Dedkov EI, Zheng W, Christensen LP, Weiss RM, MahlbergGaudin F, Tomanek RJ. Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen. Am J Physiol Heart Circ Physiol 293: H590-H598, 2007. First published March 23, 2007; doi:10.1152/ajpheart.00047.2007.-We tested the hypothesis that chronically reducing the heart rate in infarcted middle-aged rats using ivabradine (IVA) would induce arteriolar growth and attenuate perivascular collagen and, thereby, improve maximal perfusion and coronary reserve in the surviving myocardium. Myocardial infarction (MI) was induced in 12-mo-old male Sprague-Dawley rats, which were then treated with either IVA (10.5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ; MI ϩ IVA) or placebo (MI) via intraperitoneal osmotic pumps for 4 wk. Four weeks of IVA treatment limited the increase in left ventricular end-diastolic pressure and the decrease in ejection fraction but did not affect the size of the infarct, the magnitude of myocyte hypertrophy, or the degree of arteriolar and capillary growth. However, treatment reduced interstitial and periarteriolar collagen in the surviving myocardium of MI ϩ IVA rats. The reduced periarteriolar collagen content was associated with improvement in maximal myocardial perfusion and coronary reserve. Although the rates of proliferation of periarteriolar fibroblasts were similar in the MI and MI ϩ IVA groups, the expression levels of the AT 1 receptor and transforming growth factor (TGF)-␤1 in the myocardium, as well as the plasma level of the ANG II peptide, were lower in treated rats 14 days after MI. Therefore, our data reveal that improved maximal myocardial perfusion and coronary reserve in MI ϩ IVA rats are most likely the result of reduced periarteriolar collagen rather than enhanced arteriolar growth. myocardial infarction; coronary circulation; coronary vessels; reninangiotensin system A MYOCARDIAL INFARCTION (MI) initiates progressive structural remodeling within the surviving left ventricular (LV) myocardium. Features of such remodeling include cardiac myocyte hypertrophy, fibroblast proliferation, and interstitial/perivascular fibrosis (4, 26). These alterations compromise maximal coronary blood perfusion and coronary reserve in the remaining LV myocardium (5,6,15,16,18,20).Since adequate tissue perfusion is key for survival and effective function of hypertrophied myocytes in the remaining overloaded LV myocardium, the recovery of normal tissue perfusion in this region has become a major focus of several studies (14, 15), including those from our laboratory (5, 20). Because the major cause of limited myocardial perfusion and coronary reserve in post-MI hearts was long thought to be a failure to match the adaptive growth of the intramyocardial vasculature to the degree of myocyte hypertrophy, earlier studies, which were conducted on young and young-adult rats, were designed either to reduce myocyte hypertrophy (14,24) or to promote the growth of the coronary vasculature (20).MI i...

Background-We tested the hypothesis that induction of chronic bradycardia would trigger an upregulation of key growth factors and receptors, which would then lead to angiogenesis and improve coronary reserve in the left ventricle after myocardial infarction. Methods and Results-Bradycardia was induced in rats by administering alinidine via osmotic pumps beginning 1 day after coronary artery ligation. Echocardiographic analysis was conducted before and after treatment. Morphometric analysis was used in perfusion-fixed hearts to document arteriolar and capillary growth. Western blots were used to evaluate growth factor and receptor changes. During the first week of treatment, vascular endothelial growth factor (VEGF), VEGF receptor 1 (Flt-1), and basic fibroblast growth factor proteins were higher in the treated group, whereas VEGF receptor 2 (Flk-1), angiopoietin-1, and angiopoietin-2 were not affected by treatment. After 3 weeks, VEGF protein remained elevated, and bradycardia was associated with a higher capillary length density in the border (40%) and remote (14%) regions and a higher arteriolar length density in the septum (62%), despite a greater increase in left ventricular mass. Although arteriolar length density increased in all size classes, the greatest increase occurred in the smallest (terminal) arterioles. This vascular growth was associated with a 23% greater coronary reserve. Echocardiography revealed a smaller increase in ventricular volume and a greater preservation of ejection fraction in rats treated with bradycardia. Conclusions-Pharmacologic induction of bradycardia enhances vascularity and coronary reserve, preserves function of surviving myocardium, and therefore, is a noninvasive, therapeutic avenue that provides an alternative to gene therapy.

Dedkov, Eduard I., Lance P. Christensen, Robert M. Weiss, and Robert J. Tomanek. Reduction of heart rate by chronic ␤1-adrenoceptor blockade promotes growth of arterioles and preserves coronary perfusion reserve in postinfarcted heart. Am J Physiol Heart Circ Physiol 288: H2684 -H2693, 2005. First published January 28, 2005 doi:10.1152/ajpheart.01047.2004.-Adequate growth of coronary vasculature in the remaining left ventricular (LV) myocardium after myocardial infarction (post-MI) is a crucial factor for myocyte survival and performance. We previously demonstrated that post-MI coronary angiogenesis can be stimulated by bradycardia induced with the ATP-sensitive K ϩ channel antagonist alinidine. In this study, we tested the hypothesis that heart rate reduction with ␤-blockade may also induce coronary growth in the post-MI heart. Transmural MI was induced in 12-mo-old male Sprague-Dawley rats by occlusion of the left anterior descending coronary artery. Bradycardia was induced by administration of the ␤-adrenoceptor blocker atenolol (AT) via drinking water (30 mg/day). Three groups of rats were compared: 1) control/sham (C/SH), 2) MI, and 3) MI ϩ AT. In the MI ϩ AT rats, heart rate was consistently reduced by 25-28% compared with C/SH rats. At 4 wk after left anterior descending coronary ligation, infarct size was similar in MI and MI ϩ AT rats (67.1 and 61.5%, respectively), whereas a greater ventricular hypertrophy occurred in bradycardic rats, as indicated by a higher ventricular weight-to-body weight ratio (3.4 Ϯ 0.1 vs. 2.8 Ϯ 0.1 mg/g in MI rats). Analysis of LV function revealed a smaller drop in ejection fraction in the MI ϩ AT than in the MI group (ϳ24 vs. ϳ35%). Furthermore, in MI ϩ AT rats, maximal coronary conductance and coronary perfusion reserve were significantly improved compared with the MI group. The better myocardial perfusion indexes in MI ϩ AT rats were associated with a greater increase in arteriolar length density than in the MI group. Thus chronic reduction of heart rate induced with ␤-selective blockade promotes growth of coronary arterioles and, thereby, facilitates regional myocardial perfusion in post-MI hearts. myocardial infarction; angiogenesis; coronary circulation; resistance vessels; capillaries A LARGE TRANSMURAL MYOCARDIAL infarction (MI) of the left ventricle (LV) causes the sudden loss of a substantial number of cardiac myocytes, which leads to increased diastolic wall stress and chronic functional overload of the remaining portion of LV myocardium. As a result, the LV undergoes progressive structural remodeling, consisting of thinning and scarring of the infarcted region, chamber dilation, and eccentric hypertrophy of the surviving portion of the LV myocardium (1,27,30).Because scar tissue is not capable of contracting, LV function after MI is entirely dependent on the hypertrophied portion of the surviving LV myocardium. However, to accommodate an increased O 2 demand in the surviving overloaded cardiac myocytes, an adaptation of the vascular bed is necessary. Two basic me...

We compared the effects of heart rate reduction (HRR) by the hyperpolarization-activated pacemaker current (I(f)) channel inhibitor ivabradine (MI+Iva) and the beta(1)-blocker atenolol (MI+Aten) on ventricular remodeling and perfusion after myocardial infarction (MI) in middle-aged (12 mo) Sprague-Dawley rats. Mean HRR was virtually identical in the two treated groups (19%). Four weeks after coronary artery ligation, maximal myocardial perfusion fell in the MI group but was preserved in infarcted rats treated with either Iva or Aten. However, coronary reserve in the remodeled hearts was preserved only with Iva, since Aten treatment elevated baseline perfusion in response to a higher wall stress. The higher maximal perfusion noted in the two treated groups was not due to arteriogenesis or angiogenesis. Plasma levels of angiotensin (ANG) II and myocardial ANG type 1 (AT(1)) receptor and transforming growth factor (TGF)-beta1 were reduced during the first week of treatment by both Iva and Aten. Moreover, treatment also reduced arteriolar perivascular collagen density. Despite these similar effects of Iva and Aten on vascularity and ANG II, Iva, but not Aten, attenuated the decline in ejection fraction and lowered left ventricular (LV) end-diastolic volume (LVEDV)-to-LV mass ratio, determined by echocardiography. In conclusion, 1) Iva has advantages over Aten in postinfarction therapy that are not due to differential effects of the drugs on heart rate, and 2) age limits growth factor upregulation, angiogenesis, and arteriogenesis in the postinfarcted heart.