ELECTRICAL REMODELING: NOVEL OPPORTUNITIES FOR ARRHYTHMIA CONTROL

Release Date:  November 2, 1999

RFA: HL-00-003

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date: February 4, 2000
Application Receipt Date: February 25, 2000

THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN  RESPONSE TO THIS RFA.

PURPOSE

The objective of this initiative is to elucidate mechanisms responsible for 
functional, molecular, and structural myocardial changes due to electrical 
remodeling and leading to arrhythmias.  The overall goal is to stimulate 
innovative multidisciplinary research to develop new strategies for treatment 
of arrhythmias causing high rates of morbidity and mortality.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2000," a PHS-
led national activity for setting priority areas.  This Request for 
Applications (RFA), ELECTRICAL REMODELING: NOVEL OPPORTUNITIES FOR ARRHYTHMIA 
CONTROL is related to one or more of the priority areas.  Potential 
applicants may obtain a copy of "Healthy People 2000" at 
http://odphp.osophs.dhhs.gov/pubs/hp2000.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, 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.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) 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 RFA may 
not exceed 4 years.  This RFA is one-time solicitation.  Future unsolicited 
competing continuation applications will compete with all investigator-
initiated applications and be reviewed according to the customary peer review 
procedures.  The anticipated award date is September 30, 2000.

FUNDS AVAILABLE

The NHLBI intends to commit approximately $2,500,000 in FY 2000 to fund 5 to 
7 new grants in response to this RFA. An applicant may request a project 
period of up to 4 years and a budget for direct costs for up to 10 modules of 
$25,000 each per year, including Facilities and Administrative Costs on 
consortium arrangements.  Because the nature and scope of the research 
proposed may vary, it is anticipated that the size of each award will also 
vary. Although the financial plans of the NHLBI provide support for this 
program, awards pursuant to this RFA are contingent upon the availability of 
funds and the receipt of a sufficient number of applications of outstanding 
scientific and technical merit.  At this time, it is not known if competing 
renewal applications will be accepted and/or if this RFA will be reissued.

RESEARCH OBJECTIVES

Background

Arrhythmias remain a major medical challenge and pose a significant public 
health burden.  Present therapeutic strategies for arrhythmia abatement are 
often ineffective or require device implantation only after persistent 
changes in cardiac electrical and conduction characteristics occur to 
increase risk for intractable life-threatening arrhythmia progression.  
Recognition of electrical remodeling as a phenomenon provides new 
opportunities for development of novel arrhythmia control and prevention 
strategies before persistent changes occur.

Most arrhythmias are associated with high morbidity or mortality, or both.  
Atrial fibrillation (AF) is the most prevalent arrhythmia, annually affecting 
more than two million Americans; it is associated with a twofold increase in 
mortality.  The most virulent arrhythmia, sudden cardiac death (SCD) due to 
ventricular fibrillation, has an unexpected onset and fatal outcome in more 
than 300,000 individuals each year.  With heart failure alone, SCD accounts 
for 30 to 50% of the nearly 45,000 annual deaths.

Electrical remodeling represents a persistent alteration in cardiac 
characteristics after a temporary, abnormal heart rhythm change.  For 
instance, electrical remodeling accounts for the maintained shortening of 
atrial refractoriness after transient heart rate increases.  This change 
increases likelihood of AF recurrence.  Similar ventricular changes following 
transient rhythm alterations likely increase propensity for SCD development.  
Such events may dominate particularly in heart failure and ischemia where a 
multitude of ongoing molecular, structural, and functional changes result in 
dysfunctional or dying cells that reduce cardiac output and increase risk of 
ventricular fibrillation and SCD.  

Clearly, electrical remodeling is involved in sustained arrhythmia recurrence 
and maintenance.  Arrhythmias usually progress, their frequency and intensity 
becoming more severe and treatment resistant over time.  For example, initial 
AF episodes are infrequent and self-terminating, but these eventually become 
chronic, sustained, and more difficult to control.  A similar sequence of 
events results in ventricular electrical, mechanical, and structural 
remodeling that predispose to arrhythmogenesis.  Arrhythmia control using 
conventional therapeutic agents is too often ineffective, while intracardiac 
devices (ICDs) that detect and terminate arrhythmias are only effective after 
arrhythmia risk has been well established.  Clarification of the role of 
specific signaling pathways, cellular messengers (e.g. cytokines and 
neuropeptides), ion channels, and other factors in electrical remodeling is 
needed to permit design of new therapeutic interventions for arrhythmia 
prevention.  Recent clinical findings suggest that prompt termination of 
transient episodes of rapid atrial rates prevents and reverses electrical 
remodeling plus subsequent AF progression.  Interventions that target the 
electrical remodeling process should also allow control and prevention of 
ventricular arrhythmias, including those that occur in the setting of 
decreased myocardial function accompanying heart failure and ischemia.

Genetic differences likely affect individual susceptibility to electrical 
remodeling.  More than 100 families, for example, have been identified now 
that share common genetic loci and a high incidence of either AF or 
idiopathic ventricular tachycardia.  Identification of the structures and 
physiological functions controlled by these and other loci will explain the 
bases for these arrhythmias.  Examination of families with other inherited 
arrhythmias such as arrhythmogenic right ventricular dysplasia (ARVD) will 
similarly help identify structures and processes involved in electrical 
remodeling to provide targets for new antiarrhythmic therapy strategies.

Some persistent differences in ion channel structure and activity that affect 
electrical impulse generation are now recognized after intermittent increases 
in heart rate.  Rapid rhythms are also associated with structural remodeling 
expressed as changes in mRNA levels for proteins associated with myofibrillar 
realignment and cytoskeletal architecture that impact mechanical function.  
Understanding and identification of alterations in ion channel structure and 
function related to electrical remodeling now provide exciting opportunities 
for new therapeutic interventions to prevent arrhythmia recurrence.  It is 
impressive, for example, that calcium channel blockers prevent electrical 
remodeling in pacing-induced arrhythmia models, and that verapamil treatment 
in patients reduces AF recurrence in preliminary studies.  These responses 
stress the important role electrical remodeling induced changes in cellular 
calcium handling play in arrhythmia recurrence and indicate one beneficial 
therapeutic intervention to prevent them.  The findings also hint that 
cellular calcium handling defects are a shared phenomenon common to 
myocardial remodeling associated with rhythm changes.

Proposed Research

This initiative is directed at elucidation of processes influencing 
electrical remodeling at the molecular, cellular, tissue, and organ levels.  
It is critical that applications combine study of mechanisms responsible for 
initiation and maintenance of sustained arrhythmias with development of 
preclinical strategies to prevent arrhythmia progression.  Studies focusing 
on cellular and molecular mechanisms, genetic susceptibility, pharmacologic 
intervention, identification of populations at risk, and development of novel 
strategies to prevent progression and recurrence of arrhythmias are sought.  
The following aims are examples of the scope of the solicitation:

o     Characterize alterations in selected gene and protein expression and 
induction of molecular changes associated with both deleterious and 
protective electrical characteristics.  This would include modulation 
of processes involved in impulse generation and conduction; e.g., ion 
channel and gap junction expression, structure, function, and 
regulation.

o	Develop clinically relevant therapeutic interventions that prevent and 
reverse alterations in electrical remodeling signal transduction 
pathways.

o	Characterize neurohumoral factors involved in initiation and 
progression of arrhythmias and develop clinically targeted strategies 
to recognize and modify their punitive role.

o	Study well-characterized populations to identify and characterize 
arrhythmia-associated genes that influence electrical remodeling, and 
develop strategies targeting expression of these to alter alter 
arrhythmia progression.


INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and 
their subpopulations must be included in all NIH supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification is provided that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of 
the research.  This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43

All investigators proposing research involving human subjects should read the 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research," which was published in the Federal Register of March 28, 1994 (FR 
59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 
11, March 18, 1994, available on the web at: 
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by 
the NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in 
Research Involving Human Subjects that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html

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

LETTER OF INTENT

Prospective applicants are asked to submit 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 
a subsequent application, the information that it contains allows NHLBI staff 
to estimate the potential review workload and avoid conflict of interest in 
the review.

The letter of intent is to be mailed, or faxed, by the letter of intent 
receipt date listed in the heading of this RFA to: 

Dr. C. James Scheirer
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220, MSC 7924
Bethesda, MD 20892-7924
Telephone: (301) 435-0266
FAX: (301) 480-3541
Email: js110j@nih.gov.

APPLICATION PROCEDURES

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 
Complete and  detailed instructions and information on Modular Grant 
applications can be found at  
http://grants.nih.gov/grants/funding/modular/modular.htm

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only 
when there is a possibility for an award. It is anticipated that these 
changes will reduce the administrative burden for the applicants, reviewers 
and Institute staff.  The research grant application form PHS 398 (rev. 4/98) 
is to be used in applying for these grants, with the modifications noted 
below.

The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants.  These forms are available at most institutional 
offices of sponsored research and from the Division of Extramural Outreach 
and Information Resources, National Institutes of Health, 6701 Rockledge 
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: 
GrantsInfo@nih.gov.

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
affixed to the bottom of the face page of the application.  Type the RFA 
number on the label. Failure to use this label could result in delayed 
processing of the application such that it may not reach the review committee 
in time for review.  In addition, the RFA title and number must be typed on 
line 2 of the face of the face page of the application for and the YES box 
must be marked.

The sample RFA label available at:  
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has 
been modified to allow for this change.  Please note this is in pdf format.



Submit a signed, typewritten original of the application, including the 
Checklist, and three signed, photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application must be 
sent to:

Dr. C. James Scheirer
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220, MSC 7924
Bethesda, MD 20892-7924
Telephone: (301)435-0266
FAX: (301)480-3541
Email: js110j@nih.gov.

Applications must be received by the application receipt date listed in the 
heading of this RFA.  If an application is received after that date, it will 
be returned to the applicant without review.
  
The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed. This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must 
include an introduction addressing the previous critique.

BUDGET INSTRUCTIONS

Modular Grant applications  will request direct costs in $25,000 modules, up 
to a total direct cost request of $250,000 per year. The total direct costs 
must be requested  in accordance with the  program guidelines and  the 
modifications made to the standard  PHS 398 application  instructions 
described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in 
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular 
Total Direct plus Facilities and Administrative  (F&A) costs] for the initial 
budget period Items 8a and 8b should be completed indicating the Direct and 
Total Costs for the entire proposed period of support.

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 
of the PHS 398. It is not required and will not be accepted with the 
application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the 
categorical budget table on Form Page 5 of the PHS 398. It is not required 
and will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative 
page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for 
sample pages.) At the top of the page, enter the total direct costs requested 
for each year.  This is not a Form page.

o Under Personnel, List key project personnel, including their names, percent 
of effort, and roles on the project. No individual salary information should 
be provided. However, the applicant should use the NIH appropriation language  
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the 
nearest $1,000. List the individuals/organizations with whom consortium or 
contractual arrangements have been made, the percent effort of key personnel, 
and the role on the project. Indicate whether the collaborating institution 
is foreign or domestic. The total cost for a consortium/contractual 
arrangement is included in the overall requested modular direct cost amount.  
Include the Letter of Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by  
reviewers in the assessment of each individual's qualifications for a 
specific role in the proposed project, as well as to evaluate the overall 
qualifications of the research team. A biographical sketch is required for 
all key personnel, following the instructions below. No more than three pages 
may be used for each person. A sample biographical sketch may be viewed at:  
http://grants.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;

o CHECKLIST - This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate the 
type of agreement and the date. All appropriate exclusions must be applied  
in the calculation of the F&A costs for the initial budget period and all 
future budget years.

o The applicant should provide the name and phone number of the individual to 
contact concerning fiscal and administrative issues if additional information 
is necessary following the initial review. 

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
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 by an appropriate peer review group 
convened by the NHLBI in accordance with the review criteria stated below.  
As part of the initial merit review, a process will be used by the initial 
review group in which applications 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 the applications under review, 
will be discussed, assigned a priority score, and receive a second level 
review by the NHLBI National Advisory Council.

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 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?

(2) 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?

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

(4) 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)?

(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?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

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

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project  
proposed in the application.

Additional scientific/technical merit criteria specific to the objectives of 
the RFA and the mechanism used must be included if they are to be used in the 
review.

Schedule

Letter of Intent Receipt Date: February 4, 2000
Application Receipt Date: February 25, 2000
Peer Review Date: May/June 2000
Council Review: September 7-8, 2000
Earliest Anticipated Start Date: September 30, 2000

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

David A. Lathrop, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Two Rockledge Center, Suite 9186
6701 Rockledge Drive
Bethesda, MD  20892-7940
Telephone:  (301)435-0529
FAX:  (301) 480-1454
Email: LathropD@gwgate.nhlbi.nih.gov

Robin Boineau, M.D.
Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
Two Rockledge Center, Suite 
6701 Rockledge Drive
Bethesda, MD  20892-7940
Telephone:  (301) 435-0455
FAX:  (301) 480-1667
Email: BoineauR@gwgate.nhlbi.nih.gov

Direct inquiries regarding fiscal matters to:

Ms.  Jane Davis
Grants Operations Branch
National Heart, Lung, and Blood Institute
Two Rockledge Center, Suite 7174
6701 Rockledge Drive
Bethesda, MD  20892-7926
Telephone:  (301)435-0166
FAX:  (301)480-3310
Email: davisj@gwgate.nhlbi.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.837, (use appropriate program number).  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 NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  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 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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