Calcium alternans induced by enhanced dephosphorylation of phospholamban predisposes to inducibility of ventricular tachycardia in the type I diabetic Akita mouse (1078.9)

Abstract

Introduction: Diabetes mellitus is associated with increased risk of sudden cardiac death. Little evidence exists to support specific mechanisms to account for this association. We studied the inducibility of ventricular tachycardia (VT) in the type I diabetic Akita mouse and ionic and molecular mechanisms of arrhythmogensis. Methods: Inducibility of VT was studied by programmed ventricular stimulation and optical mapping. Left ventricular myocytes were isolated for electrophysiology and calcium imaging studies. Sarcomere shortening and Ca2+ transients were measured using the Ionoptix system. Results: Programmed ventricular stimulation of Akita mice resulted in VT in 80% of mice compared to 20% of WT. Optical mapping of perfused hearts demonstrated multifocal breakthroughs which occasionally gave rise to short lived rotors consistent with focal initiation and maintenance of VT. Both contractile and Ca2+ transient alternans were observed in single ventricular myocytes of Akita mice at field stimulations above 4 Hz. 100nM Iso induced triggered activity in 90% of myocytes from Akita and 7% in WT mice. Ventricular myocytes from Akita mice demonstrated decreased SR Ca2+ reuptake (τ= 170±10 ms vs.138±7ms, n=20, p<0.01) compared to WT and increased cytosolic Ca2+[[Unsupported Character ‐ Codename ­]][[Unsupported Character ‐ Codename ­]]. Caffeine induced Ca2+ release was significantly decreased in Akita mice vs. WT. Western blot analysis showed that phosphorylated ser16 phospholamban (PLB) and the ratio of SERCA2a/total PLB were significantly decreased in Akita mice. Conclusions: Increased dephosphorylation of PLB caused abnormal SR Ca2+ loading resulting in cardiac alternans predisposing to the development of VT in type 1 diabetic Akita mice.Grant Funding Source: NIH