The translation from mechanistic, more reductionist basic science research to clinical outcome studies is not a linear, rational process but fraught with many surprises such that the prediction of a clinically meaningful endpoint even from a robust preclinical endpoint is difficult. Such translational gap is not genuine for the field of cardioprotection, but particularly prominent here since there are literally thousands of basic science studies on cardioprotective interventions, drugs and signalling mechanisms but just one phase III trial with improved clinical outcome as primary endpoint.1 In the more robust experimental studies, cardioprotection has been evidenced as a reduction of infarct size following a protocol of transmural myocardial ischaemia and reperfusion, and infarct size has been—in line with solid pathophysiology—normalized for the ischaemic area at risk, without or with additional consideration of residual collateral blood flow. In clinical trials, benefit from adjunct cardioprotection in patients with acute myocardial infarction is measured by reduced MACE rate after months to years of follow-up.2 The discrepancy of success when viewed from an experimental vs. a clinical perspective is therefore obvious and the lack of translation accordingly not so surprising.3 How can we do better? I approach this question from the experimentalist’s view: Promising substances and interventions, which have been developed in reductionist experimental approaches must be validated in large animal models. At this point, validation of already identified interventions and substances is needed more than the development of novel targets in the established comfort zone of each single laboratory. As demanding this may be on resources and expenses, validation is mandatory in large animal models of advanced age and with those comorbidities and co-medications, which are typical in patients with acute myocardial infarction in current clinical practice.4 Comorbidities and co-medications are not simply confounding bystanders of an acute myocardial infarction or of a cardioprotective substance and intervention, but they apparently also change the clinical pathophysiology of the acute myocardial infarction per se, as also reflected by the contemporary shift from ST segment elevation to non-ST segment elevation myocardial infarction. Plaque erosion5 rather than plaque rupture, the involvement of platelets and of circulating and resident inflammatory cells, the release of particulate and soluble substances from the epicardial culprit lesion and their wash-in into the coronary microcirculation must receive more attention.6 To accomodate for such change in in the underlying pathophysiology, the use of a complete epicardial coronary artery occlusion by an external ligation or by an internal balloon obstruction may be too simplistic and no longer appropriate. The most robust endpoint of experimental cardioprotection studies, i.e. a reduction of infarct size as a fraction of the area at risk, is not the subject of clinical consideration. Clinically, the area at risk is never measured outside of clinical trials and at best grossly estimated from the site of the occlusion on angiography. Also, infarct size in absolute terms is, outside of clinical trials with imaging, at best grossly estimated from biomarker release. In contrast, clinical benefit is apparent by reduced MACE rate during follow-up. Left ventricular (LV) function (as a surrogate for remodelling) and heart failure are often neglected criteria for the power of a given drug or intervention. In any event, clinical follow-up encompasses not only the pathophysiological process of acute myocardial ischaemia/reperfusion injury but also those of infarct healing, repair, and remodelling.7 Indeed, infarct size is a major determinant of prognosis in patients with acute myocardial infarction. However, different from experimental animal studies where infarct size per area at risk size is the gold standard endpoint of cardioprotection, it is infarct size as a percent of LV mass, which determines patients’ prognosis in terms of LV function and survival during follow-up.8,9 There is a huge gap between a solid preclinical study in a pig model with infarct size per area at risk size as the gold standard endpoint as compared to a clinical outcome study where absolute infarct size as such counts. I am using a typical example from our own experiments10: in anaesthetized Goettingen minipigs (n = 127) total LV weight is 91 ± 12 g, the area at risk after LAD ligation distal to the second diagonal branch is 23 ± 5% of left ventricle i.e. 21 ± 5 g, infarct size after 60 min coronary occlusion and 180 min reperfusion is 40 ± 13% of the area at risk, i. e. 8 ± 3 g. The reduction of infarct size by an ischaemic conditioning intervention is from 40 ± 13 to 25 ± 14% of the area at risk, i.e. from 8 ± 3 to 5 ± 3 g. This is a perfectly robust experimental effect. However, would we believe that the salvage of 3 g of tissue would impact on LV function or even survival of these pigs after 1 year? There is certainly no evidence for it until we prove it, and there is not even a power analysis because we cannot estimate an effect size from existing data. Therefore, experimental studies in large animals of advanced age, with comorbidities and co-medications must be extended to follow-up for months up to at least 1 year to permit a judgement on success in terms of MACE rate and LV function (Figure 1). If we neglect species differences between pigs and humans, the range of infarct sizes <10% of left ventricle, which is used in the above experimental studies is associated with an event rate of <5%8 or an annual mortality of <1%.9 Experimental studies with event-related endpoints after longer follow-up will therefore certainly require largely greater cohorts than currently used for infarct size studies. Figure 1 View largeDownload slide Schematic diagram of the biological process from acute myocardial infarction with subsequent reperfusion, repair, remodelling to left ventricular dysfunction, heart failure, and clinical events. Experimental studies have their strength in early stages, whereas clinical studies have limited data on the initial event but their strength during follow-up. The proposal is to use an integrative large animal model and pursue the entire process from acute myocardial infarction to events with a 1 year follow-up. Figure 1 View largeDownload slide Schematic diagram of the biological process from acute myocardial infarction with subsequent reperfusion, repair, remodelling to left ventricular dysfunction, heart failure, and clinical events. Experimental studies have their strength in early stages, whereas clinical studies have limited data on the initial event but their strength during follow-up. The proposal is to use an integrative large animal model and pursue the entire process from acute myocardial infarction to events with a 1 year follow-up. I realize that the pharmaceutical industry is reluctant to spend time and money for extensive preclinical research, notably chronic large animal studies, but prefer to jump into patient studies once they have a promising drug candidate. Often then, phase I safety studies are overinterpreted and ‘abused’ as efficacy studies once a surrogate endpoint turns out positive. Phase II studies to properly define dosing and timing of a cardioprotective drug or intervention are not existent.3 However, to be provocative, is it ethical to then subject hundreds of patients with an acute myocardial infarction to a phase III trial with clinical outcome as the primary endpoint as long as we don’t even know that an otherwise healthy pig would have a better outcome? The purpose of my article is not to discredit solid experimental studies on novel cardioprotective strategies or targets but to highlight the huge gap between such studies and large scale phase III trials with clinical endpoints after prolonged follow-up. I realize that such studies as I propose will be extremely demanding in terms of personal, technical and financial resources but, in my view, they are mandatory before expecting to see clinical benefit in phase III clinical trials. Indeed, with such more sophisticated experimental studies we will leave the comfort zone, and their design and conduct will require the formation of consortia with very substantial funding. The NIH-funded CAESAR consortium11 in the US and the EU CARDIOPROTECTION COST-ACTION consortium are promising initial steps. However, funding for the CAESAR consortium has unfortunately been discontinued, and the funding for the EU CARDIOPROTECTION COST-ACTION is for communication and networking only but not for projects. Ideally, a consensus on the most promising cardioprotective intervention with the most promising predictive endpoint could be worked out in such network and then a respective multi-centre preclinical study be funded by an EU or NIH programme. Even then, given the continuous progress in the treatment of acute myocardial infarction, which is largely determined by better logistics and reperfusion technology, it will be increasingly difficult to translate a novel cardioprotective intervention to clinical use. Of course, it would be most appropriate if the envisioned more sophisticated experimental studies were matched by proof-of-concept clinical phase I/II trials which focus on large anterior myocardial infarcts where cardioprotection is most needed and by solid phase II dose-finding trials before going into larger phase III trials.12 A premature phase III trial without prior preclinical data (which turned out even to be negative after subsequent publication) is the worst example of poor translation of cardioprotection.13 In contrast, the best evidence for cardioprotection in patients with acute myocardial infarction is currently available for remote ischaemic conditioning.14 The CONDI 2/ERIC-PPCI is a very well designed trial to study the effects of remote ischaemic conditioning on clinical outcome at 30 days (as primary endpoint) and on infarct size (by troponin and by MRI at 6 months),15 and it will be interesting to see whether the surrogate endpoint infarct size goes along with clinical outcome. After all, despite all failures, there is still an unmet medical need for better adjunct cardioprotection,2 and the preclinical studies are still very promising and not optimally tested. Funding This work was supported by the German Research Foundation (He 1320/18-3 and SFB 1116 B8 to G.H.) and the EU Cardioprotection COST-ACTION (CA 16225). Conflict of interest: none declared. References 1 Gaspar A, Lourenco AP, Pereira MA, Azevedo P, Roncon-Albuquerque RJr, Marques J, Leite-Moreira AF. Randomized controlled trial of remote ischaemic conditioning in ST-elevation myocardial infarction as adjuvant to primary angioplasty (RIC-STEMI). Basic Res Cardiol 2018; 113: 14. Google Scholar CrossRef Search ADS PubMed 2 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. Google Scholar PubMed 3 Heusch G. Critical issues for the translation of cardioprotection. Circ Res 2017; 120: 1477– 1486. Google Scholar CrossRef Search ADS PubMed 4 Ferdinandy P, Hausenloy DJ, Heusch G, Baxter GF, Schulz R. Interaction of risk factors, comorbidities and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev 2014; 66: 1142– 1174. Google Scholar CrossRef Search ADS PubMed 5 Partida RA, Libby P, Crea F, Jang IK. Plaque erosion: a new in vivo diagnosis and a potential major shift in the management of patients with acute coronary syndromes. Eur Heart J 2018; doi:10.1093/eurheartj/ehx786. 6 Crea F, Libby P. Acute coronary syndromes: the way forward from mechanisms to precision treatment. Circulation 2017; 136: 1155– 1166. Google Scholar CrossRef Search ADS PubMed 7 Heusch G, Libby P, Gersh B, Yellon D, Böhm M, Lopaschuk G, Opie L. Cardiovascular remodeling in coronary artery disease and heart failure. Lancet 2014; 383: 1933– 1943. Google Scholar CrossRef Search ADS PubMed 8 Lonborg J, Vejlstrup N, Kelbaek H, Holmvang L, Jorgensen E, Helqvist S, Saunamaki K, Ahtarovski KA, Bøtker HE, Kim WY, Clemmensen P, Engstrom T. Final infarct size measured by cardiovascular magnetic resonance in patients with ST elevation myocardial infarction predicts long-term clinical outcome: an observational study. Eur Heart J Cardiovasc Imaging 2013; 14: 387– 395. Google Scholar CrossRef Search ADS PubMed 9 Stone GW, Selker HP, Thiele H, Patel MR, Udelson JE, Ohman EM, Maehara A, Eitel I, Granger CB, Jenkins PL, Nichols M, Ben-Yehuda O. Relationship between infarct size and outcomes following primary PCI: patient-level analysis from 10 randomized trials. J Am Coll Cardiol 2016; 67: 1674– 1683. Google Scholar CrossRef Search ADS PubMed 10 Skyschally A, Amanakis G, Neuhauser M, Kleinbongard P, Heusch G. Impact of electrical defibrillation on infarct size and no-reflow in pigs subjected to myocardial ischemia-reperfusion without and with ischemic conditioning. Am J Physiol Heart Circ Physiol 2017; 313: H871– H878. Google Scholar CrossRef Search ADS PubMed 11 Jones SP, Tang XL, Guo Y, Steenbergen C, Lefer DJ, Kukreja RC, Kong M, Li Q, Bhushan S, Zhu X, Du J, Nong Y, Stowers HL, Kondo K, Hunt GN, Goodchild TT, Orr A, Chang CC, Ockaili R, Salloum FN, Bolli R. The NHLBI-sponsored consortium for preclinicAL assESsment of cARdioprotective therapies (CAESAR): A new paradgm for rigorous, accurate, and reproducible evaluation of putative infarct-sparing interventions in mice, rabbits, and pigs. Circ Res 2015; 116: 572– 586. Google Scholar CrossRef Search ADS PubMed 12 Hausenloy DJ, Garcia-Dorado D, Erik Botker H, Davidson SM, Downey J, Engel FB, Jennings R, Lecour S, Leor J, Madonna R, Ovize M, Perrino C, Prunier F, Schulz R, Sluijter JP, Van Laake LW, Vinten-Johansen J, Yellon DM, Ytrehus K, Heusch G, Ferdinandy P. Novel targets and future strategies for acute cardioprotection: position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart. Cardiovasc Res 2017; 113: 564– 585. Google Scholar CrossRef Search ADS PubMed 13 Atar D, Arheden H, Berdeaux A, Bonnet JL, Carlsson M, Clemmensen P, Cuvier V, Danchin N, Dubois-Rande JL, Engblom H, Erlinge D, Firat H, Halvorsen S, Hansen HS, Hauke W, Heiberg E, Koul S, Larsen AI, Le CP, Nordrehaug JE, Paganelli F, Pruss RM, Rousseau H, Schaller S, Sonou G, Tuseth V, Veys J, Vicaut E, Jensen SE. Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: MITOCARE study results. Eur Heart J 2015; 36: 112– 119. Google Scholar CrossRef Search ADS PubMed 14 Heusch G. 25 years of remote ischemic conditioning: from laboratory curiosity to clinical outcome. Basic Res Cardiol 2018; 113: 15. Google Scholar CrossRef Search ADS PubMed 15 Hausenloy DJ, Kharbanda R, Rahbek Schmidt M, Moller UK, Ravkilde J, Okkels Jensen L, Engstrom T, Garcia Ruiz JM, Radovanovic N, Christensen EF, Sorensen HT, Ramlall M, Bulluck H, Evans R, Nicholas J, Knight R, Clayton T, Yellon DM, Botker HE. Effect of remote ischaemic conditioning on clinical outcomes in patients presenting with an ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Eur Heart J 2015; 36: 1846– 1848. Google Scholar PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: email@example.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
European Heart Journal – Oxford University Press
Published: May 2, 2018
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