ABSTRACT
Because the cardiac myocyte has a limited capacity for regeneration, most forms of heart disease, including ischemic heart disease, are characterized by a loss of cardiomyocytes.13 Therefore, the protection of ischemic myocardium from cell death has been a major focus for basic and applied research over the past 40 years. Despite the seminal observation by Tennant and Wiggers that the regional dysfunction which accompanies coronary artery occlusion remains reversible if the ischemic period is brief (less than 20 minutes),4 and despite the morphological characterization of the ischemic myocardium submitted to temporary coronary occlusion,5 ‘it was widely assumed in the 1960s that myocardium perfused by a vessel which became acutely occluded was irreversibly injured’.6 From the pathological studies, it became clear, however, that reversibility of ischemic damage could be promoted by limiting the time of hypoperfusion, which provided the experimental basis for early reperfusion in patients with acute myocardial infarction.7,8
Despite the establishment of the concept of myocardial reperfusion, any evidence of prolonged left ventricular dysfunction following myocardial ischemia was thought at that time to be due to irreversible myocyte damage. In the 1970s, this concept was challenged when the ultrasonic dimension technique permitted measurements of discrete segments of regional myocardial contraction in the chronically instrumented conscious animal.9,10 These studies demonstrated that complete occlusion of a major coronary artery induced modest hyperkinesis, i.e. increased contraction, in the remote non-ischemic territory, but either dyskinesis (paradoxical bulging), or akinesis (no systolic contraction) in the central ischemic zone, and hypokinesis (depressed contraction) adjacent to the central ischemic zone (Fig. 14.1). These studies carefully described the time course of changes in regional wall motion compared with changes in myocardial blood flow, regional electrograms and systolic and diastolic function following acute coronary artery occlusion and subsequent reperfusion.9-12 These studies on coronary occlusion and reperfusion led to the discovery in the dog heart that a relatively short episode of ischemia (up to 15 minutes) is followed by a period of severe postischemic dysfunction, including dyskinesis, despite the full restoration of blood flow and resolution of the electrocardiogram (ECG) changes, complete absence of irreversible damage, and eventually full functional recovery (Fig. 14.2) ,9,10 This condition became known as ‘myocardial stunning’,13 and was the first evidence that severely dysfunctional myocardium does not necessarily represent irreversibly injured myocardium. In the 1980s, this concept of progressive functional
reversibility in a setting of acute ischemia-reperfusion was extended by several observations in patients that long-term myocardial dysfunction due to coronary
artery disease does not necessarily result in irreversible damage, but may be reversed upon revascularization,14 a condition coined ‘myocardial hibernation’.15,16 Its characterization in patients was greatly facilitated by the emergence of imaging techniques of flow and metabolism. Simultaneously, the observation that short episodes of ischemia limit infarct size if the myocardium is submitted to a subsequent severe coronary occlusion was described as ‘ischemic preconditioning’.17 The discovery and characterization of ischemic preconditioning illustrates a mechanism of cardio protection that remains the ‘gold standard’ of cardiac survival mechanisms, but most of all, it was the first demonstration that, all other parameters remaining equal, infarct size can be reduced therapeutically.
