Molecular mechanisms in remote ischaemic preconditioning: from the research lab to clinical routine?

Abstract

Since the phenomenon of remote ischaemic preconditioning (RIPC) was first described by Przyklenk et al. in 1993 [1], researchers and clinicians have tried to bring the cardioprotective effects induced by RIPC from the laboratory into the clinic. The first clinical trial of RIPC in cardiac surgery was published in 2006 [2]. Several trials investigating whether RIPC can benefit patients undergoing heart surgery followed. A majority of clinical trials have primarily focused on postoperative release of cardiac markers as an indirect and rather crude estimate of perioperative myocardial protection. Although several studies documented beneficial effects, overall the results are mixed [3, 4]. Recently, it has been demonstrated that ischaemic preconditioning during acute myocardial infarction improves myocardial salvage in patients treated with primary angioplasty [5]. Without doubt, it is important to establish whether RIPC does evoke clinically relevant effects. However, we still lack an understanding of the mechanisms of RIPC and this may contribute to the varied results observed in clinical trials. Although a limited number of studies have aimed to explore mechanisms behind RIPC in cardiac surgery [6, 7], we still only understand parts of the puzzle. In this issue, CabreraFuentes et al. [8] look into the molecular mechanisms behind RIPC in patients undergoing cardiac surgery. Cabrera-Fuentes et al. investigated levels of circulating extracellular RNA (eRNA), RNase1 activity and tumour necrosis factor (TNF-α) in association with RIPC in patients undergoing cardiac surgery. They found that activity levels of RNase1 were elevated immediately after RIPC, and that while eRNA levels were similar in both RIPC and ‘sham’ groups preoperatively, lower levels of eRNA and TNF-α were demonstrated intraoperatively in patients who underwent RIPC. Previous work by the same research group demonstrated that eRNA and TNF-α induced cardiomyocyte death in a mouse model of ischaemia–reperfusion injury, and RNase1 decreased the injurious results of myocardial ischaemia–reperfusion [9]. These findings lead the authors to conclude that RNase1may contribute to a protective effect of RIPC in cardiac surgery. As the authors acknowledge, these findings are associative and the study is limited by its small sample size, a diversity of surgical procedures, as well as differences in duration of aortic cross-clamping and extracorporeal circulation between the groups. Still, the study provides valuable insight into the mechanisms involved in RIPC and provides guidance for further investigations. The idea of pinpointing a circulating factor that could evoke cardioprotection in a clinical setting is appealing. Further investigations are required to obtain a complete picture of the mechanisms behind this intriguing phenomenon. Understanding the molecular mechanisms behind RIPC may help us clarify whether it has a place in the clinic, as well as potentially reveal therapeutic targets for enhancement of its cardioprotective effects, for example by pharmacological activation of the protective signalling pathways.