Abstract 3493: Peroxisome Proliferators Activated Receptor-Gamma Attenuate Atrial Fibrosis and Atrial Fibrillation Promotion in Ventricular Tachy-Pacing Rabbits
Atrial structural remodeling contributes to the maintenance of atrial fibrillation (AF) in heart failure (HF). A peroxisome proliferator-activated receptor-gamma activator, pioglitazone, has been demonstrated to increase adiponectin which exerts protective actions on the heart. We hypothesized that pioglitazone would attenuate AF substrate and assessed the effects of pioglitazone on arrhythmogenic atrial structural remodeling compared with those of an angiotensin II type 1 receptor blocker (ARB), candesartan, which attenuates AF. Rabbits (each group; n=15) subjected to ventricular tachypacing (VTP) at 380 – 400 bpm for 4 weeks in the absence and presence of pioglitazone, and candesartan which started 2 weeks before and continued during VTP, were assessed with electrophysiological studies and atrial fibrosis measurements analyses. We also measured plasma adiponectin levels and the expressions of transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α) and mitogen-activated protein kinases (p38, ERK and JNK) in left and right atriums. Mean duration of burst pacing-induced AF (DAF) was increased after VTP compared with non-paced controls (DAF: 8.0±1.4 s, 0.6±0.1 s, p<0.001). Pioglitazone reduced DAF (3.5±0.2 s, p<0.01) after VTP and attenuated atrial structural remodeling with significant reductions in inter-atrial activation time (50±2 versus 41±2 ms, p<0.05) and atrial fibrosis (16.8±0.8 versus 10.9±0.7%, p<0.05; control 1.6±0.2%), efficacies comparable to candesartan (DAF, activation time and fibrosis: 3.0±0.2 s, 44±2 ms and 9.4±0.6%, respectively). Treatment of pioglitazone also increased plasma adiponectin levels approximately two-hold before VTP. Both pioglitazone and candesartan reduced transforming growth factor-β1, tumor necrosis factor-α and extracellular signal-regulated kinase expression similarly, but neither affected p38-kinase nor c-Jun N-terminal kinase activation. Pioglitazone attenuated HF-induced atrial structural remodeling and AF promotion with efficacies similar to those of ARB. In addition, pioglitazone, but not ARB, could increase adiponectin production. PPARγ may be a potential therapeutic target for human AF.