Remote ischemic preconditioning for myocardial protection: update on mechanisms and clinical relevance

Abstract

Ischemic heart disease is the leading cause of death for both men and women worldwide, accruing 7.4 million deaths in 2012. There has been a continued search for better cardioprotective modalities that would reduce myocardial ischemia-reperfusion injury. Among these attempts, a more convenient model of ischemic preconditioning, known as remote ischemic preconditioning (RIPC) was first introduced in 1993 by Przyklenk and colleagues who reported that brief regional occlusion-reperfusion episodes in one vascular bed of the heart render protection to remote myocardial tissue. Subsequently, major advances in myocardial RIPC came with the use of skeletal muscle as the ischemic stimulus. To date, numerous studies have revealed that RIPC applied to the kidney, liver, mesentery, and skeletal muscle, have all exhibited cardioprotective effects. The main purpose of this review article is to summarize the new advances in understanding the molecular mechanisms of RIPC during the past 5 years, including those related to capsaicin-activated C sensory fibers, hypoxia-inducible factor 1α, connexin 43, extracellular vesicles, microRNA-144, microRNA-1, and nitrite. In addition, we have discussed results from several recent human clinical trials with RIPC. Taken together, the emerging clinical evidence supports the concept that the effectiveness of RIPC paired with its low-cost and non-invasive features makes it an ideal treatment before reperfusion after sustained ischemia. More carefully designed studies are warranted to fully exploit the clinical benefits of RIPC and its potential implications in patients with cardiovascular disease.

Remote Ischemic Preconditioning

“…Brief episodes of ischemia with intermittent reperfusion are introduced at, for example, a limb, leading to systemic protection against subsequent insults as evinced on kidney, heart, liver, and other tissues. 17 We have recently identified a general mechanism that underlies the systemic protection conferred through RIPC 18 ; remote blood occlusion leads to serotonin release from platelets, which stimulates endothelial Vegf secretion to upregulate in target organs Il10 and Mmp8, acting in concert for protection. Interrupting this serotonin-Vegf-Il10/Mmp8 axis at any point renders RIPC inefficient in protecting against hepatic IR.…”

“…25 Although the latter effects are systemic and may affect virtually any organ, 17,18,26 other benefits of RIPC may extend to processes such as fracture healing, fibrotic prevention, acute mountain sickness, exercise performance, or pancreatitis. 18,[27][28][29][30] On the contrary, the variety of potential action mechanisms may pose limits to the clinical application of RIPC.…”

Remote ischemic preconditioning versus intermittent hypoxia training: a comparative analysis for cardioprotection

“…Potential mechanisms of RIPC are good described in recent reviews [20,33]. Authors consider that despite the uncertainty in fundamental RIPC mechanisms, they can be divided into three main components: (1) humoral, (2) neural, and (3) systemic factors of cardioprotection.…”

“…Gill and coauthors [33] characterize these factors as substances that act locally at the remote ischemic territory via afferent neural pathways. The same adenosine or bradykinin acts not directly, but through the afferent nerve fibers, which then relay to efferent nerve fibers terminating on the myocardium to confer cardioprotection.…”

Nanoparticle-Mediated Delivery of Pitavastatin to Monocytes/Macrophages Inhibits Left Ventricular Remodeling After Acute Myocardial Infarction by Inhibiting Monocyte-Mediated Inflammation

“…1) Although therapeutic advancements including coronary intervention technologies and medical treatments (ACE inhibitors, angiotensin receptor blockers, β blockers, etc.) have been shown to decrease the acute phase mortality of AMI, 2,3) the prevalence of chronic heart failure in MI survivors is increasing and the long-term mortality of post-MI patients remains high.…”