What determines the optimal pharmacological treatment of atrial fibrillation? Insights from in silico trials in 800 virtual atria
What determines the optimal pharmacological treatment of atrial fibrillation? Insights from in silico trials in 800 virtual atria
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DOI：
10.1113/jp284730
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发表时间：
2023-07-20
影响因子：
5.5
通讯作者：
Rodriguez，Blanca
中科院分区：
文献类型：
--
作者：
Dasi，Albert;Pope，Michael T. B.;Rodriguez，Blanca
心房颤动（AF）患者的最佳药物治疗尚不清楚。我们的目标是在800个虚拟心房中利用AF模拟来识别关键的患者特征，以指导抗心律失常药物的最佳选择。虚拟队列考虑了电生理学和低压区（LVA）的变异性，并根据从离子电流到ECG的实验和临床数据进行了开发和验证。494例（62%）心房持续性房颤，心房内钾电流（IK 1）和钠/钾泵（INaK）密度增大（IK10.11 ± 0.03vs. 0.07± 0.03 S mF-1; INaK 0.68 ± 0.15vs. 0.38± 26 S mF-1;持续vs.非持续性AF）。在左房严重重构，左房后壁扩大超过40%的患者中，维持房颤需要较高的IK 1（中位密度0.12 ± 0.02 S mF-1），转子位于健康的右房。对于较低的LVA延伸，转子也可以锚到LVA，在心房中表现出短的不应期（中值L型Ca 2+电流，ICaL，密度0.08 ± 0.03 S mF-1）。这种心房不应性，由ICa和快Na+电流（INa）调节，决定了小和大LVA的药物治疗成功率。维那卡兰对长时间不应性心房有效（平均CaL密度为0.13 ± 0.05 S mF-1）。对于短期不应期，高INa心房（中位密度8.92 ± 2.59 S mF-1）对胺碘酮的反应优于氟卡尼，而在低INa的心房中则相反在800个人心房的硅药物试验中，确定内向电流对于AF患者药物治疗的最佳分层至关重要，关键点心房颤动（AF）的维持是由小的L-型钙电流（ICaL）和大的内向整流钾电流（IK 1）和Na+/K+泵促进的。在严重重构的左心房中，低电压区（LVA）覆盖后壁的40%以上，持续性AF需要较高的IK 1，转子位于健康的右心房。对于较低的LVA延长，转子也可以锚到LVA，如果心房呈现短不应期（低ICaL），Vernakalant对呈现长不应期（高ICaL）的心房有效。对于短期不应期，快速钠电流（INa）上调的心房对胺碘酮的反应优于氟卡尼，而低INa的心房则相反。内向电流（ICaLandINa）对于房颤患者药物治疗的最佳分层至关重要，并且与左心房LVA扩展一起，对于准确分型房颤动力学至关重要。
AbstractThe best pharmacological treatment for each atrial fibrillation (AF) patient is unclear. We aim to exploit AF simulations in 800 virtual atria to identify key patient characteristics that guide the optimal selection of anti‐arrhythmic drugs. The virtual cohort considered variability in electrophysiology and low voltage areas (LVA) and was developed and validated against experimental and clinical data from ionic currents to ECG. AF sustained in 494 (62%) atria, with large inward rectifier K+current (IK1) and Na+/K+pump (INaK) densities (IK10.11 ± 0.03vs. 0.07 ± 0.03 S mF–1;INaK0.68 ± 0.15vs. 0.38 ± 26 S mF–1; sustainedvs. un‐sustained AF). In severely remodelled left atrium, with LVA extensions of more than 40% in the posterior wall, higherIK1(median density 0.12 ± 0.02 S mF–1) was required for AF maintenance, and rotors localized in healthy right atrium. For lower LVA extensions, rotors could also anchor to LVA, in atria presenting short refractoriness (median L‐type Ca2+current,ICaL, density 0.08 ± 0.03 S mF–1). This atrial refractoriness, modulated byICaLand fast Na+current (INa), determined pharmacological treatment success for both small and large LVA. Vernakalant was effective in atria presenting long refractoriness (medianICaLdensity 0.13 ± 0.05 S mF–1). For short refractoriness, atria with highINa(median density 8.92 ± 2.59 S mF–1) responded more favourably to amiodarone than flecainide, and the opposite was found in atria with lowINa(median density 5.33 ± 1.41 S mF–1).In silicodrug trials in 800 human atria identify inward currents as critical for optimal stratification of AF patient to pharmacological treatment and, together with the left atrial LVA extension, for accurately phenotyping AF dynamics.Key pointsAtrial fibrillation (AF) maintenance is facilitated by small L‐type Ca2+current (ICaL) and large inward rectifier K+current (IK1) and Na+/K+pump.In severely remodelled left atrium, with low voltage areas (LVA) covering more than 40% of the posterior wall, sustained AF requires higherIK1and rotors localize in healthy right atrium. For lower LVA extensions, rotors can also anchor to LVA, if the atria present short refractoriness (lowICaL)Vernakalant is effective in atria presenting long refractoriness (highICaL). For short refractoriness, atria with fast Na+current (INa) up‐regulation respond more favourably to amiodarone than flecainide, and the opposite is found in atria with lowINa.The inward currents (ICaLandINa) are critical for optimal stratification of AF patient to pharmacological treatment and, together with the left atrial LVA extension, for accurately phenotyping AF dynamics.