UC Davis

Evidence on cellular/molecular mechanisms leading to atrial fibrillation (AF) are scanty. Increased expression of Rho kinase (ROCK) and myosin-phosphatase-target subunit-1 (MYPT-1), ROCK activitys marker, were shown in AF patients, which correlated with connexin 40 (Cx40) expression, membrane protein of heart gap junctions, key for rapid action potentials cell-cell transfer. AF is the most frequent arrhythmia in dialysis patients who present increased MYPT-1 phosphorylation, which correlates with left ventricular (LV) mass. Given ROCKs established role in cardiovascular-renal remodeling, induction of impaired cell-to-cell coupling/potential conduction promoting AF initiation/perpetuation, we evaluated in dialysis patients with AF, MYPT-1 phosphorylation, Cx40 expression, and their relationships to support their involvement in AF. Mononuclear cells MYPT-1 phosphorylation, Cx40 expression, and the ROCK inhibitor fasudils effect were assessed in dialysis patients with AF (DPAFs), dialysis patients with sinus rhythm (DPs), and healthy subjects (C) (western blot). M-mode echocardiography assessed LV mass and left atrial systolic volume. DPAFs phospho-MYPT-1 was increased vs. that of DPs and C (1.57 ± 0.17 d.u. vs. 0.69 ± 0.04 vs. 0.51 ± 0.05 respectively, p < 0.0001). DPs phospho-MYPT-1 was higher vs. that of C, p = 0.009. DPAFs Cx40 was higher vs. that of DPs and C (1.23 ± 0.12 vs. 0.74 ± 0.03 vs. 0.69 ± 0.03, p < 0.0001). DPAFs phospho-MYPT-1 correlated with Cx40 (p < 0.001), left atrial systolic volume (p = 0.013), and LV mass (p = 0.014). In DPAFs, fasudil reduced MYPT-1 phosphorylation (p < 0.01) and Cx40 expression (p = 0.03). These data point toward ROCK and Cx40s role in the mechanism(s) leading to AF in dialysis patients. Exploration of the ROCK pathway in AF could contribute to AF generations mechanistic explanations and likely identify potential pharmacologic targets for translation into treatment.