Full Text PA-95-074

AGING, VASCULAR STIFFNESS, AND CARDIOVASCULAR FUNCTION

NIH GUIDE, Volume 24, Number 24, June 30, 1995

PA NUMBER:  PA-95-074

P.T. 34

Keywords: 
  Aging/Gerontology 
  Cardiovascular Diseases 
  Risk Factors/Analysis 


National Institute on Aging

PURPOSE

The purpose of this program announcement (PA) is to foster research
that will enhance our understanding of vascular stiffness in aging
and in cardiovascular disease.  Ascertaining the importance of
vascular stiffness, as a risk factor for cardiovascular morbidity and
mortality, may suggest approaches to prevention and treatment
including early modification of risk factors and/or adverse
lifestyles to prevent, delay, and/or reverse vascular stiffening and
its potential deleterious sequelae as well as novel treatment in
persons with established stiffness or cardiac disease.  The
Geriatrics Program, National Institute on Aging (NIA), invites grant
applications on clinically-relevant research focusing on aging and
vascular stiffness.

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 PA,
Aging, Vascular Stiffness, and Cardiovascular Function, is related to
the priority area of heart disease and stroke.  Potential applicants
may obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0 or Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC Program Director or Principal Investigator should be included
with the application.

MECHANISM OF SUPPORT

This program will use the NIH investigator-initiated research project
grant (R01) and FIRST (R29) award mechanisms.  The total project
period for an application submitted in response to this program may
not exceed five years.  Because the nature and scope of the research
proposed in response to this program may vary, it is anticipated that
the size of awards will vary as well.  It is not the intent of this
program to encourage submission of large, multi-center, clinical
trials.  Awards will be administered under PHS grants policy as
stated in the Public Health Service Grants Policy Statement, DHHS
Publication No. (OASH) 94-50,000 (rev. 4/1/94).

RESEARCH OBJECTIVES

Background

Cardiovascular diseases are the most common cause of death among the
elderly and the percentage of deaths due to these diseases increases
significantly with age throughout the later years of life.  Age is
the main risk factor for cardiovascular diseases, including heart
attacks and stroke.  Age-related changes in cardiac function,
circulatory hemodynamics, blood pressure regulation, and lipid
metabolism all contribute significantly to morbidity and mortality in
the elderly.  Although age is a potent risk factor for high blood
pressure, stroke, coronary artery disease, and heart failure, the
precise reasons for this observation are presently unknown.

Other than age per se, a potential risk factor that may underlie
cardiovascular morbidity in the elderly is a stiffening of the large
and medium-sized elastic arteries (e.g., the aorta).  Arterial
stiffening increases during aging in healthy persons and is
accompanied by an elevation in systolic blood pressure, within the
normal range, which averages 25-35 mm Hg between the third and eighth
decades of life.  In approximately half of older Americans age 65 and
beyond, the degree of vascular stiffening may become large enough to
lead to the development of isolated systolic hypertension (defined as
a systolic blood pressure of 140 mm Hg or greater and a diastolic
blood pressure less than 90 mm Hg).  This observation is important
because high blood pressure is the major risk factor for stroke and
is also an important independent risk factor for coronary artery
disease, myocardial infarction, and heart failure in older Americans
regardless of gender or racial/ethnic background.

The increased arterial pressure (i.e., increased afterload) may
affect cardiac function in aging.  For example, the moderate increase
in left ventricular mass in many individuals observed between the
third and ninth decades of life may, in part, be mediated by the
increased arterial pressure and/or vascular stiffness.  Importantly,
left ventricular hypertrophy represents a major independent risk
factor for morbid cardiovascular events including myocardial
infarction and cardiac death.

According to The Fifth Report of the Joint National Committee on
Detection, Evaluation, and Treatment of High Blood Pressure, African
Americans have one of the highest frequencies of high blood pressure
in the world.  The Third National Health and Nutrition Examination
Survey (NHANES III) reports that in non- Hispanic blacks, age 60 and
older, high blood pressure is present in approximately 71 percent of
the population.  Moreover, in comparison to whites, high blood
pressure in African Americans is earlier in onset and of greater
severity at any decade of life. As a result, African Americans have a
greater rate of stroke, heart disease, and end-stage renal disease
than whites.  Yet, the importance of vascular stiffening during
aging, in contributing to the development of these morbid
cardiovascular events in African Americans is currently unknown.
Taken together, the available data suggest that vascular stiffening
may be implicated in the etiology and progression of several
cardiovascular disorders that affect a high proportion of older
Americans regardless of gender or racial/ethnic background.

Vascular stiffening has been considered a part of "normal" aging and
neither treatment for increased arterial stiffness nor lifestyle
modification nor pharmacologic intervention has been advocated to
blunt vascular stiffening and its potential deleterious sequelae.
Recent data from the literature, including data from the Baltimore
Longitudinal Study of Aging (BLSA) suggest that measurement of aortic
pulse wave velocity (i.e., the speed of transmission with which the
arterial pulse wave is propagated down the arterial tree) and
applanation tonometry (i.e., measurement of late systolic
amplification of the carotid artery pressure pulse) are important
markers for age-associated changes in vascular stiffness.

In a normotensive, carefully screened, healthy population of BLSA
volunteers (age range: 21-90), increasing age is associated with
progressive vascular stiffening.  Importantly, at any age, men and
women who have higher aerobic capacity (as indexed by maximal oxygen
consumption during exercise), demonstrate lower vascular stiffness
than their less aerobically fit peers.  Moreover, when compared to
their untrained age matched peers, endurance trained older men
demonstrate a markedly lower arterial stiffness.  These data suggest
an important inverse relationship between maximal oxygen consumption
and vascular stiffness and also imply that physical conditioning to
improve aerobic capacity in older Americans may blunt the arterial
stiffening that accompanies aging (Vaitkevicius et al., Circulation
88 (part 1): 1456-1462, 1993).  Other ongoing collaborative studies
suggest that novel pharmacologic therapy (vasodilators) in older
subjects, by decreasing central arterial stiffness, eliminates the
age- associated difference in cardiac volumes and ejection parameters
seen in older versus younger individuals during maximal exercise.
Thus, pharmacologic therapy may have potential for improving both
vascular stiffness and cardiac performance in older persons.

In other clinical studies, data have accumulated suggesting that
differences in chronic dietary salt intake may affect vascular
stiffness.  In a rural Chinese population who consume approximately
50 percent less salt than an urban Chinese population with a higher
prevalence of high blood pressure, arterial pulse wave velocity is
consistently lower and increases by a smaller amount with age when
compared to the urban group. Moreover, arterial pulse wave velocity
is lower in rural group subjects, as compared to age-matched urban
group subjects with the same arterial pressure (Avolio et al.
Circulation 71: 202-210, 1985).  In a different study population,
normotensive adult volunteers who follow a low salt diet for an
average of two years demonstrate a reduced vascular stiffness, as
indexed by arterial pulse wave velocity, when compared to age- and
arterial pressure-matched control subjects consuming a regular salt
diet (Avolio et al. Arteriosclerosis 6:166-169, 1986).  Collectively,
these data suggest that differences in dietary salt intake may affect
vascular stiffness and moreover, that the effect of salt may be
independent of arterial pressure.  Thus, modification of diet may
also prove beneficial in altering age-associated increases in
vascular stiffness.

Another focus of this program is to stimulate research on the
development of new indices of vascular stiffness and how these new
indices compare to well established indices currently in use.
Although arterial pulse wave velocity methodology is well
established, reproducible, easy to use, and amenable to study in
humans due to its non-invasiveness it does, like any other
methodology, have its limitations.  Ultrasound imaging has gained
popularity as a more direct measure of vascular stiffness but suffers
from having the requirement to also measure arterial blood pressure
changes concurrently from a different vascular site.  It has been
suggested that future progress in this field may require a consensus
for the best overall measurement of vascular stiffness, including
comparisons among various methodologies (both indirect and direct) in
prospective clinical studies (Arnett et al., Am. J. Epidemiol.
140(8): 669-682, 1994).  This program is particularly interested in
the development of new non-invasive measures of aortic impedance.

Ascertaining the importance of vascular stiffening in aging, and its
potential as a risk factor for cardiovascular morbidity and mortality
in older persons, may lead to development of preventive strategies
(e.g., early modification of risk factors and adverse lifestyles
through exercise and diet interventions) or new therapeutic
strategies (e.g., novel pharmacologic therapy) to prevent, delay,
and/or reverse vascular stiffening in aging and its potential
deleterious sequelae.  The potential public health benefit of
treating age-associated vascular stiffening, in terms of both cost
savings and improving the quality of life of older Americans, may be
considerable.

Objectives

The NIA encourages submission of clinically-relevant research
projects on vascular stiffening and the potential for vascular
stiffening as a risk factor for cardiovascular morbidity and
mortality in aging persons.  Topics of interest include, but are not
limited to:

o  Relationship between changes in vascular stiffness, arterial blood
pressure, and cardiovascular function with age in heterogenous
populations including women and ethnic/minority subgroups;

o  Relationship between vascular stiffness, arterial blood pressure,
and cardiac structure/function including left ventricular mass and
ejection parameters (i.e., systolic function) in older populations;

o  Relationship between vascular stiffness, arterial blood pressure,
and diastolic dysfunction in older populations with normal systolic
function;

o  Role of interventions including aerobic exercise, novel
pharmacologic agents, dietary modification, and/or smoking cessation
in modifying vascular stiffening (and the rate of increase in
stiffening), arterial blood pressure, and cardiac performance in
older populations;

o  Importance of vascular stiffness as a predictor of morbid
cardiovascular events in aging populations including hypertension,
atherosclerosis, stroke, coronary heart disease, and heart failure;

o  Relationship between vascular stiffness, arterial blood pressure,
atherogenic lipoproteins, and susceptibility to atherosclerosis in
aging persons;

o  Physiologic, nutritional, and genetic risk factors affecting the
rate of increase in vascular stiffening with age in humans;

o  Clinico-pathologic studies relating clinical measurements of
vascular stiffness to tissue properties of autopsy material or other
specimens;

o  Development of new indices of vascular stiffness; and

o  Comparisons between established indices of vascular stiffness and
newly developed indices in the same study population of older
persons.

These topics are neither prioritized nor meant to be restrictive.
Investigators are encouraged to submit applications in any
meritorious area of research responsive to the general research
objectives of this program.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

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

All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit. Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Grants Information Office, Division of Research
Grants, National Institutes of Health, 6701 Rockledge Drive, Suite
3032, MSC 7762, Bethesda, MD 20892-7762, telephone 301-435-0714.  The
title and number of this program announcement must be typed in
Section 2a on the face page of the application.

Applications for the FIRST (R29) award must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST (R29) award applications submitted without the
required number reference letters will be considered incomplete and
will be returned without review.

The completed original application and five legible copies must be
sent or delivered to:

DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817-7710 (for express/courier service)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established Public
Health Service referral guidelines.  Applications that are complete
will be evaluated for scientific and technical merit by an
appropriate peer review group convened in accordance with the
standard NIH peer review procedures.  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.

Review Criteria

o  Scientific, technical, or medical significance and originality of
the proposed research;

o  Appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  Qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  Availability of the resources necessary to perform the research;

o  Appropriateness of the proposed budget and duration in relation to
the proposed research;

o  Adequacy of the provisions for the protection of human and animal
subjects and safety of the research environment; and

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

Scored applications will compete for available funds with all other
scored applications assigned to that Institute/Center.  The following
will be considered in making funding decisions:

o  Quality of the proposed project as determined by peer review; o
Availability of funds; and
o  Program balance among research areas of the program announcement.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Andre J. Premen, Ph.D.
Geriatrics Program
National Institute on Aging
Gateway Building, Suite 3E327
7201 Wisconsin Avenue, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-6761
FAX:  (301) 402-1784
Email:  PremenA@gw.nia.nih.gov

Direct inquires regarding fiscal matters to:

Mr. Joseph Ellis
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
7201 Wisconsin Avenue, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  EllisJ@gw.nia.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.866.  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, USC 241 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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