AIMS: Reentrant arrhythmias often develop in the setting of myocardial infarction and ensuing slow propagation. Increased Na(+) channel expression could prevent or disrupt reentrant circuits by speeding conduction if channel availability is not limited by membrane depolarization within the diseased myocardium. We therefore asked if, in the setting of membrane depolarization, action potential (AP) upstroke and normal conduction can be better preserved by the expression of a Na(+) channel isoform with altered biophysical properties compared to the native cardiac Na(+) channel isoform, namely having a positively shifted, voltage-dependent inactivation. METHODS AND RESULTS: The skeletal Na(+) channel isoform (SkM1) and the cardiac Na(+) channel isoform (Nav1.5) were expressed in newborn rat ventricular myocyte cultures with a point mutation introduced in Nav1.5 to increase tetrodotoxin (TTX) sensitivity so native and expressed currents could be distinguished. External K(+) was increased from 5.4 to 10 mmol/L to induce membrane depolarization. APs, Na(+) currents, and conduction velocity (CV) were measured. In control cultures, elevated K(+) significantly reduced AP upstroke ( approximately 75%) and CV ( approximately 25%). Expression of Nav1.5 did not protect AP upstroke from K(+) depolarization. In contrast, in SkM1 expressing cultures, high K(+) reduced AP upstroke <50% and conduction was not significantly reduced. In a simulated anatomical reentry setting (using a void), the angular velocity (AV) of induced reentry was faster and the excitable gap shorter in SkM1 cultures compared to control for both normal and high K(+). CONCLUSION: Expression of SkM1 but not Nav1.5 preserves AP upstroke and CV in a K(+)-depolarized syncytium. The higher AV and shorter excitable gap observed during reentry excitation around a void in SkM1 cultures would be expected to facilitate reentry self-termination. SkM1 Na(+) channel expression represents a novel gene therapy for the treatment of reentrant arrhythmias.
AIMS: Reentrant arrhythmias often develop in the setting of myocardial infarction and ensuing slow propagation. Increased Na(+) channel expression could prevent or disrupt reentrant circuits by speeding conduction if channel availability is not limited by membrane depolarization within the diseased myocardium. We therefore asked if, in the setting of membrane depolarization, action potential (AP) upstroke and normal conduction can be better preserved by the expression of a Na(+) channel isoform with altered biophysical properties compared to the native cardiac Na(+) channel isoform, namely having a positively shifted, voltage-dependent inactivation. METHODS AND RESULTS: The skeletal Na(+) channel isoform (SkM1) and the cardiac Na(+) channel isoform (Nav1.5) were expressed in newborn rat ventricular myocyte cultures with a point mutation introduced in Nav1.5 to increase tetrodotoxin (TTX) sensitivity so native and expressed currents could be distinguished. External K(+) was increased from 5.4 to 10 mmol/L to induce membrane depolarization. APs, Na(+) currents, and conduction velocity (CV) were measured. In control cultures, elevated K(+) significantly reduced AP upstroke ( approximately 75%) and CV ( approximately 25%). Expression of Nav1.5 did not protect AP upstroke from K(+) depolarization. In contrast, in SkM1 expressing cultures, high K(+) reduced AP upstroke <50% and conduction was not significantly reduced. In a simulated anatomical reentry setting (using a void), the angular velocity (AV) of induced reentry was faster and the excitable gap shorter in SkM1 cultures compared to control for both normal and high K(+). CONCLUSION: Expression of SkM1 but not Nav1.5 preserves AP upstroke and CV in a K(+)-depolarized syncytium. The higher AV and shorter excitable gap observed during reentry excitation around a void in SkM1 cultures would be expected to facilitate reentry self-termination. SkM1Na(+) channel expression represents a novel gene therapy for the treatment of reentrant arrhythmias.
Authors: M A Allessie; P A Boyden; A J Camm; A G Kléber; M J Lab; M J Legato; M R Rosen; P J Schwartz; P M Spooner; D R Van Wagoner ; A L Waldo Journal: Circulation Date: 2001-02-06 Impact factor: 29.690
Authors: 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 Journal: Circ Arrhythm Electrophysiol Date: 2012-06-21
Authors: Gerard J J Boink; David H Lau; Iryna N Shlapakova; Eugene A Sosunov; Evgeny P Anyukhovsky; Helen E Driessen; Wen Dun; Ming Chen; Peter Danilo; Tove S Rosen; Nazira Őzgen; Heather S Duffy; Yelena Kryukova; Penelope A Boyden; Richard B Robinson; Peter R Brink; Ira S Cohen; Michael R Rosen Journal: Cardiovasc Res Date: 2012-02-27 Impact factor: 10.787
Authors: Evgeny P Anyukhovsky; Eugene A Sosunov; Yelena N Kryukova; Kevin Prestia; Nazira Ozgen; Mathilde Rivaud; Ira S Cohen; Richard B Robinson; Michael R Rosen Journal: Cardiovasc Res Date: 2010-09-07 Impact factor: 10.787
Authors: Gerard J J Boink; Lian Duan; Bruce D Nearing; Iryna N Shlapakova; Eugene A Sosunov; Evgeny P Anyukhovsky; Eugene Bobkov; Yelena Kryukova; Nazira Ozgen; Peter Danilo; Ira S Cohen; Richard L Verrier; Richard B Robinson; Michael R Rosen Journal: J Am Coll Cardiol Date: 2013-02-06 Impact factor: 24.094