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Myocardial ischaemia–reperfusion injury and cardioprotection in perspective

Nature Reviews Cardiology volume 17, pages 773–789 (2020)Cite this article

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Abstract

Despite the increasing use and success of interventional coronary reperfusion strategies, morbidity and mortality from acute myocardial infarction are still substantial. Myocardial infarct size is a major determinant of prognosis in these patients. Therefore, cardioprotective strategies aim to reduce infarct size. However, a perplexing gap exists between the many preclinical studies reporting infarct size reduction with mechanical and pharmacological interventions and the poor translation into better clinical outcomes in patients. This Review revisits the pathophysiology of myocardial ischaemia–reperfusion injury, including the role of autophagy and forms of cell death such as necrosis, apoptosis, necroptosis and pyroptosis. Other cellular compartments in addition to cardiomyocytes are addressed, notably the coronary microcirculation. Preclinical and clinical research developments in mechanical and pharmacological approaches to induce cardioprotection, and their signal transduction pathways, are discussed. Additive cardioprotective interventions are advocated. For clinical translation into treatments for patients with acute myocardial infarction, who typically are of advanced age, have comorbidities and are receiving several medications, not only infarct size reduction but also attenuation of coronary microvascular obstruction, as well as longer-term targets including infarct repair and reverse remodelling, must be considered to improve patient outcomes. Future clinical trials must focus on patients who really need adjunct cardioprotection, that is, those with severe haemodynamic alterations.

Key points

  • Sustained myocardial ischaemia–reperfusion induces various modes of cardiomyocyte death and coronary microvascular injury.

  • Ischaemic conditioning (cycles of brief ischaemia–reperfusion in the heart or in a tissue remote from the heart) reduces infarct size and coronary microvascular injury.

  • The signalling pathways triggered by ischaemic conditioning are complex and include activation of sarcolemmal receptors and cytosolic kinases, as well as reduced mitochondrial permeability transition pore opening, Ca2+ overload and proteolysis.

  • Ischaemic postconditioning and remote ischaemic conditioning reduced infarct size in patients with ST-segment elevation myocardial infarction in proof-of-concept trials.

  • Remote ischaemic conditioning improved clinical outcomes in patients with ST-segment elevation myocardial infarction in one phase III clinical trial.

  • In future studies, the use of additive cardioprotective strategies and a focus on patients with severe haemodynamic alterations (such as cardiogenic shock or those in Killip class III–IV) are advocated.

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Fig. 1: Cardioprotective strategies for acute myocardial infarction.
Fig. 2: Infarct size as a function of ischaemia duration and residual blood flow.
Fig. 3: Infarct size reduction with cardioprotective strategies.
Fig. 4: Cardiomyocyte and coronary microvascular injury induced by ischaemia–reperfusion.
Fig. 5: Clinical trials on ischaemic postconditioning and remote ischaemic conditioning.
Fig. 6: Cardioprotective signalling of ischaemic conditioning.
Fig. 7: Mitochondrial cardioprotective signalling of ischaemic conditioning.
Fig. 8: Role of the vago–splenic axis in remote ischaemic preconditioning.

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Article 10 October 2019

Bruce C. V. Campbell, Deidre A. De Silva, … Geoffrey A. Donnan

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Acknowledgements

The author receives support from the German Research Foundation (SFB 1116, B8) and the European Union COST ACTION (CA 16225).

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  1. Institute for Pathophysiology, West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany

    Gerd Heusch

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Glossary

Mitochondrial permeability transition pore

(MPTP). High-conductance channel in the inner mitochondrial membrane that opens in response to increased concentrations of Ca2+ and inorganic phosphate. The molecular identity of the MPTP is not fully clear but seems to be formed from F1/F0 ATP synthase. MPTP opening is modulated by cyclophilin D.

Necrosome

Complex of phosphorylated specific receptor-interacting serine/threonine-protein kinases with phosphorylated mixed-lineage kinase domain-like proteins; formation of this complex indicates the activation of necroptosis.

No-reflow phenomenon

Lack of flow into the coronary microcirculation despite reopening of the previously occluded epicardial coronary artery; a consequence of vascular injury by ischaemia–reperfusion.

Pre-infarction angina

Angina caused by reversible myocardial ischaemia in the hours and days before an acute myocardial infarction with irreversible injury.

Killip class

Grading classification for the haemodynamic consequences of acute myocardial infarction, from I (no signs of heart failure) to IV (cardiogenic shock).

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Heusch, G. Myocardial ischaemia–reperfusion injury and cardioprotection in perspective. Nat Rev Cardiol 17, 773–789 (2020). https://doi.org/10.1038/s41569-020-0403-y

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