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Comparative Study
. 2013 Jun;6(3):546-54.
doi: 10.1161/CIRCEP.113.000400. Epub 2013 May 6.

Cardiac resynchronization therapy improves altered Na channel gating in canine model of dyssynchronous heart failure

Takeshi Aiba  1 , Andreas S Barth, Geoffrey G Hesketh, Yasmin L Hashambhoy, Khalid Chakir, Richard S Tunin, Joseph L Greenstein, Raimond L Winslow, David A Kass, Gordon F Tomaselli
Affiliations
Comparative Study

Cardiac resynchronization therapy improves altered Na channel gating in canine model of dyssynchronous heart failure

Takeshi Aiba et al. Circ Arrhythm Electrophysiol. 2013 Jun.

Abstract

Background: Slowed Na⁺ current (INa) decay and enhanced late INa (INa-L) prolong the action potential duration (APD) and contribute to early afterdepolarizations. Cardiac resynchronization therapy (CRT) shortens APD compared with dyssynchronous heart failure (DHF); however, the role of altered Na⁺ channel gating in CRT remains unexplored.

Methods and results: Adult dogs underwent left-bundle branch ablation and right atrial pacing (200 beats/min) for 6 weeks (DHF) or 3 weeks followed by 3 weeks of biventricular pacing at the same rate (CRT). INa and INa-L were measured in left ventricular myocytes from nonfailing, DHF, and CRT dogs. DHF shifted voltage-dependence of INa availability by -3 mV compared with nonfailing, enhanced intermediate inactivation, and slowed recovery from inactivation. CRT reversed the DHF-induced voltage shift of availability, partially reversed enhanced intermediate inactivation but did not affect DHF-induced slowed recovery. DHF markedly increased INa-L compared with nonfailing. CRT dramatically reduced DHF-induced enhanced INa-L, abbreviated the APD, and suppressed early afterdepolarizations. CRT was associated with a global reduction in phosphorylated Ca²⁺/Calmodulin protein kinase II, which has distinct effects on inactivation of cardiac Na⁺ channels. In a canine AP model, alterations of INa-L are sufficient to reproduce the effects on APD observed in DHF and CRT myocytes.

Conclusions: CRT improves DHF-induced alterations of Na⁺ channel function, especially suppression of INa-L, thus, abbreviating the APD and reducing the frequency of early afterdepolarizations. Changes in the levels of phosphorylated Ca²⁺/Calmodulin protein kinase II suggest a molecular pathway for regulation of INa by biventricular pacing of the failing heart.

Keywords: Na+ channels; arrhythmias; cardiac resynchronization therapy; electrophysiology; heart failure.

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Conflict of interest statement

Conflict of Interest Disclosures: None

Figures

Figure 1
Figure 1
CRT partially reverses DHF-induced altered Na+ channel currents. A: Representative families of Na+currents (INa) in myocytes from non-failing (NF), DHF and CRT dogs. Cells were held at −120 mV and currents were elicited by 50 ms test pulses to potentials ranging from −100 to +40 mV. B: Peak current-voltage (I-V) relationships of INa in NF, DHF and CRT ventricular myocytes. C and D: The voltage-dependence of activation (G/Gmax) (C) and steady-state inactivation (I/Imax) of INa in NF, DHF and CRT myocytes (D), the data were fit with Boltzmann functions of the form: G/Gmax= 1/[1+exp(V1/2-V)k]. E: The time course of recovery from inactivation of INa F: Kinetics of entry into slow inactivated states of INa in NF, DHF and CRT ventricular myocytes. The values in parentheses are the number of cells studied in this and all remaining figures.
Figure 1
Figure 1
CRT partially reverses DHF-induced altered Na+ channel currents. A: Representative families of Na+currents (INa) in myocytes from non-failing (NF), DHF and CRT dogs. Cells were held at −120 mV and currents were elicited by 50 ms test pulses to potentials ranging from −100 to +40 mV. B: Peak current-voltage (I-V) relationships of INa in NF, DHF and CRT ventricular myocytes. C and D: The voltage-dependence of activation (G/Gmax) (C) and steady-state inactivation (I/Imax) of INa in NF, DHF and CRT myocytes (D), the data were fit with Boltzmann functions of the form: G/Gmax= 1/[1+exp(V1/2-V)k]. E: The time course of recovery from inactivation of INa F: Kinetics of entry into slow inactivated states of INa in NF, DHF and CRT ventricular myocytes. The values in parentheses are the number of cells studied in this and all remaining figures.
Figure 2
Figure 2
CRT hastens the Na current decay slowing induced by DHF. A: Superimposed representative INa in NF, DHF and CRT elicited by 50ms depolarizations to −40 mV (from −120 mV) ([Na+]o= 10mM). The decay phase of the current during a voltage step was fit with a biexponential function of the form: I(t)= Af·exp(−τ/f) + As·exp(−τ/s), where Af and As are fractions of fast and slow inactivating components, respectively. B: Plots of the voltage-dependent change of the initial (τ fast) and late (τ slow) time constant of INa decay. CRT normalized DHF-induced prolongation of τ slow.
Figure 3
Figure 3
CRT reverses DHF-induced enhanced late Na current. A: Representative normalized TTX-sensitive currents in NF, DHF and CRT canine myocytes ([Na+]o= 10mM). Late INa was elicited by 800 ms depolarizations to −20 mV (from −140 mV) in the presence and absence of TTX. The average amplitude of the TTX-sensitive late current between 100 and 500 ms was normalized to the peak INa B: Bar plot of the magnitude of late current normalized to the peak for each condition in low external [Na+]. C: Representative late Na currents (INa-L) recorded in physiological Na+ concentration ([Na+]o=140mM) in absence (baseline) or presence of ranolazine (10µM) in myocytes from NF, DHF and CRT ventricles. INa-L was elicited by 2000 ms depolarization to −40 mV (from −140 mV). INa-L was measured as the average amplitude of the current between 200 and 220 ms. D: Bar plot of the magnitude of late current normalized to the peak for each condition in physiological external [Na+]. DHF increased INa-L in both low and physiological Na+ conditions, and CRT dramatically reduced the DHF-induced increase of INa-L. Ranolazine reduced INa-L in myocytes from DHF but not NF or CRT hearts. ‡ :p<0.01 vs. NF, #:p<0.01 vs. DHF by ANOVA with Bonferroni test. *: p<0.05 vs. control by unpaired t-test.
Figure 3
Figure 3
CRT reverses DHF-induced enhanced late Na current. A: Representative normalized TTX-sensitive currents in NF, DHF and CRT canine myocytes ([Na+]o= 10mM). Late INa was elicited by 800 ms depolarizations to −20 mV (from −140 mV) in the presence and absence of TTX. The average amplitude of the TTX-sensitive late current between 100 and 500 ms was normalized to the peak INa B: Bar plot of the magnitude of late current normalized to the peak for each condition in low external [Na+]. C: Representative late Na currents (INa-L) recorded in physiological Na+ concentration ([Na+]o=140mM) in absence (baseline) or presence of ranolazine (10µM) in myocytes from NF, DHF and CRT ventricles. INa-L was elicited by 2000 ms depolarization to −40 mV (from −140 mV). INa-L was measured as the average amplitude of the current between 200 and 220 ms. D: Bar plot of the magnitude of late current normalized to the peak for each condition in physiological external [Na+]. DHF increased INa-L in both low and physiological Na+ conditions, and CRT dramatically reduced the DHF-induced increase of INa-L. Ranolazine reduced INa-L in myocytes from DHF but not NF or CRT hearts. ‡ :p<0.01 vs. NF, #:p<0.01 vs. DHF by ANOVA with Bonferroni test. *: p<0.05 vs. control by unpaired t-test.
Figure 4
Figure 4
CRT abbreviates DHF-induced prolongation of APD by reducing late Na current. A: Representative APs recorded from myocytes isolated from the lateral wall of the LV in NF, DHF and CRT canine ventricles at baseline and after ranolazine (1µM) at a paced cycle length of 2000 ms. B: Action potential duration at 90% repolarization (APD90) at baseline and after ranolazine at a paced CL of 2000 ms in NF, DHF and CRT, and C: Fractional change in APD90 by ranolazine in each group. D: Development of EADs at baseline and after ranolazine in ventricular myocytes from NF, DHF and CRT dogs. E: Alteration of INa-L in a canine mathematical AP model mimicking DHF and CRT reproduced the experimental effects of DHF and CRT on the APD. ‡ :p<0.01, †:p<0.05 vs. NF, #:p<0.01 vs. DHF by ANOVA with Bonferroni test. **:p<0.01, *: p<0.05 vs. baseline by paired t-test.
Figure 4
Figure 4
CRT abbreviates DHF-induced prolongation of APD by reducing late Na current. A: Representative APs recorded from myocytes isolated from the lateral wall of the LV in NF, DHF and CRT canine ventricles at baseline and after ranolazine (1µM) at a paced cycle length of 2000 ms. B: Action potential duration at 90% repolarization (APD90) at baseline and after ranolazine at a paced CL of 2000 ms in NF, DHF and CRT, and C: Fractional change in APD90 by ranolazine in each group. D: Development of EADs at baseline and after ranolazine in ventricular myocytes from NF, DHF and CRT dogs. E: Alteration of INa-L in a canine mathematical AP model mimicking DHF and CRT reproduced the experimental effects of DHF and CRT on the APD. ‡ :p<0.01, †:p<0.05 vs. NF, #:p<0.01 vs. DHF by ANOVA with Bonferroni test. **:p<0.01, *: p<0.05 vs. baseline by paired t-test.
Figure 5
Figure 5
CRT partially normalizes the DHF-induced increase of CaMKII. A: Total CaMKII protein expression in NF, DHF and CRT canine ventricle. B: Phosphorylation of CaMKII (p-Thr 287) in NF, DHF and CRT ventricular myocardium. ANT: anterior, LTR: lateral myocardium. † :p<0.05 vs. NF, #:p<0.05 vs. DHF by ANOVA with Bonferroni test.
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