Abstract 368: Mechanisms of Arrhythmogenic Substrates in Lipotoxic Heart

• Published in: Circulation research 2020-07, Vol.127 (Suppl_1)
• Main Authors: Martinez -Mateu, Laura, Zhang, Xusheng, Leduc, Charles, Leibel, Rudolph, Saiz, Javier, Aromolaran, Ademuyiwa
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.127.suppl_1.368

Abstract only Obesity is associated with dangerous pathologies including insulin resistance, hyperglycemia, and diabetes all of which are present as independent risks to developing fatal arrhythmias, which lead to sudden cardiac death. Cardiac lipotoxicity is a common mechanism that links these pathologies to cardiac dysfunction. The molecular mechanisms of cardiac lipotoxicity in obese heart are unknown. We investigated the effects of high-fat diet (HFD)-induced lipotoxicity on atrial electrical remodeling. Electrophysiology and rapid atrial pacing (RAP) were used to evaluate the effects of cardiac lipotoxicity in obese guinea pig hearts that show no signs of hyperglycemia or inflammation. HFD atria were associated with increased voltage-dependent potassium (I K ) and decreased L-type calcium current (I Ca,L ) densities, spontaneous beats, and increased vulnerability to atrial tachycardia with pacing. Further we see a marked reduction in I Kur and increased I K1 phenotype only after RAP. Human cardiac computer simulation studies underscore the translational relevance, as results were identical to data in lipotoxic guinea pig model. The data are the first to show that I K and I Ca,L underlie initiation of atrial arrhythmogenesis, while IK ur and IK 1 may act to sustain the arrhythmia. RNA sequencing assay in lipotoxic myocytes further revealed upregulation of PI3K and/or downregulation of AMPK as prime candidates for modulation of atrial ionic currents. The data provide a unique mechanism-based insight for targeted treatment options in patients.