9th Hatter Biannual Meeting: position document on ischaemia/reperfusion injury, conditioning and the ten commandments of cardioprotection

Basic Res Cardiol (2016) 111:41 DOI 10.1007/s00395-016-0558-1 REVIEW 9th Hatter Biannual Meeting: position document on ischaemia/ reperfusion injury, conditioning and the ten commandments of cardioprotection R. M. Bell1 • H. E. Bøtker2 • R. D. Carr1,3 • S. M. Davidson1 • J. M. Downey4 • D. P. Dutka5 • G. Heusch6 • B. Ibanez7 • R. Macallister8 • C. Stoppe9 • M. Ovize10 • A. Redington11 • J. M. Walker1 • D. M. Yellon1 Received: 23 March 2016 / Accepted: 3 May 2016 / Published online: 10 May 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract In the 30 years since the original description of ischaemic preconditioning, understanding of the pathophysiology of ischaemia/reperfusion injury and concepts of cardioprotection have been revolutionised. In the same period of time, management of patients with coronary artery disease has also been transformed: coronary artery and valve surgery are now deemed routine with generally excellent outcomes, and the management of acute coronary syndromes has seen decade on decade reductions in cardiovascular mortality. Nonetheless, despite these improvements, cardiovascular disease and ischaemic heart disease in particular, remain the leading cause of death and a significant cause of long-term morbidity (with a concomitant increase in the incidence of heart failure) worldwide. The need for effective cardioprotective strategies has never been so pressing. However, despite unequivocal evidence of the existence of ischaemia/reperfusion in animal models providing a robust rationale for study in man, recent phase 3 clinical trials studying a variety of cardioprotective strategies in cardiac surgery and acute ST-elevation myocardial infarction have provided mixed results. The investigators meeting at the Hatter Cardiovascular Institute workshop describe the challenge of translating strong pre-clinical data into effective clinical intervention strategies in patients in whom effective medical therapy is already altering the pathophysiology of ischaemia/reperfusion injury—and lay out a clearly defined framework for future basic and clinical research to improve the chances of successful translation of strong pre-clinical interventions in man. & D. M. Yellon 7 Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain 8 Centre for Clinical Pharmacology, University College London, London, UK 9 Department of Anesthesiology, University Hospital Aachen, Aachen, Germany 10 Centre de recherche en Cancérologie de Lyon, Université Lyon, Lyon, France 11 Department of Pediatric Cardiology, the Heart Institute at Cincinnati Children’s Hospital, Cincinnati, OH, USA 1 2 The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, 67 Chenies Mews, London WC1E 6HX, UK Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark 3 MSD A/S, Copenhagen V, Denmark 4 Department of Physiology, University of South Alabama College of Medicine, Mobile, AL, USA 5 Department of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge, UK 6 Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany Keywords Ischaemia
Reperfusion
Injury
Infarction
Pre-clinical
Basic research
Clinical trials
Ischaemic
Preconditioning
Postconditioning
Conditioning
RISK pathway
SAFE pathway
p2y12
Opiates
Asprin
Beta blockers
Statins
Metoprolol
Cyclosporine
CABG
123 41 Page 2 of 13 Basic Res Cardiol (2016) 111:41 Valve replacement
Cardiac surgery
Mitochondrial transition pore
Necrosis
Apoptosis
Necroptosis
Autophagy
Pyroptosis
DNA Background Since the original description of ischaemic conditioning by Murry, Jennings and Reimer in 1986 [56], the understanding of the mechanisms of cell death arising from injurious ischaemia and reperfusion injury has been transformed: no longer a purely necrotic model, it is now recognised as a complex, multifaceted pathophysiological process [37], involving not only necrosis, but also cellular signalling, apoptosis, necroptosis [16] and the complex interaction of autophagy [15] through to inflammatory injury and pyroptosis [78] (Fig. 1). In parallel, identification of numerous pharmacological targets, both in modifying cell death pathways and in up-regulating canonical conditioning signalling Reperfusion Injury Salvage Kinase (RISK) [30] and Survivor Activating Factor Enhancement (SAFE) [48] pathways that culminate in the inhibition of the mitochondrial transition pore (mPTP, Fig. 2) have provided irrefutable proof of the existence of reperfusion injury following injurious ischaemia in animal models [32]. Moreover, the evolution of remote ischaemic conditioning the phenomenon whereby transient ischaemic stress of one organ can lead to protection of another, remote organ such as the heart against injurious ischaemia/reperfusion injury [33, 47] as a putative therapeutic intervention that can be applied prior to or immediately upon onset of reperfusion has supported the existence of ischaemia/reperfusion injury in man—both in proof-of-concept and meta-analysis of phase 2 clinical trials [46]. Over the concomitant period of time, clinical epidemiological data have clearly demonstrated what all practicing cardiologists already knew: the rates of cardiovascular mortality have been falling year-on-year over the last three decades [55, 64]—through a combination of social changes secondary to health education, improving primary and secondary prevention and improved management of acute coronary syndromes—not least through the introduction of primary percutaneous intervention (PCI) and optimised medical therapy. Nonetheless, while the efforts of cardioprotective strategies such as primary PCI have led to reduced early cardiovascular mortality, the ‘‘cardioprotection paradox’’ has been the incremental increase in the number of patients living with the consequence of myocardial injury: ischaemic cardiomyopathy and heart failure [10, 55]. Ischaemic injury is the leading aetiology of heart failure worldwide [55] and given that the propensity to develop heart failure is related to the extent of the 123 Fig. 1 Cartoon of injurious ischaemia/reperfusion injury and the different forms of cell death. Necrosis is the prototypical form of cell death resulting from prolonged ischaemia. Through high-energy phosphate depletion, the cells cease to maintain electro-chemical gradients and the cells and the intracellular organelles swell. Histologically, the cytoplasmic membranes become progressively more lucent, before rupturing leading to the dispersal of cellular contents into the extracellular space (although the nuclei may persist). The cellular contents, including both nucleic and mitochondrial DNA, form damage associated molecular patterns (DAMPs); signals that are also released into the extracellular space by (...truncated)