What is the clinical evidence from this study?

Study design: Other. Population: Sinus bradycardia / Long QT syndrome model (n=37). Intervention: ERG1 B knockout vs. Wild-type mice. Primary outcome: Abrupt spontaneous episodes of sinus bradycardia.

February 28, 2003Open Access

Selective Knockout of Mouse ERG1 B Potassium Channel Eliminates I Kr in Adult Ventricular Myocytes and Elicits Episodes of Abrupt Sinus Bradycardia

Key Result

Selective knockout of the ERG1 B potassium channel in adult mice eliminated IKr expression and elicited abrupt spontaneous episodes of sinus bradycardia in 6 of 21 mice, compared to 0 of 16 wild-type mice.

PICO

Population

37 adult mice (21 ERG1 B knockout and 16 wild-type) evaluated for electrocardiographic abnormalities and IKr expression.

Exposure / Comparator

ERG1 B knockout vs Wild-type mice

Primary Outcome

Abrupt spontaneous episodes of sinus bradycardia

Main Result

Absolute Event Rate: 28.6% vs 0%

Limitations

The knockout model does not lengthen the QT interval, limiting its utility as a complete model for human long QT2 syndrome.
The study cannot discern whether the abrupt bradycardias relate to abnormalities in ERG1 B expression in the sinus node or autonomic ganglia.

Abstract

The ERG1 gene encodes a family of potassium channels. Mutations in human ERG1 lead to defects in cardiac repolarization, referred to as the long QT syndrome. Through homologous recombination in mouse embryonic stem cells the ERG1 B potassium channel transcript was eliminated while the ERG1 A transcript was maintained. Heterologous expression of ERG1 isoforms had previously indicated that the deactivation time course of ERG1 B is 10-fold more rapid than that of ERG1 A. In day-18 fetal +/+ myocytes, I(Kr) exhibited two time constants of deactivation (3,933 +/- 404 and 350 +/- 19 ms at -50 mV), whereas in age-matched ERG1 B(-/-) mice the rapid component was absent. Biexponential deactivation rates (2,039 +/- 268 and 163 +/- 43 ms at -50 mV) were also observed in adult +/+ myocytes. In adult ERG1 B(-/-) myocytes no I(Kr) was detected. Electrocardiogram intervals were similar in +/+ and -/- mice. However, adult -/- mice manifested abrupt spontaneous episodes of sinus bradycardia (>100 ms of slowing) in 6 out of 21 mice. This phenomenon was never observed in +/+ mice (0 out of 16). We conclude that ERG1 B is necessary for I(Kr) expression in the surface membrane of adult myocytes. Knockout of ERG1 B predisposes mice to episodic sinus bradycardia.

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