Ionic and cellular mechanisms underlying the development of acquired Brugada syndrome in patients treated with antidepressants.
Ionic and cellular mechanisms underlying the development of acquired Brugada syndrome in patients treated with antidepressants.
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DOI：
10.1111/j.1540-8167.2011.02196.x
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发表时间：
2012-04
影响因子：
2.7
通讯作者：
Antzelevitch C
中科院分区：
文献类型：
--
作者：
Minoura Y;Di Diego JM;Barajas-Martínez H;Zygmunt AC;Hu D;Sicouri S;Antzelevitch C
已知三环类抗抑郁药在治疗剂量或超治疗剂量下可诱导心律失常。据报道，三环类抗抑郁药阿米替林可诱导右心前区心电图（ECG）导联ST段抬高，从而揭示Brugada综合征（BrS）。抗抑郁药诱导BrS表型和相关猝死的机制尚未完全确定。同时记录离体犬右心室楔状体冠状动脉灌注的心外膜和心内膜部位的动作电位（AP），以及跨壁伪ECG。单独的阿米替林（0.2 μM-1 mM）不能诱导BrS表型。NS 5806（8 μM）是一种瞬时外向钾通道电流（Ito）激动剂，用于产生模拟BrS遗传易感性的电流外向偏移。在存在NS 5806的情况下，治疗浓度的阿米替林（0.2 μM）加重了心外膜AP切迹，导致ECG ST段抬高。在一些心外膜部位（而非其他部位）的全或无复极在9份制剂中的6份中引起2相折返和多形性室性心动过速（VT）。异丙肾上腺素（100 nM）或奎尼丁（10 μM）可逆转阿米替林中止2期折返和VT的作用（4/4）。应用电压钳技术对离体犬心室肌细胞进行研究，发现0.2 μM阿米替林对钠通道电流（INa）产生使用依赖性抑制，而对Ito无显著影响（n = 5）。我们的数据表明，阿米替林诱导的INa抑制揭示了Brugada ECG表型，并通过产生复极异质性促进了仅在遗传易感性背景下的致心律失常底物的发展，从而引起2相折返和VT。
Tricyclic antidepressants are known to induce cardiac arrhythmias at therapeutic or supratherapeutic doses. The tricyclic antidepressant, amitriptyline, is reported to induce ST segment elevation in the right precordial electrocardiogram (ECG) leads, thus unmasking Brugada syndrome (BrS). The mechanism by which antidepressants induce the BrS phenotype and associated sudden death is not well established. Action potentials (AP) were simultaneously recorded from epicardial and endocardial sites of isolated coronary-perfused canine right ventricular wedge preparations, together with a transmural pseudo-ECG. Amitriptyline alone (0.2 μM–1 mM) failed to induce a BrS phenotype. NS5806 (8 μM), a transient outward potassium channel current (Ito) agonist, was used to produce an outward shift of current mimicking a genetic predisposition to BrS. In the presence of NS5806, a therapeutic concentration of amitriptyline (0.2 μM) accentuated the epicardial AP notch leading to ST-segment elevation of the ECG. All-or-none repolarization at some epicardial sites but not others gave rise to phase-2-reentry and polymorphic ventricular tachycardia (VT) in 6 of 9 preparations. Isoproterenol (100 nM) or quinidine (10 μM) reversed the effects of amitriptyline aborting phase 2 reentry and VT (4/4). Using voltage-clamp techniques applied to isolated canine ventricular myocytes, 0.2 μM amitriptyline was shown to produce use-dependent inhibition of sodium channel current (INa), without significantly affecting Ito (n = 5). Our data suggest that amitriptyline-induced inhibition of INa unmasks the Brugada ECG phenotype and facilitates development of an arrhythmogenic substrate only in the setting of a genetic predisposition by creating repolarization heterogeneities that give rise to phase 2 reentry and VT.
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影响因子：
5.5
作者：
Burashnikov, Elena;Pfeiffer, Ryan;Barajas-Martinez, Hector;Delpon, Eva;Hu, Dan;Desai, Mayurika;Borggrefe, Martin;Haeissaguerre, Michel;Kanter, Ronald;Pollevick, Guido D.;Guerchicoff, Alejandra;Laino, Ruben;Marieb, Mark;Nademanee, Koonlawee;Nam, Gi-Byoung;Robles, Roberto;Schimpf, Rainer;Stapleton, Dwight D.;Viskin, Sami;Winters, Stephen;Wolpert, Christian;Zimmern, Samuel;Veltmann, Christian;Antzelevitch, Charles
通讯作者：
Antzelevitch, Charles
DOI：
10.1046/j.1540-8167.2001.00061.x
发表时间：
2001-01-01
影响因子：
2.7
作者：
Rouleau, F;Asfar, P;Victor, J
通讯作者：
Victor, J
影响因子：
37.8
作者：
Fish, JM;Welchons, DR;Antzelevitch, C
通讯作者：
Antzelevitch, C
影响因子：
8.4
作者：
Delpon, Eva;Cordeiro, Jonathan M.;Antzelevitch, Charles
通讯作者：
Antzelevitch, Charles
影响因子：
5.5
作者：
Giudicessi, John R.;Ye, Dan;Tester, David J.;Crotti, Lia;Mugione, Alessandra;Nesterenko, Vladislav V.;Albertson, Richard M.;Antzelevitch, Charles;Schwartz, Peter J.;Ackerman, Michael J.
通讯作者：
Ackerman, Michael J.