肺高血圧モデルにおける右心機能および心室間相互作用に対する心拍数抑制効果の検討

背景：β受体阻滞剂改善实验性肺动脉高压(PAH)的双室功能障碍，但心率减慢(HRR)与非变时性β受体阻滞剂的作用尚不清楚。我们用IF电流抑制剂伊夫拉定观察HRR对实验性PAH大鼠双心功能的影响，并与肾上腺素能受体阻滞剂卡维地洛进行比较。方法和结果：大鼠随机分为：1)假手术对照组，2)野百合碱(MCT)PAH组，3)MCT-PAH+伊维拉定组。结果与先前报道的卡维地洛治疗PAH大鼠进行了比较。MCT后2周开始口服伊夫拉定(10 mg/kg/d)和卡维地洛(15 mg/kg/d)，持续3周，直至实验结束。超声心动图在实验前和实验结束时用压力-容量血流动力学进行评估。免疫印迹法检测右、左室肥厚、纤维化及其分子信号转导。尽管右室收缩压显著升高，伊夫拉定仍可降低双室纤维化面积(右室：13.4±6.5vs6.7±2.6%，p&lt；0.001)、转化生长因子β(rv转化生长因子β/3-磷酸甘油醛脱氢酶比值：1.16±0.39vs.0.7±0.54，p&lt；0.05)和结缔组织生长因子(rv CTGF/GAPDH值：0.49±0.06vs0.28±0.12，p&lt；结论：HRR可改善实验性PAH的双室纤维化和功能，不依赖肾上腺素能受体阻滞剂。在PAH中使用阻滞剂调节心率值得进一步研究，作为一种有前景的策略，利用β阻滞剂可以在避免负性肌力抑制的同时受益。

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.