Rivaud Mathilde R, Marchal Gerard A, Wolswinkel Rianne, Jansen John A, van der Made Ingeborg, Beekman Leander, Ruiz-Villalba Adrián, Baartscheer Antonius, Rajamani Sridharan, Belardinelli Luiz, van Veen Toon A B, Basso Cristina, Thiene Gaetano, Creemers Esther E, Bezzina Connie R, Remme Carol Ann
Department of Clinical and Experimental Cardiology, Amsterdam UMC, Heart Center, Academic Medical Center, Room K2-104.2, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Department of Medical Physiology, University Medical Center, Utrecht, The Netherlands.
Europace. 2020 Oct 1;22(10):1579-1589. doi: 10.1093/europace/euaa127.
SCN5A mutations are associated with arrhythmia syndromes, including Brugada syndrome, long QT syndrome type 3 (LQT3), and cardiac conduction disease. Long QT syndrome type 3 patients display atrio-ventricular (AV) conduction slowing which may contribute to arrhythmogenesis. We here investigated the as yet unknown underlying mechanisms.
We assessed electrophysiological and molecular alterations underlying AV-conduction abnormalities in mice carrying the Scn5a1798insD/+ mutation. Langendorff-perfused Scn5a1798insD/+ hearts showed prolonged AV-conduction compared to wild type (WT) without changes in atrial and His-ventricular (HV) conduction. The late sodium current (INa,L) inhibitor ranolazine (RAN) normalized AV-conduction in Scn5a1798insD/+ mice, likely by preventing the mutation-induced increase in intracellular sodium ([Na+]i) and calcium ([Ca2+]i) concentrations. Indeed, further enhancement of [Na+]i and [Ca2+]i by the Na+/K+-ATPase inhibitor ouabain caused excessive increase in AV-conduction time in Scn5a1798insD/+ hearts. Scn5a1798insD/+ mice from the 129P2 strain displayed more severe AV-conduction abnormalities than FVB/N-Scn5a1798insD/+ mice, in line with their larger mutation-induced INa,L. Transverse aortic constriction (TAC) caused excessive prolongation of AV-conduction in FVB/N-Scn5a1798insD/+ mice (while HV-intervals remained unchanged), which was prevented by chronic RAN treatment. Scn5a1798insD/+-TAC hearts showed decreased mRNA levels of conduction genes in the AV-nodal region, but no structural changes in the AV-node or His bundle. In Scn5a1798insD/+-TAC mice deficient for the transcription factor Nfatc2 (effector of the calcium-calcineurin pathway), AV-conduction and conduction gene expression were restored to WT levels.
Our findings indicate a detrimental role for enhanced INa,L and consequent calcium dysregulation on AV-conduction in Scn5a1798insD/+ mice, providing evidence for a functional mechanism underlying AV-conduction disturbances secondary to gain-of-function SCN5A mutations.
SCN5A突变与心律失常综合征相关，包括Brugada综合征、3型长QT综合征（LQT3）和心脏传导疾病。3型长QT综合征患者表现出房室（AV）传导减慢，这可能有助于心律失常的发生。我们在此研究了尚未明确的潜在机制。
我们评估了携带Scn5a1798insD/+突变的小鼠AV传导异常背后的电生理和分子改变。与野生型（WT）相比，Langendorff灌注的Scn5a1798insD/+心脏显示AV传导延长，而心房和希氏束-心室（HV）传导无变化。晚期钠电流（INa,L）抑制剂雷诺嗪（RAN）使Scn5a1798insD/+小鼠的AV传导恢复正常，可能是通过防止突变诱导的细胞内钠（[Na+]i）和钙（[Ca2+]i）浓度增加。事实上，Na+/K+-ATP酶抑制剂哇巴因进一步提高[Na+]i和[Ca2+]i会导致Scn5a1798insD/+心脏的AV传导时间过度增加。来自129P2品系的Scn5a1798insD/+小鼠比FVB/N-Scn5a1798insD/+小鼠表现出更严重的AV传导异常，这与其更大的突变诱导的INa,L一致。横向主动脉缩窄（TAC）导致FVB/N-Scn5a1798insD/+小鼠的AV传导过度延长（而HV间期保持不变），慢性RAN治疗可预防这种情况。Scn5a1798insD/+-TAC心脏在房室结区域的传导基因mRNA水平降低，但房室结或希氏束无结构变化。在缺乏转录因子Nfatc2（钙-钙调神经磷酸酶途径的效应器）的Scn5a1798insD/+-TAC小鼠中，AV传导和传导基因表达恢复到WT水平。
我们的研究结果表明，增强的INa,L及其导致的钙调节异常对Scn5a1798insD/+小鼠的AV传导具有有害作用，为功能获得性SCN5A突变继发的AV传导障碍提供了功能机制的证据。
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