Department of Biomedical Engineering, University of Wisconsin-Madison , Madison, Wisconsin.
Department of Mechanical Engineering, Colorado State University , Fort Collins, Colorado.
J Appl Physiol (1985). 2018 May 1;124(5):1244-1253. doi: 10.1152/japplphysiol.00725.2017. Epub 2018 Jan 25.
Pulmonary arterial hypertension (PAH) is a rapidly fatal disease in which mortality is due to right ventricular (RV) failure. It is unclear whether RV dysfunction initiates at the organ level or the subcellular level or both. We hypothesized that chronic pressure overload-induced RV dysfunction begins at the organ level with preserved Frank-Starling mechanism in myocytes. To test this hypothesis, we induced PAH with Sugen + hypoxia (HySu) in mice and measured RV whole organ and subcellular functional changes by in vivo pressure-volume measurements and in vitro trabeculae length-tension measurements, respectively, at multiple time points for up to 56 days. We observed progressive changes in RV function at the organ level: in contrast to early PAH (14-day HySu), in late PAH (56-day HySu) ejection fraction and ventricular-vascular coupling were decreased. At the subcellular level, direct measurements of myofilament contraction showed that RV contractile force was similarly increased at any stage of PAH development. Moreover, cross-bridge kinetics were not changed and length dependence of force development (Frank-Starling relation) were not different from baseline in any PAH group. Histological examinations confirmed increased cardiomyocyte cross-sectional area and decreased von Willebrand factor expression in RVs with PAH. In summary, RV dysfunction developed at the organ level with preserved Frank-Starling mechanism in myofilaments, and these results provide novel insight into the development of RV dysfunction, which is critical to understanding the mechanisms of RV failure. NEW & NOTEWORTHY A multiscale investigation of pulmonary artery pressure overload in mice showed time-dependent organ-level right ventricular (RV) dysfunction with preserved Frank-Starling relations in myofilaments. Our findings provide novel insight into the development of RV dysfunction, which is critical to understanding mechanisms of RV failure.
肺动脉高压（PAH）是一种迅速致命的疾病，其死亡率归因于右心室（RV）衰竭。尚不清楚 RV 功能障碍是从器官水平还是亚细胞水平开始，或者两者兼而有之。我们假设慢性压力超负荷引起的 RV 功能障碍首先从器官水平开始，心肌细胞中的 Frank-Starling 机制保持完好。为了验证这一假设，我们在小鼠中用苏根（Sugen）加缺氧（HySu）诱导 PAH，并通过体内压力-容积测量和体外小梁长度-张力测量，分别在多达 56 天的多个时间点测量 RV 整体器官和亚细胞功能变化。我们观察到 RV 功能在器官水平上的进行性变化：与早期 PAH（14 天 HySu）相比，晚期 PAH（56 天 HySu）的射血分数和心室-血管耦联降低。在亚细胞水平上，对肌丝收缩的直接测量表明，在 PAH 发展的任何阶段，RV 收缩力均相似增加。此外，在任何 PAH 组中，横桥动力学均未改变，力发展的长度依赖性（Frank-Starling 关系）与基线无差异。组织学检查证实，PAH 的 RV 中肌细胞横截面积增加，血管性血友病因子表达减少。总之，RV 功能障碍首先从器官水平开始，肌丝中的 Frank-Starling 机制保持完好，这些结果为 RV 功能障碍的发展提供了新的见解，这对于理解 RV 衰竭的机制至关重要。
