Translation, Translation, Translation
2018; Lippincott Williams & Wilkins; Volume: 123; Issue: 8 Linguagem: Inglês
10.1161/circresaha.118.313947
ISSN1524-4571
AutoresGerd Heusch, Andreas Skyschally, Petra Kleinbongard,
Tópico(s)Cardiac electrophysiology and arrhythmias
ResumoHomeCirculation ResearchVol. 123, No. 8Translation, Translation, Translation Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTranslation, Translation, TranslationThe Need for Large Animal Studies in Cardioprotection Research Gerd Heusch, Andreas Skyschally and Petra Kleinbongard Gerd HeuschGerd Heusch Correspondence to Gerd Heusch, MD, Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Hufelandstraße 55, 45122 Essen, Germany. Email E-mail Address: [email protected] From the Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School. , Andreas SkyschallyAndreas Skyschally From the Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School. and Petra KleinbongardPetra Kleinbongard From the Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School. Originally published27 Sep 2018https://doi.org/10.1161/CIRCRESAHA.118.313947Circulation Research. 2018;123:931–933This article is a commentary on the followingEffect of Intracoronary Metformin on Myocardial Infarct Size in SwineThe only way to salvage ischemic myocardium from impending infarction is timely reperfusion, and this is a current clinical practice by use of thrombolysis or better a primary percutaneous coronary intervention. However, even with timely reperfusion, the mortality from acute myocardial infarction remains high, for example, 7% at 1 year in the CIRCUS trial (Does Cyclosporine Improve Clinical Outcome in ST-Elevation Myocardial Infarction Patients),1 and the surviving patients often develop disabling heart failure. Thus, there is an unmet medical need for adjunct cardioprotection beyond reperfusion.2 Cardioprotection in the strictest sense is achieved by any intervention or substance that reduces infarct size after coronary occlusion with subsequent reperfusion. The ischemic conditioning interventions and many substances that were derived from mechanistic analyses of ischemic conditioning's signal transduction have effectively reduced infarct size in literally thousands of preclinical studies, ranging from cellular preparations over isolated perfused heart preparations to in vivo studies in a large variety of species from mice to larger mammals.3–5 Ischemic preconditioning and pretreatment with substances before ischemia are probably more of paradigmatic value for mechanistic analyses rather than of clinical relevance for patients with acute myocardial infarction because its occurrence cannot be predicted. Perconditioning (during coronary occlusion) or postconditioning (just at reperfusion) approaches are of greater relevance for clinical translation. Smaller proof-of-concept studies have indeed also provided evidence for cardioprotection by perconditioning or postconditioning approaches in patients with acute ST-segment–elevation myocardial infarction, using biomarkers or imaging to evidence reduced infarct size.6 Nevertheless, the translation of preclinical and early clinical proof-of-concept studies to larger patient cohorts with clinical outcome as primary end point has been largely disappointing.7,8 Currently, there is only one study that demonstrated reduced mortality and reduced incidence of heart failure as the result of remote ischemic conditioning in patients with ST-segment–elevation myocardial infarction.9,10 The reasons for the translational gap are multiple and complex, with the reductionist preclinical approaches on one extreme and patients of advanced age with multiple comorbidities and comedication on the other. Large animal studies, notably studies in pigs, are well suited to bridge the translational gap because pigs are much closer to humans in cardiac anatomy and hemodynamic function than rodents and because the clinical scenario of acute myocardial infarction with interventional reperfusion can be well simulated under controlled circumstances, including the precise assessment of duration of coronary occlusion, area at risk, and infarct size.Article, see p 986Canty et al11 have now used metformin as an example to achieve cardioprotection in a closed-chest pig model with a 60-minute left anterior descending coronary artery occlusion and 7-day reperfusion. Metformin is a well-chosen example to address the translational gap. Metformin is a frequently used antidiabetic drug, and diabetes mellitus is a frequent comorbidity in patients with acute myocardial infarction. Patients on chronic metformin treatment have smaller infarct size on a retrospective analysis.12 There are several preclinical studies in rodent models of myocardial ischemia/reperfusion in which metformin, when given at reperfusion, reduced infarct size. In such studies, the effect of metformin was not related to glucose lowering; in fact, activation of AMPK (AMP-activated protein kinase), phosphorylation of eNOS (endothelial NO synthase), and increased formation of adenosine were identified as potential underlying mechanisms of cardioprotection. On the contrary, in the GIPS-III trial (Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST-Segment–Elevation Myocardial Infarction), oral metformin started within 3 hours after primary percutaneous coronary intervention in patients without diabetes mellitus did not improve left ventricular (LV) function during 4 months13 or exert a beneficial long-term effect during 2 years of follow-up.14 Of note, there is currently no clinical study on true cardioprotection by metformin with reduced infarct size as end point.In the randomized and blinded present study by Canty et al,11 metformin, when given intravenously for 8 minutes before reperfusion and in addition intracoronarily for 15 minutes during immediate reperfusion, reduced infarct size as a fraction of area at risk by 14% in 10 treated pigs as compared with 10 placebo pigs. The sample size was derived from a power analysis with an expected 36% reduction of infarct size. The achieved infarct size reduction was not significant and thus the study results neutral. Likewise, an 88% increase in anterior regional wall thickening and a 6% increase in LV ejection fraction after 7 days of reperfusion were not significant. The authors are to be congratulated for their rigor in study design and use of state-of-the-art methodology, and the results are convincing. The neutral result of the present study questions the translatability of the prior results from the above rodent models of acute myocardial ischemia/reperfusion. The neutral result of the present study also makes the GIPS-III trial, which went from rodent models of acute myocardial ischemia/reperfusion straight into patient studies with potential long-term effects after reperfusion, appear premature. Such premature translation from reductionist rodent models of acute myocardial ischemia/reperfusion to clinical trials has been seen before with other substances.7 In principle, the pig model is particularly suited to facilitate translation by identifying interventions and substances that have been operative in rodent models but are also operative in larger mammals and by working out details of their mode and dose of administration before going into clinical trials.What could still be done better in future large animal studies on translation of cardioprotection? The left anterior descending coronary artery occlusion in the study by Canty et al11 was performed under anesthesia, whereas patients with acute myocardial infarction are usually conscious. The use of propofol anesthesia is of particular concern because propofol per se is cardioprotective and might have minimized differences between the metformin and the placebo group. Moreover, propofol interferes with cardioprotection by remote ischemic conditioning15 and might also interfere with other forms of cardioprotection. In the future, the acute myocardial infarction should be induced in analgosedation rather than general anesthesia or under volatile anesthesia, which is also cardioprotective per se but does not interfere with other cardioprotective interventions. Importantly, regardless of the mode of anesthesia, a positive control is needed to provide unequivocal evidence that the model used can indeed reflect cardioprotection. The effect size in the power analysis of the present study was derived from the CAESAR trial (Consortium for Preclinical Assessment of Cardioprotective Therapies) in which pigs were anesthetized with a barbiturate. Also, CAESAR did report robust infarct size reduction by ischemic preconditioning but not for a postconditioning approach.16 When taking regional or LV function as end point, the observation period should be extended to several months when repair and remodeling might have occurred. At 7 days of reperfusion, the impact of infarction on contractile function is probably still mixed up with stunning, and clinical studies usually measure LV function at 4 to 6 months after infarction. To really fill the translational gap, it would be good if the studies in pigs could also pick up on prior mechanistic findings. In the present study, LV biopsies and coronary venous blood samples could have been taken to look for AMPK and eNOS activation and for adenosine release. Such data could have revealed whether metformin failed to activate its purported signaling mechanisms or whether these signaling mechanisms were activated but did not induce cardioprotection.Ultimately, it remains unclear whether or not metformin just before and at reperfusion induced cardioprotection in the present model. The expected effect size of 36% infarct size reduction was arbitrary for a postconditioning approach (see above), and the observed 14% infarct size reduction might be a true effect. If so, a much larger (≈200) pig cohort would need to be studied to ascertain such moderate infarct size reduction, as detailed by Canty et al.11 However, with respect to clinical translation, a cohort of 200 individuals appears still moderate and an effect of 14% less infarction not so small—a clinical study with 14% infarct size reduction in a cohort of 200 patients with ST-segment–elevation myocardial infarction would seem perfectly fine. Whether 14% less infarction then impacts on LV function and mortality would also need to be seen in a larger cohort with more long-term observations, and only a beneficial clinical outcome would be a solid ground for translation to clinical practice. We fully realize the difficulties of the proposed endeavor: a cardioprotection study in 200 pigs with long-term follow-up, including permission from regulatory authorities, funding, facilities, and personnel. Nevertheless, we firmly believe that exactly such study on a well-selected cardioprotective intervention or substance is needed to move the cardioprotection field forward, and such endeavor will probably require a concerted action, such as CAESAR or the European Union Cost Action Cardioprotection Consortium.Sources of FundingG. Heusch and P. Kleinbongard were supported by the German Research Foundation (SFB 1116 B08) and the European Union (Cardioprotection Cost Action CA16225).DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Gerd Heusch, MD, Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Hufelandstraße 55, 45122 Essen, Germany. Email gerd.[email protected]deReferences1. Cung TT, Morel O, Cayla G, et al. Cyclosporine before PCI in patients with acute myocardial infarction.N Engl J Med. 2015; 373:1021–1031. doi: 10.1056/NEJMoa1505489CrossrefMedlineGoogle Scholar2. Heusch G, Gersh BJ. The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge.Eur Heart J. 2017; 38:774–784. doi: 10.1093/eurheartj/ehw224MedlineGoogle Scholar3. 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Circulation Research. 2018;123:986-995 September 28, 2018Vol 123, Issue 8 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.118.313947PMID: 30355042 Originally publishedSeptember 27, 2018 Keywordsmyocardial ischemiamyocardial infarctionhumansEditorialsreperfusionPDF download Advertisement SubjectsAnimal Models of Human DiseaseBasic Science ResearchIschemiaTranslational Studies
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