PDF(Pubmed)
Abstract：
BACKGROUND: Gain-of-function (GOF) mutations in the KATP channel subunits Kir6.1 and SUR2 cause Cantu syndrome (CS), a disease characterized by multiple cardiovascular abnormalities.
OBJECTIVE: The purpose of this study was to better determine the electrophysiologic consequences of such GOF mutations in the heart.
METHODS: We generated transgenic mice (Kir6.1-GOF) expressing ATP-insensitive Kir6.1[G343D] subunits under α-myosin heavy chain (α-MHC) promoter control, to target gene expression specifically in cardiomyocytes, and performed patch-clamp experiments on isolated ventricular myocytes and invasive electrophysiology on anesthetized mice.
RESULTS: In Kir6.1-GOF ventricular myocytes, KATP channels showed decreased ATP sensitivity but no significant change in current density. Ambulatory ECG recordings on Kir6.1-GOF mice revealed AV nodal conduction abnormalities and junctional rhythm. Invasive electrophysiologic analyses revealed slowing of conduction and conduction failure through the AV node but no increase in susceptibility to atrial or ventricular ectopic activity. Surface ECGs recorded from CS patients also demonstrated first-degree AV block and fascicular block.
CONCLUSIONS: The primary electrophysiologic consequence of cardiac KATP GOF is on the conduction system, particularly the AV node, resulting in conduction abnormalities in CS patients who carry KATP GOF mutations.
OBJECTIVE: The purpose of this study was to better determine the electrophysiologic consequences of such GOF mutations in the heart.
METHODS: We generated transgenic mice (Kir6.1-GOF) expressing ATP-insensitive Kir6.1[G343D] subunits under α-myosin heavy chain (α-MHC) promoter control, to target gene expression specifically in cardiomyocytes, and performed patch-clamp experiments on isolated ventricular myocytes and invasive electrophysiology on anesthetized mice.
RESULTS: In Kir6.1-GOF ventricular myocytes, KATP channels showed decreased ATP sensitivity but no significant change in current density. Ambulatory ECG recordings on Kir6.1-GOF mice revealed AV nodal conduction abnormalities and junctional rhythm. Invasive electrophysiologic analyses revealed slowing of conduction and conduction failure through the AV node but no increase in susceptibility to atrial or ventricular ectopic activity. Surface ECGs recorded from CS patients also demonstrated first-degree AV block and fascicular block.
CONCLUSIONS: The primary electrophysiologic consequence of cardiac KATP GOF is on the conduction system, particularly the AV node, resulting in conduction abnormalities in CS patients who carry KATP GOF mutations.
摘要：
背景：KATP通道亚基Kir6.1和SUR2中的功能增益（GOF）突变导致Cantu综合征（CS），以多种心血管异常为特征的疾病。
目的：本研究的目的是更好地确定心脏中这种GOF突变的电生理后果。
方法：我们产生了在α-肌球蛋白重链（α-MHC）启动子控制下表达ATP不敏感Kir6.1[G343D]亚基的转基因小鼠（Kir6.1-GOF），特异性地靶向心肌细胞中的基因表达，并对分离的心室肌细胞进行膜片钳实验，对麻醉小鼠进行侵入性电生理实验。
结果：在Kir6.1-GOF心室肌细胞中，KATP通道显示ATP敏感性降低，但电流密度无明显变化。Kir6.1-GOF小鼠动态心电图记录显示房室结传导异常和交界性节律。侵入性电生理分析显示，通过房室结的传导和传导衰竭减慢，但对心房或心室异位活动的敏感性没有增加。从CS患者记录的表面ECG也显示出一级房室传导阻滞和束状传导阻滞。
结论：心脏KATPGOF的主要电生理后果是传导系统，特别是AV节点，导致携带KATPGOF突变的CS患者的传导异常。
目的：本研究的目的是更好地确定心脏中这种GOF突变的电生理后果。
方法：我们产生了在α-肌球蛋白重链（α-MHC）启动子控制下表达ATP不敏感Kir6.1[G343D]亚基的转基因小鼠（Kir6.1-GOF），特异性地靶向心肌细胞中的基因表达，并对分离的心室肌细胞进行膜片钳实验，对麻醉小鼠进行侵入性电生理实验。
结果：在Kir6.1-GOF心室肌细胞中，KATP通道显示ATP敏感性降低，但电流密度无明显变化。Kir6.1-GOF小鼠动态心电图记录显示房室结传导异常和交界性节律。侵入性电生理分析显示，通过房室结的传导和传导衰竭减慢，但对心房或心室异位活动的敏感性没有增加。从CS患者记录的表面ECG也显示出一级房室传导阻滞和束状传导阻滞。
结论：心脏KATPGOF的主要电生理后果是传导系统，特别是AV节点，导致携带KATPGOF突变的CS患者的传导异常。
