Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery
Basic Res Cardiol (2016) 111:70
DOI 10.1007/s00395-016-0588-8
MEETING REPORT
Ischaemic conditioning and targeting reperfusion injury:
a 30 year voyage of discovery
Derek J. Hausenloy1,2,3,4 • Jose A. Barrabes5 • Hans Erik Bøtker6 • Sean M. Davidson1 • Fabio Di Lisa7 •
James Downey8 • Thomas Engstrom9 • Péter Ferdinandy10,11 • Hector A. Carbrera-Fuentes3,4,12,13 •
Gerd Heusch14 • Borja Ibanez15,16 • Efstathios K. Iliodromitis17 • Javier Inserte5 • Robert Jennings18 •
Neena Kalia19 • Rajesh Kharbanda20 • Sandrine Lecour21 • Michael Marber22 • Tetsuji Miura23 •
Michel Ovize24,25 • Miguel A. Perez-Pinzon26,27,28 • Hans Michael Piper29 • Karin Przyklenk30 •
Michael Rahbek Schmidt3 • Andrew Redington31 • Marisol Ruiz-Meana5 • Gemma Vilahur32 •
Jakob Vinten-Johansen33 • Derek M. Yellon1,2 • David Garcia-Dorado5
Received: 2 October 2016 / Accepted: 11 October 2016 / Published online: 20 October 2016
Ó The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract To commemorate the auspicious occasion of the
30th anniversary of IPC, leading pioneers in the field of
cardioprotection gathered in Barcelona in May 2016 to
review and discuss the history of IPC, its evolution to IPost
and RIC, myocardial reperfusion injury as a therapeutic
target, and future targets and strategies for cardioprotection. This article provides an overview of the major topics
discussed at this special meeting and underscores the huge
importance and impact, the discovery of IPC has made in
the field of cardiovascular research.
& Derek J. Hausenloy
9
Department of Cardiology, Rigshospitalet, Copenhagen
University Hospital, Copenhagen, Denmark
& David Garcia-Dorado
10
Department of Pharmacology and Pharmacotherapy,
Semmelweis University, Budapest, Hungary
11
Pharmahungary Group, Szeged, Hungary
12
Institute for Biochemistry, Medical Faculty Justus-LiebigUniversity, Giessen, Germany
13
Department of Microbiology, Kazan Federal University,
Kazan, Russian Federation
1
2
The Hatter Cardiovascular Institute, University College
London, London, UK
The National Institute of Health Research University
College London Hospitals Biomedical Research Centre,
London, UK
Keywords Ischaemic conditioning Myocardial
reperfusion injury Cardioprotection RISK and SAFE
pathway Mitochondria
3
Cardiovascular and Metabolic Disorders Program, DukeNational University of Singapore, 8 College Road,
Singapore 169857, Singapore
14
Institute for Pathophysiology, West-German Heart and
Vascular Center, University of Essen Medical School, Essen,
Germany
4
National Heart Research Institute Singapore, National Heart
Centre Singapore, Singapore, Singapore
15
Centro Nacional de Investigaciones Cardiovasculares Carlos
III (CNIC), Madrid, Spain
5
Department of Cardiology, Vall d’Hebron University
Hospital and Research Institute, Universitat Autònoma,
Barcelona, Spain
16
IIS-Fundación Jiménez Dı́az Hospital, Madrid, Spain
17
2nd University Department of Cardiology, National and
Kapodistrian University of Athens, Athens, Greece
18
Duke University, Durham, NC, USA
19
Institute of Cardiovascular Sciences, University of
Birmingham, Birmingham, UK
20
Oxford Heart Centre, The John Radcliffe Hospital, Oxford
University Hospitals, Oxford, UK
6
Department of Cardiology, Aarhus University Hospital
Skejby, 8200 Aarhus N, Denmark
7
Department of Biomedical Sciences and CNR Institute of
Neurosciences, University of Padova, Padua, Italy
8
Department of Physiology and Cell Biology, College of
Medicine, University of South Alabama, Mobile, AL, USA
123
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Basic Res Cardiol (2016) 111:70
Introduction
Ischaemic preconditioning
The year 2016 marks the 30th anniversary since Murry,
Jennings and Reimer first discovered the phenomenon of
ischaemic preconditioning (IPC) [180]. The seminal discovery in 1986, that brief episodes of ischaemia and
reperfusion could dramatically reduce myocardial infarct
(MI) size, gave rise to the field of cardioprotection, and has
resulted in over 10,000 publications in the research literature. Over the last 30 years enormous efforts have been
made to understand the mechanisms underlying IPC and
have provided huge insights into the mechanisms of cardiomyocyte death during acute ischaemia/reperfusion
injury (IRI), and the complex signalling pathways underlying cytoprotection within the cardiomyocyte and beyond.
In addition, the last 30 years have witnessed enormous
efforts to translate this endogenous cardioprotective strategy into the clinical setting for patient benefit. In this
regard, the evolution of IPC to an intervention which could
be applied at the time of reperfusion [ischaemic postconditioning (IPost)] [276] and to a remote organ or tissue
[remote ischaemic conditioning (RIC)] [200] has facilitated
the translation of IPC into the clinical setting.
To commemorate the auspicious occasion of the 30th
anniversary of IPC, leading pioneers in the field of cardioprotection gathered in Barcelona in May 2016 to review
and discuss the history of IPC (Fig. 1), its evolution to
IPost and RIC, myocardial reperfusion injury as a therapeutic target, and future targets and strategies for cardioprotection. This article provides an overview of the major
topics discussed at this special meeting and underscores the
huge importance and impact, the discovery of IPC has
made in the field of cardiovascular research.
In IPC, several minutes of acute coronary occlusion followed
by reperfusion delay the onset of MI from a subsequent
period of prolonged lethal ischaemia and reperfusion. The
description of IPC 30 years ago in 1986 by Murry et al. [180]
was a landmark discovery. It proved once and for all that the
final size of a MI was not only a function of the area-at-risk
(AAR), ischaemic time and collateral flow, but could indeed
be reduced, as had been originally proposed by Braunwald
and colleagues years before [165]. The Jennings laboratory
was pursuing the observation that a brief ischaemic episode
slowed the rate of ATP consumption when the heart was
subjected to subsequent episodes of ischaemia. Since virtually no ATP is present in dead cardiomyocytes, they
hypothesised that delaying ATP depletion would attenuate
the development of cardiomyocyte death [181].
Considering the huge number of papers eventually
published on IPC since 1986, it is amazing that it took
4 years before the first confirmatory paper by another
laboratory appeared on the subject [149]. However, after
that virtually everyone who tried to replicate IPC was able
to observe protection that lasted for several hours [258]. In
1991, Liu et al. [153] showed that the preconditioned state
resulted from protective signal transduction. Infusing adenosine or an adenosine A1 receptor-selective agonist into
the coronary arteries for 5 min prior to occluding a coronary branch put the heart into a protected state identical to
IPC. Conversely, an adenosine receptor antagonist completely (...truncated)
