Arrhythmias in the congenital long QT syndrome: how often is torsade de pointes pause dependent?

Viskin, Sami; Fish, Roman; Zeltser, David; Belhassen, Bernard; Heller, Karin; Brosh, David; Laniado, Shlomo; Barron, Hal V.

doi:10.1136/heart.83.6.661

Cited by 85 publications

(68 citation statements)

References 71 publications

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“…In contrast to previous studies, 21 we did not find that the proportion of pause dependence was greater in female than male patients.…”

Section: Discussioncontrasting

confidence: 56%

“…37 Also, because ␤-blocker treatment is less effective in LQT2, TdP may still be readily observed during admission. Whatever the cause, the difficulty in obtaining ECG documentation of TdP onset in LQT1 may explain why the reported proportion of pause-dependent TdP onset in congenital LQTS is as high as 74% in some studies, 21 although it should be only a little over 50%, given that TdP is rarely pause dependent in LQT1 and that LQT1 constitutes almost 50% of congenital LQTS. This discrepancy may be caused by underrepresentation of LQT1 patients because these patients are less easily included in such analyses.…”

Section: Study Limitationsmentioning

confidence: 96%

“…Previous studies have used other arbitrary cutoff values, ie, any increment, 15 a 20-ms increment, 36 or a 40-ms increment 21 over I (-2) . To study whether the choice for any particular cutoff value may confound our primary analysis, we also analyzed the proportions of pause-dependent TdP onset in LQT1 and LQT2 when cutoff values other than 50% were used to define "pause dependence" (Figure 8).…”

Section: Study Limitationsmentioning

confidence: 99%

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Genotype-Specific Onset of Arrhythmias in Congenital Long-QT Syndrome

et al. 2006

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Background-The identification of the molecular-genetic substrate underlying the various forms of the congenital long-QT syndrome (LQTS) has sparked studies into possible genotype-phenotype correlations with the aim of developing genotype-tailored therapy. The onset of torsade de pointes (TdP) may differ among LQTS patients, being pause dependent in some but not all. This disparity may point to different arrhythmia mechanisms and may affect therapy strategies. We studied whether the proportion of pause-dependent TdP onset varies among LQTS genotypes. Methods and Results-We studied all LQT1 (nϭ10), LQT2 (nϭ34), and LQT3 (nϭ6) patients from 4 centers for whom ECGs of TdP onset were available and analyzed whether pauses preceded TdP onset (first available ECG per patient). Pauses preceded TdP significantly more often in LQT2 (68%) than in LQT1 (0%), and the interval immediately before TdP (pause interval) was significantly longer in LQT2 than in LQT1.

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“…In contrast to previous studies, 21 we did not find that the proportion of pause dependence was greater in female than male patients.…”

Section: Discussioncontrasting

confidence: 56%

Section: Study Limitationsmentioning

confidence: 96%

Section: Study Limitationsmentioning

confidence: 99%

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Genotype-Specific Onset of Arrhythmias in Congenital Long-QT Syndrome

et al. 2006

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“…In myocytes isolated from mice heterozygous for a knock-in KPQ deletion (⌬KPQ), diastolic arrhythmogenic activity is significantly more prevalent than in myocytes isolated from WT littermates. Because pause-dependent arrhythmias were previously reported in ECG measurements in these mice, 11 and because clinical, in vivo animal and computational studies have demonstrated correlation between the spontaneous arrhythmias in LQTSs following pauses in stimulation, 26,27 we focused our studies on pause-dependent activity that might occur in myocytes. Our results show that even in WT myocytes, prolonged depolarization can lead to spontaneous activity (I TI s).…”

Section: Discussionmentioning

confidence: 99%

Altered Na ⁺ Channels Promote Pause-Induced Spontaneous Diastolic Activity in Long QT Syndrome Type 3 Myocytes

Fredj

Lindegger

Sampson

et al. 2006

Circulation Research

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Abstract-Long QT syndrome (LQTS) type 3 (LQT3), typified by the ⌬KPQ mutation (LQT3 mutation in which amino acid residues 1505 to 1507 [KPQ] are deleted), is caused by increased sodium entry during the action potential plateau resulting from mutation-altered inactivation of the Na v 1.5 channel. Although rare, LQT3 is the most lethal of common LQTS variants. Here we tested the hypothesis that cellular electrical dysfunction, caused not only by action potential prolongation but also by mutation-altered Na ϩ entry, distinguishes LQT3 from other LQTS variants and may contribute to its distinct lethality. We compared cellular electrical activity in myocytes isolated from mice heterozygous for the ⌬KPQ mutation (⌬KPQ) and myocytes from wild-type littermates. Current-clamp pause protocols induced ratedependent spontaneous diastolic activity (delayed after depolarizations) in 6 of 7 ⌬KPQ, but no wild-type, myocytes (nϭ11) tested. Voltage-clamp pause protocols that independently control depolarization duration and interpulse interval identified a distinct contribution of both depolarization duration and mutant Na ϩ channel activity to the generation of Ca i 2ϩ -dependent diastolic transient inward current. This was found at rates and depolarization durations relevant both to the mouse model and to LQT3 patients. Flecainide, which preferentially inhibits mutation-altered late Na ϩ current and is used to treat LQT3 patients, suppresses transient inward current formation in voltage-clamped ⌬KPQ myocytes. Our results demonstrate a marked contribution of mutation-altered Na ϩ entry to the incidence of pause-dependent spontaneous diastolic activity in ⌬KPQ myocytes and suggest that altered Na ϩ entry may contribute to the elevated lethality of LQT3 versus other LQTS variants.

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“…Similarly, dAPC data on the A1330P mutant give an insight into the mechanism underlying AP prolongation and arrhythmogenesis in the carrier of this mutation. Facilitated (re)openings of the cardiac sodium channels due to mutation are likely to cause a rise in intracellular Na Literature data suggest that sudden pauses play a major role in the genesis of spontaneous arrhythmias in the congenital LQT syndrome (Viskin et al 2000). Patients with LQT3 are at a greater risk of cardiac events during rest or bradycardia than during exercise when heart rate is elevated Veldkamp et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Long‐QT syndrome‐related sodium channel mutations probed by the dynamic action potential clamp technique

Berecki¹,

Zegers²,

Bhuiyan

et al. 2006

The Journal of Physiology

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Long-QT3 syndrome (LQT3) is linked to cardiac sodium channel gene (SCN5A) mutations. In this study, we used the 'dynamic action potential clamp' (dAPC) technique to effectively replace the native sodium current (I Na ) of the Priebe-Beuckelmann human ventricular cell model with wild-type (WT) or mutant I Na generated in a human embryonic kidney (HEK)-293 cell that is voltage clamped by the free-running action potential of the ventricular cell. We recorded I Na from HEK cells expressing either WT or LQT3-associated Y1795C or A1330P SCN5A at 35• C, and let this current generate and shape the action potential (AP) of subepicardial, mid-myocardial and subendocardial model cells. The HEK cell's endogenous background current was completely removed by a real-time digital subtraction procedure. With WT I Na , AP duration (APD) was longer than with the original Priebe-Beuckelmann model I Na , due to a late I Na component of ∼30 pA that could not be revealed with conventional voltage-clamp protocols. With mutant I Na , this late component was larger (∼100 pA), producing a marked increase in APD (∼70-80 ms at 1 Hz for the subepicardial model cell). The late I Na magnitude showed reverse frequency dependence, resulting in a significantly steeper APD-frequency relation in the mutant case. AP prolongation was more pronounced for the mid-myocardial cell type, resulting in increased APD dispersion for each of the mutants. For both mutants, a 2 s pause following rapid (2 Hz) pacing resulted in distorted AP morphology and beat-to-beat fluctuations of I Na . Our dAPC data directly demonstrate the arrhythmogenic nature of LQT3-associated SCN5A mutations.

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Arrhythmias in the congenital long QT syndrome: how often is torsade de pointes pause dependent?

Cited by 85 publications

References 71 publications

Genotype-Specific Onset of Arrhythmias in Congenital Long-QT Syndrome

Genotype-Specific Onset of Arrhythmias in Congenital Long-QT Syndrome

Altered Na ⁺ Channels Promote Pause-Induced Spontaneous Diastolic Activity in Long QT Syndrome Type 3 Myocytes

Long‐QT syndrome‐related sodium channel mutations probed by the dynamic action potential clamp technique

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Arrhythmias in the congenital long QT syndrome: how often is torsade de pointes pause dependent?

Cited by 85 publications

References 71 publications

Genotype-Specific Onset of Arrhythmias in Congenital Long-QT Syndrome

Genotype-Specific Onset of Arrhythmias in Congenital Long-QT Syndrome

Altered Na + Channels Promote Pause-Induced Spontaneous Diastolic Activity in Long QT Syndrome Type 3 Myocytes

Long‐QT syndrome‐related sodium channel mutations probed by the dynamic action potential clamp technique

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Altered Na ⁺ Channels Promote Pause-Induced Spontaneous Diastolic Activity in Long QT Syndrome Type 3 Myocytes