Full Text HL-96-005

THE ETIOLOGY OF EXCESS CARDIOVASCULAR DISEASE IN DIABETES MELLITUS

NIH GUIDE, Volume 24, Number 41, December 1, 1995

RFA:  HL-96-005

P.T. 34

Keywords: 
  Cardiovascular Diseases 
  Diabetes 
  Etiology 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  January 2, 1996
Application Receipt Date:  February 9, 1996

PURPOSE

The National Heart, Lung, and Blood Institute (NHLBI) invites
applications for program project grants for research on the etiology
of cardiovascular diseases (CVD) associated with diabetes mellitus.
This initiative will support investigators with outstanding programs
of basic and human subjects research on one or more diabetes
associated cardiovascular complications.  In addition, with the
encouragement of the NHLBI, the programs that receive awards will
participate in a coordinated effort to evaluate the metabolic and
environmental factors responsible for the pathogenesis of CVD in
existing, defined population groups.

A program project grant (P01) is for the support of a broadly-based
multidisciplinary or multifaceted research program that has a
specific major objective or central theme.  Each program project
application and award in response to this solicitation must have both
basic research and human subjects components.

Applications should be submitted to and will be reviewed by the NIH
according to the usual NIH peer review procedures.  Applications
judged meritorious will be jointly funded by NHLBI and the Juvenile
Diabetes Foundation International (JDFI).  To have an application
considered for funding by the JDFI, an applicant must authorize in
writing the NHLBI to provide a copy of the letter of intent,
application, and NIH prepared summary statement of the initial review
to the JDFI.

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,
The Etiology of Excess Cardiovascular Disease in Diabetes Mellitus,
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 for-profit and non-profit domestic
institutions, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local government and
eligible agencies of the Federal government.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.  Although program project awards
cannot be made to foreign institutions, a subproject of high
scientific merit may be eligible for support.

The principal investigator should be an established research
scientist with the expertise and experience to provide scientific
leadership, ensure quality control, and effectively administer 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, the research project for which the principal
investigator is the project leader is not recommended for further
consideration, the entire program project application will not be
considered further.  If the project of the principal investigator is
judged by peer review to be of low scientific merit, the overall
scientific merit ranking assigned to the entire application by the
review committee will be markedly reduced.  Project leaders must
agree to commit at least 20 percent effort to each project for which
they are responsible.

Exclusions

This RFA is intended to support program project grants that have both
a basic research and human population component.  Therefore,
applications that include only basic or only clinical research will
not be responsive to this RFA.  This solicitation is intended to
redress the inadequate information on the etiology of excess
cardiovascular disease in patients with diabetes mellitus.
Therefore, applications that do not focus on this aspect of diabetes
and cardiovascular disease will not be considered.  Large population
studies or large clinical trials will be considered unresponsive to
this RFA.

MECHANISM OF SUPPORT

It is the intention of NHLBI and JDFI to stimulate collaboration
among investigators with different but complementary areas of
expertise.  This research will be supported by the National
Institutes of Health (NIH) Program Project research grant mechanism
(P01).  Responsibility for planning the proposed project will be
solely that of the applicant.  The total project period requested by
an application submitted in response to the present RFA may not
exceed five years.

A program project grant is for the support of a broadly-based
multidisciplinary or multifaceted research program that has a
specific major objective or central theme.  The award may support
research components and core functions.  Collectively, these
components should demonstrate essential elements of unity and
interdependence and result in a greater contribution to program goals
than if each activity were pursued individually.  Each applicant will
be expected to propose both basic and human subjects based research
components, with concentration on one or more major risk factors as
related to the increased risk of CVD in diabetic patients.  Efforts
will be made by the NHLBI to facilitate collaboration both during
development of applications and after the program is established.

Applications must be prepared and awards will be made according to
NHLBI Program Project policies.  NHLBI Guidelines for the preparation
of Program Project Grant applications may be obtained from Dr C.
James Scheirer at the address listed under LETTER OF INTENT.
Approximately 50 percent of the total costs of each grant will be
funded by the NHLBI and the same amount by the JDFI.  Funding rules,
including the determination of allowable indirect costs, will take
into consideration those of each sponsor.  Post award administration
will be according to current policies and requirements that govern
the research grant programs of the NIH and the JDFI as appropriate.

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

Upon initiation of this program, the NHLBI and JDFI plan to sponsor a
meeting to encourage the exchange of information among investigators,
foster collaborative efforts among program grantees, and identify
resources that would enhance the productivity of several grantees.
In many cases, combining proposed measures in highly characterized
population subgroups may provide the most information.  Where
appropriate, additional joint protocols will be developed.  After
this planning phase, collaborative investigations will be conducted.
Subsequent meetings will take place approximately yearly.  For this
purpose, requests for travel funds for a two-day meeting (two in year
01 and one per year thereafter) should be included in the budget
section of the application (assume meeting will be held in Bethesda,
MD).  Applicants should include a statement in their applications
indicating their willingness to participate in such meetings and to
cooperate with other researchers at other interdisciplinary research
program sites.

Support will be provided for up to five years.  Continued funding
will be contingent on satisfactory completion of proposed
investigations.  In addition to a continuing series of reports on
results of individual investigations, an overall report will be
produced at the conclusion of the program.

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
Program Project grant application, but it is imperative that a
consortium application be prepared so that the programmatic, fiscal,
and administrative considerations are explained fully.  The published
policy governing consortia is available in the business offices of
institutions that are eligible to receive Federal grants-in-aid.
Consult the latest published policy governing consortia before
developing the application.  If clarification of the policy is
needed, contact William Darby, (301) 435-0177.  Applicants for
Program Project grants should clearly describe the interactions of
the participants and the integration of the consortium project(s)
with those of the parent institution, because synergism and
cohesiveness can be diminished when projects are located outside the
group at the parent institution. Indirect costs paid as part of a
consortium agreement are excluded from the limit on the amount of
direct costs that can be requested.

FUNDS AVAILABLE

Approximately $1.4 million in total costs will be provided for the
first year of support for the program by NHLBI with an equivalent
amount provided by JDFI.  Applicants may request up to $650,000
direct costs, not including indirect costs for collaborating
institutions, in the first year with a maximum increase of no more
than four percent in each additional year requested in the
application.  Funding rules, including the determination of allowable
indirect costs, will take into consideration those of each sponsor.
It is anticipated that three to four grants will be awarded under
this program.  Although this program is provided for in the financial
plan of the NHLBI, award of grants pursuant to this RFA is contingent
upon receipt of funds for this purpose.  Administrative adjustments
in project period and/or amount of support may be required at the
time of the award.

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

RESEARCH OBJECTIVES

General Background

Additional investigations of the etiology of macrovascular
complications of diabetes mellitus are needed.  Such studies should
include population, clinical, and basic research and involve experts
in both diabetes and cardiovascular diseases.  JDFI has embarked on a
major long term capital fund raising campaign to establish programs
of excellence in diabetes research.

Diabetes mellitus is a complex metabolic disorder that affects not
only glucose metabolism but several other metabolic processes.  Some
of these effects are acute and appear related to concentrations of
glucose and/or insulin.  Other effects develop over many years and
are related to other metabolic derangements of diabetes or are of
uncertain etiology.  Recent advances in understanding the process of
atherogenesis and the pathogenesis of chronic diabetic complications
indicate that diabetes may accelerate atherosclerosis and the
development of clinical cardiovascular disease through several
mechanisms.

Scientific Background

The association between overt diabetes mellitus and excess risk of
cardiovascular disease (CVD) has been documented in diabetic
populations throughout the world, but the pathogenic mechanisms for
the relationship are only partially understood.  Among diabetic
patients, both the incidence and mortality rates from myocardial
infarction are increased, as are the risks of recurrent infarction,
congestive heart failure, cerebrovascular disease, and peripheral
vascular disease.  The increased risk of CVD associated with diabetes
appears to be greater in women than in men.  In general, about 50
percent of excess heart disease in diabetics is attributed to
associated abnormalities in other known CVD risk factors but levels
of these factors may be in part determined by the degree of diabetic
control.  Milder abnormalities of glucose tolerance are also
associated with an increased risk of cardiovascular disease, but
glucose level in this group generally has not been an independent CVD
risk factor.  In these patients, an underlying multiple risk factor
syndrome may be a major contributor to accelerated macrovascular
disease.

Approximately 12 to 14 million Americans have diabetes and up to an
additional 18 million may have impaired glucose tolerance or glucose
levels between those of diabetes and normoglycemia.  Cardiovascular
disease is the cause of death in 60 to 75 percent of this combined
group.  Insulin dependent diabetes mellitus (IDDM) is a leading cause
of premature cardiovascular disease.  Non-insulin dependent diabetes
(NIDDM) is a significant risk factor for cardiovascular disease in
middle and older ages.  As the U.S. population ages, the importance
of glucose intolerance as a risk factor for CVD will increase since
its prevalence increases markedly with age, reaching over 50 percent
in those above age 65 years.  Moreover, with improved methods of
glucose control, the anticipated decline in chronic microvascular
complications of diabetes may be offset by an increase in the rates
of major cardiovascular complications.

It is not clear whether the pathogenesis of excess CVD is the same in
IDDM and NIDDM.  It is also important to recognize that improved
glucose control in diabetic patients may not by itself be sufficient
to eliminate the excess risk of diabetic cardiovascular
complications.  While recent data from the Diabetes Control and
Complication Trial (DCCT) suggest a reduction in cardiovascular
events in the group achieving near normoglycemia, the number of CVD
events in this generally young cohort is small.  Preliminary results
from a pilot study of intensive treatment of hyperglycemia in Type II
diabetic veterans fail to suggest any short term benefit of improved
glucose control, showing fewer cardiovascular events in the
conventional than in the intensive treatment group.  No relative
reduction in CVD was observed in the variable dose insulin treated
group of the University Group Diabetes Program that achieved the best
degree of glucose control.  These observations may be particularly
relevant to the Type II diabetic patient with the multiple
cardiovascular risk factor syndrome (Syndrome X of Reaven) where
control of hyperglycemia only partially ameliorates the other CVD
risk factor abnormalities.  Finally, the relative benefits of glucose
control and other CVD risk factor control may vary depending upon the
race and gender of the patient and whether or not atherosclerotic
disease is already advanced.  Thus, the treatment most appropriate to
prevent long term macrovascular complications in a young Type I
diabetic with labile hyperglycemia may not be best for an elderly
Type II diabetic with mild hyperglycemia.  More information is needed
in all of these areas to design better and more specific treatment
and prevention regimens.

Available data on hyperglycemia and insulin levels as risk factors
for CVD have numerous limitations.  Many of the frequently cited
studies are old and utilized techniques of risk factor and disease
measurement that are crude by today's standards.  Until recently,
most population studies of diabetes have included only rudimentary
measures of vascular disease.  Many studies of CVD and associated
risk factors measured diabetes crudely and, in others, particularly
several large clinical trials, diabetics were excluded.  Among
several early studies that indicated a risk for CVD associated with
hyperglycemia, it is now probable that at least part of the risk can
be explained by subsequently identified risk factors that were not
measured at the time of the studies, such as hyperinsulinemia,
elevated insulin resistance, abnormalities in coagulation factors,
platelet function, or lipoprotein particle size or composition.  In
fact, two of the frequently cited studies indicating elevated insulin
level is an independent risk factor for CVD did not measure
HDL-cholesterol.  The relative importance of hyperglycemia,
hyperinsulinemia, and elevated insulin resistance as factors in the
excess CVD of diabetes has not been assessed in prospective studies.
Relative to studies on other major CVD risk factors such as
hypertension and hypercholesterolemia, evaluations of the role of
glucose intolerance and its related abnormalities as causes of CVD
have been limited.

The many complex metabolic abnormalities associated with diabetes and
their potential interactions with risk factors for atherosclerosis
make collaboration among investigators with different expertise
essential.  While diabetes increases the risk of CVD in all
populations studied, the observed CVD event rates vary widely,
suggesting that important environmental and probably genetic factors
may modify the adverse effects of hyperglycemia.  Collaboration
between experts in cardiovascular disease and diabetes and among
basic researchers, clinical investigators, and epidemiologists will
be essential to maximize progress in understanding the causes of
cardiovascular disease among diabetic patients and to develop new
therapeutic approaches for preventing this major chronic
complication.

Objectives

The primary objective of this initiative is to understand how the
presence of diabetes increases the risk of cardiovascular disease.
To accelerate this understanding, this initiative will bring together
basic, clinical, and population based investigators to develop a
research program to address this question at the laboratory,
clinical, and population levels.  Although the control of
hyperglycemia is clearly associated with a reduction in the
development of microvascular complications of diabetes, its role in
the prevention of the macrovascular complications of diabetes is less
certain.  As a consequence, optimal interventions to prevent these
two major categories of complications may differ.  Proposed studies
should focus on how diabetes increases the risk of macrovascular
disease and the relative importance of hyperglycemia compared to
other cardiovascular disease risk factors associated with glucose
intolerance in the pathogenesis of the macrovascular disease in
diabetic patients.

Key questions include:

o  Does hyperglycemia directly cause the macrovascular disease?

o  Does hyperglycemia increase the risk of macrovascular disease
primarily by altering other CVD risk factors?

o  Is the excess risk of CVD in diabetics largely independent of the
level of glucose?

o  Does hyperglycemia have differing importance as a CVD risk factor
in Type I (insulin dependent) compared to Type II (non-insulin
dependent) diabetic patients?

o  Is the observed variation in rates of cardiovascular complications
among diabetic patients in different populations secondary to genetic
and/or environmental factors?

Answers to these questions will be important in formulating
recommendations for therapy of diabetic patients and, potentially,
for the design of a future clinical trial to test treatment to
prevent diabetes associated CVD.  Investigators selected for
participation in this program will be expected both to direct
innovative research at their institutions and to collaborate with
other members of the study group to apply this information to human
populations.

This initiative will support a broad program to understand the
etiology of the accelerated macrovascular disease found in diabetic
patients.  It will not necessarily support investigations in all
relevant areas, but will attempt to select and promote collaboration
among the most promising applicant groups.  Applicants will be
selected for participation based upon, among other things, the
overall evaluation of the importance and innovative aspects of their
proposed program and their plans for evaluating these findings in
defined populations.

Specifically, this initiative may support research in several areas,
for example:

o  To evaluate the roles of hyperglycemia, glycosylation of proteins,
and advanced glycosylation end products (AGEs) in the development of
diabetic macrovascular disease.

o  To evaluate the role of hypertension and its interactions with
other risk factors in the development of diabetic macrovascular
disease.

o  To evaluate the role of modifications of lipids and lipoproteins
(oxidation and glycosylation) in the development of diabetic
macrovascular disease.

o  To evaluate the role of altered coagulation factors, abnormalities
in platelet function, and alterations in blood viscosity in the
development of diabetic macrovascular disease.  To evaluate the role
of hyperinsulinemia and/or insulin resistance in the development of
diabetic macrovascular disease.

o  To evaluate the role of vascular wall factors in the development
of vascular disease in the presence of hyperglycemia.

o  To evaluate the role of the co-occurrence or "clustering" of CVD
risk factor abnormalities including hypertension, dyslipidemia,
hyperglycemia, and obesity in the development of diabetic
macrovascular disease.

o  To evaluate the role of genetic and environmental factors in the
variation in prevalence of diabetic macrovascular disease among
racial and ethnic groups.

A unique aspect of this RFA is the recognition that much relevant
work on the pathogenesis of atherosclerosis has been conducted that
has not yet been related to the link between diabetes and
atherosclerosis.  A goal of this initiative is to establish
collaborations among groups who have been pursuing separate paths.
For example, extensive work on lipid oxidation has taken place, the
importance of this process in diabetes has been recognized, but
research to assess its importance in diabetic vascular disease is
limited.  Similarly, extensive work has been done on insulin and
insulin resistance.  The potential importance of these factors in the
multiple CVD risk factor syndrome and in atherosclerosis has been
recognized, but research to assess their atherogenicity in the
diabetic is limited.  Many additional examples were evident in the
presentations at the 1992 Workshop on Diabetes and Mechanisms of
Atherogenesis (Getz, 1993).

Advances in basic research during the past decade have greatly
improved understanding of the metabolic abnormalities of diabetes and
the process of atherogenesis. Further work may lead to unique ways of
preventing or treating the atherosclerosis associated with diabetes.
Because of this, a major portion of this initiative will be devoted
to advancing fundamental knowledge of the atherosclerotic process in
diabetics and to clarifying whether the same processes are
responsible for the excess risk in all diabetic patients.  A key
question is whether the process in diabetic patients is the same or
different from that in nondiabetics.  Many research opportunities,
many of which are interrelated, were identified in the workshop
mentioned above (Getz, 1993).  Several areas appear appropriate for
emphasis:

Dyslipidemias and diabetes:

Prevalence rates of cardiovascular disease are low among diabetic
patients in populations with low levels of total and LDL cholesterol.
Several studies have shown alterations in the levels and composition
of lipid particles in diabetic subjects.  In addition to the long
recognized abnormalities such as elevated triglyceride and lowered
HDL-cholesterol levels, numerous other abnormalities including
changes in lipoprotein particle size and composition, protein
glycosylation and oxidation of lipoproteins have recently been
reported.  While the basic lipid changes have been found in all
populations studied, their magnitude varies considerably, both within
groups and within individual diabetic patients, suggesting the
effects of diabetes can be substantially modified by environmental or
underlying genetic factors.  The reasons some individuals and groups
appear to be protected are unknown and represent a promising area for
further investigations.  Lipid metabolism is also an area where
differences occur between Type I and Type II diabetic patients with
more adverse alterations generally found in Type II diabetics.

Hypertension and diabetes:

Hypertension is more common in diabetic patients than in age-matched
normoglycemics and its presence increases the risk of both micro- and
macrovascular complications of diabetes.  Many questions need further
exploration in this area including the origins of the excess
hypertension.  The relationship of elevated blood pressure to
subclinical renal disease and to the multiple CVD risk factor
syndrome are promising areas for further investigation.  In addition,
recent studies have suggested that the choice of drugs to treat
hypertension may be important in postponing both micro- and
macrovascular complications of diabetes.  The role of renal
dysfunction and the significance of microalbuminuria as a predictor
of both micro- and macrovascular disease needs to be evaluated.

Hemostasis and diabetes:

Several abnormalities in the coagulation system of diabetics have
been identified.  Abnormalities include changes in level and
structure of coagulation factors, alterations in platelet function,
and alterations in blood and plasma viscosity.  Many of the studies
are small and the techniques used for measurement were sometimes
controversial.  The associations among coagulation factors and other
recognized CVD risk factors require clarification.  This is one of
the least explored areas of diabetes associated CVD risk, but
potentially very important and much work remains to be done.

Hyperglycemia, insulinemia, and insulin sensitivity and diabetes:

These risk factors have generally been the province of diabetologists
studying the development of diabetes but recent reports have
suggested they may be independent cardiovascular disease risk
factors.  Critical questions center around the absolute and relative
importance of each of these factors in the acceleration of
atherosclerosis.  If hyperglycemia is "atherogenic," then improved
blood glucose levels should lead to a decrease in the risk of CVD.
In contrast, if hyperinsulinemia is "atherogenic," improvement of
blood glucose levels by intensive insulin treatment may reduce the
risk of microvascular disease (as demonstrated in the DCCT) but might
increase the risk of macrovascular disease.  Treatment regimens may
have different effects in Type I and Type II diabetic patients.

Vascular biology:

The past decade has produced major advances in the understanding of
atherogenesis at the cellular and molecular level.  It is now
recognized that the vascular endothelium is a complex organ that
senses its environment and responds in numerous ways to injury and to
recognized CVD risk factors.  Independently, major advances have
occurred in understanding how diabetes produces modifications at the
cellular and molecular level.  Much less is known about how these
diabetic modifications may interact with other atherogenic factors in
the local environment of the vessel wall to initiate and propagate
atherosclerotic plaques in diabetic patients.  In fact, it is not
known whether atherosclerosis in diabetics is simply a more rapidly
progressing common atherosclerotic plaque or whether differences
exist in its composition and in the pattern of cellular responses and
gene expression.  An area of particular opportunity is the study of
the regulation of growth factor and cytokine expression by mildly
oxidized low density lipoprotein and advanced glycosylation end
products (AGEs).

Genetic and Environmental Factors:

Rates of diabetic macrovascular complications vary widely in
different populations.  For example, some American Indian tribes,
despite extraordinary rates of diabetes, appear relatively protected
against cardiovascular complications. Some potential explanations for
these differences have been outlined above.  Clarifying the effects
of genetic and environmental factors on risk factor levels (and/or
composition) and on the susceptibility of the vascular wall to
atherosclerosis is of critical importance for the design of future
preventive measures.

In addition to improving understanding of the basic processes that
lead to excess macrovascular disease in diabetic patients, a major
goal of this initiative is to apply this information to human
studies.  This initiative will also provide support for limited
clinical and population studies which can either enhance
understanding of the pathophysiology of cardiovascular complications
of diabetes or provide information important for developing new
therapeutic interventions.  Because of their cost, support for
establishing new epidemiologic studies of populations or clinical
trials to test reduction of disease risk cannot be provided through
this initiative.

The NHLBI has already established several large populations to study
risk factors for cardiovascular disease.  Many of these studies have
collected information on glucose tolerance and historical information
on diagnosis and treatment of diabetes.  They include extensive
characterization of CVD risk factors and assessments of clinical and
subclinical cardiovascular disease, making it possible to describe
risk factor patterns prior to their alteration by drug therapy or
clinical disease.  In addition, these studies include men and women
and representatives of multiple racial and ethnic groups, providing
an opportunity to look at the contrast in risk of cardiovascular
complications among different diabetic groups.  Overall, they
represent a valuable resource for studies of cardiovascular
complications in Type II diabetic patients.  Other important
populations have been identified and characterized with support from
other funding sources. Some include substantial numbers of Type I
diabetic patients.  Investigators applying for support from this
initiative are strongly encouraged to propose collaborative efforts
with existing population studies since this will be the most
efficient way to develop a clinical component. Investigators are free
to propose other clinical components, especially if they offer unique
advantages.  To obtain further information on NHLBI supported
population studies, contact Dr. Peter Savage at the address listed
under INQUIRIES.

It is anticipated that each program project will have several
discrete subprojects conducted by several investigators under the
overall direction of the Principal Investigator.  Each application
should include laboratory investigations and also include a clinical
and/or population component.

Studies initiated in one of these components should lead to
application in the others.  For example, lipid abnormalities
described in a population study could be studied further in the
laboratory using cell or animal models, then translated into small
clinical trials of drug efficacy.  Other examples could involve
investigations of the effects of hyperinsulinemia or elevated insulin
resistance that include studies of their effect on the isolated
vascular wall lesion, induction of hyperinsulinemia in animal models,
pharmacologic alteration of levels of insulin resistance in small
clinical studies, and assessment of the relative importance of
insulin and insulin resistance on other risk factors in population
studies containing several racial or ethnic groups.  Such examples
are not meant to suggest specific studies, but to indicate the
spectrum of research and type of collaboration that this initiative
is designed to support.

In most cases, human subjects will be selected from an existing
population on the basis of previously measured evidence of clinical
or subclinical disease or risk factor profiles.  In many cases, such
studies may be conducted on stored samples.  For more complex tests
requiring extensive subject participation or collection of additional
samples, care must be taken to not interfere with the ongoing study.
Existing policies in current multicenter population studies for
approval and reporting of ancillary studies will apply.  NHLBI
Project Scientists will expedite the collaborative aspects of study
design and will facilitate joint research with existing NHLBI funded
studies, as appropriate.

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

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

All investigators proposing research involving human subjects should
read the "NIH Guidelines on the Inclusion of Women and Minorities as
Subjects in Clinical Research," which was reprinted in the Federal
Register of March 28, 1994 (59 FR 14508-14513) to correct typesetting
errors in the earlier publication, and reprinted 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 January 2, 1996, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the principal
investigator, the identities of other key personnel and participating
institutions, and the number and title of the RFA in response to
which the application may be submitted.  Although a letter of intent
is not required, is not binding, and does not enter into the review
of subsequent applications, the information that it contains allows
NHLBI staff to estimate the potential review workload and avoid
conflict of interest in the review.

Letters of intent may be sent by U.S. mail or by fax.  The letter of
intent is to be sent to:

Dr. C. James Scheirer,
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220
Bethesda, MD  20892-7924
Telephone:  (301) 435-0266
FAX:  (301) 480-3541
Email:  James_Scheirer@NIH.GOV

Letter of Authorization

To be considered for funding by the JDFI, applicants must submit a
brief letter to the NHLBI indicating that they will allow their
applications to be considered by the JDFI.  All materials relating to
the application will be promptly forwarded to the JDFI by NHLBI.  The
summary statements for such applications will be shared with the JDFI
at the time of their availability. Letters of authorization should be
prepared by the Principal Investigator and co-signed by the official
signing for the applicant institution.  This letter may be combined
with the letter of intent or may be submitted directly to Dr. Savage
or Dr. Robinson at the address listed under INQUIRIES.

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 Office of Grants Information, Division of Research Grants,
National Institutes of Health, 6701 Rockledge Drive, Room 3032, MSC
7762, Bethesda, MD 20892-7762, telephone 301-435-0714, email:
girg@drgpo.drg.nih.gov.

Applicants must follow the instructions provided in the RFA.  The RFA
label available in the PHS 398 application form must be affixed to
the bottom of the face page of the application.  Failure to use this
label could result in delayed processing of the application such that
it may not reach the review committee in time for review.  In
addition, to identify the application as a response to this RFA,
check "YES", enter the title, "Etiology of Excess Cardiovascular
Disease in Diabetes Mellitus" and the RFA number HL-96-005 on Line 2
of the face page of the application.

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

DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
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 Dr. James Scheirer,
Chief, Review Branch, Centers and Special Projects Section at the
address listed under LETTER OF INTENT.  It is important to send these
two copies at the same time as the original and three copies are sent
to the Division of Research Grants, otherwise the NHLBI cannot
guarantee that the application will be reviewed in competition for
this RFA.

Applications must be received by February 9, 1996.  If an application
is received after that date, it will be returned to the applicant.
The Division of Research Grants (DRG) will not accept any application
in response to this RFA that is essentially the same as one currently
pending initial review, or is essentially the same as one already
reviewed.  This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by DRG
and for responsiveness by the NHLBI.  Incomplete and/or non-
responsive applications 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 in accordance with the
review criteria stated below by an appropriate peer group convened by
the NHLBI.  As part of the initial merit review, all applications
will receive a written critique and undergo a process in which only
those applications deemed to have the highest scientific merit,
generally the top half of applications under review, will be
discussed, assigned a priority score, and receive a second level
review by the appropriate national advisory council or board.

Neither site visits nor reverse site visits are planned as a part of
the review process.  Therefore, each application should be complete
on submission.  Following the initial review group consideration,
secondary review of applications will be conducted by the National
Heart, Lung and Blood Advisory Council and the Juvenile Diabetes
Foundation International Advisory Board.

The criteria for review of applications will be those used regularly
for the review of program project grant applications by the NHLBI.  A
complete and detailed description of these criteria is contained in
"Program Project Grant:  Preparation of the Application", NHLBI, US
DHHS, August 1992, a copy of which may be obtained from Dr Scheirer
at the address listed under LETTER OF INTENT. Awardees will be
selected on the basis of the priority score of their individual
applications, subproject scores, and the ability of that proposal to
contribute to a comprehensive investigation of diabetic
cardiovascular disease.

Review criteria for RFAs are generally the same as those for
unsolicited interdisciplinary research grant applications, and
include:

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

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

o  if applicable, the technical merit and justification of each core
unit;

o  the qualifications, experience, and commitment of the Program
Project Principal Investigator and his/her ability to devote adequate
time and effort to provide effective leadership;

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

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

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

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

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

AWARD CRITERIA

The most important criterion in selecting awardees will be the
scientific merit as reflected in the priority score. However, factors
such as program balance and available funds may enter into selection
from among meritorious applications.  Applications must be received
by February 9, 1996.  An application not received by this date will
be considered ineligible.

Schedule

Letter of Intent Receipt Date:    January 2, 1996
Application Receipt Date:         February 9, 1996
Initial Review:                   March/April 1996
Review by NHLB Advisory Council:  June 1996
Review by JDFI Advisory Board:    June 1996
Anticipated Award Date:           June 28, 1996

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Peter J. Savage, M.D.
Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 8154
Bethesda, MD  20892-7934
Telephone:  (301) 435-0702
FAX:  (301) 480-1667
Email:  Peter_Savage@NIH.GOV

David M. Robinson, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive,, Room 10193, MSC 7956
Bethesda, MD  20892-7956
Telephone:  (301) 435-0545
FAX:  (301) 480-2849
Email:  drw@cu.nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Mr. William Darby
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7128
Bethesda, MD  20892-7926
Telephone:  (301) 435-0177
FAX:  (301) 480-3310
Email:  William_Darby@NIH.GOV

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance number 93.387, Heart and Vascular Diseases.  Awards are
made under the authority of the Public Health Service Act, Section
301 (42 USC 241) and administered under PHS grant policies and
Federal regulations, most specifically 42 CFR Part 52 and 45 CFR Part
74.  This program is not subject to the intergovernmental review
requirements of Executive Order 12372, or to Health Systems Agency
Review.

The 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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