Ischemic heart disease causes -600,000 deaths/year (-20% of all deaths). An estimated 1.3 million Americans have a myocardial infarction every year;because their prognosis is determined by the size of the infarct, reducing infarct size is of paramount importance to alleviate morbidity and mortality. For more than 30 years the NHLBI has invested enormous resources (at least several hundred million dollars) in preclinical studies aimed at developing infarct-sparing therapies, and several hundred (if not thousands) therapies have been claimed to limit infarct size in preclinical models. Unfortunately, due to methodological problems, this enormous investment has not produced any notable clinical application, and no cardioprotective therapy is currently available for clinical use. After >30 years of futile efforts, a new approach is needed to overcome the problems that have impeded the translation of cardioprotective therapies. The time has come to apply to preclinical research the same standards of scientific rigor that are applied to clinical trials. Using the clinical trials networks established by the NHLBI as a model for developing a collaborative infrastructure for research sharing, we propose a preclinical consortium that will operate in a manner analogous to a clinical network. Six Institutions will work together to conduct blinded, randomized, and adequately powered studies using a rigorous design, full dose-response analyses, optimal statistical methods, independent data analysis and statistical Cores, histology, plasma biomarkers, and relevant animal models (including conscious animals and models of comorbidities) in three species (mouse, rabbit, pig). To ensure reproducibilitv. each study will be performed in two Centers using identical protocols. This unique infrastructure will enable rigorous preclinical evaluation of promising cardioprotective therapies and will serve the entire scientific community (both in academia and in biomedical industry), thereby constituting a public resource. Proposals for studying therapies will be solicited from the entire scientific community and reviewed by an independent Protocol Review Committee, which will select those that will be implemented. At least 3 therapies/year will be tested. The consortium structure will ensure that it will be a true public resource available to all interested investigators and that all proposed studies will be evaluated in an equitable fashion. The need for this infrastructure is attested to by 30 letters (Appendix). This will be a paradigm shift in cardioprotection. By screening promising therapies and identifying those that are reproduciblv effective in relevant experimental models and, thus, most likely to be effective in patients, the consortium will dramatically advance our ability to rationally translate basic findings into clinical use. This proposal addresses an issue that has major importance for the NHLBI mission and for public health at large, namely, the failure to translate experimental studies of cardioprotection into clinical therapies. Ischemic heart disease is the number one cause of death and disability in America. Since ~1.3 million Americans have a myocardial infarction each year and their prognosis is determined by the size of the infarct, reducing infarct size will have a major impact on their morbidity and mortality and, thus, enormous implications for public health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Resource-Related Research Projects--Cooperative Agreements (U24)
Project #
5U24HL094373-03
Application #
8316321
Study Section
Special Emphasis Panel (ZHL1-CSR-H (O1))
Program Officer
Evans, Frank
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$2,197,000
Indirect Cost
$387,622
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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Kondo, Kazuhisa; Bhushan, Shashi; King, Adrienne L et al. (2013) HýýýS protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase. Circulation 127:1116-27
Zhao, Yu; Bhushan, Shashi; Yang, Chuntao et al. (2013) Controllable Hydrogen Sulfide Donors and Their Activity against Myocardial Ischemia-Reperfusion Injury. ACS Chem Biol :
Nicholson, Chad K; Lambert, Jonathan P; Chow, Chi-Wing et al. (2013) Chronic exercise downregulates myocardial myoglobin and attenuates nitrite reductase capacity during ischemia-reperfusion. J Mol Cell Cardiol 64:1-10
Polhemus, David J; Kondo, Kazuhisa; Bhushan, Shashi et al. (2013) Hydrogen sulfide attenuates cardiac dysfunction after heart failure via induction of angiogenesis. Circ Heart Fail 6:1077-86
Jang, Hyejeong; Conklin, Daniel J; Kong, Maiying (2013) Piecewise nonlinear mixed-effects models for modeling cardiac function and assessing treatment effects. Comput Methods Programs Biomed 110:240-52

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