Abstract 477: Selective Heart Rate Reduction Via Inhibition Of The I F -current Prevents Atherosclerosis And Improves Endothelial And Erectile Function In Apoe −/− Mice

Introduction : Elevated resting heart rate (HR) is associated with increased risk for cardiovascular morbidity and mortality. Erectile dysfunction is associated with endothelial dysfunction and atherosclerosis due to similar risk factors. We hypothesized that HR reduction may influence endothelial- and erectile function and tested the effects of the I f -current inhibitor ivabradine in ApoE−/− mice. Methods and Results: Male ApoE−/− mice fed a high-cholesterol diet were treated with ivabradine (iva) (10 mg/kg/d p.o.) or vehicle (n=10 per group) for 6 weeks. Treatment with ivabradine reduced HR by 13.4% (iva 472±9 bpm vs vehicle 545±11 bpm, p<0.01). High cholesterol feeding led to severe atherosclerosis in the aortic sinus and the aorta. Ivabradine reduced atherosclerotic plaque size in the aortic root from 32±4% to 18±2% and in the ascending aorta from 26±4% to 7±1% (p<0,05). Endothelium dependent relaxation of aortic rings and corpora cavernosa to carbachol was significantly improved in ivabradine fed ApoE−/− mice compared to controls (p<0.01). Aortic eNOS mRNA expression, quantified by real time PCR with the TaqMan system was upregulated to 156±11% (p<0.05) in aortic rings after treatment with ivabradine. HR reduction led to attenuation of NADPH oxidase activity to 48±6% as measured by a lucigenin-enhanced chemiluminescence assay and decreased L-012 chemiluminescence to 24±9% (both p<0.05). Lipidperoxidation was reduced to 65±8% in the vasculature of the iva group compared to vehicle treatment (p<0.05). DHE fluorescence microscopy in aortic sections detected reduction of ROS release to 62±4% in ivabradine treated mice (p<0.01). Conclusions : Selective HR reduction improves endothelial as well as erectile function and reduces atherosclerotic plaque formation in ApoE−/− mice. Those functional effects are mediated by decreased oxidative stress and upregulation of endothelial NOS (eNOS). These results identify HR as a risk factor for vascular disease and support the importance of heart rate reduction in vascular prevention.