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

Abstract

Background— 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. Methods and Results— 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. Conclusions— 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.

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

“…Despite this, a recent study found that ivabradine did not have beneficial effects in patients with stable coronary artery disease but without heart failure 10 , suggesting that its vasculoprotective effects may be restricted to patients with heart failure. The mechanism for the protective effects of ivabradine has been studied using animal models [11][12][13][14] . The administration of ivabradine reduced experimental atherosclerosis in hyperlipidaemic murine 13 and rabbit models 14 .…”

“…The mechanism for the protective effects of ivabradine has been studied using animal models [11][12][13][14] . The administration of ivabradine reduced experimental atherosclerosis in hyperlipidaemic murine 13 and rabbit models 14 . However, molecular targets of ivabradine have not been identified in vascular cells and the atheroprotective effects of ivabradine are not due to a lipid-lowering effect of ivabradine, since the drug had no effects on cholesterol levels [11][12][13] .…”

Ivabradine therapy and correction of the target organ pathology in patients with ischemic chronic heart failure

“…В исследованиях на животных получены плейо-тропные эффекты ивабрадина -такие, как антиокси-дантный, антиатеросклеротический, улучшение эндотелиальной дисфункции. Так в работе F. Custodis et al установлено, что снижение ЧСС с помощью 6-недельного применения ивабрадина уменьшает выработку маркеров оксидативного стресса, улуч-шает функцию эндотелия и уменьшает размеры ате-росклеротической бляшки у мышей независимо от АД и уровня липидов [26]. M. Baumh kel et al пока-зали, что у мышей на фоне эндотелиальной дисфунк-ции, индуцированной диетой с высоким содержа-нием холестерина, 3-месячная терапия ивабрадином способствует уменьшению размеров атеросклероти-ческих бляшек и улучшению эндотелиальной дис-функции [27].…”

The Apoe-/- Mouse PhysioLab® Platform: A Validated Physiologically-based Mathematical Model of Atherosclerotic Plaque Progression in the Apoe-/- Mouse

“…Their effects are amplified when production of atheroprotective endothelial nitric oxide (NO) is reduced by EC dysfunction. Both increased ROS and reduced endothelial NO [14][15][16][17][18][19] have been implicated in accelerating plaque progression in Apoe -/-mice and are represented in the model.…”