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: https://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: https://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 https://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 301/710-0267, 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: https://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 https://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: https://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.
Return to NIH Guide Main Index
Office of Extramural Research (OER) |
National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892 |
Department of Health and Human Services (HHS) |
||||||||
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files. |