PHARMACOLOGICAL MODULATION OF CARDIAC FIBROBLAST FUNCTION

The cardiac interstitium is composed of nonmyocyte cells and a structu ral protein network which plays a dominant role in governing the struc ture, architecture, and mechanical behavior of the myocardium. The het erogeneity in myocardial structure, created by the altered behavior of nonmyocyte cells, particularly cardiac fibroblasts which are responsi ble for myocardial collagen metabolism and fibrous tissue accumulation , may largely explain the appearance of diastolic and/or systolic myoc ardial failure. Regulatory mechanisms that are related to the fibrous tissue response in various cardiovascular diseases, e.g., hypertensive heart disease, dilated cardiomyopathy or post myocardial infarction, are of primary clinical interest. A better understanding of the hither to neglected role of cardiac fibroblasts in mediating an adverse struc tural remodeling of the myocardium will lead to specific pharmacologic agents that interfere with the fibrous tissue response. Several lines of evidence based on in vivo and in vitro studies suggest that circul ating and tissue renin-angiotensin-aldosterone systems (RAAS) are invo lved in the structural remodeling of the nonmyocyte compartment, inclu ding the cardioprotective effects of angiotensin converting enzyme (AC E) inhibition or aldosterone receptor antagonism that was found to pre vent myocardial fibrosis in the rat with renovascular or genetic hyper tension. In cultured adult cardiac fibroblasts, an angiotensin (Ang)I I- or aldosterone-mediated dose-dependent increase in collagen synthes is could be completely abolished by the use of AngII type 1 or mineral ocorticoid receptor antagonists, respectively. Likewise, the AngII-med iated decrease in the activity of matrix metalloproteinase 1, the key enzyme for interstitial collagen degradation, could be antagonized by AngII receptor blockade. In the rat with genetic hypertension, establi shed left ventricular hypertrophy and abnormal myocardial diastolic st iffness due to interstitial fibrosis, RAAS inhibition resulted in rest oration of myocardial structure and function to normal. Likewise, in r enovascular hypertension myocardial fibrosis could be regressed by chr onic ACE inhibition. These cardioreparative effects of ACE inhibitors may be valuable in improving left ventricular dysfunction in hypertens ive heart disease, dilated cardiomyopathy or following myocardial infa rction in man.