The coronary circulation in acute myocardial ischaemia/reperfusion injury: a target for cardioprotection
SPOTLIGHT REVIEW
Cardiovascular Research (2019) 115, 1143–1155
doi:10.1093/cvr/cvy286
The coronary circulation in acute myocardial
ischaemia/reperfusion injury: a target for
cardioprotection
1
Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore; 2National Heart Research Institute Singapore, National Heart
Centre, Singapore, Singapore; 3Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore; 4The Hatter Cardiovascular Institute, University College London,
London, UK; 5The National Institute of Health Research, University College London Hospitals Biomedical Research Centre, Research & Development, London, UK; 6Department of
Cardiology, Barts Heart Centre, St Bartholomew’s Hospital, London, UK; 7Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44,
Rootstown, OH 44272, USA; 8Department of Cardiovascular and Thoracic Sciences, F. Policlinico Gemelli—IRCCS, Università Cattolica Sacro Cuore, Roma, Italy; 9Department of
Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; 10Pharmahungary Group, Szeged, Hungary; 11Department of Cardiology, Vascular Biology and Metabolism
Area, Vall d’Hebron University Hospital and Research Institute (VHIR), Universitat Autónoma de Barcelona, Barcelona, Spain; 12Instituto CIBER de Enfermedades Cardiovasculares
(CIBERCV), Instituto de Salud Carlos III, Madrid, Spain; 13Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands; 14Institute of Physiology,
Justus-Liebig University Giessen, Giessen, Germany; and 15Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany
Received 23 September 2018; revised 15 October 2018; editorial decision 16 October 2018; accepted 14 November 2018; online publish-ahead-of-print 14 November 2018
Abstract
The coronary circulation is both culprit and victim of acute myocardial infarction. The rupture of an epicardial atherosclerotic plaque with superimposed thrombosis causes coronary occlusion, and this occlusion must be removed to induce reperfusion. However, ischaemia and reperfusion cause damage not only in cardiomyocytes but also in the coronary circulation, including microembolization of debris and release of soluble factors from the culprit lesion, impairment of endothelial
integrity with subsequently increased permeability and oedema formation, platelet activation and leucocyte adherence,
erythrocyte stasis, a shift from vasodilation to vasoconstriction, and ultimately structural damage to the capillaries with
eventual no-reflow, microvascular obstruction (MVO), and intramyocardial haemorrhage (IMH). Therefore, the coronary
circulation is a valid target for cardioprotection, beyond protection of the cardiomyocyte. Virtually all of the above deleterious endpoints have been demonstrated to be favourably influenced by one or the other mechanical or pharmacological
cardioprotective intervention. However, no-reflow is still a serious complication of reperfused myocardial infarction and
carries, independently from infarct size, an unfavourable prognosis. MVO and IMH can be diagnosed by modern imaging
technologies, but still await an effective therapy. The current review provides an overview of strategies to protect the coronary circulation from acute myocardial ischaemia/reperfusion injury. This article is part of a Cardiovascular Research
Spotlight Issue entitled ‘Cardioprotection Beyond the Cardiomyocyte’, and emerged as part of the discussions of the
European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.
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Keywords
Coronary circulation
•
Microvascular obstruction
•
Cardioprotection
•
Ischaemia
•
Reperfusion
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This article is part of the Spotlight Issue on Cardioprotection Beyond the Cardiomyocyte.
1. Introduction
Reperfusion is the only way to salvage ischaemic myocardium from infarction, but reperfusion per se also inflicts additional injury, such that the
resulting myocardial infarct (MI) size is determined by both ischaemiaand reperfusion-induced injury.1–3 There is still an unmet medical need
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for adjunct cardioprotection on top of timely reperfusion.4,5 In type II
myocardial infarction and in the absence of epicardial coronary artery
occlusion, the distinction of ischaemia and reperfusion is less obvious,
but there is still infarction and cardioprotection is needed.6 Numerous
animal experiments have provided robust evidence that MI size can be
* Corresponding authors. Tel: þ65 6516 6719; fax: þ65 6221 2534, E-mail: (D.J.H.); Tel: þ49 (0) 201-723-44 80; fax: þ49 (0) 201-723-44 81, E-mail:
(G.H.)
C The Author(s) 2018. For permissions, please email: .
Published on behalf of the European Society of Cardiology. All rights reserved. V
Derek J. Hausenloy1–6*, William Chilian7, Filippo Crea8, Sean M. Davidson4,
Peter Ferdinandy9,10, David Garcia-Dorado11,12, Niels van Royen13, Rainer Schulz14, and
Gerd Heusch15*; on behalf of the EU-CARDIOPROTECTION COST Action (CA16225)
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reduced by mechanical or pharmacological interventions before (preconditioning), during (perconditioning), or after (postconditioning) myocardial ischaemia. However, the translation of cardioprotection to
clinical practice has been largely disappointing so far, for many reasons,
including lack of rigor and reproducibility in experimental studies, as well
as conceptual and technical faults in clinical trial design.7–10 One important conceptual reason for failure of translation may relate to the focus
of cardioprotection studies on the cardiomyocyte, and the neglect of
other tissues in the heart, notably the coronary circulation.11
The coronary circulation is both culprit and victim of acute myocardial ischaemia/reperfusion injury (IRI), and as such a prime target for cardioprotection. Acute ST-segment elevation myocardial infarction (STEMI) is
induced by rupture of an epicardial coronary atherosclerotic plaque with
superimposed thrombosis, which occludes the epi (...truncated)
