Full Text HL-93-06

ISCHEMIC HEART DISEASE, SUDDEN CARDIAC DEATH, HEART FAILURE

NIH GUIDE, Volume 21, Number 39, October 30, 1992

RFA:  HL-93-06-H

P.T. 04

Keywords: 
  Cardiovascular Diseases 
  Etiology 
  Pathophysiology 
  Biomedical Research, Multidiscipl 
  Diagnosis, Medical 
  Disease Prevention+ 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  June 1, 1993
Application Receipt Date:  August 2, 1993

PURPOSE

This initiative seeks to foster an innovative research approach to
the study of Ischemic Heart Disease, Sudden Death, or Heart Failure.
This will be accomplished by soliciting applications for Specialized
Centers of Research (SCOR) for each of these three diseases.  The
program is open to all investigators, including those who are
participating in the current SCOR program and those who are not.  The
emphasis of this new solicitation is on creative, interdisciplinary
approaches to elucidation of the etiology and pathophysiology of
these diseases at the molecular, cellular, and tissue levels and the
translation of research findings into improved diagnosis, treatment
and prevention.  Applicants are required to select a single theme
pertaining to Ischemic Heart Disease or Sudden Cardiac Death or Heart
Failure and to develop a cluster of research projects clearly
focussed on that theme.  The goal is to foster a synergistic
environment for integrating basic science and clinical
investigations.  All projects must have clearly stated hypotheses and
include original and innovative ideas with respect to the problem to
be studied.

A given institution may respond to more than one of the current
topics in this solicitation, but may not submit more than one
application for a given topic.  Additionally, because a SCOR is a
major research commitment, each application must have a different
principal investigator and preferably no overlap in professional
personnel between the SCOR applications.  Applications must relate
clearly to the theme of a specific solicitation.  Potential
applicants are therefore urged to consult with staff to determine
which solicitation offers the best fit for their research needs.

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.  The RFA,
Specialized Centers of Research in Ischemic Heart Disease, Sudden
Cardiac Death, and 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).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic, for-profit, and non-profit
organizations, public and private, such as universities, units of
State and local governments, and eligible agencies of the Federal
government that have established clinical programs in cardiology and
the capability to conduct relevant basic research. Applications from
minority individuals and women are encouraged.  Foreign organizations
are ineligible. International collaborations in domestic applications
will only be accepted if the resources are clearly shown to be
unavailable to the United States.

The program director must devote at least 25% effort to the SCOR and
be the project leader on at least one project or core.  All project
leaders must propose at least 20% effort.  Applications not
fulfilling these requirements will be ineligible for participation in
the competition.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) specialized
center grant mechanism (P50).  Responsibility for planning the
proposed project will be solely that of the applicant.  The total
project period for applications submitted in response to the present
RFA may not exceed five years.  The anticipated date of award is
January 1, 1995.

Although multidisciplinary approaches are required, it is not the
intent of this announcement to solicit applications for large
clinical trials or large epidemiological studies. In general, funds
will not be provided for the purchase and installation of expensive,
new equipment.

Upon initiation of the program, the Division of Heart and Vascular
Diseases will sponsor periodic meetings to encourage exchange of
information among investigators who participate in this program, and
to stimulate collaboration.  Applicants should request travel funds
for a one-day meeting each year, most likely to be held in Bethesda,
Maryland.  Applicants should also include a statement in their
applications indicating their willingness to participate in these
meetings.

This RFA will be the final solicitation for the area of ischemic
heart disease.

FUNDS AVAILABLE

Approximately $18 million in total cost will be provided for the
first year of support for the entire program.  However, no applicant
may request more than $1 million in direct costs in the first year of
support.  Indirect costs associated with subcontracts are not
included in calculations of the upper limit.  Future years may be
escalated at no more than four percent.  It is anticipated that 10-12
grants will be awarded under this program.  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 plan of the NHLBI, awards pursuant to this RFA are
contingent upon the availability of funds for this purpose.
Administrative adjustments in project period and/or amount of support
may be required at the time of the award.

RESEARCH OBJECTIVES

Background (NHLBI Specialized Centers of Research)

A SCOR consists of three or more closely related projects and one or
more core units which provide specialized services to several of the
projects.  At least one of the projects must be clinical and involve
human subjects.  All SCOR applications must include an administrative
core which serves as a focal point for the SCOR program.

The purpose of the NHLBI SCOR program is the translation of new
scientific information into improved care of patients. Its structure
is designed to create an environment in which investigators work
together on projects related to a specifically defined theme.  A SCOR
contains both basic science and clinical elements and includes
features that: (1) encourage the rapid transfer of new scientific
information to patient care; (2) facilitate the ability to exploit
new scientific opportunities; and (3) take advantage of economies of
scale through the use of one or more core resource units which
perform specialized services for several or all projects.

An essential feature of a SCOR is a Director capable of providing
effective scientific and administrative leadership to a cluster of
related individual research projects involving basic, applied and
clinical investigations.  In addition, the Director must devote 25%
effort to the SCOR and be the project leader of at least one
subproject.  The Director is responsible for the organization and
operation of the Center and for all communication with NHLBI on
scientific and operational matters.  Each SCOR Director should
encourage and support close collaboration between individual SCOR
investigators by means of frequent meetings and seminars.

There are two recent NHLBI policies of which potential applicants to
this RFA should take note.  The first is that it is anticipated that
SCOR programs will receive a maximum of ten years support.  To
implement this policy, applicants already participating in the SCOR
program are allowed to apply for one final renewal in the category in
which they are currently funded.  New SCORs established as a result
of the current competition will have the opportunity to compete for
one five year renewal.  This policy will only be waived if deemed
advisable after thorough programmatic review.

The second policy relates to a limitation of $1 million in the amount
of direct costs which may be requested in response to this
solicitation in either new or renewal applications.  Applications
requesting larger amounts will be returned to the applicant.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  In such a case, a letter of agreement from
either the GCRC program director or Principal Investigator could be
included with the application.

Background (Scientific)

Ischemic Heart Disease (IHD)

Although the number of deaths from coronary heart disease continues
to decline, mortality remains high.  There were 498,000 deaths in
1989 compared in 489,000 in 1990.  In spite of a gratifying decline
in mortality, there is no evidence of a similar decline in morbidity.
The prevalence of coronary heart disease in the United States
population is 6.1 million and the estimated total economic burden is
$54.2 billion annually.

Moreover, IHD is the leading cause of mortality and morbidity
throughout the world and despite the research effort that has been
made to date, a number of outstanding problems remain.  The following
discussion represents a few of those problems.  Applicants are urged
to consider other themes that might represent important research
areas not discussed below.

In terms of diagnosis, there is a continuing need for improved
strategies to assess myocardial perfusion and viability.  There is
also a need to understand the physiologic bases for chest pain and
silent ischemia.  One neglected area of research is that of the
cardiac microcirculation.  Evidence has accumulated that, in a subset
of patients with normal coronary anatomy and chest pain, ischemia
occurs because of increased resistance in the small arterial vessels.
This is thought to be of importance in hypertensive patients, in
patients with diabetes and in many women who present with chest pain.
The cell biology, physiology and pathophysiology of the
microcirculation have received little attention from cardiovascular
investigators yet it is clear from studies with nitroglycerin that
the properties of the microvessels differ from those of the large
coronary arteries.  Moreover, hypercholesterolemia and hypertension
have recently been shown to lead to microvascular dysfunction and
impairment of endothelial-dependent increases in blood flow.  Thus
there are opportunities for research at all levels including the
basic properties of the cells of the microvascular wall, factors
controlling microvascular resistance and responses to pharmacologic
agents.

While major advances have been made in the treatment of stenosed and
occluded coronary arteries, a number of important questions remain.
Several current clinical trials have been designed to refine the
administration of thrombolytic agents for maximum clinical benefit
and minimal reocclusion and side effects, especially intracerebral
hemorrhage.   Further definition of optimal therapeutic regimens
could be rapidly advanced by fundamental research aimed at further
elucidation of the regulatory mechanisms which are perturbed in
coronary thrombosis.  The pathophysiology surrounding formation of a
mural thrombus, its growth and regression, the relationship of
unstable plaque to thrombus formation, the effect of disordered
endothelium, vasospasm and the various mechanisms underlying these
phenomena need further research.

Percutaneous transluminal coronary angioplasty (PTCA) has been
increasingly used as an alternative to coronary artery bypass
surgery, but even with current improvements in techniques the
restenosis rate remains at 20-40%.  It has been clearly shown that
restenosis relates to vascular injury with deendothelialization and
exposure of the underlying vessel structure directly to blood. In
addition to platelet activation, the healing response includes
intimal hyperplasia.  It has also been observed that even when
healing includes reendothelialization, the endothelium does not
function normally as a non-thrombogenic surface until several months
later.  It would also appear that the endothelium fails to function
normally with respect to control of vascular smooth muscle activity.
Moreover, there are perturbations of the mechanisms which control
growth of the extracellular matrix.  Finding a solution to the
problem of restenosis in terms of patient care requires further
investigation at the molecular and cellular level and translation of
those results into clinical interventions.

Reperfusion injury is a problem which spans all therapeutic
approaches to the treatment of acute ischemic heart disease.
Although much research has been done on this topic there is no clear
indication at the present time of a clinical regimen which would
prevent its occurrence.  This represents an area where there is a
great need for an interdisciplinary approach to the problem.

Sudden Cardiac Death (SCD)

SCD is a major health problem.  It is most commonly defined as
cardiac death occurring within one hour of onset of cardiovascular
symptoms.  In the United States there are approximately 250,000
sudden cardiac deaths per year, the majority occurring at home.
About half of the deaths in patients with known coronary heart
disease are sudden and unexpected.  These figures may actually
underestimate the size of the problem, given the various definitions
of SCD and their translation into death certificate entries. Current
research efforts are not well integrated and there is a compelling
need to sponsor a coordinated, interdisciplinary program which will
provide new insights into this catastrophic condition.

Treatment of SCD is generally effective if it can be applied very
rapidly, as demonstrated by coronary care units and by more recent
experience with automatic external defibrillators.  The majority of
these patients have not had irreparable cardiac damage and can
readily be converted to normal cardiac rhythm if they can be treated
quickly. However, since most SCD occurs outside the hospital setting,
and time to resuscitation is critical, the overall survival to
hospital discharge is only about 20% for the acute event.

The SCD population is dominated by coronary artery disease although
some of the most disturbing instances of sudden cardiac death are not
due to ischemic heart disease.  Many resuscitated patients have not
had an acute myocardial infarction as the precipitating cause for
SCD, though many have had prior myocardial damage and show evidence
of coronary artery lesions.  It should be noted, however, that SCD
occurs in virtually all chronic cardiac disorders, including
idiopathic cardiomyopathy, valvular heart disease, left ventricular
hypertrophy and long QT interval syndromes.  It also occurs after
cardiac surgical procedures, such as valve replacement and repair of
congenital heart defects.  Patients with diabetic autonomic
neuropathy, without evidence of cardiac disease, have also been shown
to have QT interval prolongation which increases their risk for SCD.

In the group with coronary artery disease, the population of patients
at risk has been identified, but the findings are not specific.
About a third have a left ventricular ejection fraction below 0.30,
but almost 30% have a value above 0.50.  Approximately 95% have at
least one significant coronary stenosis, and most patients have some
type of left ventricular contractile abnormality.

To a large extent, the little that is known about the
pathophysiologic factors leading to SCD has been gleaned by detailed
study of the population of patients who have survived an episode of
SCD, and have had a recurrent episode.  The recurrence rate of SCD is
substantial and this population may provide investigators with the
best opportunity to learn more about this problem.

The arrhythmic mechanism in the vast majority of the patients is
ventricular fibrillation, sometimes preceded by ventricular
tachycardia.  Asystole is uncommon as the first event, although it
may ultimately be found after a period of ventricular fibrillation.
It is generally agreed that chronic atherosclerotic lesions are the
dominant pathologic finding, but there is less agreement about the
frequency with which an acute thrombotic event is associated with
SCD.  In one study about 80% of patients were found to have a
coronary thrombus at autopsy.  According to the limited information
available, electrocardiographic monitoring has generally failed to
show the presence of acute ischemia immediately preceding the event.
The cellular mechanisms provoking ventricular fibrillation are not
known.

In the congenital heart disease population, about 80% of the children
enter adulthood, i.e. about 25,000 enter the adult population each
year.  All of the patients with postoperative cyanotic lesions and
20% of those with acyanotic lesions are at risk for sudden cardiac
death, which occurs at about 0.5% per year.  It is estimated that
about 1,250 patients in this population die suddenly each year.
Moreover, excluding sudden infant death syndrome and congenital heart
disease, there are a number of children and young adults who die
suddenly.  The most publicized group are athletes, but there are many
others for whom no cause is apparent.  Still others may succumb to
sudden cardiac death because of idiosyncratic or adverse responses to
legal and illegal drugs (e.g. cocaine).

The recent randomized trials of antiarrhythmic drugs for patients at
risk for SCD after myocardial infarction showed a higher mortality
for patients receiving flecainide, encainide and moricizine than
those receiving placebo. These unexpected results may have had their
roots in unknown facts about fundamental properties of the drugs,
which have been incompletely explored in the setting of diseased
tissue and the whole organism.  There is also a lack of understanding
of the triggers of SCD.  Thus, much knowledge is needed of
antiarrhythmic drug effects on normal and ischemic myocardium as well
as on possible physiological activity of drug metabolites.

Implantation of the automatic cardioverter-defibrillator has achieved
some success but has been used for those who have already survived
one episode of SCD.  In addition, this device is very expensive and
requires major surgery. Although it offers great hope to those at
high risk for SCD, the problem remains of identifying the susceptible
population before the first life-threatening event.

Research is needed in several major directions; namely, (1) to
acquire knowledge of the precipitating mechanisms which lead to the
lethal event, (2) to identify the substrate with which the
precipitating factor interacts and (3) to devise improved strategies
for identifying specific patients at risk.  Greater understanding of
the molecular and cellular events leading to SCD should provide a
rational basis for developing strategies to identify patients at risk
and for acquiring knowledge of points in the pathophysiologic cascade
where intervention could be applied.

Fundamental to our understanding of the mechanisms of
arrhythmogenesis and the actions of antiarrhythmic drugs is increased
knowledge of the structure and function of specific ion channels.
Purification and sequence determination of ion channels in the heart
are already progressing well and are prerequisites for deducing
structural models accounting for their function.  Among the questions
that remain to be answered are the molecular basis for ion permeation
and gating characteristics, i.e., the basis for selectivity, voltage
sensitivity, activation by neurotransmitters, modification by drugs,
and regulation by other endogenous factors such as cyclic
nucleotides. This information could provide a rational basis for the
design of drugs of greater selectivity and potency, and may set the
stage for a greater understanding of the biochemical basis of
cardiovascular dysfunction.

Identification and purification of ion channels should facilitate the
production of highly specific antibodies to these proteins.
Immunocytochemical localization of specific ion channels can define
their distribution and density in cardiac cells.  Since the response
of an electrically excitable cell is defined by the molecular
machinery responsible for ion conductance, localizing these channels
may help to quantitatively predict the electrical properties and
responses of such cells, and the occurrence of perturbations in
disease states.

Knowledge of the structure of ion channels is also required to
explore the mechanism of action of drugs whose receptor sites are ion
channels.  Once the structure of ion channels is understood,
sophisticated techniques such as x-ray and neutron diffraction can be
used to study the location and conformation of drug molecules in
biological membranes.  In combination with other techniques, the
interactions of drugs and their receptors in biological membranes can
be studied.

The pathogenesis of cardiac arrhythmias cannot be understood by
cellular studies alone.  Investigations are also needed to elucidate
the mechanisms underlying abnormalities of propagation that persist
in the patient with ischemic heart disease.  Although abnormalities
in cell-to-cell coupling as well as sarcolemmal channel function
could lead to slow conduction, the basis of the disturbance in
propagation in the chronic phase of ischemic heart disease is still
obscure.  Potential causes of slow conduction include scar tissue
formation, changes in metabolic activity within cells, neural and
hormonal factors and the physiological consequences of a coronary
artery plaque rupture or thrombotic event.

The Framingham study has shown that left ventricular hypertrophy
(LVH) as assessed by ECG is a risk factor for sudden cardiac death.
LVH makes the heart more vulnerable to ventricular fibrillation when
coronary occlusion occurs and it would appear that coronary artery
disease, which might otherwise be insignificant, may have
pathophysiologic importance in the presence of LVH.  Another possible
mechanism for sudden cardiac death in LVH is the presence of fibrous
tissue formation which is frequently associated with the hypertrophic
process.  Thus, study of the relationship of altered substrates to
biochemical changes and ion channels may provide additional insight
into the pathogenesis of SCD.

Although the extent and structure of scar tissue are known to affect
impulse propagation, little is known about the biochemical and
structural properties which contribute to alterations in conduction
velocity and to re-entrant tachycardias.  In animal models with
chronic infarcts, transmembrane action potentials recorded from sites
of fragmented electrograms were normal.  Proof that surviving cells
in the subendocardium form re-entrant pathways is lacking.  Further
studies of scar tissue are needed to eliminate or illuminate its role
in re-entrant arrhythmias.

Recent research with PET technology shows that it is possible both in
humans and animal models to measure the metabolic status of the heart
under ischemic and reperfused conditions as well as to simultaneously
observe ECGs.  This technique offers the possibility of studying the
post- ischemic metabolic events which may precipitate a lethal
arrhythmia.  It may also provide information about the ECG changes
associated with myocardial metabolic abnormalities.

Both the central and autonomic nervous systems have been implicated
in the cascade of events leading to a lethal arrhythmia and
experiments have been performed which clearly demonstrate neural
effects.  However, the mechanisms involved remain obscure.  It is not
known, for example, whether the biological effects of neural and
other peptides are important.  Furthermore, since innervation of the
heart in man may differ from that of animal models, human studies are
needed.

In summary, there are a variety of mechanisms which may contribute to
SCD and relatively few have been adequately defined, although a large
amount of descriptive clinical and epidemiologic data have been
accumulated with regard to some aspects of the problem.  Thus, it is
important to develop hypotheses and concepts for the foundation of
basic and clinical research.

Heart Failure (HF)

HF is the final common pathway of a variety of primary cardiovascular
disease entities, such as coronary artery disease, hypertension,
valvular heart disease, and the sequelae of infection, toxin exposure
or diabetes, among others.  The incidence of and mortality from heart
failure have increased steadily since 1968, despite the overall
improvement in mortality from cardiovascular diseases.  Heart failure
is now the underlying cause of death in over 41,000 persons annually;
in 1990 it was the first listed hospital discharge diagnosis in
722,000 persons, and the most common discharge diagnosis in patients
over 65 years of age.  Death from heart failure is 1.5 times higher
in black than in white Americans.  The estimated economic cost of
heart failure in the United States is reported to be $10.2 billion
annually.  At present, the only effective palliation of the end-stage
disease is cardiac transplantation, with mechanical circulatory
support sometimes used as a bridge to transplantation.  The Institute
of Medicine report on the artificial heart strongly recommended
increased emphasis on research to prevent and treat heart failure.

Heart failure is associated with a variety of structural forms.  Much
clinical information has been accumulated, but little is known about
how abnormalities found in heart failure patients relate to
progression of the disease. Research is needed to understand the
molecular mechanisms that produce the various forms of heart failure
and to understand whether these result from similar pathways, from
convergence to a final common pathway, or from different mechanisms
producing the same end result.  Elucidating the mechanisms involved
may provide insight into the optimal choice and timing of
interventions to prevent further deterioration of cardiac function or
to reverse damage to the myocardium.

Diagnostic evaluation of heart failure patients has not kept pace
with the available new information about the pathobiology of the
condition.  Thus functional status, while providing useful clinical
data about functional disability, does not correlate well with
hemodynamic variables or predict the course of disease.  Relatively
little is known about interactions among the observed phenomena or
precisely how the process relates to the clinical features of heart
failure.  More sensitive detection of features such as cardiac
remodeling might permit diagnosis of heart failure risk before
clinical symptoms appear. Imaging techniques using single photon or
positron emission tomography or nuclear magnetic resonance may allow
detection of myocardial restructuring that predicts a future
transition to overt heart failure well in advance, and thus provide a
greater opportunity for therapeutic intervention.  These methods may
also have the power to extend understanding of changes in the
efficiency of energy utilization in the structurally compromised
heart.  More information about the features and implications of
energy utilization in the failing heart may provide further insight
into the mechanism(s) of functional disability in the disorder.
Other lines of evidence suggest that neuroendocrine activation is a
reliable predictor of worsening heart failure.  Research is needed to
understand whether neuroendocrine excess can be considered a global
predictor of decline in heart failure patients and, if so, to
correlate its onset with specific functional and physiological
deficits.

A growing body of clinical evidence has now clearly demonstrated an
improvement in the clinical course of heart failure patients with
vasodilators.  The results from the Studies of Left Ventricular
Dysfunction (SOLVD) and the Veterans Administration-Heart Failure
Trial (V-HeFT II) show that angiotensin converting enzyme (ACE)
inhibitors provide improvement in life expectancy.  Further
improvement in treatment outcome requires earlier detection of the
need for treatment and more specific therapeutic remedies.  The
recent suggestion that ACE inhibitors have the potential to reverse
structural remodeling of the myocardium may provide avenues for the
development of more effective treatments.

Recent observations in patients, animal models and cell cultures have
demonstrated that heart failure is associated with programmed changes
in cardiac tissue.  It appears to involve a fundamental deviation
from the normal program of adult gene expression, including changes
in actin and myosin, down-regulation of calcium ATPase and de novo
expression of atrial natriuretic peptide by ventricular myocytes,
among others.  The cellular pathobiology has been shown to include
the reactivation of a program of gene expression normally observed
during fetal development. These changes can be induced by a number of
purified or recombinant growth factors, for example acidic fibroblast
growth factor.   Research is progressing to describe the chain of
events occurring in the early stages of the progression to heart
failure.  Further work is required to investigate the physiologically
relevant signals and pathways involved.

New information from a variety of models suggests that cell signaling
molecules such as angiotensin, endothelin and immune cytokines may
play a role in determining adaptations in heart failure.  Important
substances arising locally in myocardial, vascular endothelial,
interstitial or microcirculatory compartments may play individual
roles in developing the long-term response to insult; such substances
are likely also to interact in a complex system of cross-talk
throughout the heart, whether through endocrine, paracrine or
autocrine mechanisms.  Systemic factors may also be involved.  Taken
together, these observations suggest new avenues of investigation for
the elucidation of the complex physiological phenomena leading to the
development of cardiac failure.

Objectives and Scope

All applications must be focused on only one of the listed topics and
must include both clinical and basic projects that are clearly
inter-related.  Research focussed mainly on areas which traditionally
fall under the purview of the atherosclerosis and hypertension SCOR
programs will be unresponsible to this solicitation.

Proposed Research

The suggestions provided below are for illustrative purposes only.
They do not represent the full range of possible research projects
which would be responsive to this solicitation nor do they represent
Institute priorities.  Applicants are urged to develop their own
programs of research that would advance knowledge, treatment and
prevention of the disease they are investigating.

Ischemic Heart Disease

o  Pathologic and animal model studies to elucidate the structural
and functional changes which occur in the microvasculature as
sequelae of cardiac hypertrophy and ischemia, including the role of
cells of the immune system in this pathophysiology.

o  Investigation of the contribution of disease/dysfunction of
intramyocardial arteries to chest pain in the absence of documented
disease of the large coronary arteries

o  Study of the cell biology and physiology of normal and
dysfunctional endothelial and vascular smooth muscle cells of
intramyocardial resistance vessels and their responses to
pharmacologic agents

o  Roles of diabetes, dyslipidemia and hypertension in the etiology
of microvascular disease including molecular and cellular studies to
elucidate the underlying mechanisms which are perturbed

o  Investigations designed to distinguish the morphologic and
functional characteristics of coronary arteries which restenose
compared to those which do not

o  Evaluation of innovative therapies to control vascular smooth
muscle cell proliferation and migration following endothelial cell
injury

o  Studies designed to understand the factors which contribute to
reocclusion following thrombolysis

o  Innovative approaches to the prevention of reperfusion injury
following recanalization of coronary arteries

o  Improved imaging for detection of stunned myocardium, and other
manifestations of ischemic dysfunction

o  Contributions of altered protein structures of myocytes to
contractile dysfunction

o  Gene expression of heat shock proteins and growth factors and
their potential pathophysiologic or protective roles in ischemia and
reperfusion injury

o  Evaluation of the hypothesis that an occluding thrombus may
release factors which, directly or indirectly, affect impulse
propagation and conduction

Sudden Cardiac Death

o  Development of novel, relevant animal models to simulate SCD and
to examine specific hypotheses which might lead to elucidation of the
pathophysiology of SCD

o  Elucidation of the molecular basis for the dysfunction of ion
channels and intercellular communication in electrically unstable
myocardium

o  Development of transgenic animals with specific alteration in
cardiac ion channels as models to study physiology and secondary
effects on the myocardium

o  Identification and testing of genes responsible for susceptibility
to SCD and elucidation of the physiologic correlates of altered gene
expression

o  Evaluation of the regulatory role of cyclic nucleotides and
calcium in relation to arrhythmogenesis and altered
electrophysiological properties both in vitro and in vivo

o  Elucidation of the mechanisms whereby cardiac hypertrophy results
in disorders of cardiac rhythm

o  Analysis of cardiac rhythms using non-linear dynamics, including
deterministic chaos and fractal mathematics

o  Examination of the concept that fibrosis and the activities of the
cells of the cardiac interstitium influence impulse propagation in
the myocardium

o  Evaluation of the hypotheses that the pathophysiology of sudden
cardiac death involves altered myocardial metabolism, autonomic
nervous system dysfunction and changes in the cardiac interstitium

o  Elucidation of the molecular, cellular and metabolic basis for the
arrhythmogenic properties of anti-arrhythmic drugs

o  Evaluation of the hypothesis that an occluding thrombus or
infarcting myocardium may release factors which, directly or
indirectly, affect impulse propagation and conduction

o  Studies of preventive therapies such as new drugs, surgical and
ablative techniques and a new, smaller defibrillator which can be
inserted by intravenous route to prevent SCD

HEART FAILURE

o  Elucidation of the mechanisms that transduce hypertrophic stimuli
from the cell surface to the nucleus, such as adrenergic or stretch
receptors, cytoplasmic receptors, second messenger systems, and local
nuclear transducing molecules

o  Understanding differences at the cellular and molecular levels
that differentiate the phenotype associated with successfully
compensated hypertrophy from that associated with cardiac failure

o  Study of the changes in cardiac myocyte structure and function
that lead to pump failure

o  The effect of altered gene expression on the mechanisms of calcium
handling in the failing myocardium

o  Experiments to determine how increased or decreased expression of
myocardial proteins affects the resistance of the myocyte to
deleterious effects of hypertrophic stimuli

o  Investigation of potential mechanism(s) that control the ability
of the myocyte to produce specific growth factors and hormones

o  Clinical and basic science issues related to diastolic and
systolic dysfunction

o  Identification of biochemical markers of early heart failure that
predict clinical course

o  Experiments that describe which of the known abnormalities
described in heart failure patients are physiologically important,
and which are epiphenomena

o  Investigation of the relationship between neuroendocrine activity
and worsening clinical picture

o  Development of diagnostic tools for detecting myocardial
remodeling by noninvasive imaging methods

o  Investigation of potential treatment options arising from new
molecular knowledge about the cell biology of heart failure

o  The basis for exercise intolerance in heart failure. For example,
experiments on peripheral adaptations to central changes in the
weakened heart

o  Investigation of the interaction between renal and cardiac
influences on blood volume regulation and pressure and their effect
on outcome for heart failure patients

SPECIAL INSTRUCTIONS FOR INCLUSION OF WOMEN AND MINORITIES IN
CLINICAL RESEARCH STUDIES

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
women on study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed-population based studies, a clear
compelling rationale must be provided.

The composition of the proposed study population must be described in
terms of gender.  In addition issues of gender 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 adequate numbers of
women.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and prevention strategies), 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 excluded.  However,
every effort should be made to include human tissues from women 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 not be accepted for review.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women is inadequate to answer the scientific question(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.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by June 1, 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.

The letter of intent is to be sent to:

Chief, Centers and Special Projects Section
Review Branch/Division of Extramural Affairs
National Heart, Lung and Blood Institute
Westwood Building, Room 553 A
Bethesda, MD  20892

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 and may be obtained from
the Office of Grants Inquiries, Division of Research Grants, National
Institutes of Health, Westwood Building, Room 449, Bethesda, MD
20892, telephone 301-496-7441.

Applicants must follow the instructions provided in the supplement to
the RFA.

The RFA label available in the PHS 398 application form must be
affixed to the bottom of the fact page of the application.  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, to identify the application as a response
to this RFA, Check "YES", enter the title "Ischemic Heart Disease,
Sudden Cardiac Death, Heart Failure", and the RFA number HL-93-06-H
on Line 2a of the face page of the application.

Send or deliver a signed, typewritten original of the application,
including the checklist, and three signed photocopies, in one package
to:

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

Send two additional copies of the application to Chief, Centers and
Special Projects Section at the address listed under LETTER OF
INTENT.  It is important to send these two copies at the same time as
the original and three copies are sent to the Division of Research
Grants (DRG), otherwise the NHLBI cannot guarantee that the
application will be reviewed in competition for this RFA.

Applications must be received by August 2, 1993.  If an application
is received after that date, it will be returned to the applicant.
The DRG will not accept any application in response to this
announcement that is essentially the same as one currently pending
initial review, or is essentially the same as one already reviewed.
This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.

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, it will be returned.

Applications will be triaged on the basis of relative competitiveness
by a peer review group convened by the NHLBI.  The NIH will withdraw
from further competition those applications judged to be
non-competitive for award and notify the applicant Principal
Investigator and institutional official.  Those applications judged
to be competitive will undergo further scientific merit review.  They
will be evaluated in accordance with the criteria stated below for
scientific/technical merit by an appropriate peer review group
convened by the NHLBI.  The initial review may include a site visit
or applicant interview.  The second level of review will be provided
by the National Heart, Lung, Blood Advisory Council.

Review criteria for RFAs are generally the same as those for
unsolicited interdisciplinary research grant applications.

o  the scientific merit of each proposed project in the application,
including originality, feasibility of the approach, and adequacy of
the experimental design;

o  the integration of the clinical and fundamental research into a
coherent enterprise with adequate plans for interaction and
communication of information and concepts among the collaborating
investigators;

o  the technical merit and justification of each core unit;

o  the qualifications, experience, and commitment of the SCOR
Director and his/her ability to devote adequate time and effort to
provide effective leadership;

o  the competence of the project investigators to accomplish the
proposed research goals, their commitment, and the time they will
devote to the program;

o  the adequacy of facilities to perform the proposed research
including the laboratory and clinical facilities, access to subjects,
instrumentation, and data management systems when needed;

o  the scientific and administrative structure of the program,
including adequate internal and external arrangements and procedures
for monitoring and evaluating the proposed research and for providing
ongoing quality control and scientific review;

o  the institutional commitment to the program and the
appropriateness of the institutional resources and policies for the
administration of a research program of the type proposed; and

o  the appropriateness of the budget for the proposed program.

AWARD CRITERIA

Applications must fulfill all the eligibility criteria in order to be
considered for funding.  Since a variety of approaches would
represent valid responses to this announcement, it is anticipated
that there will be a range of costs among individual grants awarded.
The most important criterion in selecting awardees will be the
scientific merit as reflected in the priority score.  However,
factors such as program balance and available funds may enter into
selection from among meritorious applications.

Since a variety of approaches would represent valid responses to this
announcement it is anticipated that there will be a range of costs
among individual grants awarded. The anticipated date of award is
January 1, 1995.

INQUIRIES

Inquiries regarding this announcement may be directed to:

Dr. Constance Weinstein
Cardiac Diseases Branch
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Federal Building, Room 3C06
Bethesda, MD  20892
Telephone:  (301) 496-1081
FAX:  (301) 480-6282

Inquiries regarding fiscal and administrative matters may be directed
to:

Mr. William Darby
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A11
Bethesda, MD  20892
Telephone:  (301) 496-7536
FAX:  (301) 402-1200

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.837, Heart and Vascular Diseases.  Awards will be
made under the authority of the Public Health Service Act, Section
301 (42 USC 241) and administered under PHS grants policies and
Federal regulations, most specifically 42 CFR Part 52 and 45 CFR Part
74.  This program is not subject to the intergovernmental review
requirements of Executive Order 12372, or to Health Systems Agency
review.

.

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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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