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Computational Modeling for Antiarrhythmic Drugs for Atrial Fibrillation According to Genotype

 Inseok Hwang  ;  Je-Wook Park  ;  Oh-Seok Kwon  ;  Byounghyun Lim  ;  Myunghee Hong  ;  Min Kim  ;  Hee-Tae Yu  ;  Tae-Hoon Kim  ;  Jae-Sun Uhm  ;  Boyoung Joung  ;  Moon-Hyoung Lee  ;  Hui-Nam Pak 
 FRONTIERS IN PHYSIOLOGY, Vol.12 : 650449, 2021-05 
Journal Title
Issue Date
PITX2 ; antiarrhythmic drugs ; atrial fibrillation ; gene ; modeling
Background: The efficacy of antiarrhythmic drugs (AAD) can vary in patients with atrial fibrillation (AF), and the PITX2 gene affects the responsiveness of AADs. We explored the virtual AAD (V-AAD) responses between wild-type and PITX2 +/--deficient AF conditions by realistic in silico AF modeling. Methods: We tested the V-AADs in AF modeling integrated with patients' 3D-computed tomography and 3D-electroanatomical mapping, acquired in 25 patients (68% male, 59.8 ± 9.8 years old, 32.0% paroxysmal type). The ion currents for the PITX2 +/- deficiency and each AAD (amiodarone, sotalol, dronedarone, flecainide, and propafenone) were defined based on previous publications. Results: We compared the wild-type and PITX2 +/- deficiency in terms of the action potential duration (APD90), conduction velocity (CV), maximal slope of restitution (Smax), and wave-dynamic parameters, such as the dominant frequency (DF), phase singularities (PS), and AF termination rates according to the V-AADs. The PITX2 +/--deficient model exhibited a shorter APD90 (p < 0.001), a lower Smax (p < 0.001), mean DF (p = 0.012), PS number (p < 0.001), and a longer AF cycle length (AFCL, p = 0.011). Five V-AADs changed the electrophysiology in a dose-dependent manner. AAD-induced AFCL lengthening (p < 0.001) and reductions in the CV (p = 0.033), peak DF (p < 0.001), and PS number (p < 0.001) were more significant in PITX2 +/--deficient than wild-type AF. PITX2 +/--deficient AF was easier to terminate with class IC AADs than the wild-type AF (p = 0.018). Conclusions: The computational modeling-guided AAD test was feasible for evaluating the efficacy of multiple AADs in patients with AF. AF wave-dynamic and electrophysiological characteristics are different among the PITX2-deficient and the wild-type genotype models.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kwon, Oh-Seok(권오석)
Kim, Min(김민) ORCID logo https://orcid.org/0000-0002-8132-9873
Kim, Tae-Hoon(김태훈) ORCID logo https://orcid.org/0000-0003-4200-3456
Park, Je Wook(박제욱)
Pak, Hui Nam(박희남) ORCID logo https://orcid.org/0000-0002-3256-3620
Uhm, Jae Sun(엄재선) ORCID logo https://orcid.org/0000-0002-1611-8172
Yu, Hee Tae(유희태) ORCID logo https://orcid.org/0000-0002-6835-4759
Lee, Moon-Hyoung(이문형) ORCID logo https://orcid.org/0000-0002-7268-0741
Lim, Byounghyun(임병현)
Joung, Bo Young(정보영) ORCID logo https://orcid.org/0000-0001-9036-7225
Hong, Myunghee(홍명희)
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