Cardiac fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities.

Cardiac fibrosis is a common pathophysiologic companion of most myocardial diseases, and is associated with systolic and diastolic dysfunction, arrhythmogenesis, and adverse outcome. Because the adult mammalian heart has negligible regenerative capacity, death of a large number of cardiomyocytes results in reparative fibrosis, a process that is critical for preservation of the structural integrity of the infarcted ventricle. On the other hand, pathophysiologic stimuli, such as pressure overload, volume overload, metabolic dysfunction, and aging may cause interstitial and perivascular fibrosis in the absence of infarction. Activated myofibroblasts are the main effector cells in cardiac fibrosis; their expansion following myocardial injury is primarily driven through activation of resident interstitial cell populations. Several other cell types, including cardiomyocytes, endothelial cells, pericytes, macrophages, lymphocytes and mast cells may contribute to the fibrotic process, by producing proteases that participate in matrix metabolism, by secreting fibrogenic mediators and matricellular proteins, or by exerting contact-dependent actions on fibroblast phenotype. The mechanisms of induction of fibrogenic signals are dependent on the type of primary myocardial injury. Activation of neurohumoral pathways stimulates fibroblasts both directly, and through effects on immune cell populations. Cytokines and growth factors, such as Tumor Necrosis Factor-α, Interleukin (IL)-1, IL-10, chemokines, members of the Transforming Growth Factor-β family, IL-11, and Platelet-Derived Growth Factors are secreted in the cardiac interstitium and play distinct roles in activating specific aspects of the fibrotic response. Secreted fibrogenic mediators and matricellular proteins bind to cell surface receptors in fibroblasts, such as cytokine receptors, integrins, syndecans and CD44, and transduce intracellular signaling cascades that regulate genes involved in synthesis, processing and metabolism of the extracellular matrix. Endogenous pathways involved in negative regulation of fibrosis are critical for cardiac repair and may protect the myocardium from excessive fibrogenic responses. Due to the reparative nature of many forms of cardiac fibrosis, targeting fibrotic remodeling following myocardial injury poses major challenges. Development of effective therapies will require careful dissection of the cell biological mechanisms, study of the functional consequences of fibrotic changes on the myocardium, and identification of heart failure patient subsets with overactive fibrotic responses.