ATP1A3-Encoded Sodium-Potassium ATPase Subunit Alpha 3 D801N Variant Is Associated With Shortened QT Interval and Predisposition to Ventricular Fibrillation Preceded by Bradycardia.
ATP1A3-Encoded Sodium-Potassium ATPase Subunit Alpha 3 D801N Variant Is Associated With Shortened QT Interval and Predisposition to Ventricular Fibrillation Preceded by Bradycardia.
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DOI：
10.1161/jaha.120.019887
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发表时间：
2021-09-07
影响因子：
5.4
通讯作者：
Landstrom AP
中科院分区：
文献类型：
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作者：
Moya-Mendez ME;Ogbonna C;Ezekian JE;Rosamilia MB;Prange L;de la Uz C;Kim JJ;Howard T;Garcia J;Nussbaum R;Truty R;Callis TE;Funk E;Heyes M;Dear GL;Carboni MP;Idriss SF;Mikati MA;Landstrom AP
ATP1A3 编码的钠钾 ATP 酶 (ATP1A3) 的致病变异是导致儿童交替性偏瘫 (AHC) 的原因。尽管这些癫痫患者意外猝死率很高，但这种风险的病理生理学基础仍然未知。目的是确定 ATP1A3 遗传变异对通过 QT 和校正 QT (QTc) 测量确定的心脏结果的作用。我们分析了 62 名接受 AHC 评估的患者（男性受试者 = 31，女性受试者 = 31）的 12 导联心电图记录。根据 AHC 表现（典型与非典型）、ATP1A3 变异状态（阳性与阴性）和 ATP1A3 变异（D801N 与其他变异）对患者进行分组。由 2 名儿科电生理学家手动重新测量 QT 间期和计算 QTc。 ATP1A3 变异状态呈阳性的患者 (P<0.001) 的 QTc 测量值显着短于基因型阴性状态的患者，ATP1A3-D801N 变异的患者的 QTc 测量值显着短于其他变异的患者 (P<0.001)。 ATP1A3-D801N 的平均 QTc 为 344.9 毫秒，随年龄变化不大，并且在整个成年期保持 <370 毫秒。通过多变量回归分析，ATP1A3 基因型状态与 QTc 缩短显着相关。两名携带 ATP1A3-D801N 变异的患者出现心室颤动，导致 1 名患者死亡。在一大群因心律失常和不明原因猝死而转诊的基因型阴性患者中发现了 ATP1A3 的罕见变异。携带 ATP1A3-D801N 变异的 AHC 患者的 QTc 间期显着缩短，并且出现与危及生命的心律失常相关的心动过缓的可能性增加。 ATP1A3 变异可能是不明原因猝死的独立原因。应评估 AHC 患者以确定猝死的风险。
Pathogenic variation in the ATP1A3‐encoded sodium‐potassium ATPase, ATP1A3, is responsible for alternating hemiplegia of childhood (AHC). Although these patients experience a high rate of sudden unexpected death in epilepsy, the pathophysiologic basis for this risk remains unknown. The objective was to determine the role of ATP1A3 genetic variants on cardiac outcomes as determined by QT and corrected QT (QTc) measurements. We analyzed 12‐lead ECG recordings from 62 patients (male subjects=31, female subjects=31) referred for AHC evaluation. Patients were grouped according to AHC presentation (typical versus atypical), ATP1A3 variant status (positive versus negative), and ATP1A3 variant (D801N versus other variants). Manual remeasurements of QT intervals and QTc calculations were performed by 2 pediatric electrophysiologists. QTc measurements were significantly shorter in patients with positive ATP1A3 variant status (P<0.001) than in patients with genotype‐negative status, and significantly shorter in patients with the ATP1A3‐D801N variant than patients with other variants (P<0.001). The mean QTc for ATP1A3‐D801N was 344.9 milliseconds, which varied little with age, and remained <370 milliseconds throughout adulthood. ATP1A3 genotype status was significantly associated with shortened QTc by multivariant regression analysis. Two patients with the ATP1A3‐D801N variant experienced ventricular fibrillation, resulting in death in 1 patient. Rare variants in ATP1A3 were identified in a large cohort of genotype‐negative patients referred for arrhythmia and sudden unexplained death. Patients with AHC who carry the ATP1A3‐D801N variant have significantly shorter QTc intervals and an increased likelihood of experiencing bradycardia associated with life‐threatening arrhythmias. ATP1A3 variants may represent an independent cause of sudden unexplained death. Patients with AHC should be evaluated to identify risk of sudden death.