Escape capture bigeminy: phenotypic marker of cardiac sodium channel voltage sensor mutation R222Q.
BACKGROUND
Electrocardiographic signature of escape capture bigeminy that spans generations and clusters in a family has not been linked to a sodium channel voltage sensor mutation.


OBJECTIVE
To characterize the clinical and biophysical consequences of the R222Q mutation in the voltage sensor of cardiac sodium channels.


METHODS
Comprehensive clinical assessment, invasive electrophysiologic study, genetic analysis, and patch-clamp studies were undertaken.


RESULTS
Uniquely, 5 members had the same electrocardiographic pattern of a junctional escape ventricular capture bigeminy. Genetic analysis of 3 family members revealed the same mutation (R222Q) in the cardiac sodium channel gene, SCN5A (nucleotide change was 665 G→A that led to missense amino acid substitution Arg 222 Gln, located in the S4 voltage sensor in domain I). Catheterization and mapping revealed that there was no consistent evidence of bundle branch reentry or fascicular potentials preceding ectopic beats. The bigeminy was suppressed by the intravenous administration of the sodium channel blocker, lidocaine. Patch-clamp studies revealed unique differential leftward voltage-dependent shifts in activation and inactivation properties of human voltage-gated Na(+) channels with the R222Q mutation, consistent with increasing channel excitability at precisely the voltages corresponding to the resting membrane potential of cardiomyocytes.


CONCLUSIONS
The R222Q mutation enhances cardiac sodium channel excitability, resulting in an unusual, highly penetrant phenotype of escape capture bigeminy and cardiomyopathy. These findings support the conclusion that a mutation in the voltage sensor of cardiac sodium channels can cause bigeminal arrhythmia associated with cardiomyopathy.
Division of Cardiology, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.
Krishnakumar
K
Nair
Roman
R
Pekhletski
Louise
L
Harris
Melanie
M
Care
Chantal
C
Morel
Talha
T
Farid
Peter H
PH
Backx
Elod
E
Szabo
Kumaraswamy
K
Nanthakumar
D000328:Adult; D000368:Aged; D009202:Cardiomyopathies / Q000235:genetics*; D016009:Chi-Square Distribution; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D018879:Ventricular Premature Complexes / Q000235:genetics*
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human