Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen

Abstract

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...

Heart Rate Reduction With Ivabradine Protects Against Left Ventricular Remodeling by Attenuating Infarct Expansion and Preserving Remote‐Zone Contractile Function and Synchrony in a Mouse Model of Reperfused Myocardial Infarction

“…In this study, ivabradine was shown to reduce heart rate in a mouse model of reperfused MI to a degree similar to previously studied animal models 15, 17. We also believe this to be the first report of mouse echocardiography performed after lateral thoracotomy via the third intercostal space.…”

“…These studies have also shown post‐MI ivabradine treatment to attenuate increases in LV end‐diastolic pressure17 and reduce markers of neuroendocrine activation 14. These effects are likely a combination of the direct effects of ivabradine treatment as well as downstream effects of improved remodeling.…”

“…While this study focused on in vivo, functional parameters of cardiac remodeling, previous studies have demonstrated reduced interstitial and periarteriolar collagen density,13, 17 as well as improved cardiac calcium handling15, 16 and preserved energy metabolism14 in ivabradine‐treated animals after MI. These studies have also shown post‐MI ivabradine treatment to attenuate increases in LV end‐diastolic pressure17 and reduce markers of neuroendocrine activation 14.…”

Protective Effects of Ivabradine (Alone and Combined With Atenolol or Enalapril) on Experimentally-Induced Acute Myocardial Infarction in Albino Rats

“…Also, serum levels of CK-MB, hs-CRP and cTnI and infarct size % in this group were significantly lower than that of the control MI group. These results are consistent with that obtained by Dedkov et al [40] , Dominguez-Rodriguez et al [41] , Heusch et al [42] , Monnet et al [43] and Vilaine et al [44] . The mechanism of the cardioprotective effect of ivabradine could be self-explained in the present study by its significant HR reduction, significant decrease of the apoptotic factor Bax and significant increase of the antioxidant markers SOD& GSH.…”

The Funny Current in Cardiac Non-Pacemaker Cells: Functional Role and Pharmacological Modulation

“…Studies were performed in animal models to assess whether selective pharmacological intervention able to control heart rate were able to revert and/or ameliorate functional remodeling of ventricular tissue in cardiac diseases. In a rat model of myocardial infarction it was documented that reduction of heart rate with a www.intechopen.com selective bradycardic agent (ivabradine, see below for further details) is able to improve maximal myocardial perfusion and coronary reserve (Dedkov et al, 2007). On the basis of this evidence, we tested whether heart rate reduction with ivabradine in post-infarcted rats could counteract the electrophysiological remodeling of ventricular myocytes.…”