Background

Electrophysiological (EP) properties have been studied mainly in the monocrotaline model of pulmonary arterial hypertension (PAH). Findings are confounded by major extrapulmonary toxicities, which preclude the ability to draw definitive conclusions regarding the role of PAH per se in EP remodeling.

Objective

The purpose of this study was to investigate the EP substrate and arrhythmic vulnerability of a new model of PAH that avoids extracardiopulmonary toxicities.

Methods

Sprague-Dawley rats underwent left pneumonectomy (Pn) followed by injection of the vascular endothelial growth factor inhibitor Sugen-5416 (Su/Pn). Five weeks later, cardiac magnetic resonance imaging was performed in vivo, optical action potential (AP) mapping ex vivo, and molecular analyses in vitro.

Results

Su/Pn rats exhibited right ventricular (RV) hypertrophy and were highly prone to pacing-induced ventricular tachycardia/fibrillation (VT/VF). Underlying this susceptibility was disproportionate RV-sided prolongation of AP duration, which promoted formation of right-sided AP alternans at physiological rates. While propagation was impaired at all rates in Su/Pn rats, the extent of conduction slowing was most severe immediately before the emergence of interventricular lines of block and onset of VT/VF. Measurement of the cardiac wavelength revealed a decrease in Su/Pn relative to control. Nav1.5 and total connexin 43 expression was not altered, while connexin 43 phosphorylation was decreased in PAH. Col1a1 and Col3a1 transcripts were upregulated coinciding with myocardial fibrosis. Once generated, VT/VF was sustained by multiple reentrant circuits with a lower frequency of RV activation due to wavebreak formation.

Conclusion

In this pure model of PAH, we document RV-predominant remodeling that promotes multiwavelet reentry underlying VT. The Su/Pn model represents a severe form of PAH that allows the study of EP properties without the confounding influence of extrapulmonary toxicity.

中文翻译：

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纯肺动脉高压模型中的右主导电重构促进折返性心律失常

 背景

主要在肺动脉高压（PAH）的野百合碱模型中研究了电生理（EP）特性。研究结果因主要的肺外毒性而令人困惑，这使得无法就 PAH 本身在 EP 重塑中的作用得出明确的结论。

 客观的

本研究的目的是研究避免心肺毒性的新型 PAH 模型的 EP 底物和心律失常脆弱性。

 方法

Sprague-Dawley 大鼠接受左肺切除术 (Pn)，然后注射血管内皮生长因子抑制剂 Sugen-5416 (Su/Pn)。五周后，进行了体内心脏磁共振成像、离体光学动作电位（AP）绘图以及体外分子分析。

 结果

Su/Pn 大鼠表现出右心室 (RV) 肥大，并且极易出现起搏引起的室性心动过速/颤动 (VT/VF)。这种易感性的基础是右心侧 AP 持续时间不成比例的延长，这促进了右侧 AP 交替以生理速率形成。虽然 Su/Pn 大鼠的传播在所有速率上均受到损害，但传导减慢的程度在出现传导阻滞的室间线和 VT/VF 开始之前立即最为严重。心脏波长的测量显示 Su/Pn 相对于对照有所降低。 PAH 中 Nav1.5 和总连接蛋白 43 表达没有改变，而连接蛋白 43 磷酸化降低。 Col1a1 和 Col3a1 转录本上调与心肌纤维化同时发生。一旦产生，VT/VF 由多个可重入电路维持，由于波断的形成，RV 激活频率较低。

 结论

在这个纯 PAH 模型中，我们记录了以 RV 为主的重塑，促进了 VT 下的多小波折返。 Su/Pn 模型代表了 PAH 的一种严重形式，允许研究 EP 特性，而不会受到肺外毒性的混杂影响。