TY - JOUR
T1 - Computational Modeling for Antiarrhythmic Drugs for Atrial Fibrillation According to Genotype
AU - Hwang, Inseok
AU - Park, Je Wook
AU - Kwon, Oh Seok
AU - Lim, Byounghyun
AU - Hong, Myunghee
AU - Kim, Min
AU - Yu, Hee Tae
AU - Kim, Tae Hoon
AU - Uhm, Jae Sun
AU - Joung, Boyoung
AU - Lee, Moon Hyoung
AU - Pak, Hui Nam
N1 - Publisher Copyright:
© Copyright © 2021 Hwang, Park, Kwon, Lim, Hong, Kim, Yu, Kim, Uhm, Joung, Lee and Pak.
PY - 2021/5/13
Y1 - 2021/5/13
N2 - 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.
AB - 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.
KW - PITX2
KW - antiarrhythmic drugs
KW - atrial fibrillation
KW - gene
KW - modeling
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U2 - 10.3389/fphys.2021.650449
DO - 10.3389/fphys.2021.650449
M3 - Article
AN - SCOPUS:85107020303
SN - 1664-042X
VL - 12
JO - Frontiers in Physiology
JF - Frontiers in Physiology
M1 - 650449
ER -