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Introduction: Right heart (RH) diseases (RHDs) are associated with atrial fibrillation (AF). A recently discovered autacoid family called resolvins prevents fibrotic remodeling in renal, lung and liver disease. We noted that rats with monocrotaline (MCT)-induced RHD show enhanced AF vulnerability. Hypothesis: Resolvin therapy can prevent MCT-induced atrial arrhythmogenic remodeling in MCT-induced RHD. Methods: RHD was produced in Wistar male rats with a single i.p. injection of 60 mg/kg MCT. An intervention group received resolvin D1 (RvD1: 2 μg/kg/day i.p.). Cardiac function was assessed by echocardiography. Atrial conduction was evaluated with right atrial (RA) optical mapping. Atrial fibrosis was assessed with Masson trichrome staining and fibrosis-related genes by qPCR. Results: MCT induced pulmonary hypertension and right ventricular hypertrophy (RVH: Figure A) vs control (CTRL). In vivo transesophageal pacing induced atrial tachyarrhythmia in no CTRL rats, vs 100% MCT-only rats and 33% RvD1-treated MCT rats (*P<0.05) (Figure A). AF duration averaged 8.9±2.5 s in MCT alone vs 2.1±1.4 s in MCT+RvD1 (***P<0.001). Conduction velocity was significantly decreased at shorter cycle lengths by MCT, an effect attenuated by RvD1 (Figure B). RHD was associated with RA dilation and fibrosis (Figure C). While RvD1 attenuated RA fibrosis, it had no effect on RA dilation (Figure C) or RVH (Figure A). MCT increased the expression of fibrosis-related genes Col 3α1 and PDGFR-α; this was significantly attenuated by RvD1 (Figure D). Conclusions: RH remodeling induced in a rat model of PH leads to enhanced AF vulnerability. RvD1 attenuates atrial arrhythmogenic remodeling associated with RHD. This effect appears to be due to the selective suppression of fibrotic remodeling, as structural remodeling (RVH and RA dilation) is not affected. RvD1 is a promising potential lead compound for novel drug development to combat atrial arrhythmogenic fibrotic remodeling. [ABSTRACT FROM AUTHOR]

Introduction: A variety of conditions affecting the right heart (RH), including diseases of the lung and pulmonary circulation, promote atrial fibrillation (AF), but the mechanisms are poorly understood. Hypothesis: 1) Atrial arrhythmia susceptibility will be increased in a rat model of RH disease caused by severe pulmonary hypertension (PH); 2) Discrete underlying mechanisms can be identified. Methods: Severe PH was induced in Wistar male rats with a single i.p. injection of 60 mg/kg of monocrotaline (MCT); these were compared to control (CTRL) rats followed for the same time without MCT injection. AF vulnerability was assessed with transesophageal pacing. Activation and arrhythmia mechanisms were evaluated by optical mapping of the right atrium. Atrial fibrosis was quantified by Masson Trichrome staining and collagen (Col) expression by qPCR. Results: Twenty-one days following MCT injection, RH hypertrophy was manifested by increased Fulton's Index (from 0.19±0.04 to 0.41±0.03***, ***P<0.001). Pacing-induced atrial tachyarrhythmia was seen in 100% MCT rats vs. 6% CTRLs and AF duration increased significantly in rats suffering from RH hypertrophy (Figure A). Optical Mapping with di-4-ANEPPS revealed that conduction velocity was significantly slowed and APD80 was increased in the right atrium of MCT rats (Figure B). Histology revealed significantly increased right atrial fibrous tissue content (from 3.0±0.6% to 16.0±0.5% ***; Figure C). The mRNA expression of fibrosis-related genes Col 3α1 and fibronectin, FN-1, were increased in right and left atrium, as well as right ventricle, in MCT rats (Figure D). Optical mapping revealed arrhythmia maintenance by reentrant rotors in the majority of MCT rats. Conclusions: 1) RH disease in a rat model creates a substrate for AF vulnerability and maintenance; 2) Conduction abnormalities related to atrial fibrosis play an important role in arrhythmia susceptibility. [ABSTRACT FROM AUTHOR]