Abstract 13233: Increase in Action Potential Duration Caused by Persistent Late Sodium Current is Responsible for Arrhythmias in LMNA Related Dilated Cardiomyopathy
Dilated cardiomyopathy (DCM), characterized by left ventricular dilatation and systolic dysfunction, constitutes a significant cause for heart failure, sudden cardiac death or lethal arrhythmia. Mutations in LMNA gene that codes for Lamin A/C protein of the nuclear lamina, is frequently associated with DCM. A missense mutation (N195K) in the A-type lamins results in DCM and sudden death due to arrhythmias. However, the pathogenic mechanism of arrhythmia caused by the N195K mutation remains unknown. Altered expression and function of the cardiac voltage gated ion channels in DCM is commonly associated with arrhythmia. We hypothesized that an altered expression and function of the ion channel subunits is arrhythmogenic in LmnaN195K related DCM. To investigate this we used a mouse line expressing N195K mutation of the Lamin (LmnaN195K/N195K), which die at early age of 6-7 weeks due to DCM and arrhythmia. A genome wide comparative cDNA microarray analysis from LmnaN195K/N195K and the wild type (WT) control ventricles at 6 weeks age revealed alterations in the expression of a number of genes including ion channel subunits, NaVβ4 of the cardiac Na+ channel and Cavβ2 subunit of the L-type Ca2+ channel, the scaffolding protein caveolins, and many caveolae associated proteins. Western blot analysis confirmed a significant alteration in the expression of many caveolae-associated proteins including Cav-3, protein kinase A, AKAP150 and Cavβ2. Whole-cell patch clamp analysis using ventricular myocytes isolated from LmnaN195K/N195K mice hearts demonstrated significant increase in the peak Na+ and Ca2+ currents and persistent increase in late Na+ current (INaL) compared to ventricular myocytes isolated from WT litter mates. Furthermore, a significant increase in action potential duration was observed in ventricular myocytes where APD90 was 56.89±9 in mutants vs.17.88±1ms in wild types. We conclude that the increase in the peak and persistent late INa,L in the ventricular myocytes causes increase in action potential duration which results in arrhythmia in the Lmna-N195K mutation related dilated cardiomyopathy.
- © 2011 by American Heart Association, Inc.