Original-experimentalCellular basis for arrhythmogenesis in an experimental model of the SQT1 form of the short QT syndrome
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 (IKr and IKs) and the inward rectifier potassium channel current (IK1) 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 Tpeak-Tend 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 IKr, IKs, or IK1 agonists, the only previously developed models of SQTS were ones in which the activator of the adenosine triphosphate–sensitive potassium current (IK-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 IKr agonist, PD-118057.13 Available data indicate that PD-118057 binds to the IKr 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 IKr channel. The mutation abolishes rectification of IKr current at positive voltages within the voltage range of the action potential, leading to a marked gain of function. We used the novel IKr 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, Tpeak-Tend, and APD90 (endo stimulation)
Figure 1 illustrates the effect of the IKr 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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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.