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 duration (APD) in atrial cells. Here, we predicted whether KCNQ1 G229D mutation affects ventricular fibrillation generation, although it shortens APD slightly compared with the atrial cell. We analyzed the effects of G229D mutation on electrical and mechanical ventricle behaviors (not considered in previous studies). We compared action potential shapes under wild-type and mutant conditions. Electrical wave propagations through ventricles were analyzed during sinus rhythm and reentrant conditions. I enhancement due to G229D mutation shortened the APD in the ventricular cells (6%, 0.3%, and 8% for endo, M, and epi-cells, respectively). The shortened APD contributed to 7% shortening of QT intervals, 29% shortening of wavelengths, 20% decrease in intraventricular 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.

ERβ Accelerates Diabetic Wound Healing by Ameliorating Hyperglycemia-Induced Persistent Oxidative Stress

“…Diabetes delays wound healing due to its contribution to the defective regulation of complicated molecular and cellular events in the proper healing process (1). Diabetic foot ulcer (DFU) is one of the most serious diabetic complications that results from poor wound healing, which subsequently results in a major health problem in patients, causing high mortality and disability (2, 3). Diabetic wound healing is involved with multiple complex pathophysiological mechanisms with many extrinsic and intrinsic factors (4).…”

Proarrhythmogenic Effect of the L532P and N588K KCNH2 Mutations in the Human Heart Using a 3D Electrophysiological Model

“…Second, we only provide the electrophysiological analysis of the two mutations without considering the mechanical behavior, which previously observed for D172N, G229D, S140G, and V241F mutations. 25 31 32 33 Third, we were unable to compare our simulation results with experimental data due to the limited availability of patients with N588K or L532P mutations. Nonetheless, this computational study demonstrated the relationship between the L532P and N588K mutations with atrial arrhythmia and AF.…”

Prediction of Cardiac Mechanical Performance From Electrical Features During Ventricular Tachyarrhythmia Simulation Using Machine Learning Algorithms

“…From the combination of first and second methods, we performed 96 cases of ventricular tachyarrhythmia simulations. Lastly, we implemented ventricular tachyarrhythmia induced by the following five genetic mutations KCNQ1 S140G (Kharche et al, 2012;Jeong and Lim, 2018), KCNQ1 V241F (Ki et al, 2014;, KCNQ1 G229D (Hasegawa et al, 2014;Yuniarti et al, 2018), hERG L532P, and hERG N588K (Loewe et al, 2014). Thereby, we simulated 20 cases of ventricular tachyarrhythmia according to the types of mutations.…”

“…There are many cardiac models to elucidate the mechanism of the development and maintenance of tachyarrhythmia and the resulting hemodynamic response (Ten Tusscher et al, 2009;Panfilov et al, 2010). In previous studies, we succeeded in predicting cardiac mechanical responses to various hereditary tachyarrhythmias using the electromechanical-hemodynamic coupling model developed by our research team (Lim et al, 2012(Lim et al, , 2015Choi et al, 2013;Jeong and Lim, 2018;Yuniarti et al, 2018). In this study, we extracted electrical instability features from ventricular tachyarrhythmia simulation.…”