Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, The Netherlands; Cardiovascular Center-laboratory for Experimental Cardiology, Graduate School of Medical Sciences, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, The Netherlands; Cardiovascular Center-laboratory for Experimental Cardiology, Graduate School of Medical Sciences, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
J Mol Cell Cardiol. 2015 Feb;79:244-53. doi: 10.1016/j.yjmcc.2014.11.024. Epub 2014 Dec 5.
Right ventricular failure (RVF) due to pressure load is a major cause of death in congenital heart diseases and pulmonary hypertension. The mechanisms of RVF are unknown. We used an experimental approach based upon clinical signs of RVF to delineate functional and biological processes associated with RVF.
Wistar rats were subjected to a pulmonary artery banding (PAB n=12) or sham surgery (CON, n=7). After 52±5days, 5/12 PAB rats developed clinical symptoms of RVF (inactivity, ruffled fur, dyspnea, ascites) necessitating termination (PAB+CF). We compared these to PAB rats with RVF without clinical symptoms (PAB-). PAB resulted in reduced cardiac output, RV stroke volume, TAPSE, and increased end diastolic pressure (all p<0.05 vs. CON) in all rats, but PAB+CF rats were significantly more affected than PAB-, despite similar pressure load (p=ns). Pressure-volume analysis showed enhanced contractility (end systolic elastance) in PAB- and PAB+CF, but diastolic function (end diastolic elastance, end diastolic pressure) deteriorated especially in PAB+CF. In PAB+CF capillary density was lower than in PAB-. Gene-array analysis revealed downregulation of both fatty acid oxidation and carbohydrate metabolism in PAB+CF.
Chronic PAB led to different degrees of RVF, with half of the rats developing severe clinical symptoms of RVF, associated with progressive deterioration of diastolic function, hypoxia-prone myocardium, increased response to oxidative stress and suppressed myocardial metabolism. This model represents clinical RVF and allows for unraveling of mechanisms involved in the progression from RV adaptation to RV failure and the effect of intervention on these mechanisms.
由压力负荷引起的右心室衰竭（RVF）是先天性心脏病和肺动脉高压患者死亡的主要原因。RVF 的机制尚不清楚。我们采用了一种基于 RVF 临床症状的实验方法，以描绘与 RVF 相关的功能和生物学过程。
Wistar 大鼠接受肺动脉缩窄（PAB，n=12）或假手术（CON，n=7）。52±5 天后，12 只 PAB 大鼠中有 5 只出现 RVF 的临床症状（活动减少、毛发蓬乱、呼吸困难、腹水），需要终止实验（PAB+CF）。我们将这些与没有临床症状的 PAB 大鼠（PAB-）进行了比较。PAB 导致所有大鼠的心输出量、RV 每搏量、TAPSE 和舒张末期压力降低（与 CON 相比，所有 p<0.05），但 PAB+CF 大鼠的影响明显大于 PAB-，尽管压力负荷相似（p=ns）。压力-容积分析显示 PAB-和 PAB+CF 的收缩性（收缩末期弹性）增强，但舒张功能（舒张末期弹性、舒张末期压力）恶化，尤其是在 PAB+CF 中。在 PAB+CF 中毛细血管密度低于 PAB-。基因阵列分析显示，PAB+CF 中脂肪酸氧化和碳水化合物代谢均下调。
慢性 PAB 导致 RVF 程度不同，其中一半大鼠出现严重的 RVF 临床症状，与舒张功能进行性恶化、缺氧性心肌、氧化应激反应增加和心肌代谢抑制有关。该模型代表了临床 RVF，并允许阐明从 RV 适应到 RV 衰竭的进展过程中涉及的机制，以及这些机制的干预效果。
