Targets for pharmacological modulation of cardiac fibrosis

The heart consists of the myocytes to produce force, the extracellular matrix to provide structural support and the blood vessels to supply nutrients and remove waste products. Studies on the mechanisms of cardiovascular disease, especially heart failure, have traditionally emphasised either deficiencies in myocyte function as the major cause of heart failure or inadequate perfusion as the major cause of ischaemic disease, for example atherosclerosis leading to coronary heart disease and myocardial infarction. The interest in the role of the third component, the extracellular matrix, in cardiovascular disease is much more recent and has emphasised the role of the collagens. The studies of Karl Weber and his colleagues [1-4] have played a key role in the realisation that excessive interstitial and perivascular collagen deposition, termed reactive fibrosis in contrast to reparative fibrosis (scar formation), is a critical component of cardiac remodelling in cardiovascular disease. Thus, Weber [4] argues that it is not the quantity but rather the quality of the myocardium that accounts for ventricular dysfunction in hypertension, the major risk factor for heart failure. This argues strongly that the extracellular matrix is a dynamic, rather than a static, component of the heart. This review will mention the biochemical processes leading to the synthesis and removal of collagens in the heart as the basis for understanding the targets for pharmacological intervention. The major emphasis of this review will be the drugs that may alter these biochemical processes involved in fibrosis. The ultimate aim of therapy with these drugs is to prevent or reverse deficits in cardiac function by controlling or reversing fibrosis to improve the quality of the myocardium.'--p. 275.