The inflammation-resolution promoting molecule resolvin-D1 prevents atrial proarrhythmic remodeling in experimental right heart disease.

AIMS 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 signaling and 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 remodeling in experimental RHD. METHODS AND RESULTS Pulmonary hypertension (PH) 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 one day before MCT administration. Right-atrial (RA) conduction and gene-expression were analyzed respectively by optical mapping and qPCR/gene-microarray. RvD1 had no or minimal effects on MCT-induced pulmonary-artery or right-ventricular remodeling. Nevertheless, in vivo transesophageal 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 versus 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, versus control. RvD1-treatment suppressed all these MCT-induced protein-expression changes. CONCLUSIONS The inflammation-resolution enhancing molecule RvD1 prevents AF-promoting RA-remodeling, while suppressing inflammatory changes and fibrotic/electrical remodeling, in RHD. Resolvins show potential promise in combating atrial arrhythmogenic remodeling by suppressing ongoing inflammatory signaling. TRANSLATIONAL PERSPECTIVE Mounting evidence suggests that chronic diseases are promoted by failure of inflammation to resolve. Here, we tested the effects of a molecule that promotes inflammation-resolution, Resolvin-D1, in a rat model of atrial arrhythmogenic remodeling caused by right-heart disease and marked by signs of persistent inflammatory signaling. Resolvin-D1 suppressed inflammatory signaling, shifted the balance of atrial macrophage-infiltration from proinflammatory M1-macrophages towards anti-inflammatory M2-macrophages and prevented atrial fibrosis. Disease-induced conduction-slowing was suppressed and atrial-fibrillation promotion was prevented. These findings support the potential value of a relatively non-toxic inflammation-resolving molecule in preventing the development of an arrhythmogenic substrate associated with chronic inflammatory signaling.