Stability and Self-Sustained Oscillations in a Ventricular Cardiomyocyte Model

Abstract

in HEK293 cells showed that it does not generate any current (n=6). We utilized recently published computational models of the human atrial and ventricular action potential (Abraham et al., J Mol Cell Cardiol. 2010 and Grandi, et al. J Mol Cell Cardiol. 2010) to determine the effect that T322M has on cardiac Action Potential Duration (APD) stimulated at 1 Hz. A 100% reduction of I Ks resulted in a prolonged APD in the atrial simulation but not the ventricular simulation. We incorporated a beta-adrenergic stimulation component into the ventricular model and found that reducing I Ks by 100% in the modified simulation increased APD. We further modified the ventricular action potential simulation to compromise 'repolarization reserve' by reducing the rapidly-activating delayed-rectifier K þ current or I Kr component. This modification exacerbated that effect that 100% block of I Ks had on ventricular APD. Based on these results we conclude that T322M prolongs the atrial APD in the absence of betaadrenergic stimulation, and prolongs the ventricular APD in the presence of beta-adrenergic stimulation and a compromised repolarization reserve. 2362-Pos Board B348 A Mathematical Model Identifies Arrhythmia Susceptibility Factors inMice with Heart Failure Vladimir E. Bondarenko, Polina S. Petkova-Kirova, Barry London, Guy Salama, Randall L. Rasmusson. Tumor necrosis factor-a (TNF-a) is significantly elevated in the serum of patients with end-stage congestive heart failure and in the myocardium of patients with dilated cardiomyopathy and ischemic heart disease. This correlation suggests that the inflammatory cytokine TNF-a plays a significant role in promoting arrhythmias. To investigate the role of TNF-a, transgenic (TG) mice were generated with cardiac-specific overexpression of TNF-a which resulted in dilated cardiomyopathy, impaired Ca 2þ dynamics, and increased mortality. In this study, we modified our model of mouse ventricular myocytes to account for the experimentally observed electrical remodeling. The resulting model demonstrated potential arrhythmogenic changes due to changes in action potential (AP) properties and cellular coupling. The simulated differences in action potential shape and duration were predominantly due to changes in the rapidly-inactivating transient outward K þ current, I Kto,f , and an ultra-rapidly activating K þ current, I Kur . The model incorporated experimental measurements of differences in Ca 2þ handling in myocytes from wild type (WT) and TG mice: reduced [Ca 2þ ] i transients and slower Ca 2þ sequestration by the sarcoplasmic reticulum (SR) in TG mice. The model also predicted that Ca 2þ alternans developed at longer basic cycle lengths in TG compared to WT mice as observed experimentally. The greater susceptibility to Ca 2þ alternans was attributed to a slower Ca 2þ sequestration rate by the SR. Programmed stimulation with a premature impulse showed that longer S1-S2 intervals were effective at eliciting re-entry in TG vs. WT mice, suggesting a mechanism for the observed increase in...