SPECIALIZED CENTERS OF RESEARCH IN ISCHEMIC HEART DISEASE

Release Date:  February 20, 1998

RFA:  HL-98-007

P.T.

National Heart, Lung, and Blood Institute
Office of Alternative Medicine

Letter of Intent Receipt Date:  June 12, 1998
Application Receipt Date:  December 29, 1998

PURPOSE

This solicitation invites grant applications for a single open competition for
Specialized Centers of Research (SCORs) in Ischemic Heart Disease, Sudden
Cardiac Death, and Heart Failure.  The emphasis of this solicitation is on
creative interdisciplinary approaches to the elucidation of the etiology and
pathophysiology of ischemic heart disease, sudden cardiac death, and heart
failure at the molecular, cellular, and tissue levels and translation of the
research findings into improved diagnosis, treatment, and prevention of these
diseases.  Applicants are required to select a single theme for their Center,
pertaining to either ischemic heart disease, 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 and clinical investigations focused on human disease.  All projects must
have clearly stated hypothesis and innovative approaches to the problem to be
studied.

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, Sudden Cardiac Death, and Heart Failure,
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
202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit
institutions, public and private, such as universities, colleges, hospitals,
and laboratories.  This RFA is intended to support SCOR grants for basic and
clinical investigations.  Applications that include only basic or only
clinical research will not be responsive to this RFA.  In addition, clinical
research projects focused on large epidemiologic studies or large
clinical trials will be considered unresponsive to this RFA.  Foreign
institutions are ineligible from receiving awards under this solicitation. 
Under exceptional circumstances, a foreign component critical to a project may
be included as a part of that project.  Women and minority investigators are
encouraged to apply as Principal Investigators or responsible project
investigators.

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 determined
non-competitive, the over all 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.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) specialized centers
(P50) mechanism to support this research program. 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 start date of award is January 1, 2000.

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

Upon initiation of the program, there will be required communications between
SCORs, usually in the setting of a biennial combined meeting of SCOR
participants.  Applicants should request travel funds for this purpose in
fiscal years 2001, 2003, and 2005 of the budget.  Applicants should also
include a statement in their applications indicating their willingness to
participate in these meetings.

Basic and Clinical Research

The overall concept of a SCOR program focuses on scientific issues related to
diseases relevant to the mission of the National Heart, Lung, and Blood,
Institute (NHLBI).  It is essential, therefore, that all applications include
both basic and clinical research projects.  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
patients/subjects, which is defined as research conducted with human
patients/subjects or on material of human origin such as tissue or other
specimens for which an investigator directly interacts with human
patients/subjects.  Support may be provided for human biomedical and
behavioral studies of etiology, pathogenesis, prevention and prevention
strategies, diagnostic approaches, and treatment of diseases, disorders or
conditions.  Small population-based epidemiologic 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.

Length of SCOR Programs

Each NHLBI SCOR program is limited to 10 years of support. Exceptions to this
policy will be made only if a thorough evaluation of needs and opportunities,
conducted by a committee composed of non-federal experts, determines that
there are extraordinarily important reasons to continue a specific SCOR
program.

Under this policy, a given SCOR grant is awarded for a five-year project
period following an open competition.  Only one five-year competing renewal is
permitted, for a total of 10 years of support, unless the SCOR program is
recommended for extension.

The SCOR program in Ischemic Heart Disease, Sudden Cardiac Death, and Heart
Failure is in the initial five-year project period and this competition is for
the second five-year competition.  The comprehensive evaluation of the SCOR
Program in Ischemic Heart Disease, Sudden Cardiac Death, and Heart Failure
will be conducted during the second project period according to the following
timetable.

Announcement of SCOR renewal competition     FY 1998

Project Period (second competition)          FY 2000 to FY 2004

Letters to SCOR Directors regarding          FY 2001 (mid-way through year 02
SCOR evaluation plans                         of the 2nd project period)

SCOR Evaluation Meeting                      FY 2001 (late in year 02 of 2nd   
                                              project period)

Notification of SCOR Directors of            FY 2002 (mid-way through year 03
NHLBI decision                                of 2nd project period)

The NHLBI does not limit the number of SCOR applications in a given SCOR
program from one institution provided there is a different SCOR principal
investigator for each application and each application is self-contained and
independent of the other(s).  This does not preclude cooperation, planned or
possible, among participants of SCORs after awards are made.  Scientific
overlap among applications will not be accepted.  If more than one application
is envisioned from an institution, the institution is encouraged to discuss
its plans with the NHLBI SCOR program administrator.

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 and can
provide scientific expertise in areas and topics that may not be readily
available at the applicant institution.  However, the consortium projects must 
not constitute greater than 50 percent of the proposed projects.  It is also
imperative that a consortium application be prepared so that the programmatic,
fiscal, and administrative considerations are explained fully. Applicants
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.  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 Ms. Marie Willett, Grants
Operation Branch, NHLBI, (301) 594-7458.

FUNDS AVAILABLE

Applicants may request up to $1,170,000 direct costs, not including indirect
costs for collaborating institutions, in the first year. Projects within a
center which focus on complementary or alternative medicine research, in the
areas defined under the RESEARCH OBJECTIVES, are not included in determining
this limit of $1,170,000 direct costs.  Competing renewal applicants may
request an increase, in their budget in the first competing year (Year 06),
not to exceed 10 percent of the costs awarded in the last noncompeting award
year (Year 05).  Applicants may request up to a two percent increase for
subsequent noncompeting years.  It is anticipated that ten SCOR grants, for a
five year project period, at an estimated first year total cost of $15.886
million, will be supported.  In addition, it is anticipated that $1.6 million
will be  available to support projects focussing on complementary or
alternative medicine, as defined below.  Requests to support complementary or
alternative medicine projects cannot exceed $400,000 in total costs (including
direct and indirect costs and project costs associated with core components)
per center.

Award of grants pursuant to this RFA is contingent upon receipt of funds for
this purpose.  Designated funding levels are subject to change at any time
prior to final award, due to unforeseen budgetary, administrative, and/or
scientific developments.

Equipment is included in the budget limitation.  However, requests for
expensive 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 justification.  Final decisions will depend on the nature
of the justification and the availability of funds.

RESEARCH OBJECTIVES

Background

This solicitation invites grant applications to enter a single open
competition for Specialized Centers of Research (SCORs) in ischemic heart
disease, sudden cardiac death, and heart failure.  The goal of the program is
to foster interdisciplinary studies of the etiology, pathophysiology,
diagnosis, and treatment of these diseases in a context that will lead to a
translation of research findings into the clinical setting and thereby reduce
the morbidity and mortality of cardiac diseases.  The specific objectives of
the program are: (1) to exploit the latest techniques of genetic and molecular
biology, and cellular and organ physiology, to elucidate the underlying
mechanisms which are perturbed in these disease states; and (2) to apply
fundamental knowledge and modern technology to improve the diagnosis,
treatment and prevention of these diseases in patients.  To these ends,
investigators must present applications that encompass both basic and clinical
science and include studies of patients. The program is open to all
investigators, including those who are participating in the current program.

NHLBI Specialized Centers of Research in Ischemic Heart Disease, supported
since 1975, were an outgrowth of the Myocardial Infarction Research Units
(MIRUs) supported by NHLBI from 1968 through 1974.  The first 15 years of the
SCOR program focussed exclusively on ischemic heart disease.  In 1990 this
program was broadened to include SCORs in Coronary and Peripheral Vascular
Diseases, Heart Failure, and Congenital Heart Disease.  In 1991 the Cardiology
Advisory Committee recommended that the program redirect its focus to Ischemic
Heart Disease, Sudden Cardiac Death, and Heart Failure, and, accordingly,
these three categories were encompassed in the solicitation for the SCOR
program awarded in 1995.  This current announcement again solicits
applications in the areas of Ischemic Heart Disease, Sudden Cardiac Death, and
Heart Failure.  Although it was stated in the predecessor RFA that the
Ischemic Heart Disease area would not be renewed, it has been included because
of its fundamental importance in the area of heart disease and to maintain the
continuity of the program.

A Specialized Center of Research (SCOR) provides the opportunity for
investigators to engage in interdisciplinary and collaborative,
hypothesis-driven 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 the
chosen disease area.  The clinical component should be strongly linked to the
basic science projects, while the basic science studies should be chosen so
that their hypotheses elaborate in detail the hypotheses 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.  All SCOR projects must be designed to
comply with NIH policies regarding gender and ethnicity unless exceptions can
be scientifically justified.

Need And Justification

Although the number of deaths from coronary heart disease has continued to
decline over the last two decades, mortality remains high. There were in
excess of 487,000 deaths in 1994 from coronary heart disease.  In spite of a
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
13.5 million and the estimated total economic burden is approximately $50
billion annually.  Thus, there is a need for continued research both with
respect to prevention and improved treatment.

Sudden death of cardiac origin claims approximately 250,000 lives each year in
the United States and accounts for about 50% of coronary heart disease
mortality.  It represents the actual mechanism of death in many patients with
acute heart attack, as well as others with more delayed etiologies, such as
congestive heart failure, cardiomyopathy, and congenital heart diseases that
result in a compromised, electrically unstable myocardium.  SCD also results
in the unexpected loss of hundreds of other, apparently healthy individuals,
who die with little or no warning, largely as a result of a silent, but lethal
inherited susceptibility.  Fatalities are usually caused by fibrillation of
the muscle of the heart and resultant loss of effective pump function. Risk
factors are primarily those of complicating cardiovascular disease, age, sex,
environmental or drug exposure, and genetic predisposition.

Heart failure is the final common pathway of a variety of primary
cardiovascular diseases.  In contrast to the overall trend of decreasing death
rates attributable to ischemic heart disease and stroke, the prevalence of
heart failure and the resultant death toll are greater than ever before.  In
the US, approximately 400,000 new cases of heart failure occur annually.  Due
to increased life expectancy, the number of patients and deaths keep rising at
a steady rate.  Of the nearly 5 million patients afflicted with heart failure,
75% are older than 65 years of age.  Congestive heart failure is the
first-listed diagnosis in 875,000 hospitalizations, and direct health care
costs total $17.8 billion each year.  Death from heart failure is 1.5 times
higher in black than in white Americans.

It is acknowledged that the use of alternative, unconventional medicine in the
United States is widespread.  Extrapolation of demographic data on alternative
medical approaches to the population of the United States suggests that
Americans made approximately 425 million visits to providers of complementary
or alternative medicine (CAM) therapy during 1990 and expenditures associated
with CAM therapies appear similar to non-reimbursed expenses incurred for all
hospitalizations.  Most people use CAM therapies for chronic rather than
life-threatening medical conditions.  In addition, most users of alternative
therapies do not inform their primary care physicians of such use.  Thus
alternative medicine modalities occupy a larger role in the health care of
U.S. citizens than previously understood.  Despite the broad use of
alternative medicine treatments, there is a relative paucity of data available
to demonstrate convincingly whether many of the complementary or alternative
medicine practices lead to positive clinical outcomes, improve quality of
life, reduce or eliminate adverse symptoms, prevent disease, promote or
enhance health, and are efficacious, safe and/or beneficial.

Proposed Research

Ischemic Heart Disease

Ischemic heart disease (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
addresses a few of those problems.  Applicants are urged to consider other
themes which 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 function.  Post-ischemic ventricular
dysfunction, as a result of myocardial stunning or hibernation, is a recently
recognized clinical entity.  Studies on this topic remain controversial and
many issues remain to be resolved.  While there is a need for suitable animal
models to study the mechanisms of both stunning and hibernation, accurate
diagnosis and clinical delineation of these conditions are important goals to
guide the treatment of patients.

While major advances have been made in the treatment of occluded coronary
arteries, a number of important questions remain.  Research on the vascular
pathophysiology associated with the formation of a mural thrombus, plaque
growth and regression, the relationship of unstable plaque to thrombus
formation, the effect of disordered endothelium, vasospasm, and the various
mechanisms underlying these phenomena is urgently needed.  Research into
mechanisms associated with the occlusion of coronary vessels in both men and
women could further provide preventive strategies and extend our understanding
across a broad spectrum of the population.  Studies directed at imaging the
unstable plaque would provide important information into the development and
rupture of the plaque and offer diagnostic modalities that could be of
preventive and therapeutic benefit.

Ischemic preconditioning is a cardio-protective mechanism in which short
periods of ischemia appear to attenuate the cellular damage associated with
subsequent episodes of ischemia.  Understanding the molecular basis for
preconditioning thus offers the potential for providing therapeutic options
for the treatment of ischemic heart disease.  However, research in this area 
has been slow to advance and an understanding of the biochemical processes
underlying this protection remains elusive.  Further studies into the
molecular physiology of preconditioning are needed.  Such studies could
benefit from an integrated approach to understanding the physiology and
biochemistry of preconditioning.

Post-ischemic injury is a problem spanning all therapeutic approaches to the
treatment of acute ischemic heart disease.  While much research has been done
on this topic, there remains no clear understanding of the underlying causal
factors associated with injury following an ischemic episode, and there is no
obvious indication at the present time of a clinical regimen which would
prevent or ameliorate its occurrence.  This represents an area where there is
a great need for an interdisciplinary approach to the problem.

Myocardial insufficiency resulting from the cumulative death of adult cardiac
myocytes remains a pressing clinical problem.  However, through the use of
emerging new molecular technologies, it may be possible to regenerate
functional myocardium in the damaged heart via cell mediated repair
mechanisms.  Such repair mechanisms could involve restoration of the
proliferative capacity of adult myocytes by designing strategies to manipulate
cell division based on an understanding of the molecular basis for inhibition
of myocardial cell division.  Basic studies aimed at understanding the genetic
and biological control of myocyte development could also lead to techniques
for transforming cells in non-contracting myocardium into functional myocytes. 
Finally, the transplantation of viable myocytes into areas of myocardial
damage also offers a means to alleviate myocardial insufficiency.  This
approach, however, requires methodologies for generating or isolating cells
for transplant and an understanding of the cell biology of donor-host myocyte
interactions.  Thus, a better understanding of cell cycle control,
differentiation, gene transfer, and cell transplantation offers exciting, new
effective treatment methods for alleviating myocardial insufficiency and the
death and disability associated with myocardial dysfunction.

Coronary heart disease is a complex disease, involving the interaction of
genetic and environmental factors.  Genes controlling a number of pathways,
including lipoproteins, hemostatic factors, energy metabolism, blood pressure,
and the immune system, can influence the genetic susceptibility to coronary
heart disease.  Studies in both humans and animals are beginning to identify
genetic loci associated with heart disease. A major bottle neck is not knowing
the protein products or the function of most of these genes.  Meeting this
challenge is an unparalleled opportunity for the physiologist and physician
scientist.  The definition of the genetic factors involved in coronary heart
disease can offer the benefit of identifying presymptomatic individuals,
thereby allowing the initiation of preventive strategies, improved early
diagnosis, and the enhancement of therapeutic approaches to alleviate or cure
the disease.  Studies are needed at the molecular genetic level to identify
genetic loci involved in heart disease and at the whole animal and organ level
to understand the interaction of these genes with environmental factors.  The
SCOR creates a unique opportunity to integrate gene identification with the
physiology of protein products of genes and to relate these findings to human
disease.

Sudden Cardiac Death

The occurrence of Sudden Cardiac Death (SCD) is most commonly defined as the
initiation of ventricular fibrillation, which carries a high probability of
unexpected death within an hour after the onset of cardiovascular symptoms. 
It is most common in cardiac patients with compromised myocardial function
following episodes of ischemia, acute stress or as a consequence of pathologic
structural and electrical remodeling.  Onset is, most often, due to transient,
destabilizing, "triggering" events, such as sympathetic challenge or
parasympathetic imbalance, which initiate tachyarrhythmia in an
electrogenically compromised "substrate" myocardium or abrupt bradycardia. 
Populations at highest potential risk are adults with advanced IHD and those
with myocardial structural disruption or scarring.  SCD is an associated risk
in congestive heart failure and contributes to a large proportion of deaths
among these patients.  It can also occur following unintended exposure to
proarrhythmic agents, such as some therapeutic drugs (e.g., the antihistamine,
terfenadine) and drugs of abuse (e.g., cocaine).  SCD is a common clinical
consequence in some inherited cardiac diseases, for example, familial
hypertrophic cardiomyopathy and long QT syndrome, and occurs in pediatric
patients with a variety of congenital conditions.

Therapeutic approaches to SCD have utilized three strategies.  First, through
the reduction of excitability thresholds by amelioration of neural, endocrine,
and especially sympathetic "triggers" with so-called Class II agents, such as
beta adrenergic blockers.  Second, by controlling electrogenesis at the level
of myocardial ion pumps and channels (i.e., "substrate").  Third, as a last
resort, via the implantation of automated electrical devices which have the
capacity to detect and abort fibrillation, but do not address its underlying
cause.

While most drug strategies have been largely limited to simple blockage of
different ionic currents, basic studies aimed at understanding channel
proteins offer an opportunity for regulatory modulation of relevant channel or
exchange proteins, their activation state, and mechanisms of integration or
control.  Through the identification of "triggers" which initiate arrhythmic
events, it may be possible to devise therapeutic strategies that can
ameliorate these events.  Recent observations suggest non-invasive measures,
such as heart rate variability, alternans, QT dispersion, baroreflex
sensitivity, or fractal indices, may provide improved means of identifying
susceptibility.  Developments in this area are among the more promising lines
of current research.

Genetic studies of familial forms of arrhythmias have provided exciting new
information concerning these inherited diseases, their underlying etiology,
and treatment.  In addition, they provide clues to understanding the
arrhythmogenic process.  Mathematical and physical modeling studies, made
possible by new technological strides, are providing knowledge concerning the
conditions promoting, and the mechanisms underlying, electrical propagation in
the heart.  The manipulation of specific gene products in animals is helping
to further elucidate the multitude of regulatory factors contributing to the
arrhythmogenic process and sudden cardiac death.  Integration of these
fundamental studies with our knowledge of the human physiology of sudden
cardiac death should help to further diagnostic and therapeutic options.

Due to enormous strides made at the cellular and molecular level, we may be in
a position to offer new treatment strategies that can be employed to limit the
prevalence of sudden cardiac death.  The SCOR mechanism provides the
opportunity to bring basic studies of arrhythmogenesis to the clinical setting
and improve the outlook for ameliorating and preventing sudden cardiac death.

Heart Failure

Heart failure (HF) is a complex syndrome of mixed etiology.  While great
strides have been made toward understanding many of the components of the
syndrome, an integrated understanding of the human disease has remained
elusive.  However, with many clues now available from fundamental studies, it
may be timely to exploit those findings in the interdisciplinary setting of
the SCOR mechanism.

Hypertrophy of the myocardium is a response of the heart to a number of
conditions that increase work of the heart and is thought to compensate for
the stress on the overloaded heart and to normalize cardiac function.  When a
transition from compensation to decompensation occurs, the result is heart
failure, but it remains a mystery as to the mechanism whereby compensatory
growth appears to play a causal role in heart failure.  Cellular and molecular
mechanisms contributing to the onset of heart failure and those pathways
responsible for the hypertrophic response need to be elucidated and
understood.  The role of metabolism, energetics, and oxygen supply during the
decompensation process are all important avenues of research.  Recent
developments in the area of apoptosis and its role in heart failure offer
exciting new research opportunities with potential rewards in terms of
therapeutic and diagnostic options.

Studies have shown that the mechanism of hypertrophic growth involves
remodeling of cardiac tissue compartments: myocytes, matrix, and vasculature,
and is associated in cardiac myocytes with a molecular expression profile
bearing similarity to the fetal phenotype.  Mechanisms, such as the
immediate/early gene response and peptide growth factor expression, have been
implicated in this molecular switching, but little is known about their role
in the overall ventricular remodeling which occurs in vivo.  Dilatation occurs
in 60% to 70% of patients dying with heart failure and is by far the more
common cause for cardiac transplantation particularly in the young.  Whether
dilatation is an impaired growth response or just a mechanical defect remains
to be determined. Inherited monogenic disorders that exhibit only hypertrophy
or dilatation could shed some insight on the pathogenesis of these cardiac
responses.  Understanding the molecular basis for these responses should
provide insights into the remodeling changes that occur in the ventricle in
response to a variety of diseases. 

In the face of the increasing prevalence of heart failure, little is known
about the disease at the molecular level.  In many cases the level of
disability is proportional to the degree of heart damage, yet there is great
variability in residual heart function.  Differences may exist in other
functions, such as the autonomic nervous system, that may influence the
contractility of myocardium.  Studies using transgenic animals in which
adrenergic receptors and myocardial proteins have been manipulated demonstrate
both positive and negative effects on myocardial contractility.  In addition,
animal models that more closely approximate the human condition of heart
failure are being developed and utilized to elucidate underlying physiologic
and metabolic abnormalities associated with heart failure.  Nevertheless, more
research must be done in animal models and patient studies to understand the
basic molecular mechanisms inherent in heart failure with a goal to
identifying suitable therapeutic targets and preventive strategies.

An avalanche of genes relevant to the structure and function of the
cardiovascular system are rapidly being identified.  Among the genes that are
candidates for study are those controlling cardiac myocyte proliferation,
differentiation, hypertrophy, apoptosis, and the expression of cell signaling
molecules such as angiotensin, endothelin, atrial natriuretic peptide (ANP),
and immune cytokines.  Other 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 through the heart, whether through endocrine, paracrine or
autocrine mechanisms.  This represents an exciting new avenue of research that
awaits exploration.

Complementary or Alternative Medicine Approaches

The NHLBI and Office of Alternative Medicine (OAM) are committed to
investigating the efficacy and mechanisms of complementary and alternative
medicine (CAM) for treating or preventing ischemic heart disease, sudden
cardiac death, and heart failure.  In particular, the NHLBI and OAM are
interested in supporting studies to establish the methodical feasibility and
strengthen the scientific rationale for proceeding to full scale randomized
clinical trials on the use of CAM, as well to advance our understanding of the
underlying mechanisms of these therapies.  For the purposes of this RFA,
applicants are limited to investigations of the following categories of CAM:

o  Phytotherapy or Herbalism (e.g., ginkgo biloba, garlic, Hawthorne)

o  Orthomolecular Medicine - This category includes the use of products, many
of which may be used as nutritional and food supplements, when investigated
for therapeutic or preventive purposes. These products are usually used in
combinations and at high doses (e.g., magnesium, Co-enzyme Q, carnitine).  For
the purposes of this RFA, orthomolecular medicine may be integrated within
comprehensive lifestyle changes based on indigenous or non-orthodox systems of
medicine (e.g., Ornish or Pritikin programs).

Studies of the above therapies should concentrate on investigating
standardized combination approaches of CAM as they are used by the public and
CAM practitioners.  When feasible, the research team should include expert
practitioners of these approaches.

SPECIAL REQUIREMENTS

Special features of SCOR grants are:

o  They provide opportunities for investigators with mutual or complementary
interests to engage in multidisciplinary research focusing on a specific
cardiovascular disorder.

o  Inherent in the SCOR program is a special interaction between the SCOR
director, the grantee institution and the Division of Heart and Vascular
Diseases.  Funds are specifically allocated in a SCOR grant for investigators
from different SCORs to meet and discuss problems of mutual interest and to
participate in workshops addressing common research areas.

o  The Division's overall SCOR program and each SCOR grant undergo periodic
evaluation.  The progress reports are prepared for the information of the
National Heart, Lung, and Blood Advisory Council, the Division of Heart and
Vascular Diseases staff, and ad hoc members of SCOR evaluation groups.

Requirements of SCOR grants:

o  Research conducted at the individual centers must include both basic and
clinical research to ensure that advances in the basic sciences are translated
rapidly into clinical applications and that clinical needs will provide a
direction for the basic research. Therefore, each SCOR grant application and
award must include one or more research projects involving human
patients/subjects. The basic research projects should clearly relate to the
disease focus and contribute to elucidation of mechanisms underlying the
disease, or to improved diagnosis or management of the disease.

o  Each component project requires a well-described hypothesis, preliminary
data and a time-table for conducting the proposed investigations.

o  If core facilities are included, the relationship of each component project
to each core should be described.

o  The principal investigator should be an established 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.

o  Project leaders must agree to commit at least 20 percent effort to each
project for which they are responsible.  Investigators with minimal research
experience, but promising credentials, may participate; however, it is
expected that most of the project directors will be investigators with
significant research experience.

o  Each SCOR must have a well-delineated organizational structure and
administrative mechanism that foster interactions between investigators,
accelerate the pace of research, and ensure a productive research effort.

o  If a project director transfers to another institution, support for the
project will normally not be continued as a consortium.

Because of the size and complexity of a SCOR, prospective applicants are urged
to consult with the staff of the Division of Heart and Vascular Disease early
in the preparation of the application (see INQUIRIES Section).

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 policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).

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
(FR59 14508-14513), and in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18,
1994, Volume 23, Number 11.

Investigators may obtain copies from these sources or from the program staff
or contact person listed below.  Program staff may also provide additional
relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by June 1, 1998, 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, it assists the NHLBI staff
to estimate the potential review workload and to avoid conflict of interest in
the review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7093, MSC 7924
Bethesda, MD  20892-7924

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) 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 Division of
Extramural Outreach and Information Resources, National Institutes of Health, 
6701 Rockledge Drive, MSC 7910 Bethesda, MD 20892-7910; telephone (301)
710-0267; Email: [email protected]; and from the NIH program administrator
listed under INQUIRIES.  Specific instructions for preparing a SCOR
application are also available from the program contact listed under
INQUIRIES.

The RFA label included in grant application form PHS 398 (rev. 5/95) 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, the RFA
title and number must be typed on line 2 of the face page of the application
form and the "YES" box must be marked.

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

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

Send two additional copies of the application to Chief, Review Branch 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
Center for Scientific Review (CSR); otherwise, the NHLBI cannot guarantee that
the application will be reviewed in competition for this RFA.

Applications must be received by December 29, 1998.  If an application is
received after that date, it will be returned to the applicant without review. 
CSR will not accept any application in response to this RFA that is
essentially the same as one currently pending initial review, unless the
applicant withdraws the pending application. The Center for Scientific Review
will not accept any application that 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 CSR and
responsiveness by the NHLBI staff.  Incomplete applications or applications
deemed not responsive to the RFA will be returned to the applicant without
further consideration.

Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened by
the NHLBI in accordance with the review criteria stated below.  Each
application must be thorough and complete enough to stand on its own because
no site visits nor reverse site visits will be held.  As part of the initial
merit review, a process 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 be
assigned a priority score, and will also receive a second level of review by
the National Heart, Lung, and Blood Advisory Council.  Applications determined
to be non-competitive will be withdrawn from further consideration and the
principal investigator and the official signing for the applicant organization
will be notified.

Factors to be considered in the evaluation of each application will be similar
to those used in review of traditional research grant applications and, in
addition, will include overall proposed interactions among basic and clinical
research projects.  Major factors to be considered in the evaluation of
applications include:

o  Scientific merit of the proposed basic and clinical research projects
including significance, importance, and appropriateness of the theme;
innovation, originality, and feasibility of the approach; and adequacy of the
experimental design.

o  Leadership, scientific stature, and commitment of the program director;
competence of the investigators to accomplish the proposed research goals and
their time commitment to the program; and the feasibility and strength of
consortium arrangements.

o  Collaborative interaction among basic and clinical research components, the
balance between them, and plans for transfer of potential findings from basic
to clinical studies.

o  Adequacy of the environment for performance of the proposed research
including clinical populations and/or specimens; laboratory facilities;
proposed instrumentation; quality controls; administrative structure;
institutional commitment; and, when needed, data management systems.

o  Appropriateness of the budget for the proposed program.

AWARD CRITERIA

The anticipated date of award is January 1, 2000 (FY 2000) for the SCORs in
Ischemic Heart Disease, Sudden Cardiac Death, and Heart Failure. Awards will
be made according to priority score, availability of funds, and programmatic
priorities.

INQUIRIES

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

Direct inquiries regarding programmatic issues and requests for supplemental
instructions to:

John Fakunding, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 9200, MSC 7940
Bethesda, MD  20892-7940
Telephone:  (301) 435-0505
FAX:  (301) 480-1454
Email:  [email protected]

Direct inquiries regarding fiscal matters to:

Marie Willett
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7156, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0144
FAX:  (301) 480-3310
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.838.  Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42
U.S.C. 2241 and 285) and administered under PHS grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review.

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

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