Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice

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 center dot kg(-1) center dot 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 center dot kg(-1) center dot 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.