Abstract 18884: Ryanodine Receptor Hyperphosphorylation Induces Arrhythmias in Diabetes

Background: Type-2 diabetes (T2D) heightens the risk of heart failure, arrhythmias and sudden cardiac death, but the underlying mechanisms are poorly understood. Hypothesis: Spontaneous Ca2+ release from the sarcoplasmic reticulum (i.e., SR Ca2+ leak) is elevated in T2D hearts and contributes to the triggering of ventricular arrhythmias. Methods: We compared hearts from rats with late-onset T2D (HIP rats) that develop cardiac hypertrophy, diastolic and systolic dysfunction and ventricular tachyarrhythmias vs. control, non-diabetic rats. Results: The frequency of spontaneous Ca2+ sparks was elevated in myocytes from HIP vs. non-diabetic rats (2.6±0.2 vs. 1.9±0.2 sparks/100 μm/s), despite a significant reduction in the SR Ca2+ content (the peak of caffeine-induced Ca2+ transient was 2.9±0.2 in HIP rat myocytes compared to 5.4±0.8 in control). This result indicates an augmented activity of SR Ca2+ release channels (ryanodine receptors, RyR) in HIP myocytes. RyR activity is closely regulated by several posttr...