Effect of Skeletal Muscle Na+ Channel Delivered Via a Cell Platform on Cardiac Conduction and Arrhythmia Induction

Gerard J. J. Boink; Jia Lu; Helen E. Driessen; Lian Duan; Eugene A. Sosunov; Evgeny P. Anyukhovsky; Iryna N. Shlapakova; David H. Lau; Tove S. Rosen; Peter Danilo; Zhiheng Jia; Nazira Ozgen; Yevgeniy Bobkov; Yuanjian Guo; Peter R. Brink; Yelena Kryukova; Richard B. Robinson; Emilia Entcheva; Ira S. Cohen; Michael R. Rosen

doi:https://doi.org/10.1161/CIRCEP.111.969907

Effect of Skeletal Muscle Na+ Channel Delivered Via a Cell Platform on Cardiac Conduction and Arrhythmia Induction

Gerard J. J. Boink, Jia Lu, Helen E. Driessen, Lian Duan, Eugene A. Sosunov, Evgeny P. Anyukhovsky, Iryna N. Shlapakova, David H. Lau, Tove S. Rosen, Peter Danilo, Zhiheng Jia, Nazira Ozgen, Yevgeniy Bobkov, Yuanjian Guo, Peter R. Brink, Yelena Kryukova, Richard B. Robinson, Emilia Entcheva, Ira S. Cohen, Michael R. Rosen

Research output: Contribution to journal › Article › Academic › peer-review

12 Citations (Scopus)

Abstract

Background-In depolarized myocardial infarct epicardial border zones, the cardiac sodium channel is largely inactivated, contributing to slow conduction and reentry. We have demonstrated that adenoviral delivery of the skeletal muscle Na+ channel (SkM1) to epicardial border zones normalizes conduction and reduces induction of ventricular tachycardia/ventricular fibrillation. We now studied the impact of canine mesenchymal stem cells (cMSCs) in delivering SkM1. Methods and Results-cMSCs were isolated and transfected with SkM1. Coculture experiments showed cMSC/SkM1 but not cMSC alone and maintained fast conduction at depolarized potentials. We studied 3 groups in the canine 7d infarct: sham, cMSC, and cMSC/SkM1. In vivo epicardial border zones electrograms were broad and fragmented in sham, narrower in cMSCs, and narrow and unfragmented in cMSC/SkM1 (P <0.05). During programmed electrical stimulation of epicardial border zones, QRS duration in cMSC/SkM1 was shorter than in cMSC and sham (P <0.05). Programmed electrical stimulation-induced ventricular tachycardia/ventricular fibrillation was equivalent in all groups (P>0.05). Conclusion-cMSCs provide efficient delivery of SkM1 current. The interventions performed (cMSCs or cMSC/SkM1) were neither antiarrhythmic nor proarrhythmic. Comparing outcomes with cMSC/SkM1 and viral gene delivery highlights the criticality of the delivery platform to SkM1 antiarrhythmic efficacy. (Circ Arrhythm Electrophysiol. 2012;5:831-840.)

Original language	English
Pages (from-to)	831-840
Journal	Circulation. Arrhythmia and electrophysiology
Volume	5
Issue number	4
DOIs	https://doi.org/10.1161/CIRCEP.111.969907
Publication status	Published - 2012

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https://doi.org/10.1161/CIRCEP.111.969907

Cite this

Boink, G. J. J., Lu, J., Driessen, H. E., Duan, L., Sosunov, E. A., Anyukhovsky, E. P., Shlapakova, I. N., Lau, D. H., Rosen, T. S., Danilo, P., Jia, Z., Ozgen, N., Bobkov, Y., Guo, Y., Brink, P. R., Kryukova, Y., Robinson, R. B., Entcheva, E., Cohen, I. S., & Rosen, M. R. (2012). Effect of Skeletal Muscle Na+ Channel Delivered Via a Cell Platform on Cardiac Conduction and Arrhythmia Induction. Circulation. Arrhythmia and electrophysiology, 5(4), 831-840. https://doi.org/10.1161/CIRCEP.111.969907

@article{804ed07277c6411983def0592afe3895,

title = "Effect of Skeletal Muscle Na+ Channel Delivered Via a Cell Platform on Cardiac Conduction and Arrhythmia Induction",

abstract = "Background-In depolarized myocardial infarct epicardial border zones, the cardiac sodium channel is largely inactivated, contributing to slow conduction and reentry. We have demonstrated that adenoviral delivery of the skeletal muscle Na+ channel (SkM1) to epicardial border zones normalizes conduction and reduces induction of ventricular tachycardia/ventricular fibrillation. We now studied the impact of canine mesenchymal stem cells (cMSCs) in delivering SkM1. Methods and Results-cMSCs were isolated and transfected with SkM1. Coculture experiments showed cMSC/SkM1 but not cMSC alone and maintained fast conduction at depolarized potentials. We studied 3 groups in the canine 7d infarct: sham, cMSC, and cMSC/SkM1. In vivo epicardial border zones electrograms were broad and fragmented in sham, narrower in cMSCs, and narrow and unfragmented in cMSC/SkM1 (P <0.05). During programmed electrical stimulation of epicardial border zones, QRS duration in cMSC/SkM1 was shorter than in cMSC and sham (P <0.05). Programmed electrical stimulation-induced ventricular tachycardia/ventricular fibrillation was equivalent in all groups (P>0.05). Conclusion-cMSCs provide efficient delivery of SkM1 current. The interventions performed (cMSCs or cMSC/SkM1) were neither antiarrhythmic nor proarrhythmic. Comparing outcomes with cMSC/SkM1 and viral gene delivery highlights the criticality of the delivery platform to SkM1 antiarrhythmic efficacy. (Circ Arrhythm Electrophysiol. 2012;5:831-840.)",

author = "Boink, {Gerard J. J.} and Jia Lu and Driessen, {Helen E.} and Lian Duan and Sosunov, {Eugene A.} and Anyukhovsky, {Evgeny P.} and Shlapakova, {Iryna N.} and Lau, {David H.} and Rosen, {Tove S.} and Peter Danilo and Zhiheng Jia and Nazira Ozgen and Yevgeniy Bobkov and Yuanjian Guo and Brink, {Peter R.} and Yelena Kryukova and Robinson, {Richard B.} and Emilia Entcheva and Cohen, {Ira S.} and Rosen, {Michael R.}",

year = "2012",

doi = "https://doi.org/10.1161/CIRCEP.111.969907",

language = "English",

volume = "5",

pages = "831--840",

journal = "Circulation. Arrhythmia and electrophysiology",

issn = "1941-3149",

publisher = "Lippincott Williams and Wilkins",

number = "4",

}

Boink, GJJ, Lu, J, Driessen, HE, Duan, L, Sosunov, EA, Anyukhovsky, EP, Shlapakova, IN, Lau, DH, Rosen, TS, Danilo, P, Jia, Z, Ozgen, N, Bobkov, Y, Guo, Y, Brink, PR, Kryukova, Y, Robinson, RB, Entcheva, E, Cohen, IS & Rosen, MR 2012, 'Effect of Skeletal Muscle Na+ Channel Delivered Via a Cell Platform on Cardiac Conduction and Arrhythmia Induction', Circulation. Arrhythmia and electrophysiology, vol. 5, no. 4, pp. 831-840. https://doi.org/10.1161/CIRCEP.111.969907

TY - JOUR

T1 - Effect of Skeletal Muscle Na+ Channel Delivered Via a Cell Platform on Cardiac Conduction and Arrhythmia Induction

AU - Boink, Gerard J. J.

AU - Lu, Jia

AU - Driessen, Helen E.

AU - Duan, Lian

AU - Sosunov, Eugene A.

AU - Anyukhovsky, Evgeny P.

AU - Shlapakova, Iryna N.

AU - Lau, David H.

AU - Rosen, Tove S.

AU - Danilo, Peter

AU - Jia, Zhiheng

AU - Ozgen, Nazira

AU - Bobkov, Yevgeniy

AU - Guo, Yuanjian

AU - Brink, Peter R.

AU - Kryukova, Yelena

AU - Robinson, Richard B.

AU - Entcheva, Emilia

AU - Cohen, Ira S.

AU - Rosen, Michael R.

PY - 2012

Y1 - 2012

N2 - Background-In depolarized myocardial infarct epicardial border zones, the cardiac sodium channel is largely inactivated, contributing to slow conduction and reentry. We have demonstrated that adenoviral delivery of the skeletal muscle Na+ channel (SkM1) to epicardial border zones normalizes conduction and reduces induction of ventricular tachycardia/ventricular fibrillation. We now studied the impact of canine mesenchymal stem cells (cMSCs) in delivering SkM1. Methods and Results-cMSCs were isolated and transfected with SkM1. Coculture experiments showed cMSC/SkM1 but not cMSC alone and maintained fast conduction at depolarized potentials. We studied 3 groups in the canine 7d infarct: sham, cMSC, and cMSC/SkM1. In vivo epicardial border zones electrograms were broad and fragmented in sham, narrower in cMSCs, and narrow and unfragmented in cMSC/SkM1 (P <0.05). During programmed electrical stimulation of epicardial border zones, QRS duration in cMSC/SkM1 was shorter than in cMSC and sham (P <0.05). Programmed electrical stimulation-induced ventricular tachycardia/ventricular fibrillation was equivalent in all groups (P>0.05). Conclusion-cMSCs provide efficient delivery of SkM1 current. The interventions performed (cMSCs or cMSC/SkM1) were neither antiarrhythmic nor proarrhythmic. Comparing outcomes with cMSC/SkM1 and viral gene delivery highlights the criticality of the delivery platform to SkM1 antiarrhythmic efficacy. (Circ Arrhythm Electrophysiol. 2012;5:831-840.)

AB - Background-In depolarized myocardial infarct epicardial border zones, the cardiac sodium channel is largely inactivated, contributing to slow conduction and reentry. We have demonstrated that adenoviral delivery of the skeletal muscle Na+ channel (SkM1) to epicardial border zones normalizes conduction and reduces induction of ventricular tachycardia/ventricular fibrillation. We now studied the impact of canine mesenchymal stem cells (cMSCs) in delivering SkM1. Methods and Results-cMSCs were isolated and transfected with SkM1. Coculture experiments showed cMSC/SkM1 but not cMSC alone and maintained fast conduction at depolarized potentials. We studied 3 groups in the canine 7d infarct: sham, cMSC, and cMSC/SkM1. In vivo epicardial border zones electrograms were broad and fragmented in sham, narrower in cMSCs, and narrow and unfragmented in cMSC/SkM1 (P <0.05). During programmed electrical stimulation of epicardial border zones, QRS duration in cMSC/SkM1 was shorter than in cMSC and sham (P <0.05). Programmed electrical stimulation-induced ventricular tachycardia/ventricular fibrillation was equivalent in all groups (P>0.05). Conclusion-cMSCs provide efficient delivery of SkM1 current. The interventions performed (cMSCs or cMSC/SkM1) were neither antiarrhythmic nor proarrhythmic. Comparing outcomes with cMSC/SkM1 and viral gene delivery highlights the criticality of the delivery platform to SkM1 antiarrhythmic efficacy. (Circ Arrhythm Electrophysiol. 2012;5:831-840.)

U2 - https://doi.org/10.1161/CIRCEP.111.969907

DO - https://doi.org/10.1161/CIRCEP.111.969907

M3 - Article

C2 - 22722661

SN - 1941-3149

VL - 5

SP - 831

EP - 840

JO - Circulation. Arrhythmia and electrophysiology

JF - Circulation. Arrhythmia and electrophysiology

IS - 4

ER -