title: 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.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Steven P
authors.initials: SP
authors.lastname: Jones
authors.affiliation: 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.).
authors.forename: Xian-Liang
authors.initials: XL
authors.lastname: Tang
authors.affiliation: 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.).
authors.forename: Yiru
authors.initials: Y
authors.lastname: Guo
authors.affiliation: 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.).
authors.forename: Charles
authors.initials: C
authors.lastname: Steenbergen
authors.affiliation: 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.).
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
authors.affiliation: 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.).
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Kukreja
authors.affiliation: 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.).
authors.forename: Maiying
authors.initials: M
authors.lastname: Kong
authors.affiliation: 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.).
authors.forename: Qianhong
authors.initials: Q
authors.lastname: Li
authors.affiliation: 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.).
authors.forename: Shashi
authors.initials: S
authors.lastname: Bhushan
authors.affiliation: 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.).
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhu
authors.affiliation: 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.).
authors.forename: Junjie
authors.initials: J
authors.lastname: Du
authors.affiliation: 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.).
authors.forename: Yibing
authors.initials: Y
authors.lastname: Nong
authors.affiliation: 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.).
authors.forename: Heather L
authors.initials: HL
authors.lastname: Stowers
authors.affiliation: 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.).
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Kondo
authors.affiliation: 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.).
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Hunt
authors.affiliation: 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.).
authors.forename: Traci T
authors.initials: TT
authors.lastname: Goodchild
authors.affiliation: 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.).
authors.forename: Adam
authors.initials: A
authors.lastname: Orr
authors.affiliation: 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.).
authors.forename: Carlos C
authors.initials: CC
authors.lastname: Chang
authors.affiliation: 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.).
authors.forename: Ramzi
authors.initials: R
authors.lastname: Ockaili
authors.affiliation: 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.).
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
authors.affiliation: 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.). CAESAR@Louisville.edu.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003299:Cooperative Behavior; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000592:standards; D005260:Female; D017408:Guidelines as Topic; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods* / Q000592:standards; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D054555:National Heart, Lung, and Blood Institute (U.S.); D011237:Predictive Value of Tests; D011817:Rabbits; D015203:Reproducibility of Results; D012107:Research Design / Q000592:standards; D013045:Species Specificity; D013552:Swine; D013997:Time Factors; D019210:Troponin I / Q000097:blood; D014481:United States
chemical_list: D015415:Biomarkers; D002317:Cardiovascular Agents; D019210:Troponin I
keywords: heart; ischemic preconditioning; randomized controlled trial; reperfusion injury