Ischemic Cardiac Dysfunction
Ischemia/hypoxia results in both systolic dysfunction (loss of inotropy) and diastolic dysfunction (impaired relaxation and reduced compliance). Both contraction and relaxation of the heart muscle require ATP, which becomes depleted during ischemia/hypoxia. An accumulation of metabolites such as lactic acid and acidosis contribute to the dysfunction.
Myocardial Stunning and Hibernation
Acute coronary occlusion causes a rapid decline (within seconds) in ventricular performance. If coronary flow is reestablished, ventricular function will slowly return to normal. The duration of reduced performance (myocardial stunning) depends on the duration of the preceding ischemia. Stunning is completely reversible, and therefore there is no permanent damage to the myocardium. The stunned myocardium, however, is less responsive to inotropic drugs and cardiogenic shock can result. Stunning is found following coronary angioplasty, thrombolysis, coronary vasospasm, and cardiopulmonary bypass.
Myocardial hibernation is a term used to describe the condition in which regional cardiac function is depressed because of chronic ischemia. Restoration of normal coronary flow (e.g., by coronary bypass) will restore normal function in the affected region.
The mechanisms of stunning and hibernation are not completely understood, but there is evidence that it is related to impaired Ca++ handling by the sarcoplasmic reticulum and due to damage caused by oxygen free radicals.
Hypoxia resulting from coronary occlusion is a major factor in cardiac stunning and infarct development. However, there is a second component that can contribute to impaired function, electrical disturbances, and infarct size. This component is associated with coronary reperfusion and is termed reperfusion injury. When the ischemic myocardium is reperfused and oxygen reintroduced, there is a sudden burst of oxygen free radical production, particularly by neutrophils. This leads to the formation of other damaging reactive oxygen species such as hydroxyl radicals, hydrogen peroxide, and peroxynitrite. These reactive oxygen species damage cell membranes and impair cellular function. Reperfusion also up-regulates the expression of endothelial and leukocyte adhesion molecules, causing leukocyte adhesion to the vascular endothelium, leukocyte activation, and leukocyte accumulation within tissues. Inflammatory mediators released by activated leukocytes result in further tissue damage and functional impairment. Studies have shown that inhibiting leukocyte adhesion or scavenging oxygen free radicals can reduce reperfusion-associated ventricular dysfunction, arrhythmias, and infarct size.
Intermittent Ischemia and Preconditioning
Short, repeating episodes of ischemia do not result in cumulative damage, but protect the heart from subsequent damage caused by a larger ischemic insult. This adaptive response by the heart is termed preconditioning and may be a significant protective mechanism in anginal patients.