Structural remodeling in the development of chronic systolic heart failure: Implication for treatment

Ventricular remodeling is a complex process that results from interactions between the initial myocardial injury and neurohormonal factors that are capable of modifying the cardiomyocyte phenotype and of inducing changes in the extracellular matrix. At the cellular level, myocyte hypertrophy, necrosis, apoptosis, interstitial fibrosis, and degradation of collagen are the major features of myocardial remodeling. Each of these components of the remodeling process contributes importantly to the development and progression of heart failure (HF). At the level of the ventricular chamber, remodeling is associated with progressive ventricular hypertrophy, enlargement, and cavity distortion that is directly related to deterioration in ventricular performance and to long-term adverse clinical outcomes. The mechanisms responsible for ventricular remodeling and deterioration of ventricular structure and function are not entirely clear, but are related to neurohormonal and cytokine activation. These factors in combination with increased wall stress and mechanical stretch of the myocytes upregulate a large number of signaling pathways. This leads to structural and functional changes in the myocyte and nonmyocyte compartments, contributing to ventricular dysfunction and the progression of HF. Although, initially, it may be compensatory in certain pressure and volume-overload conditions, progressive ventricular remodeling is ultimately a maladaptive process. After myocardial infarction, however, progressive hypertrophy and remodeling of noninfarcted myocardium may be harmful from the start. Ventricular remodeling has emerged as an important therapeutic target and a credible surrogate end point in HF. Agents that have beneficial effects in HF also generally attenuate or reverse ventricular remodeling, whereas agents that fail to improve clinical outcomes either have no effect on remodeling or have been associated with adverse remodeling. An important goal in the treatment of HF is to slow or reverse remodeling to improve long-term outcome.