Gene therapy for repair of cardiac fibrosis: a long way to Tipperary.

Because of the increase in life expectancy and a high survival rate after myocardial infarction, cardiac fibrosis is becoming one of the most important problems in cardiology. It is characterized by excessive accumulation of fibrillar collagen in the extracellular space, either because of a loss of cardiomyocytes (replacement fibrosis) and/or as an interstitial response to various chronic cardiovascular diseases such as hypertension, myocarditis, and congestive heart failure (reactive fibrosis).1 In humans, cardiac fibrosis is universal in the aging heart. Activated fibroblasts play a pivotal role in the formation and maintenance of fibrous tissue by the production of various extracellularmatrix proteins, including collagen and fibronectin. It is now recognized that even in areas with long-standing fibrosis, such as postinfarction scars, fibroblasts remain metabolically active.2 Their activity is regulated by various autocrine and paracrine factors, such as angiotensin II, aldosterone, endothelins, cytokines, and growth factors.3 The renin-angiotensin-aldosterone system is considered to be of major importance for the regulation of cardiac fibrosis. Increased tissue levels of angiotensin II have shown to promote, and ACE inhibitors are able to delay the development of, cardiac fibrosis.4,5