Metabolic disarrangement in ischemic heart disease and its therapeutic control.

The term myocardial ischaemia describes a condition which exists when fractional uptake of oxygen in the heart is not sufficient to maintain the rate of cellular oxidation. This leads to extremely complex situations which have been extensively studied in recent years. A large amount of experimental research has been directed to establish the precise sequence of biochemical events leading to myocyte necrosis as such knowledge could lead to rational treatments designed to delay myocardial cell death. At the present time there is no simple answer to the question of what determines cell death and no recovery on reperfusion. Problems arise because: (1) ischaemic damage is not homogeneous and many factors may combine to cause cell death; (2) severity of biochemical changes and development of necrosis are usually associated (both processes being dependent on the duration of the ischaemia) and it is impossible to establish a causal relationship; (3) the inevitability of necrosis can only be assessed by reperfusion of the ischaemic myocardium. Restoration of flow, however, might result in numerous further negative consequences, thus directly influencing the degree of recovery. From the clinical point of view, I have recently learned that there are several potential manifestations and outcomes associated with myocardial ischaemia and reperfusion. Without doubt ventricular dysfunction (either systolic or diastolic) of the ischaemic zone is the most reliable clinical sign of ischaemia, since ECG changes and symptoms are often absent. The ischaemia-induced ventricular dysfunction, at least initially, is reversible, as early reperfusion of the myocardium results in restoration of normal metabolism and contraction. In the ischaemic zone, recovery of contraction might occur instantaneously or, more frequently, with a considerable delay, thus yielding the condition recently recognized as the stunned myocardium. On the other hand, when ischaemia is severe and prolonged, cell death might occur. Reperfusion at this stage is associated with the release of intracellular enzymes, disruption of cell membranes, influx of calcium, persistent reduction of contractility, and eventual necrosis of at least a portion of the tissue. This entity has been called reperfusion damage by those who believe that much of the injury is the consequence of events occurring at the moment of reperfusion rather than as result of changes occurring during the period of ischaemia. The existence of reperfusion damage, however, has been questioned, and it has been argued that, with the exception of the induction of arrhythmias, it is difficult to be certain that reperfusion causes further injury. The existence of such an entity has clinical relevance, as it would imply the possibility of improving recovery with specific interventions applied at the time of reperfusion. In 1985 Rahimtoola described another possible out-come of myocardial ischaemia. He demonstrated that late reperfusion (after months or even years) of an ischaemic area showing ventricular wall-motion abnormalities might restore normal metabolism and function. He was the first to introduce the term hibernating myocardium, referring to ischaemic myocardium in which the myocytes remain viable but in which contraction is chronically depressed. Our data on metabolic changes occurring during ischaemia followed by reperfusion obtained either in the isolated and perfused rabbit hearts or in CAD patients undergoing intracoronary thrombolysis or aortocoronary by-pass grafting will be reviewed.