Remote ischaemic preconditioning - translating cardiovascular benefits to humans

Abstract

Remote ischaemic preconditioning (RIPC), induced by intermittent periods of limb ischaemia and reperfusion, confers cardiac and vascular protection from subsequent ischaemia-reperfusion (IR) injury. Early animal studies reliably demonstrate that RIPC attenuated infarct size and preserved cardiac tissue. However, translating these adaptations to clinical practice in humans has been challenging. Large clinical studies have found inconsistent results with respect to RIPC eliciting IR injury protection or improving clinical outcomes. Follow-up studies have implicated several factors that potentially affect the efficacy of RIPC in humans such as age, fitness, frequency, disease state and interactions with medications. Thus, realizing the clinical potential for RIPC may require a human experimental model where confounding factors are more effectively controlled and underlying mechanisms can be further elucidated. In this review, we highlight recent experimental findings in the peripheral circulation that have added valuable insight on the mechanisms and clinical benefit of RIPC in humans. Central to this discussion is the critical role of timing (i.e. immediate vs. delayed effects following a single bout of RIPC) and the frequency of RIPC. Limited evidence in humans has demonstrated that repeated bouts of RIPC over several days uniquely improves vascular function beyond that observed with a single bout alone. Since changes in resistance vessel and microvascular function often precede symptoms and diagnosis of cardiovascular disease, repeated bouts of RIPC may be promising as a preclinical intervention to prevent or delay cardiovascular disease progression.

Keywords: endothelial function; flow-mediated dilatation; ischaemia-reperfusion injury; microvascular function; repeated remote ischaemic preconditioning; skin blood flow; vascular; vascular smooth muscle.

Figure 1. Schematic representation of the triggers and cardiovascular benefits of remote ischaemic preconditioning

Figure 2. Proposed mechanism of remote ischaemic preconditioning for a single bout, both first and second windows of protection, and following repeated bouts

AA, arachidonic acid; ACh, acetylcholine; CaN, calcineurin; CGRP, calcitonin gene‐related peptide; CGRP‐R, calcitonin gene‐related peptide receptor; COX, cyclooxygenase; CYP, cytochrome P450; EDHF, endothelium‐derived hyperpolarizing factor; ERK1/2, extracellular signal‐regulated kinases 1 and 2; eNOS, endothelial nitric oxide synthase; HIF‐1α, hypoxia‐inducible factor 1α; HSP, heat shock protein; iNOS, inducible nitric oxide synthase; IP₃, inositol 1,4,5‐trisphosphate; LOX, 5‐lipoxygenase; MAPK, mitogen activated protein kinase; MnSOD, manganese superoxide dismutase; mPTP, mitochondrial permeability transition pore; NFAT, nuclear factor of activated T cells; NF‐κB, nuclear factor κB; NO, nitric oxide; PGI₂, prostaglandin I₂; PI3K, phosphoinositide 3‐kinase; PIP₂, phosphatidylinositol 4,5‐bisphosphate; PKA, protein kinase A; PKC, protein kinase C; PKG, protein kinase G; PLA2, phospholipase A2; ROS, reactive oxygen species; sGC, soluble guanylate cyclase; TRPV, transient receptor potential cation channel subfamily V; VEGFR2, vascular endothelial growth factor receptor 2.