Date Published: April 1, 2018
Publisher: American Physiological Society
Author(s): Merry L. Lindsey, Roberto Bolli, John M. Canty, Xiao-Jun Du, Nikolaos G. Frangogiannis, Stefan Frantz, Robert G. Gourdie, Jeffrey W. Holmes, Steven P. Jones, Robert A. Kloner, David J. Lefer, Ronglih Liao, Elizabeth Murphy, Peipei Ping, Karin Przyklenk, Fabio A. Recchia, Lisa Schwartz Longacre, Crystal M. Ripplinger, Jennifer E. Van Eyk, Gerd Heusch.
Myocardial infarction is a prevalent major cardiovascular event that arises from myocardial ischemia with or without reperfusion, and basic and translational research is needed to better understand its underlying mechanisms and consequences for cardiac structure and function. Ischemia underlies a broad range of clinical scenarios ranging from angina to hibernation to permanent occlusion, and while reperfusion is mandatory for salvage from ischemic injury, reperfusion also inflicts injury on its own. In this consensus statement, we present recommendations for animal models of myocardial ischemia and infarction. With increasing awareness of the need for rigor and reproducibility in designing and performing scientific research to ensure validation of results, the goal of this review is to provide best practice information regarding myocardial ischemia-reperfusion and infarction models.
Ischemia occurs when blood flow to the myocardium is reduced (129). Ischemia of prolonged duration induces myocardial infarction (MI), and MI is a common cause of heart failure (295). Ischemic cardiomyopathy is the most common cause of heart failure and can arise from remodeling after an acute ST segment elevation myocardial infarction (STEMI) from multiple small nontransmural infarctions or from chronic repetitive ischemia in the absence of infarction (15). Ischemia can range in its extent from low flow to total coronary occlusion, can be of short to long duration, can be successfully reversed by reperfusion in a timely manner or not reperfused at all, and can induce injury or provide cardioprotection. Likewise, there is a diverse variety of animal models to address each type of ischemia within this spectrum. Figure 1 shows the range of models that reflect the scale of ischemia and variety of models available to better understand how the heart responds to ischemia and the mechanisms whereby the heart can either adapt to ischemia or progress to failure.
There is currently no established intervention, aside from timely reperfusion, that limits damage to hearts of patients experiencing myocardial ischemia to the extent that clinical outcome is improved (133, 138). Discussions of prior failures and hope for future successes have been reviewed elsewhere (120, 127, 176). Several elements missing from preclinical studies of infarct size reduction have been identified and include absence of critical investigator blinding, statistical weaknesses (underpowered studies), and insufficient methodological detail. These deficiencies explain in part the failure to translate preclinical results into effective infarct-sparing treatments in patients. Thus, many have questioned the reproducibility of interventions to protect from MI (i.e., reduce infarct size).
As highlighted throughout these guidelines, ischemia and I/R have multiple consequences that show temporal variation in terms of both incidence and influence on outcomes and may be model dependent. Examples range from acute effects (including biochemical perturbations in cardiomyocytes and other cardiac cell types, disruption in cardiac conduction and development of arrhythmias, contractile dysfunction, abnormalities in endothelial, and vascular reactivity) to longer term outcomes (such as cardiomyocyte death, microvascular obstruction and no-reflow, scar healing, and LV remodeling) and, ultimately, major adverse cardiac events, including heart failure and death (136). Figure 1 shows the diversity in models available to assess ischemia across its spectrum, and Tables 4 and 5 show general recommendations for rigor and reproducibility in ischemia studies.
We acknowledge support from the following: National Institutes of Health Grants HL-002066, HL-051971, HL-056728, HL-061610, HL-075360, HL-078825, HL-088533, HL-092141, HL-093579, HL-107153, HL-111600, HL-112730, HL-112831, HL-113452, HL-113530, HL-116449, HL-128135, HL-129120, HL-129823, HL-130266, HL-131647, HL-132075, HL-135772, GM-103492, HL-131647, HL-76246, HL-85440, GM-104357, GM-114833, GM-115428, and UL1-TR-001412; American Heart Association Grants 16GRNT30960054 and 16CSA28880004; Grand Challenge Award; Department of Defense Grants 16W81XWH-16–1-0592, PR151051, PR151134, and PR151029; Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Awards 1IO1BX002659 and I01BX000505; Australian National Health and Medical Research Council Research Fellowship APP1043026; Bundesministerium für Bildung und Forschung Grant BMBF01 EO1004; and German Research Foundation Grants DFG He 1320/18-3 and SFB 1116 B8. R. A. Kloner reports grant support from Stealth Biotherapeutics, Servier, Inc., and Faraday to test experimental compounds in experimental myocardial infarction models.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, American Heart Association, United States Department of Defense, United States Veterans Administration, National Health and Medical Research Council, or German Research Foundation.
No conflicts of interest, financial or otherwise, are declared by the authors.
M.L.L. and G.H. conceived and designed research; M.L.L., R.G.G., K.P., C.M.R., and G.H. prepared figures; M.L.L., R.B., J.M.C., X.-J.D., N.G.F., S.F., R.G.G., J.W.H., S.P.J., R.K., D.J.L., R.L., E.M., P.P., K.P., F.A.R., L.S.L., C.M.R., J.E.V.E., and G.H. drafted manuscript; M.L.L., R.B., J.M.C., X.-J.D., N.G.F., S.F., R.G.G., J.W.H., S.P.J., R.K., D.J.L., R.L., E.M., P.P., K.P., F.A.R., L.S.L., C.M.R., J.E.V.E., and G.H. edited and revised manuscript; M.L.L., R.B., J.M.C., X.-J.D., N.G.F., S.F., R.G.G., J.W.H., S.P.J., R.K., D.J.L., R.L., E.M., P.P., K.P., F.A.R., L.S.L., C.M.R., J.E.V.E., and G.H. approved final version of manuscript.