| 研究実績の概要 |
Background: Beta-blockers improve biventricular dysfunction in experimental pulmonary arterial hypertension (PAH), but heart rate reduction (HRR) versus non-chronotropic beta-blocker effects is unknown. We investigated HRR, using the If current inhibitor ivabradine, on biventricular function in experimental PAH comparing results to the adrenergic-receptor blocker carvedilol.
Methods and Results: Rats were randomized to: 1) Sham controls, 2) monocrotaline (MCT) PAH, 3) MCT-PAH + ivabradine. Results were compared to previously reported carvedilol treated PAH rats. Oral ivabradine (10mg/kg/d) and carvedilol (15mg/kg/d) were started 2-weeks after MCT and continued for 3-weeks until terminal experiment. Echocardiography was assessed at baseline and at terminal experiment with pressure-volume hemodynamics. Right (RV) and left ventricular hypertrophy, fibrosis and its molecular signaling were analyzed by western blots. Despite similar severely elevated RV systolic pressures, ivabradine reduced biventricular fibrosis area (RV: 13.4±6.5 vs 6.7±2.6 %, p<0.001), transforming growth factor β (TGFβ) (RV TGFβ/ glyceraldehyde 3-phosphate dehydrogenase (GAPDH) ratio; 1.16±0.39 vs. 0.7±0.54, p<0.05) and connective tissue growth factor (CTGF) (RV CTGF/GAPDH ratio: 0.49±0.06 vs 0.28±0.12, p<0.05).
Conclusions: HRR improves biventricular fibrosis and function in experimental PAH independent of adrenergic receptor blockade. If blockers to modulate heart rate in PAH warrants further study as a promising strategy utilizing beta blockers benefits while avoiding negative inotrope.
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