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.

Insights into research on myocardial ischemia/reperfusion injury from 2012 to 2021: a bibliometric analysis

“…In addition, a variety of pharmacological approaches to cardioprotection, such as adenosine and glucose insulin potassium, have progressed to clinical testing for treatment of MI/R damage. Unfortunately, most clinical studies fail to provide evidence of the cardioprotective effects of conditioning strategies and pharmacological approaches [ 2 , 38 ]. There are several reasons why clinical translation fails, and here we present three major ones [ 39 ]: The pathophysiological mechanism of MI/R injury is complex, and understood only partially.…”

“…In addition, a variety of pharmacological approaches to cardioprotection, such as adenosine and glucose insulin potassium, have progressed to clinical testing for treatment of MI/R damage. Unfortunately, most clinical studies fail to provide evidence of the cardioprotective effects of conditioning strategies and pharmacological approaches [2,38].…”

PFKFB2 Inhibits Ferroptosis in Myocardial Ischemia/Reperfusion Injury Through Adenosine Monophosphate–Activated Protein Kinase Activation

“…4 Effective clinical treatment to avoid reperfusion injury in patients is still elusive. 5 Therefore, it is important to research new strategies for mitigating reperfusion injury.…”

The Shexiang Baoxin Pill Protects Myocardial Cells from Multiple Targets of MIRI through the PI3K/Akt/eNOS Signal Pathway

“…The reasonable combination of different protection strategies will help to activate complementary survival pathways and/or inhibit harmful cell death pathways, resulting in improved cardioprotective effects [15]. Animal experiments have recently confirmed that ischemic preconditioning protects against MIRI in diabetic rats by activating the serine/threonine protein kinase (Akt)-related signaling pathway and inhibiting apoptosis[13]. Therefore, multi-target therapy for MIRI is a novel approach for its treatment[15].…”