What is the clinical evidence from this study?

Study design: Other. Population: Atrial Fibrillation (n=25). Intervention: Virtual Class IC antiarrhythmic drugs (flecainide, propafenone) in PITX2+/- deficient model vs. Wild-type AF model. Primary outcome: AF termination rate with class IC AADs (p=0.018).

What question did this study set out to answer?

To evaluate virtual antiarrhythmic drug (AAD) responses across wild-type and PITX2-deficient atrial fibrillation (AF) states using personalized in silico modeling.

May 13, 2021Frontiers in Physiology7 citationsOpen Access

Computational Modeling for Antiarrhythmic Drugs for Atrial Fibrillation According to Genotype

IHInseok Hwang ZJZe Jin JPJe‐Wook Park

Key Result

In a computational model of atrial fibrillation, PITX2+/- -deficient AF had a significantly higher termination rate with class IC antiarrhythmic drugs compared to wild-type AF (26.0% vs 12.0%).

Key Points

To evaluate virtual antiarrhythmic drug (AAD) responses across wild-type and PITX2-deficient atrial fibrillation (AF) states using personalized in silico modeling.
Integrated 3D-computed tomography and 3D-electroanatomical mapping data from 25 patients with AF (68% male, mean age 59.8 ± 9.8 years, 32.0% paroxysmal AF) into realistic AF models.
Simulated electrophysiological ion currents representing wild-type and PITX2+/− deficiency under exposure to five virtual AADs (amiodarone, sotalol, dronedarone, flecainide, and propafenone).
Baseline PITX2+/− models exhibited shorter APD90 (p < 0.001), lower Smax (p < 0.001), lower mean dominant frequency (p = 0.012), fewer phase singularities (p < 0.001), and longer AF cycle length (AFCL, p = 0.011) compared to wild-type.
AAD-induced AFCL lengthening (p < 0.001) and reductions in conduction velocity (p = 0.033), peak dominant frequency (p < 0.001), and phase singularities (p < 0.001) were significantly greater in PITX2+/− models.
PITX2+/− deficient AF achieved significantly higher termination rates with class IC AADs than wild-type AF (p = 0.018).

Structured PICO

Do virtual antiarrhythmic drugs alter electrophysiological parameters and AF termination rates differently in PITX2+/- deficient versus wild-type AF models?

Population

25 patients with atrial fibrillation (68% male, 59.8 ± 9.8 years old, 32.0% paroxysmal type) whose clinical 3D-computed tomography and 3D-electroanatomical mapping data were used to create realistic in silico AF models.

Intervention

Virtual antiarrhythmic drugs (amiodarone, sotalol, dronedarone, flecainide, and propafenone) applied to PITX2+/- deficient in silico AF models.

Comparator

Virtual antiarrhythmic drugs applied to wild-type in silico AF models.

Outcome

Action potential duration (APD90), conduction velocity (CV), maximal slope of restitution (Smax), dominant frequency (DF), phase singularities (PS), and AF termination rates.surrogate

Patient-specific computational modeling demonstrates that PITX2+/- deficient atrial fibrillation has distinct wave dynamics and is more susceptible to termination by class IC antiarrhythmic drugs than wild-type AF.

Main Result

Absolute Event Rate: 26% vs 12%

p-value: p=0.018

Limitations

The left atrial model was designed as a monolayer, lacking epicardial conduction and wall thickness representation
Fiber orientation was simplistic
Multisite induction was not conducted to reflect complicated AF dynamics
Detailed analysis of sarcoplasmic reticular calcium leaking and triggered activity was not performed
The approach requires invasive mapping data

Abstract

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 (APD 90 ), 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 APD 90 ( 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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