Evolution of atrial remodeling and atrial arrhythmogenicity in a rat model of chronic pulmonary artery constriction: A “trialogue” between right heart disease, cardiac inflammation, and atrial fibrillation inducibility

Abstract

Among all cardiac arrhythmias, atrial fibrillation (AF) is the most commonly diagnosed. Aging and comorbid pathological conditions such as obesity, sleep apnea or myocardial infarction increase the prevalence and incidence of AF. Clinical and experimental evidence have shown that pulmonary hypertension (PH) can initiate the development of right heart disease (RHD), which is also considered an important AF risk factor. Inflammation emerges as a common denominator between cardiovascular comorbidities and AF susceptibility. The underlying mechanisms linking (a) RHD, (b) atrial inflammation, and (c) the development of AF, remain unclear. We hypothesize that a constriction of the pulmonary artery trunk (PAT) progressively generates atrial inflammation and fibrosis responsible for increasing AF susceptibility. Describe the evolution of atrial inflammation and fibrosis in a rat model of RHD. RHD was induced on anesthetized Wistar rats (225–275 g) by performing a Pulmonary Artery Banding (PAB) which permanently reduced the PAT diameter to 1 mm. Sham animals had a PAB-mimicking surgery without suture. At day 0, 7, 14 and 21 post-surgery echocardiography and electrophysiological studies were performed in vivo on every animal. Optical mapping, histological study using Masson's trichrome, qPCR and immunoblotting were performed to analyze atrial tissues at each timepoint. PAB rats showed myocardial hypertrophy and cavity dilation affecting the right atrium (RA) and right ventricle (RV). Optical mapping performed on the RA showed that the conduction velocity was slower, the effective refractory periods were shorter, and the action potential durations were smaller in PAB rats compared to Sham. These electrical and structural remodeling were associated with significantly increased AF inducibility in PAB rats starting at day 7 until day 21 post-surgery. RA Fibrous area was also significantly higher in PAB rats compared to Sham at day 14 to day 21 post-PAT ligation. Inflammation and fibrosis-related genes such as IL6, TGFβ1 and CO1LA1 were progressively and significantly increased in the RA from PAB rats compared to Sham, from the 7th to 21st day post-PAT constriction. PAB-induced RHD provoked a progressively aggravating right atrial inflammatory and fibrotic profile leading to an increased risk of AF in rats.