Full Text AG-93-005

PATHOPHYSIOLOGIC EFFECTS OF IMPAIRED MYOCARDIAL FUNCTION IN OLDER
PERSONS

NIH GUIDE, Volume 22, Number 8, February 26, 1993

RFA:  AG-93-005

P.T. 34, CC

Keywords: 
  Cardiovascular Diseases 
  Pathophysiology 
  Aging/Gerontology 


National Institute on Aging

Letter of Intent Receipt Date:  May 15, 1993
Application Receipt Date:  July 1, 1993

PURPOSE

The National Institute on Aging (NIA) invites applications for
research projects to study the pathophysiologic effects of impaired
myocardial systolic and/or diastolic function in persons with or
without conventionally-defined heart failure.  The purpose of this
program is to define the major pathophysiologic links between
impaired myocardial contractile function and resulting frailty or
disability.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), Pathologic Effects of Impaired Myocardial
Function in Older Persons, is related to the priority areas of heart
disease and chronic disabling conditions. Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00473-1) or "Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202/783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.  Women
and minority investigators are encouraged to apply.

MECHANISM OF SUPPORT

Support of this program will be through the research project grant
(R01).  Awards will be administered under PHS grants policy as stated
in the PHS Grants Policy Statement, DHHS Publication No. (OASH)
90-50,000, rev. 10/91.

This RFA is a one-time solicitation.  Generally, future unsolicited
competing continuation applications will compete with all
investigator-initiated applications and be reviewed by a DRG study
section.  If it is determined that there is a sufficient continuing
program need, the NIA may announce a request for competitive
continuation applications.  The requested total funding (direct and
indirect costs) for individual grant applications for the first-year
may not exceed $200,000, with increases of no more than 4 percent for
subsequent years.  The total project period for applications
submitted in response to the present RFA may not exceed four years.
The anticipated award date will be July 1, 1994.

FUNDS AVAILABLE

It is estimated that $1.2 million will be available to fund  grants
under this RFA.  This level of support is dependent on the receipt of
a sufficient number of applications of high scientific merit.
Although this program is provided for in the financial plans of the
NIA, the award of grants pursuant to this RFA is also contingent upon
the availability of funds for this purpose.  Total support may not
exceed four years.

RESEARCH OBJECTIVES

Background

Myocardial contractile dysfunction is an important cause of
disability in older people.  Heart failure is the most common
hospital discharge diagnosis in persons over age 65 years.  It was
the first listed diagnosis in 533,000 admissions of people over 65 in
1988.  The U.S. prevalence of heart failure among over-65 persons is
estimated at over 2.5 million people (1).  The prevalence of heart
failure is expected to rise as population trends reflect the increase
in proportion of people over age 65 years.

Heart failure may be defined in various ways.  As a clinical
syndrome, heart failure is associated with reduced exercise
tolerance, dyspnea, and fatigue, as well as shortened life span.
Most definitions include diminished heart pumping capacity and
inadequate cardiac output.  There may be elements of systolic and/or
diastolic dysfunction.  Myocardial contractile dysfunction of varying
degrees can occur without clinical heart failure.

Impaired cardiac pumping capacity may cause inadequate blood supply
to peripheral muscles, and inadequate muscle blood supply may be an
important contributor to decreased exercise capacity.  It may also
contribute to subjective feelings of fatigue and shortness of breath
in persons with heart failure.  However, although it was once felt to
be a sufficient explanation for decreased overall functional capacity
in people with heart failure, it is now recognized that pumping
action, at least as measured as left ventricular systolic function,
is poorly related to exercise capacity (2).

For example, subjects with moderately decreased ejection fractions
may or may not have symptoms of heart failure.  In the project,
"Studies of Left Ventricular Dysfunction" (SOLVD), 40 subjects were
studied who were totally free of symptoms even though they had
ejection fractions less than 35 (mean 29 q 5%).  None had symptoms of
exertional fatigue or dyspnea, nor did they limit their normal
physical activity, and all were New York Heart Association functional
class I.  They did, however, have a reduced peak aerobic capacity
(3).

Several studies support the concept that systolic pumping efficiency,
at least as measured by left ventricular ejection fraction, is an
inadequate single predictor of symptoms of heart failure, and
symptoms may improve without an improvement in ejection fraction.  A
number of other potential determinants of symptoms need to be
considered.

(1) Diastolic dysfunction.  Individuals with normal left ventricular
function may have congestive heart failure from diastolic dysfunction
(4,5).  Diastolic dysfunction is often defined as a decrease in the
volume rate of change in diastole (dV/dt) or filling rate integral,
changes that may occur with age alone.  Diastolic dysfunction may be
associated with or cause an elevation in pulmonary wedge pressure,
which may be the source of most symptoms in heart failure (6).  Other
pulmonary changes or disease may contribute to symptoms in other
cases.  Confounding the problem, subjects with other heart disease,
but with preserved left ventricle function, also may have heart
failure symptoms.  In one study, heart failure symptoms were
associated with chronic obstructive pulmonary disease and age (7).

(2) Skeletal muscle changes.  Changes in skeletal muscle typically
occur with aging, and may result in a decline in physical capacity.
Such changes may result from altered glycogenolysis, changes in
adrenergic stimulation, or loss of type II skeletal muscle fibers
(8).  Heart failure has also been associated with skeletal muscle
changes (9).  Atrophy in Type I muscle fibers occurs in subjects with
heart failure, along with other metabolic changes (10,11).  Muscle
inorganic phosphate to phosphocreatine ratio, a measure of
bioenergetic efficiency, may be abnormal in persons with heart
failure, but may improve with local muscle training without an
overall training effect (12).  Myopathy of heart failure may be the
result of muscle disuse secondary to fatigue, or may result from
another mechanism.  Muscles such as the quadriceps may be used less
because the subject has decreased exercise tolerance; however, the
diaphragm is unlikely to be less used in subjects with heart failure,
and may be used at a higher rate due to shortness of breath.
Diaphragm muscle biopsies from human subjects with heart failure also
show changes suggestive of myopathy (13).  The myopathy possibly may
be due to circulating elements or to central nervous system changes.
Muscle vascular reactivity is decreased in heart failure, limiting
blood flow during exercise (14).  Decreased reactivity may be due to
alterations in central nervous system sympathetic outflow (15).

(3) Physical fitness.  Cardiopulmonary function may be affected by
age, but physical fitness contributes significantly to physiologic
function (16).  Exercise, pre-morbid fitness, and conditioning
activities may modify the impact of heart failure in ways other than
through myopathic changes in skeletal muscle.  Physical training can
increase peak aerobic capacity, even in subjects with severe systolic
dysfunction.  In one study, subjects with mean LV ejection fraction
of 19 percent were able to significantly improve peak oxygen
consumption with a program of home-based bicycle exercise (17).

(4) Neuroendocrine and other hormones.  Sympathetic activity
increases in heart failure, but reactive beta receptor downregulation
is variable (18).  Exercise-provoked catecholamine response is
greater in subjects with heart failure (19).  Variable "resistance"
to catecholamines may explain differences in exercise capacity.  The
renin-aldosterone-angiotensin system is also activated in heart
failure, and possibly is interactive with the catecholamine system.
Hyponatremia, presumably related to aldosterone, vasopressin and
baroreceptor function, is significantly predictive of death in severe
heart failure (20), but has apparently not been related to exercise
capacity or other symptoms.  Such relationships are difficult to
study in humans due to the confounding effect of pharmacologic
treatment.  Tumor necrosis factor (TNF) may be produced with
reperfusion following myocardial ischemia (21).  TNF may be a
mediator of adverse systemic consequences in ischemic-related heart
failure.
(5) Nutritional changes in subjects with myocardial impairment may
contribute to muscle changes and symptoms of weakness.  Protein
malnutrition may contribute to "myopathy of failure."  Obesity may
contribute to fatigue and dyspnea.

(6) Other variables.  Medication.  Digitalis, widely used to treat
heart failure, is known to produce dysphoria even at less than
"toxic" levels.  Diuretics may cause magnesium deficiency, which in
turn may cause weakness and fatigue.  Depression prevalence increases
with age over 50.  The association of depression, heart failure, and
functional capacity and symptoms has not been adequately studied.
Psychological factors such as locus of control may affect an
individual's response to a chronic illness such as heart failure.
Abnormal pulmonary function (with or without diastolic dysfunction)
may be a major determinant of symptoms in many persons with impaired
myocardial contractility.

Research Goals

Research funded under this RFA should increase the understanding of
the pathophysiologic mechanisms by which impaired myocardial
contractile function produces symptoms and impaired functional
capacity.  A large variety of diverse and possibly related factors
should be considered. Examples of parameters for study include, but
are not limited to:

o  Effects on exercise tolerance and functional abilities in
activities such as walking and stair climbing, of various myocardial
contractile impairments

o  Effects on and interactions with pulmonary physiology, function,
and pathology

o  Effects on skeletal muscle physiology, function, and pathology,
including "myopathy of heart failure;" interactions with nutrition

o  Symptomatic effects such as dyspnea and fatigue

o  Effects of endocrine and neuroendocrine systems leading to
secondary pathophysiologic changes in other organs, mood, and other
effects

o  Secondary effects of impaired myocardial function on the
myocardium, cardiac conduction system, or coronary circulation
leading to progressive myocardial dysfunction

o  Relationship of different types of myocardial dysfunction to
mortality rates, hospitalization rates, nursing home admissions,
other care needs, and health costs

These examples are illustrative, but not restrictive.  Investigators
are expected to use an integrated collaborative approach, enlisting
the assistance of expertise in appropriate disciplines as necessary.
Because of co-morbidity in the older population, the design of
proposed projects should permit a separation of the potentially
confounding effects of these conditions from the effects of impaired
myocardial function per se.  Analytic methods to compensate for
variable interactions and confounding must be considered.
Elucidation of specific effects of interactions of impaired
myocardial function with other pathologies is encouraged.

The focus of these studies should be subjects over age 65 with
myocardial dysfunction, including men and women.  Subjects of younger
age groups may be necessary to make age-related comparisons.  Because
of the great population differences between the "young old" (under
age 80) and "old old" (over age 80), designs that include adequate
numbers in the latter age category for analyses specific to that
group are strongly encouraged.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULAITONS

It is NIH policy that women and minorities must be included in
clinical study populations unless there is a good reason to exclude
them.  The study design must seek to identify any pertinent gender or
minority population differences.  The composition of the proposed
study population must be described in terms of gender and
racial/ethnic groups, together with a rationale for its choice.  In
addition, gender and racial/ethnic issues should be addressed in
developing a research design and sample size appropriate for the
scientific objectives of the study.  This information should be
included in the form PHS 398 in Sections 1-4 of the Research Plan AND
summarized in Section 5, Human Subjects.

Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However,
NIH recognizes that it may not be feasible or appropriate in all
research projects to include representation of the full array of
United States racial/ethnic minority populations (i.e., Native
Americans (including American Indians or Alaskan Natives,
Asian/Pacific Islanders, Blacks, Hispanics).  The rationale for
studies on single minority populations should be provided.  For the
purpose of this policy, clinical research includes human biomedical
and behavioral studies of etiology, diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are exempt.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.  For
foreign awards, the policy on inclusion of women applies fully; since
the definition of minority differs in other countries, the applicant
must discuss the relevance of research involving foreign population
groups to the United States' populations, including minorities.

If the required information is not contained within the application,
the application will be returned without review.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study is inadequate to answer the scientific
questions(s) addressed and the justification for the selected study
population is inadequate, it will be considered a scientific weakness
or deficiency in the study design and will be reflected in assigning
the priority score to the application.

LETTER OF INTENT

Prospective applicants are asked to submit, by May 15, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name, address and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number and title of the RFA in response to
which the application may be submitted.

Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains is helpful in planning for the review of
applications.  It allows NIA staff to estimate the potential review
workload and to avoid possible conflict of interest in the review.
The letter of intent should be sent to Dr. Cooper at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Inquiries, Division of Research Grants, National Institutes of
Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone
301-496-7441; and from the program administrator named below.

The RFA label available in the application form must be affixed to
the bottom of the face page.  Failure to use this label could result
in delayed processing of the application such that it may not reach
the review committee in time for review.  In addition, the RFA title
and number must be typed on line 2a of the face page of the
application form and check the YES box.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, exact photocopies, in one package
to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At time of submission, two additional copies of the application must
also be sent to:

Michael A. Oxman, Ph.D.
National Institute on Aging
Gateway Building, Room 2C212
7201 Wisconsin Avenue
Bethesda, MD  20892

Applications must be received by July 14, 1993.  If an application is
received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) will not
accept any application in response to this announcement that is
essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application.  The DRG will not
accept any application that is essentially the same as one already
reviewed.  This does snot preclude the submission of substantial
revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique.

Relationship to Existing Programs

The National Heart, Lung, and Blood Institute (NHLBI) sponsors
research on heart failure and mechanisms of myocardial dysfunction.
This RFA is aimed at older populations and the mechanisms that
produce frailty.  The NHLBI will receive assignment on appropriate
applications.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by NIH staff for
completeness and responsiveness.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, NIA staff will contact the
applicant to determine whether to return the application to the
applicant or submit it for review in competition with unsolicited
applications.

Those applications that are complete and responsive will be evaluated
in accordance with the criteria stated below for scientific/technical
merit by an appropriate peer review group convened by the NIA.
Applications may be subjected to triage by an NIA peer review group
to determine their scientific merit relative to other applications
received in response to this RFA.  The NIH will withdraw from further
competition those applications judged by triage to be noncompetitive
for award and notify the applicant Principal Investigator and
institutional official.  Those applications judged to be competitive
will undergo further scientific merit review.  The second level of
review will be provided by the National Aging Advisory Council.

Review criteria for this RFA are the same as those for unsolicited
research grant applications.

o  Scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly but not exclusively in the area
of the proposed research;

o  availability of resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research; and

o  Involvement of women and minorities in subject populations will
also be considered when reviewers assign a priority score

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify issues or questions from potential
applicants is welcome.

Direct inquiries regarding programmatic issues to:

James K. Cooper, M.D.
Geriatrics Program
National Institute on Aging
Gateway Building, Room 3E327
Bethesda, MD  20892
Telephone:  (301) 496-6761

Direct inquiries regarding fiscal matters to:

Barbara Cunningham
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Room 2N212
Bethesda, MD  20892
Telephone:  (301) 496-1472

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.866.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78-410, as
amended by Public Law 99-158, 42 USC 241 and 285) and administered
under PHS grants policies and Federal Regulations 42 CFR 52 and 45
CFR Part 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency
review.

References

1.  Thom T.  1991 Personal communication

2.  Myers J, Froelicher VF.  Hemodynamic determinants of exercise
capacity in chronic heart failure.  Annals Internal Med 1991;
115:377-86

3.  LeJemtel TH, et al.  Depressed peak aerobic capacity in
asymptomatic patients with moderate to severe left ventricular
dysfunction at rest:  a substudy of the studies of left ventricular
dysfunction (SOLVD).  Presented at the Amer. Heart Assoc mtg, Nov 3,
1990

4.  Grossman W.  Diastolic dysfunction in congestive heart failure.
New Engl J Med 1991; 325:1557-64

5.  Gaasch WH.  Congestive heart failure in patients with normal left
ventricular systolic function:  a manifestation of diastolic
dysfunction. Herz 1991; 16:22-32

6.  Packer M.  Abnormalities of diastolic function as a potential
cause of exercise intolerance in chronic heart failure.  Circulation
1990; 81 (Suppl III):III-78-III-86

7.  Judge KW.  Congestive heart failure symptoms in patients with
preserved left ventricular systolic function:  analysis of the CASS
registry.  J Am Coll Cardiol 1991; 18:377-82

8.  Chick TW, et al.  The effect of aging on submaximal exercise
performance and recovery.  J Gerontology:  Bio Sci 1991; 46: B34-38

9.  Mancini DM, et al.  Contribution of skeletal muscle atrophy to
exercise intolerance and altered muscle metabolism in heart failure.
Circulation 1992; 85: 1364-73

10.  Sullivan MJ, Green HJ, Cobb FR.  Skeletal muscle biochemistry
and histology in ambulatory patients with long-term heart failure.
Circ 1990; 81: 518-27

11.  Drexler H, et al.  Alterations of skeletal muscle in chronic
heart failure.  Circulation 1992; 85:1751-59

12.  Minottie JR, et al.  Skeletal muscle response to exercise
training in congestive heart failure.  J Clin Invest 1990; 86: 751-8

13.  Lindsay D.  Personal communication, 1991

14.  Solal AC, Gourgon R.  Assessment of exercise tolerance in
chronic congestive heart failure.  Am J Cardiology 1991; 67: 36C-40C

15.  Ferguson D.  Sympathetic mechanisms in heart failure:
pathophysiological and pharmacological implications.  Scientific
conference on heart failure, Am Heart Assoc, Aug 4, 1991

16.  Neyers DA et al.  Relationship of obesity and physical fitness
to cardiopulmonary and metabolic function in healthy older men.  J.
Gerontology:  Med Sci 1991; 46: M57-65

17.  Coats AJS, et al.  Effects of physical training in chronic heart
failure.  Lancet 1990; 335: 63-6

18.  Forfar JC.  Neuroendocrine activation in congestive heart
failure. Am J Cardiology 1991; 67: 3C-5C

19.  Chidsey CA, Harrison DC, Braunwald E.  Augmentation of plasma
norepinephrine response to exercise in patients with congestive heart
failure.  N Engl J Med 1962;267: 650-54

20.  Parameshwar J, Keegan J, Sparrow J, et al.  Predictors of
prognosis in severe chronic heart failure.  Am Heart J 1992;
123:421-26

21.  Lefer AM, Tsao P, Aoki N, Palladino MA.  Mediation of
cardioprotection by transforming growth factor-beta.  Science 1990;
249: 61-64

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