Ivabradine reduces heart rate while preserving metabolic fluxes and energy status of healthy normoxic working hearts

Abstract

Heart rate reduction (HRR) is an important target in the management of patients with chronic stable angina. Most available drugs for HRR, such as β-blockers, have adverse effects, including on cardiac energy substrate metabolism, a well-recognized determinant of cardiac homeostasis. This study aimed at 1) testing whether HRR by ivabradine (IVA) alters substrate metabolism in the healthy normoxic working heart and 2) comparing the effect of IVA with that of the β-blocker metoprolol (METO). This was assessed using our well-established model of ex vivo mouse heart perfusion in the working mode, which enables concomitant evaluation of myocardial contractility and metabolic fluxes using 13 C-labeled substrates. Hearts were perfused in the absence (controls; n = 10) or presence of IVA (n = 10, 3 μM) with or without atrial pacing to abolish HRR in the IVA group. IVA significantly reduced HR (35 ± 5%) and increased stroke volume (39 ± 9%) while maintaining similar cardiac output, contractility, power, and efficiency. Effects of IVA on HR and stroke volume were reversed by atrial pacing. At the metabolic level, IVA did not impact on substrate selection to citrate formation, rates of glycolysis, or tissue levels of high-energy phosphates. In contrast, METO, at concentrations up to 40 μM, decreased markedly cardiac function (flow: 25 ± 6%; stroke volume: 30 ± 10%; contractility: 31 ± 9%) as well as glycolysis (2.9-fold) but marginally affected HR. Collectively, these results demonstrate that IVA selectively reduces HR while preserving energy substrate metabolism of normoxic healthy working mouse hearts perfused ex vivo, a model that mimics to some extent the denervated transplanted heart. Our results provide the impetus for testing selective HRR by IVA on cardiac substrate metabolism in pathological models.Address for reprint requests and other correspondence: C. Des Rosiers, Laboratory of Intermediary Metabolism, Montreal Heart Institute, Research Center, 5000 Bélanger St., Rm. 5350, Montreal, QC, Canada, H1T 1C8 (christine.des.rosiers@umontreal.ca CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptKeywords substrate metabolism; isolated working heart; ivabradine; β-blockers Heart rate reduction (HRR) is an important target in the management of patients with ischemic heart disease, a major cause of morbidity and mortality in developed countries (for reviews, see Refs. 6 and 45). Given their well-described beneficial effects on cardiovascular outcomes after myocardial infarction and in heart failure, β-blockers remain the first line treatment for many patients with ischemic heart disease (5, 12, 28). However, even new classes of β-blockers exhibit undesirable side effects on cardiac energy substrate metabolism (4, 28), which is now a well-recognized determinant of energy production, redox status, contractile function, ion fluxes, and oxygen consumption as well as hypertrophy development and progression to heart failure (33, 41).Specifically, acute administration of β-blockers to the isolated perfu...

Mouse strain differences in metabolic fluxes and function of ex vivo working hearts

“…All mice had similar body weight and heart wet weight (in grams, heart wet weight: 129S6/SvEvTac, 0.28 Ϯ 0.03; SJL/JCrNTac, 0.25 Ϯ 0.03; C57Bl/6J, 0.28 Ϯ 0.03; and C57Bl/6NCrl, 0.28 Ϯ 0.03; body weight: 129S6/SvEvTac, 25.58 Ϯ 0.40; SJL/JCrNTac, 25.61 Ϯ 0.44; C57Bl/6J, 25.54 Ϯ 0.37; and C57Bl/6NCrl, 25.56 Ϯ 0.54). It is noteworthy that the measured heart wet weights are consistent with our previously published data (26,27,30), but because oedema occurs following ex vivo heart perfusion with a crystalloid perfusion buffer, a factor of 8.9 Ϯ 0.2 (n ϭ 29) had previously been determined for conversion of measured gram wet weight to gram dry weight (41).…”

“…Our previous work with various transgenic mouse models does, however, provide some evidence of differences among commonly used control mouse strains, particularly in the partitioning of exogenous long-chain fatty acids (LCFA) for oxidation and storage between hearts from 129S6/SvEvTac versus various C57Bl/6 or C57Bl/10 substrains (17,18,26,27,30). These results were all obtained in our validated experimental paradigm, namely, ex vivo perfusion in working mode, with concomitant evaluation of myocardial contractility and metabolic fluxes with 13 C-labeled substrates.…”

Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries

“…The underlying mechanism has remained elusive because ivabradine-targets have not been identified in vascular cells and ivabradine did not influence plasma lipid levels 11,13 . Given that ivabradine alters heart rate, stroke volume and coronary perfusion 22 , we tested the hypothesis that ivabradine may exert protective effects of arteries indirectly by altering hemodynamics which has been tightly linked to cardiovascular disease [15][16][17] . Our study demonstrated that ivabradine significantly altered flow in the murine aorta leading to enhanced WSS magnitude at both atheroprone and atheroprotected sites.…”

“…The effects of ivabradine on cardiovascular hemodynamics and physiology partially mimic protection afforded by physical exercise which can also lower resting pulse rate and enhance stroke volume 22 . In clinical studies, exercise at 140-180% above resting heart rate enhanced peak blood flow velocity and increased WSS in the aorta 33,34 .…”

“…VCAM-1) that promote lesions [18][19][20] , whereas high unidirectional WSS induces anti-inflammatory genes such as eNOS 21 . Although ivabradine is known to increase stroke volume and coronary perfusion 22 , its effects on WSS have not been studied. Here we tested the hypothesis that ivabradine protects arteries by enhancing WSS which reduces inflammatory activation of arterial EC.…”