to use it in their
studies.

Epidemiological data will be forthcoming from the Hypertension Detec-
tion and Follow-up Program (HDFP) which began its operational phase
in February 1973. Population data from 14 communities will become
available to characterize prevalence of hypertension by a limited
number of demographic, socioeconomic, and occupational characteris-
tics. Follow-up of the 5,000 participants in the Regular Care Group
will provide general population data on the progression of high blood
pressure and its complications. An important component of the Hyper-
tension Detection and Follow-up Program involves behavioral research
as it relates to the identification of factors which enhance adher-
ence to therapy or impede such adherence among individuals placed
on antihypertensive drug management.

Data on high blood pressure are now available from six prospective
epidemiological studies in populations which have had follow-up
observations and blood pressure measurements over 4 to 18 years.
Systematic analysis of these data is underway. Data from Puerto
Rican, Israeli, Yugoslavian, Honolulu Japanese American, and
Hiroshima Japanese populations are available to compare with the
present 18-year follow-up data from Framingham.

An increasing number of projects deal with the role of stress in
the genesis of hypertension. A pilot clinical trial of antihyper-
tensive therapy in mild hypertension is being planned. This trial,
jointly supported with the Veterans Administration (VA) , is pro-
posed for initiation in four VA hospitals.

An intensive study of the pharmacokinetic actions of antihyperten-
sive drugs is underway. Combinations of available drugs are being
tested in individual patients. It appears possible that therapy
may soon be tailored to the functional aberrations found in an indi-
vidual hypertensive subject.

future We do not know how beneficial treatment may be for mild forms of
challenges high blood pressure. Since an estimated 19 million people have

mild hypertension, it is important that this information be devel-
oped. About 4 million people at any given time have hypertension
of a degree known to be harmful. It can be controlled by medica-
tion with appropriate drugs. However, currently available drugs
require close medical supervision and often have unpleasant side
effects which make them difficult to use for long periods of time
in asymptomatic individuals. We need to develop better pharmaco-
logic agents without such side effects and without the need for
meticulous, individually adjusted dosage.

Behavioral and motivational considerations similar to those men-
tioned under Arteriosclerosis are particularly important to the
successful maintenance of antihypertensive therapy, since patients
with high blood pressure seldom have characteristic symptoms until
catastrophic complications occur. Rational treatment and preven-
tion of hypertension will require an intensive investigation of its
etiology and pathogenesis. While some current information about
the formation and modulation of vasopressor polypeptides and related
enzyme systems helps to explain pathogenetic mechanisms, we know
little about etiology.

Dissemination of information about high blood pressure and the bene-
fits of treatment represents a major challenge discussed in the
section on Prevention, Control, and Education.

ACTIONS

The Institute plans to:

1. Emphasize research on the etiology and pathogenesis of hyper-
tension, including its epidemiology, in many of the individual
and specialized laboratories working on this problem.

2. Implement clinical trials of antihypertensive therapy in mild
and labile hypertension.

3. Evaluate new pharmacologic approaches to the treatment of hyper-
tension utilizing existing research centers and pharmacologic
expertise, with emphasis on new drug formulations.

schedule Present programs will continue to receive emphasis. The prevalence
studies of hypertension in children will be completed as mentioned
in the section on Arteriosclerosis. Continuing and new actions will
increase somewhat in FY 75 and increase further by FY 79. Part
of this increase is attributable to the proposed clinical trial of
therapy for mild hypertension. Additional increases will occur in
the pathogenesis and pharmacology of hypertension.

3. CEREBROVASCULAR DISEASE

PROGRAM
GOALS

Cerebrovascular disease due to arteriosclerosis and especially due
to hypertension is the basis for the great majority of strokes.
An estimated 1.7 million adults in the United States have this dis-
ease, and of this number, about 200,000 persons will die of stroke
each year. While the National Institute of Neurological Diseases
and Stroke is primarily responsible for programs on those aspects
of stroke that deal with brain injury and its consequences, the NHLI
is responsible for programs on the cerebrovascular pathology that
underlies the stroke.

The goal of the NHLI program is to decrease the
incidence of stroke through studies of the pathology
and pathogenesis of cerebrovascular disease.

recent A liaison Joint Council Subcommittee has been drawn from the
progress Advisory Councils of the National Institute of Neurological Dis-
eases and Stroke and the National Heart and Lung Institute, and
other appropriate experts and Institute staffs for the purpose of
coordinating and exchanging information on cerebrovascular diseases.
During the past several years, this Subcommittee has served as a
focus for information exchange, development of bibliographies, con-
ferences and workshops and similar activities related to the National
Program in cerebrovascular disease.

Currently within the National Program, only a small number of primar-
ily human studies are concerned with the cerebral vasculature and its
relationship to stroke. A few animal studies are concerned with the
effects of hypertension on vessels, but do not relate primarily to
the cerebral vessels. The experimental modeling of the vascular
pathology of stroke in animals is a largely inactive research area
for investigators in arteriosclerosis and has had only limited inves-
tigation in hypertensive models. There are no current studies of
the combined effects of arteriosclerosis and hypertension on the
cerebral blood vessels.

future To determine the etiology and prevention of stroke, we need to con-
Challenges duct animal studies of the effects of chronic arteriosclerosis and

chronic hypertension on the arteries of the brain. Little knowledge
is available as yet about chronic changes in animal models, partic-
ularly in nonhuman primates appropriate for neurological examination.
The goals of these animal studies will be to elucidate, by methods
not applicable to man, the vascular pathology that leads to stroke.
Insofar as cerebrovascular disease is closely related to arterio-
sclerosis and hypertension, the future challenges discussed in the
sections on Arteriosclerosis and Hypertension also apply to Cerebro-
vascular Disease.

ACTIONS

The Institute plans to:

1. Initiate studies in animals of the pathology of the lesions of
chronic atherosclerosis and hypertension in the cerebrovascular
arteries. Emphasis will be placed on those lesions that may
contribute to ischemic stroke or arterial brain hemorrhage. The
chronic and special animal resources referred to in the sections
on Arteriosclerosis and Hypertension can be utilized with minor
expansion or redirection for the study of cerebrovascular disease.

2. Continue prospective epidemiologic studies dealing with the
identification of environmental factors and personal attributes
which predispose to increased risks of stroke; maintain surveil-
lance of stroke end-points in the clinical trials discussed in
the sections on Arteriosclerosis and Hypertension.

schedule The planned actions in animal studies and clinical research will
gradually increase the current program effort in the cerebrovas-
cular area through FY 79.

4. CORONARY HEART DISEASE

program Coronary heart disease is the major manifestation of atheroscle-
goals rosis. It is the predominant form of heart disease in the adult

American, causing 1.25 million heart attacks a year and responsible
for chronic illness in 4 million Americans, 2.5 million below the
age of 65.

Of the five major and well-established risk factors for coronary
artery disease, namely age, male sex, high blood lipids, high
blood pressure and cigarette smoking, the latter three can be modi-
fied, and two of these are known to result in reduced cardiovascu-
lar risk when deliberately decreased. Cessation of cigarette smok-
ing will decrease the enhanced risk of heart attacks among smokers,
and reduction of moderate or severe hypertension reduces stroke and
some other complications of high blood pressure. Its effect on
heart attack or sudden cardiac death is unknown but may be appre-
ciable. The Institute has implemented three large-scale trials to
evaluate the cardiovascular effects of risk factor modification.
These are described in the previous sections on Arteriosclerosis
and Hypertension.

A research program focused on patients with acute heart attacks
has developed extensive information about pathophysiology; prog-
gnostic factors; pharmacological, surgical, and circulatory assist
therapy; and techniques and instruments for conducting research in
the acutely ill patient. These developments can now be built upon
and more broadly used.

A primary goal of the program is to develop informa-
tion that will lead to improved diagnosis, prevention,
therapy, rehabilitation, and understanding of the
mechanisms resulting in symptomatic coronary disease.

Coronary artery bypass surgery has been developed to supplement
medical management of coronary heart disease, particularly in the
case of angina pectoris. This technique uses a blood vessel graft
to bypass a narrowed or occluded segment of a coronary artery.
Over 25,000 such operations are done annually in the United States
with hospitalization costs in excess of $5,000 for each operation.

• A second goal is to establish the indications for and
the effects of coronary artery surgery in the treat-
ment of various forms of coronary heart disease.

Each year about 400,000 deaths from coronary heart disease occur
before hospitalization, half of these almost instantaneously or
unwitnessed. Over three-quarters of these victims have known
heart disease or high blood pressure before their sudden deaths,
but in the rest, sudden cardiac death is the first evidence of
heart disease.

• A third goal is to develop and assess emergency med-
ical care methods for heart attack victims and to
develop and evaluate prophylactic treatment with
drugs to prevent sudden cardiac death.

Following heart attack or other manifestation of heart disease,
tens of thousands of Americans annually are left with substantial
impairment of their ability and freedom to function and to con-
tribute fully to society.

• A fourth major goal of the program is to assess the
needs and opportunities for cardiac rehabilitation
with respect to physical, physiological, and societal
factors to prevent disability and to bring back into
the mainstream of life those who have suffered cardio-
vascular disease.

In addition to topics identified under Coronary Heart Disease,
closely related work is included in the sections on Arteriosclero-
sis, Arrhythmias, Heart Failure and Shock, and in the section on
Prevention, Control, and Education.

recent In 1972 and 1973, the Institute implemented three large-scale clin-
progress ical trials, as described in the sections on Arteriosclerosis and

Hypertension, directed toward evaluating the cardiovascular effects
of risk factor modification. After two to five years of planning,
the Hypertension Detection and Follow-Up Program, Lipid Research
Clinic, and Multiple Risk Factor Intervention trials have begun
patient recruitment. Within this decade, we should know the impact
of lowering lipids on heart attack in certain types of lipid dis-
orders, the impact of controlling hypertension on heart attack, as
well as the impact of controlling simultaneously the three major
risk factors.

Plans for Specialized Centers to conduct research on the various
manifestations of coronary heart disease have been developed. Phase
I of the Collaborative National Study on Coronary Artery Surgery is
completed. The US-USSR Cooperative Study on Management of Ischemic
Heart Disease is moving forward on schedule. The results of present
studies on mechanisms and factors precipitating acute cardiovascular
events and their prodromata are being evaluated. Pilot testing of
antiarrhythmic drugs to be given to patients following hospitaliza-
tion for acute myocardial infarction is progressing satisfactorily.

Studies for early administration of prophylactic antiarrhythmic
drugs in the emergency care settings have begun but are proceeding
slowly. A task force has been established to assess the needs and
opportunities for the physiological, psychological, and societal
rehabilitation of patients with cardiovascular disease.

Scientific research in the past has resulted in the current treat-
ment of heart attack, specifically relief of pain and prevention
or reversal of rhythm disturbances which can be lethal. Recent
investigations (more fully described in the section on Heart Fail-
ure and Shock) have shown that the size of the infarct (the amount
of dead heart muscle) is directly related to death or disability
from a heart attack. Studies are currently underway to develop
better ways to assess infarct size as well as to assess therapies
for limiting the size of infarcts. For example, for many years,
physicians have administered oxygen to patients with heart attack,
although firm scientific evidence for its usefulness has not existed.
Recent animal experiments show that inhalation of oxygen decreases
the extent of damage to heart muscle. This suggests that there is
indeed rationale for its continued use in patients. The use of a
pump to assist the heart in patients with heart attack has been
shown to relieve pain, and if applied early in the course of the
attack, limits the amount of heart muscle destroyed. In combina-
tion with certain drugs, the effect is even more striking.

future The emphasis in patient-oriented research must shift from its cur-
challenges rent focus upon acute heart attack to the inclusion of other impor-
tant aspects of coronary heart disease — angina pectoris, heart fail-
ure, arrhythmias, and sudden death. Attention must be paid to further
development and evaluation of therapy, rehabilitation, and measurement
techniques. The fundamental question of why chronic coronary artery
disease is finally manifested as acute heart disease — heart attack
or sudden death — must be answered. These research areas have been
emphasized by the National Heart and Lung Advisory Council. The
study of susceptible patients requires specialized facilities that
are complex, expensive, and staffed with personnel who are available
for emergencies. Importantly, such specialized cardiological facil-
ities will be very useful for research on other forms of heart dis-
ease as well.

It is widely recognized that coronary artery surgery brings relief
of symptoms for a majority of patients with severe angina pectoris.
However, the benefits and side effects, the value compared to con-
ventional drug therapy, and the effects upon lifespan and quality
of life require further research.

Recent studies have shown that the final step in sudden cardiac
death is usually ventricular fibrillation, which is largely prevent-
able during hospitalization by drugs given intravenously. Thus,
finding drugs to prevent ventricular fibrillation in high risk
patients is an important research task, and agents must be found
that can be used immediately upon the development of heart attack
symptoms .

The high frequency of out-of-hospital deaths and the favorable
experience with improved systems of emergency cardiac care under-
score the need for further development of emergency-related tech-
niques and resources for use in cardiac patients. A strengthened
scientific basis for rehabilitation programs and a more comprehen-
sive scope of action for these programs are needed. Development
and testing of new hypotheses and methods are critical to continued
clinical and fundamental research into the cause, diagnosis, and
treatment of coronary heart disease.

actions The Institute plans to:

1. Establish approximately 12 specialized units to conduct research
upon the various manifestations of coronary heart disease. Com-
prehensive clinical investigation will be supported by related,
fundamental laboratory studies.

2. Establish a collaborative national program to determine the indi-
cations for and the long-term effects of coronary artery surgery
in the management of coronary heart disease. Randomized studies
will be utilized in patients with sharply defined clinical con-
ditions and coronary arterial involvement. A registry will be
used to follow patients in whom the indications for surgery or
exclusively medical treatment seem sufficiently clear that ran-
domized allocation would be improper, but in whom follow-up
clinical data are important for assessing the validity of present
clinical judgments.

3. Implement the US-USSR cooperative study on the management of
ischemic heart disease by medical and surgical techniques.

4. Promote studies to elucidate the mechanisms and factors which
precipitate acute coronary events and to determine the charac-
teristics of individuals at highest risk for these events.

5. Promote studies on the prodromata of acute coronary events and
of patients' reactions and coping behavior in this setting with
a view toward earlier diagnosis and treatment.

6. Develop and test techniques of emergency cardiovascular diag-
nosis and therapy suitable for incorporation into emergency
medical care systems .

7. Design, pilot test, and subsequently implement large-scale
trials of chronically administered antiarrhythmic drugs in
patients at high risk for sudden cardiac death.

8. Implement the US-USSR cooperative study on the prevention of
sudden cardiac death.

9. Design, pilot test, and subsequently implement large-scale

trials of the early administration of prophylactic antiarrhythmic
drugs immediately upon the development of heart attack symptoms.

10. Assess the needs and opportunities for cardiac rehabilitation
in terms of physical, psychological, and societal factors,
and implement appropriate programs of research.

schedule The present long-term study of lipid-lowering drugs aimed at pre-
venting recurrence of heart attack or death from coronary heart
disease (the "Coronary Drug Study") is being completed in FY 74 and
will be terminated by FY 75. The Myocardial Infarction Research
Units, which have focused upon heart attacks, will be discontinued
by FY 75. Continuing and new actions in coronary heart disease will
emphasize manifestations other than heart attack, particularly
angina pectoris and sudden cardiac death. In part, this will be
accomplished through the development of specialized units. The
emphasis will shift toward electrophysiological and surgical inves-
tigations, with specific attention to prevention of acute events.

5. PERIPHERAL VASCULAR DISEASES

PROGRAM
GOALS

Peripheral vascular diseases are the cause of considerable suffering
and disability. Surgeons have developed techniques to replace dis-
eased peripheral artery segments with vascular or prosthetic grafts.
Otherwise, peripheral arterial disease has been the focus of only a
limited research effort, and peripheral venous disease and disorders
of the lymphatics have received even less emphasis.

• The goals of this program are to improve diagnosis,
therapy, and rehabilitation, and to improve under-
standing of the mechanisms causing peripheral arterial,
venous, and lymphatic diseases.

RECENT
PROGRESS

Some epidemiological data on the prevalence, incidence, and poten-
tiality of risk factors are being obtained from prospective popu-
lation studies. The bulk of developments related to Peripheral
Vascular Diseases is described in the section on Arteriosclerosis.

FUTURE
CHALLENGES

Methods must be developed for diagnosing peripheral vascular dis-
eases before they reach an advanced state, for more effective
medical management, and for extending surgical therapy to small
vessels. Understanding the basic cause of the diseases is most
important and will require study of the role of neural control of
vascular tone, mechanism of action of smooth muscle, pathogenesis
of peripheral atherosclerosis, and the importance and significance
of risk factors.

actions The Institute plans to:

Encourage clinical, laboratory, and epidemiological research
into the causes, diagnosis, and treatment of diseases of the
peripheral arteries, veins, and lymphatics.

Implement related programs described in the section on Arterio-
sclerosis, and the programs on noninvasive instrumentation dis-
cussed in the section on Bleeding and Clotting Disorders under
Blood Diseases and Blood Resources.

schedule Continuing and new Actions in peripheral vascular diseases will
emphasize clinical and basic investigation. Emphasis will be on
diagnostic techniques for small vessels, and the relation of phys-
iology and pathophysiology to clinical manifestations of disease.
Multidisciplinary approaches will be emphasized as well as specific
approaches .

6. ARRHYTHMIAS

program Important new concepts are developing about the correlation of
GO ALS electrical signals from the heart and the extent, severity, and

prognosis of heart disease. Information is being accumulated about
the different causations of arrhythmias and their differential
responses to drug therapy. Most of the drugs currently effective
in the treatment and control of arrhythmias have side effects which
limit their applicability.

• A major goal of the program is to develop methods for
the prevention of arrhythmias which specifically cause
sudden cardiac death.

Identification of arrhythmias that carry a high risk of sudden
cardiac death is fundamental to preventive measures and has been
emphasized by the National Heart and Lung Advisory Council. The
analysis of spontaneous rhythms and the influence of drugs must be
assessed by quantitative analysis of extensive electrocardiographic
tape recordings. Substantial progress has been made toward per-
forming this task automatically, rapidly, and quantitatively by
computer .

Arrhythmias and other electrical disturbances of the heart cause
important symptoms and aggravate many forms of heart disease.

• Another goal of the program is to improve currently
available methods for prevention, diagnosis, and
management of arrhythmias and other electrical dis-
turbances of the heart.

recent Clinical studies are in progress to identify chronic or intermit-
progress tent disturbances of rhythm, and several projects are primarily
directed at the electrophysiology and therapy of rhythm disturb-
ances associated with inadequate blood supply to the heart. A
collaborative study is being developed to describe significant
arrhythmias in specific groups of patients and their modification
by drug therapy. Improved automated arrhythmia analysis of electro-
cardiographic records is being achieved.

A previously undefined syndrome of potentially major clinical
importance has recently been described. This new syndrome is called
the Primary Ventricular Fibrillation Syndrome or the Instantaneous
Death Syndrome. Clinically, those patients fortunate enough to be
resuscitated following their sudden collapse exhibit disturbance
of heart rhythm, absence of recent or evolving myocardial infarction,
chronic coronary artery disease, and a very high incidence of sudden
death (at 30 percent per year) subsequent to resuscitation. Patho-
logically, from medical examiners' series, the syndrome is charac-
terized by severe chronic coronary artery disease, absence of recent
coronary artery lesions, and no evidence of recent myocardial
necrosis.

This syndrome, which may comprise up to 50 percent of all cases of
sudden cardiac death, can be differentiated from other cases of
sudden cardiac death which have been characterized clinically by
ventricular fibrillation, a high incidence of premonitory symptoms,
recent or evolving acute myocardial infarction, and a lower occur-
rence of subsequent sudden death (at 2 percent per year) . The
recognition of this new syndrome presents a challenge for preventing
premature death from coronary artery disease.

future A better understanding of the electrical behavior of ischemic
challenges heart muscle is essential to the prevention of sudden cardiac death.
Several drugs which are effective agents in the setting of the coro-
nary care unit need to be evaluated for benefits and side effects
as prophylactic agents outside the hospital in patients suspected
of having myocardial infarction. Particular attention needs to be
paid to the effect of heart rate upon automaticity and rhythm dis-
turbances as well as upon the work load and consequent potential
damage to the heart. Antiarrhythmic drugs, which can be taken
orally over long periods of time, and which have shown promise in
limited clinical trials, need to be evaluated in larger-scale trials.
Fundamental to all these clinical studies is the development of
systems for quantifying electrocardiographic rhythm signals auto-
matically and rapidly. In addition to the efforts focused upon
ventricular fibrillation and the prevention of sudden cardiac death,
disturbances of the conduction system of the heart, as well as other
important rhythm disturbances, must be managed more effectively.
Closely related topics are also discussed under the section on
Coronary Heart Disease.

ACTIONS

The Institute plans to:

1. Expand current programs for the prevention of arrhythmias
causing sudden cardiac death, focusing particularly upon the
electrophysiology and therapy of rhythm disturbances associated
with inadequate blood supply to heart muscle and upon clinical
studies to identify chronic or intermittent disturbances of
heart rhythm which indicate an increased risk for sudden death.

2. Augment the development of automated, quantitative techniques
for analyzing electrocardiographic rhythm signals to facilitate
clinical investigation of arrhythmias.

schedule it is anticipated that the current major emphasis on descriptive
aspects of conduction disturbances will be somewhat diminished.
Continuing and new Actions related to arrhythmias will emphasize
those fundamental to understanding sudden cardiac death. There
will be an overall expansion of program activity with a peak in
currently projected programs in FY 78 and FY 79, and subsequent
levelling off of activity by FY 80.

7. HEART FAILURE AND SHOCK

program Heart failure and shock may be the end result of many different
GOALS diseases. The National Heart and Lung Advisory Council has given
priority to studies of heart failure. In a heart attack, blood
supply to a part of the heart muscle becomes so severely reduced
that the muscle undergoes irreversible damage. It can no longer
contract or pump and is ultimately replaced by a scar. The amount
of irreversibly damaged muscle is not predetermined at the onset
of the heart attack; there is a zone which is in jeopardy but has
not yet progressed to the point of no return. Current research has
identified several promising means for protecting this zone of
potentially reversible damage and for promoting its recovery. Some
of these approaches are being investigated in initial clinical feasi-
bility trials; other promising techniques are being tested in animal
studies .

A major goal is to minimize heart failure associated
with and following heart attack by enhancing the sur-
vival of damaged heart muscle.

Methods to quantify the amount of heart muscle which is inadequately
perfused or which has undergone irreversible damage are crucial to
the evaluation of therapeutic interventions. Recently, several such

methods have shown promise. They may make it possible to test new
approaches more economically and in fewer patients than is now
required for evaluation by gross clinical criteria.

• A second goal is to develop more satisfactory means
of quantifying the extent of heart muscle which is
inadequately perfused with arterial blood or which
has undergone irreversible damage.

Other aspects of the diagnosis, etiology, therapy, and prevention
of heart failure and shock warrant emphasis. These include research
on improving the pumping function of heart muscle, as well as under-
standing and treating the disturbances of the regulation of periph-
eral blood vessels, the related endocrine functions of the body, and
the functioning of the kidney.

• A third goal of the program is to improve understanding
and management of heart failure and shock due to cardio-
vascular causes.

recent The biochemical and physiological studies fundamental to the sur-
progress vival of heart muscle and to the development of methods to prevent
heart muscle damage are continuing. Pilot studies with a variety
of therapeutic agents are underway and some show considerable thera-
peutic promise. Examples of such agents are cited in the section on
Coronary Heart Disease. Progress is also being made in radioiso-
topic quantification of heart muscle which is underperfused or
damaged.

future Current therapy to enhance the survival of ischemic heart muscle
challenges must be evaluated on a larger scale by more definitive clinical
studies than those now underway. The effects upon infarct size
must be quantified and survival assessed. Ischemic heart muscle
must be studied at the cellular and subcellular levels, in an
effort to develop more effective therapy.

The techniques for quantifying the degree of heart muscle damage
must be validated. Subsequent use of the best techniques would min-
imize the number of patients needed for evaluation of new modes of
therapy. Electrocardiographic, enzymatic, and radioisotope tech-
niques show promise.

Studies of heart failure and shock need to be expanded to include
other organ systems. Thus, as the National Heart and Lung Advisory
Council has recommended, the dynamics and the neural and endocrine
control of the circulation must be studied in the periphery as well
as in the heart, kidney, and other organs.

actions The Institute plans to:

1. Enlarge biochemical and physiological studies of the fundamen-
tal processes associated with heart muscle survival both in
laboratory and clinical studies. Based upon these studies,
develop methods for minimizing the extent of heart muscle dam-
age in a heart attack.

2. Establish clinical studies, contingent upon success of current
pilot studies, to assess the therapeutic efficacy of promising
techniques for minimizing the extent of heart muscle damage.

3. Expand the program for quantifying the extent of heart muscle
which is inadequately perfused or which has undergone irrevers-
ible damage.

4. Implement the US-USSR cooperative program on myocardial metab-
olism.

schedule Continuing and new Actions related to cardiac failure and shock
will emphasize the pathophysiology of ischemic myocardium and
methods of quantifying this condition, as well as directing atten-
tion to systemic responses to heart failure and shock. Clinical
trials will be ready for phase-in in FY 75 and FY 76; a number of
promising techniques have progressed to a stage where they are ready
for clinical evaluation on a moderate scale. These new efforts were
initiated in FY 74. The program will peak in FY 79, and begin to
level off by FY 80.

8. CONGENITAL AND RHEUMATIC HEART DISEASES

program Congenital and rheumatic heart diseases are important disorders of
goals childhood, and may form the basis for considerable impairment of
the quality of life of the patient surviving into adulthood.

The earliest surgical successes in the treatment of heart diseases
were in the correction or palliation of congenital heart disease.
These successes are being expanded in the development of diagnostic
and surgical techniques applicable to the newborn. Important in-
sights have also been gained into the development of the cardio-
vascular system. However, in most cases, science still does not
know what makes the heart develop abnormally before a baby is born.

• The major goals of the program are to understand better
the causes of congenital heart disease, to improve diag-
nosis and therapy, and to rehabilitate patients with
congenital heart disease, particularly the newborn.

Rheumatic heart disease is an immunological disturbance that fre-
quently occurs years after initial rheumatic fever and prior
streptococcal infection. It can not only shorten life, but also
seriously impair the quality of the patient's life. Improved
understanding and control of immunological problems could thus be
important in the identification of susceptibility and the preven-
tion of rheumatic heart disease, as well as in the success of
cardiac transplants and in the prevention or treatment of cardio-
myopathy and possibly other forms of heart disease.

• Another important goal is to attain a better under-
standing of the immunological problems associated
with heart diseases.

Closely related programs are discussed in the section on Prevention,
Control, and Education, and deal with the management of congenital
heart diseases in the newborn.

recent The Institute has maintained a continuing long-term effort focused
progress upon all facets of the problems of congenital and rheumatic heart
disease, resulting in a steady improvement in the clinical manage-
ment of these patients. Extremely delicate operations that were
inconceivable a few decades ago are now performed routinely in most
of the major medical centers. It is now possible to perform very
complex repair of the heart even in young infants.

future Essential to the prevention of congenital heart disease is a better
challenges understanding of the normal development of the cardiovascular

system and the causes of abnormal development. The National Heart
and Lung Advisory Council has recommended that the Institute con-
duct an "intensive interdisciplinary study of all aspects of the
etiology and pathophysiology of congenital heart disease and the
neonatal cardiovascular system." The roles of maternal infection
and toxic exposures during pregnancy are particularly relevant.
The emphasis on diagnosis, therapy, and rehabilitation of congen-
ital heart disease patients must increasingly involve the newborn,
as well as school age children. Particular attention must be paid
to measures that will "assure the first few hours of life."
Research challenges in the management of congenital heart d:'. eases
in the newborn are closely related to programs discussed further
in the section on Prevention, Control, and Education.

The roles and nature of immune mecha: » ;ms as they relate to the
heart need to be better understood. Therapy for the suppression
of harmful immunological responses must be developed and evaluated.

Both clinical and fundamental research on causes, diagnosis, and
therapy of congenital heart disease, rheumatic ^ever, and rheumatic
heart disease must be continued with periodic updating of approaches.

ACTIONS

The Institute plans to:

1. Establish Specialized Centers of Research in Congenital Heart
Disease at two to four locations in FY 76. The research in
these Centers will emphasize such topics as cardiovascular
development and improved diagnostic techniques and therapy,
particularly in the newborn.

2. Establish a targeted effort to study immunological problems in
heart disease and their management, specifically in relation

to rheumatic heart disease, cardiac transplantation, and cardio-
myopathies.

3. Implement the US-USSR cooperative study on congenital heart
disease.

schedule There will be a diminished emphasis on the hemodynamic and surgical
aspects of these diseases in older children and adults. The con-
tinuing and new actions will emphasize the causes of both congenital
and rheumatic heart diseases . In coordination with the National
Institute of Child Health and Human Development, the National Heart
and Lung Institute will give special attention to the role of infec-
tions, drugs, and other toxic exposures during pregnancy in congen-
ital heart disease. For congenital heart disease, there will be
an increasing clinical emphasis on the neonatal period.

9. CARDIOMYOPATHY AND INFECTIONS OF THE HEART

program Cardiomyopathy and infections of the heart, which are diseases of

goals the heart muscle and its lining, cause enlargement of the heart,

heart failure, irregularities of heart rhythms, and occasionally

sudden death. The prevalence of these diseases, caused by a
variety of factors, is unknown.

The goals of the program are to prevent, diagnose,
and treat the various cardiomyopathies and infec-
tions of the heart, with particular emphasis on
improved understanding of their causes.

recent New ways of studying these diseases have been developed. Cardio-
progress myopathies and infections of the heart are being recognized with
increasing frequency. The importance of toxic substances, viral
infections, and immunological phenomena is widely recognized,
although a number of causes remain unknown. Accordingly, the
National Program is giving priority to identification of the eti-
ologies of cardiomyopathy. The advent of antibiotics has substan-
tially diminished heart disease caused by bacterial infections.
However, new problems have arisen, such as infections on pros-
thetic heart valves.

future There is particular need to understand the causes of cardiomy-
CHALLENGES opathies and myocarditis. Cellular and subcellular biochemical
and immunological studies offer opportunities for improving our
understanding of these problems. The roles of toxic substances,
including drugs and alcohol, and of viral infections and genetic
disorders need to be investigated. Better diagnostic and thera-
peutic approaches to these diseases must be developed. Since
these diseases stem from a variety of causes, research efforts
need to be broadly based and involve multiple disciplines.

ACTIONS

The Institute plans to:

1. Focus attention on studies of the etiologies of cardiomyopathies
and infections of the heart, emphasizing epidemiological methods,
viral and immunological research, the development and utiliza-
tion of animal models, and the determinations of mechanisms
of myocardial damage by application of biochemical, physio-
logical, physical, and pharmacological techniques. (See also
Congenital and Rheumatic Heart Diseases, Action #2 on immuno-
logical problems.)

schedule Continuing and new actions, with initial emphasis on causation,
will permit increase in activity as this unresearched field is
developed, with progressive increases in funding through FY 80.

10. CIRCULATORY ASSISTANCE

program Present and foreseeable techniques of general and pharmacological
goals management of acute and chronic cardiac insufficiency and shock

still leave a substantial fraction of patients with compromised or
fatally impaired heart function. By mechanical supportive means,
it is possible to substitute some of the pumping function of the
heart and to relieve its work load. Presently, such techniques
are possible briefly in man and for longer periods in the experi-
mental animal.

• A major goal of the program is to develop and assess
therapeutically effective, safe, and reliable cardiac
assist and total replacement heart devices for support-
ing or taking over the work load of the heart.

Methods for assessing and quantifying the degree of circulatory
impairment are also necessary to evaluate patients with all forms
of suspect or known heart disease and particularly for patients
with heart failure and shock.

• A second goal is to develop the instrumentation and
techniques for the assessment of cardiovascular per-
formance .

recent Partial and totally implantable left ventricular assist devices
progress may be significant in the future in terms of correcting acute and
chronic cardiac insufficiency. In recent experiments, a left ven-
tricular assist device has performed successfully in vivo in calves.
In ten acute implantations, excellent results were obtained in
terms of cardiac output, heart rate, and blood pressure.

Left ventricular assist with intra-aortic balloon counterpulsation
was introduced into clinical studies about a decade ago. Studies
showed that this form of mechanical assist could temporarily
reverse shock in subjects refractory to all forms of medical therapy,
permitting additional diagnostic and therapeutic procedures. Addi-
tionally, in a small group of patients with severe refractory shock,
an occasional life could be salvaged. However, the overall impact
of this form of therapy in patients with acute myocardial infarction
remained to be determined, especially in relation to the morbidity
and mortality in those patients less critically ill. Recent patient
studies have now shown a definite reduction of infarct size associ-
ated with the use of this mechanical device. This reduction of
infarct size, which previously could only be demonstrated in animal
studies, may represent a promising method to decrease subsequent
patient morbidity and mortality.

future Mechanical techniques for augmenting or substituting for the per-
CHALlenges formance of the heart must be expanded to encompass emergency

temporary devices for short-term management, extracorporeal assist
pumps for intermediate periods of use, long-term implanted heart
assist devices, and total cardiac replacements. An associated
opportunity and need exist for research on the physiology of assisted
circulation, as well as on the development of the requisite compo-
nents of the systems — compatible biomaterials , pumps, actuators,
energy transforming devices, implantable energy systems, transcu-
taneous transmission of energy, and the control system for the
devices.

Plans for the future include chronic in_ vivo assist experiments in
calves, followed potentially by clinical application in man for
short-term left-heart bypass support. Eventually, longer-term
implantation in man for the purpose of supporting or totally
replacing a weakened heart may result.

These types of studies with mechanical circulatory assist are very
promising, and further work is now clearly indicated. Smaller
infarct size has been associated with a better patient prognosis,
but the effect of reducing infarct size on prognosis has not been
definitely proven. Finally, the subgroup of acute myocardial
infarction patients who might benefit most from this relatively
invasive type of procedure must be determined before this inter-
vention is widely recommended.

actions The Institute plans to:

1. Continue the research, development, and assessment of emergency
temporary, circulatory support devices directed at short-term
management of heart failure and shock to stabilize the clinical
condition and permit its reversal.

2. Expand the research, development, and assessment of implantable
heart assist devices capable of taking over a significant frac-
tion of the work of the heart for extended periods of time.

3. Undertake research, development, and assessment of external
heart assist devices capable of taking over a significant frac-
tion of the work of the heart, and requiring minimal surgery
for connection and removal.

4. Expand research, development, and assessment of implantable
heart replacement devices for permanent implantation.

5. Expand research and development upon circulatory assist and
artificial heart systems, including the development of com-
patible biomaterials , appropriate pumps, actuators, energy
transforming devices, implantable energy systems, transcutane-
ous transmission of energy, and control systems for the devices.

6. Expand research and development of noninvasive and invasive
instruments and techniques for the assessment of cardiovascular
performance.

schedule Present programs in the development of circulatory assist devices
will continue. An assessment will be made of long-range goals to
include the relative needs and opportunities for the development
of devices which offer substantial clinical benefit, yet fall short
of the most ambitious goals of totally implantable and permanently
energized long-term cardiac assist or replacement.

The selective termination of targeted activities as their objectives
are met will be outweighed by the need for larger-scale reliability
and performance tests prior to and with the advent of substantial
long-term clinical implants.

LUNG DISEASES

The National Heart, Blood Vessel, Lung, and Blood Act encourages the Institute
to place greater emphasis on lung diseases in the National Program.

Lung Diseases covered by the Program account for an estimated 150,000 deaths each
year in the United States, cause 60 million days lost from work, 40 million days
of bed-restricted activity, and cost the economy about $6 billion a year in lost
productivity and wages and medical care costs.

In 1972, the National Heart and Lung Institute convened a task force to assist
in identifying high-priority problems and approaches for immediate and long-
range plans to expand the attack on lung diseases in our country. In this effort,
188 scientists assessed the magnitude of respiratory disease problems in the U.S.,
reviewed available knowledge on the causes of respiratory diseases and the methods
for diagnosis and treatment; pointed to disparities between current efforts and
needs in controlling these diseases; and recommended ways to strengthen present
research programs.

The task force report became a primary resource document for the Lung Diseases
Panel, convened in the fall of 1972 in response to the legislation. The recom-
mendations of this Panel were reviewed by the Institute, the National Heart
and Lung Advisory Council, and the Interagency Technical Committee, and formed
the basis for developing the Institute's expanded program on lung diseases, as
well as for developing the plans for coordination of the overall National Pro-
gram in Lung Diseases.

The initial lung program has been reviewed and updated by the Institute during
the past eight months. The updated National Program is presented here and repre-
sents an assessment and orderly expansion of NHLI activities in respiratory dis-
eases. The Program continues to be responsive to the Legislative Act, which
encourages special attention to childhood diseases and chronic lung diseases,
including the establishment of National Research and Demonstration Centers.
The Institute's program, which addresses immediate as well as long-range objec-
tives, centers on three specific approaches of comparable importance and urgency:

Research on the structure and function of the lung in order to
gain fundamental information which will improve our understanding
of important factors in the promotion of health and the preven-
tion and treatment of lung diseases.

Expansion and development of our knowledge base on specific
diseases which constitute national health problems, but which
represent areas where current information is insufficient to
provide immediate solutions.

Application of available technical resources to solve specific
problems whose solutions are expected to pay immediate divi-
dends in improving the health of our nation.

The updated program goals, recent progress, future challenges, actions, and
schedules for implementation are discussed below for each program area:

1. Structure and Function of the Lung

2. Pediatric Pulmonary Diseases

3. Emphysema and Chronic Bronchitis

4. Fibrotic and Immunologic Lung Diseases

5. Respiratory Failure

6. Pulmonary Vascular Diseases

7. Inhalation Diseases

8. Respiratory Assistance.

The first five program areas are continuations of those outlined in the initial
Plan. The last three areas have been added this year and given increased empha-
sis in the updated lung diseases program. The Institute's revised Plan incor-
porates most of the Actions set forth in the initial Plan without change or only
slight revision. Seven new research Actions have been added this year for the
three new program areas. The respiratory diseases addressed by the Institute
do not include cancer of the lung, which is the concern of the National Cancer
Institute, nor upper respiratory infections or pulmonary tuberculosis, which
are the concern of the National Institute of Allergy and Infectious Diseases,
and, in certain cases, of the Center for Disease Control.

1. STRUCTURE AND FUNCTION OF THE LUNG

program Our current capability to deal with the problems of lung disease
goals i n the United States is severely limited by our lack of fundamental
knowledge about the lung. This knowledge must be gained before
truly definitive preventive and therapeutic measures can be designed.
Current remedies are not only very costly but are also only tempo-
rary, stopgap techniques which need to be replaced by more specific
and longer-term methods yet to be discovered through research.
Thus, the most important priority now in the Institute's lung dis-
eases program is to expand research on the lung and its biology in
order to identify factors critical to the health of the lungs.
Recent progress in basic scientific disciplines, such as molecular
biology, biochemistry, immunology, and ultrastructural anatomy
offer new opportunities for making major advances toward combating
emphysema, chronic bronchitis, pulmonary fibrosis, asthma, pediatric
pulmonary diseases, respiratory failure, pulmonary vascular dis-
eases, and inhalation diseases.

While it is essential to first focus studies on the
cellular biology of the normal lung, the ultimate
goals of the program are to increase understanding
of the disease processes and develop effective methods
for prevention, diagnosis, and therapy of lung dis-
eases.

RECENT
PROGRESS

Recently, a major step has been taken toward an understanding of
lung disease mechanisms. The lung — an organ with numerous functions
that include gas exchange, defense against diseases, and removal of
inhaled substances such as dust — is made up of about 40 different
types of cells. Recent progress in studies at the cellular level
has contributed to understanding relationships between lung struc-
ture and function. Studies have advanced to the point that it
should be possible to describe the multiple functions of the various
types of lung cells in terms of cellular and biochemical changes
associated with different respiratory diseases.

However, before such abnormalities can be understood, it is neces-
sary to have a firmer knowledge of normal lung cell structure and
function. This is a difficult research task because of the multi-
functional nature of the lung and because of the various roles
performed by different lung cells. Unless the different types of
lung cells can be isolated and studied separately, the changes
associated with various disease states will be impossible to pin-
point. Recently, an enzymatic procedure has been developed for
dispersing lung tissue into separate viable cells, thereby providing
an opportunity to isolate and culture individual cell populations
from whole lung tissue.

The major advantage of using cell culture techniques is that large
quantities of a single cell type can be accumulated and readily
used in experiments. Once techniques are developed to culture
single cell types, the specialized requirements for cell growth may
be examined, and ultimately a comparison made of cells grown from
normal individuals and those from individuals with specific lung
diseases.
i

future The next several years of research activity will provide infor-
challenges mation relating structural and biochemical characteristics of

individual lung cells. As this information develops, investiga-
tions into the molecular basis of lung disease should be possible.
This is an essential step toward effective prevention and treat-
ment.
i

Specific opportunities and needs for the future include studies of
the quantities, composition, and mechanisms of development of var-
ious components in normal lung tissues, and their chemical precur-
sors and possible variations with age, sex, and environmental influ-
ences. Structural proteins, lipids, and hormones may be involved
in diffuse pulmonary fibrosis and in various types of obstructive
disease of the airways. The in_ vivo balance and interaction among
proteolytic enzymes and their potential for altering the connective
tissue in the lungs need to be elucidated. The turnover rates of
lung cells and alterations in these rates with disease require fur-
ther study.

Failure of the lung's defense mechanisms may play an important
part in disease processes. The structure, synthesis, and physico-
chemical properties of bronchial mucus, one of these defense mech-
anisms, need to be investigated. The cilia in the bronchial tree
are another vital defense mechanism. Information on their struc-
ture and function is crucial to understanding lung clearance and
host defense.

Some classical areas of pulmonary physiology require continued
study and correlation with new knowledge of cellular biology, struc-
ture, and function. Physiologic studies will continue to develop
information on the mechanical properties of the lungs and the pul-
monary blood vessels, and the coupling of mechanical events to the
neurophysio logical regulation of ventilation.

ACTIONS

The Institute plans to:

1. Encourage investigator-initiated research in metabolism, cellu-
lar biology, and defense mechanisms of the lung. This will be
supplemented as needed by targeted research addressed to topics
not adequately covered by investigator-initiated research.

2. Develop multidisciplinary approaches, such as program projects
or Specialized Centers of Research, in the area of normal lung
structure and function. In addition, we will initiate new types
of targeted programs for collaboration and exchange of informa-
tion between basic scientists such as biochemists, immunologists,
and cell biologists, who are not yet focusing on the lung, and
pulmonary specialists who need to develop information in basic
science areas.

3. Seek new information on the structural components of the lung.
Encourage studies on the alterations in proteins and cells
associated with dissolution of lung tissue as a consequence of
injury.

schedule New research programs in lung cell separation and culture are being
encouraged. A program on the separation and characterization of
lung elastin is being developed. Synthetic inhibitors for the
enzyme elastase will be prepared and distributed to the research
community. A workshop will be sponsored to encourage research on
metabolic functions of the lung. Programs which are not included
in the planned priority actions relating to structure and function
of the lung will not be further developed. Continuing and new
actions in pulmonary structure and function will be divided between
multidisciplinary and specific approaches with gradually increasing
activity through FY 79.

2. PEDIATRIC PULMONARY DISEASES

PROGRAM
GOALS

Among childhood disorders involving the lung, cystic fibrosis, and
hyaline membrane disease are health problems of national signifi-
cance. Respiratory distress syndrome (hyaline membrane disease)
is the most common cause of death in the newborn in the United
States, and affects between 50,000 and 100,000 babies each year,

about half of whom die. Bronchiolitis, also covered in the National
Program, is one of the major obstructive airway diseases of children
and may be important in the development of adult chronic lung dis-
ease. The cause of respiratory distress syndrome of the newborn,
the nature of cystic fibrosis, and the possible long-term effects
of early childhood bronchiolitis need to be determined and under-
stood.

• Until research has uncovered ways to prevent hyaline
membrane disease, early diagnosis and prompt initi-
ation of therapy are essential to save the lives of
babies born with this disorder. Primary goals of this
program are to develop improved methods for early diag-
nosis and to design more effective modes of therapy.

• Similarly, present modes of therapy for cystic fibrosis,
a genetically determined disease, are at best palliative.
The primary goal at this time is to develop a rational
basis for therapy through an understanding of the patho-
genesis of this disease.

• There is reason to believe that bronchiolitis in chil-
dren may be related to chronic lung disease in the adult.
Therefore, an important goal is to conduct long-term,
follow-up epidemiologic studies of children who have

had bronchiolitis.

recent Two important breakthroughs have occurred in the detection and
progress treatment of hyaline membrane disease. First, it is now possible
to detect the disease before birth. Secondly, an important thera-
peutic breakthrough has occurred which dramatically reduces the
mortality from this dreaded disease.

The novel and provocative diagnostic technique involves sampling
amniotic fluid (amniocentesis) and promises to result in exciting
new therapeutic and preventive measures. Surfactant material is
produced and secreted by the fetal lung into the amniotic fluid.
Thus, the surfactant levels in amniotic fluid reflect the fetal
lung's ability to produce and secrete surfactant. A rapid and
easy test of surfactant in amniotic fluid has been developed, and
studies are underway to improve the accuracy of the diagnosis.
The ability to predict hyaline membrane disease in the fetus per-
mits the earliest possible medical care for the newborn child and
opens up new avenues of approach to this disorder by detecting
prematurity of the infant and preventing immaturity of the lung.

Survival of infants with hyaline membrane disease is usually deter-
mined within a matter of days to 1 to 2 weeks. Therapeutic efforts
have focused on methods of keeping the airways patent and main-
taining adequate oxygenation of the blood through artificial venti-
lation and other aspects of intensive care usually available in

large hospital centers. Unfortunately, this was not sufficient
and more than half of these infants died. A provocatively simple
technique, albeit one that requires scrupulously attentive patient
care, has resulted in survival of up to 90 percent of these babies.
This therapy, known as continuous positive airway pressure (CPAP) ,
is used in conjunction with artificial ventilation. CPAP keeps
the lungs expanded and the oxygen exchanging portions open and
functioning. Thus, the blood is readily oxygenated and the baby's
overtaxed heart is relieved. CPAP still requires further study
since it may result in circulatory alterations and possibly adverse
effects on the airways. However, many of these problems can be
overcome through application of available intensive care techniques.
With increasing acceptance of this exciting therapeutic achievement
by neonatal intensive care units throughout the country, the mortal-
ity due to this disease should be drastically reduced.

A conference has been held which explored the clinical aspects of
cystic fibrosis and its treatment as well as the underlying genetic
and physiologic alterations. Although this disease affects many
organs, the pulmonary impairment which may be related to recurrent
infections and abnormalities in mucus production commonly causes
disability or death. The Institute's program is addressed to eval-
uation of cardiac and pulmonary functions and their alteration with
therapy. The biochemistry of the mucus abnormality is also being
investigated, and a meeting has been held to exchange information
and stimulate new approaches in the study of mucin.

Several groups are engaged in research on methods for early diag-
nosis of airway disease in newborns and young children. A spi-
rometer designed for compliance measurements in premature and term
newborn infants is in the developmental stage. A system which is
designed to measure pressure-volume curves of the lung and thorax,
and functional residual capacity in anesthetized subjects is also
being evaluated. Investigators have initiated a long-term study
of effects of viral lower respiratory tract illness in children on
later development of adult lung disease. Serum alpha-1-antitrypsin
(an enzyme) activity and serum antibody titers to common respira-
tory viruses are being measured in children with bronchiolitis.

future Understanding the biochemistry and molecular biology of surfactant
challenges during normal maturation and hyaline membrane disease in order to
develop methods of modifying or preventing the disease is a major
challenge. Therapy for hyaline membrane disease should be improved
by development of new devices and approaches and ways to initiate
treatment as soon as possible. The efficacy of present methods of
treatment needs to be assessed and knowledge about such methods
widely disseminated. A better understanding of the etiology and
pathogenesis of hyaline membrane disease is expected with new
methods of prevention and improved therapy.

The cause of the mucus abnormalities in cystic fibrosis and the
pulmonary derangements which result must be discovered before
effective and meaningful therapeutic and preventive measures can
be undertaken.

As a first step in determining whether bronchiolitis in childhood
predisposes to chronic lung disease in the adult, criteria for
diagnosis of bronchiolitis and protocols for long-term study need
to be established.

actions The Institute plans to:

1. Extend interdisciplinary studies of biochemical changes associ-
ated with hyaline membrane disease through Specialized Centers
of Research. In addition, programs will be initiated to study
biochemical changes associated with the development of cystic
fibrosis.

2. Test various supportive measures for patients with cystic
fibrosis, including mist-tent therapy and bronchodilators .

3. Improve management and therapy of hyaline membrane disease
through the development of programs for rapid transfer of
infants with this disease to intensive care units. Programs
will be initiated for research and development of new or
improved devices for treatment and controlled clinical trials
of available methods of treating hyaline membrane disease and
cystic fibrosis.

4. Initiate epidemiologic studies to determine prospectively the
long-term effects of bronchiolitis in childhood on the occur-
rence of chronic lung disease in the adult.

schedule Because recent findings hold great promise for an effective thera-
peutic approach to hyaline membrane disease, and because of
increasing awareness of the importance of the pulmonary manifesta-
tions of cystic fibrosis to morbidity and mortality from this
childhood disease, the programs in pediatric pulmonary diseases
will be increased beginning in FY 75 and maintained at a level
that includes modest increments until FY 79, when a levelling off
will occur. Since early initiation of treatment of hyaline mem-
brane disease is essential for infant survival, the NHLI will
initiate early in FY 75 plans for a program of recognition and
early treatment of neonatal respiratory insufficiency and respira-
tory failure. During this period, there will be a phase-in and
gradual expansion of the education program, described in the sec-
tion on Prevention, Control, and Education.

3. EMPHYSEMA AND CHRONIC BRONCHITIS

program Chronic obstructive pulmonary disease (COPD) is a major health
GOALS problem in this country. Each year, direct and indirect costs of
COPD amount to approximately $1.8 billion and 90,000 man-years of
lost productivity. Emphysema and chronic bronchitis are the two
main diseases which, when considered together, are referred to as
COPD. Both emphysema and chronic bronchitis produce breathlessness,
cough, and increased susceptibility to respiratory failure and
death. COPD attacks middle-aged men and women and is particularly
common in smokers. It is now believed that early abnormalities
(physiologic and biochemical) related to emphysema and chronic
bronchitis may be detected at a stage when lung damage is still
reversible.

Because of the nature of these disease problems, a
goal of the program is to prevent development of
these diseases by early diagnosis and identifica-
tion and control of risk factors.

At the same time, because of the great number of
individuals suffering from already established and
progressive disease, another goal is to improve
treatment and rehabilitation programs.

To understand the mechanisms and causes of these
diseases is also an important goal and will be
greatly aided by the development of basic knowledge
of normal lung biochemistry, metabolism, response
to injury, and repair processes. (See the section
on Structure and Function of the Lung.)

recent Emphysema is the fastest growing cause of death in the United
progress States and is now the third leading cause of death from respira-
tory disease. The NHLI is currently placing major emphasis on
efforts to identify the risk factors of COPD. There are many
different kinds of emphysema, none well understood. Cigarette
smoking has long been recognized as a major risk factor for emphy-
sema, but attempts to identify other causes and risk factors have
often ended in failure. New lines of research have opened up
through the recent discovery of a genetic basis for one type of
emphysema. Environmental risk factors are being identified in a
variety of occupations.

A genetic enzyme defect known as alpha- 1-anti trypsin deficiency
has recently been identified as a factor in the development of
emphysema. When inherited from both parents, this enzyme defect
has been shown to be associated with the development of a severe
form of familial emphysema which attacks young adults. This

emphysema is rapidly progressive, resulting in death by the early
40 's — a time of peak earning potential and productivity. It is
not known for sure whether individuals with only one gene for the
defect (i.e., inherited from only one parent) are also at higher
risk, but early results indicate that at least one group of such
carriers may be at particularly high risk.

Alpha-1-antitrypsin deficiency may be responsible for as much as
one-third of the emphysema in the United States today. Early
detection and treatment can do much to prevent this tragic waste.

A screening test for alpha-1-antitrypsin deficiency has been devel-
oped. This test is now being performed on a number of population
groups to determine the frequencies of the affected and carrier
states, and to identify persons who are affected but who have not
yet developed emphysema, in order to begin preventive treatment
and possibly genetic counseling. At the same time, investigations
are underway to define the underlying genetic defect and to find
possible methods for prevention of the associated emphysema.

Early detection is an important step toward prevention of COPD.
A new and promising method has been developed for the early detec-
tion of changes in lung function and structure which appear to be
the first sign of chronic obstructive pulmonary disease. This
method, measurement of closing volume (the amount of air remaining
in the lungs after smaller airways collapse at the end of expira-
tion) , detects early changes in the lung which are thought to even-
tually progress to the clinical signs and symptoms of COPD. It is
presently believed that in persons with abnormal closing volume
measurements, but with otherwise normal lung function tests, the
progression of disease may be reversed and the development of dis-
abling disease prevented with proper treatment and the cessation
of smoking. This method is being used on selected populations to
evaluate its usefulness in mass screening of COPD. A standardized
protocol for using the method has been prepared to assure compara-
bility of different studies.

A workshop on animal models for emphysema was held which identified
new areas for research into the basic mechanisms of this disease.
Because cigarette smoking plays a key role in the development of
COPD, animal models for smoking are being developed to identify the
agents and mechanisms responsible for lung damage caused by smoking.
Many investigators are working to define the role of certain enzymes,
particularly proteolytic enzymes, in the development of emphysema.
The role of macrophages (a cell found in the lung) in the develop-
ment of emphysema and chronic bronchitis is also being investigated.

Advances made in the understanding of the structure and function
of the lung (described in the preceding section) will also be impor-
tant to the eventual success in controlling chronic bronchitis and
emphysema.

future Recent research progress has been achieved in identifying genetic
challenges factors associated with COPD. The most immediate challenge for

the future is how to influence people who are at risk, because of
genetic factors, to modify their life style in order to avoid
environmental risks that may lead to COPD. Another challenge is
to identify the factors in cigarette smoke that produce lung damage.
Studies to determine the mechanisms by which the lung clears itself
of particles inhaled in cigarette smoke, the modification of these
mechanisms by pollutants in the environment, and prospective epi-
demiologic studies of individual differences in response to the
harmful effects of tobacco are planned or in progress. Measures
to modify the smoking habits of the population need to be developed
in collaboration with behavioral scientists, and especially needed
are programs to decrease smoking in the young.

Other host factors, some genetic in origin, may be determinants of
emphysema and chronic bronchitis. A systematic search for inherited
enzyme abnormalities that predispose to development of COPD is an
essential part of the program on host factors.

We need to develop improved techniques and devices to detect bio-
chemical, immunologic, or physiologic abnormalities associated
with emphysema and chronic bronchitis sufficiently early to effect
reversal of the process, something now believed possible. The
closing volume test has been shown to be abnormal significantly
more frequently in smokers than in nonsmokers — in fact, few smokers
show normal test results. However, the full significance of this
test is still unclear, and studies are in process to determine the
relationship of an abnormal closing volume measurement to future
development of COPD. If, indeed, it can be documented through pre-
liminary screening studies that this test can identify persons with
a potentially reversible (and preventable) stage of COPD, then we
will have a potent new screening test that can be applied to large
populations in order to detect early disease at a stage when cure
can be accomplished.

ACTIONS

The Institute plans to:

1. Develop a multidisciplinary program addressed to the problem
of smoking. This program will include investigation of the
mechanisms and agents responsible for cigarette smoke injury

in emphysema and chronic bronchitis, as well as efforts to modify
smoking habits by means of psychological and pharmacological
approaches.

2. Elucidate the role of host factors, including genetic ones, in
the development of emphysema and chronic bronchitis by conduct-
ing and extending epidemiological studies.

3. Enlarge efforts in emphysema and chronic bronchitis prevention
through the development of improved techniques and devices for
early detection of reversible diseases and application of new
knowledge from studies of risk factors and their control. Epi-
demiological screening studies may be required at a later date
if this program proves successful.

4. Initiate controlled clinical trials to evaluate the efficacy
of current and newly developed approaches to therapy and reha-
bilitation.

schedule Present programs relating to pathophysiology and diagnosis of

advanced disease are being reduced in FY 74 and will be further
reduced by FY 80. Current and new actions in emphysema and chronic
bronchitis research are being increased. By early FY 75, a collab-
orative study on the closing volume test will be extended to popu-
lation screening for early airways disease, and a joint program will
be initiated with other Federal and state agencies on the role of
chronic bronchitis in the development of coal miner's pneumoconiosis.
New activities in early diagnosis, clinical trials, and multidis-
ciplinary approaches to smoking reflect increased efforts through
FY 80. Development of increased interagency contact, begun in
FY 74 between the NHLI and the National Institute of Mental Health
to identify studies of mutual interest regarding behavior, smoking,
and lung disease, will be pursued. Host factor research will
decrease in FY 76 as ongoing programs on alpha-1-antitrypsin are
concluded. As new information on other host factors becomes avail-
able, this program approach will increase in activity again in FY 78.

4. FIBROTIC AND IMMUNOLOGIC LUNG DISEASES

program Fibrotic and immunologic lung diseases result from the interaction
goals f a variety of environmental and host factors. These include viral
and bacterial infections, diseases of the connective tissue, radia-
tion damage, exposure to substances such as molds and dust that ini-
tiate hypersensitivity reactions, and inhalation diseases resulting
from exposure to substances such as coal dust, silica, asbestos, and
pollutant gases such as nitrogen dioxide, ozone, and sulfur dioxide.
Fibrotic and immunologic lung diseases can be prevented or treated
if the offending substances can be removed or their effects suppressed.
Therefore, a primary goal of the National Program in this area is
to disseminate information about the causes of these diseases, as
these are discovered through research, and how to avoid them. (See
section on Prevention, Control, and Education). The Institute's
current research program on fibrotic and immunologic lung diseases

focuses on asthma, pulmonary fibrosis, hypersensitivity pneumonitis,
and noninfectious granulomatosis. In cases where exposure cannot
be avoided or the disease prevented, effective treatment depends
on understanding the processes leading to disease and minimizing
their impact on the lungs.

The research goal is to conduct fundamental investi-
gations essential to the development of improved
therapy.

recent Asthma is an immunologic disease specifically mentioned in the
PROGRESS National Heart, Blood Vessel, Lung, and Blood Act of 1972. The
NHLI program focuses primarily on the nature of the pulmonary
functional impairment. To learn more about the unusually irritable
airways of asthmatics, the possible interaction between the inhaled
antigens that stimulate bronchial spasms and nonantigenic inhaled
pollutants (e.g., sulfur dioxide) are being studied, and the effects
of pharmacologic mediators (e.g., histamine) are being evaluated.
Immunologic and allergic bases of asthma are research areas within
the mandate of other NIH Institutes.

Early diagnosis of fibrotic and immunologic lung diseases, while
they are still reversible and curable, is a primary research objec-
tive. The methacholine challenge test for detecting preclinical
asthma is currently undergoing evaluation. A multidisciplinary
group is identifying specific antigens associated with hypersensi-
tivity pneumonitis and preparing and testing diagnostic skin tests.
Other investigators are utilizing animal models to investigate the
role of the immune system in these disorders and to seek ways to
develop early diagnostic tests.

Studies in asthmatics following exercise have been performed and
will now permit attempts at modifying the course of the response.
Approaches to therapy include: investigations of lung innervation
to provide an understanding of neural control of bronchoconstriction
and the basis for developing rational pharmacologic therapy; studies
of lung mechanics, gas exchange, and blood flow to determine precise
clinical indications for bronchopulmonary lavage — a therapeutic
measure used in some resistant asthmatic attacks; and studies of
behavioral conditioning as a possible way of controlling respiratory
resistance in asthmatics.

Pulmonary fibrosis, which may result from chemical, physical
(radiation) , and microbial injury as well as hypersensitivity
reactions, includes a group of diseases for which no apparent cause
has been identified. Studies are underway to elucidate the immuno-
logic mechanisms that lead to pulmonary injury. Basic information

is being developed regarding connective tissue protein metabolism
(collagen and elastin) , and a major effort is being made to stimu-
late research in this area. Methods for studying cell-mediated
immunologic responses and circulating antibodies in humans and
animals have been developed and applied to lung diseases.

Hypersensitivity pneumonitis, usually a consequence of inhalation
of allergens, occurs among pigeon breeders, farmers, and workers
exposed to detergent enzymes. Several multidisciplinary centers
are conducting research focused on the epidemiology of hypersensi-
tivity and diffuse interstitial lung diseases. Technology for
mass screening, both in pulmonary function and immunology, has
been developed to facilitate epidemiologic studies, and population
groups have been identified and are being studied. Attempts at
correlating the levels of exposure with functional and structural
deterioration of the lung will hopefully result in improved and
safer environmental and industrial standards.

Among noninfectious granulomatoses, sarcoidosis is of particular
epidemiologic interest due to its unusual prevalence among the
black population in this country (10 to 17 times more common than
in the white population) and because it is twice as common among
females as among males. An epidemiologic study of sarcoidosis is
being developed.

Animal models of fibrotic and immunologic lung diseases have been
developed and are valuable for investigating etiologic and patho-
genetic mechanisms. An animal model of allergic asthma is now
available and is being used to study the neurologic mechanisms in
this disorder. Several multidisciplinary projects are utilizing
animal models of hypersensitivity and diffuse interstitial lung
disorders, and a program is being initiated to develop animal models
of sarcoidosis.

future Where population groups are known to have a high prevalence of
challenges pulmonary fibrosis or immunologic lung diseases, epidemiological

studies should be carried out to identify the factors responsible.
This identification of specific etiological agents is crucial to
the development of effective control measures aimed at eliminating
these factors. The Institute will seek to coordinate epidemiologic
programs through use of standardized methods and protocols and
increased communication, so that data can be compared.

Advances in biochemistry, pharmacology, and immunology have not
yet been brought adequately to bear on problems of lung disease.
These basic scientific disciplines need to be drawn upon in the
development of therapy, prevention, and control of immunologic and
fibrotic lung diseases. Understanding the role of certain endoge-
nous mediators and their composition and mechanism of action, though
difficult to achieve, is essential. The specific roles of molec-
ular mechanisms involved in cell-mediated and antibody-mediated

immunologic responses in lung disease must be defined. It is anti-
cipated that the inflammatory and bronchoconstricting responses
mediated by certain hormonal agents will be better understood in
the future. The mechanisms of collagen synthesis and degradation
need to be studied in order to develop therapy directed at specific
events in the chain of metabolic changes leading to disease. It
is anticipated that specific components of collagen will be identi-
fied and that improved methods of assaying elastin will allow
better understanding of its metabolism in the lung. Techniques for
diagnosing sarcoid are being developed, and a better understanding
will be sought of immunologic and neurologic mechanisms of fibrotic
and environmental lung diseases, asthma, and sarcoid.

Many animal models of immunologic and fibrotic lung diseases are
available and represent opportunities for study of the pathogenesis
of these diseases.

ACTIONS

The Institute plans to:

Seek new information about the synthesis and degradation of
collagen and the immunologic responses and defense mechanisms
of the lung through continued and extended multidisciplinary
programs. These will involve collaboration by immunologists,
biochemists, physicians, and physiologists.

Initiate programs to develop pharmacologic agents that will
modify the alterations in connective tissue metabolism that
lead to pulmonary fibrosis, and study the use of immunologic
techniques to stimulate tissue defense mechanisms against
immunologic lung diseases.

Initiate epidemiologic studies to investigate etiologic factors
in population groups characterized by unusual prevalence of
fibrotic and immunologic lung diseases.

schedule Attention currently focuses on characterizing the lung structural

proteins, collagen and elastin, at the biochemical level. Programs
which are oriented to the synthetic and degradative processes of
collagen and elastin are being implemented. Programs concerned
with epidemiology, animal models, and development of a simple
in vitro test of sarcoidosis will continue through FY 78. Epi-
demiologic studies of hypersensitivity pneumonitis and fibrotic
lung disease will begin to produce useful information on the patho-
genesis and natural history of these disorders by FY 77. By
redirecting funds from other program areas , both new actions and
the total program in fibrotic and immunologic lung diseases will
undergo a substantial increase between FY 76 and FY 80. All of
the action areas — multidisciplinary approaches, targeted programs,
etiology and epidemiology — reflect incremental activity between
FY 76 and FY 80.

5. RESPIRATORYFAILURE

program Respiratory failure may occur in many different disorders, both
GOALS acute and chronic, pulmonary and nonpulmonary . Despite consider-
able progress in the development of sophisticated therapy, respira-
tory distress syndromes (acute respiratory insufficiency) of the
adult remain among the most common causes of postoperative mortal-
ity and of death related to major trauma. Because acute respira-
tory insufficiency is potentially reversible if recognized early
and if treatment is initiated promptly, the major research emphasis
at present is on identification of factors that predispose to these
syndromes, studies of the effects of oxygen toxicity, and develop-
ment of therapeutic devices, especially ventilatory assist devices
and oxygenators. (See section on Respiratory Assistance.)

• A program goal is to develop improved techniques for
detection of potential respiratory failure.

• Another goal is to develop monitoring devices and
modes of therapy that are less costly, less compli-
cated to administer, and more readily available than
those now in use for respiratory failure.

recent Various techniques and devices have been developed for detecting
progress impending respiratory failure. A sensitive spirometer that measures
the peak acceleration which occurs early in forced expiration is
currently being evaluated for its ability to detect early airway
obstruction. Methods have been developed and are being evaluated
for assessment of the degree of pulmonary edema. Powdered tantalum,
as a roentgenographic contrast medium, has been clinically used to
study the structure and function of bronchi, bronchioles, and
alveoli in diseased lungs. Further developments relative to treat-
ment of respiratory failure are discussed in the section on Respira-
tory Assistance.

future The specific challenges in this area are to improve the devices
challenges anc j techniques used to detect potential respiratory failure and to
provide the attending physician with a better description of lung
function during the period of respiratory failure, thus making it
possible for the physician to be more responsive to the need for
improved respiratory care during this critical care period. We
need to evaluate critically current devices and techniques for
early detection and subsequent monitoring of respiratory failure.
New devices that can be easily used by physicians and allied health
personnel need to be developed to provide more effective management.
As new devices and techniques are developed, their efficacy must
be tested in controlled clinical trials.

Future challenges include the development of a portable, rugged, and
reliable mass spectrometer for continuous measurements of respira-
tory gases. Also, microsized, reliable, and stable electrodes need
to be developed for the continuous in_ vivo gas measurements of p02
and pC02- In addition to the improved, continuous measurement of
respiratory and blood gases, a more complete assessment of changes
in pulmonary function and structure during the period of respira-
tory failure is a significant challenge. The development and eval-
uation of new noninvasive devices and techniques are required to
support the therapeutic measures provided in critical care settings.
A newly developed technique to continuously measure the ventilation/
perfusion ratio may provide an important contribution. In addition,
new and innovative techniques of lung imagery hold promise for moni-
toring lung function.

Despite the fact that respiratory support with positive pressure
and high oxygen concentrations presently provides the basis for
therapy during respiratory failure, the long-term effects of high
oxygen concentrations and continuous mechanical ventilation on the
lung are still not well understood. Further studies on the effects
of long-term ventilation, with and without positive pressure, on
the lung function and structure are needed. In addition, studies
of the potential dangers to the lung of high oxygen concentrations
for extended periods must be continued in order to complete our
understanding of this problem.

ACTIONS

The Institute plans to:

1. Initiate development of devices and techniques for monitoring
of respiratory function in patients with impaired lungs.

2. Develop and test improved invasive and noninvasive instruments
for blood and respiratory gas analysis in patients with lung
disease.

3. Develop devices and techniques to detect and monitor resistance
in small airways and structural and functional abnormalities of
diseased lung. (See section on Emphysema and Chronic Bronchitis.)

schedule During the coming year, the initial phase of several programs in

Respiratory Failure will be completed. The design and development
of a lightweight, sensitive, and reliable mass spectrometer will
be completed and ready for clinical test and evaluation. Likewise,
the design, fabrication, and feasibility test for two new types of
continuous, in_ vivo blood gas sensors will be completed, and the
clinical use of the continuous ventilation/perfusion technique will
be evaluated. Program development will subsequently continue to
increase gradually through FY 79 with primary emphasis on providing
improved diagnostic and monitoring capabilities.

6. PULMONARY VASCULAR DISEASES

PROGRAM
GOALS

Pulmonary vascular diseases, which include cor pulmonale, pulmonary
hypertension, and pulmonary edema, are serious lung disorders with
often devastating consequences, and as such are the focus in this
new program area in lung diseases. Reliable data on incidence and
prevalence of pulmonary vascular diseases, as well as on the effec-
tiveness of present modes of therapy, are not available. This is
largely because present methods for diagnosis and for assessing
therapeutic progress involve procedures that cannot readily be used
on very ill or large numbers of patients. If these diseases could
be reliably identified early in their course they could be effec-
tively treated. If simple techniques that could be used repeatedly
without undue discomfort to the patient were available, it would
be possible to study the course of these disorders and assess the
long-term benefits of therapy. The causes and development of these
diseases need to be investigated through the use of animal models
in an interdisciplinary setting.

A primary goal of this new program area is to stimu-
late development of reliable, noninvasive techniques
for assessing the ventricular hypertrophy associated
with cor pulmonale, and for diagnosing pulmonary
hypertension without the need for cardiac catheter-
ization.

Another goal is to encourage development of animal
models of cor pulmonale and pulmonary hypertension
to be used in the investigation of pathogenetic
mechanisms of these diseases.

Multidisciplinary studies must be fostered toward
understanding the dynamics of fluid, electrolyte,
and protein exchange in pulmonary edema.

recent Although it is not accurately known how many patients suffer from
progress cor pulmonale, this disorder is most often a consequence of emphy-
sema and chronic bronchitis, themselves chronic respiratory diseases
of national impact. Autopsy data suggest that pulmonary hyperten-
sion is also underestimated because at present it can only be diag-
nosed by catheterization, a procedure not amenable to screening
large numbers of persons or to use in the very ill. Pulmonary edema
is more prevalent than generally realized but is usually reported
only when it is the admitting diagnosis and not when it arises in
the course of hospitalization or is treated in the outpatient clinic.
It is a common occurrence in cardiovascular and renal diseases, as
well as in many pulmonary disorders. With the methods presently
available, pulmonary edema can only be detected late in its clinical
course, making prompt therapy of the condition impossible, and thus
contributing to its morbidity and mortality.

future Early diagnosis is the first step in treating these pulmonary
challenges vascular diseases effectively while they are still reversible. To
evaluate the efficacy of therapy, serial assessments must be made
of the patient's condition over long periods. Both of these needs
depend upon development of reliable techniques that are noninvasive,
safe, and cause minimal discomfort to the patient. Some noninvasive
techniques have been developed, but none have sufficient promise to
meet the clinical needs for diagnosing and screening for pulmonary
hypertension, cor pulmonale, or pulmonary edema. A major challenge
is to develop promising diagnostic techniques which would make it
possible to screen large numbers of persons . These techniques
would be used to identify population groups for the study of eti-
ologic factors and pathogenetic mechanisms, and for assessing thera-
peutic regimens.

New and better animal models need to be developed in the future to
study the pathogenesis and pathophysiology of cor pulmonale and
pulmonary hypertension at the molecular and biochemical levels, and
to further assess diagnostic and therapeutic techniques. Available
animal models do not adequately represent the disease processes
known to occur in humans. Fundamental studies are also needed to
elucidate neural, endocrine, and electrolyte factors in the patho-
physiology of pulmonary hypertension. Limited work in this area
shows great promise of yielding information necessary for future
preventive, therapeutic, and diagnostic efforts. Studies of the
lung's interaction with vasoactive materials and of the ultrastruc-
tural and biochemical aspects of vascular smooth muscle need to be
extended.

The early diagnosis and prompt therapy of pulmonary edema require
a thorough understanding of basic pathogenetic mechanisms in terms
of ultrastructural, metabolic, and molecular changes. Results to
date suggest that these approaches will pay large dividends, and
extension of this work with application of new approaches is neces-
sary.

ACTIONS

The Institute plans to:

1. Extend multidisciplinary efforts to elucidate the dynamics of
exchange of water, protein, and electrolytes, the biochemistry
of edema fluid, and metabolic alterations in the edematous
lung.

2. Encourage the development of safe, noninvasive methods for
detecting pulmonary hypertension, cor pulmonale, and pulmonary
edema. These methods or devices should be sufficiently sensi-
tive to assess both the presence and progression of the
disease.

3. Promote multidisciplinary approaches on the pathogenesis and
pathophysiology of cor pulmonale and pulmonary hypertension.
Investigators will be encouraged to develop animal models of
these diseases , to apply ultrastructural and biochemical tech-
niques to the study of vascular smooth muscle, and to study the
metabolism of vasoactive amines by the lung.

4. Develop epidemiologic programs aimed at determining the true
impact of cor pulmonale and pulmonary hypertension on the
population, identifying host factors and other agents respon-
sible for the etiology and pathogenesis of these diseases, and
collecting patient populations for evaluating diagnostic and
therapeutic methods .

schedule The above actions will be initiated in FY 75, and these efforts will
be increased gradually through FY 78.

7. INHALATION DISEASES

program This new program area is addressed to respiratory diseases that
goals result from the direct effects of inhaled dusts, vapors, or gases
and which can be prevented by removal of the offending substances
or by protecting individuals from them. Therefore, a primary goal
of the National Program is to disseminate information about the
causes of these diseases and how to avoid them. (See section on
Prevention, Control, and Education.)

• The research goal is to improve detection of the known
causes of these diseases and thereby prevent their
development.

recent A great deal is already known about types of environmental agents
progress that are associated with industries and occupations. Industrial
progress often brings related problems; it has brought us many
benefits, but also pollution. The introduction of the pneumatic
drill was a tremendous boon to the mining and construction industry,
but it also greatly increased the incidence of lung disease caused
by the inhalation of dust particles in the air. Of all occupational
illnesses, dust inhalation diseases, medically known as pneumoconi-
oses, are the most serious health problem. The dusts responsible
for pneumoconioses are not the familiar dusts we wipe off our cars
and furniture, but the heavy, often harmful dusts that millions of
American workers (coal miners, insulation workers, foundrymen,
stone cutters, and other occupational workers) breathe in every
day on the job. So fine are these dusts that they escape the natural
cleansing mechanism of the upper respiratory tract and lodge perma-
nently, inextricably, in the lungs. Some are relatively harmless;

others can be deadly. Eventually, if exposure is sufficiently high
and prolonged, the accumulated particles may cause fibrosis, or scar-
ring of the lung tissue. In many cases, this leads to serious dis-
ability and even death.

future Not long ago, the hazard of pneumoconioses was considered confined
challenges to certain jobs in specific occupations. Today, it is recognized
that the problem is far more complicated and that sources of these
diseases have greatly widened. It has been found that not only are
workers themselves potentially at risk, but also their co-workers
and, in some cases, the community at large. This last possibility —
environmental lung disease associated with agents usually encoun-
tered only by certain workers — has given the problem considerably
more dimension and importance .

Authorities who have studied the problem believe that with the
cooperation of Federal and state agencies, management and labor,
practically all cases of pneumoconioses can be prevented. Each
dust-producing job must be studied to decide the best method of
prevention. Sometimes dust levels can be reduced easily by proper
ventilation of work areas, removal of dust by suction as it is
produced, wetting down of materials before they are worked on, or
by switching from a hazardous material to one that does not cause
disease. In other cases, the control of dust diseases is an
extremely complicated matter, involving elaborate and costly
measures .

The pulmonary changes resulting from specific inhalation diseases
are usually fibrotic in nature but may also involve immunologic
alterations. Consequently, as more is learned about the causes of
these disorders, it is anticipated that they may be transferred to
the Fibrotic and Immunologic Lung Diseases program area.

actions The Institute plans to:

1. Develop programs to improve the prevention, detection, and
relief of inhalation diseases.

schedule The Institute's program on inhalation diseases will emphasize Pre-
vention, Control, and Education efforts. Research on detection and
relief of inhalation diseases will be initiated in FY 75 and gradu-
ally increased through FY 78.

8. RESPIRATORY ASSISTANCE

program The development of techniques and devices for providing respiratory
goals assistance is an important component of the Institute's research

efforts to combat all diseases of the lung, and especially respira-
tory failure, and as such is called out as a separate program area
in this updated plan. Because respiratory failure is a debilitat-
ing and often fatal disorder that is an eventual complication of
nearly every respiratory disease, the development of effective
therapeutic devices is of the greatest importance.

The major goal of this program area is to apply new
technology to the treatment of respiratory failure
and to develop improved rehabilitation devices and
techniques .

RECENT
PROGRESS

The most significant progress in this program area to date has been
the development and testing of membrane oxygenators in animals and
humans. These oxygenators have demonstrated sufficient promise to
warrant testing in clinical trials under highly controlled condi-
tions. If such trials demonstrate the efficacy of the devices,
they could become a valuable mode of therapy to be widely used in
support of infants with respiratory distress syndrome and adults
in respiratory intensive care units.

Research on respirators has led to development of a compact, por-
table, ventilatory-assist device which can be patient-cycled for
the changeover from the expiratory to inspiratory phase. This
device also has automated sigh capability and ability to provide
a positive end-expiratory pressure. Clinical trials are presently
underway.

Despite the therapeutic importance of oxygen inhalation devices
for patients in respiratory failure, elevated concentrations of
inspired oxygen may be potentially dangerous . A recent workshop
provided a forum for review of research progress, exchange of views,
and assessment of future needs to insure oxygen therapy without con-
comitant oxygen toxicity.

future An immediate challenge for providing prompt respiratory assistance
challenges i s the clinical determination of which patients in respiratory dis-
tress may benefit from long-term (days) membrane oxygenator support
and when in the course of their distress such support should be
administered. Such criteria could provide needed direction to the
effective clinical use of this new support device and the maximum
exploitation of its potential.

Continued development of artificial lung systems is anticipated.
New approaches and materials could lead to systems with greater
clinical utility. For example, the search for and testing of new
oxygenator materials may lead to a device that requires less complex
blood management during its clinical use. Techniques of blood man-
agement required by currently available membrane oxygenators pre-
clude their use in many patients requiring respiratory assistance.

The search for and testing of various materials for use in oxygen-
ators will continue. These efforts will lead to improved manage-
ment of patients with acute and chronic respiratory insufficiency.
Progress is also anticipated in the development of noninvasive methods
to assess lung function during respiratory insufficiency and to deter-
mine the subsequent need for oxygenator support.

ACTIONS

The Institute plans to:

1. Expand programs addressed to ventilatory-assist devices and
oxygenators to insure improvements in available devices and
development of new ones.

2. Test presently available and promising new devices in con-
trolled clinical studies.

3. Develop programs to insure the early initiation of treatment.

4. Continue and extend Specialized Centers of Research where
sophisticated techniques are available in order to capitalize
on what is known and to improve present modes of therapy.

schedule a collaborative program will be initiated soon to establish clin-
ical criteria for the therapeutic use of membrane oxygenators in
the management of acute respiratory failure. In addition, the
design, fabrication, and feasibility studies for several new and
novel oxygenator designs will be completed. Analysis and moni-
toring of other forms of respiratory assistance devices will con-
tinue to be increased in subsequent years, reaching a peak by
FY 78, in order to provide more effective support to those in
respiratory distress.

BLOOD DISEASES AND BLOOD RESOURCES

The NHLI program in Blood Diseases and Blood Resources is intimately related
to the Institute's responsibilities in cardiovascular and pulmonary diseases.
Blood is a vital part of the circulatory system since it is the vehicle in
which oxygen, nutrients, and other body chemicals are carried through the blood
vessels to every part of the body, to be exchanged for carbon dioxide, waste
products, and chemicals which in turn need to be transported away.

Problems in the blood are often reflected in disorders of the cardiovascular
and pulmonary systems. Life-threatening situations can arise if the blood clots
within the heart, blood vessels, and lungs, or if it escapes from the cardiovas-
cular system, as in hemorrhage, into the tissues (e.g., stroke) or outside of
the body. Blood that has lost its capacity to clot, such as in the bleeding
disorders (e.g., hemophilia) can also give rise to life-threatening situations.

Blood is an organ in its own right, composed of many different elements. In
addition to the important functions mentioned above, it participates in the
body economy in a number of ways. It contains important chemicals such as hor-
mones and enzymes, protective agents (antibodies) against certain diseases,
factors important in preventing clotting of blood within the cardiovascular
system, and factors important in promoting clotting of blood when it acciden-
tally escapes from within the heart and blood vessels. The blood cells defend
the body against invading organisms and aid in the repair of organs, including
the vascular system and the lungs. An adequate volume of blood within the cir-
culatory system is important in maintaining normal blood pressure and perfusion
of blood to all parts of the body.

Blood is a very important life-saving therapeutic tool in medicine as well as
in surgery. Millions of Americans are saved each year by blood or blood com-
ponent therapy. Many of these individuals would previously have met with cer-
tain death. Almost 10 million units of blood and 1.7 million liters of plasma
(the equivalent of an additional 8.5 million units of blood) were collected in
the United States in 1971 for use in therapy. Studies of blood preservation
and efforts to reduce immune responses to transfused blood are important in
the area of organ transplantation as well.

The plans for developing the Institute's program on blood diseases and blood
resources as well as the plans for coordination of the National Program were
outlined in the National Heart and Lung Institute Summary (Volume 1) of the
National Heart, Blood Vessel, Lung, and Blood Program on May 1, 1973.

The updated National Program presented here represents an orderly review and
assessment of NHLI activities in the field of blood diseases and blood resources
and continues to be responsive to the Legislative Act which specifically requires
"studies and research into blood diseases and blood, and into the use of blood
for clinical purposes and all aspects of the management of its resources in this
country . . . . "

The program goals, actions, and schedules as set forth in 1973 in the National
Program, have been reviewed and updated by the Institute and its advisors.
Recent progress and future challenges for each program area have been identified.
This updated Program for the next five years, together with the recent progress
and future challenges identified, are presented here.

The four areas addressed by the Institute's research programs in blood are:

1. Bleeding and Clotting Disorders

2. Sickle Cell Disease and Related Disorders of the Red Blood Cell

3. Biomaterials

4. Blood Resources.

The first, second, and fourth program areas were identified separately in 1973;
the third, already included in the 1973 Plan, is given separate status in the
updated research program presented here. In revising its Plan for blood dis-
eases and blood resources, the Institute has modified some Actions and integrated
others, resulting in an overall decrease of 15 specific research Actions in the
updated Plan. These modifications in the program are made in order to take
advantage of recent progress and future challenges.

1. BLEEDING AND CLOTTING DISORDERS

Blood clotting abnormalities are a major cause of death and disability in the
United States. The National Program addresses two important areas related to
disordered hemostasis: the hemophilias and the thromboembolic disorders. In
the case of the hemophilias, life-threatening situations occur as a result of
excessive uncontrolled bleeding because of failure of the patient's blood to
clot normally. In the case of thromboembolic disorders, the opposite is true:
the blood clots too readily, e.g., in the heart, the brain, or the lungs, causing
life-threatening complications such as heart attacks, strokes, or pulmonary
embolism.

The Hemophilias

program The hemophilias constitute a major national health problem for
GOALS several reasons. First, treatment must be continued throughout
the patient's lifetime at enormous costs; the alternative is
crippling and death. Second, treatment of this single disease
places one of the largest demands on the nation's blood supply.
Finally, the impact of this disease on the patient and his immedi-
ate family is catastrophic in terms of social, psychological, and
economic costs. The hemophilias are a family of hereditary dis-
orders in which the patient's blood clots very slowly or not at
all causing uncontrolled bleeding on injury or during surgery
unless the appropriate clotting factor is supplied promptly.

• A major goal of this program is to understand the
genetic mechanisms which result in the bleeding dis-
orders known as hemophilias.

• A second goal is to improve methods of preparing and
distributing the necessary plasma fractions so that
they are available to all who need them at reason-
able cost.

• A third goal is to allow the hemophiliac and his
family to improve the quality of their life and to
make informed decisions about their future, through
programs of education, screening, and genetic coun-
seling as described in the section on Prevention,
Control, and Education.

RECENT
PROGRESS

Research advances in the last two decades have completely changed
the outlook for hemophilia care. The clotting factors needed by
the hemophiliac have been identified, partially characterized and
can now be mass produced from normal donor plasma. Given the
increasingly more sophisticated management of our national blood
resource, the hemophiliac can look to better, cheaper, and more
widely available products for the treatment of his disease. Recent
experiments in self -administered home care provide the basis for
the expectation that antihemophilic factor may be used, as is
insulin in diabetes, to prevent the manifestations of hemophilia —
the crippling, suffering, expense, and time loss from school or
work that have been characteristic in the past. Recent experiments
also indicate that it may be possible to identify the carrier state
in the prospective mother and through genetic counseling to reduce
the prevalence of the disease. The NHLI ' s national survey of hemo-
philia treatment provides an informational basis on which to develop
effective plans for study and treatment of the disease.

FUTURE
CHALLENGES

Additional progress can be expected in the medical management of
hemophilia. It is likely that home therapy may become feasible
and economical in the near future. Self-administration of anti-
hemophilic factor (AHF) immediately upon the first sign of bleeding
may help prevent serious side effects such as crippling of joints.
There is the further possibility that AHF may eventually be used
prophylactically by the patient in his home to prevent bleeding
altogether. The concept of comprehensive long-term management of
hemophilia has not yet achieved wide acceptance and methods of such
management and counseling need further study and dissemination to
the public and to the medical profession. (See section on Preven-
tion, Control, and Education.) In the future it may also become
possible to transplant normal blood-forming tissue into these
patients, thereby permanently correcting the disorder.

Despite the research advances described earlier, basic knowledge
of hemophilia remains incomplete. A fuller knowledge of the molec-
ular structure of the clotting factors could lead to even better
therapeutic approaches through the identification of biologically
active molecular fragments. Furthermore, the application of newer
technology can lead to greater production efficiency and reduction
in cost of antihemophilic factor. Antihemophilic factor derived
from animal blood should be studied clinically to determine its
value in treating the occasional patient who develops an antibody
to the human factor. One common complication of replacement therapy
is the transmission of the hepatitis virus. Still to be fully
explored are methods of removal or inactivation of the virus in
antihemophilic factor preparations.

actions The Institute plans to:

1. Support fundamental research on hemophilia, especially on the
molecular structure of the clotting factors, the chemistry of
protein fractionation, the physiology of the coagulation sys-
tem, and molecular genetics; apply these investigations as
they mature to solve the clinical problems, e.g., greater effi-
ciency in the production of antihemophilic factor from donor
blood, the identification of effector sites on the molecule,
and the isolation of active molecular fragments; extend the
clinical experiments which indicate that inhibition of the clot-
dissolving system is useful in the treatment of the bleeding
crises of hemophilia.

2. Establish Specialized Centers of Research for the bleeding dis-
orders. These should cover the full range of disciplines neces-
sary for a comprehensive approach to hemophilia care. They
should provide for both basic and clinical research.

schedule Current targeted research efforts are scheduled for completion by
FY 75, while grant activities will expand through FY 77. New
Specialized Centers of Research are planned for FY 75 through FY 77,
and their support will peak in FY 77.

Thromboembolic Disorders

program Thrombosis (clotting of the blood within the blood vessels) and
goals embolism (clot fragments carried in the blood from their site of
origin) are often responsible for the crippling or lethal mani-
festations of heart and blood vessel diseases. They are implicated
in several of the major causes of death in the United States. Arte-
rial thrombosis plays a role in heart attacks, stroke, and chronic
renal disease. Venous thrombosis can result in pulmonary embolism,
a disorder which hospitalizes some 300,000 persons and contributes
to the death of more than 50,000 patients annually. Thrombosis and
hemorrhage in the microcirculation play primary or contributory
roles in hypertension, stroke, diabetes, cancer, sickle cell anemia,
and many other disorders affecting virtually every organ in the
body. The relationship of thrombosis to atherosclerosis is of
fundamental importance to the nation's health and has far-reaching
therapeutic implications.

• The major goal is to increase understanding of the funda-
mental mechanisms of thrombosis, especially the role played
by the individual components of clotting and their relation-
ship to the microcirculation.

• A second goal is to facilitate detection and treatment of
thromboembolic disorders.

The approaches to both venous and arterial thromboembolism share
two important concepts: (1) their causes involve an interplay of
the blood coagulation system, the platelets (one of the formed
elements in the blood) , the vessel lining, and the properties of
flowing blood, and (2) application of previously accumulated and
newly generated knowledge in these areas can be expected to pro-
vide health benefits to a large number of American people.

RECENT
PROGRESS

Risk factors for thrombosis and embolism have been recognized and
high risk clinical situations have been identified. It is clear
for instance that patients suffering from hip fracture or under-
going hip surgery are at very high risk for venous thrombosis and
subsequent pulmonary embolism. Patients, especially the elderly,
who are immobilized for any cause are at high risk. Venous throm-
bosis commonly occurs as a complication of heart failure. Throm-
bosis is often the first overt manifestation of some forms of
cancer. Women using oral contraceptives have an increased risk,
and thrombus formation is the leading complication of prosthetic
valves and vessels and of the rejection phenomenon in organ trans-
plantation.

Recently, advances have been made in the sensitivity of diagnostic
methods for detecting deep venous thrombosis. Pathologic evidence
indicates that venous thrombosis is so common that it was found in
more than 50 percent of autopsied patients who died from any cause.
The vast majority of these had been unsuspected. There is both a
pressing need and an opportunity for increasing the acuity of diag-
nostic methods .

Work in the last decade on the clot-dissolving agents, urokinase
and streptokinase, demonstrates that these agents have an important
potential as treatments for a wide range of thromboembolic disease.
For example, it has been demonstrated that these agents signifi-
cantly accelerate the resolution of clots in the lungs (pulmonary
embolism) .

Perhaps most exciting is the promise offered by drugs which prevent
the formation of blood clots by inhibiting the aggregation of blood
platelets in the blood vessels. Recent laboratory and clinical
studies indicate that these agents may have an important potential
in the prevention of a wide range of thrombotic disorders including
heart attacks.

FUTURE
CHALLENGES

Further efforts are needed to capitalize on past progress in methods
for detecting venous thrombosis. Hepatitis-free fibrinogen must be
made available for clinical clot detection studies. Further efforts
are well justified to identify fibrin and fibrinogen breakdown prod-
ucts as a key to the diagnosis of thrombosis in the microcirculation.

In the treatment of thrombotic disease, the greatest opportunity
exists for full exploration of the potential of the clot-dissolving
agents, urokinase and streptokinase, for treatment of patients with
heart attacks, certain types of strokes, and other thromboembolic
complications of cardiovascular disorders.

Prevention of thrombotic disease would have by far the greatest pub-
lic health effect and, fortunately, an opportunity is presented by
recent studies of blood platelets and the demonstration that the
platelet aggregation phenomenon is susceptible to drug inhibition.
Clinical studies are urgently needed to identify the best drugs,
the most appropriate drug regimens, and the clinical conditions in
which they should be used.

ACTIONS

The Institute plans to:

1. Encourage fundamental research in thrombosis and in the relation-
ship between thrombosis and atherosclerosis; support study of
the function and pathophysiology of the microcirculation; study
the relation between lipid metabolism and platelet function;

and encourage study of the role of the coagulation system in
sickle cell crises.

2. Support the development of techniques and instrumentation for
sensitive, reliable, specific detection of thromboembolic dis-
ease.

3. Devise and support clinical trials of platelet-inhibiting drugs
in the prevention of thrombosis in patients at high risk.

4. Conduct clinical trials of the efficacy of clot-dissolving drugs
in the treatment of thromboembolic disorders, especially heart
attacks .

schedule Present targeted programs will be completed in FY 77. Basic research
in clotting will receive increased support between FY 76 and FY 79.
Trials of antithrombotic drugs and studies of methods for early diag-
nosis of thrombosis will receive additional support, with the former
peaking in FY 77.

2. SICKLE CELL DISEASE AND RELATED DISORDERS OF THE RED BLOOD CELL

The three groups of disorders considered in this section include Sickle Cell
Anemia and Sickle Cell Trait, conditions closely related to sickle cell disease
such as Cooley's Anemia, and defects affecting the Red Blood Cell Membrane and
Enzyme Systems.

Sickle Cell Anemia and Sickle Cell Trait

PROGRAM
GOALS

Sickle cell trait, the most common inherited disorder in the United
States, is believed to be present in more than 2 million U.S. citi-
zens, primarily black. The trait is a relatively benign "carrier"
form in almost all of these 2 million persons. However, approxi-
mately 1 in every 500 black babies is born with the life-threatening
form of the disease called sickle cell anemia. Such individuals
undergo painful episodes called sickle cell crises. The research
goals of the sickle cell disease program are to:

Develop improved therapy for sickle cell disease crisis;
increase knowledge of the fundamental biology of the
disease and its complications; and develop effective
and acceptable methods for education, screening, and
counseling.

The goal of educating the public and the medical profession about
sickle cell disease is discussed in the section on Prevention, Con-
trol, and Education.

recent Recent advances have been made in fundamental research on sickle
progress cell disease. The disease is due to a genetically determined change
in the chemical substance (hemoglobin) responsible for the oxygen-
carrying capacity of the blood. The presence of the changed hemo-
globin (hemoglobin S) is accompanied by distortions in the shape of
the normally biconcave red blood cells carrying the hemoglobin,
making these cells less able to survive in the blood circulation and
less able to move freely through the smaller blood vessels. The
presence of hemoglobin S in the red blood cells may lead to anemia
(reduction in the number of red blood cells) and intermittent block-
age of blood vessels, precipitating occlusive sickle cell crises.

The NHLI continues to coordinate the HEW Sickle Cell Disease Program
initiated by the President in 1971. The major objectives of this
program are: (1) to foster research and development both at the
fundamental and clinical levels; (2) to initiate and expand commu-
nity education, screening, and counseling programs; (3) to educate
medical and allied health professionals about the problems of sickle
cell disease; and (4) to improve clinical care for victims of sickle
cell disease. The last three of these objectives are discussed fur-
ther in the section on Prevention, Control, and Education.

Studies are currently in progress to develop information about the
mechamisms involved in precipitating and sustaining the painful
occlusive crises and to find ways to deal with it effectively.
Recent results show that the sickling process may possibly be related
to ATP (an energy-rich substance) depletion and calcium accumulation

in the cell membrane. The possibility of an associated zinc defi-
ciency has been observed in some patients. The reasons for the
increased susceptibility to infection in patients with sickle cell
disease are being studied.

Techniques have been developed which improve the ability to detect,
measure, and study the structure of abnormal hemoglobins, and to
identify them in the prenatal period, in cord blood and at birth.
Progress has also been made in screening and diagnostic testing of
hemoglobin abnormalities.

It has now been demonstrated that intravenous urea is ineffective
as an anti-sickling agent in patients in painful crises. However,
the search for therapeutic approaches continues, and clinical
studies are planned to test the efficacy of sodium cyanate, a prom-
ising new agent .

Collaboration has been developed with other institutions interested
in sickle cell disease. An agreement has been entered into with
the Center for Disease Control to continue to conduct workshops in
hemoglobin detection techniques for the demonstration service proj-
ects, to set up a hemoglobin proficiency testing program for the
Federally supported sickle cell projects, and to serve as a refer-
ence laboratory for abnormal hemoglobins during the coming year .

future Despite knowledge of the precise defect in the sickle hemoglobin
challenges molecule, the areas of ignorance about sickle cell disease are
probably greater than the areas of understanding. Therefore, a
balanced program must address a variety of problems, from under-
standing of the red cell to treatment of the patient and education
of the community.

The biology of the red cell, the mechanisms of sickling, the effects
of combinations of sickle hemoglobin and other abnormal hemoglobins,
the effect on the red cell of agents that may prevent or reverse
sickling are some of the problems that must be addressed to gain the
knowledge necessary for rational therapy.

We must continue to search for therapeutic measures that are effec-
tive, safe, and simple. As promising therapies are developed, they
must be tested in clinical trials. Better screening techniques
need to be developed to detect hemoglobin variants, including sickle
hemoglobin. We need simple, rapid, accurate, and reliable methods
suitable for screening.

Projects in screening and diagnostic testing of hemoglobin abnor-
malities are presently in an early phase. Future challenges in this
area include development of accurate prenatal diagnosis of abnormal
hemoglobins and of innovative methods of education and genetic

counseling. The greatest immediate need is for dissemination of
accurate information and for education of the public regarding the
meaning of sickle cell trait and sickle cell anemia. (See section
on Prevention, Control, and Education.)

In developing interfaces with other agencies and organizations, the
greatest challenge for the future is to develop a well-coordinated
and uniform approach in all Federal departments and agencies on
matters pertaining to abnormal hemoglobins .

ACTIONS

The Institute plans to:

Sustain and expand support of studies to understand better the
molecular structure of sickle hemoglobin, interactions of other
abnormal hemoglobins with sickle hemoglobin, differences in
flow patterns between normal and sickle red cells , and the effect
of various agents on all of these.

Implement development and testing of improved techniques for
screening and diagnostic testing of hemoglobin abnormalities in
patients with sickle cell, Cooley's anemia, and other related
blood diseases.

Continue to develop interfaces with other Institutes of the
National Institutes of Health and other Federal agencies:
National Institute of Arthritis, Metabolism and Digestive Dis-
eases; Health Services Administration; Department of Defense;
Department of Labor; and Veterans Administration.

schedule in FY 75, more emphasis will be placed on control, including infor-
mation, education, and demonstration as discussed later in the sec-
tion on Prevention, Control, and Education.

Interfaces with other Institutes within the NIH (National Institute
of Arthritis, Metabolism, and Digestive Diseases; General Medical
Sciences) and other Federal agencies (Health Services Administration,
Department of Defense, Department of Labor, Center for Disease Con-
trol, and Veterans Administration) will continue in the general area
of hemoglobinopathies with emphasis on sickle cell disease and
Cooley's anemia.

Cooley's Anemia and Related Hemoglobin Variants

program Anemia is a broad term which designates a decrease in the number of
goals red blood cells. Cooley's anemia (thalassemia) is an inherited dis-
ease resulting from defective production of the hemoglobin molecule
which in turn leads to rapid destruction of the patient's red cells.

On a worldwide basis, thalassemia is the most common inherited
disease resulting from a single gene mutation. Reliable data on
its prevalence in the United States are not available. However,
it is estimated that it occurs in at least 5,000 Americans, largely
of Mediterranean ancestry. The goals of the research programs in
Cooley ' s anemia are to :

Develop a simple screening technique to identify
carriers; develop better information on the effec-
tiveness of transfusion programs and means of
removing excess tissue iron; determine the effec-
tiveness of splenectomy (removal of the spleen) in
thalassemia and explore other possible modalities
of treatment; and increase fundamental knowledge
regarding control of synthesis of the hemoglobin
molecule with a view toward achievement of preven-
tive measures .

recent Several important advances have been made in this program area.

progress a method has been developed to synthesize hemoglobin in a cell-
free system using components isolated from human red blood cells.
This has subsequently led to the determination that the molecular
defect in Cooley 's anemia is transmitted by a messenger RNA (a sub-
stance carrying genetic information) . A biologically active mes-
senger RNA has been isolated from bone marrow and peripheral cells
in patients with beta thalassemia. Full understanding and subse-
quent control of this material may ultimately lead to the capability
of controlling the error resulting in thalassemia.

Through a coordinated effort with other institutes and agencies,
plans are underway to develop an inexpensive, accurate diagnostic
test and to evaluate treatment of this disorder. Pilot studies
have been conducted of a simple screening technique for Cooley 's
trait.

FUTURE
CHALLENGES

We know a considerable amount about the molecular abnormality in
Cooley 's anemia, but we do not know how to correct it. Present
treatment is limited to frequent transfusions. While this gives
temporary relief from the anemia, it burdens the body with excess
iron that cannot be eliminated. Development of a substance, free
of serious side effects and effective in reducing the iron over-
load, would prolong the life of patients with Cooley 's anemia. A
rational basis for therapy will depend upon further understanding
of events at the molecular level; therefore, fundamental research
must be continued.

We presently have no simple, accurate method for screening for
Cooley's anemia trait, and therefore, no way of identifying carriers.
Such a technique needs to be developed. Future challenges include
the standardization of methods and establishment of a bank of hemo-
globinopathies which will provide laboratories with standards and
controls, the development of better modes of diagnosis, better
chelating agents (for removing excess iron) , other treatment
approaches and ultimately a method to alter the gene leading to
the defect.

ACTIONS

The Institute plans to:

1. Continue efforts in Cooley's anemia in coordination with other
Institutes at the National Institutes of Health and with other
Federal agencies. These programs will include studies on the
mechanism of hemoglobin synthesis, clinical research to deter-
mine the effect of splenectomy and transfusion programs on the
course of the disease, development of agents for removal of
excess iron, prenatal diagnostic approaches, and better labora-
tory methods for detecting the carrier state.

schedule Most of the Institute's intramural program in blood diseases is
directly concerned with the acquisition of fundamental knowledge
in Cooley's anemia and sickle cell anemia. The two diseases are
inseparably linked at the fundamental level and programs will be
continued jointly. The programs for research in Cooley's anemia
and related red blood cell disorders will increase gradually
through FY 79 and will involve investigator- initiated as well as
targeted efforts.

Red Blood Cell Membrane and Enzyme Systems

PROGRAM
GOALS

Disorders of the red cell membrane and enzyme systems are respon-
sible for a small but significant number of clinically important
cases of anemia. Perhaps more importantly, the red cell provides
an easily accessible model for studying physiologic mechanisms
and metabolic controls common to many cell systems. Red cells
preserved outside the body (as in blood prepared for transfusion)
depend on intact metabolism and membrane function for survival
and function. Therefore, better understanding of these systems
is applicable not only to blood preservation, but also to the
preservation of other body cells, tissues, and organs.

• The major goal of this program is to obtain funda-
mental answers about membrane structure, function,
and intracellular metabolic activity and to apply
this information to clinical medicine.

recent Progress is being made in a number of areas important to under-
PROGRESS standing the membrane and enzyme systems of red blood cells. The
properties of red blood cells which contribute to their viability
and which support their physiologic function in the circulation
are being explored, e.g., oxygen transport and regulation of metab-
olism. Also in progress are studies of physical properties such
as deformability, adhesiveness, and viscosity; physicochemical
factors involved in the interaction of blood cells with one another
and with their suspending medium; and investigation of biochemical,
clinical, hematological, and genetic factors in diseases in which
there is an inborn error in the metabolism of the red cells. Other
studies are concerned with the problems of transport across cell
membranes, the relationship of chemical properties and functions
to cell types, transition from fetal to adult characteristics of
membrane transport, and effects of various agents and conditions
on permeability.

FUTURE
CHALLENGES

The mechanism of anemia resulting from the interaction of drugs and
agents with G6PD (an enzyme) deficient red cells requires further
study. Better understanding of the factors which regulate red cell
metabolism is necessary in order to extend the preservation of red
cells beyond a few weeks. Reference laboratories for diagnosing
and investigating red cell membrane and enzyme disorders must be
identified and supported. Efforts are being made to encourage those
institutions that possess the capability of diagnosing rare red
blood cell deficiencies to submit grant applications for the estab-
lishment of such facilities.

The primary challenge for the future is to identify areas that may
be neglected, to stimulate interest in pursuing these areas, and
to encourage investigators to collaborate with each other when this
seems the most advantageous way of meeting national goals.

ACTIONS

The Institute plans to:

1. Continue to support research on normal and abnormal red cell
enzyme and membrane disorders, and identify reference labora-
tories for the diagnosis and investigation of these abnormalities.

SCHEDULE These activities will be expanded gradually in conjunction with
investigator- initiated work in Cooley's anemia and related hemo-
globin variants .

3. BIOMATERIALS

program An understanding of the basic interactions between blood and the
goals properties of natural and synthetic materials is essential to the
development of implantable diagnostic devices, circulatory assist
devices, oxygenators, and other artificial organs, as well as the
understanding of the genesis of arteriosclerosis.

• The goal of the program is to explore the interactions
between blood and natural and synthetic materials in
order to develop blood compatible materials for specific
uses.

recent Several classes of biomaterials show both promising biocompati-
progress bility and suitable mechanical properties for use in circulatory
assist devices and oxygenators as discussed in the sections on
Circulatory Assistance and Respiratory Assistance. Refined sur-
face grafting and bonding processes have made possible the develop-
ment of improved cannulas for a variety of applications. Tissue
culture research has opened the possibility of lining surfaces with
living cells and this may represent a promising alternate path to
the use of synthetic materials in contact with blood. Basic
research is yielding further information about the changes which
take place when blood interacts with natural and synthetic surfaces.

A family of polymers, segmented polyether-urethanes, has been
developed which combines good mechanical performance with fairly
good blood compatibility. These materials are currently being
developed for use in circulatory assist devices. Other polymers,
sulfonated polystyrenes, also exhibit promising blood compatibility.
Polyalkylsulfones are other candidate materials which can be modi-
fied to suit a variety of end uses. Their blood compatibility has
not been evaluated fully at this time. Other promising artificial
materials are interpenetrating polymer networks with hydrophilic
polymers and silicone elastomers which show good blood compatibil-
ity properties as well as high gas transfer rates for oxygen and
carbon dioxide. These are being developed for use in artificial
lungs (oxygenators).

One current study deals with the physicochemical and mechanical
evaluation of a new class of so-called "springy" polypropylene
which has a unique combination of properties for potential pros-
thetic applications. Preliminary results indicate that the mate-
rial does not undergo mechanical changes during extended exposure
to whole blood and is uniquely similar to certain tissues in its
visco-elastic properties. The required blood compatibility may be
imparted to this polymer by a variety of surface treatments.

Significant progress has been made in the development of new
techniques to impart blood compatibility to otherwise noncompat-
ible polymers. In particular, certain hydrogel materials have
been successfully grafted by covalent bonding onto a variety of
polymeric materials. Further refinement has been achieved in the
process of ionic bonding of heparin (an anticoagulant) to poly-
meric substrates. This technique represents a practical tool for
imparting short-range thromboresistance to some polymers , in par-
ticular silicone elastomers .

Improvements have been made in the test systems for assessing the
blood compatibility of biomaterials . The best synthetic materials
to date in terms of producing minimal blood changes are hydrogel-
grafted surfaces and low- temperature isotropic carbons. Good
results have also been obtained with certain segmented polyether-
urethanes, mentioned earlier.

Further progress has been made in evaluating the long-range
mechanical and physical performance of synthetic polymers in the
biological environment. The absorption of blood components gives
rise to highly significant changes which not only affect the
mechanical performance of the material but also change its surface
morphology and, hence, biological performance. Studies are in prog-
ress to establish the long-term bulk and surface characteristics
of polymeric materials used for cardiac and pulmonary devices. The
initial work has focused on certain segmented polyether-urethanes.

future Increased emphasis must be placed on the fundamental aspects of
challenges the interactions between blood and biomaterials. Improved bio-
materials suitable for specific physiologic requirements need to
be developed and improved techniques for modifying and grafting
surfaces must be explored.

A better understanding of the mechanical and physicochemical
properties of natural tissues needs to be developed so that this
basic information can be used for the synthesis of new materials
for specific biomedical applications. There is a tremendous
future challenge in using the natural tissues as models to create
synthetic systems with properties approximating those of the
natural tissues. This applies not only to the blood/surface inter-
actions (blood compatibility) but also to the entire physicochemi-
cal and mechanical performance of the system. The conformational
changes which occur during the adsorption of blood proteins on
biomaterials need further clarification. Better tests for blood
compatibility are needed since the currently used test systems
have relatively small surface areas and involve expensive animal
work.

actions The Institute plans to:

Support basic research into interactions of blood components
with both synthetic materials and natural biopolymers.

Explore the synthesis and preparation of a variety of bio-
compatible materials suitable for specific uses in medicine.

Develop improved methods for the physicochemical and biological
evaluation and characterization of biomaterials .

schedule Expansion of the basic science aspects of this program and develop-
ment of improved testing systems will occur during FY 75 and FY 76.
The program should reach full strength by FY 78 by which time clin-
ical trials will be underway.

4. BLOOD RESOURCES

The supply of blood and blood components is a critical national problem. Blood
is a very important therapeutic tool. The demand for blood and blood fractions
is increasing with no foreseeable limit except that dictated by the practical
considerations of limited supply. In the face of an increasing demand and a
limited supply of blood, it is important that economical and efficient use be
made of the available blood resources. Critical national problems that need to
be dealt with are: the current wastage of blood, the lack of uniformity of
blood collected, and the lack of uniform criteria for usage.

The National Heart, Blood Vessel, Lung, and Blood Act of 1972 significantly
expands the authority and responsibility of the Federal Government in areas
which include the use of blood and blood products and the management of blood
resources. The Act also requires the NHLI to develop a plan for research and
educational activities related to implementation of a national blood policy.
Such a plan was presented in the National Heart and Lung Institute Summary
(Volume I) of the National Heart, Blood Vessel, Lung, and Blood Program on
May 1, 1973.

The updated 5-year Plan in Blood Resources is presented here. Four program
areas are discussed in this section: a Nationwide Blood System, Safety of
Blood Therapy, Blood Component Therapy, and Transplantation Biology. These
four areas are discussed in terms of their recent progress, future challenges,
and actions. One Action, the development of Specialized Centers of Research,
is applicable to all of the program areas. This Action, together with the
schedule for the entire blood resources program, is discussed last under Over-
all Action and Overall Schedule. The program goals are also applicable to all
program areas and are discussed first as Overall Program Goals.

Overall

Program

Goals

The present blood resources complex, while providing essential
services and products, has not consistently maintained an adequate
supply or achieved the highest attainable quality of blood therapy.
The goals which the National Program recognizes in the provision
of blood services to the people of the United States are to promote
and maintain:

• Adequate blood supply

• Highest attainable quality

Access to the supply for everyone in need

Efficiency in the collection, processing, storage,
and utilization of blood.

Nationwide Blood System

recent The Institute continues to collaborate with the Office of the
progress Secretary of the Department of Health, Education, and Welfare,

the Bureau of Biologies of the Food and Drug Administration, and
the private sector in order to foster the rapid implementation
of a truly nationwide blood program. The Institute also continues
to support research which will assist in the future implementation
of a Blood Data Collection Center to supply comprehensive and con-
tinuous information on the supply, size, distribution, and use of
blood and blood products. Development of a standardized cost-
finding methodology for blood banks is in progress. Regionaliza-
tion of blood supply systems is being investigated. Recently, the
blood banking sector was charged by the Secretary of the Depart-
ment of Health, Education, and Welfare to submit its plans for
implementing the National Blood Policy. The Institute will con-
sider these plans in determining future funding of research pri-
marily aimed at fostering the implementation of a nationwide blood
program.

future The present nationwide blood system is fragmented and poorly
challenges coordinated at a national level. The result is an inefficient

use of resources and a compromise in quality. What is known often
has been applied slowly. Despite these shortcomings, the blood
service complex has enormous strengths and, in the main, has served
the American people well.

The specific future challenge for both the National Heart and
Lung Institute and other government and private agencies is to
encourage the development of an appropriate mechanism for imple-
menting cost-effective systems and regionalization. Other

important challenges are improved approaches to determine the
utilization of blood and blood products for specific blood dis-
eases and other clinical conditions and to assess their immediate
and future impacts (e.g., projected expansion to supply new needs
in coronary artery surgery) on the limited national blood resource.

actions The Institute plans to:

1. Coordinate its efforts with private and public organizations
involved in blood banking in the creation of an all-voluntary
blood donation system and regional integration to increase
effectiveness .

2. Assist in the implementation of a Federal Blood Data Collection
Center, in cooperation with the Bureau of Biologies and the
Department of Commerce, to provide comprehensive and continuous
information and evaluation concerning the nation's blood supply,
its size, distribution, and use.

SCHEDULE

See Overall Schedule at the end of this section.

Safety of Blood Therapy

recent Three ad hoc committees have been established to coordinate
progress extramural hepatitis research funded by government agencies or

institutes. One of the committees supported a workshop on future
work on hepatitis epidemiology. From this workshop, the National
Heart and Lung Institute has developed its hepatitis epidemiology
program.

A recently completed study indicates that hepatitis B immune
globulin has no effect in the treatment of acute fulminant hepa-
titis. Technological improvements in the test for hepatitis
carriers have made this assay more sensitive and specific. The
chronic carrier state does not appear to be due to a generalized
immunodeficiency and no specific deficiency has been found. The
studies of the efficacy of hepatitis immune globulin in the pre-
vention of hepatitis in high-risk patients are in progress and
should yield important answers in this fiscal year.

Presently available data are inconclusive as to whether cytomegalo-
virus (CMV) infection results from transmission by transfused
blood or by activation of latent virus in the recipient. A coop-
erative trial is presently underway to determine the clinical
importance of blood transfusion in cytomegalovirus infection.

Fail-safe systems for donor-recipient identification have been
developed and tested in limited but successful clinical trials
at local hospitals. Within the coming year, three devices will
each undergo extensive trial, and the most effective device will
be identified.

The safety of transfused blood is also the underlying concern in
studies of blood bag materials. Toxicology studies are underway
on di-2-ethylhexylphthalate (DEHP) , a substance present in blood
bag materials. Current data show that DEHP is leached from blood
bags and circulated to the patient's tissues during transfusion.
The clinical importance of this finding is under investigation.

future In spite of rapid advances in the understanding of hepatitis,
challenges primarily serum hepatitis, there is still no way to ensure that
blood from a given donor will not transmit this disease. Cyto-
megalovirus disease is also emerging as a common cause of death
in transfused patients whose immune mechanisms are depressed.
The role of the blood donor and/or the recipient in the trans-
mission of cytomegalovirus must be elucidated and means of pre-
vention developed and implemented. Human error in matching donor
and recipient remains a major hazard in transfusion therapy and
fail-safe systems need to be developed and applied.

Retransf using the patient's own blood constitutes the safest form
of transfusion therapy. Means must be explored to develop further
this form of therapy, termed autotransfusion, both by having the
patient bank his blood prior to need, and by returning to him
blood lost during surgery. In addition to increasing safety, this
form of therapy might be expected to reduce significantly the
demand on the nation's blood resources.

The final test for hepatitis in blood may have to await the
identification of new antigens or the development of an entirely
new approach to testing, perhaps involving a bioassay method.
Elimination of any chronic virus carrier state by some interven-
tion technique is not possible at present. We are at present
only able to define the carrier state without affecting its course.

The magnitude of the CMV problem remains to be determined. Should
blood be conclusively proven as the primary mode of CMV transmission,
a method to detect infectious blood applicable to mass screening
would be needed to reduce the morbidity and mortality associated
with CMV. Methods to prevent contamination and to remove the
contaminating agent would also be explored.

Future challenges for fail-safe systems of donor-recipient
identification on the national scale involve the general, large-
scale acceptability of devices and the high cost of acquiring and
maintaining them. The potential toxicity of plastics in contact
with the blood needs further study.

ACTIONS

The Institute plans to:

1. Participate with other agencies in a concerted attack on
hepatitis which will include development and use of more
sensitive and practical tests for detecting carriers, studies
of the carrier state, removal of hepatitis from blood and
blood products, and development of methods for passive and
active immunization.

2. Continue studies in the areas of toxicology of plastic devices
having contact with blood, the evaluation of fail-safe donor-
recipient identification systems, and studies which will iden-
tify the risk of cytomegalovirus infections caused by blood
donors and/or recipients.

SCHEDULE

See Overall Schedule at the end of this section.

Blood Component Therapy

recent Research is in progress to explore new methods of plasma frac-
progress tionation to determine if the components presently being pre-
pared can be recovered more efficiently and economically. Plans
have been formulated to develop new fractionation products, and
these efforts will be implemented shortly.

future The medical demand for red blood cells, as distinguished from
challenges other blood components, sets the pace for the collection of whole
blood. Patients who need red cells often do not need other com-
ponents. Currently, whole blood is used in more than three-
fourths of all transfusions, although experts indicate that it
is necessary in less than one-fourth of the cases. Reducing the
use of whole blood not only constitutes good medical practice,
but will increase the availability of components often in short
supply and needed by other patients.

Specific research efforts are needed to improve methods for
storing blood cells, for collecting blood, for maintaining via-
bility and function of platelets and white blood cells, and for
improving methods of fractionating blood into its various compo-
nents. These efforts will require a dynamic cooperative program
which will involve other government agencies as well as the pri-
vate sector.

actions

The Institute plans to:

1. Support and participate actively with other interested

organizations to insure that new fractionation methods are
devised and/or supported which would cope with the ever
increasing demands being placed on blood resources, to assure
adequate amounts of coagulation factors, particularly Factor
VIII for hemophilia.

Develop means to enhance and evaluate the appropriateness of
blood utilization through clearer indications for the use of
blood components and better methods to assess their effective-
ness.

Implement the US-USSR cooperative program on blood transfusion,
particularly in relation to cardiovascular surgery.

SCHEDULE

See Overall Schedule at the end of this section.

Transplantation Biology

RECENT
PROGRESS

Investigators are actively pursuing means to prevent the sensiti-
zation of the transplant patient by lowering or eliminating histo-
compatibility antigens (HL-A) in transfused blood, and studies are
underway to determine the indications for HL-A typing in platelet
transfusions. Current studies of in_ vitro methods for removing
histocompatibility antigens will be followed by clinical trials
on renal dialysis patients to determine if sensitization to HL-A
antigens can be reduced or prevented.

Many methods of removing histocompatibility antigens from blood
have been studied. Freezing blood appears to destroy histocompat-
ibility antigens with maximum preservation of red cells, but cost
factors and the lack of freezing facilities at most institutions
limit the present utility. Another method of removing histocom-
patibility antigens by a double centrifugation process is relatively
simple and appears promising. The clinical studies have demon-
strated trends which indicate more rapid sensitization in prepara-
tions with intact leukocytes and platelets but statistically
significant results have not yet been obtained.

FUTURE
CHALLENGES

In addition to handling blood, a nationwide blood system may also
be responsible for the preservation, storage, and typing of tissues
and organs for transplantation. Fundamental knowledge in trans-
plantation biology will be necessary before transplantation can
be used more widely and more successfully. Studies of the preven-
tion of graft-versus-host reactions, the development of better
immunosuppressive techniques, and the prevention and treatment of
infection will be undertaken.

The development of organ preservation devices is required before
a system of regional or national organ procurement is feasible.
The design and development of such devices will have to follow
extensive fundamental research in organ preservation so that the
factors relevant to successful preservation can be included in the
design of devices.

ACTIONS

The Institute plans to:

1. Encourage fundamental research (in conjunction with other
Institutes) in immunology, immunogenetics , and other aspects
of transplantation biology.

2. Initiate clinical studies (in conjunction with other Institutes)
to improve the management of the post- transplant state, such as
prevention of graft-versus-host reaction, the development of
better immunosuppressive techniques, and the prevention and
treatment of infection.

3. Implement studies to improve organ preservation and procurement.

SCHEDULE

See Overall Schedule below.

Overall
Action

Applicable to all of the above blood diseases and blood resource
problems are Specialized Centers of Research. The Institute plans
to:

1. Establish one or two Specialized Centers of Research in Blood
Diseases and Blood Resources. These Centers could emphasize
improved blood therapy using cellular components, particularly
white cells and platelets, and plasma components including
those used in treatment of hemophilia, and may contain pilot
plants to test new methods developed for plasma fractionation.

Overall Increased activities relating to the National Blood Policy are
Schedule expected in FY 75 and FY 76. The hepatitis program will expand

through FY 77 at which time peak funding will be reached. Research
in Transplantation Biology will double by FY 77 and expand gradu-
ally through FY 79. A Center in Blood Resources will be established
in FY 75.

PREVENTION, CONTROL, AND EDUCATION

Prevention, rather than treatment, of heart, blood vessel, lung, and blood
diseases offers the greatest promise of reducing death and disability in the
United States. More effective application of existing knowledge will materi-
ally reduce disability and death from the complications of these diseases.
The Institute has provided for expanded future emphasis on bridging the gap
between research findings and clinical applications by establishing an Office
of Prevention, Control, and Education. An Assistant Director for Health Infor-
mation has been recruited from within the Institute. This position is mandated
by Section 413(d) of Public Law 92-423. The function of this office will be to
expand and coordinate the various NHLI programs directed toward the goals set
forth in this section of the Plan. Identification of priority areas is already
underway. The National High Blood Pressure Education Program (see below) was
initiated in 1972 and will serve as a model for other education programs iden-
tified as high priority and launched in the future. Through the study of the
impact of the various segments of the High Blood Pressure Education Program,
and consultation with authorities in educational technology and motivational
analysis, the Institute has begun planning for a more effective national pro-
gram in public and professional information and education designed to implement
five overall Actions in the Plan.

Overall
Actions

Develop education programs for each of the categorical program
areas of the Institute.

2. Develop better mechanisms, using all media of communication,
to disseminate knowledge about heart, blood vessel, lung, and
blood diseases and blood resources.

3. Establish improved means for direct communication with the
public.

4. Expand programs to aid health professionals in improving the
public's understanding and application of new health knowledge
and concepts.

5. Establish improved means for communication with the scientific
community and the medical profession.

The overall goal of the Prevention, Control, and Education Programs
of the Institute is to hasten the control and, in the long run, to
prevent or lower the prevalence of cardiovascular, pulmonary, and
blood diseases in the population. The emphasis will be on preven-
tion of disease, but in order to achieve optimal success, it will
often be necessary to aid the existing health care delivery system
in detection of individuals at high risk for a variety of diseases.
Improved detection will depend in part on increasing the level of
awareness within the population about risk factors, how to enter

the health care system, and the importance of patient adherence
to management regimens once diagnosis has been established. The
educational components of the Institute's control programs will
receive the highest priority.

Professional education and rapid dissemination of research knowl-
edge from clinical investigation will be stressed to control dis-
ease. Education and use of paraprofessionals in community efforts
toward control and prevention of disease will be stimulated. The
concept of health care delivery team approaches, including team
members specializing in patient education, is gaining rapid accep-
tance. Although categorical disease approaches to education, pre-
vention, and control will be used, the Institute will attempt to
coordinate and give highest priority to those programs which can
serve as models for application to other diseases.

As resources become available, NHLI intends to provide funding for
local and regional demonstration programs of prevention, control,
and education which embrace the above principles. These programs
must involve the several components of the health care system
within a given geographical area, although they may be primarily
based in medical schools or major medical centers. In order to be
maximally effective, funding of these programs will need to insure
a reasonable degree of long-term, stable support. As stated
earlier, these programs are not intended to fund health care deliv-
ery per se , but rather to help effect the transmission of funda-
mental research advances to the public. The manpower necessary
for coordination, provision of educational opportunities, and prep-
aration and dissemination of educational or informational material
will require support. These programs will be funded on the basis
of merit as determined by national competition.

Shorter-term demonstration projects are also envisioned as part of
the Institute's programs. These demonstration projects will deal
with specific techniques (e.g., methods of detection) which are
not currently accepted or commonly in use for disease control. The
intent of a demonstration project should be to provide clear evi-
dence that the new technique is applicable to a community situation,
does not overload the existing health care system, is cost-effective,
and results in an improved ability of the local health care system
to respond to the need which the new technique addresses. Once
the demonstration project has confirmed the feasibility of its
approach, NHLI funding will be discontinued. Results will be made
available to the medical community at large by description in
national publications, through National Research and Demonstration
Centers, and through voluntary and other health organizations.
Staff from NHLI and from the demonstration projects themselves will
be available as consultants to other communities who wish to adopt
the technique to their own needs. Other examples of demonstration
projects might be new approaches to continuing education of physi-
cians in cardiovascular and pulmonary subjects, an improved system
of assessing patient compliance with antihypertensive regimens, or
a rapid method for on-site diagnosis and treatment of dangerous
arrhythmias .

In order to be maximally responsive to available opportunities,
both the grant and contract mechanisms should be available for
funding of the time-limited demonstration projects and the longer-
term programs for prevention, control, and education. Applicants
should be able to seek support on a regular basis for ideas in
these program areas, either by the grant mechanism or by unsolic-
ited proposals for contract support. In addition to such projects,
the Institute plans to support demonstrations solicited through pro-
gram announcements for support of projects or programs of high pri-
ority under the 5-Year National Plan.

For FY 75, the highest priority program areas are hypertension,
arteriosclerosis, inhalation lung diseases, and sickle cell dis-
ease, in which modest funds are currently available for educational
programs. In addition, as resources become available, new efforts
need to be directed to cardiac rehabilitation and emergency cardiac
medical services, nutrition and coronary artery disease risk fac-
tors, early diagnosis (including prenatal diagnosis) of respiratory
distress syndrome in the newborn, emergency treatment of respira-
tory failure secondary to severe trauma, smoking as a risk factor,
and improved approaches to blood component therapy. Specific plans
relating to heart and blood vessel, lung, and blood disease and
blood resource programs are summarized below.

HEART AND BLOOD VESSEL DISEASES

Considerable knowledge is already available on the prevention and control of
heart and blood vessel diseases. However, achieving the most effective means
for applying this knowledge to individuals in need requires more specific
research and evaluation efforts. The prevention and control programs, there-
fore, seek immediate application of presently available knowledge for prevention
and control and at the same time strive to make prevention and control measures
more effective.

Particular emphasis will be placed on the testing and evaluation of a program
for the prevention of the two major cardiovascular disorders — hypertension and
arteriosclerosis. For these two disorders, a sufficient base of knowledge
exists which could effect substantial reductions in morbidity and mortality if
the knowledge were implemented through coordinated and comprehensive programs.
Prevention or amelioration of other cardiovascular disorders requires attention
in implementing the National Program. Specific programs for hypertension,
arteriosclerosis, coronary heart disease, and congenital heart disease are dis-
cussed in this section. The activities described under hypertension and arterio-
sclerosis are continuations of activities already underway. The activities
described under coronary heart disease and congenital heart disease are new,
planned initiatives.

1. HYPERTENSION

PROGRAM
GOALS

Drug therapy to control blood pressure reduces the incidence of
strokes and heart failure among persons with moderate and severe
hypertension. However, only about 12 percent of hypertensives
are currently receiving adequate treatment. Immediate efforts to
expand current program initiatives through existing medical net-
works are urgently needed to bring individuals with moderate and
severe hypertension under effective treatment. Sustained effec-
tive blood pressure management in such persons should result in
a reduction of disability and death by as much as 40 percent when
compared with expected rates for untreated hypertension.

• A national goal of the program is to motivate all
adults to have their blood pressure checked annually
and for those found to be hypertensive, to urge them
to obtain proper therapy.

• Another national goal is to make current knowledge
of antihypertensive drug management available to and
effectively practiced by the general practitioners
as well as the specialists from whom the individuals
with high blood pressure seek proper therapy.

RECENT
PROGRESS

The National High Blood Pressure Education Program, initiated in
1972, has completed the preliminary studies of the needs of the
program, and the Hypertension Information and Education Advisory
Committee has submitted its recommendations to the Secretary,
Department of Health, Education, and Welfare. Implementation of
some recommendations addressed to immediately recognizable needs
is being planned or has already been initiated.

In the Hypertension Detection and Follow-up Program, over 10,000
hypertensive patients from 14 communities of all races and several
ethnic groups, and both men and women, are being invited to partic-
ipate in a treatment program. Over one- third of the participants
will be black and include both rural and inner city residents.
Special educational efforts are being undertaken to encourage
patients to attend clinics and to take their medication regularly.

FUTURE
CHALLENGES

Important challenges in prevention and control of high blood
pressure include the development of simplified medical regimens
using available antihypertensive drugs and the creation of sys-
tems which will optimize the utilization of nurses and allied
health professionals in educational and therapeutic programs under
physicians' supervision. The problem of motivating patients to
take and adhere to long-term antihypertensive drug therapy requires

100

further research. The use of demonstration programs which seek
effective implementation of hypertension detection, diagnosis,
treatment, and follow-up systems in the community in cooperation
with existing medical and community health resources, needs to
be explored.

ACTIONS

The Institute plans to:

Continue the Hypertension Information and Education Program
to expand public and professional knowledge of the dangers of
high blood pressure and the benefits of effective treatment.

Establish an education research program aimed at testing
hypotheses that will lead to new knowledge in methods of edu-
cation that will (a) increase awareness of the problem;
(b) define cost-effective methods of delivering patient care
and patient education, and/or (c) identify methods of increas-
ing patient compliance.

Continue a Hypertension Detection and Follow-up Program to
determine the effectiveness of a systematic approach using
antihypertensive therapy in reducing mortality among those
with elevated blood pressure in community-based populations.

schedule The NHLI ' s current activity in this area will be continued with
increased emphasis over the next two years and receive sustained
support thereafter.

2. ARTERIOSCLEROSIS

program A number of factors that increase susceptibility to atheroscle-
GOALS rosis and coronary heart disease have been identified. These

include elevated blood lipids, high blood pressure, and cigarette
smoking. These risk factors can be modified and the public needs
to know how this can be done.

The program goal is to reduce disability and death
from arteriosclerotic disease of the blood vessels to
the heart, brain, and extremities through the preven-
tion and control of risk factors.

RECENT
PROGRESS

A working group drawn from the National Heart and Lung Institute,
United States Department of Agriculture (USDA) , and Food and Drug
Administration (FDA) has been established and has met several
times. The interests, plans, and priorities of these three agencies

101

with regard to prevention and control of hypertension have been
explored. The FDA's new voluntary food labeling regulations and
the USDA's planned nutrient data bank (which has been approved
by the food industry) will eventually make available a wealth of
nutrition information.

The National Heart and Lung Institute helps to support certain
studies by the USDA's Consumer and Food Economic Institute of the
Agriculture Research Service. These include a literature search
and documentation and identification of the nutrient composition
of foods .

A continuing dialogue between these three government agencies is
underway. A long-term objective is to evaluate the need for a
national food analysis laboratory to complement the USDA's planned
nutrient data bank.

The nutritional support staffs of both the Multiple Risk Factor
Intervention Trial (MRFIT) and Lipid Research Clinic (LRC) trials
(see section on Arteriosclerosis under Research) have been actively
interacting with university groups and the American Heart Associ-
ation to explore all available avenues for promoting nutrition
education. Although the development of education materials and
techniques appropriate for the MRFIT and LRC trials is the imme-
diate goal, such material and methods will eventually find more
general use. General interest in nutrition and heart disease has
increased throughout the country. The Institute has become increas-
ingly involved in professional education programs sponsored by
voluntary and official agencies. The NHLI has also revised its
informational series on the dietary management of hyperlipoprotein-
emia. These revised diet manuals are available for physicians and
nutritionists .

future It is now possible to identify persons who may be at increased
challenges risk of developing coronary heart disease, stroke, or peripheral
vascular disease by measuring their blood lipids, blood glucose,
blood pressure, and weight, and by obtaining information on ciga-
rette smoking. An electrocardiogram further improves the predic-
tion of risk.

Using these factors as indicators, we can identify the 20 percent
of the population who are most likely to develop 40 percent of
the coronary heart attacks, 50 percent of the strokes, and 50 per-
cent of the clinical peripheral vascular events over a subsequent
six-year period. This is not an absolute because heart attacks,
strokes, and peripheral vascular disease also occur in persons
without such risk factors. However, the highest priority should
be given to identification of these high-risk susceptible individ-
uals by relatively simple procedures.

102

Once susceptible individuals have been identified, measures can
be initiated to reduce their risk status through dietary measures,
drugs for lowering lipids or blood pressure, and modification of
life styles. This is a difficult task and how to achieve such
changes in an acceptable manner for large segments of the popula-
tion remains to be determined.

ACTIONS

The Institute plans to:

1. Cooperate with the Department of Agriculture and other Federal
agencies having a nutrition-related interest to establish poli-
cies and education programs on the role of nutrition in heart
disease; develop, evaluate, and apply dietary survey and coun-
seling methods in the treatment of hyper lipidemia.

2. Support, in cooperation with the Department of Agriculture and
the Food and Drug Administration, a special program to update
the information on composition of foods in the American market-
place.

schedule The Information Program for risk factor detection and prevention

will be increased in FY 76 and receive sustained support thereafter.
It is projected that support for nutrition programs will increase
substantially in FY 75 and increase incrementally thereafter.

3. CORONARY HEART DISEASE

program As discussed in the Research section on Coronary Heart Disease,
GOALS emergency medical care for the person with suspected heart attack
is a major problem, since there are about 400,000 deaths annually
from coronary heart disease prior to hospitalization.

• A goal of this control program is to introduce the
developments in emergency medical care for the cardiac
patient into comprehensive emergency care systems.

• An additional goal is to conduct research on improved
methods for rehabilitation.

recent The Institute has been supporting research actions to develop
progress information for the design and evaluation of emergency care sys-
tems and is participating with other agencies in an Interdepart-
mental Committee on Emergency Medical Services.

103

The NHLI has convened a task force to study the present state of
our knowledge as it relates to cardiac rehabilitation. Recommen-
dations will be developed for clinical implementation of what is
known and practical, and for initiating effective research where
necessary.

future A saving in lives and probably a decrease in disability from heart
challenges attacks can be achieved by improved emergency medical systems for
the cardiac patient. In addition, once a heart attack or other
serious cardiac illness has occurred, the rate and completeness of
return toward normal functioning in society and enjoyment of life
remain inadequate. Present studies indicate that disability can
be minimized and recovery hastened by appropriate attention to the
medical and psychological factors associated with cardiac rehabil-
itation. However, the optimal, practical methods for achieving
such rehabilitation need to be developed, assessed, and demonstrated.

ACTIONS

The Institute plans to:

Contribute, in collaboration with other Federal agencies, to
the design and analysis of the cardiac elements of emergency
care systems. Such programs will emphasize the implementation
of research developments under Actions in the Research section
on Coronary Heart Disease.

Explore, in collaboration with the Social and Rehabilitation
Service, the establishment of demonstration programs for the
rehabilitation of patients with cardiovascular disease.

schedule The schedule for the first Action is contingent upon scheduling of
the comprehensive Emergency Medical System; NHLI components could
be initiated in FY 75 and continued through FY 78. Collaborative
efforts on rehabilitation programs were initiated in FY 74 and will
be continued through FY 80 .

4. CONGENITAL HEART DISEASE

program Recognition of congenital heart disease is particularly difficult
GOALS during the newborn period. Yet this is the period during which a

substantial fraction of deaths from congenital heart disease occurs.

• The goal of this control program is to recognize and
manage congenital heart disease in the newborn.

104

RECENT
PROGRESS

New investigations and the development of a variety of diagnostic
techniques are providing capabilities for more ready and accurate
assessment of congenital heart disease. Also, there has been an
increased understanding of the pathophysiology of the disease pro-
cesses and their symptoms. These new developments are being com-
bined to allow for better and earlier recognition of congenital
heart disease in the neonate by nursery staff and physicians. For
example, new investigations recently begun in the field of ultra-
sonic imaging by acoustical holography provide a new capability
for examining the anatomy of a newborn child in the manner of low
resolution X-ray fluoroscopy, but without the use of X-rays. Thus,
normal and abnormal anatomical structures and physiologic functions
(e.g., movement of joints, flow of blood in specific vessels, opera-
tion of heart valves) can be visualized directly in a way believed
to be nonhazardous to the infant. The nontraumatic nature of the
method has resulted in rapidly increasing application of ultra-
sonic imaging examinations to large numbers of pregnant women in
the United States and abroad.

future A substantial saving in lives can probably be achieved by early
challenges recognition of cardiac problems in the newborn and the establish-
ment of specialized groups to deal with these problems.

ACTIONS

The Institute plans to:

Explore the feasibility of demonstration programs for the early
recognition of cardiac (and respiratory) problems in the new-
born. Such programs will emphasize intensive professional edu-
cation, development of instrumentation for improved detection,
better interhospital communication and transport, and the avail-
ability of diagnostic and surgical facilities for treating crit-
ically ill infants.

SCHEDULE

The program will be initiated in FY 76 and continue through FY 80.

LUNG DISEASES

The major emphasis in prevention, control, and education in the lung diseases
area will focus on control programs in inhalation diseases . Other efforts
include programs in fibrotic and immunologic lung diseases, pediatric pulmonary
diseases, respiratory failure, and smoking in emphysema and chronic bronchitis.

1. INHALATION DISEASES

program This new program area is directed toward preventing or treating
goals inhalation diseases by removal of the offending substance or by
protecting individuals against exposure to them.

105

A primary goal is to disseminate information about
the types of dusts, vapors, and gases that can cause
inhalation diseases and how to avoid them.

recent Improved standards in terms of exposure levels have been developed
progress f or asbestos-related industries. Anticipated in the future are
improved and safer standards for silica as well.

FUTURE
CHALLENGES

A great deal is already known to the scientific community about the
types of environmental agents associated with industries and occu-
pations. It is essential that this information be widely dissemi-
nated to community physicians and the lay public.

actions The Institute plans to:

1. Develop a program of education for physicians and the lay pub-
lic with regard to inhalation diseases. This will be accom-
plished through workshops for physicians, literature for the
public, and control programs addressed to avoidance of noxious
dust, vapors, or gases.

schedule This new activity was initiated in FY 74 and will undergo incre-
mental increases through FY 80.

2. FIBROTIC AND IMMUNOLOGIC LUNG DISEASES

PROGRAM
GOALS

Fibrotic and immunologic lung diseases are induced by external
agents and can be prevented or treated by removal of these agents
or suppression of their effects.

• A primary program goal is to disseminate information
about the causes of fibrotic and immunologic lung
diseases and how to avoid them.

RECENT
PROGRESS

FUTURE
CHALLENGES

A symposium, oriented toward fibrotic and inflammatory lung dis-
eases, was held during a recent New York Academy of Science meet-
ing. This symposium, attended by general physicians as well as
researchers in the field, was important in encouraging the exchange
of information necessary for preventing these diseases.

Available knowledge about external agents implicated in the devel-
opment of immunologic and fibrotic lung diseases needs to be widely
disseminated to the lay public as well as to physicians. This is

106

essential to prevention of these diseases. Specific future
challenges for the Institute include the organization of meetings
and workshops for the public and general practitioners, and the
preparation of literature for dissemination.

actions The Institute plans to:

1. Develop a program of education of physicians and the lay pub-
lic with regard to environmental agents implicated in pulmonary
fibrosis and immunologic lung diseases. This will be accom-
plished through workshops for physicians, literature for the
public, and control programs addressed to avoidance of etio-
logic agents in the community.

SCHEDULE

The program in education regarding fibrotic and immunologic lung
diseases will increase incrementally from FY 76 to FY 80.

3. PEDIATRIC PULMONARY DISEASES

program About 50,000 babies are born each year with hyaline membrane
goals disease. More than half of these will die unless given prompt

treatment. Research programs in pediatric pulmonary diseases are
focused upon the development of more effective diagnostic and
therapeutic methods. Until sufficient knowledge is gained about
prevention of hyaline membrane disease, the only hope for these
patients lies in prompt diagnosis and treatment.

The primary goal will be to initiate prompt diagnosis
and therapy of hyaline membrane disease.

RECENT
PROGRESS

While specific demonstrations have not been initiated, research
results with respect to continuous positive pressure ventilation
and early diagnosis have been disseminated through journals and
at meetings. In addition, a workshop on pediatric pulmonary dis-
ease has been held and a report disseminated to the pulmonary
community.

future In order to initiate prompt diagnosis and therapy, available
challenges information about pediatric pulmonary disease needs to be dissem-
inated to appropriate forums in a meaningful way. The major chal-
lenge in this area is to improve communication between the Institute
and the pulmonary biomedical community.

107

ACTIONS

The Institute plans to:

Develop education programs, addressed to pulmonary and commu-
nity physicians, to provide presently available information
about treatment of hyaline membrane disease. This will be
done through demonstration projects and workshops.

schedule These education programs will be phased-in subsequent to the
steadily increasing activities in therapy described under the
Research sections on Pediatric Pulmonary Diseases and Structure
and Function of the Lung. They will thus be able to capitalize
on information accruing from other new actions .

4. RESPIRATORYFAILURE

program Considerable progress has been made in the development of therapy,
goals but unless treatment is initiated promptly by experienced person-
nel, respiratory failure will lead to death in more than half of
those affected.

The first goal of the program in this area is to
disseminate the knowledge needed to save lives through
early recognition and treatment of respiratory failure.

RECENT
PROGRESS

The information available on hyaline membrane disease is being
applied in several medical centers, resulting in significant
decreases in infant mortality rates. To improve and evaluate the
effectiveness of continuous positive airway pressure as primary
treatment in many cases of severe respiratory distress syndrome,
several groups of investigators are using common criteria for
diagnosis of the syndrome and for initiation and termination of
the treatment.

Two groups are now working on adult positive ventilation tech-
niques in intensive care units, and further improvement and dis-
semination of this and other recently developed procedures are
anticipated.

future Available knowledge about detection and treatment of respiratory
challenges failure needs to be widely disseminated to community physicians
and allied health personnel, as well as to pulmonary physicians.
Specific future challenges are to increase the number of centers
participating in the treatment of infant and adult respiratory
distress and to simplify the procedures and equipment so that
smaller hospital units, as well as the larger centers, may apply
this knowledge.

108

actions The Institute plans to:

1. Initiate demonstration projects in which available information
will be widely disseminated to educate pulmonary and community
physicians and allied health personnel in what is known about
respiratory failure.

schedule The major new activity will be demonstration programs. Educational
activity will undergo a delayed increase, capitalizing on new infor-
mation accruing from treatment studies .

5. EMPHYSEMA AND CHRONIC BRONCHITIS

program Cigarette smoking is believed to be a prime factor in the etiology
goals or exacerbation of chronic bronchitis and emphysema, and a contrib-
uting factor to environmental lung diseases, including the pneu-
moconioses and hypersensitivity lung diseases. Up to 20 percent
of smokers have chronic obstructive lung disease and almost all
patients with this disease are smokers. Extensive studies document
conclusively that cigarette smokers are far more likely to develop
emphysema than nonsmokers. Also, once developed, emphysema pro-
gresses much more swiftly in those who smoke. Repeated exposure to
pollutants in the air also contributes to the development and pro-
gression of the disease.

The principal cause of chronic bronchitis is prolonged irritation
of the bronchial tube linings. Smoking, air pollution, and recur-
rent infections are the main irritants for chronic bronchitis, as
well as for emphysema. The public needs to be informed about the
potential seriousness of persistent or recurrent coughs and short-
ness of breath and about ways to protect against progression of
these diseases.

The program goal is to modify the smoking habits of
persons at risk of developing lung diseases, and to
extend successful anti-smoking programs to the general
population.

recent The difficulties in modifying human behavior are well-recognized.

progress to achieve the stated program goal, research is urgently needed on
the behavioral aspects of smoking. Institute Actions in support
of such research are discussed in the section on Research programs.

In instituting an educational program on emphysema and chronic bron-
chitis for the lay public, NHLI has issued information pamphlets for
the public and has informed community physicians of its programs at
a recent meeting of the American Lung Association.

109

Research programs designed to promote early detection of emphysema
and chronic bronchitis should ultimately provide a basis for inter-
vention and/or prevention. In addition, environmental risk factors
are being identified, which will provide a necessary first step
toward prevention.

future A first step is the identification of persons at risk of develop-
challenges i n g chronic obstructive pulmonary disease, especially those indi-
viduals who are predisposed because of genetic characteristics.
When populations have been identified, education programs effec-
tive in preventing smoking will need to be devised. The difficulty
of motivating people not to smoke is well-known and presents a
major challenge for the future. Sophisticated motivation approaches
must be developed in cooperation with behavioral scientists to
modify the smoking habits of persons at risk and, in general, large
population groups. Those who have not yet acquired the habit should
be discouraged from doing so through effective educational programs.

We also need to prevent or modify smoking in persons who live or
work in environments with unusually high concentrations of air
pollutants, dusts, or other environmental agents implicated in the
development of lung diseases.

ACTIONS

The Institute plans to:

1. Develop a program, in collaboration with experts from other
Federal agencies, to modify effectively the habits of smokers.

2. Develop an education program to alert the lay public to the
dangers of smoking in relation to chronic obstructive pulmonary
diseases and environmental lung diseases, and urge smokers in
populations at special risk to participate in programs to modify
their smoking habits .

These programs on smoking will be developed in collaboration with
scientists concerned with the harmful effects of smoking on the
cardiovascular system as well.

schedule Behavioral and educational programs will be initiated in FY 75 to
continue for five years .

BLOOD DISEASES AND BLOOD RESOURCES

Blood diseases and blood resources, as discussed in the Research section, are
closely interrelated with heart, blood vessel, and lung diseases, and are impor-
tant and integral parts of the National Program. Major prevention, control, and
education programs in these areas are addressed to Sickle Cell Anemia and Cooley's

110

Anemia. These programs will emphasize education of the public, screening, and
counseling. The NHLI is also supporting other programs in blood diseases and
blood resources which focus on hemophilia, thromboembolic disease, and educa-
tion about the nation's blood resources, control of hepatitis, and various
aspects of organ transplantation. All of these programs are discussed below.

1. SICKLE CELL ANEMIA AND COOLEY'S ANEMIA

PROGRAM
GOALS

Despite the fact that much is known about sickle cell disease and
Cooley's anemia, the general public, including actual and potential
victims, have a poor understanding of these disorders and their
significance. Both diseases can cause great suffering. It is
estimated that somewhat less than 50,000 Americans suffer painful
episodes, or "crises," due to sickle cell disease, and at least
5,000 Americans suffer the effects of Cooley's anemia and require
repeated blood transfusions in order to survive. In both cases,
the diseases are transmitted by carriers to their offspring, if
both parents carry the trait. Thus, education and control programs
are important to the prevention of these diseases. The Institute
is developing a program to expand community education to increase
public awareness of these diseases and to educate these individuals.

The goals of the control program are to inform the
public about sickle cell disease and Cooley's anemia
and to demonstrate techniques for appropriate screen-
ing and counseling.

recent Programs are being developed to further expand the dissemination
progress f information on sickle cell disease, utilizing nongovernment

participation. Continuing education programs are being provided
for physicians and paramedical personnel to emphasize established
approaches as well as new developments in sickle cell disease
through the programs in the Comprehensive Sickle Cell Disease Cen-
ters. Standardized techniques of screening (electrophoresis fol-
lowed by confirmatory solubility) are being incorporated into
comprehensive screening programs.

FUTURE
CHALLENGES

We need to determine the prevalence and distribution of sickle cell
disease and Cooley's anemia in this country, particularly the prev-
alence of carriers of the trait; provide accurate and up-to-date
information on these diseases; initiate and expand appropriate
community education, screening, and counseling programs; educate
the medical and allied health professions about the problems of
these diseases; identify and provide guidance for the management
of the resulting psychological, sociological, and economic problems;
and assist individuals with these disorders to attain their maximum
potential in life.

Ill

actions The Institute plans to:

1. Develop, in collaboration with other Federal agencies, programs
to provide accurate information on sickle cell disease and
Cooley's anemia; education for the general public, population
groups at risk, health professionals, allied health profes-
sionals, educators, employers, and insurers of individuals who
have these disorders; methods to best counsel affected individ-
uals; and proper rehabilitation approaches when applicable.

2. Evaluate clinical approaches for the treatment of these dis-
orders and other developments in the field and insure that the
ones that are effective are incorporated into the health deliv-
ery system.

schedule Screening and Education Clinics for sickle cell disease will con-
tinue to be heavily supported in FY 75. Information and education
programs on both sickle cell disease and Cooley's anemia will be
supported in FY 75 with a gradual reduction of activity from FY 76
to FY 80.

2. HEMOPHILIA

PROGRAM Public awareness is fundamental to management and prevention of
goals hemophilia. Although severe hemophilia affects only a known popu-
lation of 25,000 in this country, it is a major national health
problem. Treatment is very costly and must be continued throughout
the patient's lifetime, thus demanding a large fraction of the
nation's blood resources. Since the disease is hereditary, edu-
cation of the public can be instrumental in its prevention.

The goal of this prevention program is to educate
the patient, the physician, and the general public so
that patients with hemophilia and their families may
make informed decisions regarding their own lives.

RECENT
PROGRESS

There are no current education efforts in this area. The Institute
is cooperating with the National Hemophilia Foundation and other
national organizations to develop programs for the future. A Center
for Blood Disease is in the planning stages and methods of education
and counseling for hemophilia may be studied through this mechanism.

FUTURE
CHALLENGES

The NHLI plans to study methods of genetic counseling and its impact
on the hemophilia community, techniques of "total care" for hemo-
philiacs, and methods of minimizing the cost of hemophilia care for

112

the patient. Plans will also be developed for education programs
directed toward the affected individual, the individual's family,
the medical profession, and the general public. These efforts
will be coordinated with those of the National Hemophilia Founda-
tion.

ACTIONS The Institute plans to:

1. Explore, in cooperation with other agencies, information, edu-
cation, and genetic counseling techniques aimed at improving
hemophilia therapy and preventing hemophilia.

schedule Information, education, and approaches to genetic counseling in
hemophilia will receive increased support in FY 76 and FY 77.

3. THROMBOEMBOLIC DISEASE

program Thromboembolic disease causes or contributes to a great variety
GOALS f diseases in all parts of the body, including heart attacks,

kidney failure, stroke, pulmonary embolism, and disorders of the
microcirculation. Key to the prevention and control of thrombo-
embolic disease is the identification of persons who may be at
risk. Several risk factors associated with high risk for thrombo-
embolic disease are known and it is now possible to identify those
persons who may be at increased risk of stroke, pulmonary embolism,
and thrombophlebitis and to take steps to prevent these disorders.

• The major program goal is to reduce disability and

death from thromboembolic disorders by prevention and
control of risk factors.

recent Added emphasis is currently being placed on this program. Inter-
progress national congresses on thrombosis and hemostasis were held in

1972 and 1973 and have provided a forum for discussion of throm-
bosis as a major world health problem and as part of a planned
attack on this problem. Another more modest conference focused
on clot-stabilizing enzymes and a workshop was conducted to review
existing knowledge about the relationship of thrombosis to the
development of myocardial infarction.

future Because rapid communication is important for advance in thrombosis
challenges an( j related fields, conferences on timely topics are planned to
disseminate information as it is developed through research.

113

ACTIONS

The Institute plans to:

Explore, in coordination with other agencies, techniques for
educating the medical community and the general public about
risk factors and preventive measures in thromboembolic disease.

schedule This program was initiated at a modest level in FY 74 and will be
receiving gradually increased emphasis through FY 80.

4. BLOOD RESOURCES

program An adequate supply of blood resources is vital to the treatment,
goals prevention, and control of many major diseases, including the ones
addressed by the National Program. Not only must there be adequate
supply of these resources, but they must also be of high quality
in order to provide effective treatment and to avoid transmission
of disease, such as hepatitis. Currently, neither adequate supply
nor high quality blood is fully assured by the nation's operating
blood service complex. Whole blood and blood components are col-
lected by this complex and distributed throughout the nation.
Special efforts are needed to assess the problems involved and to
encourage more effective and economic utilization of these resources.
A continuing program must be carried out for professional and public
information and education about blood resources and the use of
effective blood management systems. This is especially true of
blood component therapy.

• The goal of this program is to achieve better manage-
ment of the nation's blood resources.

RECENT
PROGRESS

Two types of education efforts are being developed: (1) Education
of technical/medical professionals to assure that whole blood is
separated into its component parts and that the components are
appropriately stored and made available to users; and (2) Efforts
to influence the demand sector of the blood banking complex
regarding optimal use of blood components in order to moderate
the demand on the nation's blood resources.

future We need to develop ways to educate physicians regarding optimal
challenges use f blood components in order to moderate their demands on the
nation's blood resources. The target population for the technical
education efforts is the regional component of the coordinated
nationwide blood system which is currently evolving in the United
States. To stimulate optimal use of blood, attention will be
directed at hospital blood banks and, at least initially, selected

114

populations of physicians, in particular, surgeons and anesthesi-
ologists. Efforts also need to be made to evaluate the impact of
the hepatitis program on the nation's health and to bring the
results to the practicing physician, blood banker, high risk indi-
vidual, and the general public.

The NHLI also plans to assess the psychologic, sociologic, and
economic aspects of organ donation and transplantation. Motivation
for organ donation and regionalization of "organ banks" will be
investigated and evaluated in concert with the National Blood
Program.

ACTIONS

The Institute plans to:

1. Support efforts to educate and influence physicians regarding
optimal use of blood components and autotransfusion in order
to moderate demands on the nation's blood resources.

2. Develop a coordinated program for hepatitis epidemiology and
control.

3. Encourage efforts to develop a system of organ procurement on
a regional and national basis.

4. Promote public dialogue on the ethical and legal problems
associated with organ transplantation.

schedule The Institute's efforts in education programs in blood therapy will
be increased gradually over the next five years.

115

IV. PROGRAM COORDINATION

The National Heart, Blood Vessel, Lung, and Blood Program is designed to use
national resources to attain the national long-term goal of improving the health
of the American people. The achievement of a truly National Program remains a
major challenge to the Institute. While we must not belittle the many real
problems that remain in terms of National Program coordination, the Institute
has made considerable progress in mobilizing interest in the Program. Through
the National Program, the NHLI has a great opportunity to stimulate collabora-
tive efforts at all levels and with all sectors of our society. In this manner
the resources and direct efforts of the Institute have a multiplier effect far
beyond what has been previously possible.

The Institute has, in the past, participated in many key collaborative efforts
with other organizations throughout the nation. Such collaboration will con-
tinue to be expanded. During the planning stages of the National Program, both
public and private sectors were called upon for inputs. These inputs to the
Program, as detailed in the National Heart and Lung Institute Summary (Volume I,
dated May 1, 1973), include other Bureaus, Divisions, and Institutes of the
National Institutes of Health, other Federal agencies, and private, non-Federal
and voluntary organizations.

In implementing the Program, this Institute continues to serve as the principal
coordinator of a management system depicted in Volume I and reprinted here
(Figure 1). As the focal point, the Institute can:

Promote coordination of research and prevention, control, and
education activities with many other organizations

Assess the ordered sequence of program activities from basic
research to demonstration in the community

Evaluate the overall National Program in terms of ongoing and
projected activities

Gauge the impact of the Program on the health of the American
people.

117

♦

New Program
Concepts

Agency
Resource
Allocation

Health
Impact

Interagency
Coordination
• Program Scope
► Priorities

PROGRAM EMPHASIS AS DERIVED
FROM AGENCY MISSION

♦

Acquisition

of New
Knowledge

Development
of Existing
Knowledge

Application
of Existing
Knowledge

* *

« ♦

* »

PROGRAM EVALUATION

Health

Care

Delivery

♦

Public and Professional

formation and Educat

Figure 1. Coordination and Implementation of the National Program

From a central position, the Institute can review current knowledge and activi-
ties in each program area addressed by the National Program and thereby assure
balance among the program areas. Most importantly, the Institute as coordina-
tor of the National Program will be able to stimulate the development and dis-
semination of information to the public and the medical professions in a respon-
sible and timely manner.

Key collaborative efforts in areas related to the problems addressed in the
National Program are conducted through a variety of mechanisms. Some of these
national efforts are summarized below. Highlights of relevant cooperative agree-
ments between the NHLI and other countries are also presented, insofar as these
represent extensions of a National Program which addresses transnational disease
problems.

118

NATIONAL COLLABORATION

A key formal mechanism for coordinating national efforts related to the National
Program is the Interagency Technical Committee on Heart, Blood Vessel, Lung, and
Blood Diseases and Blood Resources (IATC) . The IATC was established by the Sec-
retary of the Department of Health, Education, and Welfare in November 1972, in
accordance with the National Heart, Blood Vessel, Lung, and Blood Act of 1972.
This Committee, chaired by the Director of the National Heart and Lung Institute,
is responsible for coordinating Federal agency activities related to heart, blood
vessel, lung, and blood diseases and blood resources to assure their adequacy and
technical soundness. The Committee provides a forum for communication and exchange
of necessary information.

The Committee is comprised of representatives from the following components of the
Department of Health, Education, and Welfare:

Alcohol, Drug Abuse, and Mental Health Administration

Center for Disease Control

Food and Drug Administration

Health Resources Administration

Health Services Administration

National Institutes of Health

Social and Rehabilitation Service

Social Security Administration.

Also on the Committee are representatives from other Federal departments and
agencies as follows:

Department of Agriculture

Department of Defense

Department of Transportation

Atomic Energy Commission

Environmental Protection Agency

National Aeronautics and Space Administration

National Science Foundation

Veterans Administration.

119

During the initial planning effort, the Committee provided input to the National
Program by advising on goals, opportunities, and needs. It also assisted the
Institute in compiling an inventory of ongoing programs related to the National
Program. This inventory, published as Volume V of the National Heart, Blood
Vessel, Lung, and B.'.oorl Program, identified, within only the agencies represented
on the Committee, £.;?prc ximately 3,500 research areas related to the National Pro-
gram. These programs •represented more than $130 million in Federal outlays above
the NHLI ' s budget for these related programs .

Presently, the Committee is updating the information contained in Volume V (by
provision of FY 73 data) and reviewing the status of past and present interagency
coordination and the prospects for broadened agency participation in the National
Program.

In addition to the information displayed in Volume V last year, there are other
Federal organizations which are not represented on the IATC, but which conduct
or sponsor related research and/or prevention, control, and education activities
in heart, blood vessel, lung, and blood diseases and resources. Furthermore,
24 non-Federal voluntary organizations with related programs were identified in
Volume I last year. The NHLI already collaborates with many of the Federal and
non-Federal organizations and plans even greater collaboration in the future
among all the sectors of our society concerned with these disease problems. Dis-
cussed below, for each major disease category, are some key ongoing collaborative
efforts in which the NHLI participates.

HEART AND BLOOD VESSEL DISEASES

Many major collaborative and cooperative efforts already exist with Federal and
non-Federal organizations, professional societies, and the private sector. Exam-
ples given below include Nutrition; Hypertension; High Blood Pressure Education
Program: Devices; Emergency Medical Services; Pacemakers and the Artificial Heart;
Rehabilitation; Cardiac Reconditioning; and Manpower Development.

• Nutrition. The NHLI is collaborating directly with the U.S. Depart-
ment of Agriculture (USDA) and the Food and Drug Administration
(FDA) in defining data gaps and updating and publishing a new
authoritative nutrient composition source book to supersede a
previous edition outdated by the new processed and convenience
foods. Completion of this effort will provide the basic data
necessary to enumerate dietary constituents for research on the
effect of diet on blood lipids and heart disease. Information
received from the FDA on its new voluntary food labeling regu-
lations and commercial food analyses made by the Grocery Manu-
facturers of America for the USDA's National Food Data Bank are
now being channeled directly to the NHLI.

120

Hypertension. The National High Blood Pressure Education Program
has as its major goal the reduction of morbidity and mortality
from high blood pressure and its sequelae. The NHLI has lead
responsibility for coordinating this program which is an inter-
agency, Federal/non-Federal cooperative effort. The Health Ser-
vices Administration, Health Resources Administration, Food and
Drug Administration, Veterans Administration, and Department of
Defense have all designated representatives to the program.
During the first year of the program, the Veterans Administra-
tion, Food and Drug Administration, Health Services and Mental
Health Administration, and National Institutes of Health were
represented on four Task Forces which made recommendations on
data base, professional education, community education, and
national resources and impact assessment. The Department of
Defense was also represented on the Professional Education Task
Force.

Besides representation in the planning effort, several agencies
took responsibility for implementing some of the Action items
during the past year. The Health Services and Mental Health
Administration sponsored the development of mass media educa-
tional materials; the Food and Drug Administration sponsored a
workshop on professional education and is sponsoring a survey
of physicians on high blood pressure; the NHLI sponsored a
public attitude survey on high blood pressure and a national
conference on high blood pressure education; and various other
activities were sponsored jointly by several agencies.

The program has a policy of cooperating with any organization
which wants to produce educational materials, and will supply
technical advice and allow the use of the logo, provided the
material does not endorse any particular product (s), is not
for sale, and is factually correct. The response from the pri-
vate sector has been gratifying. Educational materials for the
public and the medical professionals have been produced with
a consistent message. Professional and voluntary organizations
such as the American Medical Association, American Heart Asso-
ciation, National Medical Association, American Public Health
Association, and American Red Cross have endorsed the program.
The program also cooperates closely with a newly formed group,
the Citizens for the Treatment of High Blood Pressure.

High Blood Pressure Education Program: Devices. Hypertension is recognized
as a significant community health problem. Mass screening pro-
grams for the detection of hypertension are currently being ini-
tiated. In view of the needs of these programs, several commu-
nity groups have asked for guidance in choosing an automated
device for measuring blood pressure. For this reason the NHLI,
as the lead agency for the National High Blood Pressure Educa-
tion Program, has initiated a review of the status of automated

121

blood pressure measuring devices with a task force to assess
these devices. Representatives from the Food and Drug Admin-
istration and the Veterans Administration are among those help-
ing in the evaluation. The NHLI will also work with the Amer-
ican Heart Association through the Committee on Criteria and
Methods of the Council on Epidemiology. A proposal for evalu-
ating automated blood pressure measuring devices, as well as
criteria for a suitable device, has been developed by the Amer-
ican Heart Association committees. This work will be of great
help to the NHLI Task Force as it attempts to look at all the
devices currently available and to assess them in terms of
suitability criteria.

Emergency Medical Services. In the fall of 1972, the Secretary of
Health, Education, and Welfare established an Interdepart-
mental Committee on Emergency Medical Services with the
then Health Services and Mental Health Administration assum-
ing the lead role. The Associate Director for Cardiology,
Division of Heart and Vascular Diseases, NHLI, was appointed
the NIH representative. The NHLI has collaborated with the
Emergency Medical Services Branch of the Health Resources
Administration on topics of mutual interest and importance,
including co-sponsorship of the Second National Conference
on Emergency Health Services and of the meeting on Cardio-
pulmonary Resuscitation sponsored by the American Red Cross
and the National Science Foundation. Within the context of
the National Program, the NHLI will be responsible for the
elucidation of the pathophysiology of heart disease in its
earliest emergency phases and for the development of methods
of care suitable for incorporation into emergency medical
care systems.

Pacemakers and the Artificial Heart. Collaborative efforts between the
Atomic Energy Commission (AEC) and the NHLI date back to
1965, when the AEC initiated a program for a radioisotope-
powered cardiac pacemaker with the consultative advice of
the NHLI. The reliability of these devices, tested in
animals by the NHLI, has been demonstrated at a level suf-
ficient to permit clinical implantation in approximately
50 patients throughout the nation, including several within
the clinics of NHLI.

From the inception of the Artificial Heart Program in the
early 1960's, the NHLI and the AEC have collaborated in deter-
mining feasibility and exchanging technological information.
Initial feasibility studies were jointly funded and assessed.
There has been a renewed and markedly strengthened effort at
regular scientific interchange and semi-annual formal meet-
ings between the NHLI and the AEC with respect to artificial

122

heart development. Through these contacts and the interchange
of documents, the NHLI has made available to the AEC recent
progress and research information on its programs. The AEC,
in turn, is making available to the NHLI a 33-watt encapsulated
Plutonium source for conducting important studies.

Rehabilitation. Coronary artery disease is responsible for chronic
disease in several million Americans, including 2.5 million
Americans less than 65 years old. The NHLI has convened a
task force to study the present state of our knowledge as it
relates to cardiac rehabilitation. This task force will assess
the state of the art, the medical and social import of cardiac
rehabilitation, and present techniques and their scientific
bases. Recommendations will be developed for clinical imple-
mentation of what is known and practical, and for initiating
effective research where necessary. Representatives from com-
munity and governmental agencies (including the American Heart
Association, the Council of State Administrators of Vocational
Rehabilitation, the Rehabilitation Services Administration,
the Social and Rehabilitation Service) are working closely with
the NHLI to develop and implement an overall plan on cardiac
rehabilitation.

Cardiac Reconditioning. The NHLI is using the results of and collab-
orating in research and implementation of activities related
to cardiac functions with the National Aeronautics and Space
Administration (NASA) . In collaboration with NASA, NHLI is
evaluating the effects of weightlessness on cardiovascular func-
tion. Although previous NASA studies of astronauts returning
from space missions indicate that profound, but apparently
reversible, changes occur in various bodily functions, the effect
of prolonged weightlessness on cardiac function is unknown.
Several observations which suggest that the heart may be affected
adversely include: (1) necropsy studies on the three Soviet cos-
monauts who died during re-entry suggested that the heart might
have undergone severe degenerative changes during their space
voyage; (2) heart size as determined from frontal X-rays on
American astronauts have demonstrated the heart to be smaller
immediately post-flight as compared to pre-flight; (3) pos-
tural hypotension is an invariable early post-flight finding;
and (4) NASA scientists have determined that, when compared
to control pre-flight studies, cardiac output during exercise
often is markedly reduced shortly after splashdown.

To follow up on these observations, the NHLI is collaborating
with the biomedical staff of NASA to systematically evaluate

123

the effects of prolonged weightlessness on cardiovascular
function. Pre- flight studies on the astronauts and back-
up crew of the Skylab III mission have been completed.
Post-flight repeat studies are planned.

Over the past three years, the NHLI has been refining the
technology of echocardiography and applying this technology
to the evaluation of patients with all types of cardiac
disease. Echocardiography is a diagnostic procedure that
utilizes ultrasound to visualize noninvasively the internal
structures of the heart. This technique will be used to
help determine whether prolonged weightlessness leads to
myocardial atrophy, whether myocardial function is impaired,
or whether all of the observations to date can be explained
by a decrease in circulating blood volume. The adequacy of
baroreceptor-mediated reflexes will also be investigated.
Finally, by serial measurements over the course of weeks or
months, these collaborative studies will assess the reversi-
bility of any abnormalities that develop and the time it
takes for return to normal function. These studies could
result in generally applicable information concerning, for
example, reversibility of certain types of cardiac abnormali-
ties.

Manpower Development. As described in the chapter on Manpower
Development, the NHLI has collaborated with a number of pro-
fessional and private organizations to conduct an in-depth
assessment of current manpower status and future needs in a
variety of disciplines related to the National Program in
heart and blood vessel diseases. Examples of these organiza-
tions are the American College of Cardiology, American Associa-
tion for Thoracic Surgery, and the American Heart Association.

LUNG DISEASES

Two major cooperative programs reinforce the Institute's Actions for prevention,
control, and education activities in smoking and black lung. Other cooperative
programs relate to structure and function of the lung and to manpower develop-
ment. These are described below:

Smoking. Cooperative efforts to reduce smoking and its harm-
ful effects on health are being conducted with the National
Cancer Institute (NCI) , National Clearinghouse for Smoking
and Health, and the Veterans Administration. The goals of
these efforts are to develop a less hazardous cigarette and
to study smoking behavior and its modification, and to

124

utilize these findings in developing an intervention program

in the general population. Two specific programs funded jointly

by NCI and NHLI to achieve these goals are:

Experiments to Determine Effects of High and Low Nico-
tine Cigarettes . The purpose of these experiments being
conducted by the Veterans Administration is to determine
whether nicotine is involved in the harmful effects pro-
duced by inhalation of cigarette smoke over many months.

Comprehensive Smoking Withdrawal Program . This program,
also funded by the National Clearinghouse for Smoking
and Health, is designed to conduct a research and demon-
stration project aimed at developing a community-based
comprehensive control program which would provide ser-
vices on an individual referral basis as well as to indus-
try, civic, and community organizations.

• Pneumoconioses (Black Lung). Because coal miners are at high risk
of developing respiratory diseases from exposure to airborne
dusts, a joint committee, the Working Party on Respiratory
Diseases Among Coal Miners, has been established, at the
request of the Governor of Pennsylvania, to define the types
of efforts most urgently required to prevent or treat work-
related respiratory diseases. This committee has members from
Federal (National Institute for Occupational Safety and Health,
National Institute of Environmental Health Sciences, U.S.
Bureau of Mines, and NHLI), State (Commonwealth of Pennsylva-
nia), non-profit (New York Academy of Sciences, American Lung
Association) , industry (such as U.S. Steel and others) , and
university organizations.

The Working Party has four subcommittees: (1) Subcommittee
on Clinical Problems, with the charge to develop an optimal
clinical management program, develop simple tests for diag-
nosis and effectiveness of therapy, and develop specific
graduate educational and physician education programs; (2)
Subcommittee on Research Perspectives in Epidemiology and
Small Airway Disease, with the charge to study small airway
disease in coal workers and investigate the epidemiology of
coal worker's respiratory disease; (3) Subcommittee on Research
Perspectives Concerning Biologically Important Particles in
Coal Worker's Pneumoconiosis, with the charge to study the
ultramicroscopic particles in relation to the problem and
investigate the inactivation of dust in the lungs; (4) Sub-
committee on Prevention and Treatment of Coal Worker's Res-
piratory Disease, with the charge to investigate the patho-
genesis of Progressive Massive Fibrosis and investigate the
cellular biology approach to the problem. The Working Party
has scheduled a series of meetings to identify and delineate
areas for further development and action.

125

Pressure and Underwater Biomedical Research. The NHLI is participating in
a National Cooperative Program of Pressure and Underwater Bio-
medical Research and Operation Development with the Department
of the Navy and the National Oceanic and Atmospheric Adminis-
tration. The objective of this program is to identify criti-
cal biomedical problems related to respiration and underwater
pressure and to recommend steps for their solution. The focus
of the program is on determining alterations in the various
body systems when responding to increasing physical and physi-
ological stresses over long periods of time. As one system is
progressively stressed, e.g., the respiratory system, the ef-
fects are initially compensated by alterations in other sys-
tems, e.g., the circulatory or renal systems. As the limit of
compensatory processes are reached, failure in functions begins
and may progress to complete failure if the stress continues.
The respiratory system is the prime target of this research
which promises to provide important insights into the structure
and function of the lung.

Manpower Development. The NHLI has collaborated with the American
Thoracic Society and the American College of Physicians in
surveying the national needs for manpower in pulmonary diseases.
Conclusions drawn from these surveys are presented in the chap-
ter on Manpower Development. The Institute is also coordinating
its activities in this area with the American Lung Association
and other voluntary organizations interested in the implementa-
tion of the National Program.

BLOOD DISEASES AND BLOOD RESOURCES

The National Program in blood diseases and blood resources sets forth a number
of key research and prevention Actions for ameliorating the effects of sickle
cell disease, Cooley's anemia, hemophilia, and hepatitis, and for improving the
management of our nation's blood resources so vital to the treatment of disease.
Important cooperative efforts relevant to the National Program have been initi-
ated. Examples of these efforts related to the above Actions are described
below.

Sickle Cell Disease. Cooperative efforts between NHLI, the Health
Services Administration (HSA) , and the Center for Disease
Control (CDC) are ongoing in this area. Demonstration, screen-
ing, and education programs have been developed by NHLI and
HSA. Cooperative efforts have been developed with CDC to carry
out (1) workshops in hemoglobinopathy detection, (2) a profi-
ciency testing program for DHEW- funded projects, and (3) the
establishment of reference laboratories for abnormal hemoglobins.

126

•

Cooley's Anemia. NHLI cooperation with other NIH components, with
private organizations involved with Cooley's anemia, and with
the scientific community has led to agreement regarding priori-
ties for research in this area.

Hemophilia. The NHLI maintains a cooperative working relationship
with the National Hemophilia Foundation. Collaborative activi-
ties include program planning, information exchange, and research.
The Foundation had significant input into the development of the
National Program, and discussions are now in progress to assure
that the programs of the NHLI and the Foundation are complemen-
tary and mutually supportive of each other. With the assistance
of the Foundation, the NHLI recently published a pilot study of
hemophilia treatment in the United States.

Hepatitis. A Hepatitis Liaison Committee composed of representa-
tives from all government organizations funding hepatitis research
has been established to coordinate information exchange and to
advise all research organizations on program needs and poten-
tials. This Committee has supported a workshop on the future
of epidemiologic studies in hepatitis. A Hepatitis Policy Liai-
son Committee (Bureau of Biologies, NHLI, and National Institute
of Allergy and Infectious Diseases) coordinates extramural hepa-
titis research activities funded by the component agencies.

Blood Resources. The NHLI maintains continuing liaison with the
three major blood suppliers in the U.S.: the American National
Red Cross, the American Association of Blood Banks, and the
Council of Community Blood Centers. These organizations have
been charged by the Secretary of Health, Education, and Welfare
to develop implementation plans for a National Blood Policy.
The NHLI works closely with the Food and Drug Administration
in regulatory areas relating to safety and efficacy of blood
products and handling.

Manpower Development. The NHLI, in cooperation with the National
Institute of Arthritis, Metabolism, and Digestive Diseases
(NIAMDD) and the American Society of Hematology (ASH) , has
drafted a proposal for manpower development in research hema-
tology in the United States. This proposal was drafted with
input from a broad segment of the academic hematologic commu-
nity.

127

INTERNATIONAL COLLABORATION

The disease problems addressed by the National Program are transnational. They
are major problems encountered by all peoples throughout the world. Implementa-
tion of the National Program provides a real opportunity for exchange of infor-
mation between countries on problems of heart, blood vessel, lung, and blood dis-
eases and blood resources. The planned research and prevention, control, and
education programs in the United States can be greatly enhanced through coopera-
tion with other countries which are trying to solve these problems within their
own borders. Cooperation with other countries enhances and strengthens the capa-
bility of the Institute for effective national collaboration for the benefit of
our citizens. During FY 73, the Institute supported 34 foreign projects and
fellowships in areas related to the National Program. The recently initiated
US-USSR Health Exchange Program is a highly structured, collaborative interna-
tional program related to the goals of the National Program.

In 1956, the National Heart Institute participated for the first time in the
US-USSR Scientific Exchange Missions. Since that time, American scientists have
visited research and treatment centers in the Soviet Union and Soviet scientists
have visited heart research centers in the United States. An expansion of coop-
eration, including mutual planning and execution of joint research activities,
between the two countries in the field of health and medical science was agreed
upon in February 1972. A five-year agreement was signed three months later.
The cardiovascular area was one of the first three areas recommended for such
expanded cooperation. The Director of the National Heart and Lung Institute
is the overall U.S. coordinator for the cardiovascular studies. Key activities
related to the National Program which are being implemented under this agreement
are briefly described below:

Pathogenesis of Arteriosclerosis. Arteriosclerosis is the most common
type of cardiovascular disease and the chief cause of death
in both the U.S. and the U.S.S.R. A joint clinical study has
been undertaken to determine the prevalence in both countries
of hyperlipidemias and ischemic heart disease, and the effect
of modifying blood lipids by diet or drugs on the risk of devel-
oping these diseases. This is the first study of its kind in
the world. It involves large numbers of well-characterized sub-
jects in two countries, comprehensively studied according to
identical techniques based on carefully worked out research pro-
tocols, and analyzed by highly standardized techniques.

• Management of Ischemic Heart Disease. Ischemic heart disease is the most
common clinical complication of arteriosclerosis and the most
common complication leading to death. The U.S., through the
NHLI, and the U.S.S.R. are conducting a comparative study of dif-
ferent approaches for medical and surgical treatment of ischemic
heart disease. This project, also the first of its kind, will
evaluate and compare chronic angina and heart attack disability
treatment methods that have been developed in each country.

128

Myocardial Metabolism. This topic involves the study of the activi-
ties and functions of both the healthy and the diseased heart.
Thus, it is relevant to the study of all types of heart disease.
During the past year, American and Russian scientists have
exchanged information on methods to limit the extent of heart
muscle damaged by heart attack. These findings will be pub-
lished jointly.

Congenital Heart Disease. Congenital heart disease affects an esti-
mated 25,000 children born in the U.S. each year and a corre-
sponding number born in the U.S.S.R. each year. The objectives
of this collaborative study are to develop diagnostic techniques
and methods of post-operative care, to study the mechanisms of
development of pulmonary hypertension, to search for new ways
of reducing mortality from the surgical treatment of tetralogy
of Fallot, and to study diagnostic techniques and surgical
treatment of complex heart defects.

Sudden Death. This problem is a new initiative for collaboration
in the cardiovascular area. Exchange of information, exchange
of health professionals, and meetings between Russian and Amer-
ican specialists are in progress to develop detailed plans for
scientific cooperation.

Blood Transfusion, Blood Components, and Prevention of Hepatitis, with Particular
Reference to Cardiovascular Surgery. This problem is also a new initia-
tive for collaboration in the cardiovascular area. Exchange
of information, exchange of health professionals, and meetings
between Russian and American specialists are being held to
develop plans for scientific cooperation.

Technological Development. A joint program in mechanical circulatory
assistance is under development.

The actions and schedules for these programs are updated annually by the joint
US-USSR committee in light of recent progress and future challenges.

129

V. MANPOWER DEVELOPMENT

The development and maintenance of highly skilled manpower at all levels are of
great importance in the planning and implementation of our national effort against
heart, blood vessel, lung, and blood diseases. This is true both from the stand-
point of the professionals participating in the Program and the public paying for
and benefiting from the Program. Recruitment, selection, training, development,
and support of talented young scientists are critical to the continued success of
the National Program. The search for new solutions to these disease problems will
make new demands on the nation for adequate numbers of well- trained personnel.
The scientists, physicians, and allied health professionals engaged in this effort
must be familiar with many new and complex technologies and must be educated to
draw experience from old technologies. They must be ready and willing to engage
in intellectual pursuits which will help in finding new answers.

The National Heart and Lung Advisory Council, in both its initial Report of April
1973 and in its first Annual Report of December 1973, places great emphasis on the
need to develop skilled manpower. This is needed not only to replace losses from
the present pool through attrition, but also to search for innovative approaches
to the disease problems addressed by the National Program. The NHLI Summary of
May 1973 recognized the importance of manpower development. However, the Insti-
tute's position was that any specific recommendations should be keyed to documented
needs in specific areas. Therefore, recommendations were deferred at that time,
pending results of a major review of manpower needs in those disciplines that
affect implementation of the National Program.

In considering the manpower needs for the expanded national effort, three factors
must be given careful consideration:

• Manpower development, research, and health care are three

segments of an interrelated continuum, and manpower develop-
ment cannot be considered separately from research or health
care any more than research per se can be considered separately
from health care.

131

Manpower development needs will continue to grow as the store
of knowledge (now doubling every ten years) grows through
research, as the population grows, and as the public demands
new and increasingly sophisticated approaches to health care.

There is an increasing demand for public accountability of
all health professionals, since the public is the source of
funds as well as the ultimate beneficiary of manpower devel-
opment, health research, and health care. Thus, the public
must be given confidence that every effort is being made to
assure high quality of professional performance throughout
the program — in planning, research, prevention, education,
control, evaluation, and coordination.

Data so far collected indicate the positive need for a vigorous manpower devel-
opment program for the advancement of future research and investigation. This
is based on analysis of a number of surveys and assessments by Institute staff,
members of the National Heart and Lung Advisory Council, voluntary agencies,
and professional organizations. The estimates below are conservative and were
derived by assessing:

• The minimum number of research investigators needed for
the maintenance of selected, vital research activities

• The minimum number of trained investigators currently
needed to fill documented and budgeted faculty vacancies
directly related to the mission of the NHLI

• The particular talents, disciplines, or areas that need
additional manpower for implementing a vigorous National
Program .

HEART AND BLOOD VESSEL DISEASES

There are approximately 11,000 active cardiologists in this country, with a con-
siderable variation in geographic distribution. In a recent survey, fully 5 per-
cent of the active cardiology training programs had no full-time faculty member.
Furthermore, almost 30 percent of the training programs had an average of two
staff positions that were budgeted but unfilled, representing a national total of
150 to 180 positions in this category. A separate survey revealed that only 94
medical centers in the United States had certified pediatric cardiologists on
their staffs, representing a shortage of approximately 100 pediatric cardiologists
in this country. Taking annual losses into account, it is estimated that 350 to
400 individuals would have to be added to the research manpower pool each year

132

merely to maintain the present status of heart and blood vessel research efforts.
Thus, the Institute estimates that, at a minimum, approximately 600 individuals
should be enrolled in fellowship or trainee programs related to heart and blood
vessel diseases in order to maintain the present level and to implement the Action
items in the National Program.

• The NHLI proposes to place special emphasis on training in
those areas in which research skills are currently in short
supply, namely: pediatric cardiology, behavioral and moti-
vational disciplines, bioengineering (with a particular view
to improving noninvasive diagnostic instrumentation) , genetics
(as related to a variety of disease states such as hyperten-
sion and abnormal lipid metabolism) , pediatric nutrition and
metabolism (as related to lipid metabolism) , microcirculation
(including aspects of blood flow and tissue metabolism) ,
immunochemistry, and epidemiology and biostatistics.

LUNG DISEASES

A recent survey of professional manpower revealed that 130 currently funded but
unfilled vacancies exist on medical school faculties in lung diseases and at
least 20 additional vacancies exist at research institutes. It is estimated that,
within the next two to three years, approximately 550 well-trained individuals will
be required for the staffs of medical schools and research institutions engaged in
lung disease activities.

Research in the pulmonary disease area has now developed special and almost unique
requirements. Increasingly, it has become possible to study lung diseases by
investigation of underlying mechanisms, and physicians and scientists must now
draw upon fundamental disciplines that are comparatively new to the lung field,
such as biochemistry, cell biology, immunology, and bioengineering.

Because of the great need for interdisciplinary research and training in the lung
diseases area, the Institute plans to give high priority to such programs. To
date, basic scientists have not been conversant with the problems of lung diseases,
and pulmonary clinicians have been generally uninformed about the basic studies
that might contribute to their research.

• The NHLI believes that for these special interdisciplinary
research training programs, where new and basic contribu-
tions can be made, between 150 and 200 research fellows
should be supported in the immediate future.

133

BLOOD DISEASES AND BLOOD RESOURCES

Two separate studies of staff positions in academic hematology, focusing upon
institutions with academic programs in blood diseases and blood resources, re-
vealed that about 10 percent of the positions in academic hematology are unfilled.
Research areas with the largest number of unfilled positions included hemoglobin-
opathies, coagulation, immunohematology, and blood banking — all areas of major
concern in the National Program.

The development of manpower for blood banking is one of special urgency in the
United States. Not only is there a lack of adequately trained manpower in blood
banking, but there are also insufficient training faculties and resources. These
limitations have prevented the effective application of newer techniques and
knowledge in this area of health care vital for the American people.

The Institute estimates that approximately 200 research
fellows should be trained now in the blood research areas
addressed by the National Program. The efforts in this
regard will be coordinated with other Institutes of the
NIH involved in hematology manpower development. The
areas of special need include: blood banking, platelet
function and abnormalities, thrombosis in the microcircu-
lation, thromboembolism, abnormal hemoglobins including
sickle cell disease, red blood cell membranes and enzyme
systems, and the biology of transplantation of tissues
and organs .

Since the training required in all of the above areas is highly specialized, it
will take several years or more before the individuals enrolled in the programs
will be ready to contribute fully to the activities of the National Program.
Prompt initiation of these manpower development programs is of major importance.
Otherwise, implementation and progress of the National Program will be impeded.

134

VI. IMPLEMENTATION OF OTHER PROVISIONS OF THE ACT

The passage of the National Heart, Blood Vessel, Lung, and Blood Act of 1972 sig-
nificantly expanded the Institute's mandate and responsibilities. To implement
the new and increased activities authorized by the Act in an efficient and timely
manner, the National Heart and Lung Institute has made significant changes in its
organizational structure, program management, and ways of communicating and col-
laborating with the public and the professional community in the National Program.
Five areas of special importance to the successful implementation of the National
Program are discussed in this chapter:

National Research and Demonstration Centers

Construction

Mechanisms of Support

Administrative Changes

Program Review and Evaluation.

NATIONAL RESEARCH AND DEMONSTRATION CENTERS

P.L. 92-423 states that the Director of the Institute may provide for the develop-
ment of National Research and Demonstration Centers: up to 15 Centers for problems
related to heart, blood vessel, and blood diseases, and up to 15 Centers for prob-
lems related to chronic lung diseases. The purpose of the Centers' program is to
facilitate and expedite the translation of research results to clinical practice
in local communities across the nation. The Legislative Act specifies that the
programs of such Centers would encompass basic and clinical research into, train-
ing in, and demonstration of, advanced diagnostic, prevention, and treatment methods
for the respective diseases. In the initial" National Plan, the NHLI proposed to

135

establish approximately five Centers in FY 74 and an additional five in FY 75,
at an initial level of about $1 million per Center in the first year, rising
incrementally to about $3 million per Center in the third year. After further
study and on advice of the National Heart and Lung Advisory Council, we now
estimate the initial operational cost per Center at approximately $3 million
per year.

A Program Announcement and Guidelines, developed with advice from the National
Heart and Lung Advisory Council, were released in August 197 3. A National
Research and Demonstration Center is defined as a national resource attached to
a major medical complex and dedicated to working in close collaboration with the
Institute to further the goals of the National Program. A Center preferably
should focus on one major area — heart and blood vessel diseases, lung diseases,
blood diseases, or blood resources. However, a combination of areas would be
acceptable if shown to be more effective in meeting the goals of the National
Program. The guidelines require that each Center must include programs in fun-
damental research, clinical research and clinical application, an environment
conducive to the training of young scientists, and an information and education
program.

A meeting of potential applicants was held at the National Institutes of Health
early in October 1973. More than 300 representatives from interested institu-
tions attended and NHLI staff answered questions and clarified specific aspects
of the program. Approximately 7 5 letters-of -intent to apply have been received:
31 in heart and blood vessel diseases, 21 in lung diseases, 15 in blood, 5 com-
bining heart and lung diseases, and a few not classified. Formal applications
are due early in 1974.

Proposals for the Centers will be reviewed in the spring of 1974 by panels of
expert consultants and by the National Heart and Lung Advisory Council. The
ability of the Institute to make any awards for National Research and Demonstra-
tion Centers is contingent upon the availability of appropriated funds. The
Institute plans to activate the program early in FY 75. Additional Centers may
be activated in the future as the effectiveness of the first group is determined,
and as experience is gained in the planning, monitoring, and execution of these
multidisciplinary programs.

CONSTRUCTION

The National Heart and Lung Advisory Council, in its first Annual Report, reit-
erates the need for funds for construction of facilities to develop the required
capabilities for full implementation of the National Program. This is particu-
larly true for the National Research and Demonstration Centers. Funds for con-
struction are not included in the NHLI fiscal allocation plan for FY 74. There-
fore, initial Centers must provide for all facilities and resources necessary
to initiate the program. However, the Centers will serve as national resources
for expediting the transfer of research results to national clinical practices,

136

and additional facilities will be needed as each Center becomes fully opera-
tional. In the initial NHLI Plan, the Institute estimated the net space require-
ments of each Center as approximately 80,000 to 100,000 square feet, and further
estimated that approximately 60 percent of this space might have to be newly
constructed. Projections are included in the budget for 450,000 square feet
in FY 76, 225,000 square feet in FY 77, and 225,000 square feet in FY 78 to pro-
vide for new construction for the Centers, and an additional 60,000 square feet
for other specialized research facilities for the National Program. These esti-
mates are based on the establishment of 15 Centers, each with a space requirement
of approximately 100,000 square feet, and assuming that the government will pay
for the 60 percent which is newly constructed.

A long lead time for planning and executing construction projects is not unusual.
Therefore, the Institute again recommends that funds appropriated for this pur-
pose remain available through the year subsequent to the one in which they are
appropriated, with the proviso that they be used for construction only.

MECHANISMS OF SUPPORT

Implementation of the programs of research and prevention, control, and education
that collectively make up the National Program involves the participation of a
broad range of biomedical professionals. Support is provided through a variety
of mechanisms. As outlined in the initial NHLI plan, these mechanisms range
from the traditional research project grant, for the independent investigator
who wishes to contribute to the National Program by carrying out relevant research
according to a plan initiated by himself, to highly structured research contracts,
for investigators who wish to participate in programs which are addressed to
sharply targeted goals and solicited and monitored by the Institute. Between
these two mechanisms are larger multidisciplinary programs, such as the current
Specialized Centers of Research and the proposed National Research and Demonstra-
tion Centers. These multidisciplinary efforts, although grant-supported, com-
bine a degree of investigator independence with mission-orientation and a close
working relationship with the Institute in order to integrate the efforts of one
Center with the activities of other Centers and with those of the Institute.

The Institute will continue to use the fiscal mechanisms most appropriate to
given activities. Independent research must continue and be fostered as a major
source of new and fresh ideas for scientific advance. At the same time the
Institute has a responsibility to society to facilitate the transfer of these
scientific advances to the American health care system. Table 3 shows the allo-
cation of funds between grants and contracts in FY 73. We would expect that
the distribution of funds among these mechanisms will remain substantially
unchanged in FY 74. The Institute does not plan any significant change in this
ratio of distribution in the near future. The Intramural Research noted in the
table is the in-house program of basic and clinical research carried out at the
National Institutes of Health.

137

Table 3. NHLI Resource Allocation by Major Activity

Activity

Percent of Funds

FY 1973

Research Grants

Training Grants and Fellowships

Research Contracts

Intramural Research

Research Management and Program Services

54.8
8.9

24.0
7.6
4.7

TOTAL

100.0%

ADMINISTRATIVE CHANGES

During the past year, the National Heart and Lung Institute has made four major
administrative changes:

• Reorganization of the Institute

• Appointment of an Assistant Director for Health Information
Programs

• Creation of an Office of Prevention, Control, and Education

• Expansion of the National Heart and Lung Advisory Council.

The Institute's activities during the past three years have broadened to include
additional programs in lung and blood diseases, demonstration and control respon-
sibilities, and additional program-oriented efforts, such as National Research
and Demonstration Centers. In line with these program changes, the NHLI examined
its basic organization and concluded that the Institute had developed to a stage
where the primary organization should be mainly by subject matter rather than
by mechanism of support. Consequently, the Institute has been reorganized into
five divisions: Division of Heart and Vascular Diseases, Division of Lung Dis-
eases, Division of Blood Diseases and Resources, Division of Intramural Research,
and Division of Extramural Affairs.

138

The National Heart, Blood Vessel, Lung, and Blood Act authorizes the Director
of the Institute to appoint an Assistant Director for Health Information Pro-
grams responsible for disseminating health information with particular emphasis
on risk factors and preventive measures. The Act also authorizes the Director
to establish Prevention, Control, and Education Programs for Heart, Blood Vessel,
Lung, and Blood Diseases. Both provisions have been implemented. The Assistant
Director for Health Information Programs heads the newly activated Office of Pre-
vention, Control, and Education which is responsible for the prevention and con-
trol programs outlined in Chapter III of this report. The first programs under
its aegis are already operational and relate to hypertension and to sickle cell
disease.

The Act considerably expands the National Heart and Lung Advisory Council, both
in membership and in responsibilities. In addition to developing its own Annual
Report on the National Program, the Council plays an active role in development
of the Institute's long-range program plans. The Act authorizes appointment of
an Executive Secretary of the Council to assist the membership as needed. This
position has been filled by a member of the professional staff of the Institute.

PROGRAM REVIEW AND EVALUATION

Approximately 300 biomedical specialists were involved in developing the National
Program in heart, blood vessel, lung, and blood diseases and blood resources less
than a year ago. Since that time, the activities of the National Program have
been extensively reviewed and evaluated. Program goals, progress, challenges,
actions, and schedules have been examined in terms of their relative importance
to the overall program. As a result of this review process, a revised program
structure was developed and changes were made in program direction (as set forth
in Chapter III) . These revisions form the basis for this annual report and updated
5-year Plan. Review and evaluation continues at each level of the Institute's
programs and will continue to form the basis for each Annual Report of the Director
and each annual updating of the 5-year Plan.

Furthermore, in implementing the program strategy (outlined in Chapter I) , the
Institute will review and evaluate each program as activities move in an ordered
sequence from research to testing to application. Programs will be reviewed both
before and after application in health care delivery systems. The Institute is
developing procedures for ensuring that these review processes are both appro-
priate and effective.

In addition, a number of specific evaluation efforts are underway or planned.
These studies involve the effectiveness of Specialized Centers of Research pro-
grams, the effectiveness of contract programs in lung diseases and the Pulmonary
Academic Award Program, rehabilitation of the patient after myocardial infarction,
management of the national blood resource, assessment of the status of left heart
assist devices, and the role of cultural factors in the development of heart and
blood vessel diseases.

139

An Artificial Heart Assessment Panel was convened to assess the economic, ethi-
cal, legal, medical, psychiatric, and social implications of clinical applica-
tion of a totally implantable artificial heart. The recommendations of this
Panel have been submitted to the Institute and will be considered in future
program developments.

Several studies of manpower availability have been supported in order to deter-
mine the manpower needs in various areas related to the National Program. These
studies are discussed in Chapter V in this report. Training opportunities and
manpower needs will be continually reviewed by the Institute since these factors
will play a vital role in implementing the 5-Year National Plan.

140

VII. RESOURCE ALLOCATION PLAN

The problems of heart, blood vessel, lung, and blood diseases represent both
an indictment and an opportunity for action. As stated in Chapter I, "The
United States, despite its high state of technology, lags behind many other
Western nations in the health of its citizens. In fact, it ranks 24th in the
world with respect to life expectancy for men. The high mortality from heart
and blood vessel diseases is the major contributing factor to this shortened
life expectancy." The National Heart, Blood Vessel, Lung, and Blood Program
is an effort to correct these problems. It will require revision of national
priorities and redistribution of resources to better serve the health needs of
the American people.

In developing this report, the Institute has taken a hard look at ways in which
the quality and comprehensiveness of the National Program can be improved. It
has reexamined the priorities within each program area, developed plans to shift
resources to more productive use, and revised its planned course of action over
the next five years accordingly. Specifically, the NHLI has reviewed:

• The needs and opportunities for research, prevention,
control, and education in heart, blood vessel, lung, and
blood diseases and blood resources. (See Chapter III.)

• The real challenge of coordinating national efforts in
these areas. (See Chapter IV.)

• Related manpower development requirements. (See Chapter V.)

• Facilities and mechanisms of support needed for implementa-
tion of the National Program. (See Chapter VI.)

This program review and evaluation has focused on national priorities and
health needs of the American people. Program requirements have been devel-
oped within this framework by key personnel in the National Heart and Lung
Institute with the advice of the National Heart and Lung Advisory Council.
Our priority actions are described in earlier chapters of this report, and
the resources needed to fulfill these NHLI-supported actions are presented
here. Contributions to the National Program by non-NHLI-supported activities
are not included in these resource projections.

141

FISCAL SUMMARY AND PROJECTIONS

The resource projections discussed in this section are based on scientific and
professional judgement as to the resources required to accomplish program objec-
tives within the time frame indicated. However, it is recognized that the allo-
cation of national resources to execute the program must be determined in rela-
tionship to other competing national needs at any given time.

Acting upon the results of its program review and evaluation, the Institute has
revised and updated the fiscal projections presented in the initial National
Heart, Blood Vessel, Lung, and Blood Program (Volume I) in May 1973. The major
reasons for these revisions are:

• Program monitoring and evaluation of research programs has
resulted in identification of both expanded and reduced
opportunities and needs in some program action areas. (See
section on Research in Chapter III.)

• As indicated in Chapter II recent research findings have
opened potentially new vistas which require exploration of
new initiatives.

• Research and prevention, control, and education pilot program
results have suggested or proven the need for and capability
of expanding our prevention, control, and education programs.
(See section on Prevention, Control, and Education in Chapter
III.)

• Recently completed studies have provided us with a clearer
insight into both manpower and facilities requirements.
(See Chapters V and VI.)

The projected resource estimates for FY 76 to FY 80 are shown in Table 4. This
projection is provided so that the planning process will stay in phase with the
overall departmental planning and budgeting cycle. The table, organized accord-
ing to the program activity categories discussed earlier in this report, provides
fiscal projections for:

• Extramural research programs in heart and blood vessel diseases,
in lung diseases, and in blood diseases and blood resources.
Research allocations are also shown for each subprogram within
these major disease categories.

• Continued implementation of special NHLI programs authorized
by Public Law 92-423: the National Research and Demonstration
Centers; Prevention, Control, and Education Programs; and
construction of facilities.

142

Table 4. Projected Resource Allocations* for the National Heart, Blood Vessel, Lung, and Blood Program

FY 76 -FY 80
(Dollars in Millions)

Fiscal Years

Program Activities

1976

1977

1978

1979

1980

Extramural Research Programs

Heart and Blood Vessel Diseases

Arteriosclerosis

$ 57.20

$ 58.40

$ 60.40

$ 62.40

$ 60.10

Hypertension

31.20

32.20

33.30

33.80

32.30

Cerebrovascular Disease

3.80

3.90

4.00

4.10

Coronary Heart Disease

42.50

43.50

46.10

47.30

44.80

Peripheral Vascular Diseases

4.10

4.20

4.30

4.40

Arrhythmias

16.50

17.20

19.00

19.20

18.20

Heart Failure and Shock

20.60

21.30

23.60

24.90

23.70

Congenital and Rheumatic Heart Diseases

9.60

9.90

10.40

10.60

Cardiomyopathy and Infections of the Heart

3.80

3.90

5.20

6.50

7.00

Circulatory Assistance

19.90

20.90

23.90

30.90

34.80

Subtotal Heart and Blood Vessel Diseases

209.20

215.40

230.20

244.10

240.00

Lung Diseases

Structure and Function of the Lung

7.70

8.00

8.60

9.20

8.80

Pediatric Pulmonary Diseases

10.30

10.80

11.20

12.00

11.50

Emphysema and Chronic Bronchitis

8.40

8.90

9.80

10.30

10.60

Fibrotic and Immunologic Lung Diseases

8.50

9.00

9.10

10.50

10.90

Respiratory Failure

7.10

7.20

7.60

8.00

Pulmonary Vascular Diseases

2.20

2.30

2.50

2.30

2.00

Inhalation Diseases

2.20

2.60

3.00

2.50

2.00

Respiratory Assistance

.80

1.00

1.20

Subtotal Lung Diseases

47.20

49.80

53.00

56.00

55.00

Blood Diseases and Blood Resources

Bleeding and Clotting Disorders

19.54

20.08

19.98

19.73

18.03

Sickle Cell Disease and Related Disorders of

the Red Blood Cell

18.05

18.77

19.44

20.32

19.32

Blood Resources

14.81

14.95

17.18

19.65

18.65

Biomaterials

3.10

4.00

4.20

4.00

Subtotal Blood Diseases and Blood Resources

55.50

57.80

60.80

63.90

60.00

National Research and Demonstration Centers

25.25

48.50

55.20

56.70

58.70

Prevention, Control, and Education Programs

31.80

38.30

39.00

37.50

38.30

Construction

60.00

30.00

—

Manpower

20.80

21.90

22.70

Intramural Research Programs

25.00

26.00

27.00

Research Management and Program Services

21.66

25.16

23.67

24.69

24.43

TOTAL

$496.41

$511.76

$539.77

$531.59

$526.13

'This tabulation gives the primary thrust of activities, e\

en though

these act

vities gens

;rally

involve more than one subprogram.

143

• NHLI ' s Intramural Research Programs, Manpower Development
Programs, and Research Management and Program Services.

The resource allocations presented in Table 4 are consistent with the program
activities projected and discussed in Chapters III, IV, V, and VI of this report.
These allocations have been distributed in such a way as to build on past accom-
plishments and to anticipate future opportunities in specific program areas.
In accordance with the legislation, at least 15 percent of the fiscal resources
are projected for diseases of the lung and at least 15 percent toward the prob-
lems of blood diseases and resources.

It is important to point out that the projected resource allocations give the
primary thrust of activities , even though these activities generally involve
more than one subprogram, with some activities fundamental to many subprograms.
Since subprograms cannot be made mutually exclusive, the allocation of a given
project may be somewhat arbitrary. For example, a project involving the effects
of arrhythmias in coronary heart disease upon heart failure would be categorized
according to its primary thrust. A project on the movement of ions across cell
membranes, which is fundamental to the causation and prevention of arrhythmias
and heart failure and is applicable to all forms of heart disease and even to
symptoms of cerebrovascular disease, would be allocated to multiple categories.

The fiscal requirements for the National Program total approximately $496 mil-
lion in FY 76, an increase of $91 million over the previously recommended budget
for FY 76. These requirements will increase incrementally to $540 million in
FY 78; in FY 79, construction funds will not be required and the budget will
decline to $532 million, followed by a subsequent reduction to $526 million in
FY 80. The rationale for increased resource projections for certain programs
in the 5-Year Plan was delineated in earlier sections of this report; however,
we summarize in the following paragraphs the proposed program actions which
require overall budget increases in the revised estimates projected here for
FY 76 through FY 80. Figure 2 gives a comparison of the projected resource
allocations for the Program in the 1973 and 1974 NHLI plans. It should be
emphasized that resource projections have not been adjusted upward for infla-
tionary increases since the 1973 plan was prepared. Similarly, the projections
for fiscal years 1976 through 1980 are based on 1973 estimates of the costs of
accomplishing program objectives.

There has been no change in the total projected estimates for the Extramural
Research Programs in Heart and Blood Vessel Diseases, Lung Diseases, and Blood
Diseases and Blood Resources. However, there have been internal readjustments
of resources among subprograms in each of these program areas, reflecting revised
priorities, new opportunities for action, and redistribution of resources to new
programs. The total estimates for the NHLI ' s Intramural Research Program remain
the same. Increased budget estimates have been projected over the next five
years for the following extramural programs: Arteriosclerosis, Hypertension,
Cerebrovascular Disease, Arrhythmias, Circulatory Assistance, Structure and Func-
tion of the Lung, and Pediatric Pulmonary Diseases.

144

Authorization

FY 73 =

$400 M

FY 74 =

$460 M

FY 75 =

$520 M

National Heart & Lung
632_ Advisory Council Report
--^* December 1973

National Heart &
Lung Advisory
Council Report
April 1973

Updated NHLI
5- Year Plan,
1974"

Initial NHLI 5 Year
Plan, 1973*

650

600

550

a 500

z 450

g 400

350

300

76 77

FISCAL YEAR

"Does not include Research Management and Program Services, estimated at 4.87% of total estimated program costs.
"Includes Research Management and Program Services.

Figure 2. Comparison of Projected Resource Allocations for the
National Heart, Blood Vessel, Lung, and Blood Program (FY 73 Through FY 80)

Although the fiscal projections for the remaining extramural subprograms
represent decreases or no change since last year's projections, most of these
programs will increase through FY 79, and decline in FY 80, in accordance with
projected activities. Circulatory Assistance and Biomaterials , which were
included under other subprograms in last year's Plan, have been given separate
status in the revised Plan. The addition of three new program areas in lung
diseases is balanced by a reduction in other areas of lung diseases. Two of
these new areas are projected to increase slightly through FY 78 and decline
thereafter through FY 80; the third, Respiratory Assistance, will grow gradually
between FY 76 and FY 80. No major revisions have been made in the projected
resource allocations for blood diseases and blood resources in FY 76, and grad-
ual increments are currently projected in these areas between FY 76 and FY 79,
closely following the projections in the initial Plan. The Intramural Research
Program is, similarly, projected to gradually increase between FY 76 and FY 80
at the levels projected last year.

Five of the program activity areas listed in Table 4 account for the entire
increase in the total revised resource allocation recommended for FY 76, as
well as for the total budget increases projected from FY 76 through FY 80.
These areas are: National Research and Demonstration Centers; Prevention,
Control, and Education Programs; Construction; Manpower; and Research Manage-
ment and Program Services. Among these five expanding areas, it is currently
projected that construction funds will be required in fiscal years 1976, 1977,
and 1978. Research Management and Program Services, which were not included
in the May 1, 1973, estimates, account for about $22 million of the $91 million
increase in the FY 76 projected estimates.

145

Within the overall fiscal limitations identified above, the major increases that
have been projected in the revised fiscal allocations are required in order to
support heightened program activity in each area. Key aspects of these activities
are summarized as follows:

Arteriosclerosis. Research has provided significant new knowledge
about the causes and development of arteriosclerosis. Current
research supports the feasibility of early diagnosis (including
at birth) ; expanded programs are required to evaluate these
research opportunities. The relationship of genetic factors to
the development of arteriosclerosis is strongly suggested;
increased human and animal studies are needed to determine the
exact role of these factors. Special multiple intervention
clinic programs for populations at high risk will be initiated.
A US-USSR cooperative risk factor study will be implemented.
(For further discussion, see Arteriosclerosis under Research in
Chapter III.)

Hypertension. Building on research advances in the genesis of
hypertension, a pilot clinical trial for therapy of mild hyper-
tension is proposed. Emphasis will also be expanded on new drug
formulations to control hypertension. Hypertension detection
and follow-up programs will be continued to determine the effec-
tiveness of therapy. (See Hypertension under Research in
Chapter III.)

Cerebrovascular Disease. Animal studies will be initiated to deter-
mine the contribution of chronic arteriosclerosis and hyper-
tension to stroke from brain hemorrhage. Other programs will
be continued. (See Cerebrovascular Disease under Research in
Chapter III.)

Arrhythmias. Fundamental research programs will be expanded to
increase our understanding of arrhythmias in order to pre-
vent those which cause sudden cardiac death. Expanded activ-
ities will focus particularly on the electrophysiology and
therapy of rhythm disturbances, on clinical studies to iden-
tify chronic or intermittent disturbances, and on the devel-
opment of techniques for analyzing electrocardiographic
rhythm signals. (See Arrhythmias under Research in Chapter
III.)

Circulatory Assistance. The majority of activities in this program
area are continuations formerly classified in other program
areas, primarily heart failure and shock. Expanded efforts
will include development of heart assist and replacement
devices. (See Circulatory Assistance under Research in Chap-
ter III.)

146

Structure and Function of the Lung. Recent research advances at the cell-
ular level hold great promise for understanding the mechanisms
involved in the development of lung diseases. Individual and
collaborative research efforts will be expanded in order to
build on these advances. (See Structure and Function of the
Lung under Research in Chapter III.)

Pediatric Pulmonary Diseases. Recent important breakthroughs have
occurred which make possible effective detection and therapy
of hyaline membrane disease. Plans are being developed for
improved management of hyaline membrane disease through pro-
grams for rapid transfer of infants with this disease to
intensive care units. Programs will be initiated for improved
treatment of cystic fibrosis and long-term follow-up of chil-
dren with bronchiolitis. (See Pediatric Pulmonary Diseases
under Research in Chapter III.)

National Research and Demonstration Centers. The Centers will provide an
important mechanism by which the Institute can assure that
the advances gained through research are translated to improved
health care in the community. (See Chapter VI.)

• Prevention, Control, and Education Programs. Major program emphases discussed
in Chapter III which will necessitate increased support are as
follows:

Hypertension information and education programs

Community hypertension control demonstration projects

Increased nutrition and other risk factor detection and
prevention efforts related to arteriosclerosis

- Collaborative emergency care and rehabilitation programs
related to coronary heart disease

Early recognition and treatment demonstration programs
for cardiac and respiratory diseases of the newborn

Professional and public educational programs concerning
avoidance of noxious dust, vapors, or gases

Collaborative education programs related to smokers

Education programs for sickle cell disease and Cooley's
anemia

Screening and education clinics for sickle cell disease

147

Education programs in hemophilia

Hepatitis epidemiology and control programs

Evaluation of technical, social, ethical, and legal prob-
lems associated with organ transplantation

Professional education regarding optimal use of blood
resources .

Construction. Construction of appropriate and adequate facilities
will be important to the planned increases in program activity.
The projected establishment of National Research and Demonstra-
tion Centers in FY 75 particularly requires that additional
funds be available. (See Chapter VI.)

Manpower. Funds for the development and maintenance of highly
skilled manpower are necessary in order to ensure that well-
trained scientists, physicians, and allied health professionals
will be available to assume the increased responsibilities
inherent in the implementation of a National Program. (See
Chapter V.)

NHU STAFF ALLOCATION PLAN

The Act also requires that the Plan for the National Program include a statement
regarding the NHLI staffing needs for implementing the Program. The Institute
Summary of May 1973 included such a statement, noting that there were 626 autho-
rized positions for the NHLI at that time and projecting a need for 764 positions
in FY 74. As of February 13, 1974, the authorized ceiling for the NHLI is 664
positions. By judicious use of manpower resources, the Institute has been able
to initiate activity in several areas in response to the provisions of the Act.
Examples, discussed in more detail in other chapters of this report, are cited
briefly below:

• Appointment of an Executive Secretary for the National Heart
and Lung Advisory Council

• Provision of staff assistance to the Council in its expanded
role, particularly in the areas of program planning and prep-
aration of the Annual Report of the Council

•

Updating of the National Program Plan and development of this
Annual Report of the NHLI

Organization of the Interagency Technical Committee and staff
to provide support for its coordinating role

148

• Establishment of an Office of Prevention, Control, and Educa-
tion and planning for prevention, control, and education
programs in several areas

• Development and distribution of a Program Announcement and
Guidelines for National Research and Demonstration Centers,
with first competition for awards underway.

To initiate these programs, the Institute has conserved manpower in a number of
ways. One was to abolish the Division of Technological Applications and divide
its activities among the three categorical scientific divisions. Another way
was to centralize the review function for programs supported by the contract
mechanism. A third way was to consolidate some of the intramural activities.

In addition to the above efforts the scientific divisions of the NHLI have for-
mulated plans and begun implementing the Action items in the National Program:

• The Division of Heart and Vascular Diseases will establish
Specialized Centers of Research (SCOR) in Ischemic Heart Dis-
ease; bring up to full strength the ongoing clinical trials
in the areas of risk factor modification, lipid metabolism,

and hypertension; expand work on cardiovascular devices, includ-
ing circulatory assist pumps and noninvasive means for diagnos-
ing heart and blood vessel diseases; and stimulate increased
activity in fundamental and clinical research.

• The Division of Lung Diseases will expand programs that apply
the fundamental scientific disciplines to research on the nor-
mal and diseased lung; initiate and expand epidemiological
studies; initiate education and control programs; and expand
efforts related to development of life-saving respiratory assist
devices. The pace of research in lung diseases, long lagging,
is only now entering a phase of rapid acceleration.

• The Division of Blood Diseases and Resources will expand
the hemophilia program; take advantage of recently acquired
knowledge regarding hepatitis and expand the hepatitis
program; stimulate basic and clinical research in bleeding
and clotting disorders; and play a major role in the develop-
ment of the Nationwide Blood Program.

• The Division of Intramural Research will expand laboratories
devoted to lung diseases (only recently established) , the
molecular basis for sickle cell disease and Cooley's anemia,
and the molecular basis for certain lipid abnormalities.

• The Division of Extramural Affairs, responsible for initial
review of proposals in many of the above areas, of necessity
will have to expand as the demand for its services increases.

149

To operate the National Program effectively, the NHLI will need additional
staff — at the middle and upper professional levels as well as in support posi-
tions. Programs such as disease prevention, control, and education, and com-
prehensive centers are new to the Institute. Their review and administration
will require staff with knowledge and skills new to the Institute.

Over the years, authorized ceilings for staff for the NHLI have not kept pace
with appropriations. In the five years preceding the enactment of Public Law
92-423, the appropriation increased by 38 percent: from $168 million in FY 68
to $232.6 million in FY 72. In the same period, the number of authorized posi-
tions increased by only 2.9 percent from 609 to 626. Since the passage of the
Act, the obligational authority for the Institute has increased by about 23 per-
cent. If one includes the release of approximately $43 million in impounded FY
73 funds during FY 74, the increase in authority is about 41 percent. During
the same period of time, there has been a modest increase in the number of autho-
rized positions to 664. However, during this period there has been an increased
emphasis on clinical trials, other collaborative programs, and specialized pro-
grams such as Specialized Centers of Research, all of which require a high ratio
of manpower to dollar expenditure for effective management and coordination.

The NHLI Summary of May 1973 projected staff needs of 764 in FY 74, up from a
base of 626 positions in FY 73, and a further increase to approximately 810
positions in FY 76. Our current position ceiling is 664 for FY 74 and the same
number for FY 75. These position allocations are substantially below our esti-
mates of staffing needs for the program outlined in this report, even in view
of the above-mentioned efforts to conserve manpower.

150

APPENDIX A
NATIONAL HEART, BLOOD VESSEL, LUNG, AND BLOOD ACT OF 1972

Public Law 92-423

92nd Congress, S. 3323

September 19, 1972

9n2ct

To amend the Public Health Service Act to enlarge the authority of the .National
Heart and Lung Institute In order to advance the national attack against
diseases .if the heart and Wood vessels, the lungs, ami Miaul, and for other
purposes.

He it enacted by the. Senate and Howe, of ffepiimnitiitim of Hie
I 'lilted State* of A me lira in Congre** mmemb/eil. National Heart,

Blood Vessel,

SHORT TITLE LU "«' ^J? .f^

Act of 1972.

Section 1. This Act may be cited as the "National Heart. Wood
Vessel, Lung, and Blood Act of 1972".

FINDINGS AND DECLARATION OF I'l RIN1KK

Sec. 2. (a) Congress finds and declares that —

(1) diseases of the heart and blood vessels collectively cause
more than half of all the deaths each year in the United States
and the combined effect of the disabilities and deaths from such
diseases is having a major social and economic impart on the
Nation;

(2) elimination of heart and blood vessel diseases as significant
causes of disability and death could increase the average Ameri-
can's life expectancy by about eleven years and could provide for
annual savings to the economy in lost wages, productivity, and
costs of medical care of more than $30,000,000,000 per year ;

(3) chronic lung diseases have been gaining steadily in recent
years as important causes of disability and death, with emphysema
alone being the fastest rising cause of death in the United States;

(4) chronic respiratory diseases affect an estimated ten million
Americans, emphysema an estimated one million, chronic bron-
chitis an estimated four million, and asthma an estimated five
million ;

(5) thrombosis (the formation of blood clots in the vessels)
may cause, directly or in combination with other problems, many
deaths and disabilities from heart disease and stroke which can
now be prevented; . B6 g"Tj 679

,_. . , r . .—i— i « i ■ ■ ■ — : — ; — ? ofi <;t*t can

(6) blood and blood products are essential human resources 66 b ™ T - t>B0
whose value in saving life and promoting health cannot be

assessed in terms of dollars ;

(7) the provision of prompt and effective emergency medical
services utilizing to the fullest extent possible advances in trans-
portation and communications and other electronic systems and
specially trained professional and paraprofessional health care
personnel can reduce substantially the number of fatalities and
severe disabilities due to critical illnesses in connection with heart,
blood vessel, lung, and blood diseases; and

(8) the greatest potential for advancement against heart, blood
vessel, lung, and blood diseases lies in the National Heart and
Lung Institute, but advancement against such diseases depends
not only on the research programs of that Institute but also on
the research programs of other research institutes of the National
Institutes of Health.

|b) It is the purpose of this Act to enlarge the authority of the
National Heart and Lung Institute in order to advance the. national
attack upon heart, blood vessel, lung, nnd blood diseases.

63-749 O (260)

A-l

Pub. Law 92-423 - 2 - September 19, 1972

HEART, BLOOD VESSEL, I.UNU, AND BLOOD DISEASE PROI1RAMB

62 stnt. 464. Sec. 8. Part B of title IV of the Public Health Service Act is

42 use 267- amended (1) by redesignating section 413 as section 419A. (2) by

287o « redesignating section 414 as section 418, and (3) by adding after sec-

tion 412 the following new sections:

"NATIONAL HEART, BLOOD VESSEL, L0NO, AND BLOOD DISEASE PROGRAM

"Sec. 413. (a) The Director of the Institute, with the advice of the

Council, shall develop a plan for a National Heart, Blood Vessel,

Lung, and Blood Disease Program (hereafter in this part referred

to as the 'Program') to expand, intensify, and coordinate the activities

of the Institute respecting heart, blood vessel, lung, and blood diseases

(including its activities under section 412) and shall carry out the

nih, coordln- Program in accordance with such plan. The Program shall be coordi-

ation pro- nated with the other research institutes of the National Institutes of

visions. Health to the extent that they have responsibilities respecting such

diseases and shall provide for —

"(1) investigation into the epidemiology, etiology, and preven-
tion of all forms and aspects of heart, blood vessel, lung, and blood
diseases, including investigations into the social, environmental,
behavioral, nutritional, biological, and genetic determinants and
influences involved in the epidemiology, etiology, and prevention
of such diseases;

"(2) studies and research into the basic biological processes and
mechanisms involved in the underlying normal and abnormal
heart, blood vessel, lung, and blood phenomena ;

"(3) research into the development, trial, and evaluation of
techniques, drugs, and devices (including computers) used in,
and approaches to, the diagnosis, treatment (including emergency
medical service), and prevention of heart, blood vessel, lung, and
blood diseases and the rehabilitation of patients suffering from

86 stat. 660 such d iseases ;

86 stat. 681 "(4) establishment of programs that will focus and apply sci-

entific and technological efforts involving biological, physical, and
engineering sciences to all facets of heart, blood vessel, lung, and
blood diseases with emphasis on refinement, development, and
evaluation of technological devices that will assist, replace, or
monitor vital organs and improve instrumentation for detection,
diagnosis, and treatment of those diseases ;

"(5) establishment of programs for the conduct and direction
of field studies, large-scale testing and evaluation, and demon-
stration of preventive, diagnostic, therapeutic, and rehabilitative
approaches to, and emergency medical services for, such diseases ;
"(6) studies and research into blood diseases and blood, and
into the use of blood for clinical purposes and all aspects of the
management of its resources in this country, including the collec-
tion, preservation, f ractionalization, and distribution of it and its
products ;

"(7) the education and training of scientists, clinicians, and
educators, in fields and specialties (including computer sciences)
requisite to the conduct of programs respecting heart, blood ves-
sel, lung, and blood diseases ;

"(8) public and professional education relating to all aspects
of such diseases and the use of blood and blood products and the
management of blood resources :

"(9) establishment of programs for study and research into
heart, blood vessel, lung, and blood diseases of children (including
cystic fibrosis, hyaline membrane, and hemolytic ami hemophilic

A- 2

September 19, 1972 - 3 - Pub. Law 92-423

diseases) and for the development and demonstration of diagnos-
tic, treatment, and preventive approaches to these diseases; and
"(10) establishment of programs for study, research, develop-
ment, demonstrations and evaluation of emergency medical serv-
ices for people who become critically ill in connection with heart,
blood vessel, lung, or blood diseases, which programs shell
include programs for (A) the training of paraprofessionals in
( i) emergency treatment procedures, and ( ii ) utilization and oper-
ation of emergency medical equipment, (B) the development and
operation of (i) mobile critical care units (including helicopters
and other airborne units where appropriate), (ii) radio, tele-
communications, and other means of communications, and (iii)
electronic monitoring systems, and (C) the coordination with
other community services and agencies in the joint use of all forms
of emergency vehicles, communications systems, and other appro-
priate services.
The Program shall give special emphasis to the continued develop- National insti-
ment in the Institute of programs relating to atherosclerosis, hyper- tute of Neuroiog-
tension, thrombosis, and congenital abnormalities of the blood vessels lcal Diseases
as causes of stroke, and to effective coordination of such programs "") stroke, co-
with related stroke programs in the National Institute of Neurological
Diseases and Stroke.

"(b) (1) The plan required by subsection (a) of this section shall Plan development;
(A) be developed within one hundred and eighty days after the effec- transmittal to
tive date of this section, (B) be transmitted to the Congress, and (C) c°n8™ss.
set out the Institute's staff requirements to carry out the Program and 86 stat. 681
recommendations for appropriations for the Progr am. > ^86 stat. 682

"(2) The Director or the Institute shall, as soon as practicable after Report to Pres-
the end of each calendar year, prepare in consultation with the Coun- ident, trans-
cil and submit to the President for transmittal to the Congress a nittal to Con-
report on the activities, progress, and accomplishments under the e resa -
Program during the preceding calendar year and a plan for the Pro-
gram during the next five years.

"(c) In carrying out the Program, the Director of the Institute, Director, funo-
under policies established by the Director of the National Institutes tions.
of Health and after consultation with the Council and without regard
to any other provision of this Act, may —

"(1) if authorized by the Council, obtain (in accordance with
section 3109 of title 5, United States Code, but without regard to so stat. 416.
the limitation in such section on the number of days or the period
of such service) the services of not more than fifty experts or con-
sultants who have scientific or professional qualifications ;

"(2) acquire, construct, improve, repair, operate, and maintain
heart, blood vessel, lung, and blood disease laboratory, research,
training, and other necessary facilities and equipment, and related
accommodations as may be necessary, and such other real or per-
sonal property (including patents) as the Director deems neces-
sary; and acquire, without regard to the Act of March 3, 1877
(40 U.S.C. 34), by lease or otherwise, through the Administrator 19 stat. 370.
of General Services, buildings or parts of buildings in the District
of Columbia or communities located adjacent to the District of
Columbia for the use of the Institute for a period not to exceed
ten years; and

"(3) enter into Buch contracts, leases, cooperative agreements,
or other transactions, without regard to sections 3648 and 3709 of
the Revised Statutes of the United States ( 31 U.S.C. 529, 41 U.S.C.
5), as may be necessary in the conduct of his functions, with any
public agency, or with any person, firm, association, corporation,
or educational institution.

A-3

Pub. Law 92-423

- 4

September 19, 1972

Assistant Dtrec
tor for Health
Information Pro-
grams.

Cardiovascular
and pulmonary
diseases, in-
formation.

B6 STAT. 6B2
86 STAT. 663

Appropriations .

"(d) There shall be in the Institute an Assistant 1 h' rector for Health
Information Programs who shal! be appointed by the Director of the
Institute. The Director of the Institute, acting through the Assistant
Director for Health Information Programs, shall conduct a program
to provide the public and the health professions with health informa-
tion with regard to cardiovascular and pulmonary diseases. In the
conduct of such program, special emphasis shall be placed upon dis-
semination of information regarding diet, exercise, stress, hyperten-
sion, cigarette smoking, weight control, and other factors affecting the
prevention of arteriosclerosis and other cardiovascular diseases ami of
pulmonary diseases.

"heart, blood vessel, lung, and blood disease prevention and
control programs

"'Sec. 414. (a) The Director of the Institute, under policies estab-
lished by the Director of the National Institutes of Health and after
consultation with the Council, shall establish programs as necessary
for cooperation with other Federal Health agencies, State, local, and
regional public health agencies, and nonprofit private health agencies
in the diagnosis, prevention, and treatment (including the provision
of emergency medical services) of heart, blood vessel, lung, and blood
Tiseases, appropriately emphasizing the prevention, diagnosis, and
treatment of such diseases of children.

''(b) There is authorized to be appropriated to carry out this
section $25,000,000 for the fiscal year ending June 30, 1973, $35,000,000
for the fiscal year ending June 30, 1974, and $45,000,000 for the fiscal
ypar ending June 30. 1975.

"NATIONAL RESEARCH AND DEMONSTRATION CENTERS FOR HEART, BI.OOD
VESSEL, LUNG, AND BLOOD DISEASES

"Sec. 415. (a) (1) The Director of the Institute may provide for the
development of —

"(A) fifteen new centers for basic and clinical research into,
training in, and demonstration of, advanced diagnostic, preven-
tion, and treatment methods (including methods of providing
emergency medical services) for heart, blood vessel, and blood

Q1SG&SCS " &rid

"(B) fifteen new centers for basic and clinical research into,
training in, and demonstration of, advanced diagnostic, preven-
tion, and treatment methods (including methods of providing
emergency medical services) for chronic lung diseases (including
bronchitis, emphysema, asthma, cystic fibrosis, and other lung
diseases of children). .,,>,., in-

"(2) The centers developed under paragraph (1)(A) shall, in
addition to being utilized for research, training, and demonstrations,
I* utilized for the following prevention programs for cardiovascular

(iidcftscs *

"(A) Programs to develop improved methods of detecting
individuals with a high risk of developing cardiovascular disease.

"(B) Programs to develop improved methods of intervention
against those factors which cause individuals to have a high risk
of developing such disease.

"(C) Programs to develop health professions and allied health
professions personnel highly skilled in the prevention of such

"(D) Programs to develop improved methods of providing
emergency medical services for persons with such disease.

A-4

September 19, 1972 - 5 - Pub. Law 92-423

"(3) Centers developed under this subsection may be supported
under subsection (b) or under any other applicable provision of law.
The research, training, and demonstration activities carried out
through any such center may relate to any one or more of the diseases
referred to in paragraph ( 1 ) of this subsection.

"(b) The Director of the Institute, under policies established by the Public or non-
Director of the National Institutes of Health and after consultation profit agencies,
with the Council, may enter into cooperative agreements with public or cooperative
nonprofit private agencies or institutions to pay all or part of the cost a « re ™ en ' ts -
of planning, establishing, or strengthening, and providing basic oper-
ating support for, existing or new centers (including centers estab-
lished under subsection (a) ) for basic or clinical research into, training
in. and demonstration of, advanced diagnostic, prevention, and treat-
ment methods for heart, blood vessel, lung, or blood diseases. Funds Use of funds.
paid to centers under cooperative agreements under this subsection
may be used for —

"(1) construction, notwithstanding section 405, 58 stat. 708.

"(2) staffing and other basic operating costs, including such 42 usc 265 -

patient care costs as are required for resear ch, 86 stat. 683

"(3) training, including training for allied health professions B6 STAT - 684
personnel, and
"(4) demonstration purposes.
The aggregate of payments (other than payments for construction) Limitations.
made to any center under such an agreement may not exceed $5,000,000
in any year. Support of a center under this subsection may be for a
period of not to exceed five years and may be extended bv the Director
of the Institute for additional periods of not more than five years each,
after review of the operations of such center by an appropriate scien-
tific review group established by the Director. As used in this section, "Construction."
the term 'construction' does not include the acquisition of land.

"interagency technical committee

"Sec. 416. (a) The Secretary shall establish an Interagency Tech- Establishment,
nical Committee on Heart, Blood Vessel, Lung and Blood Diseases
and Blood Resources which shall be responsible for coordinating those
aspects of all Federal health programs and activities relating to heart,
blood vessel, lung, and blood diseases and to blood resources to assure
the adequacy ana technical soundness of such programs and activities
and to provide for the full communication and exchange of informa-
tion necessary to maintain adequate coordination of such programs and
activities.

"(b) The Director of the Institute shall serve as Chairman of the
Committee and the Committee shall include representation from all
Federal departments and agencies whose programs involve health
functions or responsibilities as determined by the Secretary.

"national heart and lino advisory council

"Sec. 417. (a) There is established in the Institute a National Heart Establishment;
and Lung Advisory Council to be composed of twenty-three members membership,
as follows :

"(1) The Secretary, the Director of the National Institutes of

Health, the Director of the Office of Science and Technology, and

the chief medical officer of the Veterans' Administration (or their

designees), and a medical officer designated by the Secretary of

Defense, shall be ex officio members of the Council.

"(2) Eighteen members appointed by the Secretary.

Eleven of the appointed members shall be selected from among the

leading medical or scientific authorities who are skilled in the sciences

A- 5

Pub. Law 92-423

- 6

September 19, 1972

Terms.

66 STAT. 684

relating to diseases of the heart, blood vessels, lungs, and blood; two
of the appointed members shall be selected from persons enrolled in
residency programs providing training in heart, blood vessel, lung, or
blood diseases; and five of the appointed members shall be selected
from members of the genera] public who are leaders in the fields of
fundamental or medical sciences or in public affairs.

"(b) (1) Each appointed member of the Council shall be appointed
for a term of four years, except that —

"(A) any member appointed to fill a vacancy occurring prior
to the expiration of the term for which his predecessor was

86 STAT. 685

National Ad-
visory Heart
Council, re-
placement pro-
visions.
64 Stat. 446.
42 USC 218.

5 USC 5332
note.

80 Stat. 499 j
83 Stat. 190.

Executive Sec-
retary.

appointed shall be appointed for the remainder of such term ; and

(B) of the members first appointed after the effective date of

this section, five shall be appointed for a term of four years, five

shall be appointed for a term of three years, five shall be appointed

for a term of two years, and three shall be appointed for a term

of one year, as designated by the Secretary at the time of

appointment.

Appointed members may serve after the expiration of their terms until

their successors have taken office.

"(2) A vacancy in the Council shall not affect its activities, and
twelve members of the Council shall constitute a quorum.

"(3) The Council shall supersede the existing National Advisory
Heart Council appointed under section 217, and the appointed mem-
bers of the National Advisory Heart Council serving on the effective
date of this section shall serve as additional members of the National
Heart and Lung Advisory Council for the duration of their terms
then existing, or for such shorter time as the Secretary may prescribe.

" (4) Members of the Council who are not officers or employees of
the United States shall receive for each day they are engaged in the
performance of the functions of the Council compensation at rates
not to exceed the daily equivalent of the annual rate in effect for grade
GS-18 of the General Schedule, including traveltime ; and all mem-
bers, while so serving away from their homes or regular places of
business, may be allowed travel expenses, including per diem in lieu
of subsistence, in the same manner as such expenses are authorized by
section 5703 of title 5, United States Code, for persons in the Govern-
ment service employed intermittently.

"(c) The Secretary (or his designee) shall be the Chairman of the
Council.

"(d) The Director of the Institute shall (1) designate a member of
the staff of the Institute to act as Executive Secretary of the Council,
and (2) make available to the Council such staff, information, and
other assistance as it may require to carry out its functions.

" (e) The Council shall meet at the call of the Chairman, but not less
often than four times a year."

Ante, p. 680.

AUTHORIZATION OF APPROPRIATIONS FOR PART B Or TITLE IV OF THE PUBLIC
IIF-ALTIt 8ERVICF. ACT

Sec. 4. Part B of title IV of the Public Health Service Act is
amended by adding at the end thereof the following new section :

AUTHORIZATION OF APPROPRIATIONS

"Sec. 419B. For the purpose of carrying out this part (other than
Ante , p. 682. section 414), there is authorized to be appropriated $375,000,000 for
the fiscal year ending June 30, 1973, $425,000,000 for the fiscal year
ending June 30, 1974, and $475,000,000 for the fiscal year ending
June 30, 1975. Of the sums appropriated under this section for any
fiscal year, not less than 15 per centum of such sums shall be reserved

A-6

September 19. 1972 - 7 - Pub. Law 92-423 g6 „„_ M6

for programs under this part respecting diseases of the lung and not
less than 15 per centum of such sums shall lie reserved for programs
under this part for programs respecting diseases of the blood."

At TIIOR1TY OF THE DIRECTOR OF THE NATIONAL HEART AND l.l'XU
INST1TI TE TO APPROVE GRANTS

Sec. .">. Section 41!)A of the Public Health Service Act (as so
redesignated hy section 3 of this Act ) is amended —

(1) by striking out "grants-in-aid" in subsection (a) anil
inserting in lieu thereof "except as provided in subsection (<•),
grants-in-aid": and

(2) by adding after subsection (b) the following new
subsection :

"(c) Older procedures approved by the Director of the National
Institutes of Health, the Director of the. National Heart and Lung
Institute may approve grants under this Act for research and training
ill heart, blood vessel, lung, and blood diseases —

"(1 ) in amounts not to exceed $35,000 after appropriate review Limitations.
for scientific merit but without review and recommendation by
the Council, and

"(2) in amounts exceeding $35,000 after appropriate review
for scientific meril and recommendation for approval bv the
Council/'

CONFORMING AMENDMENTS TO PART 11 OF TITLE IV OF THE Pl'BI.K' HEALTH
SERVICE ACT

Sec. *>. (a) Section 411 of the Public Health Service Act is amended 62 Stat. 465.
by striking out "National Heart Institute" anil inserting in lieu 4 j usc 2ii.
thereof "National Heart and Lung Institute".

(b) Section 412 of such Act is amended — *2 usc 287a.

(1) by striking out "heart" each place it occurs (except in the
heading) and inserting in lieu thereof "heart, blood vessel, lung,
and blood";

(2) by striking out "Surgeon General" and inserting in lieu
thereof "'Secretary" :

(3) by striking out "National Advisory Heart Council" and
inserting in lieu thereof "National Heart and Lung Advisory
Council";

(4) by redesignating paragraphs (a), (b), (c), (d), (e), (f),
and (g) as paragraphs (1). (2), (3), (4). (5), (6), and (7),
respectively : and

(5) by amending the section heading to read as follows:

•'RESEARCH AND TRAINING IN DISEASES OF THE HEART, BLOOD VESSELS,
LFXG. AND BLOOD"

(1) by inserting "(a)" immediately after "Sec 418." and by-
adding at the end thereof the following new subsection :

"(b)(1) The Council shall advise and assist the Director of the
Institute with respect to the Program established under section 413. Ante, p. 680.
The Council may hold such hearings, take such testimony, and sit and
art at such times and places, as the Council deems advisable to inves-
tigate programs and activities of the Program.

"(2) The Council shall submit a report to the President for trans- Report to Pres-
mittal to the Congress not later than January 31 of each year on the ident, trans-
progress of the Program toward the accoinplishment of its objectives." ™l ttal to c ° n -

A-7

Pub. Law 92-423 - 8 - September 19, 1972

86 STAT. 687

(2) by striking out "Surgeon General" each place it occurs
(except paragraph (f ) ) and inserting in lieu thereof "Secretary";

(3) by striking out "heart" each place it occurs and inserting
in lieu thereof "heart, blood vessel, lung, and blood";

(4) by striking out "Surgeon General" in paragraph (f ) and
inserting in lieu thereof "Secretary, the Director of the National
Institutes of Health, and the Director of the. National Heart and
Lung Institute" ; and

(5) by redesignating paragraphs (a), (b), (c), (d), (e), and
(f) as paragraphs (1), (2), (3), (4), (5), and (6), respectively.

(d) Section 419A of such Act (as so redesignated by section 3 of
this Act) is amended —

(1) in subsection (a), by (A) striking out "Surgeon General"
and inserting in lieu thereof "Secretary", and (B) striking out
"heart" and inserting in lieu thereof "heart, blood vessel, lung,
and blood" ; and

(2) in subsection (b), by (A) striking out "The Surgeon Gen-
eral shall recommend to the Secretary acceptance of conditional

58 stat. 709. gifts, pursuant to section 501," and inserting in lieu thereof "The

42 use 219. Secretary may, in accordance with section 501, accept conditional

gifts", and (B) striking out "heart" and inserting in lieu thereof

"heart, blood vessel, lung, and blood".

(e) The heading for part K of such Act is amended to lead as
follows :

"Part B — National Heart and Lung Institute".

CONFORMINC. AMENDMENTS TO OTHER PROVISIONS OF THE PUBLIC
HEALTH SERVICE ACT

64 stat. 446. ^ EC - ?■ ( a ) Section 217 of such Act is amended —

42 use 218. ' <1) by striking out "the National Advisory Heart Council,"

each place it occurs in subsection (a) ;

(2) by striking out "heart diseases," in subsection (a) and by

striking out "heart," in subsection (b).
58 stat. 692; (b) Sections 301(d) and 301(i) of such Act are each amended by

62 Stat! 601j striking out "National Advisory Heart Council" and inserting in lieu
79 stat. 448. thereof "National Heart and Lung Advisory Council".
42 USC 241.

REPORT TO CONGRESS

Review. Sec. 8 - The Secretary of Health, Education, and Welfare shall carry

out a review of all administrative processes under which the National
Heart, Blood Vessel, Lung, and Blood Disease Program, established

Ante , p. 680. under part B of title IV of the Public Health Service Act, will operate,
including the processes of advisory council and peer group reviews, in
order to assure the most expeditious accomplishment of the objectives
of the Program. Within one year of the date of enactment of this Act,
the Secretary shall submit a report to the Congress of the findings of
such review and the actions taken to facilitate the conduct of the Pro-
gram, together with recommendations for any needed legislative
changes.

A- 8

September 19, 1972 - 9 - Pub. Law 92-423

86 STAT,

EFFECTIVE DATE

Sec. 9. This Act and the amendments made by this Act shall take
effect sixty days after the date of enactment of this Act or on such Publication in
prior date after the date of enactment of this Act as the President Federal Register.
shall prescribe and publish in the Federal Register.

Approved September 19, 1972.

LEGISLATIVE HISTORY :

HOUSE REPORTS: No. 92-1108 aooompanying H.R. 15081 (Comm. on

Interstate and Foreign Commerce) and No. 92-1349
(Comm. of Conference).
SENATE REPORTS: No. 92-733 (Comm. on Labor and Publio Welfare) e

No. 92-1068 (Comm. of Conference).
CONGRESSIONAL RECORD, Vol. 118 (1972):

Apr, 7, considered and passed Senate.

July 18, considered and passed House, amended, in lieu

of H.R. 15081.
Aug. 18, House agreed to oonferenoe report,
Sept. 6, Senate agreed to oonferenoe report.
WEEKLY COMPILATION OF PRESIDENTIAL DOCUMENTS, Vol. 6, No. 39:
Sept, 20, Presidential statement.

A-9

APPENDIX B
DEFINITION OF MAJOR PROBLEM AREAS

APPENDIX B

DEFINITION OF MAJOR PROBLEM AREAS

The major problem areas addressed by the National Heart, Blood Vessel, Lung,
and Blood Act of 1972 are heart and blood vessel diseases, lung diseases, and
blood diseases and blood resources. This appendix includes for each major prob-
lem area definitions of the disease problems covered by the program, discussion
of the relationship of the disease problem to other diseases and/or disorders,
and statistical data on the impact and scope of the disease problem in the United
States. This appendix is reprinted directly from Section II, Volume I, the
National Heart and Lung Institute Summary (May 1, 1973) of the National Heart,
Blood Vessel, Lung, and Blood Program. Two additional lung disease problems,
which have been designated major problem areas in the updated 5-year Plan, have
been added at the end. Circulatory Assistance, Respiratory Assistance, and
Biomaterials are not disease problem areas. However, they constitute three of
the 22 major program elements and play important roles in the treatment of sev-
eral of the major diseases in the National Program. A brief definition of each
has also been added to this appendix.

B-l

DEFINITION OF MAJOR PROBLEM AREAS

The four major problem areas covered by the National
Heart, Blood Vessel, Lung and Blood Act are discussed
separately in the following three sections: Heart and
Blood Vessel Diseases, Lung Diseases, Blood Diseases
and Blood Resources. As pointed out in the Report of
the Panel Chairmen, there are many interrelationships
among these problem areas. The Chairmen state:
"Disordered biological functions seldom involve a
single area. As examples, pulmonary embolism begins
with thrombosis and involves the lung and its circula-
tion as well as the heart. Effective delivery of oxygen
to the tissue depends on the lung, the heart, the
amount, type, and functional states of the hemoglobin,
and the peripheral circulation."

HEART AND BLOOD
VESSEL DISEASES

For more than fifty years, heart and blood vessel dis-
eases have been the major cause of death in this
country. They now account for 54 percent of all
deaths annually (Figure 2). This is more than three
times the death rate from cancer, the next highest
cause. An estimated 28 million Americans have diseases
of the heart and blood vessels, resulting in a large bur-
den of acute and chronic illness and disability. Hence,
there is reason for referring to heart and blood vessel
diseases as the modern epidemic. Moreover, heart and
blood vessel diseases cost the economy more than $30
billion per year in wages, lost productivity, and ex-
penses for medical care.

Figure 2
DEATHS FROM ALL CAUSES
UNITED STATES. 1967

Nine major problem areas in heart and blood vessel
diseases are defined below: Arteriosclerosis, Hyperten-
sion, Cerebrovascular Disease, Coronary Heart Disease,
Peripheral Vascular Diseases, Arrhythmias, Heart Fail-
ure and Shock, Congenital and Rheumatic Heart Dis-
eases, and Cardiomyopathy and Infections of the

B-2

Heart. Of these, arteriosclerosis and hypertension are
considered the major cardiovascular disease problems
in the United States. The causes of arteriosclerosis and
most cases of hypertension are unknown.

Arteriosclerosis, or "hardening of the arteries," is
responsible for 84 percent of the deaths from heart and
blood vessel diseases. It is a chronic pathological
change in the blood vessels and its most common form
is atherosclerosis in which the inner lining of the
arteries becomes rough, thick, hard and covered with
plaques. Eventually, the inner diameter of the vessels
decreases and blood flow in the diseased arteries di-
minishes or stops completely. Atherosclerosis begins
early in life and is asymptomatic for years. Virtually all
adult American males, and postmenopausal women,
are afflicted to some degree. The disease manifests it-
self in many ways, but primarily as heart attacks,
strokes and occlusive disease of the peripheral vessels.
Therefore, if arteriosclerosis could be prevented,
hundreds of thousands of lives might be prolonged.
International statistics reveal a great variation in death
rates for coronary heart disease. For instance, in
Denmark, Norway, and Sweden, the death rate for men
under the age of 55 is less than half that for the same
age group in the United States. This difference
indicates that the high death rates due to
arteriosclerosis in the United States are neither
necessary nor inevitable.

Hypertension, or high blood pressure, is one of the
most commonly encountered forms of heart and blood
vessel diseases, affecting an estimated 23 million adult
Americans, or between 10 and 15 percent of the popu-
lation. High blood pressure is the most important
factor contributing to the development of strokes. It
also accelerates the development of atherosclerosis in
the coronary and peripheral vessels. Control of hyper-
tension would, therefore, reduce the incidence of three
major causes of death and disability: stroke, coronary
heart disease and peripheral vascular disease. High
blood pressure is easy to detect, but may exist for
many years without symptoms. It can be controlled
with presently available therapy. However, of the
millions of Americans with this disease, one half are
probably unaware that they have it, and of those who
are aware, less than one half are receiving adequate
therapy. Although hypertension is widely distributed
among Americans, it has been found to be more
common and severe among the black population.

Cerebrovascular Disease occurs when an artery
supplying blood to the brain is blocked, ruptured, or
injured. Cerebrovascular disease due to arteriosclerosis
and especially due to hypertension is the basis for the

great majority of strokes. The individual and public
health burden of death, paralysis and brain damage is
large. Of the 1.7 million adults who have this disease,
700,000 are partially or completely disabled. Stroke
kills about 200,000 persons a year, more men than
women, and at a greater rate among blacks than whites.
Each year, some 530,000 patients are discharged from
our hospitals with a diagnosis of stroke, and each year
about 250,000 individuals, between the ages of 25 and
64, are crippled mentally or physically by a stroke.
Many more lives could be saved and disabilities pre-
vented if we had effective methods for prevention and
treatment of arteriosclerosis and hypertension and if
available treatment were more widely applied. It
should be noted that, due to the recent advances in
therapy for high blood pressure, there has been an
appreciable long-term decrease in deaths from stroke.

Coronary Heart Disease refers to atherosclerosis in the
arteries that supply the heart muscle. A heart attack is
a manifestation of coronary heart disease and occurs
when a coronary artery is blocked, preventing the
blood from reaching the heart muscle. This produces
death of the heart muscle, technically called myo-
cardial infarction. Coronary heart disease is the major
manifestation of atherosclerosis. It is the predominant
form of heart disease in the adult American and causes
1.25 million heart attacks a year, and is responsible for
chronic illness in 4 million Americans, 2.5 million be-
low the age of 65. In 1969, coronary heart disease
accounted for about 675,000 deaths in this country. It
is the largest single cause of death from cardiovascular
disease and is the leading cause of death in both men
and women. Each year, approximately 130,000 per-
sons in their most productive years (below age 65) die
of coronary heart disease.

Coronary heart disease may also result in angina pec-
toris (a pain usually located in the chest and arm that is
brought on by exercise, exposure to cold, and other
factors), heart failure (impaired pumping performance
of the heart leading to accumulation of fluid in the
body and congestion in the lungs), disturbances of
heart rhythm and sudden death. Each year, 400,000
deaths from coronary heart disease occur suddenly or
before hospitalization. Half of these occur
instantaneously and unwitnessed. Either heart disease
or hypertension is evident in 300,000 of these cases,
but in 100,000, sudden cardiac death is the first
evidence of heart disease.

Peripheral Vascular Diseases are abnormalities that
occur within arteries or veins. Atherosclerotic narrow-
ing may result in inadequate blood flow through the

B-3

arteries. The veins may become dilated (varicosities) or
inflamed and obstructed by blood clots (thrombo-
phlebitis). These diseases may be painful and result in
organ damage, skin ulcerations and gangrene.
Peripheral vascular diseases are a significant cause of
disability and illness. For example, peripheral vascular
disease in the legs may affect one's ability to walk or
run. Thrombosis in the veins may produce pulmonary
embolism; i.e., clot fragments may be carried in the
blood from their site of origin to the lungs. This in turn
may result in shock and death. Leg vein thrombosis is
the cause of more than 90 percent of pulmonary
emboli which in turn are responsible for approximately
50,000 deaths a year in this country. About 265,000
patients are discharged from our hospitals each year
with a primary diagnosis of peripheral vascular disease.

Arrhythmias, or abnormal heart rhythms, occur with
many forms of heart disease and result from an altera-
tion in the normal transmission of electrical impulses
within the heart. They may also occur without rec-
ognizable disease. Many rhythm disturbances have
minor influence upon life expectancy and cause little
disability, others cause serious symptoms, and some are
almost instantaneously fatal. For example, arrhythmias
kill more than half of the patients with coronary heart
disease and are a major problem in patients with rheu-
matic heart disease.

Heart Failure and Shock represent major causes of
death and may be the end result of many different
diseases. Heart failure occurs when the heart has been
damaged so extensively that its ability to pump blood
is impaired and it can no longer meet the needs of the
body. In its chronic form, it is often associated with
shortness of breath, accumulation of fluids and
swelling of the legs. Shock is also a secondary
phenomenon characterized by an inability of the heart
and peripheral circulation to maintain adequate blood
pressure or blood perfusion. Left untreated, it rapidly
leads to irreversible damage to the tissues, and to
death. Shock can be a complication of many disorders
such as heart attacks, hemorrhage, or burns and stroke.

Heart failure and shock are the primary causes of in-
hospital deaths from heart attack and most other types
of heart disease, thus accounting for over a quarter
million deaths annually. In addition, chronic heart
failure may follow a heart attack or result from high
blood pressure or other heart diseases. Over two mil-
lion Americans have chronic heart failure, and each
year the total cost of their hospitalization exceeds
$500 million. In the majority, symptoms can be
relieved by drugs.

Congenital and Rheumatic Heart Diseases are impor-
tant diseases of children. Congenital heart disease
occurs when the heart or major blood vessels near the
heart fail to mature normally before birth. About eight
out of every 1,000 children are born with this disease,
and half of them do not survive until their first birth-
day. The causes of congenital heart diseases are general-
ly unknown. Less than 3 percent are known to be
related to a particular event or disorder occurring dur-
ing pregnancy, such as rubella infection or the use of
certain drugs, such as thalidomide. Rheumatic fever
and rheumatic heart disease were once considered lead-
ing causes of childhood illnesses. They can now be pre-
vented. Rheumatic fever is almost always preceded by
a streptococcal infection and may lead to damage of the
heart valves, thus causing rheumatic heart disease.
Rheumatic fever afflicts about 100,000 school
children. Both congenital and rheumatic heart diseases
cause substantial impairment of health in children,
and in adults in their most productive years. They
annually cause over 8,000 and 15,000 deaths, respec-
tively, in the United States. The cost of physician care
alone for patients with rheumatic fever and rheumatic
heart disease was about $28 million in 1969.

Cardiomyopathy and Infections of the Heart are dis-
eases of the heart muscle and its linings. These diseases
cause enlargement of the heart, heart failure, irregu-
larities of the heart rhythm, and occasionally sudden
death. They are the result of a variety of factors.
Known factors include toxic substances, viral
infections, alcohol, immunological phenomena,
nutritional deficiencies, muscular dystrophy, and a
number of rare diseases. The condition may be acute or
chronic and progressive. Rapidly fatal disease may be
associated with heart failure, disturbances of rhythm
and sudden death. Infections may affect the heart
muscle (myocarditis), its interior wall (endocarditis), or
its exterior surface (pericarditis). Cardiomyopathies,
myocarditis, endocarditis, and pericarditis are
increasing in frequency. However, quantitative
information concerning the prevalence of these diseases
is not available because we still lack specific diagnostic
criteria and laboratory tests.

LUNG DISEASES

The National Heart, Blood Vessel, Lung and Blood Pro
gram encompasses respiratory diseases exclusive of
cancer of the lung, upper respiratory infections and
pulmonary tuberculosis.

Respiratory diseases that represent national health
problems include chronic obstructive pulmonary dis-

B-4

eases (COPD), acute respiratory distress syndromes
(RDS), and interstitial lung diseases. The economic
cost of these diseases has been estimated at $6.3 billion
per year.

Lung diseases afflict both the young and the old. In the
newborn, the most common cause of death is the
respiratory distress syndrome which affects between
50,000 and 100,000 babies in the United States each
year, about half of whom die. RDS is implicated in the
development of adult respiratory diseases as well. Inter-
stitial lung diseases are a major cause of lung problems
in the young adult, and may cause COPD. Of the adult
respiratory diseases, emphysema and chronic bronchitis
are the major causes of death. An estimated 10 million
Americans are currently affected by these diseases, to-
gether with asthma. Emphysema and chronic bron-
chitis represent a particularly pressing health problem
since the death rate and prevalence of these conditions
have been increasing at an alarming rate over the past
15 years.

As a disabling disease, emphysema is second only to
heart disease. The illness and disability caused by
respiratory diseases are summarized in Figure 3.

Figure 3

ILLNESS AND DISABILITY

FROM RESPIRATORY DISEASES

IN THE UNITED STATES

ANNUAL INCIDENCE
OF ACUTE CONDITIONS

1.700

PRE
CHRON

77 5
million

/ALENCE OF

C CONDITIONS

900

million

396

375
million

225

217

2.5

millnn

Divi of RMncud Acti-Hy C.i« Pe , wnl Pwwm

Without Limitation With Limitation
K£Y Of Activity of Activity

SOURCE N««>ui Ceni*. (c Kwlih Sliimci. «<«qt wmUn di v t*i 1961 1967

Four major lung disease problems are defined below:
Pediatric Pulmonary Diseases, Emphysema and Chronic
Bronchitis, Fibrotic and Immunologic Lung Diseases
and Respiratory Failure.

Pediatric Pulmonary Diseases present health problems
of national dimensions. Hyaline membrane disease
(respiratory distress syndrome of the newborn), cystic
fibrosis (an inherited disease of abnormal mucus secre-
tion), and bronchiolitis (acute airway obstruction in
young children) are among the most important dis-
orders of childhood that involve the lung and the air-
ways. About 40,000 babies are born each year with
hyaline membrane disease. More than half of these will
die unless given prompt treatment, presently unavail-
able except in a few specialized facilities.

Cystic fibrosis occurs in about one of every 2,000 live
births and approximately 5 percent of the general
population in the United States carries the gene for
this disorder. Cystic fibrosis is one of the main causes
of chronic illness in children and young adults and
accounts for most of the deaths from pulmonary dis-
ease in the pediatric age group. Bronchiolitis is a
common pediatric disorder, but data are not available
on its incidence.

Emphysema and Chronic Bronchitis are among the
major causes of mortality and illness from pulmonary
diseases. Emphysema is a disease in which the thin
walls in the alveoli (air sacs) lose their elasticity and
tear. Chronic bronchitis refers to a persistent inflam-
mation of the lungs characterized by recurrent
coughing and excess mucus in the airways. These dis-
eases may be associated with certain risk factors, such
as cigarette smoking, and in some cases with genetic
determinants (e.g., deficiency of alpha! -antitrypsin
enzyme). Emphysema is a leading cause of death in this
country and an even greater cause of disability. Data
from 1967 indicate that chronic bronchitis and
emphysema account for half of the total 181,000
man-years lost due to lung diseases. The death rate for
chronic bronchitis increased by 80 percent between
1958 and 1967. The death rate for emphysema in-
creased by 172 percent in the same period to a level of
10.6 per 100,000 population.

Fibrotic and Immunologic Lung Diseases are induced
by many disease factors. Fibrotic responses (prolifera-
tion of connective tissue or scar formation) and
immunologic responses are characteristic of a variety of
lung diseases. Among the factors that may induce these
responses are exposure to substances such as coal dust,
silica, and asbestos in the environment; viral and
bacterial infections; diseases of the connective tissue
such as rheumatoid arthritis, lupus, and scleroderma;
radiation damage; and exposure to substances like
molds and dust that initiate hypersensitivity reactions.
Diseases characterized by pulmonary fibrosis and/or

B-5

immunologic reactions include pneumoconiosis, sar-
coidosis, diffuse hypersensitivity pneumonitis.
Farmer's lung and bronchial asthma. This group of lung
diseases is a major national health problem, second in
magnitude among lung diseases only to emphysema
and chronic bronchitis.

Statistical data on fibrotic lung diseases are inadequate
because these diseases are difficult to diagnose and
poorly reported. However, their national health impact
is far greater than is generally appreciated. For ex-
ample, sarcoidosis is about 12 to 15 times more
common among blacks than among whites in this
country, and now outranks tuberculosis as a cause of
disability from pulmonary insufficiency in black pop-
ulations. It is also more common in women.

Among immunologic lung diseases, asthma is the most
common, affecting about 8.6 million persons in this
country (approximately 4 percent of the population).
It is responsible for 5 percent of all chronic disabilities
and causes an annual loss of about 7 million work-days.
Other immunologic lung diseases are associated with
specific occupations where exposure to organic dusts
or molds is high; for example. Farmer's lung in the
north central states, Bagassosis among sugar cane
workers in the south, and hypersensitivity pneumonitis
from organisms growing in humidifiers and air condi-
tioners. While none of these diseases is very common in
the general population, their importance stems from
their high incidence in particular environments.

Respiratory Failure is a complication of many non-
pulmonary diseases. Acute respiratory distress syn-
dromes have been recognized as such only recently.
For these two reasons, data on incidence are not avail-
able. A conservative estimate is that 150,000 adult
cases of acute respiratory distress syndrome occur each
year with a mortality rate of 40 percent. These figures
do not include failure due to chronic pulmonary dis-
ease, (see Emphysema and Chronic Bronchitis), nor do
they adequately reflect the true incidence because so
many cases are unreported.

BLOOD DISEASES AND
BLOOD RESOURCES

Problems of the blood are intimately related to
cardiovascular and pulmonary diseases. Blood is a vital
part of the circulatory system since it is the vehicle by
which oxygen, nutrients, and other body chemicals are
carried through the blood vessels to every part of the
body, to be exchanged for carbon dioxide, waste

products and chemicals which, in turn, need to be
transported away from the tissues to other body
organs, either for excretion from the body or for use in
the life processes.

Three groups of blood problems are defined below:
Bleeding and Clotting Disorders, Sickle Cell Disease
and Related Disorders of the Red Blood Cell, and
Blood Resources.

Bleeding and Clotting Disorders are closely interrelated.
Both represent failures in maintaining the blood in an
optimal state within the blood vessels. On one hand,
failure means bleeding (hemorrhage) into surrounding
tissues or outside the body. On the other hand, failure
means inappropriate clotting (thrombosis) of the blood
within the vessels. Clotting in the arteries deprives a
part of the body of its blood supply; clotting in the
veins impedes the return of blood to the heart. When
excessive clotting affects small blood vessels and
capillaries (collectively termed the microcirculation),
tissues and cells cannot function well because they are
deprived of essential oxygen, energy, regulating hor-
mones and building blocks, and noxious waste
products cannot be removed effectively.

The particular portion of the body's defense mech-
anisms responsible for maintaining the blood in an
optimal fluid state is termed the hemostatic system.
Excessive bleeding can result from an abnormality or
deficiency, acquired or inherited, of any of the
elements in the hemostatic system. Bleeding into
organs and tissues may impair or destroy their function
and uncontrolled, external blood loss may result in
death.

The consequences of abnormal clotting depend on the
organ or region of the body in which it occurs. In
vessels of the heart, brain, lung or other vital organs,
the result can be catastrophic; in less vital areas, the
effects may be mild and transitory. With time, the
clot-dissolving mechanism restores the integrity of the
circulation. However, the speed of this process is
insufficient in the case of vital organs where even a
very brief deprivation of blood supply results in
irretrievable loss of function or death of tissue

The impact of the clotting and bleeding disorders is
considerable. Arterial thrombosis causes or complicates
a great variety of diseases in all parts of the body; for

B-6

example, thrombosis involving the vessels of the kidney
contributes to kidney failure, and arterial thrombosis
and cerebral hemorrhage play major roles in stroke.

Thrombosis in the veins may produce pulmonary
embolism; that is, clot fragments may be carried in the
blood from their site of origin to the lungs. About
300,000 persons are hospitalized annually and more
than 50,000 die with pulmonary embolism. Clotting in
the venous circulation complicates many illnesses and
surgical procedures. Autopsy studies show evidence of
venous thrombosis in about 50 percent of cases
examined, regardless of cause of death.

The microcirculation is a very important component of
the circulation system. It conveys to the cells of the
body the substances needed for their metabolism and
regulation, and carries away their products so that the
internal environment is maintained in a manner which
allows the cells to survive and perform their inter-
related tasks. Bleeding and clotting in the micro-
circulation are contributory or primary mechanisms in
hypertension, stroke, diabetes, infectious and inflam-
matory disease, autoimmune disease, host-graft rejec-
tion, cancer, sickle cell anemia, drug toxicity, mis-
matched blood transfusion, liver disease, and nephritis.
The impact is vast even if it cannot be expressed
statistically.

Thrombosis induced by contact of the blood with
foreign surfaces remains the major unsolved problem in
the development of artificial organs, prosthetic vessels
or devices that temporarily assist the circulation.

Excessive blood loss due to inadequate or disturbed
function of a component of the hemostatic mechanism
is a major cause of death and morbidity in a variety of
circumstances such as after severe injury, after surgery,
in leukemia, and in cirrhosis of the liver. The threat of
hemorrhage limits the aggressive management of some
forms of cancer.

The hemophilias are sex-linked, hereditary diseases
occurring almost exclusively in males. Although the
known hemophilic population of thib country is only
about 25,000, hemophilia constitutes a major national
health problem for two reasons. First, treatment must
be continued throughout the lifetime of the patient at
enormous cost (the current yearly cost to replace the
missing clotting factor alone is estimated to be in

excess of $6,000 per patient, or more than $120
million for the 80 percent of hemophiliacs who can
benefit from this factor). Second, treatment of the
disease presents one of the largest single demands upon
the nation's blood resources.

Sickle Cell Disease and Related Disorders of the Red
Blood Cell include sickle cell anemia, Cooley's anemia
and defects affecting the red blood cell membrane or
enzyme systems.

Sickle cell anemia, Cooley's anemia and certain defects
affecting the red blood cell membrane or enzyme
systems are all genetically determined and are presently
incurable, although they may be controlled to varying
degrees. These disorders lead to premature destruction
of the red cells in the circulation. Anemia results
because the bone marrow is unable to produce suffi-
cient numbers of new cells to keep up with the rate of
destruction.

Approximately two million individuals, primarily
black, carry the sickle cell trait. They are healthy, but
if two carriers marry, each of their children has a one
in four chance of having sickle cell anemia, a painful
and debilitating disorder. About one in 400 black
babies in this country is born with sickle cell anemia,
and somewhat less than 50,000 individuals suffer the
painful episodes known as "crises."

The cost of caring for a patient with sickle cell disease
may approach $2,500 to $5,000 a year. The loss of
time from school, from jobs and the resultant
psychological and educational problems, make this
disorder one of high social and economic importance.

Cooley's anemia results from defective production of
one of the subunits of the hemoglobin molecule,
leading to rapid destruction of the red cells. It occurs
in perhaps 5,000 Americans, largely of Mediterranean
ancestry. Its victims suffer profound anemia and
require repeated blood transfusions for survival. As
with the sickle cell trait, carriers do not have
symptoms, but offspring may be affected.

Defects in red cell membranes and red cell enzymes
also produce anemia. Such defects are relatively rare,
although one, called glucose-6-phosphate dehydro-
genase deficiency (G6PD), occurs in about 10 percent
of black males and less frequently in males of
Mediterranean ancestry. Most of these individuals are

B-7

healthy, but they are sensitive to a variety of
commonly used drugs and may develop anemia if they
take them. They also develop anemia with certain
illnesses.

Blood Resources for the nation need to be available in
an adequate supply. High quality blood and blood
products is essential for the effective treatment of
many diseases. Whole blood is made up of cellular
elements dispersed in a fluid medium called plasma.
The cells consist of red cells to deliver oxygen, platelets
to stop bleeding, and white cells to fight infection.
Plasma contains such useful products as albumin,
immunoglobulins, and clotting factors.

To give the patient enough of what he needs and when
he needs it requires recruiting the donor, collecting his
blood, separating it into its components, detecting and
eliminating disease-causing agents, matching the
components for compatibility, and administering it to
the patient in a fail-safe fashion.

In the United States, an assemblage of organizations
(which might be referred to as the blood service
complex) acquires, processes, stores, delivers and
administers blood and a variety of blood products. This
complex has an estimated gross annual income ex-
ceeding $500 million. It collects about nine million

pints of blood per year for transfusion. About 25
percent of this blood is never transfused and much of
this portion is wasted.

Whole blood is mostly collected by the blood-banking
sector of the complex. In addition, the pharmaceutical
industry, which comprises the other major sector,
collects about 1.7 million liters of plasma each year,
mainly for the preparation of plasma fractions (about
one liter of plasma is present in five units of whole
Wood).

Transfusion is not without dangers, one of which is the
possibility of hepatitis. Approximately 10 to 15
percent of the whole blood collected by the blood-
banking sector is obtained from commercial donors.
This blood accounts for about a quarter to a half of the
incidence of post-transfusion hepatitis. While nation-
wide reporting of hepatitis of any origin or type is
unreliable, it is estimated that each year post-trans-
fusion hepatitis accounts for 850 deaths, 17,000
episodes of illness which are often incapacitating for
weeks to months, and another 100,000 infections
without symptoms. If we consider only the patients
who become ill, their average hospital stay is 28 days.
The dollar cost to the nation approximates $86 million
per year; costs in terms of human suffering are
immeasurable.

B-8

Definitions of two additional lung disease problems — Pulmonary Vascular Diseases
and Inhalation Diseases — are given below.

Pulmonary Vascular Diseases include cor pulmonale, pulmonary hypertension, and
pulmonary edema. Cor pulmonale refers to enlargement of the heart due
to an increased workload of the right ventricle resulting from conditions
which affect the pulmonary circulation. Pulmonary hypertension is char-
acterized by elevation of pulmonary arterial pressure above normal levels.
The condition is considered primary when found in the absence of cardiac
or pulmonary diseases and secondary when associated with these diseases.
Primary hypertension may be caused by factors such as high altitude and
low oxygen, or ingestion of certain drugs and chemicals; secondary hyper-
tension may result from destruction of the pulmonary vascular bed, con-
genital heart disease, pulmonary vasoconstriction, or congestive heart
failure. Pulmonary edema, difficult to detect early, is a pathologic
state in which there is abnormal extravascular storage of fluid in the
lung. Reliable data on the incidence and prevalence of these diseases
are not available. However, it has been estimated that cor pulmonale
alone occurs in 40 percent of cases of emphysema and chronic bronchitis,
both of which are chronic respiratory diseases of national impact.

Inhalation Diseases are becoming more prevalent in the United States as indus-
trialization and the technological age progress. Of all occupational ill-
nesses, dust inhalation diseases, or pneumoconioses, are the most serious
health problem. The dusts inhaled are so fine that they escape the natu-
ral cleansing mechanism of the upper respiratory tract and lodge perma-
nently in the lungs. If exposure is sufficiently high and prolonged, the
accumulated particles may cause fibrosis or scarring of the lung tissue
and in many cases lead to serious disability and even death. One of the
most serious problems in our country today comes from the direct handling
of asbestos by some 200,000 workers and by another 3 to 5 million persons
who are secondarily exposed to the dust. Asbestos is believed to be a
leading factor in the deaths of over 2,000 persons each year in the U.S.
The breathing of quartz dust, or silica, is another hazard which gradu-
ally causes irreversible damage to the lungs. Of the more than 125,000
workers now engaged in coal mining in the United States, an estimated 10
to 20 percent have Coal Worker's Pneumoconiosis, or "black lung." Beryl-
lium, iron, tin, and barium dusts are also hazardous to the lung tissue.
Pneumoconioses are also caused by organic dusts from plants such as cotton
(byssinosis) , sugar cane (bagassosis) , and moldy hay (Farmer's lung).

Definitions of Circulatory Assistance, Respiratory Assistance, and Biomaterials ,
three of the 22 major program elements, are given below.

Circulatory Assistance to the failing heart may be provided by mechanical circu-
latory devices which aid or replace the pumping action of the heart.
There are many types of such devices under development. Some are applied
externally to the lower extremities in synchrony with the heart beat.

B-9

In others, the pumping action of the heart is enhanced by synchronously
expanding and collapsing a "balloon" positioned in the aorta, the artery
leading from the heart. On a very limited scale, a few devices have been
employed which require substantial surgery and the actual positioning of
a pumping device within the chest. While circulatory assist devices are
designed to improve the mechanical function of the heart, the apparatus
generally involves important electronic, pneumatic, hydraulic, and mechan-
ical systems as well.

Respiratory Assistance can be provided by mechanical devices (ventilators or
membrane oxygenators) that support the gas transfer functions of the
lung when, as a consequence of disease, the lungs are unable to maintain
proper levels of oxygen and carbon dioxide. Ventilators are devices that
mechanically inflate the lungs and can deliver increased amounts of oxygen.
Membrane oxygenators are externally placed "artificial lungs" which are
connected with the patient's circulatory system. Blood from the patient
enters the oxygenator, carbon dioxide is removed, the blood is oxygenated
and then returned to the patient's circulatory system. At present, oxygen-
ators can only be used safely for several days. Recent experience suggests
that this method of respiratory assistance holds promise for treatment of
some patients in acute respiratory failure.

Biomaterials are synthetic materials which can be implanted in the body and
used in a variety of medical devices. To be "blood compatible," such
materials must not cause damage to the various components of blood and
must not induce blood to clot. In addition, biomaterials must possess
specific properties suited for specialized functions (for example, gas
permeability for oxygenation devices) and have minimal risk of causing
chemical toxicity, allergic reactions, and neoplasia. Several approaches
are being pursued in the development of suitable biomaterials. Properties
of the vessel wall have been imitated by "hydrogels," a network structure
of long polymer chains and water. Blood compatible surfaces can be grafted
or bonded to a variety of materials which have otherwise promising physical
properties. Another approach involves the use of human cells which can
be grown in culture and attached to certain man-made materials to make
them compatible with blood. Materials can be synthesized which contain
anticoagulants, clot-dissolving enzymes, and surface-active agents. Com-
posite materials can be produced which are based on a variety of compo-
nents mentioned above.

B-10

DATE DUE

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