RELEASE DATE:  November 21, 2003
PA NUMBER:  PA-04-026

EXPIRATION DATE:  December 1, 2006, unless reissued.

Department of Health and Human Services (DHHS)
National Institutes of Health (NIH)

National Institute on Aging (NIA)



o Purpose of the PA
o Research Objectives
o Mechanism of Support
o Funds Available 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations


The goal of this program is to foster biomedical research that will 
lead to a better understanding of the biology, pathophysiology, 
clinical presentation, and medical management of the acute coronary 
syndromes (ACS) in old age.  This PA is intended to foster clinical 
research, including integrative biomedical research, some of which will 
incorporate the tools of molecular and cellular biology in the study of 
function and clinical outcome.  A long-term goal is to provide the 
necessary framework for the development of effective prevention and/or 
new treatment strategies for ACS in old age.    



The acute coronary syndromes (ACS) are defined by a spectrum of 
clinical conditions ranging from unstable angina (coronary heart 
disease-related chest pain at rest), to non-Q wave and Q-wave acute 
myocardial infarction (i.e., heart attack).  They are among the most 
common disorders seen in the emergency room and are often missed in 
many older patients who present with chest pain.  It is estimated that 
there are over 1 million episodes of ACS per year in persons aged 65 
years and older and that up to 33% of acute heart attacks are 
clinically unrecognized in the older population.  In the U.S., persons 
aged 65 years and older account for more than 60% of acute heart 
attacks and for more than 80% of heart attack deaths (Society of 
Geriatric Cardiology).  

There has been a great deal of research on the ACS in the younger 
(i.e., less than 75 years of age) population.  For example, in patients 
up to 75 years of age presenting with an acute heart attack (ST-segment 
elevation), thrombolytic therapy is associated with a significant 
reduction in mortality.  Yet, the clinical benefits of this important 
therapy in patients aged 75 years and older remain to be defined.  
Moreover, early administration of angiotensin converting enzyme (ACE) 
inhibitors is beneficial in patients up to age 75 years.  However, the 
importance of ACE inhibitors in the patient population aged greater 
than 75 years remains unanswered.  Many clinical studies, including 
clinical trials, have excluded older patients, including the very 
elderly, and have also excluded older persons with significant co-
morbidities.  Past studies have also not focused on key issues that 
assume larger, sometimes primary, importance among older patients 
including health-related quality of life and end of life issues, 
personal preferences, depression, and co-morbidity.  Available data 
suggest that elderly patients with the ACS have different clinical 
presentations, therapeutic responses, and natural histories than 
younger patients.    

A meta-analysis (Fibrinolytic Therapy Trialists’ Collaborative Group) 
has shown that elderly patients with the ACS, even with early and 
complete thrombolysis, have a higher mortality than younger patients.  
Moreover, despite recent treatment advances for the ACS, older patients 
still have a higher risk of morbidity, mortality, and complications 
following therapy.  It appears that the prognosis is worse for older 
women (versus men) and older ethnic minorities (versus Caucasians).  
Older persons have complex atherosclerotic plaque and more severe 
coronary heart disease than younger persons.  Thus, plaque 
stabilization to prevent the risk of rupture and thrombus formation 
remains an important research area.  

New research suggests the importance of inflammation in playing a major 
role in plaque vulnerability to rupture and thrombus formation.  
Development and testing of new therapies targeting the inflammatory 
component of the ACS is an important and active area of investigation.  
Data have also accumulated suggesting a limited tolerance to even short 
term ischemia in older persons that leads to early cell death 
(apoptosis), altered cardiac energetics and calcium handling, and a 
limited recovery of ventricular function following successful 
reperfusion therapy.  Animal studies suggest the importance of an age-
related impairment in angiogenesis in the response to ischemia.  
Research on the early response of the heart to ischemic injury remains 
an important area of research.
In light of the anticipated rise in the number of older persons who 
will develop cardiovascular disease over the next several decades, 
there is a compelling need now to expand basic and clinical research 
(including translational research) into the pathophysiologic 
mechanisms, clinical manifestations, treatment, and prevention of the 
ACS in old age.

Additional background information on the epidemiology, pathophysiology, 
biologic mechanisms, clinical features, therapy, and prognosis of the 
ACS in older adults is available in the summary of a recent conference 
“Acute Coronary Syndromes in the Elderly: Mechanisms and Management,” 
organized by the Society of Geriatric Cardiology with support provided 
by the NIA.  A summary of research recommendations from this conference 
can be accessed at
The Executive Summary of the conference has been published in the 
American Journal of Geriatric Cardiology (Rich, MW for the PRICE-II 
Organizing Committee and PRICE-II Investigators.  Second Pivotal 
Research in Cardiovascular Syndromes in the Elderly (PRICE-II) 
Symposium – Acute Coronary Syndromes in the Elderly: Mechanisms and 
Management.  Am. J. Geriatr. Cardiol. 2003; 12:307-318, 327).
Knowledge to be Achieved

This PA solicits proposals for research to:

1. Clarify age-related differences in risk, and for different clinical 
and cardiac functional ACS outcomes, responses to specific ACS 
interventions, and post-acute sequellae, and the causes of these 

Attention to outcomes (including subsequent disability and frailty) in 
the very old and in older patients with comorbid conditions is 
particularly encouraged. Both observational and intervention studies 
may be proposed. Studies that develop and apply methods to integrate 
information from observational studies and clinical trials to improve 
generalizability of research findings on this topic are also 

2. Identify determinants of good and poor short- and long-term outcomes 
among older ACS patients, and the mechanisms responsible for these 
outcomes.  In addition to risk factors, the identification of 
protective factors that are associated with unusually good outcomes is 
of interest. 

Clinical factors of interest in regard to possible effects on outcomes 
in older adults with the ACS include, but are not limited to: delayed 
clinical presentation, specific co-morbid conditions, atypical symptoms 
upon presentation, severity of coronary heart disease, and risk factors 
for complications from drug and/or procedural interventions.  
Physiologic factors of interest include age-related changes in 
myocardial responses to ischemia, and changes in other systems that may 
affect survival or severity of morbidity. 

3. Identify and characterize aging changes and age-related conditions 
that contribute to poor ACS outcomes in older persons; and elucidate 
the mechanisms that cause or modulate changes with important effects on 
ACS outcomes in old age. 

Examples of aging changes whose effects on ACS outcomes could be 
explored include, but are not limited to: 

o  Age-related changes in cardiovascular properties and functions such 
as: vascular and ventricular compliance, diastolic filling, endothelial 
function, beta-adrenergic responsiveness, responses to ischemic 
preconditioning, mitochondrial function, calcium homeostasis, cardiac 
myocyte apoptosis, myocardial microvasculature, myocardial angiogenic 
responses to ischemia, plaque morphology and stability, extracellular 
matrix and remodeling, and the pulmonary vasculature.  The use of 
innovative, non-invasive, imaging techniques (e.g., high resolution 
MRI) is highly desirable;  

o  Age-related changes in hemostatic and fibrinolytic systems; 

o  Age-related changes in inflammatory responses to stimuli such as 
endothelial injury in regard to ACS related outcomes such as risk of 
atherosclerotic plaque rupture, thrombus formation, and adverse 
clinical outcomes (including death) in older adults;

Studies on the effects of specific comorbid conditions (e.g., diabetes) 
on ACS outcomes in older persons, and the mechanisms responsible for 
these effects are encouraged. 

Studies on the role of age-related pathophysiologic interactions 
between different physiologic systems (e.g., interactions of 
inflammation and vascular stiffness) in adverse ACS outcomes are also 
of interest. 

4. Determine effects on ACS outcomes in older patients (or aging animal 
models of ACS) of interventions that could reverse, or counter the 
effects, of aging changes (e.g., in cardiovascular properties, 
hemostasis, fibrinolysis, or inflammation) that contribute to poorer 
outcomes in older ACS patients.   Attention to outcomes in the very old 
and in older persons with comorbid conditions is strongly encouraged.  
Both pharmacologic and lifestyle interventions (e.g., physical activity 
and weight loss) are of interest. 

5. Develop and validate novel ACS animal models that mimic the human 
condition in old age.

6. Determine the clinical features, responses to treatments, and 
prognoses of elderly women and elderly ethnic minorities with the ACS 
who tend to have more prevalent disease than men and non-ethnic 
minorities, respectively.  Studies should determine the 
pathophysiologic mechanisms underlying the observed differences in the 
clinical presentations and outcomes in these vulnerable populations.

In all the above areas, an integrative approach to the ACS, through 
collaboration between basic and clinical scientists, is highly 

These topics are neither prioritized nor meant to be restrictive.  
Investigators are encouraged to submit applications in any area of 
research addressing the general research objectives of the PA.  


This PA will use the NIH research project grant (R01) award mechanism.  
As an applicant, you will be solely responsible for planning, 
directing, and executing the proposed project.  The total project 
period for an application submitted in response to this PA may not 
exceed five years.

This PA uses just-in-time concepts.  It also uses the modular as well 
as the non-modular budgeting formats (see  
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular format.  Otherwise 
follow the instructions for non-modular research grant applications.  
This program does not require cost sharing as defined in the current 
NIH Grants Policy Statement at


NIA intends to commit $1.5 million in total costs for funding of 
meritorious applications submitted in response to this PA over the 
three year duration of the PA.  Awards made will be contingent upon 
availability of these funds and the receipt of a sufficient number of 
applications of outstanding scientific and technical merit.  
Applications will also compete for funding with all other applications 
assigned to the NIA.        


You may submit an application if your institution has any of the 
following characteristics:

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, 
hospitals and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign institutions/organizations
o Faith-based or community-based organizations 


Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with his or her 
institution to develop an application for support. Individuals from 
underrepresented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs.  


We encourage your inquiries concerning this PA and welcome the 
opportunity to answer questions from potential applicants.  Inquiries 
may fall into two areas:  scientific/research and financial or grants 
management issues:

o Direct your questions about scientific/research issues to:

Andre J. Premen, Ph.D.
Geriatrics & Clinical Gerontology Program 
National Institute on Aging
Gateway Building, Room 3C-307
Bethesda, MD  20892-9205
Telephone: (301) 496-6761
FAX: (301) 402-1784

o Direct your questions about financial or grants management matters 

Ms. Linda Whipp
Grants Management Officer
Grants and Contracts Management Office 
National Institute on Aging
Gateway Building, Room 2N212
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672


Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  Applications must 
have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) 
number as the Universal Identifier when applying for Federal grants or 
cooperative agreements.  The DUNS number can be obtained by calling 
(866) 705-5711 or through the web site at  The DUNS number should be entered on 
line 11 of the face page of the PHS 398 form.  The PHS 398 is available 
at in an 
interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email: 

The title and number of this PA must be typed on line 2 of the face 
page of the application form and the YES box must be checked.

APPLICATION RECEIPT DATES: Applications submitted in response to this 
PA will be accepted at the standard application deadlines, which are 
available at  Application 
deadlines are also indicated in the PHS 398 application kit.

requesting up to $250,000 per year in direct costs must be submitted in 
a modular grant format.  The modular grant format simplifies the 
preparation of the budget in these applications by limiting the level 
of budgetary detail.  Applicants request direct costs in $25,000 
modules.  Section C of the research grant application instructions for 
the PHS 398 (rev. 5/2001) at  includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at

YEAR: Applications requesting $500,000 or more in direct costs for any 
year must include a cover letter identifying the NIH staff member 
within one of the NIH institutes or centers who has agreed to accept 
assignment of the application.   

Applicants requesting more than $500,000 must carry out the following 

1) Contact the IC program staff member at least 6 weeks before 
submitting the application, i.e., as you are developing plans for the 

2) Obtain agreement from the IC staff member that the IC will accept 
your application for consideration for award; and,
3) Identify, in a cover letter sent with the application, the staff 
member and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended 
or revised version of these grant application types.  Additional 
information on this policy is available in the NIH Guide for Grants and 
Contracts, October 19, 2001 at
SENDING AN APPLICATION TO THE NIH:  Submit a signed, typewritten 
original of the application, including the checklist, and five 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)

APPLICATION PROCESSING:  Applications must be mailed on or before the 
receipt dates described at
The Center for Scientific Review (CSR) will not accept any application 
in response to this PA 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 a substantial revision of an unfunded version of an 
application already reviewed, but such application must include an 
Introduction addressing the previous critique.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and 
funding assignment within 8 weeks.


Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  Appropriate scientific review 
groups convened in accordance with the standard NIH peer review 
procedures ( will evaluate 
applications for scientific and technical merit.  

As part of the initial merit review, all applications will:

o Undergo a selection process in which only those applications deemed 
to have the highest scientific merit, generally the top half of 
applications under review, will be discussed and assigned a priority 
o Receive a written critique
o Receive a second level review by the appropriate national advisory 
council or board


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 evaluate 
applications in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  
The scientific review group will address and consider each of the 
following criteria in assigning the application’s overall score, 
weighting them as appropriate for each application. 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

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.

SIGNIFICANCE:  Does this study address an important problem? If the 
aims of the application are achieved, how will scientific knowledge be 
advanced?  What will be the effect of these studies on the concepts or 
methods that drive this field?

APPROACH:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of 
the project?  Does the applicant acknowledge potential problem areas 
and consider alternative tactics?

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 

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

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?

ADDITIONAL REVIEW CRITERIA:  In addition to the above criteria, the 
following items will be considered in the determination of scientific 
merit and the priority score:

human subjects and protections from research risk relating to their 
participation in the proposed research will be assessed.  (See criteria 
included in the section on Federal Citations, below).

to include subjects from both genders, all racial and ethnic groups 
(and subgroups), as appropriate for the scientific goals of the 
research will be assessed.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the 
sections on Federal Citations, below).

are to be used in the project, the five items described under Section f 
of the PHS 398 research grant application instructions (rev. 5/2001) 
will be assessed.


Sharing Research Data

Applicants requesting more than $500,000 in direct costs in any year of 
the proposed research are expected to include a data sharing plan in 
their application.  The reasonableness of the data sharing plan or the 
rationale for not sharing research data will be assessed by the 
reviewers.  However, reviewers will not factor the proposed data 
sharing plan into the determination of scientific merit or priority 
score.  Additional information can be found at
BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.


Applications submitted in response to a PA will compete for available 
funds with all other recommended applications.  The following will be 
considered in making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities


HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated 
with reference to the risks to the subjects, the adequacy of protection 
against these risks, the potential benefits of the research to the 
subjects and others, and the importance of the knowledge gained or to 
be gained. 

DATA AND SAFETY MONITORING PLAN:  Data and safety monitoring is 
required for all types of clinical trials, including physiologic, 
toxicity, and dose-finding studies (phase I), efficacy studies (phase 
II), and efficacy, effectiveness and comparative trials (phase III).  
The establishment of data and safety monitoring boards (DSMBs) is 
required for multi-site clinical trials involving interventions that 
entail potential risk to the participants.  (NIH Policy for Data Safety 
and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998:

SHARING RESEARCH DATA:  Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking $500,000 or more in 
direct costs in any single year are expected to include a plan for data 
sharing or state why this is not possible 
(  Investigators 
should seek guidance from their institutions, on issues related to 
institutional policies, local IRB rules, as well as local, state and 
Federal laws and regulations, including the Privacy Rule.  Reviewers 
will consider the data sharing plan but will not factor the plan into 
the determination of the scientific merit or the priority score.

policy of the NIH that women and members of minority groups and their 
sub-populations must be included in all NIH-supported clinical research 
projects unless a clear and compelling justification is provided 
indicating 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 

All investigators proposing clinical research should read the "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research - Amended, October, 2001," published in the NIH Guide 
for Grants and Contracts on October 9, 2001 
(; a 
complete copy of the updated Guidelines is available at  
The amended policy incorporates: the use of an NIH definition of 
clinical research; updated racial and ethnic categories in compliance 
with the new OMB standards; clarification of language governing NIH-
defined Phase III clinical trials consistent with the new PHS Form 398; 
and updated roles and responsibilities of NIH staff and the extramural 
community.  The policy continues to require for all NIH-defined Phase 
III clinical trials that: a) all applications or proposals and/or 
protocols must provide a description of plans to conduct analyses, as 
appropriate, to address differences by sex/gender and/or racial/ethnic 
groups, including subgroups if applicable; and b) investigators must 
report annual accrual and progress in conducting analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects.  You will find this policy 
announcement in the NIH Guide for Grants and Contracts Announcement, 
dated June 5, 2000, at  

The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom 
of Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application.  In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

The Department of Health and Human Services (DHHS) issued final 
modification to the "Standards for Privacy of Individually Identifiable 
Health Information", the "Privacy Rule," on August 14, 2002.  The 
Privacy Rule is a federal regulation under the Health Insurance 
Portability and Accountability Act (HIPAA) of 1996 that governs the 
protection of individually identifiable health information, and is 
administered and enforced by the DHHS Office for Civil Rights (OCR).  
Those who must comply with the Privacy Rule (classified under the Rule 
as "covered entities") must do so by April 14, 2003 (with the exception 
of small health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule 
reside with the researcher and his/her institution. The OCR website 
( provides information on the Privacy Rule, 
including a complete Regulation Text and a set of decision tools on "Am 
I a covered entity?"  Information on the impact of the HIPAA Privacy 
Rule on NIH processes involving the review, funding, and progress 
monitoring of grants, cooperative agreements, and research contracts 
can be found at

proposals for NIH funding must be self-contained within specified page 
limitations.  Unless otherwise specified in an NIH solicitation, 
Internet addresses (URLs) should not be used to provide information 
necessary to the review because reviewers are under no obligation to 
view the Internet sites.  Furthermore, we caution reviewers that their 
anonymity may be compromised when they directly access an Internet 

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of 
"Healthy People 2010," a PHS-led national activity for setting priority 
areas.  This PA is related to one or more of the priority areas.  
Potential applicants may obtain a copy of "Healthy People 2010" at

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at and is not subject 
to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.  Awards are made under the 
authorization of Sections 301 and 405 of the Public Health Service Act 
as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 
and 45 CFR Parts 74 and 92.  All awards are subject to the terms and 
conditions, cost principles, and other considerations described in the 
NIH Grants Policy Statement.  The NIH Grants Policy Statement can be 
found at 

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and to discourage the 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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