Heart Rate Reduction by Ivabradine Reduces Oxidative Stress, Improves Endothelial Function, and Prevents Atherosclerosis in Apolipoprotein E-Deficient Mice

Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, 66424 Homburg/Saar, Germany.
Circulation (Impact Factor: 14.43). 06/2008; 117(18):2377-87. DOI: 10.1161/CIRCULATIONAHA.107.746537
Source: PubMed


Elevated heart rate is associated with increased cardiovascular morbidity. We hypothesized that selective heart rate reduction may influence endothelial function and atherogenesis and tested the effects of the I(f) current inhibitor ivabradine in apolipoprotein E-deficient mice.
Male apolipoprotein E-deficient mice fed a high-cholesterol diet were treated with ivabradine (10 mg . kg(-1) . d(-1)) or vehicle for 6 weeks (n=10 per group). Ivabradine reduced heart rate by 13.4% (472+/-9 versus 545+/-11 bpm; P<0.01) but did not alter blood pressure or lipid levels. Endothelium-dependent relaxation of aortic rings was significantly improved in ivabradine-fed animals (P<0.01). Ivabradine decreased atherosclerotic plaque size in the aortic root by >40% and in the ascending aorta by >70% (P<0.05). Heart rate reduction by ivabradine had no effect on the number of endothelial progenitor cells and did not alter aortic endothelial nitric oxide synthase, phosphorylated Akt, vascular cell adhesion molecule-1, or intercellular adhesion molecule-1 expression but decreased monocyte chemotactic protein-1 mRNA and exerted potent antioxidative effects. Ivabradine reduced vascular NADPH oxidase activity to 48+/-6% and decreased markers of superoxide production and lipid peroxidation in the aortic wall (P<0.05). The in vivo effects of ivabradine were absent at a dose that did not lower heart rate, in aortic rings treated ex vivo, and in cultured vascular cells. In contrast to ivabradine, treatment with hydralazine (25 mg . kg(-1) . d(-1) for 6 weeks) reduced blood pressure (-15%) but increased heart rate (37%) and did not improve endothelial function, atherosclerosis, or oxidative stress.
Selective heart rate reduction with ivabradine decreases markers of vascular oxidative stress, improves endothelial function, and reduces atherosclerotic plaque formation in apolipoprotein E-deficient mice.

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    • "Preclinical data provide evidence that a lower heart rate improves endothelial function , in part , by influencing the shear experienced by the endothelium ( Himburg et al . 2007 ; Custodis et al . 2008 ) . The interactions among heart rate , shear and endothelial function are very complex and difficult to discern in humans . To our knowledge , this is the first study to demonstrate an association between resting heart rate and both vascular endothelial function and shear rate in healthy human subjects . Flow - mediated dilation was fo"
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    ABSTRACT: Preclinical data have demonstrated that heart rate (HR) can directly impact vascular endothelial function, in part, through a shear stress mechanism. This study sought to explore, in humans, the associations between resting heart rate and both shear and endothelial function assessed by flow-mediated dilation (FMD). The brachial artery FMD test was performed in 31 apparently healthy volunteers. Basal (B) and hyperemic (H) shear were quantified two ways using data from the FMD test: the traditional cumulative shear area under the curve up until peak dilation (Shearcum) method, and our novel method of shear summation (Shearsum), which accounts for HR by summing each individual cardiac cycle shear up until peak dilation. Data were grouped by tertiles based on resting HR: low (LHR = 43 – 56 bpm; n = 10), middle (MHR = 58 – 68 bpm; n = 11), and high (HHR = 69–77; n = 10), respectively. Within the LHR group, both B-Shearcum and H-Shearcum were significantly higher (p<0.001) than B-Shearsum and H-Shearsum, respectively, whereas B-Shearcum and H-Shearcum were significantly lower (p<0.001) than B-Shearsum and H-Shearsum in the HHR group. FMD in the LHR group (8.8±0.8%) was significantly greater than both the MHR (5.5±0.8%; p = 0.009) and the HHR group (5.9±0.8%; p = 0.024). These findings demonstrate the existence of a relationship between heart rate and both shear and endothelial function in humans. Moreover, these findings have implications for considering heart rate as an important physiological variable when quantifying shear and performing the FMD test.This article is protected by copyright. All rights reserved
    Experimental physiology 07/2014; 99(10). DOI:10.1113/expphysiol.2014.080960 · 2.67 Impact Factor
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    • "Animal models involving apolipoprotein E knockout mice fed a cholesterol-rich diet showed that ivabradine demonstrated such a protective action.23 This reduction may go beyond heart rate reduction (HRR) as demonstrated by Custodis et al23 in their animal model: ivabradine administration reduced oxidative stress by reducing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, superoxide production, and lipid peroxidation, although the mechanisms are still not well understood. These data were confirmed in several human studies.18,24–34 "
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    ABSTRACT: Elevated heart rate could negatively influence cardiovascular risk in the general population. It can induce and promote the atherosclerotic process by means of several mechanisms involving endothelial shear stress and biochemical activities. Furthermore, elevated heart rate can directly increase heart ischemic conditions because of its skill in unbalancing demand/supply of oxygen and decreasing the diastolic period. Thus, many pharmacological treatments have been proposed in order to reduce heart rate and ameliorate the cardiovascular risk profile of individuals, especially those suffering from coronary artery diseases (CAD) and chronic heart failure (CHF). Ivabradine is the first pure heart rate reductive drug approved and currently used in humans, created in order to selectively reduce sinus node function and to overcome the many side effects of similar pharmacological tools (ie, β-blockers or calcium channel antagonists). The aim of our review is to evaluate the role and the safety of this molecule on CAD and CHF therapeutic strategies.
    Drug Design, Development and Therapy 06/2014; 8:689-700. DOI:10.2147/DDDT.S60591 · 3.03 Impact Factor
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    • "In addition, experimental and clinical evidence indicates that an increased HR contributes to the pathogenesis of atherosclerosis. Oxidative stress, expanded levels of low shear-stress periods and increased mechanical burden are discussed as underlying mechanisms [8-10]. There are some clues that the HR modulates the endothelial function as well; however, results are controversial. "
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    ABSTRACT: Experimental data suggests that exclusive heart rate reduction with ivabradine is associated with the amelioration of the endothelial function. Since it is presently unknown whether this also applies to humans, the aim of this pilot study was to investigate whether heart rate reduction with ivabradine modulates the endothelial function in humans with an established coronary heart disease. Using high-sensitivity ultrasound, we analysed the flow-mediated (FMD) and nitro-mediated dilation (NMD) of the brachial artery in 25 patients (62.9 +/- 8.4 years) with a stable coronary heart disease and a resting heart rate of >=70 beats per minute (bpm). To assess acute effects, measurements were performed before and 4 hours after the first intake of ivabradine 7.5 mg. Sustained effects of an ivabradine therapy (5 mg to 7.5 mg twice daily) were investigated after 4 weeks. We found a significant decrease in heart rate, both 4 hours after the intake of 7.5 mg of ivabradine (median -8 [interquartile range (IQR) -14 to -4] bpm) and after 4 weeks of twice daily intake (median -10 [IQR-17 to -5] bpm) (p < 0.05). However, the FMD did not change significantly: neither after first dose of ivabradine nor after sustained therapy (baseline FMD: median 5.0 [IQR 2.4 to 7.9]%; FMD 4 hours after 7.5 mg of ivabradine: median 4.9 [IQR 2.7 to 9.8]%; FMD after 4 weeks of ivabradine therapy: median 6.1 [IQR 4.3 to 8.2]%). No significant changes of the NMD were observed. In regression analysis, the heart rate and FMD did not correlated, irrespective of the ivabradine intake (r2 = 0.086). In conclusion, in our study heart rate reduction through ivabradine does not improve the endothelial function in patients with a stable coronary heart disease. Moreover, we found no correlation between the heart rate and the endothelial function.
    Cardiovascular Ultrasound 01/2014; 12(1):5. DOI:10.1186/1476-7120-12-5 · 1.34 Impact Factor
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