Cardiovascular Research

Cardiovascular Research 2002 54(3):624-629; doi:10.1016/S0008-6363(02)00265-1
© 2002 by European Society of Cardiology

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Copyright © 2002, European Society of Cardiology

Rate-dependent QT shortening mechanism for the LQT3 KPQ mutant

Toshihisa Nagatomo^a,b, Craig T. January^a, Bin Ye^a, Haruhiko Abe^b, Yasuhide Nakashima^b and Jonathan C. Makielski^a,*

^aDepartment of Medicine, Cardiology Section, University of Wisconsin, Madison, WI, USA
^bThe 2nd Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan

jcm{at}medicine.wisc.edu

^* Corresponding author. University of Wisconsin Clinics and Hospitals, 600 Highland Avenue H6/349, Madison, WI 53792, USA. Tel.: +1-608-2639-648; fax: +1-608-2630-405

Received 14 November 2001; accepted 17 January 2002

	Abstract

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Abstract presented Acknowledgments References

 
Objective: For the congenital long QT (LQT) syndrome involving mutations of the cardiac sodium channel gene SCN5A, LQT3, the initiation of sudden cardiac death tends to be bradycardia- or pause-dependent, contrary to other LQT syndromes that tend to be adrenergic dependent. Enhanced shortening of the prolonged QT interval with increased heart rate has been reported in LQT3 patients. We hypothesized that the rate-dependent shortening of the QT interval may be attributed to the kinetic properties of inactivation the late sodium current (I_Na) in LQT3. Methods: The KPQ mutant of the human heart voltage-gated sodium channel -subunit was stably transfected into a mammalian cell line (HEK293). I_Na was recorded using a whole-cell patch-clamp technique. Results: A train of 50 depolarizing pulses or a train of 50 ventricular action potential waveforms was applied with different interpulse durations. Peak I_Na for the 50th pulse compared with that of I_Na in the first pulse was decreased <2% for interpulse durations as short as 20 ms, but late I_Na amplitude measured at the end of the pulse was decreased 95, 78, 68, 56 and 47% with 1000, 500, 200, 100, 20 ms interpulse intervals, respectively. Using the action potential waveform a similar rate-dependent reduction of late I_Na was found with minimal reduction of peak I_Na. Conclusions: Late I_Na amplitude in the KPQ mutation is strongly rate dependent. Rate-dependent reductions of late I_Na may cause shortening the QT interval at higher rates. This provides a mechanism correlating the genotype with the clinical phenotype, and provides a rationale for the effectiveness of pacemaker therapy in LQT3 patients.

KEYWORDS Arrhythmia (mechanisms); Long QT syndrome; Membrane currents; Na-channel; Sudden death

	1 Introduction

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Abstract presented Acknowledgments References

 
The congenital long QT syndrome (LQT) is an inherited cardiac disorder associated with ventricular arrhythmia, syncope and sudden death. One form of the disease, LQT3, is caused by mutations in SCN5A, the gene that encodes the voltage-dependent cardiac Na channel -subunit protein in humans (hH1, also called hNa_v1.5) [1–4]. Deletion of lysine, proline and glutamine (KPQ) at positions 1505–1507 in the linker between domains III and IV of hH1 is a mutation associated with LQT3. This mutant channel produces a late Na current (I_Na) that causes action potential prolongation and QT lengthening on the surface ECG [5–10].

In patients with LQT3, ventricular tachyarrhythmia and sudden cardiac death tend to occur during sleep or at rest [11,12]. This clinical phenotype differs markedly from LQT1 and LQT2 patients, where ventricular arrhythmia and sudden death occur mainly with exercise or stress [12]. Patients with LQT3 also tend to have longer resting QT intervals and enhanced rate-dependent QT interval shortening compared with other forms of LQT. Indeed it is greater than that found in normal individuals [11]. The cellular and molecular mechanisms for these clinically important observations are unknown.

We have reported that late I_Na in the KPQ mutant slowly inactivated and that it recovered more slowly from inactivation compared with peak I_Na [10]. With repetitive depolarizations at higher rates this slow recovery should decrease late I_Na because of accumulation of inactivation. This would account for the enhanced QT rate adaptation in LQT3. Using whole-cell patch clamp and action potential clamp techniques we demonstrate in this report preferential rate-dependent decrease of late I_Na in the KPQ mutant.

	2 Methods

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Abstract presented Acknowledgments References

 
2.1 Clones and construction of KPQ mutation
The human heart Na channel clone we used (hH1a) was kindly provided by Dr. H. Hartmann (Baylor College of Medicine, Houston, TX, USA). The nucleotide and amino acid numbering follow Hartmann et al. [13]. Dr. John W. Kyle and Gayle S. Tonkovich (University of Chicago, Chicago, IL, USA) kindly provided the KPQ mutation. It was made by polymerase chain reaction techniques as previously described [10].

2.2 Cell preparation and transfection
Approximately 5x10⁵ cells from a transformed human embryo kidney cell line (HEK293) were seeded on a 60 mm diameter plate (Falcon 3001) with 3 ml of culture medium a day before the transfection. Culture medium was MEM complete medium containing: minimum essential medium (Eagle's salts and L-glutamine), 10% of fetal bovine serum (FBS), 2 mM L-glutamine, 0.1 mM MEM non-essential amino acids solution, 1 mM MEM pyruvate solution, 10,000 unit penicillin and 10,000 µg streptomycin. Transfection with hH1 containing the KPQ mutation was carried out by using a cationic liposome method as described previously [10]. Late I_Na in wild type channels were not included in this study because of its small amplitude [10].

2.3 Electrophysiological recordings and analysis
I_Na was recorded using the whole-cell patch clamp method at room temperature (23 °C) as detailed elsewhere [10]. Briefly, the bath solution contained (in mM): NaCl 140, KCl 4, CaCl₂ 1.8, MgCl₂ 0.75 and HEPES 5 (pH 7.4 set with NaOH). The pipette solution contained (in mM): CsF 120, CsCl₂ 20, EGTA 5 and HEPES 5 (pH 7.4 set with CsOH). Methods to achieve and verify voltage control methods were as published previously [10]. Leak subtraction of peak and late currents was calculated off-line by extrapolating holding currents at subthreshold potentials (<–100 mV) to the potential of interest [14]. This method of measuring late I_Na was verified by saxitoxin subtraction [10]. Data were fit to model equations using non-linear regression (pClamp v6.03 or SigmaPlot 3.0). Summary data are expressed as means±standard error with n representing the number cells studied.

	3 Results

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Abstract presented Acknowledgments References

 
Representative current recordings of peak (Fig. 1, top panels) and late I_Na (Fig. 1, bottom panels) in response to pulse trains show the rate dependent decrease in the currents. To better demonstrate the amplitude and time course of the decrease, the normalized peak and late I_Na were plotted versus pulse number (Fig. 2). For peak I_Na, current amplitudes were nearly constant for all interpulse durations tested consistent with nearly complete recovery of peak I_Na during the interpulse duration. For interpulse durations of 500 ms or less, late I_Na showed a cumulative decrease during the pulse train, suggesting incomplete recovery of late I_Na from inactivation induced by the previous pulses. Faster rates (shorter interpulse durations) showed a greater decrease in late I_Na. Summary data (Fig. 3) for peak and late I_Na at the end of the train normalized to the first pulse in the train show relative amplitudes of 98±0.6, 99±0.3, 99±0.8, 98±0.7, 97±0.9% for peak I_Na and 95±2, 78±1, 68±3, 56±2, 47±3% for late I_Na with 1000, 500, 200, 100, 20 ms interpulse durations, respectively (n=8 cells). At an interpulse duration of 1000 ms, peak and late I_Na were not significantly different; for all other interpulse durations late I_Na decreased significantly.

View larger version (16K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Representative current recordings in response to trains of 50 pulses with interpulse durations (I.D.s) of 1000, 500 and 100 ms showing cumulative decrease in late INa at increased rate. Currents were elicited by 40 ms long steps from –140 to –20 mV. Upper panels show superimposed current traces to demonstrate peak INa, and the lower panels show the same traces at different amplitude (peak INa off scale) and time resolution to demonstrate late INa. Currents from the 1st, 2nd, 5th, 10th, 20th and 50th pulses in the train are shown.

 

View larger version (25K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Time course of rate-dependent reduction of INa. Pulse protocol was the same as in Fig. 1. Late INa was measured at the end of the pulse and normalized to the amplitude of late INa in the first pulse and plotted against pulse number (). Peak INa was normalized to the amplitude of peak INa in the first pulse and plotted against pulse number (). Solid lines represent exponential fits.

 

View larger version (20K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 Summary data show that late INa, but not peak INa, was significantly reduced at higher pulse rates. Currents were recorded as in Fig. 1. Bars represent the mean±S.E.M. (n=8) for peak or late INa in response to the last five pulses of the train. *Significant (p<0.0001) reduction of late INa compared with peak INa during repetitive depolarizations.

 
To more closely approximate the reduction in late I_Na that was expected during the repolarization phase of a ventricular action potential we used an action potential waveform voltage clamp command signal (Fig. 4). I_Na peaked (off scale) during phase 0, was present throughout the plateau phases 1 and 2, was increased slightly during phase 3 repolarization as the driving force for Na increased, and then decreased as I_Na was deactivated on return to phase 4 potentials. I_Na at the end of the action potential plateau showed a cumulative decrease during the pulse train, and the decrease was greater at higher rates. To evaluate the late I_Na amplitude, we used mean value measured between 240 and 280 ms for the late I_Na. Summary data (Fig. 5) for peak I_Na were 99±2, 97±1, 93±1, 89±1% and for late I_Na were 94±3, 71±2, 55±3, 47±2% for 1000, 500, 200, 100 ms interpulse durations, respectively (n=7 cells).

View larger version (23K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 4 INa during the repolarization phase of the action potential was decreased with shorter interpulse durations. Representative superimposed current recordings in response to pulse trains of action potential waveform at interpulse durations (I.D.s) of 1000, 500 and 100 ms. Currents from the 1st, 2nd, 5th, 10th, 20th and 50th pulses in the train are shown. Note that peak components are off scale in order to show late components. Inset: Action potential waveform used for stimulation. The waveform was digitized from a published action potential recorded from an intact human heart ventricular cell [28].

 

View larger version (19K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 5 Rate-dependent reduction of late INa in response to action potential stimulation. Data analyzed and plotted as in Fig. 3 (n=7) except late INa was measured as the mean amplitude between 240 and 280 ms. Late INa was significantly (*p<0.0001) reduced compared to peak INa.

 

	4 Discussion

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Abstract presented Acknowledgments References

 
In heart cells a complex balance of inward and outward currents maintains the action potential plateau. Repolarization occurs when outward current amplitude exceeds that of the inward current amplitude; thus the increased late inward I_Na in the KPQ LQT3 mutation can account for prolongation of the action potential plateau which is reflected on the surface ECG as QT interval prolongation. This prolongation is a necessary conditioning event in the generation of early after-depolarizations [15] which are thought to trigger Torsades de Pointes.

This study demonstrates rate-dependent reduction of the late I_Na for the KPQ mutant, and accounts for the clinical phenotype of LQT3. Compared with peak I_Na, late I_Na was preferentially reduced for both a square voltage clamp pulse and for an action potential clamp, with greater reductions at greater stimulation rates. This would be expected to cause an enhanced rate related decrease in action potential duration and the QT interval to diminish risk for arrhythmia at higher heart rates compared to normal individuals or patients with LQT syndromes other than LQT3. In experimental models of LQT3, enhanced shortening of action potential duration during rapid pacing has been reported [16–18]. In LQT3 patients, enhanced shortening of prolonged QT intervals with increased heart rate was first reported by Schwartz et al. [11]. Cardiac events (sudden death, syncope, palpitations) tend to occur during rest in LQT3 patients when heart rates are slow [12], and this is different from mutations involving the potassium channels, particularly LQT1, where events tend to occur with stress or activity. Also β-adrenergic blocker therapy has been shown in a relatively small group of patients to reduce cardiac events in LQT1 and LQT2 but not in LQT3 [12,19]. Thus, the inactivation properties for late I_Na demonstrated in this study provide a mechanism that can potentially account for these features of the LQT3 clinical phenotype.

Mechanisms other than inactivation of late I_Na have been proposed for the enhanced rate-dependence of the QT interval in LQT3 patients. Priori et al. [20] suggested the importance of the slowly activating inward rectifying K current I_Ks, the repolarizing current defective in LQT1, in rate-related QT shortening because I_Ks is increased at shorter cycle lengths. This does not, however, account for the differences in rate-related QT shortening with LQT2 or normal individuals where, like LQT3, I_Ks is intact. Additional mechanisms specific to I_Na must be involved in the rate-dependent shortening of prolonged action potential duration and the QTc interval in LQT3 patients. Recently Schwartz et al. [12] suggested that Na accumulation in myocytes at higher heart rates might lower the Na gradient and thereby decrease both peak and late I_Na. Although this could play a role, the preferential inactivation of late I_Na over peak I_Na at higher rates is a more powerful mechanism for action potential shortening, decreasing late I_Na up to 50% while peak I_Na is relatively unaffected (Fig. 5).

The hypothesis of preferential accumulation of inactivation of late I_Na in the KPQ mutant was suggested by our previous study showing a time dependent decay of the late I_Na in response to a long depolarization [10] and the slower recovery of this inactivation. Mutations in the C-terminus of SCN5A have been reported to alter inactivation causing the LQT3 and the Brugada syndrome simultaneously [21,22]. Interestingly, the late component of I_Na in the 1795insD and Y1795C mutants were reduced at higher pulse rates [22,23]. Consequently the rate-dependent reduction of late I_Na may not be limited to the KPQ mutant and may apply to other forms of LQT3 mutants that exhibit slowly inactivating late I_Na. Some LQT3 mutations have been reported that do not have increased late I_Na [24]. LQT3 mutations that have either no increased late I_Na, or a persistent non-decaying late I_Na, should not have enhanced rate dependent shortening of the QT interval, thus the resulting clinical phenotype may vary for each LQT3 mutant.

Does late I_Na for the wild-type channel play a role in rate adaptation in normal hearts? Although the magnitude of late I_Na in wild type is much smaller than that seen with LQT3 mutations [10], a fine balance between inward and outward currents determines the action potential plateau level and duration. Even small currents could affect the balance. Tetrodotoxin (TTX), a relatively specific blocker of I_Na, shortened cardiac action potential duration [25], a finding subsequently confirmed by many investigators. The role late I_Na might play in rate adaptation in normal hearts depends upon the kinetics of recovery of late I_Na in wild-type channels.

In conclusion, an intrinsic kinetic property of late I_Na in the LQT3 KPQ mutant, rate dependent reduction of late I_Na, may account for the shortening of QT interval at higher rates. This result provides a molecular and cellular mechanism for the clinical phenotype and the effectiveness of pacemaker therapy in LQT3 patients [26,27].

	5 Abstract presented

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Abstract presented Acknowledgments References

 
Toshihisa Nagatomo, Bin Ye, Carmen R. Valdivia, Zheng Fan, Craig T. January, Jonathan C. Makielski. Frequency-dependent reduction of late Na current caused by ultra-slow recovery in the LQT3 KPQ mutant Na channel. Circulation 1998;98(17):1–469 Suppl.

Time for primary review 29 days.

	Acknowledgments

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Abstract presented Acknowledgments References

 
We thank Ms. Deb Pittz for secretarial help, and Drs. Zheng Fan and Carmen Valdivia for helpful advice. This work was supported by grants HL56441 (J.C.M.), HL66378 (J.C.M.), HL60723 (C.T.J.), the University of Wisconsin Cardiovascular Research Center, and by grants from the Ministry of Labor and the Japan Heart Foundation and a Pfizer Grant for Cardiovascular Disease Research (T.N.).

	References

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion 5 Abstract presented Acknowledgments References

 

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