A new shield from the double-edged sword of reperfusion in STEMI

This editorial refers to ‘Cardioprotection by combined intrahospital remote ischaemic perconditioning and postconditioning in ST-elevation myocardial infarction: the randomized LIPSIA CONDITIONING trial’†, by I. Eitel et al., on page 3049. Beginning with the ‘open artery theory’ in the 1970s, the field of ST-segment elevation myocardial infarction (STEMI) management has been dominated by the fundamental principle that ‘time is muscle’, reflecting that prolonged coronary occlusion leads to myocardial injury.1 For this reason, contemporary management of STEMI focuses on rapid coronary reperfusion via balloon angioplasty and stenting to limit myocardial damage. The metric for success in STEMI therapy is a door to balloon (DTB) time of <90 min, which is defined as the interval from the first ECG showing STEMI to mechanical reperfusion of the occluded coronary artery. The DTB time is a standard part of ACC/AHA/ESC guidelines and a core quality measure of hospital and operator performance. However, recent data suggest that there may not be an incremental mortality benefit to a DTB time of <90 min in the setting of an anterior STEMI or cardiogenic shock.2 Furthermore, despite timely reperfusion, nearly 10% of acute myocardial infarction (AMI) patients die during their index hospitalization and two-thirds of survivors progress to develop chronic heart failure.3 These findings suggest that a re-examination of therapeutic priorities in the setting of AMI may be necessary. While coronary reperfusion to restore myocardial oxygen supply is ultimately necessary, the next generation of interventionalists will need to focus on alternative approaches both to improve survival and to reduce the burden of ischaemic heart failure. Described best by Braunwald and Kloner in 1985, myocardial reperfusion is a ‘double-edged sword’ due to the fact that reperfusion of ischaemic myocardium also promotes cardiomyocyte death and microvascular damage through a process referred to as myocardial ischaemia–reperfusion injury (IRI).4 Once a coronary artery becomes occluded, the ‘myocardial injury clock’ begins ticking immediately. With every passing minute, oxidative phosphorylation becomes uncoupled and mitochondrial ATP synthesis is reduced. This loss of ATP generation has two effects. First, intracellular calcium and lactate levels increase while intracellular pH decreases. Secondly, reduced ATP synthesis provides the substrate for generation of reactive oxygen species (ROS) that activate a feed-forward process known as ROS-induced ROS release. The net effect of increased ROS levels is opening of a gap in the mitochondrial membrane known as the mitochondrial permeability transition pore (mPTP). Furthermore, loss of protective signalling through the reperfusion injury salvage kinase (RISK) pathway worsens mitochondrial damage by enhancing mPTP opening. Depending on the length of time spent in this ischaemic stage (artery occluded), the myocardium may be simply stunned or transitioning to irreversible damage. Reperfusion will effectively restore blood flow to the myocardium; however, reperfusion also promotes opening of the mPTP, drives further cellular necrosis, and increases infarct size (Figure 1). There exists a need for improved strategies to limit reperfusion injury that broadly impact the multiple levels of reperfusion injury without causing further myocardial damage. The cascade of ischaemia–reperfusion injury and emerging cardioprotective strategies under active investigation. Contemporary approaches to stop the myocardial injury clock without sacrificing the absolute benefit of reperfusion therapy in STEMI are limited. Pharmacological approaches using drugs such as cyclosporine that target specific proteins involved in IRI have failed to show clear benefit in AMI.5 Global approaches such as systemic hypothermia have also been tested without clear evidence of benefit. One of the best studied cardioprotective approaches in AMI is ischaemic post-conditioning (Post-C), whereby brief, intermittent periods of reperfusion and intentional coronary occlusion are created after the onset of total coronary occlusion. The POST trial randomized 700 STEMI patients with thrombolysis in myocardial infarction (TIMI) flow grade <1 to primary PCI with our without Post-C. No difference in the rate of ST-segment resolution or 30-day major adverse cardiac events was observed between groups. One-year follow up also failed to show any impact of Post-C on death, myocardial infarction, heart failure, or stent thrombosis.6 First described in 1993, remote ischaemic conditioning (RIC) began with a ground-breaking report that intermittent periods of ischaemia in a non-ischaemic myocardial territory could reduce infarct size in an ischaemic myocardial zone.7 Nearly a decade later, researchers identified that transient limb ischaemia could also reduce myocardial infarct size in a swine model.8 Based on these early pre-clinical reports, multiple studies have explored the clinical utility of RIC as a cardioprotective measure from IRI in the setting of coronary bypass surgery, elective percutaneous coronary intervention (PCI), and AMI. More recently, several clinical studies have advanced our understanding of a potential role for RIC in STEMI management.9–11 Until now, only one previous study examined the utility of combining RIC and Post-C as a method to reduce infarct size in STEMI. The RIPOST-MI study failed to demonstrate a clear benefit of this combined approach; however, this study was limited by sample size and the use of biomarkers as surrogate measures of myocardial salvage.12 In this issue of the journal, Eitel and colleagues conducted one of the largest randomized clinical studies to test the hypothesis that the combination of RIC and Post-C would reduce myocardial infarct size in STEMI.13 Patients were randomized to receive either primary PCI (pPCI) alone, Post-C with pPCI, or the combination of RIC and Post-C. Compared with pPCI alone, the authors observed an improved myocardial salvage index (MSI) among patients treated with both RIC and Post-C as measured by cardiac magnetic resonance (CMR) imaging within 3 days after reperfusion. No difference in the MSI was observed between patients receiving Post-C alone and pPCI alone. No differences in mortality, non-fatal re-infarction, or new heart failure were observed between any of the groups at 6 months of follow up. This important study identifies the combination of RIC and Post-C as a potentially viable therapeutic approach to reduce infarct size in STEMI. While promising, there exist several major limitations to the current analysis. First, the lack of a control group receiving RIC alone is a missed opportunity to advance the field of cardioprotective science in STEMI. Without this information, we are left wondering whether the combination of RIC and Post-C is required or is RIC alone sufficient to improve the MSI. Secondly, the isolated use of CMR data 3 days after myocardial infarction limits our ability truly to understand the impact of RIC and Post-C on subsequent scar development since both RIC and Post-C could reduce myocardial oedema, inflammation, as well as myocardial necrosis. Follow-up CMR data at a later time point would help clarify the long-term impact of early improvements in the MSI. Finally, while the primary endpoint of this trial was MSI, the true impact of cardioprotective strategies such as RIC and Post-C has to be measured as a durable effect on late cardiac remodelling and the subsequent development of heart failure. The lack of benefit at 6 months follow-up may reflect an inadequate assessment of these durable endpoints, which could have included an assessment of left ventricular (LV) ejection fraction, LV end-systolic volume, New York Heart Association class heart failure symptoms, or a 6-min walk test. Based on the existing trial data available to date, RIC remains a potentially important, cost-effective, and globally available addition to the interventional armamentarium for STEMI. However, several major questions remain unanswered. First, what is the underlying mechanism behind RIC and can these pathways be harnessed as novel targets for either drug or device therapy to optimize myocardial salvage? Secondly, what is the optimal timing for application of RIC? Perhaps we should be initiating RIC, then delaying reperfusion to provide more time for myocardial conditioning and thereby yield a greater benefit in terms of myocardium salvaged. Future studies may need to study the RIC to reperfusion time (RICRT) as a determinant of clinical benefit. Finally, in what subgroups of patients (e.g. patients with cardiogenic shock in the setting of STEMI) is RIC clinically beneficial? Recent pre-clinical data from our group suggest that mechanically unloading the LV and stabilizing systemic haemodynamics with a temporary circulatory support device and delaying coronary reperfusion reduces infarct size (primary mechanical unloading).14,15 Perhaps the combination of RIC and primary mechanical unloading of the left ventricle may improve outcomes for patients with AMI complicated by haemodynamic instability. Despite system-wide advances in healthcare delivery and coronary device technology, the burden of ischaemic heart failure continues to grow exponentially as more patients with STEMI survive to hospital discharge. Therefore, our therapeutic goals have to evolve similarly to include approaches that not only restore myocardial blood flow but also protect the myocardium from reperfusion injury. Irrespective of whether myocardial conditioning is best achieved by remote ischaemia, post-reperfusion ischaemia, mechanical LV unloading, targeted pharmacology, hypothermia, hyperoxygenation, or some combination of these approaches (Figure 1), future trials will be needed to determine the effects of these interventions on durable endpoints of myocardial recovery and heart failure prevention. Conflict of interest: N.K.K. receives research support from Abiomed Inc., Cardiac Assist Inc., and Maquet Inc., and speaker/consultant honoraria from Abiomed Inc. and Maquet Inc. R.H.K. has no relevant conflicts of interest.