共 34 条
Cardiac sodium channel mutation associated with epinephrine-induced QT prolongation and sinus node dysfunction
被引:22
作者:
Chen, Jiarong
[1
]
Makiyama, Takeru
[1
]
Wuriyanghai, Yimin
[1
,2
]
Ohno, Seiko
[1
,2
,3
]
Sasaki, Kenichi
[1
]
Hayano, Mamoru
[1
]
Harita, Takeshi
[1
]
Nishiuchi, Suguru
[1
]
Yamamoto, Yuta
[1
]
Ueyama, Takeshi
[4
]
Shimizu, Akihiko
[4
]
Horie, Minoru
[2
]
Kimura, Takeshi
[1
]
机构:
[1] Kyoto Univ, Grad Sch Med, Dept Cardiovasc Med, Kyoto, Japan
[2] Shiga Univ Med Sci, Dept Cardiovasc & Resp Med, Otsu, Shiga 52021, Japan
[3] Shiga Univ Med Sci, Ctr Epidemiol Res Asia, Otsu, Shiga 52021, Japan
[4] Yamaguchi Univ, Grad Sch Med, Dept Med & Clin Sci, Ube, Yamaguchi 755, Japan
关键词:
SCN5A;
Epinephrine;
Long-UT syndrome;
Protein kinase A;
Protein kinase C;
Adrenergic stimulation;
PROTEIN-KINASE-A;
MODULATION;
PHOSPHORYLATION;
MUTANT;
MECHANISM;
NA(V)1.5;
THERAPY;
DISEASE;
COMPLEX;
SITE;
D O I:
10.1016/j.hrthm.2015.08.021
中图分类号:
R5 [内科学];
学科分类号:
1002 ;
100201 ;
摘要:
BACKGROUND Long-QT syndrome (LQTS) is an inherited arrhythmia characterized by prolonged ventricular repolarization and malignant tachyarrhythmias. LQ-LQ-T1, LQT2, and LQT3 are caused by mutations in KCNO (LQT1), KCNH2 (LQT2), and SCN5A (LQT3), which account for approximately 90% of genotyped LQTS patients. Most cardiac events in LQT1 patients occur during exercise, whereas patients with LQT3 tend to have arrhythmic events during rest or asleep. OBJECTIVE The study aimed to identify a genetic mutation in a Japanese man who presented with sinus node dysfunction and prolonged QT interval on exercise and epinephrine stress tests, as well as to clarify the electrophysiological properties of mutant channels. METHODS LQTS-related genes were screened in this patient. Electrophysiological functional assays were conducted with a heterologous expression system. RESULTS We identified a heterozygous missense SCN5A mutation, V2016M, which changes the last amino acid of the cardiac sodium channel. Electrophysiological analyses revealed that the mutant channels exhibited a loss-of-function feature, decreased peak sodium current densities (wild type 175.2 +/- 17.6 pA/pF; V2016M 97.2 +/- 16.0 pA/pF; P < .01). In addition, the mutant channels showed gain-of-function features: increased late sodium currents by protein kinase A activation (wild type 0.07 +/- 0.01%; V2016M 0.17 +/- 0.030/0; P < .05) and impaired inactivation of sodium channels by protein kinase A or C activation. CONCLUSION We identified an SCN5A mutation in a patient with sinus node dysfunction and epinephrine-induced QT prolongation, which was an atypical phenotype for LQT3. The electrophysiological properties of the mutant channels might be associated with the overlapping clinical features of the patient.
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页码:289 / 298
页数:10
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