CHAPTER 38: MOLECULAR AND CELLULAR MECHANISMS OF MYOCARDIAL ISCHEMIA/REPERFUSION INJURY

INTRODUCTION AND GENERAL CONSIDERATIONS

Acute myocardial infarction is a leading cause of mortality and morbidity worldwide. It is the result of an acute occlusion of an epicardial coronary artery. The myocardium supplied by the occluded artery suffers severe ischemia. Prolonged ischemia, if there is no collateral circulation, results in irreversible damage to heart muscle, which is replaced by fibrotic noncontracting tissue (myocardial scar). Depending on the size of the territory distal to the occlusion site, the global ventricular function can be significantly impaired, resulting in postinfarction chronic heart failure.¹ Classical studies performed in large animal models demonstrated that blood flow restoration (reperfusion) was able to limit the progression of myocardial injury in a timely manner.^2,3 Reperfusion was shown not only to limit the progression of myocardial death but also to change the pattern of myocardial tissue healing. This concept was rapidly introduced into the clinics, and a long series of successful trials demonstrated that early reperfusion was able to reduce the extent of myocardial injury and, more importantly, to reduce mortality. Since then, timely reperfusion has become the standard treatment for patients suffering an acute myocardial infarction. Extensive preclinical and clinical studies have shown that reperfusion itself induces damage to the formerly ischemic myocardium (Fig. 38–1). Since reperfusion is the prerequisite for myocardial salvage, the damage inflicted on the myocardium during a myocardial infarction is known as ischemia/reperfusion injury (IRI; ie, the result of ischemia- and reperfusion-related damage). Myocardial IRI is a complex phenomenon involving many players, all contributing to the final damage inflicted on the myocardium.¹ Figure 38–2 summarizes the highly complex process of IRI and the multiple mechanisms involved in it. The first critical player is the epicardial artery (represented as 1 in Fig. 38–2). Atherosclerotic plaque rupture with superimposed thrombus results in an abrupt cessation of oxygen and nutrient supply distal to the occlusion site. The opening of the epicardial vessel by mechanical or pharmacologic means, as well as the reduction in thrombus burden by adjuvant antiplatelet/anticoagulant therapies, is only the first step toward the salvage of myocardium. During the reperfusion process (whether it is mechanical by primary angioplasty or pharmacologic by thrombolytics), thrombus material and other plaque debris can be distally embolized, contributing to microvascular obstruction (MVO). Circulating cells contribute to the damage inflicted to the myocardium: activated platelets and leukocytes in the bloodstream not only contribute to the thrombus generation, but also can form plugins that can embolize distally into the microcirculation through resting blood flow across the culprit lesion (a process independent from plaque debris microembolization). The microcirculation is a critical player in the fate of the myocardium during ischemia/reperfusion. Once the epicardial vessel flow is restored, efficient tissue perfusion is dictated mainly by the microcirculation. Plaque debris and platelet/neutrophil aggregates can induce a mechanical obstruction of the microcirculation precluding efficient tissue perfusion despite the opening of the epicardial artery (which is known as the no-reflow phenomenon). The generation of ...