Prevention of Periprocedural Myocardial Injury During Percutaneous Coronary Intervention in Patients With Stable Coronary Artery Disease
Article ID: CJ-18-0499
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Article ID: CJ-18-0499
Percutaneous coronary intervention (PCI) is established as one of the most common procedures for the treatment of coronary artery disease (CAD), based on considerable evidence. The advances in procedural techniques, stent materials and aggressive antiplatelet therapy have decreased the incidence of major periprocedural complications of PCI. However, periprocedural myocardial injury (PMI) is still one of the inevitable complications of PCI, resulting from distal embolization, side-branch occlusion, coronary dissection and disruption of collateral flow. A previous study has reported several risk factors for PMI, including more extensive disease, multivessel disease, complex lesion morphology, coronary thrombus and calcification, left ventricular systolic dysfunction and urgent procedures.1
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Both cardiac troponins and creatine kinase MB are sensitive and specific biomarkers for quantitative diagnosis of irreversible myocardial injury, and the release of these biomarkers is associated with increased risk of death and myocardial infarction (MI).1,2 A previous report showed that a 5-fold post-procedural elevation of cardiac troponin T above normal levels is an independent predictor of a composite of death, MI, and revascularization at 1 year (hazard ratio, 2.39; 95% confidence interval, 1.09–5.26).3 Importantly, because PMI also occurs in a considerable proportion of the patients with successful procedures, there have been many attempts to prevent PMI in patients undergoing PCI. Pharmacologic interventions, such as statins and glycoprotein IIb/IIIa inhibitors, with anti-inflammatory and antithrombotic effects, respectively, are often used prior to PCI and have been shown to reduce the incidence and magnitude of myonecrosis.4,5 However, subsequent meta-analysis has revealed that increased cardiac troponin levels still occurred in 29% of the patients after PCI, and the incidence of PCI-related MI was 15%.6
Ischemic preconditioning (IPC: brief episodes of cardiac ischemia and reperfusion before a subsequent prolonged ischemia) has been shown to protect against myocardial cellular death. The underlying mechanism of IPC involves ATP-sensitive potassium (KATP) channels, the mitochondrial permeability transition pore, opioid receptors, reactive oxygen species, protein kinases and nitric oxide (NO). Activation of the KATP channels and inhibition of the opening of the mitochondrial permeability pore through multiple signaling pathways, including protein kinase C, has been implicated as a pivotal mechanism of IPC.7 Nicorandil is known as an opener of the KATP channel with a NO donor property; therefore, its effect as an agent of IPC has been investigated. The IONA study showed that oral administration of nicorandil reduced the incidence of major cardiovascular events in patients with angina pectoris.8 However, in the RINC trial, intravenous nicorandil did not reduce the incidence of PMI or the slow-flow phenomenon following elective PCI,9 and the J-WIND study refuted the beneficial effect of nicorandil against ischemia and reperfusion injury.10 Thus, it remains uncertain whether nicorandil effectively mimics IPC.
In this issue of the Journal, Ejiri et al report their subanalysis of the RINC trial, a multicenter randomized controlled study, to clarify the effect of remote IPC (RIPC) on PMI in patients with complex coronary lesions, following elective PCI.11 IPC acts protectively not only locally, but also protects remote organs, known as RIPC (Figure 1).12 A meta-analysis of randomized trials revealed that RIPC significantly reduced the increase of myocardial injury in patients undergoing coronary artery bypass graft surgery.13 The mechanisms underlying the cardioprotective effect of RIPC are similar to those reported for IPC, including neural and humoral signaling pathways (Figure 2).14 The RIPC procedure is safe and tolerable for patients, consisting of several cycles of inflation of a blood pressure cuff on the arm or leg to a pressure of 200 mmHg, followed by cuff deflation for a short period of time. The RINC trial showed no significant difference in the incidence of PMI following elective PCI,9 corresponding with the result of the meta-analysis.13 However, in the current subgroup analysis, the authors show that the incidence of PMI was similar between the control and RIPC groups of patients with simple coronary lesions, but notably lower in the RIPC group than in the control group of patients with complex coronary lesions.11 The COURAGE trial provided evidence that PCI does not improve mortality or reduce major cardiovascular events in patients with stable CAD, compared with optimal medical therapy.15 However, the prevention of PMI may lead to improved prognosis after PCI. Thus, RIPC may be a novel therapeutic option for high-risk patients undergoing PCI and improve long-term mortality. However, further studies are needed to evaluate its effect on death and cardiovascular outcomes.
Biological effects of remote ischemic preconditioning. (Reproduced with permission from reference 12.)
Molecular mechanisms of remote ischemic preconditioning. AP-1, activator protein-1; cGMP, cyclic guanosine monophosphate; CGRP, calcitonin gene-related peptide; COX2, cyclooxygenase 2; HIF-1a, hypoxia-inducible factor 1a; HSP, heat shock protein; iNOS, inducible nitric oxide synthase; JAK, Janus kinase; MEK, MAPK kinase; mPTP, mitochondrial permeability transition pore; Nrf2, nuclear factor (erythroid-derived 2)-like 2; STAT1/3, signal transducer and activator of transcription. (Reproduced with permission from reference 14.)
