Research (OER)
9000 Rockville Pike
Bethesda, Maryland 20892
and Human Services (HHS)
SPECIALIZED CENTERS OF RESEARCH (SCORS) IN ISCHEMIC HEART DISEASE IN BLACKS
Release Date: July 29, 1998
RFA: HL-98-015
P.T.
National Heart, Lung, and Blood Institute
Office of Alternative Medicine
Letter of Intent Receipt Date: May 7, 1999
Application Receipt Date: September 15, 1999
PURPOSE
This solicitation invites grant applications to enter 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 focus of 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, investigators must
present an application that encompasses both basic and clinical science,
including studies in Black patients. The goal of the program is to advance our
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. 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 Request for Applications (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 202-512-1800).
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic for-profit and non-profit institutions,
public and private, such as universities, colleges, hospitals, and laboratories.
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 strategies and retention for study subjects
so that likelihood of meeting the stated goals can be assessed. Foreign
institutions are not eligible for specialized centers (P50) grants.
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.
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 an application submitted in response to this RFA may not exceed five years.
The anticipated start date of award is September 30, 2000.
Although multidisciplinary approaches are required, it is not the intent of this
RFA 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. Because this program focuses on a particular population,
clinical studies must include Black patients. 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
SCOR evaluation plans year 02 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
NHLBI decision year 03 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 Mr. William Darby, Section Chief, 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 application which focus on complementary or alternative medicine research,
in the areas defined under the RESEARCH OBJECTIVES, are not to be 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) or $1,170,000, whichever is greater. Applicants may request up to a
two percent increase for subsequent noncompeting years. It is anticipated that
two SCOR grants, for a five year project period, at an estimated first year total
cost of $ 2.978 million, will be supported. In addition, it is anticipated that
$800,000 will be available to support projects focussing on complementary or
alternative medicine, as defined below. However, requests to support
complementary or alternative medicine projects cannot exceed $400,000 in total
costs (including direct and indirect costs and costs associated with core units)
per center.
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.
To encourage women and minority investigations to work within a SCOR project, to
facilitate recruitment of new scientists to this area of research, and to foster
cutting edge and innovative research directions, each SCOR program may support
up to two investigators by requesting no more than $50,000 per year per
investigator to fund pilot and feasibility projects. This will allow
women and underrepresented minority investigators to acquire the skills and data
to become more competitive in seeking independent research support . These funds
will not be supplements, but rather specific dollars identified in the SCOR
budget and restricted to be
used for this purpose. The recipients would be chosen for a two-year maximum
development period based on a proposal written by a SCOR investigator and
reviewed by an internal review committee at the parent institution.
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.
RESEARCH OBJECTIVES
Background
This solicitation invites grant applications to enter 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 focus of their applications. The
purpose of this initiative is to foster an interdisciplinary study of issues
surrounding the expression of heart disease in Blacks. To this end,
investigators must present an application that encompasses both basic and
clinical science, including studies in Black patients. The overall goals of the
program are to advance our 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.
Recent advances in basic sciences have provided opportunities for new research
to delineate the etiology and pathogenesis of heart disease in Blacks and,
thereby, improve the treatment and prevention of coronary heart disease in this
population. To identify new opportunities and chart a course for future research
efforts, the NHLBI convened a Working Group on Research in Coronary Heart Disease
in Blacks. The Working Group released its report in March, 1994 on RESEARCH IN
CORONARY HEART DISEASE IN BLACKS. This report provided specific recommendations
for future research in Black populations. The NHLBI strongly encourages research
into the pathogenesis of ischemic heart diseases in Blacks, and recommends that
this report be consulted.
The initial solicitation for applications for NHLBI Specialized Centers of
Research in Ischemic Heart Disease in Blacks also took place in 1994 and
encompassed some of the specific areas of research specified in the report of the
Working Group. This program also acknowledged a recognition that programs
specifically designed to focus on heart disease in Blacks and to integrate
clinical studies with relevant basic science studies were not being supported at
that time. In the fall of 1995, two awards were made under this program. This
current announcement represents the renewal of the program for a second five year
period and again solicits applications focussing on the areas of Sudden Cardiac
Death, Microvascular Disease, and Diabetic Heart Disease.
A SCOR provides the opportunity for investigators to engage in interdisciplinary
and collaborative research which 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.
Need and Justification
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 20-64 years old, clinical
data in Blacks are limited 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. 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 innovative research approaches to
understanding IHD in Blacks by studying each of three topic areas: sudden cardiac
death, diabetic heart disease and the coronary microcirculation.
Blacks have high rates of conventional IHD risk factors including hypertension,
diabetes, smoking, and obesity. But despite the high prevalence of risk factors
and worse outcomes for IHD, several series suggest that Blacks develop less
obstructive coronary atherosclerosis compared to whites. Whether there are
pathological determinants of sudden cardiac death, myocardial infarction, angina,
and other forms of symptomatic and silent ischemia that are more common or are
unique in Blacks relative to our current understanding derived from studies in
whites is unknown and presents an enormous research opportunity. Several studies
demonstrate that Blacks have higher in-hospital mortality, as well as higher post
discharge mortality rates, although these findings are not consistent across all
studies. One study of inner city residents suggests that Blacks with acute
myocardial infarction (AMI) have less chest pain and often present with pulmonary
edema, elevated blood pressure, and history of congestive heart failure. The
increased mortality with AMI in Blacks may be due to an increased history of
prior MI, elevated blood pressure, diabetes, and/or congestive heart failure but
it has not been rigorously evaluated. A failure to appreciate symptoms, lower
socioeconomic status, and lower utilization rates or reduced access to diagnostic
and therapeutic cardiologic procedures in Blacks have also been reported. Whether
differences in disease mortality are the result of differences in clinical
presentation, patient, or patient/physician factors has also not been studied.
Although angina pectoris is the prominent manifestation of IHD in whites, chest
pain in Blacks may occur in the absence of significant coronary atherosclerosis.
Anecdotal reports from clinical practices with large numbers of Blacks suggest
that this population often has atypical angina and abnormal vasomotor regulation.
Because Blacks have increased rates of diabetes and left ventricular hypertrophy
(LVH) with and without hypertension, the vasodilatory capacity of the large and
small coronary arteries may be adversely affected. In fact, differences in
vasodilatory response and the syndrome of angina-chest pain with angiographically
normal or near normal coronaries in hypertensive Blacks has been reported.
Myocardial ischemia in these patients is associated with abnormalities of the
coronary microcirculation. End organ damage as a consequence of hypertension and
diabetes parallel the progressive dysfunction of the microvasculature.
Elucidation of the role of the microvasculature in maintenance of normal cardiac
function and myocardial ischemia and damage with and without obstructive coronary
atherosclerosis may be of particular importance to Blacks and will also improve
understanding of IHD for the general population at risk.
Sudden cardiac death (SCD), defined as cardiac death within one hour of onset of
cardiovascular symptoms, is a major health problem. Vital statistics show higher
morbidity and mortality from IHD for Blacks and evidence that out-of hospital
deaths, particularly due to cardiac arrests, are higher in Blacks in all age
groups. Epidemiologic data support findings that LVH, which has a high
prevalence in Blacks, is associated with electrical instability and an increased
incidence of sudden cardiac death. Studies to define more precisely the risk of
life-threatening arrhythmias and the mechanism of SCD in Blacks with and without
LVH are needed.
Blacks (especially Black women) have an excess prevalence of diabetes. In
addition, diabetic cardiomyopathy results in heart failure independent of
atherosclerotic heart disease or hypertension. Although histopathologic
abnormalities such as small vessel disease, interstitial fibrosis and myocardial
hypertrophy have been demonstrated in patients with diabetic heart disease, the
pathogenesis of this disease is poorly understood. The presence of diabetes
accelerates the progression of atherosclerosis and hyperglycemia is associated
with alterations in endothelial vasomotion. The coexistence of diabetes and
hypertension is common in Blacks and is associated with more rapid development
of heart failure.
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.
In summary, despite the decline of death rates due to heart disease observed in
the last two decades in this country, heart disease, particularly IHD, remains
an important cause of premature morbidity and mortality for all Americans. The
role of obstructive coronary artery disease in the development of ischemia and
its consequences is well established. However, observed high rates of IHD in
Blacks despite apparent lower prevalence of coronary atherosclerosis provide an
opportunity to explore alternative mechanisms of myocardial damage and new
strategies for disease recognition, prevention, and treatment.
Proposed Research
Sudden Cardiac Death
The Black population has a higher rate of out-of-hospital SCD than the white
population. The difference, though, does not appear to 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. However, 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, especially the Black population.
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 % 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, particularly those suspected of hypertrophy, with or
without hypertension.
Blacks may have a response different from 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, and arrhythmogenesis. Quantifying
these differences 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.
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 angina-like pain in the absence of angiographic evidence of coronary
atherosclerosis. At present, tests such as the exercise ECG are of limited value
in the diagnosis of such patients, especially Black women.
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 might exacerbate Ca overload, although since animal models of
the aging heart have been shown to be less tolerant of Ca overload, and thus
more susceptible to ventricular fibrillation.
Although, 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, which may increase
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. 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. It remains to be determined whether exercise or other
factors would exert a beneficial effect on free radical scavenging in the former
population and thereby reduce the incidence of serious arrhythmias.
Hypertensive patients, who have low renin production, have been 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 the
myocardium, 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.
The following topics are for illustrative purposes only. Applicants are expected
to use their own knowledge of the field in developing their applications.
o Identification of the electrophysiological mechanisms responsible for
arrhythmias in hypertrophied myocardial tissue or 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; correlation of 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 in Blacks.
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 in Blacks.
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 to determine the relative risk of
SCD among Black men and women 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 such as 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 exclusively 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 but 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. An approach
that would enable noninvasive assessment of microvascular function concerns the
possibility that microvascular function in the forearm might reflect function in
the heart. Thus, there are opportunities to develop methods for better assessment
of the microcirculation. Several methods offer promise, including X-ray CT,
SPECT, quantitative echocardiography, and metabolic based techniques such as PET
and MRI.
Leukocyte and/or platelet plugging following an ischemic episode were once
thought to account for impaired perfusion. However, it is now believed 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. While published findings confirm this view, 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. Recent studies on the angiotensinogen genotypes
among Blacks and whites and salt sensitive hypertension strongly suggests that
genetic predisposition to vascular disease may be an important avenue of
investigation.
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.
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. These 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 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
signaling between microvascular endothelium and ventricular myocytes. 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.
The following topics are for illustrative purposes only. Applicants are expected
to develop their own research programs based on their knowledge of the field.
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 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
remodeling 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 which initiate and sustain
microvascular remodeling 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 a leading cause of death in the United States and affects
approximately 5% of the population. There is a greater prevalence of diabetes
among Blacks than among whites and over 80% of deaths among diabetic patients
result from cardiovascular complications. However, relatively little is known
about the progression of disease of the large blood vessels in the setting of
diabetes. Many traditional risk factors for coronary artery disease- such as high
blood pressure, low high-density lipoprotein (HDL) cholesterol, and high
triglycerides-are increased in type 2 diabetes, but other factors contribute to
the enhanced prevalence of coronary artery disease. High blood glucose levels
have emerged as one encompassing factor that affects nearly all these factors.
The burden of micro- and macrovascular complications associated with diabetes is
greater in nonwhite minority groups than in white diabetics. While rates are
elevated, this may relate to the increased prevalence of diabetes and other CVD
risk factors in these groups. The contribution of differences in obesity among
groups to cardiovascular complications is unclear.
Recent clinical studies have shown that mortality from coronary heart disease is
reduced in diabetic patients treated with coronary artery bypass surgery when
compared with treatment with angioplasty. Optimal medical management of
symptomatic coronary artery disease in diabetic patients, not requiring urgent
surgical intervention, represents an important and unresolved clinical question.
Because of the exceptionally high risk of this group, early invasive
revascularization, in conjunction with aggressive medical therapy, may increase
survival and reduce cardiac events. However, implementation of proven medical
therapies could cut mortality and prevent or substantially delay the onset of a
myocardial infarction. Reducing hyperglycemia may could important effects on
vascular pathology.
Diabetes is a heterogeneous disease. Clinically, it has been classified into
insulin-dependent diabetes mellitus (IDDM) and non-insulin-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, again suggesting the likely contribution of genetic factors to the
expression of this disease.
The relationship of various cardiac changes to the type of diabetes, its duration
and severity, should be studied. The majority of cardiac deaths in diabetic
patients is thought to result from cardiomyopathy rather than obstructive
coronary atherosclerotic disease, although patients with NIDDM are twice as
likely to have atherosclerosis and arteriosclerotic disease as the non-diabetic
population. NIDDM subjects frequently have both macrovascular and microvascular
disease. Macrovascular complications of diabetes tend to be associated with
dyslipidemia, hypertension, cigarette smoking, etc, while the principal risk
factors in microvascular complications are the extent and duration of
hyperglycemia. It is not clear how macrovascular and microvascular disease in
vital organs interact to potentiate the risk of atherosclerotic heart disease.
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 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. 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. Common histopathologic abnormalities include small
vessel disease, interstitial fibrosis, and myocardial hypertrophy. However, the
pathogenesis of this disorder is still uncertain. 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.
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. Although 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 which carry a genetic predisposition to develop obese NIDDM, it is
common for these species to develop abnormalities independent of 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 in animals is needed to understand the
fundamental mechanisms that account for 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, as well as irreversible changes in myocardial structure including
cell loss, replacement fibrosis and interstitial role of small vessel disease
including alterations in vascular interstitial fibrosis. The possible role of
altered myocardial energetics, increased vascular permeability and the formation
of glycosylation products in diabetics as stimuli to these adaptations should be
considered.
The following topics are for illustrative purposes only. Applicants are expected
to develop their own research programs based on their knowledge of the field.
o Development of animal models, which appropriately mimic the human condition,
especially in regard to NIDDM and hypertension and/or obesity to gain insights
into the processes underlying the damage that diabetes does to the large blood
vessels of the heart.
o Determination of the mechanisms underlying altered gene expression of
structure and contractile proteins in diabetic cardiomyopathy.
o Investigate hyperglycemia and glycation effects that alter cellular responses
to diabetes-induced injury to the heart.
o Characterize insulin action in myocardial and vascular cells, at the molecular
level, and in organs.
o Assess the importance of increased oxidation in insulin resistance and in
mechanisms of diabetes leading to heart disease.
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.
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 sudden cardiac death, microvascular disease, or diabetic
heart disease, or that address the risk factors or quality of life issues
associated with these conditions. 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. Preference will be given to those CAM
approached that can be intergrated with conventional treatments.
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 (e.g., magnesium, Co-enzyme
Q, carnitine, when investigated for therapeutic or preventive purposes. These
products are usually used in combinations and at very high doses well above the
RDA. 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).
o Mind-Body Medicine as used in the Black population. This RFA is limited to
those mind-body approaches currently in use by the public or practitioners, or
that address unconventional explanatory models. Mind-body approaches that are
already integrated into conventional medicine (e.g., patient education,
psychotherapy, etc.) will NOT be considered.
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:
- They provide opportunities for investigators with mutual or complementary
interests to engage in multidisciplinary research focusing on a specific
cardiovascular disorder.
- 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.
- 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:
- 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.
- Each component project requires a well-described hypothesis, preliminary data
and a time-table for conducting the proposed investigations.
- If core facilities are included, the relationship of each component project
to each core should be described.
- 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.
- 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.
- 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.
- 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). To provide
opportunity for such interactions, the time frame for implementation of this
program includes an ample interval between the release of this RFA and the
receipt date for applications, September 15, 1999.
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
(F59 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 under INQUIRIES. Program staff may also provide additional
relevant information concerning the policy.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. This
policy applies to all initial (Type 1) applications submitted for receipt dates
after October 1, 1998.
All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at the following URL address:
https://grants.nih.gov/grants/guide/notice-files/not98-024.html
LETTER OF INTENT
Prospective applicants are asked to submit, by May 7, 1999, 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 or 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, SCOR
in Ischemic Heart Disease in Blacks and number, HL-98-015 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 September 15, 1999. If an application is
received after that date, it will be returned to the applicant without review.
The 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 CSR 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. Applicants should
submit the highest quality applications possible to CSR as no site visits nor
reverse site visits will be held. As part of the initial merit review, a
streamlined 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 September 30, 2000 (FY 2000) for the SCORs in
Ischemic Heart Disease in Blacks. 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 Willet
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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