Overexpression of Perilipin 2 Induces Cardiac Steatosis and Atrial Fibrillation via Connexin 43 Remodeling

• Published in: Diabetes (New York, N.Y.) Vol. 67; no. Supplement_1
• Main Authors: SATO, SATSUKI, SUZUKI, JINYA, HIROSE, MASAMICHI, NAKAYA, TAKAHIRO, YAMADA, MIKA, ICHIKAWA, MAI, IMAGAWA, MICHIKO, ZENIMARU, YASUO, TAKAHASHI, SADAO, KRAEMER, FREDRIC B., KONOSHITA, TADASHI, ISHIZUKA, TAMOTSU
• Format: Journal Article
• Language: English
• Published: 01-07-2018
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db18-1903-P

Atrial fibrillation (AF) is prevalent among diabetic patients. Diabetes is also associated with myocardial lipid droplet accumulation (steatosis), which is thought to be a source of intracellular lipotoxicity. Since the relative contribution of cardiac steatosis per se to AF has not been elucidated, the current study was designed to clarify the causal effect of cardiac steatosis on AF using an aged mouse model of cardiac steatosis. Cardiac-specific perilipin (PLIN) 2-overexpressing mice (PLIN2-Tg) were created and maintained on a chow diet for >12 months. Cardiac steatosis was assessed by electron microscopy and triacylglycerol (TAG) content. AF was induced by transesophageal electrical burst pacing, and the duration of AF was measured. Atrial impulse conduction patterns were analyzed in Langendorff-perfused hearts using optical mapping technique. Myocardial localization of a gap junction protein, connexin (Cx) 43, was analyzed by confocal microscopy. Electron microscopy of the atrium of PLIN2-Tg revealed accumulation of small lipid droplets around clusters of mitochondria, and the atrial TAG content in PLIN2-Tg was 4- to 8-fold higher than that in wild type (Wt) atrium. Electrocardiograms showed significantly longer RR intervals in PLIN2-Tg compared to Wt mice. The prevalence of sustained (>5min) AF was significantly greater in PLIN2-Tg compared with Wt mice (69% vs. 24%). Confocal microscopy revealed that Cx43 was distributed at the intercalated discs in Wt atria, whereas it was heterogeneously redistributed to the lateral side of the cardiomyocytes in PLIN2-Tg atria. Isochrone mapping showed slow and heterogeneous impulse propagation in PLIN2-Tg atria compared with Wt atria. These results indicate that PLIN2-induced steatosis causes Cx43 remodeling, impaired conduction propagation, and a higher incidence of AF. Controlling cardiac steatosis might be an important target for inhibiting AF in patients with cardiac steatosis.