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Practical Guidelines for Rigor and Reproducibility in Preclinical and Clinical Studies on Cardioprotection

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Practical Guidelines for Rigor and Reproducibility in Preclinical and Clinical Studies on Cardioprotection Basic Research in Cardiology (2018) 113:39 https://doi.org/10.1007/s00395-018-0696-8 PRACTICAL GUIDELINE Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection Hans Erik Bøtker1 · Derek Hausenloy2,3,4,5,6 · Ioanna Andreadou7 · Salvatore Antonucci8 · Kerstin Boengler9 · Sean M. Davidson2 · Soni Deshwal8 · Yvan Devaux10 · Fabio Di Lisa8 · Moises Di Sante8 · Panagiotis Efentakis7 · Saveria Femminò11 · David García‑Dorado12 · Zoltán Giricz13,14 · Borja Ibanez15 · Efstathios Iliodromitis16 · Nina Kaludercic8 · Petra Kleinbongard17 · Markus Neuhäuser18,19 · Michel Ovize20,21 · Pasquale Pagliaro11 · Michael Rahbek‑Schmidt1 · Marisol Ruiz‑Meana12 · Klaus‑Dieter Schlüter9 · Rainer Schulz9 · Andreas Skyschally17 · Catherine Wilder2 · Derek M. Yellon2 · Peter Ferdinandy13,14 · Gerd Heusch17 Received: 30 May 2018 / Revised: 18 July 2018 / Accepted: 3 August 2018 © The Author(s) 2018 An initiative of the European Union—CARDIOPROTECTION COST ACTION CA16225 “Realising the therapeutic potential of novel cardioprotective therapies” (www.cardi​oprot​ectio​n.eu). 8 Department of Biomedical Sciences, CNR Institute of Neuroscience, University of Padova, Via Ugo Bassi 58/B, Hans Erik Bøtker, Derek Hausenloy, Peter Ferdinandy and Gerd 35121 Padua, Italy Heusch are joint frst and last authors, as per COST ACTION policy. 9 Institute for Physiology, Justus-Liebig University Giessen, Professors Michael V. Cohen, MD, and James M. Downey, PhD, Giessen, Germany Dept. of Physiology, University of South Alabama, Mobile, 10 Cardiovascular Research Unit, Luxembourg Institute of Health, Alabama, USA, served as guest editors for this article and were Strassen, Luxembourg responsible for all editorial decisions, including selection of 11 reviewers. Such transfer policy to guest editor(s) applies to all Department of Clinical and Biological Sciences, University manuscripts with authors from the editor’s institution. of Torino, Turin, Italy 12 Experimental Cardiology, Vall d’Hebron Institut de Recerca * Hans Erik Bøtker (VHIR), Hospital Universitari Vall d’Hebron, Pg. Vall d’Hebron [email protected] 119‑129, 08035 Barcelona, Spain * Gerd Heusch 13 Department of Pharmacology and Pharmacotherapy, Semmelweis gerd.heusch@uk‑essen.de University, Budapest, Hungary 14 1 Pharmahungary Group, Szeged, Hungary Department of Cardiology, Aarhus University Hospital, Palle‑Juul Jensens Boulevard 99, 8200 Aarhus N, Denmark 15 Centro Nacional de Investigaciones Cardiovasculares Carlos III 2 (CNIC), IIS-Fundación Jiménez Díaz, CIBERCV, Madrid, Spain The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK 16 Second Department of Cardiology, Faculty of Medicine, Attikon 3 University Hospital, National and Kapodistrian University The National Institute of Health Research, University College of Athens, Athens, Greece London Hospitals Biomedial Research Centre, Research and Development, London, UK 17 Institute for Pathophysiology, West German Heart and Vascular 4 Center, University of Essen Medical School, Essen, Germany National Heart Research Institute Singapore, National Heart Centre, Singapore, Singapore 18 Department of Mathematics and Technology, Koblenz University 5 of Applied Science, Remagen, Germany Yon Loo Lin School of Medicine, National University Singapore, Singapore, Singapore 19 Institute for Medical Informatics, Biometry, and Epidemiology, 6 University Hospital Essen, Essen, Germany Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, 8 College Road, Singapore 169857, 20 Explorations Fonctionnelles Cardiovasculaires, Hôpital Louis Singapore Pradel, Lyon, France 7 Laboratory of Pharmacology, Faculty of Pharmacy, National 21 UMR, 1060 (CarMeN), Université Claude Bernard, Lyon1, and Kapodistrian University of Athens, Athens, Greece Villeurbanne, France Vol.:(0123456789)1 3 39 Page 2 of 73 Basic Research in Cardiology (2018) 113:39 Abbreviations ERIC‑PPCI Efect of remote ischemic condition‑ ADP Adenosine diphosphate ing on clinical outcomes in ST‑segment ANOVA Analysis of variance elevation myocardial infarction patients ATP Adenosine triphosphate undergoing primary percutaneous coronary CK Creatine kinase intervention CK‑MB Creatine kinase‑muscle/brain EuroSCORE European system for cardiac operative risk CMR Cardiac magnetic resonance imaging evaluation CsA Cyclosporine A TIMI Thrombolysis in myocardial infarction ECG Electrocardiogram EGTA​ Ethylene glycol‑bis(β‑aminoethyl ether)‑ N,N,N’,N’‑tetraacetic acid Introduction FCCP Carbonyl cyanide‑4‑(trifuoromethoxy) phenylhydrazone The potential for ischemic preconditioning to reduce infarct FCS Fetal calf serum size was frst recognized more than 30 years ago [180]. HEPES 4‑(2‑hydroxyethyl)‑1‑piperazineethanesul‑ Despite extension of the concept to ischemic postcondition‑ fonic acid ing [460] and remote ischemic conditioning [202, 344] and ICH International conference on harmonization literally thousands of experimental studies in various spe‑ IFM Interfbrillar mitochondria cies and models which identifed a multitude of signaling JC‑1 Tetraethyl‑benzimidazolyl‑carbocyanine steps [199], so far there is only a single and very recent iodide study, which has unequivocally translated cardioprotection KHB Krebs–Henseleit bufer to improved clinical outcome as the primary endpoint in LDH Lactate dehydrogenase patients [155, 200]. Many potential reasons for this disap‑ LGE Late gadolinium enhancement pointing lack of clinical translation of cardioprotection have LOCF Last observation carried forward been proposed, including lack of rigor and reproducibility in MACCE Major adverse cardiac and cerebral events preclinical studies [54, 195], and poor design and conduct of MOPS 3‑(N‑morpholino)propanesulfonic acid clinical trials [196, 206]. There is, however, universal agree‑ mPTP Mitochondrial permeability transition pore ment that robust preclinical data are a mandatory prerequi‑ MTT (3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphe‑ site to initiate a meaningful clinical trial. In this context, it nyltetrazolium bromide) tetrazolium is disconcerting that the CAESAR consortium (Consortium PPCI Primary percutaneous coronary for preclinicAl assESsment of cARdioprotective therapies) intervention in a highly standardized multi‑center approach of preclini‑ RNA Ribonucleic acid cal studies identifed only ischemic preconditioning, but not ROS Reactive oxygen species nitrite or sildenafl, when given as adjunct to reperfusion, to SPECT Single‑photon emission computed reduce infarct size [230]. However, ischemic precondition‑ tomography ing—due to its very nature—can only be used in elective SSM Subsarcolemmal mitochondria interventions, and not in acute myocardial infarction [181, STEMI ST segment elevation myocardial infarction 197, 203]. Therefore, better strategies to identify robust and T2w‑CMR T2‑weighted cardiac magnetic resonance reproducible strategies of cardioprotection, which can sub‑ imaging sequently be tested in clinical trials must be developed [184]. TMRE Ethyl ester of tetramethylrhodamine We refer to the recent guidelines for experimental models of TMRM Methyl ester of tetramethylrhodamine myocardial ischemia and infarction [279], and aim to pro‑ TTC​ 2,3,5‑triphenyl tetrazolium chloride vide now practical guidelines to ensure rigor and reproduc‑ Acronyms ibility in preclinical and clinical studies on cardioprotection. In line with the above guidelines [279], we defne rigor as ARRIVE Animal research: reporting of in vivo standardized state‑of‑the‑art design, conduct and reporting experiments of a study, which is then a prerequisite for reproducibility, CAESAR Consortium for preclinical assessment of i.e. replication of results by another laboratory when per‑ cardioprotective therapies forming exactly the same experiment. CONDI‑2 Efect of remote ischemic conditioning on clinical outcomes in STEMI patients undergoing pPCI 1 3 Basic Research in Cardiology (2018) 113:39 Page 3 of 73 39 Randomization, blinding, power analysis Study design and statistics Selection of variables/endpoints Study design, randomization, blinding, power analysis, statistics According to the ICH E9 guideline [168], the primary vari‑ able “should be the variable capable of providing the most The ICH (International Conference on Harmonization) E9 relevant and convincing evidence directly related to the pri‑ guideline [168] is the most prominent guideline for sta‑ mary objective of the trial”. This is also true for experimen‑ tistical principles in clinical trials. In some analogy, the tal studies, and ideally there is only one primary endpoint. ARRIVE (Animal Research: Reporting of In vivo Experi‑ Infarct size is the gold standard primary endpoint; ventricu‑ ments) guidelines make recommendations for reporting ani‑ lar function or release of biomarkers during reperfusion may mal research [94, 212, 249], notably study design, including also be used as endpoints of cardioprotection. power analysis and sample size planning, randomization of When infarct size is used as the primary endpoint, sec‑ study groups, blinding of investigators, and adequate statisti‑ ondary endpoints can be hemodynamics such as coronary cal procedures to evaluate and interpret the data [345]. Some blood fow or ventricular function. Further, secondary end‑ journals [54, 176] have established additional guidelines for points can be mitochondrial function or expression or acti‑ planning, performing and reporting experimental studies and vation of signaling proteins. Material
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