Chronic Heart Rate Reduction Facilitates Cardiomyocyte Survival After Myocardial Infarction

Abstract

Chronic heart rate reduction (HRR) therapy following myocardial infarction, using either the pure HRR agent ivabradine or the b-blocker atenolol, has been shown to preserve maximal coronary perfusion, via reduction of perivascular collagen and a decrease in renin-angiotensin system activation. In addition ivabradine, but not atenolol, treatment attenuated the decline in ejection fraction and decreased left ventricular wall stress. In this study, we tested the hypothesis that cell survival within the infarct region was enhanced by these two pharmacological agents. Four weeks after ligating the left anterior descending coronary artery, the percentage of the LV that contained the infarct was similar in the untreated (MI) rats and those chronically treated with ivabradine (MI þ IVA) or atenolol (MI þ ATEN). However, the mean thickness (mm) of the ventricular wall containing the scar was significantly greater in the MI þ IVA, 1.54 (P 0.01) and the MI þ ATEN 1.32, compared to 1.1 in the MI group, due to a 2-fold greater area of surviving cardiomyocytes (P 0.01) in the treated rats compared to the untreated group. Regions of cell survival were usually in the subepicardium, with cardiomyocytes surrounding veins or venules. However, some hearts displayed surviving cells along the endocardium. These data suggest that HRR by either ivabradine or atenolol facilitates a more favorable O2 microenvironment via improved venous flow and decreased O2 demand. We conclude that chronic HRR by these agents may serve to limit infarct expansion and wall thinning and may serve to reduce the potential for ventricular rupture. Anat Rec,

Postinfarction healing dynamics in the mechanically unloaded rat left ventricle

“…In the granulation phase of infarct healing, our results are in agreement with previous work showing that heart rate reduction could enhance postinfarction angiogenesis by upregulating proangiogenic factors (28,30,56). Moreover, pharmacologically induced chronic heart rate reduction could give rise to a dramatic improvement of infarct size and myocardial survival in rats (55). Taken together, from the very beginning until the chronic phase after MI, LV mechanical unloading and heart rate reduction could be the key mechanisms underlying the massive myocardial salvage observed in this work.…”

Dose-Dependent Protective Effect of Ivabradine against Ischemia-Reperfusion-Induced Renal Injury in Rats

“…They also concluded that these beneficial effects resulted in the prevention of endothelial dysfunction. Recently, Zhang et al [37] declared that heart rate reduction therapy using ivabradine following myocardial infarction has been shown to preserve maximal coronary perfusion via the reduction of perivascular collagen and to decrease renin-angiotensin system activation. The researchers concluded that heart rate reduction by ivabradine facilitates a more favorable O 2 microenvironment via improved venous flow and decreased O 2 demand.…”

Structural Composition of Myocardial Infarction Scar in Middle-aged Male and Female Rats

“…However, young or even adult rodents are not suitable as models of myocardial infarction in humans, because myocardial infarctions occur primarily in middle-aged and older individuals (Bairey Merz et al 2006). The importance of using older animals in MI experiments, especially in the case of small rodents, has been compelled by the findings of studies published earlier by our group (Christensen et al 2009;Dedkov et al 2005;Dedkov, Zheng, et al 2007;Zhang et al 2010) and other laboratories (Kranz et al 1975;Wexler 1978;Raya et al 1997;Bujak et al 2008;Yang et al 2008), which In all scars, densely packed collagen fibers were noticed along the endocardial and epicardial surfaces, including subendocardial and subepicardial regions with surviving cardiac myocytes (CM) (arrows), in areas around the residual coronary arteries (A), and in the midwall layer where they occasionally embedded the remnants of mummified dead CM (arrowheads). On the other hand, loosely packed collagen fibers were dispersed through the rest of the scar.…”

“…Some of these scar components have been shown to undergo a dynamic reorganization in response to ongoing LV remodeling (Whittaker 1995;Sun and Weber 2000;Sun et al 2002;van den Borne et al 2010). Surprisingly, in the previous in vivo studies that used either male or female animals, only a few used quantitative methods to examine the structural composition of the post-MI scars (Boyle and Weisman 1993;Hayakawa et al 2003;Virag and Murry 2003;Lichtenauer et al 2011;Zhang et al 2010).…”