From Protecting the Heart to Improving Athletic Performance – the Benefits of Local and Remote Ischaemic Preconditioning

Cardiovasc Drugs Ther (2015) 29:573–588 DOI 10.1007/s10557-015-6621-6 REVIEW ARTICLE From Protecting the Heart to Improving Athletic Performance – the Benefits of Local and Remote Ischaemic Preconditioning Vikram Sharma 1,2 & Reuben Marsh 2 & Brian Cunniffe 3,4 & Marco Cardinale 4,5 & Derek M. Yellon 2 & Sean M. Davidson 2 Published online: 19 October 2015 # The Author(s) 2015. This article is published with open access at Springerlink.com Abstract Remote Ischemic Preconditioning (RIPC) is a noninvasive cardioprotective intervention that involves brief cycles of limb ischemia and reperfusion. This is typically delivered by inflating and deflating a blood pressure cuff on one or more limb(s) for several cycles, each inflation-deflation being 3–5 min in duration. RIPC has shown potential for protecting the heart and other organs from injury due to lethal ischemia and reperfusion injury, in a variety of clinical settings. The mechanisms underlying RIPC are under intense investigation but are just beginning to be deciphered. Emerging evidence suggests that RIPC has the potential to improve exercise performance, via both local and remote mechanisms. This review discusses the clinical studies that have investigated the role of RIPC in cardioprotection as well as those studying its applicability in improving athletic performance, while examining the potential mechanisms involved. Keywords Remote ischemic preconditioning . Exercise performance . Sports . Cardioprotection . Ischemia-reperfusion injury . CABG . PCI . Perconditioning . Postconditioning . Acute kidney injury * Sean M. Davidson 1 Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, USA 2 The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK 3 English institute of Sport, Bisham, Marlow, UK 4 Institute of Sport, Exercise and Health, UCL, London, UK 5 Aspire Academy, Doha, Qatar Abbreviations AAR AKI AKT AT 1 receptor ATP AUC BP CABG CGRP CK-MB CRISP stent cTnI cTnT CXCR4 ERICCA ERIC-LYSIS hs-cTnI IPC IR KATP channels kDa MACE MACCE MERIT MI miRNA mPTP MRI Area at risk Acute kidney injury Term used for protein kinase B Angiotensin II receptor type 1 Adenosine triphosphate Area under the curve Blood pressure Coronary artery bypass grafting Calcitonin gene-related peptide Creatine kinase-myocardial band Cardiac remote ischemic preconditioning in coronary stenting Cardiac troponin I Cardiac troponin I Chemokine receptor type 4 Effect of remote ischaemic preconditioning on clinical outcomes in patients undergoing coronary artery bypass graft surgery Effect of remote ischemic conditioning in heart attack patients High-sensitivity cardiac troponin I Ischemic preconditioning Ischemia and reperfusion ATP-sensitive potassium channels Kilodaltons Major adverse cardiac events Major adverse cardiac and cerebrovascular event Myocardial event reduction with ischemic preconditioning therapy Myocardial infarction micro- ribonucleic acid Mitochondrial permeability transition pore Magnetic resonance imaging 574 NSTEMI PCI PI3K PKC pPCI RIPC RIPercon RIPostC RIPOST-MI RISK SAFE SDF=1 α STAT STEMI Cardiovasc Drugs Ther (2015) 29:573–588 Non-ST elevation myocardial infarction Percutaneous coronary intervention Phosphatidylinositol-3-OH kinase Protein kinase C Primary percutaneous coronary intervention Remote ischemic preconditioning Remote ischemic perconditioning Remote ischemic post conditioning Remote ischemic post-conditioning in myocardial infarction Reperfusion injury salvage kinase Survivor activating factor enhancement Stromal cell-derived factor 1 Signal transducer and activator of transcription ST elevation myocardial infarction Introduction Ischaemic preconditioning (IPC) is a phenomenon in which transient episodes of ischemia and reperfusion administered to an organ attenuate the lethal cellular injury sustained from a subsequent, prolonged ischaemic insult of the same organ. IPC was first described in a study by Murray et al. in 1986 [1], in which, the hearts of anaesthetized dogs were preconditioned with four 5 min occlusions of the circumflex artery, each separated by 5 min of reperfusion. This was followed by a sustained 40 min occlusion and 4 days of reperfusion. The extent of myocardial infarction in the preconditioned hearts was found to be dramatically reduced to a mere 25 % of that seen in the control hearts which did not receive preconditioning [1]. Later, IPC was also shown to have the ability to prevent lethal ischemia and reperfusion injury in skeletal muscles, and to protect the endothelium [2, 3]. Subsequently, the intriguing observation was made that protection of the heart could also be achieved by applying cycles of brief ischemia, alternating with reperfusion, to a tissue or organ remote from the heart - a concept named remote ischaemic preconditioning (RIPC). A crucial intermediate step towards the discovery of RIPC was made by Przyklenk et al. [4] in 1993, who demonstrated that preconditioning the territory of the heart supplied by the circumflex coronary artery also reduced the size of the infarct arising from the subsequent occlusion of the left anterior descending coronary artery. They called this phenomenon “preconditioning at a distance” [4]. This was followed by studies showing that preconditioning of the heart could be achieved by applying the brief episodes of ischemia and reperfusion to a remote organ such as the kidney or other abdominal visceral organs [5, 6]. Birnbaum et al. made the critical observation that RIPC could also be applied to the limb. In their experiments, they combined brief cycles of blood flow restriction with electrical stimulation of the gastrocnemius muscle in the same limb in order to induce demand ischemia [7]. When applied prior to sustained coronary artery occlusion and reperfusion, this intervention reduced infarct size by more than 65 % [7]. Kharbanda et al. were the first to demonstrate that the application of an RIPC stimulus without the need for electrical stimulation, reduced the extent of myocardial infarction invivo in pigs, and also attenuated endothelial injury in humans [8]. This study paved the way for the clinical application of RIPC by recognising the possibility of a non-invasive method of protecting the heart against lethal IR injury. Other studies demonstrated that in addition to protecting the heart, limb RIPC can also protect other organs including the kidneys, lungs, brain, and liver [9], as well as the endothelium [10] from injury caused by sustained ischemia and reperfusion. In addition to the benefits of IPC and RIPC on the heart and the endothelium, both in terms of increased resistance to ischaemic injury and preservation of function in the face of ischemia and reperfusion, it has been hypothesised that IPC applied to the limb may have the potential to improve exercise performance via both local effects (i.e.,: to the limb) and remote effects (via the cardiovasc (...truncated)