Characterization of right ventricular remodeling and failure in a chronic pulmonary hypertension model
Characterization of right ventricular remodeling and failure in a chronic pulmonary hypertension model
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DOI：
10.1152/ajpheart.00246.2014
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发表时间：
2014-10-15
影响因子：
4.8
通讯作者：
Hajjar, Roger J.
中科院分区：
文献类型：
--
作者：
Aguero, Jaume;Ishikawa, Kiyotake;Hajjar, Roger J.
在肺动脉高压（PH）中，右心室（RV）功能障碍和衰竭是预后不良的主要决定因素。我们的目的是表征慢性 PH 大型动物模型中适应性 RV 重塑和进展为 RV 衰竭过程中 RV 结构和功能的差异。毛细血管后 PH 是通过手术在猪 (n = 21) 中产生的。经过 8 至 14 周的随访后，根据明显心力衰竭 (HF) 的发展情况确定两组：PH-NF（无衰竭，n = 12）和 PH-HF（n = 8）。在两组中，有创血流动力学、压力-容量关系和超声心动图证实肺压和血管阻力显着增加，与 PH 一致。组织学分析还表明两组的远端肺动脉（PA）重塑。舒张功能障碍，由更陡峭的右心室舒张末期压力-容积关系和纵向应变定义，是在没有心力衰竭作为右心室重构早期标志的情况下发现的。两组的 RV 收缩力均增加，PH-NF 动物中保留了 RV-PA 偶联，但 PH-HF 组中 RV-PA 偶联受损。 PH-HF 中存在右心室肥大，尽管有证据表明两个 PH 组中右心室纤维化增加。 PH-HF组RV肌浆网Ca2+-ATPase2a表达减少，内质网应激增加。 PH-HF 患者醛固酮水平也升高。因此，在慢性毛细血管后PH的猪肺静脉带状模型中，RV重塑发生在结构、组织学和分子水平上。舒张功能障碍和纤维化存在于适应性 RV 重塑中，而 RV 衰竭的发生与 RV-PA 解偶联、钙处理缺陷和醛固酮增多症有关。
In pulmonary hypertension (PH), right ventricular (RV) dysfunction and failure is the main determinant of a poor prognosis. We aimed to characterize RV structural and functional differences during adaptive RV remodeling and progression to RV failure in a large animal model of chronic PH. Postcapillary PH was created surgically in swine (n = 21). After an 8- to 14-wk follow-up, two groups were identified based on the development of overt heart failure (HF): PH-NF (nonfailing, n = 12) and PH-HF (n = 8). In both groups, invasive hemodynamics, pressure-volume relationships, and echocardiography confirmed a significant increase in pulmonary pressures and vascular resistance consistent with PH. Histological analysis also demonstrated distal pulmonary arterial (PA) remodeling in both groups. Diastolic dysfunction, defined by a steeper RV end-diastolic pressure-volume relationship and longitudinal strain, was found in the absence of HF as an early marker of RV remodeling. RV contractility was increased in both groups, and RV-PA coupling was preserved in PH-NF animals but impaired in the PH-HF group. RV hypertrophy was present in PH-HF, although there was evidence of increased RV fibrosis in both PH groups. In the PH-HF group, RV sarcoplasmic reticulum Ca2+-ATPase2a expression was decreased, and endoplasmic reticulum stress was increased. Aldosterone levels were also elevated in PH-HF. Thus, in the swine pulmonary vein banding model of chronic postcapillary PH, RV remodeling occurs at the structural, histological, and molecular level. Diastolic dysfunction and fibrosis are present in adaptive RV remodeling, whereas the onset of RV failure is associated with RV-PA uncoupling, defective calcium handling, and hyperaldosteronism.