Pharmacological Prevention of Reperfusion Injury in Acute Myocardial Infarction

Abstract

The concept of reperfusion injury, although first recognized from animal studies, is now recognized as a clinical phenomenon that may result in microvascular damage, no-reflow phenomenon, myocardial stunning, myocardial hibernation and ischemic preconditioning. The final consequence of this event is left ventricular (LV) systolic dysfunction leading to increased morbidity and mortality. The typical clinical case of reperfusion injury occurs in acute myocardial infarction (MI) with ST segment elevation in which an occlusion of a major epicardial coronary artery is followed by recanalization of the artery. This may occur either spontaneously or by means of thrombolysis and/or by primary percutaneous coronary intervention (PCI) with efficient platelet inhibition by aspirin (acetylsalicylic acid), clopidogrel and glycoprotein IIb/IIIa inhibitors. Although the pathophysiology of reperfusion injury is complex, the major role that neutrophils play in this process is well known. Neutrophils generate free radicals, degranulation products, arachidonic acid metabolites and platelet-activating factors that interact with endothelial cells, inducing endothelial injury and neutralization of nitrous oxide vasodilator capacity. Adenosine, through its multi-targeted pharmacological actions, is able to inhibit some of the above-mentioned detrimental effects. The net protective of adenosine in in vivo models of reperfusion injury is the reduction of the infarct size, the improvement of the regional myocardial blood flow and of the regional function of the ischemic area. Additionally, adenosine preserves the post-ischemic coronary flow reserve, coronary blood flow and the post-ischemic regional contractility. In small-scale studies in patients with acute MI, treatment with adenosine has been associated with smaller infarcts, less no-reflow phenomenon and improved LV function. During elective PCI adenosine reduced ST segment shifts, lactate production and ischemic symptoms. During the last years, three relatively large placebo-controlled clinical trials have been conducted: Acute Myocardial Infarction Study of Adenosine Trial (AMISTAD) I and II and Attenuation by Adenosine of Cardiac Complications (ATTACC). In the AMISTAD trials, the final infarct size was reduced and the LV systolic function was improved by adenosine treatment, mainly in patients with anterior MI localization. However, morbidity and mortality were not affected. In the ATTACC study, the LV systolic function was not affected by adenosine, however, trends towards improved survival were observed in patients with anterior MI localization. The possibility of obtaining a Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow in the infarct-related artery in up to 95% of patients with acute MI (increasing the occurrence of reperfusion injury) has turned back the interest towards the protection of myocardial cells from the impending ischemic and reperfusion injury in which adenosine alone or together with other cardio-protective agents may exert important clinical effects.

Intracoronary interleukin-6 levels in patients with ST segment elevation myocardial infarction treated with primary angioplasty and complicated with No Reflow

“…Some of the agonists that may confer cardio protection include the use of adenosine, verapamil and nitric oxide, in contrast there is controversy in the role of some cytokines such as bradykinin, tumor necrosis factor alpha and IL-6 [12,19]. Signaling pathways include the opening of the sarcolemma and/or Mitochondrial ATP-Dependent Potassium Channels, and the activation of kinase (AKT and ERK-1/2, protein kinase C and G) blocking the final pathway of Mitochondrial transition [18].…”

“…Clinical complications occurred more frequently in group II. The Some strategies have been used to reduce reperfusion injury such as use of adenosine [12] and thrombus aspiration [13]. However, pathophysiology is complex and mechanisms to attach appropriate therapies has not been clearly established.…”

Beneficial effect of adenosine on myocardial perfusion in patients treated with primary percutaneous coronary intervention for acute myocardial infarction

“…10 At an organ level, adenosine preserves postischaemic coronary flow reserve, coronary blood flow and postischaemic regional contractility. 11 It also reduces the accumulation of neutrophils in the area at risk. 11 In the present study, intravenous adenosine reduced reperfusion injury, improved myocardial perfusion and provided cardioprotection.…”

“…11 It also reduces the accumulation of neutrophils in the area at risk. 11 In the present study, intravenous adenosine reduced reperfusion injury, improved myocardial perfusion and provided cardioprotection. These findings are in agreement with a previous study with intracoronary adenosine that reported improved myocardial perfusion and cardiac function in AMI patients undergoing selective PCI.…”

GPCRs as therapeutic targets: a view on adenosine receptors structure and functions, and molecular modeling support

“…Adenosine itself is used as a therapeutic agent for the treatment of supraventricular paroxysmal tachycardia and arrhythmias and, as a vasodilatatory agent, in cardiac imaging [46,47]. Two adenosine products, Adenocard® and Adenoscan®, have been approved by FDA and are currently available for cardiac arrhythmias treatment and for cardiac imaging, respectively [48,49].…”