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

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

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.

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.

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.

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.