Reducing myocardial infarct size: challenges and future opportunities

Abstract

Despite prompt reperfusion by primary percutaneous coronary intervention (PPCI), the mortality and morbidity of patients presenting with an acute ST-segment elevation myocardial infarction (STEMI) remain significant with 9% death and 10% heart failure at 1 year. In these patients, one important neglected therapeutic target is 'myocardial reperfusion injury', a term given to the cardiomyocyte death and microvascular dysfunction which occurs on reperfusing ischaemic myocardium. A number of cardioprotective therapies (both mechanical and pharmacological), which are known to target myocardial reperfusion injury, have been shown to reduce myocardial infarct (MI) size in small proof-of-concept clinical studies-however, being able to demonstrate improved clinical outcomes has been elusive. In this article, we review the challenges facing clinical cardioprotection research, and highlight future therapies for reducing MI size and preventing heart failure in patients presenting with STEMI at risk of myocardial reperfusion injury.

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Figures

Figure 1

This scheme depicts the main prosurvival signalling pathways underlying ischaemic conditioning and the potential sites of actions for novel therapies which have recently been investigated in clinical studies to reduce myocardial infarct (MI) size in reperfused ST-segment elevation MI (STEMI) patients (please see tables 1–3, for details on the novel therapies and their potential sites of actions). The orange boxes indicate those therapies which have had mainly neutral effects on MI size and/or clinical outcomes (table 1) and the yellow boxes indicate those therapies which have the potential to improve clinical outcomes in reperfused patients presenting with STEMI (table 2). The signalling cascade underlying cardioprotection begins at the cardiomyocyte plasma membrane with the activation of G-protein coupled or cytokine receptors by autocoids such as adenosine, bradykinin or opioids (released in response to the ischaemic conditioning stimulus)—this results in the recruitment of signalling pathways such as the Reperfusion Injury Salvage Kinase (phosphatidylinositol 3-kinase-Akt (PI3K-Akt) and Mitogen-activated protein kinase kinase 1/2 -Extracellular signal-Regulated Kinase 1/2 (MEK1/2-Erk1/2)), Survivor Activator Factor Enhancement (SAFE), Janus kinase and Signal Transducer and Activator of Transcription (JAK-STAT) and the PKG pathways. These salvage pathways have been shown to activate downstream mediators such as endothelial Nitric Oxide Synthase (eNOS), Glycogen Synthase Kinase 3 Beta (GSK-3β), Hexokinase II (HKII), Protein Kinase C-epsilon (PKC-ε), the mitochondrial ATP-dependent potassium channel (KATP) which then mediate an inhibitory effect on mitochondrial permeability transition pore (MPTP) opening (adapted from Ref. 8).