Division of Cardiology, Labatt Family Heart Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
Division of Cardiology, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada.
J Appl Physiol (1985). 2020 Aug 1;129(2):238-246. doi: 10.1152/japplphysiol.00148.2020. Epub 2020 Jul 9.
Right ventricular (RV) dysfunction determines mortality in patients with pulmonary arterial hypertension (PAH) and RV pressure loading. Experimental models commonly use Sugen hypoxia (SuHx)-induced PAH, monocrotaline (MCT)-induced PAH, or pulmonary artery banding (PAB). Because PAH models cannot interrogate RV effects or therapies independent of pulmonary vascular effects, we aimed to compare RV function and fibrosis in experimental PAB vs. PAH. Thirty rats were randomized to either sham controls, PAB, SuHx-, or MCT-induced PAH. RV pressures and function were assessed by high-fidelity pressure-tipped catheters and by echocardiography. RV myocyte hypertrophy, fibrosis, and capillary density were quantified from hematoxylin-eosin, picrosirius red-stained, and CD31-immunostained RV sections, respectively. RV pressures and the RV-to-left ventricular pressure ratio were significantly increased in all three groups to a similar degree (PAB 65 ± 17 mmHg, SuHx 72 ± 16 mmHg, and MCT 70 ± 12 mmHg) vs. controls (23 ± 2 mmHg, all < 0.01). RV dilatation, hypertrophy, and fibrosis were similarly increased, and capillary density decreased, in the three models (RV fibrosis; PAB 13.3 ± 3.6%, SuHx 9.8 ± 3.0% and MCT 10.9 ± 2.4% vs control 5.5 ± 1.1%, all < 0.05). RV function was similarly decreased in all models vs. controls. We observed comparable RV dilatation, hypertrophy, systolic and diastolic dysfunction, fibrosis, and capillary rarefaction in rat models of PAB, SuHx-, and MCT-induced PAH. These results suggest that PAB, when sufficiently severe, induces features of maladaptive RV remodeling and can be used to investigate RV pathophysiology and therapy effects independent of pulmonary vascular resistance. Although animal models of pulmonary arterial hypertension and pressure loading are important to study right ventricular (RV) pathophysiology, pulmonary arterial hypertension models cannot interrogate RV responses independent of pulmonary vascular effects. Comparing three commonly used rat models under similar elevated RV pressure, we found that all models resulted in comparable maladaptive RV remodeling and dysfunction. Thus, these findings suggest that the pulmonary artery banding model can be used to investigate mechanisms of RV dysfunction in RV pressure overload and the effect of potential therapies.
右心室（RV）功能障碍决定了肺动脉高压（PAH）和 RV 压力负荷患者的死亡率。实验模型通常使用苏根缺氧（SuHx）诱导的 PAH、单克隆毒素（MCT）诱导的 PAH 或肺动脉结扎（PAB）。由于 PAH 模型不能在不影响肺血管效应的情况下探究 RV 效应或治疗方法，我们旨在比较实验性 PAB 与 PAH 中的 RV 功能和纤维化。30 只大鼠随机分为假手术对照组、PAB 组、SuHx 诱导的 PAH 组和 MCT 诱导的 PAH 组。通过高保真压力尖端导管和超声心动图评估 RV 压力和功能。分别从苏木精-伊红、苦味酸-天狼星红染色和 CD31 免疫染色的 RV 切片中量化 RV 心肌细胞肥大、纤维化和毛细血管密度。与对照组（23 ± 2 mmHg，均<0.01）相比，所有三组的 RV 压力和 RV 与左心室压力比值均显著升高至相似程度（PAB 65 ± 17 mmHg，SuHx 72 ± 16 mmHg 和 MCT 70 ± 12 mmHg）。RV 扩张、肥大和纤维化在三种模型中均增加，毛细血管密度降低（RV 纤维化；PAB 13.3 ± 3.6%，SuHx 9.8 ± 3.0%和 MCT 10.9 ± 2.4%与对照组 5.5 ± 1.1%，均<0.05）。与对照组相比，所有模型的 RV 功能均降低。我们观察到 PAB、SuHx 和 MCT 诱导的 PAH 大鼠模型中 RV 扩张、肥大、收缩和舒张功能障碍、纤维化和毛细血管稀疏具有相似性。这些结果表明，当 PAB 足够严重时，会引起适应性 RV 重构的特征，可用于研究 RV 病理生理学和治疗效果，而不受肺血管阻力的影响。虽然肺动脉高压和压力负荷的动物模型对于研究右心室（RV）病理生理学非常重要，但肺动脉高压模型不能在不影响肺血管效应的情况下探究 RV 对治疗的反应。在相似升高的 RV 压力下比较三种常用的大鼠模型，我们发现所有模型均导致类似的适应性 RV 重构和功能障碍。因此，这些发现表明，肺动脉结扎模型可用于研究 RV 压力超负荷和潜在治疗方法对 RV 功能障碍的机制。
