Myocardial Adaptations to Ischemia: A Continuum

Heart Failure and Functional Recovery Heart failure is a leading cause of healthcare expenditures, hospitalization, and mortality in developed countries, and its burden is growing globally. With the aging of the population and increasing prevalence of chronic diseases, including hypertension, diabetes mellitus, and obesity, the current heart failure epidemic is guaranteed to significantly worsen in the near future. Thus, new disease-modifying treatments for heart failure are needed urgently and represent an area of intense investigation. Multiple studies in humans and animals have shown that the functionality of myocardial tissue of a failing heart can be restored. First, in ischemic heart failure because of severe coronary artery stenosis, revascularization therapy is known to improve heart function in a proportion of patients. Second, the mechanical unloading of the heart by left ventricular assist device (LVAD) is associated with improvements in cardiac function. In a recent report of 80 patients with heart failure who underwent implantation of a continuous-flow LVAD, the ejection fraction increased by >50% in about one third of the patients, with corresponding improvements in LV end-systolic and end-diastolic volumes and decreases in LV mass at 6 months after LVAD unloading. In addition, normalization of echocardiographic parameters has obviated completely the need for continuing LVAD support or cardiac transplantation in several patients. Importantly, the positive effects of mechanical unloading were noted in patients with both ischemic and nonischemic heart failure, suggesting that dysfunctional but potentially salvageable segments of myocardium exist in the failing heart regardless of pathogenesis. Third, in patients with broken heart syndrome (also known as Takotsubo cardiomyopathy), characterized by a rapid and severe loss of cardiac contractility secondary to emotional stress, myocardial function normalized spontaneously, again arguing for the reversibility of heart failure. In summary, although maladaptive changes observed in failing hearts were initially considered to be terminal, the accumulating body of evidence argues strongly for the reversibility of cardiac dysfunction because of multiple and distinct pathogeneses, raising the exciting possibility of curing the failing heart. Myocardial Adaptations to Ischemia: A Continuum Initially, it was thought that myocardial ischemia resulted in either irreversible myocardial necrosis (ie, myocardial infarction) or complete and rapid recovery of myocyte function (ie, typical angina). However, it is now clear that ischemia produces a continuum of myocardial adaptive responses (Figure 1). Several animal models have shown that resting contractile dysfunction is dependent on the physiological significance of the coronary stenosis, which can progress from a state associated with normal resting flow to a state with regional reductions in resting flow. The degree of stenosis severity determines many of the intrinsic molecular adaptations of the myocardium, and this continuum of adaptations may be partly responsible for the variable time course and extent of reversibility of cardiac function after revascularization. For example, myocardial stunning is a brief, fully reversible depression of cardiac function, usually of <24 to 48 hours in duration. Myocardial stunning mostly occurs after a single brief episode of ischemia and is associated with normal resting myocardial blood flow. Heyndrickx et al demonstrated myocardial stunning by subjecting the hearts of conscious dogs to no-flow ischemia for 5 or 15 minutes and showing depression in mechanical function for 3 to >24 hours after reperfusion, respectively, but with subsequent complete recovery. Myocardial stunning can occur in several clinical settings, such as exercise in the presence of coronary stenosis and variant angina. On the contrary, myocardial hibernation develops in response to repetitive ischemia or worsening chronic coronary stenosis. It is characterized by a series of adaptations in the setting of reduced regional resting flow to preserve myocardial viability at the expense of ventricular function. Myocardial hibernation may also result from repetitive stunning because of repeated ischemia, and it is now widely thought that myocardial stunning and hibernation are part of a continuous disease spectrum. Although myocardial stunning and hibernation are both reversible, myocardial stunning is usually fully reversible within 1 to 2 days, whereas hibernating myocardium may require several days to months to recover