Cardiac Fibrosis

Heart failure, the clinical manifestation of numerous forms of cardiovascular disease, is a devastating disorder characterized by interstitial fibrosis, chamber remodeling, and reduced ventricular compliance. Heart disease remains the predominant cause of mortality in the United States, accounting for nearly 800 000 deaths per year. Furthermore, it presents a considerable economic burden, with estimated direct and indirect costs in 2011 of ≈$320 billion and predictions suggesting that costs will rise to ≈$918 billion by 2030. Despite substantial improvements in therapeutic strategies, cardiovascular disease remains the leading cause of death worldwide indicating an urgent need for innovative treatment strategies. Nearly all etiologies of heart disease involve pathological myocardial remodeling characterized by excessive deposition of extracellular matrix (ECM) proteins by cardiac fibroblasts (CFs), which reduces tissue compliance and accelerates the progression to heart failure. The CF is an essential cell type, predominantly of embryonic epicardial and endothelial origins, which resides within the myocardial interstitium, epicardial and perivascular regions. Physiologically, CFs are responsible for homeostasis of the ECM, which provides a structural scaffold for cardiomyocytes, distributes mechanical forces through the cardiac tissue, and mediates electric conduction. Previously, identification of these cells was largely based on phenotypic observations; morphologically, fibroblasts are flat, spindle-shaped cells with multiple processes when propagated on tissue culture plastic. The cardiac cellular milieu can vary greatly depending on the species being examined and between healthy and injured myocardium. Although previous studies suggested that CFs accounted for the majority of cells within the adult rodent and human myocardium, recent reports with more accurate delineation of the CF population have proposed that CFs may comprise <20% of the total cell population in the adult murine heart, substantially less than previously suggested. Although it is now appreciated that a majority of resident fibroblasts originate from the embryonic epicardium, the contribution of various resident and infiltrating cells to the population of activated cardiac myofibroblasts remains under active investigation, including further refinement of specific molecular markers for CFs. Unlike other organs, the heart has limited regenerative capacity after injury, and instead, repair processes involve the removal of necrotic cardiomyocytes followed by fibrotic scar tissue replacement that acts to preserve myocardial structural and functional integrity. To perform these functions, CFs within the connective tissue convert to their activated form, often known as myofibroblasts, which secrete elevated levels of ECM proteins to promote a profibrotic environment. Cardiac fibrosis provokes pathological changes that culminate in chamber dilatation, cardiomyocyte hypertrophy, and apoptosis, and ultimately lead to the development of congestive heart failure. Although the sources of these activated fibroblasts remain under intense investigation and debate, the refinement of molecular markers and the development of new techniques for lineage tracing are helping to enhance our understanding of their origins. Review