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

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          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.

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          Most cited references83

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          Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.

          The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known.
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            Ticagrelor versus clopidogrel in patients with acute coronary syndromes.

            Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel. In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation. At 12 months, the primary end point--a composite of death from vascular causes, myocardial infarction, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types. In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding. (ClinicalTrials.gov number, NCT00391872.) 2009 Massachusetts Medical Society
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              Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium.

              Circulation, 74(5), 1124-1136
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                Author and article information

                Contributors
                +44 (0)20 3447 9800 , d.yellon@ucl.ac.uk
                Journal
                Basic Res Cardiol
                Basic Res. Cardiol
                Basic Research in Cardiology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0300-8428
                1435-1803
                10 May 2016
                10 May 2016
                2016
                : 111
                : 41
                Affiliations
                [ ]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
                [ ]MSD A/S, Copenhagen V, Denmark
                [ ]Department of Physiology, University of South Alabama College of Medicine, Mobile, AL USA
                [ ]Department of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge, UK
                [ ]Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany
                [ ]Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
                [ ]Centre for Clinical Pharmacology, University College London, London, UK
                [ ]Department of Anesthesiology, University Hospital Aachen, Aachen, Germany
                [ ]Centre de recherche en Cancérologie de Lyon, Université Lyon, Lyon, France
                [ ]Department of Pediatric Cardiology, the Heart Institute at Cincinnati Children’s Hospital, Cincinnati, OH USA
                Article
                558
                10.1007/s00395-016-0558-1
                4863033
                27164905
                d65ebd87-84eb-4e7f-9b8f-28ce5229be35
                © The Author(s) 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 23 March 2016
                : 3 May 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000272, National Institute for Health Research;
                Funded by: FundRef http://dx.doi.org/10.13039/501100000265, Medical Research Council;
                Funded by: FundRef http://dx.doi.org/10.13039/501100000274, British Heart Foundation;
                Categories
                Review
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2016

                Cardiovascular Medicine
                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,valve replacement,cardiac surgery,mitochondrial transition pore,necrosis,apoptosis,necroptosis,autophagy,pyroptosis,dna

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