Abstract 16442: Susceptibility to Inducible Ventricular Arrhythmia in Type I Diabetic Akita Mice is Dependent on Abnormalities of Ca2+ Handling
Introduction: Diabetes mellitus is associated with increased risk of sudden cardiac death. Little evidence exists to support specific mechanisms to account for this association. Furthermore, there is no animal model which demonstrates arrhythmogenesis in the Type I diabetic heart. The Akita mouse has been shown to be a useful model for the study of the pathogenesis of secondary effects of type I diabetes. In the current study, the increased inducibility of ventricular tachycardia (VT) in the Akita mice by programmed ventricular electrical stimulation and investigate the ionic and cellular mechanism of arrhythmogenesis.
Methods: Programmed ventricular electrical stimulation was performed in Akita and wild type (WT) mice. Left ventricular myocytes were isolated for electrophysiology and calcium imaging studies. Voltage and current clamp were used to record Ca2+ currents and action potentials. Sacremere shorterning and Ca2+transient were measured using the Ionoptix system. Ca2+ sparks were recorded by confocal microscopy.
Results: Inducibility of VT in Akita mice was significantly increased (78.6%,11of 14) compared to WT (28.6%,4/14,p=0.006). Action potential duration at 90% repolarization at 1Hz was prolonged in Akita myocytes (61.5.1±7.7 ms,n=7) vs WT ( 30.5±1.3 ms, n=7, p<0.05). L type Ca2+ current densities were unchanged compared to WT. However, Ca2+ transient decay time was increased in Akita (170.9±10.3 ms, n=23) vs WT (138.6±7.3ms, n=20,p<0.05) while SERCA2a expression was decreased in the Akita heart. Furthermore, frequency of Ca2+ sparks was signifcantly increased compared to WT(0.266±0.022 sparks/µm/s, n=36 vs 0.043±0.003 sparks/µm/s, n=13, p<0.001)consistant with increased Ca2+ leak . Consequently, cytosolic Ca2+concentration was significantly elevated in Akita myocytes, leading to the occurrence of early and delayed afterdepolarizations which predispose to arrhythmia.
Conclusions: The type 1 diabetic Akita mouse demonstrated a high level of inducibility of VT which may be due to prolongation of APD and abnormalities of Ca2+ handling.
- © 2012 by American Heart Association, Inc.