572 H eart disease is the leading cause of death in the United States, and acute myocardial infarction is the primary culprit. In the United States alone, >750 000 patients expe- rience a new myocardial infarction every year. 1 Because the amount of tissue destroyed during infarction is a major determinant of prognosis, 2–4 protecting the ischemic myocar- dium remains an urgent, yet unmet, need. During the past 40 years, innumerable therapies have been claimed to be effica- cious in limiting the size of a myocardial infarction in animal models 5 ; on the basis of these positive preclinical data, many New Methods in Cardiovascular Biology © 2014 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.116.305462 Rationale: Despite 4 decades of intense effort and substantial financial investment, the cardioprotection field has failed to deliver a single drug that effectively reduces myocardial infarct size in patients. A major reason is insufficient rigor and reproducibility in preclinical studies. Objective: To develop a multicenter, randomized, controlled, clinical trial-like infrastructure to conduct rigorous and reproducible preclinical evaluation of cardioprotective therapies. Methods and Results: With support from the National Heart, Lung, and Blood Institute, we established the Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR), based on the principles of randomization, investigator blinding, a priori sample size determination and exclusion criteria, appropriate statistical analyses, and assessment of reproducibility. To validate CAESAR, we tested the ability of ischemic preconditioning to reduce infarct size in 3 species (at 2 sites/species): mice (n=22–25 per group), rabbits (n=11–12 per group), and pigs (n=13 per group). During this validation phase, (1) we established protocols that gave similar results between centers and confirmed that ischemic preconditioning significantly reduced infarct size in all species and (2) we successfully established a multicenter structure to support CAESAR’s operations, including 2 surgical centers for each species, a Pathology Core (to assess infarct size), a Biomarker Core (to measure plasma cardiac troponin levels), and a Data Coordinating Center—all with the oversight of an external Protocol Review and Monitoring Committee. Conclusions: CAESAR is operational, generates reproducible results, can detect cardioprotection, and provides a mechanism for assessing potential infarct-sparing therapies with a level of rigor analogous to multicenter, randomized, controlled clinical trials. This is a revolutionary new approach to cardioprotection. Importantly, we provide state-of-the-art, detailed protocols (“CAESAR protocols”) for measuring infarct size in mice, rabbits, and pigs in a manner that is rigorous, accurate, and reproducible. (Circ Res. 2015;116:572-586. DOI: 10.1161/ CIRCRESAHA.116.305462.) Key Words: heart ■ ischemic preconditioning ■ randomized controlled trial ■ reperfusion injury Original received October 16, 2014; revision received December 3, 2014; accepted December 10, 2014. In November, 2014, the average time from submission to first decision for all original research papers submitted to Circulation Research was 13.96 days. From the Cardiovascular Division, Department of Medicine, Institute of Molecular Cardiology, School of Medicine (S.P.J., X.-L.T., Y.G., Q.L., X.Z., J.D., Y.N., H.L.S., G.N.H., A.O., R.B.) and Department of Bioinformatics and Biostatistics, School of Public Health and Information Sciences (M.K.), University of Louisville, KY; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD (C.S.); Department of Pharmacology, Center for Cardiovascular Excellence, Louisiana State University Health Sciences Center, New Orleans (D.J.L., S.B., K.K., T.T.G., C.C.C.); and Department of Medicine—Cardiovascular, Medical College of Virginia, Richmond (R.C.K., R.O., F.N.S.). Current addresses: Pauley Heart Center, Virginia Commonwealth University, Richmond (R.C.K., R.O., F.N.S.); CorMatrix Cardiovascular, Inc, Roswell, GA (C.C.C.); and Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.). The online-only Data Supplement is available with this article at http://circres.ahajournals.org/lookup/suppl/doi:10.1161/CIRCRESAHA. 116.305462/-/DC1. This article was sent to Gerd Heusch, Consulting Editor, for review by expert referees, editorial decision, and final disposition. Correspondence to Roberto Bolli, MD, CAESAR Consortium Operations Committee, Institute of Molecular Cardiology, University of Louisville, Louisville, KY. E-mail CAESAR@Louisville.edu The NHLBI-Sponsored Consortium for preclinicAl assESsment of cARdioprotective Therapies (CAESAR) A New Paradigm for Rigorous, Accurate, and Reproducible Evaluation of Putative Infarct-Sparing Interventions in Mice, Rabbits, and Pigs Steven P. Jones, Xian-Liang Tang, Yiru Guo, Charles Steenbergen, David J. Lefer, Rakesh C. Kukreja, Maiying Kong, Qianhong Li, Shashi Bhushan, Xiaoping Zhu, Junjie Du, Yibing Nong, Heather L. Stowers, Kazuhisa Kondo, Gregory N. Hunt, Traci T. Goodchild, Adam Orr, Carlos C. 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