IMPACT OF AGING ON DEVELOPMENT OF ATRIAL FIBRILLATION

Release Date:  January 8, 1999

PA NUMBER:  PA-99-035

P.T.

National Institute on Aging
National Heart, Lung, and Blood Institute

PURPOSE

The goal of this program announcement (PA) is to foster research that will
enhance our understanding of age-related structural and functional changes in the
atria and their impact on the development of atrial fibrillation (AF) in older
persons.  This initiative is intended to foster clinically-related research,
including integrative biomedical research, some of which may incorporate the
tools of molecular and cell biology in the study of function and clinical
outcome.  A long-term goal of this program is to provide the groundwork for the
primary prevention of AF.  This program will use the traditional NIH
investigator-initiated research project grant (R01) award mechanism.

HEALTHY PEOPLE 2000

Each NIH PA addresses one or more of 22 Health Promotion and Disease Prevention
priority areas identified.  This PA, Impact of Aging on Development of Atrial
Fibrillation, is related to the priority area of heart disease and stroke.  These
areas can be found electronically at http://www.crisny.org/health/us/health7.html

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.  Disadvantaged individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.  Awards under
this program to foreign institutions will be made only for studies of very
unusual scientific merit, need, and opportunity.

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 traditional NIH investigator-initiated research project
grant (R01) award mechanism.  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the applicant.  The
total project period for an application submitted in response to this
announcement may not exceed five years.  Because the nature and scope of the
research proposed may vary, it is anticipated that the size of awards will vary
as well.  This program will not support multi-site clinical trials.

An investigator planning to submit an application requesting $500,000 or more in
direct costs for any year is advised that he or she must contact Institute
program staff before submitting the application, i.e., as plans for the research
are being developed, to obtain agreement from program staff that the Institute
will accept the application for consideration of award.  An application received
without indication of prior staff concurrence and identification of that contact
will be returned to the applicant without review.  Investigators planning to
request $500,000 or more in direct costs are referred to the policy update notice
in the NIH Guide for Grants and Contracts, Volume 25, Number 14, May 3, 1996.  
Applicants proposing human intervention studies are
strongly encouraged to read the NIA policy notice in the NIH Guide for Grants and
Contracts, Volume 25, Number 33, October 4, 1996 and also the NIH policy for data
and safety monitoring in the NIH Guide, release date: June 10, 1998.

RESEARCH OBJECTIVES

Atrial fibrillation (AF) is recognized as a condition which causes significant
morbidity, disability, and mortality related to heart disease and stroke.  Atrial
fibrillation is the most common cardiac arrhythmia seen in clinical practice
today.  This condition affects about 2.2 million Americans.  The median age for
AF in the general population is 75.  Atrial fibrillation is said to account for
about 15% of all strokes in the U.S. annually (i.e., about 75,000 cases out of
a total of 500,000).  The arrhythmia is also responsible for about 33% of strokes
in persons over 65 years of age.  The prevalence of AF rises markedly with age: 
approximately 0.1% at age 40, 6% at age 65, and 10% at age 80 and older.  The
condition may raise the risk of stroke five-fold.  The number of persons
developing AF may continue to rise as the population ages.

Recent data from the Cardiovascular Health Study suggest that age, male gender,
clinical cardiovascular disease, and left atrial size are all important risk
factors for AF.  Data from the Framingham Heart Study suggest that the risk of
stroke attributable to AF increases significantly with age, rising from 1.5% for
those aged 50-59 years to 23.5% for those aged 80-89 years.  The importance of
AF persists into the oldest and most stroke-prone decades while the impact of
other common risk factors, e.g., high blood pressure, lose their significance in
the oldest old.  About 70% of persons with AF are between 65 and 85 years of age. 
Isolated AF occurs but is uncommon and most patients diagnosed with this
arrhythmia have co-existing cardiovascular disease (e.g., ischemic heart disease,
valvular disease, hypertension, heart failure or stroke).

Although there are several treatment options available to manage AF (i.e.,
secondary prevention) including therapies to maintain sinus rhythm following
cardioversion to control ventricular rate, and therapies to prevent
thromboembolism and stroke through anticoagulation, most treatments are
associated with potentially harmful side effects.  Accordingly, the NHLBI is
sponsoring the Atrial Fibrillation Follow-up Investigation of Rhythm Management
(AFFIRM).  This ongoing trial in 5,300 elderly patients is comparing two
strategies for long-term management of AF:  antiarrhythmic agents to maintain
normal sinus rhythm and a different group of drugs and/or catheter ablation for
heart rate control only.  Yet, despite the importance of AFFIRM, more attention
needs to be directed to the importance of age-related changes (both structure and
function) in the atria and the impact of these changes on the development of AF
in older persons with co-existing cardiovascular disease.

Neither the specific molecular nor precise physiologic bases for AF are well
defined.  It has been suggested that the left atrium enlarges, stiffens, and
develops fatty infiltrations - especially within the atrial septal region.  These
changes are accompanied by other age-related changes that have been observed in
humans or animals.  These include:  increased interstitial collagen deposition
(which may interfere with normal electrical conduction); changes in elastin
content; increased cardiac amyloid deposition; shortening of atrial refractory
period; depressed sinoatrial and atrioventricular nodal function; increased
sinoatrial and atrioventricular conduction time; decreased number of atrial
myocytes, including a decrease of up to 90% in the number of sinoatrial pacemaker
cells by age 75 in humans; and atrial myocyte hypertrophy.

Age-related changes in atrial anatomy are likely to be involved in the genesis
of AF.  Compared with ventricular anatomy, atrial anatomy is exceedingly complex
in nature.  The atria are composed primarily of highly branched, distinct muscle
bundles; i.e., pectinated trabeculae.  These trabeculae provide multiple
conduction pathways that split the atrial excitation wavefront as it conducts
throughout the upper chambers of the heart.  Within this anatomical arrangement,
conduction slowing may lead to reentry of atrial excitation and induction of AF. 
Unexcitable fibrous tissue proliferation increases with age, and appearance of
this tissue may represent an important way by which atrial conduction is altered
during aging.  Understanding the interactions between fibrous tissue
(unexcitable) and atrial muscle (excitable) will help define factors leading to
AF in old age.  This information will foster development of treatment strategies
targeting atrial fibroproliferative changes.  This research, along with a better
elucidation of the electrical interactions occurring within the complex atrial
anatomy, should provide the basis for the development of new treatments for the
prevention of AF in the elderly.

Clinical studies using non-invasive imaging may also be valuable in
characterizing age-related changes in the left atrium from ongoing human
longitudinal studies.  Imaging techniques such as transesophageal
echocardiography or transthoracic ultrasound could be used in at high risk
patients for AF (e.g., those undergoing cardiac revascularization) to study
atrial features that predict the development of AF.  Studies may include, for
example, the impact of changes in left atrial size and other atrial structural
changes on increasing susceptibility to thrombus formation in the left atrium. 
Research is also needed to ascertain how other recently identified risk factors
for AF (e.g., elevations in systolic blood pressure and blood glucose) impact on
age-related changes in the atrium in the development and manifestation of this
arrhythmia in older persons.  There is limited information available on the
importance of racial and ethnic differences in the development of AF in old age. 
Therefore, more research is needed to examine this issue in greater detail.

Studies in appropriate animal-based models of AF are also encouraged.  Such
animal models, adapted for aging research, may lead to a better understanding of
the importance of age-related changes in the atria in the development of AF. 
Animal models can allow for a detailed evaluation of the potential mechanisms of
AF.  Such models or other studies on older animals may allow for carefully
constructed electrophysiologic mapping, in vivo anatomical assessment by intra-
cardiac ultrasound, and biopsy or autopsy assessment of histology or electron
microscopy ultrastructure.  Novel interventions (e.g., interventions to prevent
left atrial enlargement) could be tested in an efficient manner.  Such models
could be used as groundwork for the development of interventions to prevent the
occurrence of AF in humans.

This solicitation encourages submission of investigator-initiated R01
applications in areas related to the topics discussed above.  The topics are
neither prioritized nor meant to be restrictive.  Investigators are encouraged
to submit applications in any area of research responsive to the general research
objectives of this program.  This PA is intended to encourage new research on AF,
its causes and progression, and the effects of aging as an integrative approach
in the study of function and clinical outcome.  Collaborations between basic and
patient-oriented research scientists are highly encouraged.  Research focused on
racial/ethnic differences is also encouraged.  A long-term goal of this program
is to support new integrative biomedical research that will lay the groundwork
for the development of novel interventions to prevent the occurrence of AF.  The
public health benefit, in terms of both reducing health care costs associated
with the treatment and management of AF and improving the quality of life of
older persons (i.e., adding 'life' to years) may be considerable.

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," that was published in the Federal Register of March 28, 1994 (FR 59
14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.  The text is also available electronically at:
http://www.nih.gov/grants/guide/notice-files/not94-105.html

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.

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.  The text is also  available electronically at: 
http://www.nih.gov/grants/guide/notice-files/not98-024.html

NOTE FOR APPLICATIONS FOCUSED ON AGING RESEARCH

Applications received in response to this PA are expected to focus on scientific
issues related to aging and to aging-related aspects of disease.  In describing
the plan to recruit human subjects investigators may cite a focus on aging or on
aging-related aspects of disease as the justification for why children will be
excluded.  In this regard, applicants may use Justification 1, the research topic
to be studied is irrelevant to children, from the policy announcement.

APPLICATION PROCEDURES

Applications are to be submitted on grant application form PHS 398 (rev. 4/98)
and will be accepted on the standard application receipt dates as indicated in
the application kit.  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email:
GrantsInfo@nih.gov.  Application kits are also available electronically at:
https://grants.nih.gov/grants/forms.htm.

To identify the application as a response to the PA, the PA title and number must
be typed on line 2 of the face page of the application form and the YES box must
be marked.

Submit the signed, original, single-sided application, along with five exact,
single-sided copies and five collated sets of appendix materials to:

CENTER FOR SCIENTIFIC REVIEW (formerly the 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)

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 NIH peer review procedures.  As part of the initial merit review,
all applications will receive a written critique.  Applications will also 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.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In the
written comments, reviewers will be asked to discuss the following aspects of the
application in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in assigning the overall score, weighting them as
appropriate for each application.  Note that the application does not need to be
strong in all categories to be judged likely to have major scientific impact and
thus deserve a high priority score.  For example, an investigator may propose to
carry out important work that by its nature is not innovative but is essential
to move a field forward.

1.  Significance:  Does the project address an important problem?  If the aims
of the application are achieved, how will scientific knowledge be advanced?  What
will be the effect of the study on the concepts or methods that drive the field?

2.  Approach:  Are the conceptual framework, design (including composition of the
study population), methods, and analyses adequately developed, well-integrated,
and appropriate to the aims of the project?  Does the Principal Investigator
acknowledge potential problem areas and consider alternative tactics?

3.  Innovation:  Does the project employ novel concepts, approaches, or methods? 
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

4.  Investigator:  Is the Principal Investigator appropriately trained and well
suited to carry out the work?  Is the work proposed appropriate to the experience
level of the applicant and other researchers (if any)?

5.  Environment:  Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements?  Is there evidence of institutional support?

The scientific review group will also examine: the appropriateness of the
proposed budget and duration; the adequacy of plans to include both genders,
minorities and their subgroups, and children, as appropriate for the scientific
goals of the research, or the justification for their exclusion; plans for the
recruitment and retention of subjects; the provisions for the protection of human
and animal subjects; and the safety of the research environment.

AWARD CRITERIA

Scored applications will compete for available funds with all other scored
applications.  The following will be considered in making funding decisions: 
Quality of the proposed project as determined by peer review; Availability of
funds; and Program priority.

INQUIRIES

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
7201 Wisconsin Avenue, Suite 3E327, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-6761
FAX:  (301) 402-1784
Email:  PremenA@exmur.nia.nih.gov

David A. Lathrop, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 9186, MSC 7940
Bethesda, MD  20892-7940
Telephone:  (301) 435-0504
FAX:  (301) 480-1454
Email:  LathropD@gwgate.nhlbi.nih.gov

Direct inquires regarding fiscal matters to:

Ms. Cynthia Riddick
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  RiddickC@exmur.nia.nih.gov

Ms. Maxine Davis-Vanlue
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:  DavisM@gwgate.nhlbi.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.866 and 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 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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