Treatment of Myocardial Ischemia/Reperfusion Injury by Ischemic and Pharmacological Postconditioning

Abstract

Timely reperfusion is the only way to salvage ischemic myocardium from impending infarction. However, reperfusion also adds a further component to myocardial injury such that the ultimate infarct size is the result of both ischemia- and reperfusion-induced injury. Modification of reperfusion can attenuate reperfusion injury and thus reduce infarct size. Ischemic postconditioning is a maneuver of repeated brief interruption of reperfusion by short-lasting coronary occlusions which results in reduced infarct size. Cardioprotection by ischemic postconditioning is mediated through delayed reversal of acidosis and the activation of a complex signal transduction cascade, including triggers such as adenosine, bradykinin, and opioids, mediators such as protein kinases and, notably, mitochondrial function as effector. Inhibition of the mitochondrial permeability transition pore appears to be a final signaling step of ischemic postconditioning. Several drugs which recruit in part such signaling steps of ischemic postconditioning can induce cardioprotection, even when the drug is only administered at reperfusion, that is, there is also pharmacological postconditioning. Ischemic and pharmacological postconditioning have been translated to patients with acute myocardial infarction in proof-of-concept studies, but further mechanistic insight is needed to optimize the conditions and algorithms of cardioprotection by postconditioning.

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

“…Such discrepancy may be explained by inter-species pharmacokinetic and pharmacodynamic differences, but may also be related to the more complex nature of clinical ischemia/reperfusion scenarios, often confounded by comorbidities and comedications compared to the rather simplified experimental models. Nevertheless, pharmacological studies can provide important mechanistic insights [201, 254]. As with mechanical conditioning strategies, timing is of major importance.…”

The Coronary Circulation as a Target of Cardioprotection

“…52 Whereas ischemic injury increases with the severity and the duration of coronary blood flow reduction, there is a maximum of reperfusion injury at more moderate ischemic injury (Figure 1).…”

“…Reprinted from Heusch. 52 Copyright ©2013, American Physiological Society. consequence of a reversed acidosis and intracellular sodium and calcium overload) and interstitial edema development during reperfusion follows a bimodal pattern where an initial maximum of water content after 120 minutes is associated with a beginning leukocyte infiltration, and a secondary peak after 7 days is associated with enhanced collagen deposition.…”

Ischemic Postconditioning-Regulated miR-499 Protects the Rat Heart Against Ischemia/Reperfusion Injury by Inhibiting Apoptosis through PDCD4

“…IPC can evoke endogenous defense mechanisms that reduce infarct size, preserve endothelial function, and decrease apoptosis in order to protect the heart against myocardial ischemia [11,12]. IPC has been successfully translated to humans with ischemic heart disease and, as an effective intervention performed at immediate reperfusion, it can be used in patients undergoing interventional reperfusion of acute MI (AMI) [13].…”