Abstract 945: Opposite Effects of Metoprolol and Losartan on Cardiac Remodeling and Existence of C-kit+ Stem-Like Cells in the Left Ventricle after Myocardial Infarction
Myocardial infarction is a major cause of heart failure. Increased sympathetic activity and activation of renin-angiotensin-aldosterone system contribute to the left ventricular remodeling after myocardial infarction. There is also strong evidence for the use of angiotensin converting enzyme inhibitors and beta-blockers to reduce morbidity and mortality in patients with myocardial infarction. On the other hand, the effect of angiotensin II type I receptor blockers (ARBs) on myocardial infarction in patients at risk for cardiovascular events is less clear. Recently, stem or progenitor cells expressing surface antigens such as c-kit or MDR1 have been identified in adult myocardium. Mobilization and transfusion of bone marrow or progenitor cells reduce infarct size and improve left ventricular function after myocardial infarction. Whether drug treatments modulate cardiac stem cells is unclear. We evaluated the effects of a beta-blocker metoprolol and an ARB losartan on left ventricular remodeling and existence of c-kit+ and MDR1+ stem-like cells in left ventricle after experimental myocardial infarction. Infarction (produced by ligation of left anterior descending artery to 5– 6 rats/group) significantly decreased systolic function assessed by echocardiography. The rate of apoptosis in left ventricle increased significantly at 1 day (to 1.8-fold) and at 2 (to 6.8-fold) and 4 weeks (to 7.0-fold) after myocardial infarction. Number of c-kit+ cells increased significantly at the same time points (to 3.5-, 4.2- and 13.3-fold, respectively). Similarly, number of MDR1+ cells increased at 1 day and at 4 weeks. Two weeks treatment with metoprolol after myocardial infarction improved systolic function of the left ventricle whereas treatment with losartan worsened it. Neither treatment had significant effect on apoptosis. Number of c-kit+ cells increased by metoprolol (1.9-fold, P<0.01) whereas losartan had no significant effect on stem-like cells. These results show that the number of stem-like cells increases in the left ventricle after myocardial infarction and that metoprolol but not losartan treatment enhances this response. The beneficial effect of metoprolol may be due to increase in number of stem cells and their proliferative effects.