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.