Full Text HL-95-005

ISCHEMIC HEART DISEASE IN BLACKS

NIH GUIDE, Volume 23, Number 35, October 7, 1994

RFA:  HL-95-005

P.T. 04, FC

Keywords: 
  Cardiovascular Diseases 
  Diabetes 
  Biomedical Research, Multidiscipl 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  November 30, 1994
Application Receipt Date:  May 18, 1995

PURPOSE

This solicitation invites grant applications to enter into a single
open competition for Specialized Centers of Research (SCOR) in Ischemic
Heart Disease in Blacks.  Applicants should select one of three themes,
Sudden Cardiac Death, Microvascular Disease, or Diabetic Heart Disease
as the focusof their applications.  The goal of this initiative is to
foster an interdisciplinary study of issues surrounding the expression
of heart disease in Blacks.  To this end, applicants must present an
application that encompasses both basic and clinical science, including
studies in Black patients.

The goal of the program is to advance understanding of the expression
of heart disease in this population through exploitation of modern
methods and approaches to molecular biology, cellular and organ
physiology, and clinical practice.

A SCOR provides the opportunity for investigators to engage in
interdisciplinary and collaborative research that is focused on a
specific disease or an area within a disease category.  It is required
that SCOR applications include studies of human subjects as well as
basic studies clearly related to a disease area.  The foundation of the
clinical component should be strongly linked to the basic science
projects; the basic science studies should be driven by the needs of
the clinical projects.  Thus, a SCOR has a central theme to which all
research projects pertain.  In addition, a SCOR may include CORE units
to provide services to the various research projects and to support the
organizational and administrative aspects of the program.

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 RFA,
Specialized Centers of Research in Ischemic Heart Disease in Blacks, is
related to the priority areas of heart disease and stroke, and diabetes
and chronic disabling diseases.  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 for-profit and non-profit domestic
institutions, public and private, such as universities, colleges,
hospitals, and laboratories, units of State and local governments, and
eligible agencies of the Federal government.  Applicants must provide
evidence that there is an adequate resource of eligible Black subjects
to meet proposed recruitment goals.  In addition applicants should
provide detailed plans of recruitment and retention strategies for
study subjects so that liklihood of meeting recruitment targets can be
assessed.  Awards will not be made to foreign institutions.  However,
under exceptional circumstances, a foreign component critical to a
project may be included as a part of that project.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) specialized
center of research 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
September 1995.

Although multidisciplinary approaches are required, it is not the
intent of this RFA 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.

The principal investigator should be an established research scientist
with the ability to ensure quality control and the experience to
administer effectively and integrate all components of the program.  A
minimum time commitment of 25 percent is expected for this individual.
The principal investigator must also be the project leader of one of
the component research projects.  If, through peer review, this project
is not recommended for further consideration, the overall SCOR
application will not be considered further.  If this project is judged
by peer review to be of low scientific merit, it will markedly reduce
the overall scientific merit ranking assigned to the entire application
by the review committee.  Project leaders must agree to commit at least
20 percent effort to each project for which they are responsible.

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 is intended to support Specialized Centers of Research grants.
Therefore, applications that include only basic or only clinical
research will not be responsive to this RFA.  This solicitation is
intended to redress the inadequate data base of studies in Blacks.
Therefore, only clinical studies in Blacks will be responsive to this
RFA.  In addition, clinical research projects focused on large studies
or large clinical trials will be considered unresponsive to this RFA.

Consortium Arrangements

If a grant application includes research activities that involve
institutions other than the grantee institution, the program is
considered a consortium effort.  Such activities may be included in a
SCOR grant application, but it is imperative that a consortium
application be prepared so that the programmatic, fiscal, and
administrative considerations are explained fully.  The published
policy governing consortia is available in the business offices of
institutions that are eligible to receive Federal grants-in-aid.
Consult the latest published policy governing consortia before
developing the application.  If clarification of the policy is needed,
contact William Darby, (301) 594-7458.  Applicants of SCOR grants
should exercise great diligence in preserving the interactions of the
participants and the integration of the consortium project(s) with
those of the parent institution, because synergism and cohesiveness can
be diminished when projects are located outside the group at the parent
institution. Indirect costs paid as part of a consortium agreement are
excluded from the limit on the amount of direct costs that can be
requested.

FUNDS AVAILABLE

Approximately $4.8 million in total costs will be provided for the
first year of support for the entire program.  Applicants may request
up to $1,080,000 direct costs, not including indirect costs for
collaborating institutions, in the first year with a maximum increase
of no more than four percent in each additional year requested in the
application.  It is anticipated that up to three grants will be awarded
under this program.  Although this program is provided for in the
financial plan of the NHLBI, award of grants pursuant to this RFA is
contingent upon receipt of funds for this purpose.  Administrative
adjustments in project period and/or amount of support may be required
at the time of the award.

Equipment is included in the budget limitation.  However, requests for
special equipment that cause an application to exceed this limit may be
permitted on a case-by-case basis following staff consultation.  Such
equipment requires strong justification.  Final decisions will depend
on the nature of the justification and the availability of funds.

RESEARCH OBJECTIVESS

Background

Ischemic Heart Disease (IHD) and heart muscle disease is the leading
cause of mortality in the United States, and is particularly important
to study in Blacks due to their disproportionately high death rates.
Other minority groups (Hispanics, Asian/pacific Islanders and American
Indians) have lower death rates than Whites.  To chart a course for
future research, the NHLBI convened a working group which released its
report in March 1994 on RESEARCH IN CORONARY HEART DISEASE IN BLACKS.
This report provides specific recommendations for future research in
Black populations.  The NHLBI strongly encourages research into the
pathogenesis of diseases in Blacks, and recommends that this report be
consulted.

Scientific

IHD or myocardial damage secondary to ischemia has been a major focus
in cardiovascular research in this country. Although death due to IHD
is a leading cause of death for both White and Black populations in
this country and is a major contributor to the excess deaths among
Blacks 20 to 64 years old, studies in Blacks are minimal compared to
those available in White populations.  Racial disparities in the
clinical expression, risk factor prevalence and outcomes for IHD have
been reported.  The significance of these differences remains
uncertain.  The lower prevalence of coronary atherosclerosis observed
in several studies, despite high prevalence of risk factors and poorer
outcomes, suggests that mechanisms of myocardial damage other than
obstructive coronary atherosclerosis may be of particular importance in
this population.  Advances in cellular biology, vascular biology and
molecular genetics offer an unprecedented opportunity for exploring the
relative influences of genetic, physiological, and environmental
factors in the pathogenesis of complex diseases such as IHD which
affect Blacks disproportionately.  Understanding the clinical
expression and pathologic mechanisms of myocardial damage in Blacks may
provide more precise interventions to prevent or halt disease
progression for this population as well as the general population at
risk.  This initiative seeks to foster an innovative research approach
to understanding IHD in Blacks by studying each of three topic areas:
sudden cardiac death, diabetic heart disease, and the coronary
microcirculation.

Sudden Cardiac Death

The Black population has a higher rate of out-of-hospital SCD than the
White population.  The difference, though, does not depend on the
quality of the emergency medical care provided to the two groups.
Black patients with an AMI also have a higher morbidity and mortality
rate than White counterparts; there is speculation that the disparity
is due to a host of factors ranging from reduced utilization of medical
services to increased susceptibility to lethal arrhythmias.  The poorer
prognosis after myocardial infarction has been associated with a
greater incidence of ventricular hypertrophy and arterial hypertension
in this minority population.

Apart from socioeconomic issues, there is a fundamental concern that
racial differences in biological mechanisms may contribute to the
higher prevalence of SCD among Blacks.  Important distinctions in the
specific substrates for the genesis of arrhythmias have yet to be fully
elucidated, but offer the promise of more effective therapy for all
patients.

It is well accepted that LVH increases the risk of SCD.  Studies have
shown that left ventricular wall thickness is greater in Blacks than in
Whites when data are normalized for differences in blood pressure.
Approximately 80 percent of Blacks with ischemic heart disease also
have hypertension.  The combination of hypertrophy and hypertension
complicates interpretation of the electrocardiogram (ECG), resulting in
a higher number of false positive exercise stress tests used for the
diagnosis of IHD.  Thus, there is a need to improve the accuracy of
cardiac stress testing in Blacks suspected of hypertrophy, with or
without hypertension.

At present there are gaps in understanding how the hypertrophied
myocardium predisposes an individual to a greater risk of a serious
arrhythmia.  It is known, for instance, that the added physical load
imposed on a myocyte can activate stretch-dependent ion channels that
lead to calcium (Ca++) overload.  Blacks are hypothesized to have a
greater responsiveness of stretch-dependent channels, but no
electrophysiologic evidence has linked this finding with a greater
prevalence of arrhythmias in this population.  Moreover, it is unknown
whether differences in the kinetics of the L-type Ca++ current or the
transient outward current (Ito) might exacerbate Ca++ overload.  Since
animal models of the aging heart have been shown to be less tolerant of
Ca++ overload, and thus more susceptible to ventricular fibrillation,
it would be intriguing to determine if any alteration in Ca++ handling
correlates with the aging process.

The role of connexins in impulse propagation through gap junctions is
well established.  Alterations in connexin density or distribution may
be differentially affected during the development of hypertrophy,
thereby increasing the risk of reentrant or nonsustained ventricular
tachycardia.

Other basic electrical properties of the cardiac cell membrane may play
a decisive role in the development of serious arrhythmias.  The surface
charge on the membrane can be altered by oxygen free radicals generated
during hypoxic or ischemic stress.  Such stress is more common in
individuals with LVH, suggesting that free radical damage may also be
more prevalent.  Regular physical exercise is known to increase the
production of free radical scavenger enzymes.  Some studies have
reported that Blacks tend to be more sedentary than Whites, but it
remains to be determined whether exercise would exert a beneficial
effect on free radical scavenging in the former population and thereby
reduce the incidence of serious arrhythmias.  Other factors influencing
the extent of free radical damage in the heart, such as estrogen
replacement, may also be important in the development of substrates for
arrhythmia production.

Hypertensive patients who have a low renin production were found to
have a digitalis-like compound that inhibits the Na+/K+ ATPase pump.
In the heart, such inhibition of the electrogenic Na+/K+ pump leads to
partial depolarization of cardiac tissue, possibly forming a substrate
for impulse conduction abnormalities.  Regional heterogeneity in the
magnitude of depolarization, especially in the presence of ventricular
hypertrophy, may exacerbate conditions for arrhythmia production
associated with SCD.

Electrocardiographic variants in R wave amplitude, ST segment voltage,
and T wave morphology have long been considered normal in the Black
population.  Given the higher rates of SCD and post-MI morbidity, it
may be instructive to determine whether, in fact, such variants are
non-pathologic or a harbinger of cardiac disorders.  Understanding the
basis for such population-related variants may help explain the basis
of angina-like pain in the absence of angiographic evidence of coronary
atherosclerosis.  At present, tests like the exercise ECG are of
limited value in the diagnosis of such patients, especially Black
women.  Blacks may be more sensitive than other populations to certain
provocative stimuli.  For example, indirect evidence suggests that this
population is more sensitive to the effects of nicotine on triggering
increased platelet aggregation, vasomotor reactivity, or
arrhythmogenesis.  Quantifying this difference can lead to improvements
in diagnosis and prediction of those at increased risk of SCD or
post-MI arrhythmias.  Moreover, research may derive clinically
normative standards for measurements of the signal averaged ECG,
nonlinear analysis of rate and rhythm, and other tests that would be
especially useful when applied to Black cohorts.

Proposed Research

Sudden Cardiac Death

o  Identification of the electrophysiological mechanisms responsible
for arrhythmias in hypertrophied myocardial cells

o  Assessment of the structural and functional changes in gap junctions
and connexins associated with myocardial hypertrophy

o  Determination of the sensitivity of hypertrophied cardiac myocytes
to calcium overload; correlate any changes with the aging process

o  Assessment of the significance of normal variants in the surface ECG
with the early development of ventricular hypertrophy and the
prognostic value of such variants for the risk of serious arrhythmias

o  Utilization of basic and clinical research studies to define the
relative contribution of the autonomic nervous system and receptor
activation to the development and risk of SCD

o  Determination of the extent to which physical exercise, or other
behavior modifications, reduces the risk of SCD or post-MI arrhythmias
in Blacks

o  Utilization of state-of-the-art techniques like signal averaged ECG
or nonlinear analysis, to determine the relative risk among Black males
and females following the onset of angina-like pain, or following MI;
assessment of the predictive value of such technology

o  Determination of the sensitivity of Blacks for development of
arrhythmias in response to stressors like acute exercise, psychological
stress, exposure to nicotine, or ingestion of alcohol

Microvascular Disease

Dysfunction of the cardiac microcirculation has been reported in
patients who suffer chest pain and have electrocardiographic evidence
of ischemia despite normal or near normal angiograms.  Of Blacks
presenting with angina-like chest pain, nearly half have been reported
to have normal coronary angiograms.  Furthermore, Blacks have higher
morbidity and mortality from cardiovascular disease than White
Americans, despite the high rates of angiographically normal or
minimally diseased epicardial coronary arteries.

Studies of predominantly or purely Black populations, the major
proportion of whom were hypertensive, have demonstrated that left
ventricular mass is a strong predictor of all cause mortality
independent of the number of obstructed coronary arteries.
Hypertrophied heart muscle has an increased coronary flow demand, yet
studies have shown that the maximum blood flow that can be achieved is
subnormal in both humans and animal models.  Furthermore patients with
hypertension without hypertrophy have also been shown to have
abnormalities of coronary flow.  These abnormalities have been
attributed to impairment of vasodilatory reserve in the resistance
vessels of the microcirculation.  They appear to be more common in
younger, more severely hypertensive patient populations, including
women and Blacks.

Other investigations have suggested a relationship between left
ventricular hypertrophy, coronary atherosclerosis, extracoronary
atherosclerosis and arterial hypertrophy.  Thus, treatment of
hypertension alone may not be adequate to reduce the increased risk of
death.  Much needs to be understood about the mechanisms underlying the
vascular changes brought about by hypertension and hypertrophy of the
heart.  Research is needed to improve the diagnosis of microvascular
disease and to translate knowledge of the etiology of the disease at
the molecular, cellular and physiologic levels into new therapeutic
modalities.

Commonly used tests for screening for IHD are stress thallium-201
myocardial perfusion imaging for patients who can exercise and
dipyridamole-induced vasodilation in conjunction with thallium imaging
or echocardiography for patients who cannot exercise.  Currently there
is no ideal, clinically applicable technique for directly measuring
microcirculation in the myocardium.  Thus, there are opportunities to
develop methods for better assessment of the microcirculation.  Several
methods offer promise as for example X-ray CT, SPECT, quantitative
echocardiography, and metabolic based techniques such as PET and NMR.
An approach that would enable non-invasive assessment of microvascular
function concerns the possibility that microvascular function in the
forearm might reflect function in the heart.

Leukocyte and/or platelet plugging following an ischemic episode were
once thought to account for impaired perfusion.  However, it is now
thought that changes in the structure of capillary walls and changes in
the structure and function of endothelial cells are largely responsible
for inadequate myocardial perfusion.  Recently published findings
confirm this view.  Endomyocardial biopsies of Japanese patients with
normal coronary arteries and angina were examined by light and electron
microscopy.  Mild myocardial hypertrophy and marked perivascular
fibrosis around small arteries and arterioles were observed.  Luminal
narrowing due to a medial thickening was also seen.  Electron
microscopy revealed that the nuclei of endothelial cells tended  to be
swollen and the chromatin marginalized.  In the media smooth muscle
cell proliferation and deformation was observed reflecting the medial
thickening seen in light microscopy.  The generality of these findings
needs to be defined by biopsy or autopsy studies.  Furthermore the
mechanisms underlying these changes have yet to be explored fully in
Blacks and offer a fruitful field for basic research.

Many factors have the potential to modulate vascular tone in both the
physiologic and pathophysiologic setting, to remodel the structure of
the vessel wall, and alter the function of vascular cells.  These
include hypoxia, oxygen free radicals, altered neural and hormonal
influences, changes in secretion of autocrine and paracrine factors,
and genetic predisposition.  This latter possibility is based on a
study showing that salt sensitive and salt insensitive rats differ in
their predisposition to hypertension and microvascular injury in the
remnant kidney model.

Rats, pigs, and dogs have been used as animal models to study
intramyocardial circulation to validate imaging techniques, to examine
postmortem pathology, to elucidate the pathophysiology of microvascular
tone, and to study the effectiveness of pharmacologic preparations in
promoting microvascular dilation.  For example, intramyocardial flow
can be assessed using fluorescent or radioactive microsphere
techniques, as well as PET and NMR scanning.  Thus, the effects of
hypertension, high blood cholesterol and diabetes on intracardiac flow
can be assessed.  These methods can also be used to evaluate, by direct
observation, drug regimens with respect to their ability to improve
vasodilator reserve.  Pig (and human) cardiac microvessels can be used
to examine their reactivity profile with respect to endothelin,
arachidonic acid metabolites, catecholamines, and other vasoactive
substances; to characterize vascular ion channels which modulate
vascular smooth muscle in microvessels; and to elucidate biochemical
pathways by which endogenous vasoactive factors exert their influence.
The animal models will also provide the opportunity to observe whether
angiogenesis occurs during hypertrophy and whether the angiogenic
potential can be manipulated to improve microcirculation in the
hypertrophied heart.

Microvascular cells can now be isolated from ventricular tissue of
adult rats and their function can be studied in vitro alone and in
co-culture with ventricular myocytes.  These studies have revealed the
existence of cell-cell signalling between microvascular endothelium and
ventricular myocytes.

As stated by Kramer et al (Circulation 1992; 85:350) in a recent
review, "There is growing evidence to support the existence of a
dynamic interaction in vivo between cardiac myocytes and adjacent
microvascular endothelial cells in the regulation of both cardiac
myocyte and possibly endothelial cell phenotype and function."  These
authors speculate that endothelins may be only one of several
endogenous cytokines or autocoids that are released by the cardiac
microvascular and/or endocardial endothelium and transported
vectorially to adjacent myocytes that could modify cardiac contractile
state, perhaps in response to changes in microvascular blood flow.
Similarly, cardiac myocytes themselves could release cytokines that
could directly affect endothelial cell proliferation or angiogenesis
and indirectly elicit or modify the release of endothelium-derived
cytokines and autocoids.  Thus, in addition to modifying function,
endothelial cell-cardiac myocyte interactions may also be of importance
in the dynamic events that lead to myocardial wall remodeling and
angiogenesis during hypertrophic growth and in the response to cardiac
injury.  As an example of this, endothelin, which is secreted by
endothelial cells and numerous nonendothelial tissue sources, is a
potent vasoconstrictor and inotropic factor.  It has mitogenic effects
in vascular smooth muscle and certain other cell types, and affects
expression of proto-oncogenes such as c- fos, c-jun and erg-1 and
atrial natriuretic peptide.

Thus, the powerful tools of molecular biology and state-of-the-art
cellular physiology could be brought to bear on the problem of
microvascular disease.

Microvascular Disease

o  Diagnostic studies to evaluate patients with suspected microvascular
disease to compare a forearm test of microcirculation with results in
the heart

o  Development and testing of new and improved diagnostic procedures
for microvascular disease

o  Evaluation of treatment for hypertension coupled with treatment to
prevent remodelling, e.g., Angiotension Converting Enzyme (ACE)
inhibitors

o  Study of a possible genetic predisposition to microvascular disease
in response to hypertension in Blacks

o  Animal model studies of the progression of microvascular dysfunction
and remodelling in hypertension and cardiac hypertrophy

o  Assessment of experimental therapies for prevention and treatment of
microvascular dysfunction in animal models

o  Elucidation of the underlying mechanisms initiating and sustaining
cardiac hypertrophy in response to hypertension

o  Elucidation of the changes in gene expression that initiate and
sustain microvascular remodelling in response to hypertension and
cardiac hypertrophy

o  Investigation of the role of altered ventricular function and
myocyte structure in mediating changes in the microvasculature

o  Examination of the possibility that angiogenesis could be stimulated
in the hypertrophied heart to improve myocardial perfusion.

Diabetic Heart Disease

Diabetes is currently the third leading cause of death in the US and
affects approximately five percent of the population.  There is a
greater prevalence of diabetes among Blacks than among Whites.  Over 50
percent of deaths among diabetic patients result from cardiovascular
complications.  Diabetic cardiomyopathy is a significant cause of heart
failure in diabetic subjects and occurs more frequently in those with
microvascular complications and/or hypertension.  The pathologic
significance of diabetic cardiomyopathy is not limited to coronary
atherosclerosis.  For example, the high mortality of myocardial
infarction among diabetics may reflect in part, preexistent myocardial
dysfunction from diabetic cardiomyopathy.  There is a two- and
five-fold increase in the incidence of congestive heart failure in
diabetic men and women, respectively, as compared to non-diabetic
subjects.  The clinical significance of diabetic cardiomyopathy may be
even greater in Blacks because there is a high prevalence of
hypertension in this population.   Furthermore, subgroups at
particularly high risk of developing diabetic cardiomyopathy include
women and obese subjects.  Obesity is a significant problem in Blacks;
one out of every three young adult Black women is considered obese.
More clinical work in the area of diabetic cardiomyopathy is clearly
needed including:  (1) the evaluation of its natural history by serial,
noninvasive evaluation of myocardial size and function in a variety of
diabetic subgroups; and (2) study of the effects of tight control of
hyperglycemia and normalization of blood pressure on cardiac function.
Comparison of different antihypertensive agents in the hypertensive
diabetic population would be of particular interest.

Despite the importance of diabetic cardiomyopathy as a major cause of
morbidity and mortality in diabetic Blacks, the fundamental
pathophysiology of the process is still poorly understood.  Further
work is required to understand the basic molecular and cellular
processes responsible for the pathophysiology of diabetic
cardiomyopathy and coronary heart disease and to discover new
interventions that effectively reverse, halt, or prevent disease
progression.  Diabetes is a heterogeneous disease.  Clinically, it has
been classified into insulin-dependent diabetes mellitus (IDDM) and
noninsulin- dependent diabetes mellitus (NIDDM).  IDDM is the less
prevalent form of the disease and is characterized by severe
insulinopenia, hyperglycemia and occasional bouts of ketoacidosis.  By
contrast, NIDDM is a disease of insulin resistance and hyperglycemia.
IDDM is closely correlated with autoimmune injury of the pancreas
associated with genetic markers associated with the human leukocyte
antigen (HLA) system.  There is also strong evidence that genetic
susceptibility plays a role in the development of NIDDM, which is often
found in obese subjects.  People with NIDDM are twice as likely to die
from heart disease as are members of the non-diabetic population.
NIDDM is not uniformly distributed among ethnic groups, there is a
clustering prevalence among certain ethnic/racial groups such as
Blacks, suggesting the likely contribution of genetic factors to the
expression of this disease.  The candidate genes involved are presently
unknown.

Diabetic cardiomyopathy has been characterized as myocardial failure
independent of atherosclerotic coronary artery disease, valvular
disease or hypertension.  Noninvasive studies of diabetic subjects have
shown disorders in systolic and diastolic function, which may progress
to overt congestive heart failure.  The pathogenesis of this disorder
is still uncertain.  Common histopathologic abnormalities include small
vessel disease, interstitial fibrosis and myocardial hypertrophy.
Improved understanding of the pathophysiology of diabetic
cardiomyopathy requires study of experimental animals with either
genetically or drug induced diabetes.  A wide variety of studies in
several animal species have shown a host of alterations in the
structure and function of the myocyte, the interstitium and the
coronary vasculature.  More work is needed in order to understand the
fundamental mechanisms that account for:  (1) the wide range of
adaptive (and reversible) changes in myocyte function including
alterations in myosin, regulatory proteins, calcium transport systems
(sarcolemmal, sarcoplasmic reticular and mitochondrial) and
catecholamine turnover and catecholamine responsiveness; (2) the
possible role of altered myocardial energetics in diabetics as a
stimulus to these adaptations should be considered; (3) irreversible
changes in myocardial structure including cell loss, replacement
fibrosis and interstitial role of small vessel disease including
alterations in vascular interstitial fibrosis, and (4) the possible
roles of increased vascular permeability and the formation of advanced
glycosylation products.

Much of what is know about the pathogenesis of diabetic complications
has been gleaned from studies using animal models.  Most studies have
utilized chemically-induced diabetic rodent models or the BB
(Biobreeding) rat, whose diabetes is of autoimmune origin.  In
addition, a number of transgenic mouse models have been developed which
mimic some of the effects of IDDM.  Although NIDDM is the most
prevalent form of diabetes, less information is available on the
cardiomyopathy linked to it.  Most studies examining this condition
have employed a chemical model of NIDDM produced by treating neonatal
rats with the pancreatic toxin, streptozotocin.  While the
cardiomyopathy that develops in the IDDM and NIDDM animal models share
certain properties, they differ in some important ways, most notably in
signal transduction mechanisms, calcium transport, energy metabolism
and diastolic function.  One of the most important contractile defects
of the NIDDM cardiomyopathy, but not the disease linked to IDDM, is the
reduction in diastolic compliance and resulting reductions in left
ventricular and diastolic volume and stroke volume.  While the
chemically induced model of NIDDM exhibits most of the characteristics
of NIDDM, including insulin resistance, modest hyperglycemia, severe
glucose intolerance and normal fasting insulin plasma content, it only
mimics a subset of NIDDM subjects which are lean.  Identification of an
animal model which appropriately mimics the human condition of NIDDM in
obese persons has been problematic.  While there are a number of animal
models that carry a genetic predisposition to develop obese NIDDM, it
is common for these species to develop abnormalities independent of
diabetes.

Hyperinsulinemia is an independent risk factor for hypertension,
therefore, coexistence of diabetes and hypertension is common.
Hypertension in the diabetic subject markedly increases the risk of
heart disease, accelerates the course of cardiomyopathy, and
potentiates the severity of the disease.  Some models combining
hypertension and diabetes have been described, but only a few studies
have examined cardiomyopathy which develops in these models.  The
mechanism by which hypertension potentiates the severity of the heart
muscle disease is still poorly understood.

Diabetic Heart Disease

o  Determination of the mechanisms underlying altered gene expression
of structure and contractile proteins in diabetic cardiomyopathy

o  Elucidation of the genetic factors that are responsible for the
expression of diabetic cardiomyopathy in Blacks

o  Elucidation of the cellular and molecular mechanisms underlying the
alterations in intracellular Ca++ homeostasis and trans-sarcolemmal
receptor signals during the development of diabetic cardiomyopathy

o  Determination of the changes in myocyte function including
alterations in myosin, regulatory proteins, calcium transport systems,
altered myocardial energetics, and catecholamine responsiveness in
diabetics

o  Elucidation of the role of growth factors and cytokines in both
cellular dysfunction and structural changes including cell death,
replacement fibrosis, and interstitial fibrosis (including vascular
mechanisms and neurohumoral factors) in diabetic subjects

o  Elucidation of the role of coexistent conditions such as
hypertension in the potentiation of diabetic-induced myocardial disease

o  Elucidation of the relative pathogenic significance of the multiple
factors that may alter myocardial performance in diabetic patients

o  Elucidation of the role of metabolic control on myocardial
abnormalities and on the primary prevention or reversal of myocardial
dysfunction.

Basic and Clinical Research

The overall concept of a SCOR program focuses on scientific issues
related to diseases relevant to the mission of the NHLBI.  It is
essential, therefore, that all applications include both basic and
clinical research projects.  In the ideal SCOR, the clinical research
derives from, or is otherwise intimately linked to the basic research
proposed by the investigators.  Interactions between basic and clinical
scientists are expected to strengthen the research, enhance transfer of
fundamental research findings to the clinical setting, and identify new
research directions.  Plans for transfer of findings from basic to
clinical studies should be described.

Each SCOR grant application and award must include research involving
human/patient subjects.  Support may be provided for human biomedical
and behavior studies of prevention and prevention strategies,
diagnostic approaches, and treatment of diseases, disorders or
conditions.  Small population-based studies, where the research can be
completed within five years, may also be proposed.  In addition, basic
research projects must be included that relate to the clinical focus.
A SCOR may also contain one or more core units that support the
research projects.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

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 28, 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.

LETTER OF INTENT

Prospective applicants are asked to submit, by November 30, 1994, 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:

Dr. James Scheirer, Chief
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 553 A
Bethesda, MD  20892

Upon receipt of the letter of intent, applicants will be contacted by
program staff to discuss their proposed applications and to provide
guidance to applicants not familiar with the SCOR concept.

APPLICATION PROCEDURES

The research grant application for 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 Information, Division of Research Grants, National
Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892,
telephone 301-435-0714.

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 face 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, "Specialized Centers of Research in Ischemic Heart
Disease in Blacks" and the RFA number HL-95-005 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 Dr. James Scheirer,
Chief, Review Branch, 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, otherwise the NHLBI cannot
guarantee that the application will be reviewed in competition for this
RFA.

Applications must be received by May 18, 1995.  If an application is
received after that date, it will be returned to the applicant.  The
Division of Research Grants (DRG) will not accept any application in
response to this RFA 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 for completeness by DRG and
for responsiveness by NHLBI.  Incomplete applications will be returned
to the applicant without further consideration.  If NHLBI staff find
that the application is not responsive to the RFA, it will be returned
without further consideration.

Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
group convened by the NHLBI in accordance with the review criteria
stated below.  As part of the initial merit review, a process (triage)
may be used by the initial review group in which applications will be
determined to be competitive or non-competitive based on their
scientific merit relative to other applications received in response to
the RFA.  Applications judged to be competitive will be discussed and
will be assigned a priority score.  Applications determined to be
non-competitive will be withdrawn from further consideration and the
principal investigator/program director and the official signing for
the applicant organization will be notified.  Neither site visits nor
reverse site visits are planned as a part of the review process,
therefore each application should be complete on submission.

Review criteria for this RFA 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.

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
evaluated.

AWARD CRITERIA

Applications must fulfill all the eligibility and responsiveness
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.

The anticipated date of award is September 1995.

Schedule

Letter of Intent Receipt Date:    November 30, 1994
Application Receipt Date:         May 18, 1995
Review by NHLB Advisory Council:  September 1995
Anticipated Award Date:           September 1995

INQUIRIES

Inquiries concerning this RFA are encouraged.  the opportunity to
clarify any issues or questions from potential applicants is welcome.

Dr. Patrice Desvigne-Nickens
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Federal Building, Room 3C06
7550 Wisconsin Avenue  MSC 9070
Bethesda, MD  20892-9050
Telephone:  (301) 496-1081
FAX:  (301) 480-6282
Email:  patrice_nickens%nihhfed1.bitnet@cu.nih.gov

Inquiries regarding fiscal and administrative matters may be directed
to:

Mr. William Darby
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A11
Bethesda, MD  20892
Telephone:  (301) 594-7458
FAX:  (301) 594-7492

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
number 93.387, Heart and Vascular Diseases. Awards are 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.

The Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free workplace and promote the non-use of
all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American
people.

.

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