Elsevier

Heart Rhythm

Volume 8, Issue 5, May 2011, Pages 762-769
Heart Rhythm

Experimental genetic
Contribution of late sodium current (INa-L) to rate adaptation of ventricular repolarization and reverse use-dependence of QT-prolonging agents

https://doi.org/10.1016/j.hrthm.2010.12.026Get rights and content

Background

Abnormal rate adaptation of ventricular repolarization is arrhythmogenic. There is controversy on the underlying ionic mechanisms for rate-dependent change in repolarization.

Objective

The purpose of this study was to examine the role of the late sodium current (INa-L) in normal rate-dependence of ventricular repolarization and reverse use-dependence of QT-prolonging agents.

Methods

The effects of INa-L blockade, INa-L enhancement, IKr blockade, and changes in extracellular potassium concentration ([K+]o) on rate adaptation of the QT interval and action potential duration (APD) were examined in isolated rabbit ventricular wedges and single myocytes. Rate dependence of INa-L, delayed rectifier potassium current (IK), and L-type calcium current (ICa) was determined using a whole-cell, voltage clamp technique.

Results

At control, APD exhibited rate-dependent changes in the multicellular preparations as well as in the isolated single ventricular myocytes when [K+]o remained constant. The rate dependence of APD was significantly enhanced by reduction of [K+]o from 4 to 1 mM or by INa-L enhancement but was markedly blunted by the selective sodium channel blocker tetrodotoxin. The IKr blocker dofetilide (3 nM) amplified the QT to basic cycle length slope (71.2 ± 13.1 ms/s vs 35.1 ± 8.8 ms/s in control, n = 4, P <.05). This reverse use-dependence was abolished by tetrodotoxin at 5 μM (11.4 ± 4.3 ms/s, n = 4, P <.01). There were no significant differences in ICa or IK over the range of basic cycle lengths from 2,000 to 500 ms. However, INa-L exhibited a significant rate-dependent reduction.

Conclusion

INa-L is sensitive to rate change due to its slow inactivation and recovery kinetics and plays a central role in the rate dependence of APD/QT and in the reverse use-dependence of select APD/QT-prolonging agents.

Introduction

It is widely accepted that mammalian ventricular repolarization at steady state, represented by the QT interval on the surface ECG, is inversely proportional to heart rate and that exceptions to this rule exist1; that is, tachycardia usually shortens ventricular repolarization and bradycardia prolongs it.

The duration of the ventricular action potential is determined by a dynamic balance of a number of inward and outward ion currents through selective channels in the cell plasma membrane. The opening and closing of these channels are dependent not only on the membrane potential (i.e., voltage dependence) but also on the time elapsed after a change in membrane potential (i.e., time dependence).2 Theoretically, rate-related changes in any of three states of the ion channels (open, closed, inactivated) can influence activation, inactivation, and recovery of the channels and, subsequently, translate into changes in action potential duration (APD).

The slowly activating delayed rectifier potassium current (IKs), a major outward current contributing to repolarization in the ventricles, is generally considered to be an important modulator of rate-dependent ventricular action potential repolarization. It is popularly believed that IKs remains partially activated (open) after repolarization, and that such an activated state can accumulate during tachycardia, leading to shortening of the APD,3 although there are other explanations.4 It is also hypothesized that extracellular K+ accumulation may play an important role in the normal rate dependence of ventricular repolarization.5 The clinical correlate of rate-dependent cardiac repolarization is so-called “reverse use-dependence” observed with certain QT-prolonging agents, wherein repolarization is prolonged more during bradycardia and less during tachycardia. Summation of IKs may partially offset a drug's QT-prolonging effect during tachycardia.

On the other hand, increasing evidence suggests that late Na current (INa-L), an important inward current during ventricular repolarization, may contribute importantly to rate adaptation of ventricular repolarization. It is well known that ventricular M cells with a larger INa-L exhibit a much steeper rate dependence of APD than do epicardial and endocardial cells.6, 7 Phenomena that enhance INa-L have been shown to amplify rate-dependent changes in APD, including transgenic mice with long QT type 3 syndrome8 as well as ventricular hypertrophy and failure.9

However, the contribution of INa-L to rate adaptation of ventricular repolarization and reverse use-dependence of QT-prolonging drugs has not yet been studied systemically. The present study tested the hypothesis that INa-L is an important modulator of rate-dependent cardiac repolarization and plays a critical role in reverse use-dependence of QT-prolonging drugs in the rabbit ventricular wedge preparation and in isolated ventricular myocytes.

Section snippets

Arterially perfused rabbit left ventricular wedge preparation

The animal use of this study was approved by the institutional Animal Care and Use Committee of Main Line Health. Surgical preparation of the rabbit left ventricular (LV) wedge has been described in detail in previous publications.10, 11 The preparation was placed in a small tissue bath and arterially perfused with Tyrode's solution containing 4 mM K+ buffered with 95% O2 and 5% CO2 (temperature 35.7°C ± 0.1°C).

Electrophysiologic recordings from rabbit ventricular wedge preparations

A transmural ECG signal was recorded using extracellular silver/silver chloride

Effects of tetrodotoxin on rate adaptation of ventricular repolarization in rabbit LV wedge

Rate-dependent changes in the QT interval and endocardial APD at 90% repolarization (APD90) after reaching steady state are shown in Figure 1. QT interval was 255.8 ± 3.9 ms at a basic cycle length (BCL) of 500 ms (n = 4) vs 278.8 ± 9.0 ms (P <.05) at BCL of 1,000 ms and 309.3 ± 17 ms (P <.05) at BCL of 2000 ms after the first hour of control perfusion. Endocardial APD90 changed in parallel with QT interval (Figure 1).

Tetrodotoxin (TTX; 5 μM), a highly selective sodium channel blocker, markedly

Discussion

This study demonstrates that INa-L plays a key role in the rate dependence of ventricular repolarization and reverse use-dependence of certain QT-prolonging agents.

Conclusion

Our data demonstrate that INa-L is sensitive to a rate change due to its slow inactivation and recovery kinetics, and it plays an important and perhaps central role in normal rate dependence of APD/QT and reverse use-dependence of select APD/QT-prolonging agents.

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  • Cited by (0)

    Supported by the Sharpe-Strumia Research Foundation to Dr. Yan, the W-W-Smith Charitable Trust to Dr. Kowey, and National Institutes of Health Grant R01-HL28476 to Dr. Cox.

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