EFFECT OF KCNQ1 G229D MUTATION ON CARDIAC PUMPING EFFICACY AND REENTRANT DYNAMICS IN VENTRICLES: COMPUTATIONAL STUDY

Abstract

There is growing interest in genetic arrhythmia since mutations in gene which encodes the ion channel underlie numerous arrhythmias. Hasegawa et al. reported that G229D mutation in KCNQ1 underlies atrial fibrillation due to significant shortening of action potential (AP) duration (APD) in atrial cells. Here, we predicted whether KCNQ1 G229D mutation affects ventricular fibrillation generation, although it shortens APD slightly compared to the atrial cell. We analyzed the effects of G229D mutation on electrical and mechanical ventricle behavior (not considered in previous studies). We compared AP shapes under wild-type and mutant conditions, after applying the Hasegawa et al. modified I_Ks equation to the O'Hara et al. [1] ventricular cell models. Electrical wave propagations through ventricles were analyzed during sinus rhythm and reentrant conditions. I_Ks enhancement due to G229D mutation shortened the APD in the ventricular cells (6%, 0.3%, and 8% for endo, M, epi-cells, respectively). The shortened APD contributed to 7% shortening of QT intervals, 29% shortening of wavelengths, 20% decrease in intra-ventricular pressure, and increase in end-systolic volume 17%, end-diastolic volume 7%, and end-diastolic pressure 11%, which further resulted in reduction in stroke volume as well as cardiac output (28%), ejection fraction 33% stroke work 44%, and ATP consumption 28%. In short, using computational model of the ventricle, we predicted that G229D mutation decreased cardiac pumping efficacy and increased the vulnerability of ventricular fibrillation.

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