Both clinicians and investigators have long tended to consider cardiac fibrosis as a hopelessly unavoidable

“final common pathway” of tissue injury. We are painfully familiar with the serious consequences of myocardial fibrosis, including diastolic dysfunction and promoting reentry dysrhythmias, 1 but we seem to accept that diseased myocardium eventually develops fibrosis. However, only the most advanced fibrotic tissues are lifeless; in fact, dynamic matrix turnover in fibrosing tissues is easily demonstrated, whereas the matrix of normal tissues is, in comparison, remarkably quiescent. That we can potentially steer matrix metabolism beneficially to reduce dysrhythmias or improve ventricular function is reason enough to try to understand cardiac fibrosis. In addition, as we will briefly touch on here, recent excitement in cardiac regeneration offers us yet another important reason to unravel fibrosis, because myocardial scarring may be standing in the way of successfully repairing the heart.

Treatment options to prevent cardiac fibrosis are limited and include angiotensin converting enzyme inhibitors2 and aldosterone blockade. 3 Matrix metalloproteinase inhibition may also reduce fibrosis. 4, 5 The effects of metalloproteinase inhibition on cardiac fibrosis do not appear to be attributable to changes in collagen degradation, and there has been little recent progress on using metalloproteinase inhibition clinically. With so few weapons against cardiac fibrosis, it is therefore important to develop new strategies through understanding basic molecular pathways of matrix metabolism. There are different types of cardiac fibrosis, and some forms of fibrosis are probably at least transiently beneficial. The fibrosis of the healing infarct in the days after myocardial infarction prevents cardiac rupture, but eventually dense regions of fibrosis may be arrhythmogenic. Pressure overloaded myocardium causes fibrosis within weeks that is initially perivascular1; this is so reproducible that shamoperated mice can be easily distinguished from pressureoverloaded mice by the dramatic deposition of collagen around intramyocardial arterioles. 6 Eventually, hypertensive myocardium develops a more diffuse interstitial fibrosis, as the cardiac fibroblasts react to a cascade of myocardial factors