右心疾病大鼠模型中心房颤动的右心房机制。

Right Atrial Mechanisms of Atrial Fibrillation in a Rat Model of Right Heart Disease.

机构信息

Montreal Heart Institute (MHI), Department of Medicine, Université de Montréal, Montreal, Quebec, Canada.

Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.

出版信息

J Am Coll Cardiol. 2019 Sep 10;74(10):1332-1347. doi: 10.1016/j.jacc.2019.06.066.

DOI:10.1016/j.jacc.2019.06.066

PMID:31488271

Abstract

BACKGROUND

Conditions affecting the right heart, including diseases of the lungs and pulmonary circulation, promote atrial fibrillation (AF), but the mechanisms are poorly understood.

OBJECTIVES

This study sought to determine whether right heart disease promotes atrial arrhythmogenesis in a rat model of pulmonary hypertension (PH) and, if so, to define the underlying mechanisms.

METHODS

PH was induced in male Wistar rats with a single intraperitoneal injection of 60 mg/kg of monocrotaline, and rats were studied 21 days later when right heart disease was well developed. AF vulnerability was assessed in vivo and in situ, and mechanisms were defined by optical mapping, histochemistry, and biochemistry.

RESULTS

Monocrotaline-treated rats developed increased right ventricular pressure and mass, along with right atrial (RA) enlargement. AF/flutter was inducible in 32 of 32 PH rats (100%) in vivo and 11 of 12 (92%) in situ, versus 2 of 32 (6%) and 2 of 12 (17%), respectively, in control rats (p < 0.001 vs. PH for each). PH rats had significant RA (16.1 ± 0.5% of cross-sectional area, vs. 3.0 ± 0.6% in control) and left atrial (LA: 11.8 ± 0.5% vs. 5.4 ± 0.8% control) fibrosis. Multiple extracellular matrix proteins, including collagen 1 and 3, fibronectin, and matrix metalloproteinases 2 and 9, were up-regulated in PH rat RA. Optical mapping revealed significant rate-dependent RA conduction slowing and rotor activity, including stable rotors in 4 of 11 PH rats, whereas no significant conduction slowing or rotor activity occurred in the LA of monocrotaline-treated rats. Transcriptomic analysis revealed differentially enriched genes related to hypertrophy, inflammation, and fibrosis in RA of monocrotaline-treated rats versus control. Biochemical results in PH rats were compared with those of AF-prone rats with atrial remodeling in the context of left ventricular dysfunction due to myocardial infarction: myocardial infarction rat LA shared molecular motifs with PH rat RA.

CONCLUSIONS

Right heart disease produces a substrate for AF maintenance due to RA re-entrant activity, with an underlying substrate prominently involving RA fibrosis and conduction abnormalities.

摘要

背景

影响右心的疾病，包括肺部和肺循环疾病，会促进心房颤动（AF），但其机制尚不清楚。

目的

本研究旨在确定右心疾病是否会在肺动脉高压（PH）大鼠模型中促进心房心律失常的发生，如果是这样，那么明确其潜在机制。

方法

通过单次腹腔注射 60mg/kg 的野百合碱诱导雄性 Wistar 大鼠发生 PH，在右心疾病充分发展后 21 天进行研究。通过体内和在体评估 AF 易感性，并通过光学映射、组织化学和生物化学来确定机制。

结果

野百合碱处理的大鼠右心室压力和质量增加，同时右心房（RA）扩大。在 32 只 PH 大鼠中有 32 只（100%）在体内可诱导 AF/扑动，在 12 只 PH 大鼠中有 11 只（92%）在在体可诱导 AF/扑动，而在 32 只对照大鼠中只有 2 只（6%）和 12 只对照大鼠中的 2 只（17%）可诱导 AF/扑动（与 PH 相比，每种情况均 p < 0.001）。PH 大鼠的 RA（占横截面积的 16.1 ± 0.5%，而对照大鼠为 3.0 ± 0.6%）和左心房（LA：11.8 ± 0.5%，而对照大鼠为 5.4 ± 0.8%）纤维化明显。PH 大鼠的 RA 中多种细胞外基质蛋白，包括胶原蛋白 1 和 3、纤维连接蛋白和基质金属蛋白酶 2 和 9，表达上调。光学映射显示 RA 存在显著的速率依赖性传导减慢和转子活动，包括在 11 只 PH 大鼠中有 4 只存在稳定的转子，而在野百合碱处理的大鼠的 LA 中则没有明显的传导减慢或转子活动。转录组分析显示，与对照组相比，野百合碱处理的大鼠的 RA 中存在与肥大、炎症和纤维化相关的差异表达基因。PH 大鼠的生化结果与由于心肌梗死导致左心室功能障碍而发生心房重构的 AF 倾向大鼠进行了比较：心肌梗死大鼠的 LA 与 PH 大鼠的 RA 具有共同的分子特征。