Cellular basis for arrhythmogenesis in an experimental model of the SQT1 form of the short QT syndrome

doi:10.1016/j.hrthm.2008.01.022

Heart Rhythm

Volume 5, Issue 4, April 2008, Pages 585-590

https://doi.org/10.1016/j.hrthm.2008.01.022 Get rights and content

Background

Short QT syndrome (SQTS) is a primary electrical disease of the heart associated with a high risk of sudden cardiac death. A gain-of-function in I_Kr, due to a mutation in KCNH2, underlies SQT1.

Objective

This study sought to examine the cellular basis for arrhythmogenesis in an experimental model of SQT1 created using PD-118057, a novel I_Kr agonist.

Methods

Transmembrane action potentials were simultaneously recorded from epicardial, M, and endocardial regions of arterially perfused canine left ventricular (LV) wedge preparations, together with a pseudo-electrocardiogram.

Results

PD-118057 (10 μmol/l) abbreviated the QT interval from 267 ± 4 to 232 ± 4 ms and increased transmural dispersion of repolarization (TDR) from 33.7 ± 2.0 to 49.1 ± 3.1 ms (P <.001). T-wave amplitude increased from 18.0% ± 1.4% to 23.1% ± 1.7% of R-wave amplitude (P =.027). Reversing the direction of activation of the LV wall (epicardial pacing) resulted in an increase in QT interval from 269 ± 5 to 282 ± 5 ms and an increase in TDR from 34.1 ± 2.0 to 57.6 ± 3.3 ms (P <.001) under baseline conditions. PD-118057 abbreviated the QT interval from 282 ± 5 to 258 ± 5 ms and produced a proportional decrease in effective refractory period (ERP). TDR increased from 57.6 ± 3.3 to 77.6 ± 4.3 ms (P <.001). Polymorphic ventricular tachycardia (pVT) was induced in 10 of 20 preparations with a single S₂ applied to epicardium. Quinidine (10 μmol/l) increased the ERP and QT interval, did not significantly alter TDR, and prevented induction of pVT in 5 of 5 preparations.

Conclusion

Our results suggest that a combination of ERP abbreviation and TDR amplification underlie the development of pVT in SQT1 and that quinidine prevents pVT principally by prolonging ERP.

Introduction

Short QT syndrome (SQTS) is a recently recognized, inherited, primary electrical cardiac syndrome characterized by abnormally short QTc interval (<360 ms) and an increased propensity for development of atrial and ventricular tachyarrhythmias, including sudden cardiac arrest.1, 2, 3, 4, 5 It is a genetically heterogeneous disease, and thus far mutations of 5 different genes encoding cardiac ion channels have been identified in familial or sporadic cases. Gain-of-function mutations in KCNH2,⁶KCNQ1,⁷ and KCNJ2⁸ genes encoding for the rapidly and slowly activating potassium channel currents (I_Kr and I_Ks) and the inward rectifier potassium channel current (I_K1) give rise to the SQT1, SQT2, and SQT3 forms of SQTS. Our group recently described loss-of-function mutations in CACNA1c and CACNB2b genes encoding the α1 and β subunits of cardiac L-type calcium channels. This clinical phenotype, characterized by a new clinical entity consisting of a combined Brugada-like ST segment elevation and short QT intervals, has been designated SQT4 and SQT5.⁹

The electrocardiogram (ECG) in SQTS is characterized by shorter than normal QT intervals (QTc <360 ms), short or absent ST segment, and in some cases, tall peaked T waves and augmented T_peak-T_end intervals. The rate dependence of the QT interval or QT/RR interval relationship has been reported to be less steep than normal.4, 5, 10 Electrophysiological testing in patients with SQTS shows marked abbreviation of the atrial and ventricular refractory period. Polymorphic ventricular tachycardia (pVT) is readily inducible in a large fraction of affected individuals.3, 10

Because of the unavailability of I_Kr, I_Ks, or I_K1 agonists, the only previously developed models of SQTS were ones in which the activator of the adenosine triphosphate–sensitive potassium current (I_K-ATP), pinacidil, was used to augment outward current in canine LV wedge preparations¹¹ or Langendorff-perfused rabbit hearts.¹² The present study involves the development and characterization of a specific model of SQT1 made possible by the recent availability of a selective I_Kr agonist, PD-118057.¹³ Available data indicate that PD-118057 binds to the I_Kr channel directly and increases its open channel probability without affecting the voltage dependence and kinetics of gating parameters.

The SQT1 variant of SQTS is due to an N588K mutation in KCNH2, the gene that encodes the α subunit of the I_Kr channel. The mutation abolishes rectification of I_Kr current at positive voltages within the voltage range of the action potential, leading to a marked gain of function. We used the novel I_Kr agonist PD-118057 to mimic this gain-of-function and thus to examine the cellular basis for the electrocardiographic and arrhythmogenic manifestations of this model of SQT1. Our study also probes the mechanism underlying the antiarrhythmic effects of quinidine under SQT1 conditions.

Section snippets

Methods

All experiments were performed in conformance with the guidelines of the Institutional Animal Care Committee. The LV wedge was prepared as previously described.11, 14 Transmembrane action potentials were recorded from epicardial (Epi), subendocardial (M) and endocardial (Endo) regions of the wedge with the use of floating microelectrodes. A transmural pseudo-ECG was recorded using 2 AgCl half cells placed approximately 1 cm from the epicardial (+) and endocardial (–) surfaces of the preparation

Effect of PD-118057 on QT interval, TDR, T_peak-T_end, and APD₉₀ (endo stimulation)

Figure 1 illustrates the effect of the I_Kr agonist PD-118057 to abbreviate the QT interval and amplify transmural dispersion of repolarization (TDR). Shown are action potentials simultaneously recorded from epicardial and M cells of a canine LV wedge preparation, together with a pseudo-ECG. Figure 2 summarizes the effects of PD-118057 on APD₉₀ as recorded in 24 wedge preparations. PD-118057 abbreviated the APD₉₀ of epicardial and M cells leading to abbreviation of QT interval. QT interval

Discussion

To our knowledge, this is the first experimental model of SQTS in which the affected ion channel current is one previously shown to underlie a congenital form of the syndrome. The model recapitulates the electrocardiographic and arrhythmic manifestations of SQT1 and provides an understanding of the cellular basis for these changes utilizing the coronary-perfused LV wedge preparation. This preparation has been successfully used to reproduce the electrocardiographic and arrhythmic manifestations

Acknowledgement

The authors acknowledge the expert technical assistance of Judy Hefferon, Robert Goodrow, Jr., and Kathy Sullivan.

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Citation Excerpt :
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: This study was supported by a grant HL-47687 from the National Institutes of Health and the New York State and Florida Grand Lodges of Free and Accepted Masons.

View full text

Original-experimentalCellular basis for arrhythmogenesis in an experimental model of the SQT1 form of the short QT syndrome

Background

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Methods

Effect of PD-118057 on QT interval, TDR, Tpeak-Tend, and APD90 (endo stimulation)

Discussion

Acknowledgement

J Electrocardiol

Heart Rhythm

J Electrocardiol

Resuscitation

J Am Coll Cardiol

Idiopathic short QT interval: a new clinical syndrome?

Cardiology

ECG phenomenon of idiopathic and paradoxical short QT intervals

Cardiac Electrophysiol Rev

Short QT syndrome: a familial cause of sudden death

Circulation

Short QT syndrome: mechanisms, diagnosis and treatment

Nat Clin Pract Cardiovasc Med

Sudden death associated with short-QT syndrome linked to mutations in HERG

Circulation

Mutation in the KCNQ1 gene leading to the short QT-interval syndrome

Circulation

A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene

Circ Res

Original-experimental
Cellular basis for arrhythmogenesis in an experimental model of the SQT1 form of the short QT syndrome

Effect of PD-118057 on QT interval, TDR, T_peak-T_end, and APD₉₀ (endo stimulation)