Department of Medicine, Montreal Heart Institute (MHI), Université de Montréal, 5000 Belanger Street, Montreal, QC H1T 1C8, Canada.
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
Cardiovasc Res. 2021 Jun 16;117(7):1776-1789. doi: 10.1093/cvr/cvaa186.
Inflammation plays a role in atrial fibrillation (AF), but classical anti-inflammatory molecules are ineffective. Recent evidence suggests that failure of inflammation-resolution causes persistent inflammatory signalling and that a novel drug-family called resolvins promotes inflammation-resolution. Right heart disease (RHD) is associated with AF; experimental RHD shows signs of atrial inflammatory-pathway activation. Here, we evaluated resolvin-therapy effects on atrial arrhythmogenic remodelling in experimental RHD.
Pulmonary hypertension and RHD were induced in rats with an intraperitoneal injection of 60 mg/kg monocrotaline (MCT). An intervention group received daily resolvin-D1 (RvD1), starting 1 day before MCT administration. Right atrial (RA) conduction and gene-expression were analysed respectively by optical mapping and qPCR/gene-microarray. RvD1 had no or minimal effects on MCT-induced pulmonary artery or right ventricular remodelling. Nevertheless, in vivo transoesophageal pacing induced atrial tachyarrhythmias in no CTRL rats vs. 100% MCT-only rats, and only 33% RvD1-treated MCT rats (P < 0.001 vs. MCT-only). Conduction velocity was significantly decreased by MCT, an effect prevented by RvD1. RHD caused RA dilation and fibrosis. RvD1 strongly attenuated RA fibrosis but had no effect on RA dilation. MCT increased RA expression of inflammation- and fibrosis-related gene-expression pathways on gene-microarray transcriptomic analysis, effects significantly attenuated by RvD1 (334 pathways enriched in MCT-rats vs. control; only 177 dysregulated by MCT with RvD1 treatment). MCT significantly increased RA content of type 1 (proinflammatory) CD68-positive M1 macrophages without affecting type 2 (anti-inflammatory) M2 macrophages. RvD1-treated MCT-rat RA showed significant reductions in proinflammatory M1 macrophages and increases in anti-inflammatory M2 macrophages vs. MCT-only. MCT caused statistically significant increases in protein-expression (western blot) of COL3A1, ASC, CASP1, CASP8, IL1β, TGFβ3, CXCL1, and CXCL2, and decreases in MMP2, vs. control. RvD1-treatment suppressed all these MCT-induced protein-expression changes.
The inflammation-resolution enhancing molecule RvD1 prevents AF-promoting RA remodelling, while suppressing inflammatory changes and fibrotic/electrical remodelling, in RHD. Resolvins show potential promise in combating atrial arrhythmogenic remodelling by suppressing ongoing inflammatory signalling.
炎症在心房颤动（AF）中起作用，但经典的抗炎分子无效。最近的证据表明，炎症消退的失败会导致持续的炎症信号，而一种新型的叫做 resolvins 的药物家族可以促进炎症消退。右心疾病（RHD）与 AF 相关；实验性 RHD 显示心房炎症途径激活的迹象。在这里，我们评估了 resolvin 治疗对实验性 RHD 中心房致心律失常重塑的影响。
通过腹腔注射 60mg/kg 单克隆抗体（MCT）在大鼠中诱导肺动脉高压和 RHD。干预组在 MCT 给药前 1 天每天接受 resolvin-D1（RvD1）治疗。通过光学映射和 qPCR/基因微阵列分别分析右心房（RA）传导和基因表达。RvD1 对 MCT 诱导的肺动脉或右心室重塑没有或仅有最小的影响。然而，在体内经食管起搏诱导 AF 时，在没有 CTRL 大鼠的情况下，只有 100%的 MCT 大鼠，只有 33%的 RvD1 治疗的 MCT 大鼠（P < 0.001 比 MCT 大鼠）。MCT 显著降低了 RA 的传导速度，而 RvD1 则阻止了这一效应。RHD 导致 RA 扩张和纤维化。RvD1 强烈抑制 RA 纤维化，但对 RA 扩张没有影响。MCT 在基因微阵列转录组分析上增加了 RA 炎症和纤维化相关基因表达途径的表达，而 RvD1 显著减弱了这些作用（在 MCT 大鼠中富集了 334 个通路，而在对照组中只有 177 个通路受到 MCT 治疗的影响）。MCT 显著增加了 RA 中 1 型（促炎）CD68 阳性 M1 巨噬细胞的含量，而不影响 2 型（抗炎）M2 巨噬细胞。与 MCT 大鼠相比，RvD1 治疗的 MCT 大鼠 RA 中促炎 M1 巨噬细胞减少，抗炎 M2 巨噬细胞增加。MCT 导致 COL3A1、ASC、CASP1、CASP8、IL1β、TGFβ3、CXCL1 和 CXCL2 的蛋白表达（western blot）显著增加，而 MMP2 则减少，与对照组相比。RvD1 治疗抑制了所有这些由 MCT 诱导的蛋白表达变化。
炎症消退增强分子 RvD1 可预防 RHD 中促 AF 的 RA 重塑，同时抑制炎症变化和纤维化/电重塑。Resolvins 通过抑制持续的炎症信号，显示出在对抗心房致心律失常重塑方面的潜在前景。
Zotero 插件