Preclinical multi-target strategies for myocardial ischemia-reperfusion injury

Abstract

Despite promising breakthroughs in diagnosing and treating acute coronary syndromes, cardiovascular disease's high global mortality rate remains indisputable. Nearly half of these patients died of ischemic heart disease. Primary percutaneous coronary intervention (PCI) and coronary artery bypass grafting can rapidly restore interrupted blood flow and become the most effective method for salvaging viable myocardium. However, restoring blood flow could increase the risk of other complications and myocardial cell death attributed to myocardial ischemia-reperfusion injury (IRI). How to reduce the damage of blood reperfusion to ischemic myocardium has become an urgent problem to be solved. In preclinical experiments, many treatments have substantial cardioprotective effects against myocardial IRI. However, the transition from these cardioprotective therapies to clinically beneficial therapies for patients with acute myocardial infarction remains elusive. The reasons for the failure of the clinical translation may be multi-faceted, and three points are summarized here: (1) Our understanding of the complex pathophysiological mechanisms of myocardial IRI is far from enough, and the classification of specific therapeutic targets is not rigorous, and not clear enough; (2) Most of the clinical patients have comorbidities, and single cardioprotective strategies including ischemia regulation strategies cannot exert their due cardioprotective effects under conditions of hyperglycemia, hypertension, hyperlipidemia, and aging; (3) Most preclinical experimental results are based on adult, healthy animal models. However, most clinical patients had comorbidities and received multiple drug treatments before reperfusion therapy. In 2019, COST Action proposed a multi-target drug combination initiative for prospective myocardial IRI; the optimal cardioprotective strategy may be a combination of additive or synergistic multi-target therapy, which we support. By establishing more reasonable preclinical models, screening multi-target drug combinations more in line with clinical practice will benefit the translation of clinical treatment strategies.

Keywords: acute myocardial infarction; apoptosis; cardioprotection; multi-target strategies; myocardial ischemia-reperfusion injury (IRI).

FIGURE 1

Multitarget cardioprotective strategies to reduce myocardial infarction. Cardioprotective strategies fall into four broad categories, which may be combined in different manners to achieve multitarget cardioprotection. RISK, reperfusion injury salvage kinase; SAFE, survivor activating factor enhancement; PKG, protein kinase G. [Adapted from Davidson el al. (3)].

FIGURE 2

Hypothetical temporal relationship between reperfusion and cardioprotection in STEMI [Adapted from Bainey and Armstrong (27)].

FIGURE 3

Pathophysiological mechanism of myocardial ischemia-reperfusion injury [adapted from Heusch et al. (4)]. ROS, reactive oxygen species; MPTP, mitochondrial permeability transition pore; TNF-α, tumor necrosis factor-α;IL-6, interleukin-6.

FIGURE 4

A multi-target strategy for myocardial ischemia-reperfusion injury in animal models with specific comorbidities. IPostC, ischemic postconditioning; SPC, sevoflurane postconditioning.