Stretching the evidence in the case of cardiac growth.

Cardiac hypertrophy is not only an adaptive process in response to increased workload [l] but also one of the most important clinical complications of cardiovascular disorders. It is well known that a number of patients with cardiac hypertrophy develop heart failure, and that hypertrophy itself is one of the risk factors for an increased mortality rate [2]. Thus, understanding the molecular mechanisms involved in cardiac hypertrophy is of utmost importance. In 1984, Zak [3] showed that the activation of adrenoreceptors accompanies cardiac hypertrophy induced by hemodynamic overload. However, several lines of evidence presented below suggest that mechanical stress is a major factor for cardiac hypertrophy in response to hemodynamic overload. First, stretching of quiescent papillary muscle accelerates protein synthesis [4], and elevation of aortic pressure in beating perfused hearts causes an increase in protein synthesis [S]. Secondly, Cooper et al. [6] have reported that in aorta-constricted cats, papillary muscles without tension did not show hypertrophy, whereas neighboring stretched papillary muscle showed marked hypertrophy. Furthermore, stretching of cultured myocytes increased specific gene expression and protein synthesis without participation of neural or humoral factors [7-111. heart at both the mRNA and protein levels [13]. Recent reports have also shown that the cardiac RAS is activated in experimental left ventricular hypertrophy (LVH) induced by hemodynamic overload. Increases in angiotensinogen and ACE mRNAs have been reported in the hypertrophied left ventricle (LV) of rats [14]. In addition, subpressor doses of ACE inhibitors can cause regression of cardiac hypertrophy with no change in systemic systolic blood pressure [15]. Moreover, an increase in left ventricular mass produced by abdominal aortic constriction has been completely prevented with an ACE inhibitor without any change in afterload and plasma renin activity [16]. These results indicate that the local RAS may play a critical role in cardiac hypertrophy induced by pressure overload and that angiotensin II (AI11 may act to promote the growth of the cardiac myocytes by an autocrine/paracrine mechanism [9]. The molecular mechanisms of cardiac cellular hypertrophy induced by mechanical overload are the topic of this review.