Abstract 20062: Remodeling of Repolarization and Arrhythmia Susceptibility in a Myosin Binding Protein C Knockout Mouse Model
Background: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease (1:500 in the general population) and amongst the leading causes of sudden cardiac death (SCD) in the young. There is lack of an in-depth understanding of cellular mechanisms leading to SCD in HCM. Prior studies that explored the cellular electrophysiological alterations in HCM, focused on the role of calcium and sodium currents in the development of cardiac hypertrophy and arrhythmia. Repolarizing potassium currents in HCM have not been investigated in detail. Better definition of the cellular substrates for arrhythmias could improve risk stratification and lead to potential novel therapeutic targets for prevention of SCD.
Objective: To test the hypothesis that repolarizing potassium currents are decreased, and to characterize the arrhythmogenic phenotype and cellular electrophysiological properties in MyBPC KO mice.
Methods and results: MyBPC KO mice demonstrate overt phenotype with severe hypertrophy and cardiac dysfunction compared to wild type (WT) control mice. Telemetric electrocardiographic recordings reveal prolongation of the QTc interval in the KO compared to WT control mice (56.8 ± 3.7 vs 28.6 ± 3.4 msec, n=4 KO, 4 WT, p< 0.01) with frequent arrhythmias including preexcitation, supraventricular and ventricular tachycardia. Whole cell current and voltage clamp studies, comparing KO to WT mice, demonstrate myocyte hypertrophy (469 ± 44 vs 234 ± 15 pF, n=18 KO,15 WT, p<0.01), action potential prolongation (Action potential duration (APD)50 of 30.4 ± 4.5 vs 17.7 ± 3.2 msec, APD90 of 125.7 ± 17.3 vs 74.7± 8.1 msec, n=11 KO, 12 WT, p <0.05) and decreased repolarizing potassium currents normalized to cell capacitance (n=15 KO, 14 WT): Ik Peak (-120 to 60 mV) decrease of 33-39%, Ik1 (-120 to -60 mV) decrease of 16-30%, Iks (20 to 60 mV) decrease 21-23% and Ito (0 to 60mV) decrease of 46-61%. RT-PCR analysis reveals decreased mRNA levels of several potassium channels subunits, including KCND2, KCND3, KCNIP2, KCNA4 and KCNE1 (0.32-0.62 fold, p<0.05).
Conclusion: MyBPC KO mice demonstrate decreased transcript levels, remodeling of repolarizing potassium currents, action potential and QTc interval prolongation that could account for the arrhythmia susceptibility.
Author Disclosures: A. Toib: None. S. Mohsin: None. G. Borghetti: None. X. Zhang: None. C. Zhang: None. M. Wallner: None. Y. Yang: None. C.D. Troupes: None. H. Kubo: None. T.E. Sharp: None. E. Feldsott: None. E. Feldsott: None. R.M. Berretta: None. D.M. Trappanese: None. D.M. Trappanese: None. P. Gross: None. X. Chen: None. S.R. Houser: None.
- © 2016 by American Heart Association, Inc.