Ventricular Remodeling In Ischemic Cardiomyopathy

Abstract

Heart failure in the setting of reduced systolic pump function, if left untreated, is characterized by progressive ventricular dilation and dysfunction. Many of the major advances in pharmacologic treatments for heart failure achieved over the last two decades came with the recognition that this process, referred to as ventricular remodeling, results from abnormal mechanical stress on the myocardium (increased preload and afterload) and chronic neurohormonal activation (Figure 1). In the acute setting, loss of myocytes (as during infarction) or a defect of myocardial contraction (e.g., idiopathic cardiomyopathies) reduces overall ventricular pump function. This leads to reduced blood pressure and cardiac output, which activates autonomic reflexes that leads to increased circulating levels of neurohormones. It is believed, on a teleological basis, that these reflexes evolved in order to allow animals to cope with periods of increased energy demand (fight or flight) and to deal with acute blood loss. In parallel with autonomic reflex activation, decreased systemic blood pressure and flow lead to renal hypoperfusion, which increases aldosterone, renin and angiotensin, I (which leads to angiotensin II) production. In the short term, these factors attempt to restore cardiac output and blood pressure via mechanisms that are considered adaptive. However, if sustained, neurohormonal activation and increased mechanical stresses conspire in a maladaptive process to drive cellular hypertrophy and elongation, global recapitulation of a fetal gene program, myocardial fibrosis, ventricular enlargement and dysfunction, apoptosis1 and sets up a milieu for dyscoordinated myocardial contraction (e.g., conduction defects) and ventricular arrhythmias. A systemic inflammatory response also has been documented with increases of a multitude of cytokines which are also believed to contribute importantly to myocyte loss and disease progression.2,3