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Full Text PA-95-075


NIH GUIDE, Volume 24, Number 25, July 14, 1995

PA NUMBER: PA-95-075 (inactive per NOT-HL-00-003)

P.T. 34

  Cardiovascular Diseases 
  Biology, Cellular 
  Biology, Molecular 

National Heart, Lung, and Blood Institute


This program announcement solicits applications for research on a
molecular and cellular approach to elucidation of the signaling
mechanisms that coordinate the events that lead to deterioration of
cardiac structure and function.  Appropriate studies may include
mechanisms of action of mediators derived from myocardial,
interstitial, endothelial, endocrine, or immune cells and the
respective receptors for those mediators, as well as the factors that
affect altered gene expression of these mediators and their


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 PA,
Transit from Cardiac Hypertrophy to Overt Heart Failure, is related
to the priority area of heart disease and stroke.  Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report:
Stock No. 017-001-00474-0 or Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).


Applications may be submitted by foreign and domestic, 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.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards.


Research support mechanisms include traditional research project
grants (R01) and FIRST (R29) awards.  Traditional research project
grants (R01) provide support for up to five years.  Applications for
FIRST (R29) awards must request support for five years and are
limited to $350,000 in direct costs over the entire project period.


Congestive heart failure (CHF) is estimated to affect three million
people in the United States.  It is the final common pathway of a
variety of primary cardiovascular disease entities, such as coronary
artery disease, hypertension, valvular heart disease, genetic
disorders, diabetes and the sequelae of infection or toxin exposure,
among others.  Hospitalizations and mortality from CHF have increased
steadily since 1968, despite the overall improvement in mortality
from cardiovascular disease.  Heart failure is now the underlying
cause of death in over 39,000 persons annually.  In 1992, it was the
first listed diagnosis in 822,000 persons and is the most common
hospital discharge diagnosis in persons over 65 years of age.  The
incidence of death from CHF is 1.5 times as high in black Americans
as in whites.  The estimated direct economic cost of CHF in the
United States is reported to be $10.2 billion annually.  At present,
the only cure for end-stage CHF is cardiac transplantation.

One fundamental question that needs to be answered before progress
can be made in the prevention and treatment of heart failure is how
the compensated, hypertrophied heart progresses to failure.  In
recent years, research on the natural history of heart failure has
benefitted from the application of cell and molecular biology
techniques.  Physiological studies on the development of pathological
hypertrophy have led to the view that hypertrophy is compensatory,
but while providing a short-term adaptive response to maintain
cardiac output, it eventually becomes maladaptive.  Studies have
shown that the mechanism of hypertrophic growth involves remodeling
of all cardiac tissue compartments:  myocytes, matrix, and
vasculature, and is associated in cardiac myocytes with a molecular
expression profile bearing much similarity to the fetal phenotype.
Mechanisms such as the immediate/early gene response and peptide
growth factor expression have been implicated in this molecular
switching, but little is known about their role in the overall
ventricular remodeling that occurs in vivo.

A variety of studies suggest that the physiological function of the
myocardium is modified through complex cross-talk among vascular,
interstitial and myocyte compartments of the heart.  Thus, locally
produced mediators can act in autocrine and paracrine fashions to
modify function or induce cell death.  Research is required to
understand the mechanisms of this cross-talk which has important
consequences in the transition to heart failure.  For example,
several studies suggest a role for the endogenous vascular peptide,
endothelin.  Experiments employing the rapid pacing model
demonstrated a two-fold increase in circulating endothelin that
correlated well with known physiological markers of CHF.
Interestingly, elevated circulating endothelin levels have also been
reported in human heart failure.  Receptors for endothelin have been
identified in cultures of rat cardiac myocytes, and the peptide has
been demonstrated to have potent positive inotropic activity in rat
ventricular myocytes.

Angiotensin II (AII) levels are elevated in CHF.  This potent
vasoconstrictor peptide is produced in renal tissue and activated
both systemically and in myocardial tissue by angiotensin converting
enzyme (ACE).  The active peptide is also a secretogogue for
endothelin.  A recent report demonstrates that the AII-stimulated
release of endothelin from human endothelial cells is inhibited by
atrial natriuretic peptide (ANP).  In the adult human, ANP is
normally made and secreted only by atrial myocytes and ventricular
conduction cells.  ANP synthesis and secretion from ventricles is
stimulated in the failing heart.  A recent study has correlated the
expression of ANP in the ventricle with increasing end-diastolic
pressure or volume and worsening New York Heart Association
functional class. The release of ANP is also stimulated by
endothelin.  Thus angiotensin, endothelin and ANP may be partners in
a feedback loop which is important in determining the functional
status of the myocardium.  Research is needed to understand how these
factors mediate the changes in vascular impedance and fluid volume in
the presence of a failing heart.

Other lines of investigation suggest that the immune system, acting
through cells of the myocardium, may play a role in the transition to
heart failure but how the immune system is recruited and how it
mediates maladaptive cardiac growth and altered function is not
understood.  Similarly, such factors as impairment of alpha and beta
adrenergic receptor function, and altered phospholamban and heat
shock protein expression are associated with heart failure but the
stimulus to effect these changes is not understood.

Genetically altered animals offer much promise to study the basic
mechanisms responsible for heart failure and to develop therapy.
Information now available on genes involved with abnormal cardiac
growth may be utilized to develop new models.  Discovery of new genes
altered in the transition to heart failure may also be the source of
exciting approaches.

Proposed Research

Examples of studies that could be included under this initiative are
listed below.  The list is not meant to be exhaustive, and many other
types of studies would certainly be appropriate.

o  Elucidation of the mechanisms underlying the growth response of
the overloaded heart.

o  Identification of the origins of the peptide growth factors,
TGF-betaF, alpha-FGF and beta-FGF and their role in ventricular wall
remodeling in the adult.

o  Elucidation of the mechanisms whereby ACE inhibitors lower
peripheral vascular resistance in heart failure patients and appear
to reverse hypertrophy of damaged myocardium.

o  Elucidation of the mechanisms whereby beta-blockers have
beneficial effects on myocardial remodeling.

o  Investigations of the pathophysiological consequences of immune
cytokines in heart failure.

o  Studies of the interactions between cytokine action,
neuroendocrine activation, and growth abnormalities in the failing
heart should be investigated.

o  The development and use of genetically altered animals to explore
the molecular and physiological factors and processes responsible for
heart failure and to devise and test new therapeutic modalities.

While it is recognized that heart failure commonly occurs in the
setting of neuroendocrine excess, applications that focus exclusively
on the classical role of the neuroendocrine system in heart failure
are not encouraged.  However, studies of the effects of the
neuroendocrine system on cellular and molecular processes in the
failing myocardium would be responsive.  Strategies that employ
neonatal cardiac myocytes must demonstrate a clear relationship to
heart failure beyond descriptive similarities between the onset of
cardiac hypertrophy in the adult and fetal cardiac gene expression in
order to be considered responsive; such studies, for example, could
highlight differences in the growth responses to overload of
proliferating and terminally differentiated myocytes.


It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990.  The new policy contains some
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 20, 1994 (FR 59 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.


Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, 6701 Rockledge Drive,
Room 3032, MSC 7762, Bethesda, MD 20892, telephone 301/710-0267. The
title and number of the program announcement must be typed in Section
2a on the face page of the application.

Applications for the FIRST award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and returned without review.

The completed original application and five legible copies must be
sent or delivered to:

6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD 20817 (for express/courier service)


Applications will be assigned on the basis of established Public
Health Service referral guidelines.  Applications will be reviewed
for scientific and technical merit by study sections of the Division
of Research Grants, NIH, in accordance with the standard NIH peer
review procedures.  Following scientific and technical review, the
applications will receive a second-level review by the appropriate
national advisory council.

Applications that are complete and responsive to the program
announcement will be evaluated for scientific and technical merit by
an appropriate peer review group convened in accordance with the
standard NIH peer review procedures.  As part of the initial merit
review, all applications will receive a written critique and undergo
a process in which only those applications deemed to have the highest
scientific merit, generally the top half of applications under
review, will be discussed, assigned a priority score, and receive a
second level review by the appropriate national advisory council or

Review Criteria

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 the resources necessary to perform the research;

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

o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be

The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.


Applications will compete for available funds with all other approved
applications assigned to that IC.  The following will be considered
in making funding decisions:  Quality of the proposed project as
determined by peer review, availability of funds, and program


Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Isabella Liang, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Two Rockledge Center Suite 9044
6701 Rockledge Drive
Bethesda, MD  20892-7940
Telephone:  (301) 435-0520
FAX:  (301) 480-1335

Direct inquiries regarding fiscal matters to:

William W. Darby
Grants Operations Branch
National Heart, Lung, and Blood Institute
Two Rockledge Center Suite 7128
6701 Rockledge Drive
Bethesda, MD  20892-7128
Telephone:  (301) 435-0177
FAX:  (301) 480-3310


This program is described in the Catalog of Federal Domestic
Assistance No. 93.837.  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

The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routing education,
library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS
mission to protect and advance the physical and mental health of the
american people.


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