Remote Ischemic Preconditioning

Abstract

During the past 3 decades, several experimental studies have shown that ischemic conditioning reduces myocardial damage by modifying ischemia-reperfusion injury. A recent study in the Lancet indicates that remote ischemic preconditioning translates into clinical benefit in patients undergoing coronary artery bypass surgery. The implications of the study extend to patients undergoing elective and acute coronary angioplasty and beyond.Adjunctive therapies to reduce myocardial ischemiareperfusion injury related to cardiac surgery and percutaneous coronary interventions have yet to find their way into clinical practice, mainly because no pharmacological or mechanical cardioprotective strategy has convincingly shown clinically relevant benefit to the patient.1 That may be about to change. In a recent study by Thielmann et al, 2 329 low-risk patients undergoing elective isolated on-pump first-time coronary artery bypass grafting (CABG) were randomized to either standard CABG or CABG preceded by remote ischemic preconditioning (RIPC), achieved by 3 cycles of 5-minute upper limb ischemia through inflation of a blood pressure cuff followed by 5-minute deflation. The results indicate that RIPC confers a prognostic benefit to the patient.The study was conducted as a single-center, double-blind, randomized, controlled trial. The primary end point was perioperative myocardial injury assessed by troponin I release measured at 6, 12, 24, 48, and 72 hours after surgery. The secondary end points comprised all-cause mortality, major adverse cardiac and cerebrovascular events (MACCE), and repeat revascularization at 30 days, 1 year, and at completion of follow-up, ranging from 1 to >4 years with a mean of 1.54 years. The group demographics were well-matched, and there were no significant differences in baseline risk factors.The authors demonstrated acutely reduced myocardial injury (assessed by troponin I release), as also shown previously by others 3 but, in addition, they also found a reduction in allcause and cardiac mortality, as well as MACCE in the intervention group during the follow-up period. During the follow-up period, MACCE occurred 23 times in the control group versus 8 times in the RIPC group (P=0.011). The authors observed 11 deaths in the control group and only 3 deaths in the RIPC group (P=0.046). The combined end point (death, MACCE, and repeat revascularization) exhibited a hazard ratio of 0.38 (0.21-0.70) in favor of RIPC. There was no difference between groups regarding the need for revascularization.The present study is noteworthy because it is the first to show that the reduction in surrogate end points in patients treated with RIPC before CABG translates into clinical benefit. Although several trials have investigated the effect of RIPC in the context of CABG 3-5 and a recent meta-analysis of these trials indicates that RIPC reduces troponin release in these patients, 6 there is continued skepticism regarding the clinical efficacy of RIPC. In contrast to earlier studies, Thielmann et al 2 conducted a detail...

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Nrg1β Released in Remote Ischemic Preconditioning Improves Myocardial Perfusion and Decreases Ischemia/Reperfusion Injury via ErbB2-Mediated Rescue of Endothelial Nitric Oxide Synthase and Abrogation of Trx2 Autophagy

“…The generation of humoral factors by RIPC is confirmed by the transferability of RIPC-benefits via serum or plasma from RIPC-treated subjects to naïve subjects. 8,47 Hence, to confirm Nrg1β released into the circulation as the RIPC factor, we treated plasma from RIPC-treated animals with neutralizing Nrg1 antibody and then transferred to naïve mouse before I/R injury. While RIPC-plasma transfer conferred significant protection in naïve mice against I/R-induced tissue apoptosis (Figure 1J and 1K), Nrg1-neutralized plasma from RIPC-mice not only abolished the protection, but also resulted in two-fold higher tissue apoptosis (Figure 1K).…”

“…For example, blood from rabbits subjected to IPC can decrease the size of MI's formed in response to IPC of naive rabbits, demonstrating that RIPC releases cardioprotective factors to the circulation. 8 However, the mechanisms behind these effects are unclear, and the identity of cardioprotective factor released in response to RIPC has not been established. 5,7 Nrgs (neuregulins) are polypeptides belonging to a subclass of epidermal growth factors that are secreted by endothelial cells.…”

Proteomic analysis in cardiovascular research

“…This phenomenon is called remote ischemic preconditioning (RIPC) [ 59 ] and it has been successfully translated into coronary artery bypass surgery, where RIPC was proven as an effective method in perioperative cardiac protection and improved patient prognosis [ 60 ]. The effects of RIPC could be produced via systemic release of an unknown cardioprotective factor [ 61 ]. Plasma proteomics using both 2D-DIGE MS and liquid chromatography–mass spectrometry identified 6 and 48 proteins, respectively, which were differentially regulated in blood taken from the ischemic arm, but did not identify the protein that provided cardioprotection [ 62 ] (Table 3 ).…”