Neto-Neves Evandro M, Frump Andrea L, Vayl Alexandra, Kline Jeffrey A, Lahm Tim
Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
Department of Medicine, Division of Pulmonary, Critical Care, Occupational and Sleep Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
Physiol Rep. 2017 Oct;5(19). doi: 10.14814/phy2.13438. Epub 2017 Oct 16.
Although extensively used for the study of left ventricular function, limited experience exists with the isolated heart model in the evaluation of right ventricular (RV) function. In particular, no published experience exists with this tool in sugen/hypoxia-induced pulmonary hypertension (SuHx-PH), a frequently used model of severe and progressive PH We sought to characterize markers of RV contractile and diastolic function in SuHx-PH and to establish their relationship with markers of maladaptive RV remodeling. Hearts were excised from anesthetized Sprague Dawley rats with or without SuHx-PH and perfused via the aorta using a Langendorff preparation. We explored the Frank-Starling relationship of RV function (RV developed pressure, d/d, and d/d; all normalized to RV mass) by increasing RV end-diastolic pressure (RVEDP) from 0 to 40 mmHg. Functional studies were complemented by quantification of RV pro-apoptotic signaling (bcl2/bax), procontractile signaling (apelin), and stress response signaling (p38MAPK activation). Pearson's correlation analysis was performed for functional and biochemical parameters. SuHx-RVs exhibited severe RV dysfunction with marked hypertrophy and decreased echocardiographic cardiac output. For any given RVEDP, SuHx-RVs demonstrated less developed pressure and lower d/d, as well as less pronounced d/d, suggestive of decreased contractile and diastolic function. SuHx-RVs exhibited decreased bcl2/bax ratios, apelin expression, and p38MAPK activation. Bcl2/bax and apelin RNA abundance correlated positively with RV developed pressure and d/d and negatively with d/d p38MAPK activation correlated positively with RV developed pressure. We conclude that SuHx-RVs exhibit severe contractile and diastolic dysfunction. Increased pro-apoptotic signaling and attenuated procontractile and stress response signaling may contribute to these functional alterations.
尽管离体心脏模型在左心室功能研究中被广泛应用，但在评估右心室（RV）功能方面的经验有限。特别是，在常用的严重进行性肺动脉高压（SuHx-PH）模型中，尚无关于该工具的公开经验。我们试图表征SuHx-PH中右心室收缩和舒张功能的标志物，并确定它们与右心室适应性不良重塑标志物的关系。从有或无SuHx-PH的麻醉Sprague Dawley大鼠中取出心脏，使用Langendorff装置通过主动脉进行灌注。我们通过将右心室舒张末期压力（RVEDP）从0增加到40 mmHg来探索右心室功能的Frank-Starling关系（右心室发育压力、d/d和d/d；均相对于右心室质量进行归一化）。功能研究通过对右心室促凋亡信号（bcl2/bax）、促收缩信号（apelin）和应激反应信号（p38MAPK激活）的定量进行补充。对功能和生化参数进行Pearson相关分析。SuHx-PH组右心室表现出严重的右心室功能障碍，伴有明显的肥厚和超声心动图心输出量降低。对于任何给定的RVEDP，SuHx-PH组右心室显示出较低的发育压力和较低的d/d，以及不太明显的d/d，提示收缩和舒张功能降低。SuHx-PH组右心室表现出bcl2/bax比值、apelin表达和p38MAPK激活降低。Bcl2/bax和apelin RNA丰度与右心室发育压力和d/d呈正相关，与d/d呈负相关；p38MAPK激活与右心室发育压力呈正相关。我们得出结论，SuHx-PH组右心室表现出严重的收缩和舒张功能障碍。促凋亡信号增加以及促收缩和应激反应信号减弱可能导致这些功能改变。
