The potential benefit of heart rate reduction (HRR), independent of β-blockade, on right ventricular (RV) function in pulmonary hypertension (PH) remains undecided. We studied HRR effects on RV fibrosis and function in PH and RV pressure-loading models. Adult rats were randomized to 1) sham controls, 2) monocrotaline (MCT)-induced PH, 3) SU5416 + hypoxia (SUHX)-induced PH, or 4) pulmonary artery banding (PAB). Ivabradine (IVA) (10 mg/kg/d) was administered from 2 weeks after PH induction or PAB. Exercise tolerance, echocardiography, and pressure–volume hemodynamics were obtained at a terminal experiment 3 weeks later. RV myocardial samples were analyzed for putative mechanisms of HRR effects through fibrosis, profibrotic molecular signaling, and Ca⁺⁺ handling. The effects of IVA versus carvedilol on human induced pluripotent stem cell–derived cardiomyocytes beat rate and relaxation properties were evaluated in vitro. Despite unabated severely elevated RV systolic pressures, IVA improved RV systolic and diastolic function, profibrotic signaling, and RV fibrosis in PH/PAB rats. RV systolic-elastance (control, 121 ± 116; MCT, 49 ± 36 vs. MCT+IVA, 120 ± 54; PAB, 70 ± 20 vs. PAB+IVA, 168 ± 76; SUHX, 86 ± 56 vs. SUHX +IVA, 218 ± 111; all P < 0.05), the time constant of RV relaxation, echo indices of RV function, and fibrosis (fibrosis: control, 4.6 ± 1%; MCT, 13.4 ± 6.5 vs. MCT+IVA, 6.7 ± 2.6%; PAB, 11.4 ± 4.5 vs. PAB+IVA, 6.4 ± 5.1%; SUHX, 10 ± 4.6 vs. SUHX+IVA, 3.9 ± 2.2%; all P < 0.001) were improved by IVA versus controls. IVA had a dose–response effect on induced pluripotent stem cell–derived cardiomyocytes beat rate by delaying Ca⁺⁺ loss from the cytoplasm. In experimental PH or RV pressure loading, HRR improves RV fibrosis, function, and exercise endurance independent of β-blockade. The balance between adverse tachycardia and bradycardia requires further study, but judicious HRR may provide a promising strategy to improve RV function in clinical PH.

与β受体阻滞无关的心率降低（HRR）对肺动脉高压（PH）的右心室（RV）功能的潜在益处尚未确定。我们在PH和RV压力负荷模型中研究了HRR对RV纤维化和功能的影响。将成年大鼠随机分为1）假对照组，2）单芥子碱（MCT）诱导的PH，3）SU5416 +缺氧（SUHX）诱导的PH或4）肺动脉束带（PAB）。PH诱导或PAB后2周开始给予伊伐布雷定（IVA）（10 mg / kg / d）。3周后的最终实验获得了运动耐力，超声心动图和压力-体积血流动力学。通过纤维化，纤维化分子信号转导和Ca ⁺⁺处理，分析了RV心肌样品的HRR影响的推定机制。在体外评估了IVA和卡维地洛对人诱导的多能干细胞衍生的心肌细胞搏动率和舒张特性的影响。尽管RV收缩压持续升高，但IVA改善了PH / PAB大鼠的RV收缩和舒张功能，纤维化信号和RV纤维化。RV收缩期弹性（对照，121±116; MCT，49±36 vs. MCT + IVA，120±54; PAB，70±20 vs.PAB + IVA，168±76; SUHX，86±56 vs.SUHX + IVA，218±111；所有P  <0.05），RV松弛的时间常数，RV功能的回声指数和纤维化（纤维化：对照，4.6±1％； MCT，13.4±6.5与MCT + IVA，6.7± 2.6％; PAB，相对于PAB + IVA为6.4±5.1％，为11.4±4.5; SUHX，相对于SUHX + IVA为3.9±2.2％，10±4.6;所有P  <0.001）与对照相比均得到改善。IVA通过延缓Ca ⁺⁺对诱导的多能干细胞衍生的心肌细胞搏动率具有剂量反应作用从细胞质流失。在实验性PH或RV压力负荷中，HRR改善了RV纤维化，功能和运动耐力，而与β受体阻滞无关。不良性心动过速和心动过缓之间的平衡需要进一步研究，但明智的HRR可能为改善临床PH中的RV功能提供有希望的策略。