Abstract 14999: Calmodulin Mutation Associated With Neonatal Long-QT Syndrome Evokes Increased Persistent Sodium Current From a Fetal Nav1.5 Splice Variant
Background: Calmodulin (CaM) mutations have recently been associated with severe congenital long-QT syndrome (LQTS) causing recurrent cardiac arrest during infancy. The mechanisms responsible for LQTS associated with CaM mutations have not been elucidated. One plausible contributing mechanism is cardiac sodium channel (Nav1.5) dysfunction. Here we investigated effects of the CaM mutation D130G on Nav1.5. Given the early age-of-onset of cardiac arrhythmia in the probands, we hypothesized that CaM-D130G preferentially causes dysfunction of a fetal and neonatal heart expressed Nav1.5 splice variant.
Methods: Whole cell voltage clamp recording experiments were conducted on heterologously expressed wild-type (WT) Nav1.5 in either the canonical or fetal-expressed splice isoform (fetal Nav1.5) co-expressed with WT or mutant (D130G) CaM. Current clamp recording was performed on acutely isolated rabbit left ventricular cardiomyocytes with intracellular WT or D130G CaM polypeptides in the recording pipette.
Results: We observed that CaM-D130G co-expressed with fetal Nav1.5 evoked a significantly larger persistent sodium current (3.1 ± 1.0%, n = 9) compared to co-expression with WT CaM (0.2 ± 0.1%, n = 8). By contrast, increased persistent current was not observed when D130G was co-expressed with the canonical Nav1.5 splice isoform (0.2 ± 0.1%, n = 5). Co-expression of CaM-D130G with canonical Nav1.5 did not significantly affect activation or steady-state inactivation of the channels compared to WT-CaM. However, D130G co-expressed with the fetal splice variant of Nav1.5 results in an increased window current compared to WT-CaM. Recordings of acutely isolated rabbit ventricular myocytes revealed a significant prolongation of cardiac action potential duration in the presence of intracellular CaM-D130G compared to WT-CaM.
Conclusion: Increased persistent sodium current is one plausible mechanism contributing to the striking QT prolongation in LQTS associated with CALM1 mutation. Combination of this defect with other dysfunctional ion channels likely underlies severity of symptoms associated with CaM-D130G. The preferential effect of CaM-D130G on fetal Nav1.5 helps explain the early onset of arrhythmia in this context.
- © 2013 by American Heart Association, Inc.