Sex-specific I(KAS) activation in rabbit ventricles with drug-induced QT prolongation.
Sex-specific I(KAS) activation in rabbit ventricles with drug-induced QT prolongation.
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性别特异性I（KAS）激活在兔心室与药物诱导的QT间期延长。
DOI：
10.1016/j.hrthm.2020.07.020
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发表时间：
2021-01
期刊：
影响因子：
5.5
通讯作者：
Chen PS
中科院分区：
文献类型：
--
作者：
Wu AZ;Chen M;Yin D;Everett TH 4th;Chen Z;Rubart M;Weiss JN;Qu Z;Chen PS
女性是药物诱导的长QT综合征（diLQTS）的已知风险因素。最近，我们证明了在β-肾上腺素能刺激过程中apamin敏感的小电导Ca 2+激活的K+（SK）电流（IKAS）激活的性别差异。在diLQTS家兔模型中验证IKAS存在性别差异的假设。用光学标测技术对15只雄性和22只雌性Langendorff灌注兔心脏在心房起搏时心室复极的性别差异进行了研究。分别使用HMR 1556（IKs阻断剂）、E4031（IKr阻断剂）和海葵毒素（ATX-II，INaL激活剂）模拟1-3型LQTS。然后加入Apamin（IKAS阻断剂），以确定进一步QT延长的幅度。HMR 1556、E4031和ATX-II在300-400 ms的起搏周期长度（PCL）下均导致男性和女性心室APD 80延长。（PCL 350 ms）从187.8±4.3降至206.9±7.1（p=0.014），E4031处理组从209.9±7.8降至224.9±7.8（p=0.003），ATX-II处理组从174.3±3.3降至188.1±3.0（p=0.0002）。相比之下，apamin没有进一步延长男性心脏的APD 80。与基线相比，diLQTS患者的Cai瞬态持续时间（CaiTD）显著增加，但无性别差异。apamin对CaiTD没有显著影响。我们的结论是，IKAS是大量增加女性，但不是在男性心室diLQTS。IKAS增加有助于保护接受IKs和IKr阻断剂或INaL激活剂治疗的女性心室的复极储备。
Female sex is a known risk factor for drug-induced long QT syndrome (diLQTS). We recently demonstrated a sex difference in apamin-sensitive small-conductance Ca2+-activated K+ (SK) current (IKAS) activation during β-adrenergic stimulation. To test the hypothesis that there is a sex difference of IKAS in the rabbit models of diLQTS. We evaluated the sex differences in ventricular repolarization from 15 male and 22 female Langendorff-perfused rabbit hearts with optical mapping techniques during atrial pacing. HMR1556 (IKs blocker), E4031 (IKr blocker) and sea anemone toxin (ATX-II, INaL activator) were used to simulate types 1-3 LQTS, respectively. Apamin, an IKAS blocker was then added to determine the magnitude of further QT prolongation. HMR1556, E4031 and ATX-II led to APD80 prolongation in both male and female ventricles at pacing cycle lengths (PCLs) of 300-400 ms. Apamin further lengthened APD80 (in PCL350 ms) from 187.8±4.3 to 206.9±7.1 (p=0.014) in HMR1556 treated, from 209.9±7.8 to 224.9±7.8 (p=0.003) in E4031 treated, and from 174.3±3.3 to 188.1±3.0 (p=0.0002) in ATX-II treated female hearts. In contrast, apamin did not further lengthen the APD80 in male hearts. Compared with the baseline, the Cai transient duration (CaiTD) was significantly increased in diLQTS but without sex differences. There were no significant effects of apamin on CaiTD. We conclude that IKAS is abundantly increased in female but not in male ventricles with diLQTS. Increased IKAS helps preserve the repolarization reserve in female ventricles treated with IKs and IKr blockers or INaL activators.
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DOI：
10.1038/tpj.2012.14
发表时间：
2013-08
期刊：
The pharmacogenomics journal
影响因子：
--
作者：
Ramirez AH;Shaffer CM;Delaney JT;Sexton DP;Levy SE;Rieder MJ;Nickerson DA;George AL Jr;Roden DM
通讯作者：
Roden DM
DOI：
10.1161/circgenetics.111.960930
发表时间：
2012-02-01
期刊：
Circulation. Cardiovascular genetics
影响因子：
--
作者：
Kääb S;Crawford DC;Sinner MF;Behr ER;Kannankeril PJ;Wilde AA;Bezzina CR;Schulze-Bahr E;Guicheney P;Bishopric NH;Myerburg RJ;Schott JJ;Pfeufer A;Beckmann BM;Martens E;Zhang T;Stallmeyer B;Zumhagen S;Denjoy I;Bardai A;Van Gelder IC;Jamshidi Y;Dalageorgou C;Marshall V;Jeffery S;Shakir S;Camm AJ;Steinbeck G;Perz S;Lichtner P;Meitinger T;Peters A;Wichmann HE;Ingram C;Bradford Y;Carter S;Norris K;Ritchie MD;George AL Jr;Roden DM
通讯作者：
Roden DM
影响因子：
20.1
作者：
Chua SK;Chang PC;Maruyama M;Turker I;Shinohara T;Shen MJ;Chen Z;Shen C;Rubart-von der Lohe M;Lopshire JC;Ogawa M;Weiss JN;Lin SF;Ai T;Chen PS
通讯作者：
Chen PS
影响因子：
2.8
作者：
Burke, JH;Ehlert, FA;Kadish, AH
通讯作者：
Kadish, AH
影响因子：
5.5
作者：
Nattel, Stanley
通讯作者：
Nattel, Stanley