Dynamic extracellular matrix remodeling in the heart failure: cardiac hypertrophy, dilatation and fibrosis

Abstract Over 40% of patients awaiting heart transplant surgery suffer from dilated cardiomyopathy, a life-threatening condition of impaired muscle cell metabolism, which forces the walls of the heart to balloon out under pressure. Myocardial infarction, which leads to remodeling, thinning of the ventricle wall, dilatation and heart failure, is one of the leading causes of death. Remodeling of the myocardium following infarction is a poorly understood biological process. Remodeling, by its very nature, implies an alteration in the extracellular matrix (ECM) and in the spatial orientation of cells and intracellular components. Understanding of molecular and cellular mechanisms of remodeling are an extremely worthwhile topic for exploration. Extracellular matrix, in connection with its receptor integrins and cytoskeletal cellular matrix in a 3-D orientation, is responsible for cardiac cell alignment and myocardial structural integrity. Substances that break down the extracellular matrix, specialized proteinases as well as inhibitors of proteinases, appear to be normally balanced in maintaining the integrity of the myocardium. Myocardial infarction leads to an imbalance in proteinase antiproteinase activities allowing alterations in the stability and integrity of the extracellular matrix, leading to tissue remodeling. The latent matrix proteinases are activated following infarct-injury. The degradation of ECM induces contractile and proliferative phenotypes in cardiac fibroblast cells and transforms to myofibroblast cells. The extracellular matrix-derived peptides induce maladaptive response in myofibroblasts and activate MMPs, causing ventricular dilatation and myocardial dysfunction. This review presents new and significant information regarding the role of activated matrix proteinases and their endogenous inhibitors in ischemic heart disease. This will have a significant impact on both our understanding of the tissue remodeling and on basic cell physiology of extracellular matrix turnover, as well as potential avenues for pharmacological approaches for the treatment of ischemic heart disease and heart failure.