Two‐to‐One AV Block Associated with the Congenital Long QT Syndrome

Pruvot, Étienne; Torrenté, Antoine de; Ferrari, Gaetano M. De; Schwartz, Peter J.; Goy, J.‐J.

doi:10.1111/j.1540-8167.1999.tb00647.x

Cited by 19 publications

(17 citation statements)

References 12 publications

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“…This was assessed by the occurrence during decremental atrial pacing of systemized bundle-branch conduction defect before the 2:1 AVB with a His bundle potential occurring in all cases 90 ms after the end of the ventricular repolarization on the surface ECG. This is in accordance with Pruvot et al 27 and Gorgels et al, 26 who also evidenced at electrophysiological study a block in the HisPurkinje system in patients with 2:1 AVB. Hence, a very long rate-dependent Purkinje/ventricular effective refractory period related to mutations in cardiac ion channel genes and age-related heart rate likely contribute to the development of 2:1 AVB.…”

Section: Discussionsupporting

confidence: 80%

“…23 LQTS with AV conduction disturbances has been reported often in infants or young children with a major QTc prolongation, but without any positive familial history, [23][24][25][26][27][28] as in our case. Indeed, the fast atrial rate, which characterizes pediatric sinus rhythm, can lead to functional AV block in the setting of dramatic prolongation of ventricular repolarization as the P wave falls within the T wave.…”

Section: Discussionmentioning

confidence: 82%

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Homozygous SCN5A Mutation in Long-QT Syndrome With Functional Two-to-One Atrioventricular Block

Lupoglazoff

Cheav

Baroudi

et al. 2001

Circulation Research

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Abstract-Heterozygous mutations in genes encoding cardiac ionic channel subunits KCNQ1, HERG, SCN5A, KCNE1, and KCNE2 are causally involved in the dominant form of long-QT syndrome (LQTS) while homozygous mutations in KCNQ1 and KCNE1 cause LQTS with or without congenital deafness. In addition, two homozygous HERG mutations have been associated with severe LQTS with functional atrioventricular conduction anomalies in young children. A 2:1 atrioventricular block (AVB) with a major QTc prolongation (526 ms) was evidenced in a 5-year-old boy referred for syncope and seizure. LQTS was diagnosed and beta-blocking therapy initiated leading to normal atrioventricular conduction. Electrophysiological study provided support that location of the AVB was infra-Hisian. DNA analysis was performed in the proband and in asymptomatic family members. A novel missense mutation, V1777M, in the early C-terminal domain of SCN5A was identified. The proband was homozygous while the parents and two siblings were heterozygous carriers. Homozygote and heterozygote expression of the mutant channels in tsA201 mammalian cells resulted in a persistent inward sodium current of 3.96Ϯ0.83% and 1.49Ϯ0.47% at Ϫ30 mV, respectively, which was dramatically reduced in the presence of tetrodotoxin. This study provides the first evidence for a homozygous missense mutation in SCN5A and suggests that LQTS with functional 2:1 AVB in young children, a severe phenotype associated with bad prognosis, may be caused by homozygous or heterozygous compound mutations not only in HERG but also in SCN5A. T he congenital long-QT syndrome (LQTS) is a potentially lethal cardiac disease caused by mutations in specific ion channels. Heterozygosity for a mutation in the potassium channel genes HERG (LQT2) and KCNE2 (LQT6) causes defects in the rapid component of the delayed rectifier I Kr , whereas mutations in KCNQ1 (LQT1) and KCNE1 (LQT5) cause defects in the slow component of the delayed rectifier I Ks . 1 Mutations in SCN5A cause a persistent cardiac sodium current that is responsible for LQT3. 2 This form has been associated with a lower rate of cardiac events but a higher rate of lethal events. 3 Homozygosity for mutations in KCNQ1 and KCNE1 have been associated with the recessively inherited Jervell and Lange-Nielsen syndrome, in which QT prolongation is associated with a bilateral neurosensitive deafness. 4 -6 Nevertheless, several LQT1 recessive variants without deafness have also been described. 7,8 Recently, homozygosity for HERG mutations associated with atrioventricular (AV) conduction disturbances have been reported. 9,10 We describe the first case of an LQTS patient with functional 2:1 AV block (AVB) due to a homozygous missense mutation in SCN5A. Materials and Methods Clinical DataThe proband of a 9-member family was referred for syncope. The father originated from Senegal and the mother from Guinea without any known consanguinity. Both parents and the 7 children underwent clinical evaluation and cardiovascular examination, including a 12-lead ECG (ECG...

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 82%

Homozygous SCN5A Mutation in Long-QT Syndrome With Functional Two-to-One Atrioventricular Block

Lupoglazoff

Cheav

Baroudi

et al. 2001

Circulation Research

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“…Consequently, drugs that affect His-Purkinje conduction and refractoriness and hence exaggerate these AV conduction abnormalities likely have a major effect on arrhythmogenesis in LQTS. We demonstrate differential pharmacogenomic effects of I Kr or I Ks blockers on His-Purkinje conduction in LQT rabbits, indicating that the rarely described true infranodal AV blocks in LQTS patients (16,31) may be more frequent when LQT2 patients are exposed to I Ks blockers and, moreover, that these I Ksblocker-induced AV conduction blocks may increase the risk for arrhythmias in LQT2. Indeed, we have previously shown that I Ks -blocker-induced AV conduction blocks initiated pVT in LQT2 rabbits (29).…”

Section: Discussionmentioning

confidence: 99%

“…Atrioventricular (AV) conduction block due to markedly prolonged ventricular refractoriness, termed pseudo-AV block by Rosenbaum and Acunzo (35), has been described as the primary mechanism responsible for conduction abnormalities in patients with LQTS (14). However, a few case reports also described true infranodal AV block in these patients (16,31). Despite the relatively infrequent overall occurrence of AV conduction abnormalities (30), they are clearly associated with a poorer prognosis.…”

mentioning

confidence: 99%

Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction

Odening

Kirk

Brunner

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction. Am J Physiol Heart Circ Physiol 299: H643-H655, 2010. First published June 25, 2010; doi:10.1152/ajpheart.00074.2010.-We have generated transgenic rabbits lacking cardiac slow delayed-rectifier K ϩ current [IKs; long QT syndrome type 1 (LQT1)] or rapidly activating delayedrectifier K ϩ current [IKr; long QT syndrome type 2 (LQT2)]. Rabbits with either genotype have prolonged action potential duration and QT intervals; however, only LQT2 rabbits develop atrioventricular (AV) blocks and polymorphic ventricular tachycardia. We therefore sought to characterize the genotype-specific differences in AV conduction and ventricular refractoriness in LQT1 and LQT2 rabbits. We carried out in vivo electrophysiological studies in LQT1, LQT2, and littermate control (LMC) rabbits at baseline, during isoproterenol infusion, and after a bolus of dofetilide and ex vivo optical mapping studies of the AV node/ His-region at baseline and during dofetilide perfusion. Under isoflurane anesthesia, LQT2 rabbits developed infra-His blocks, decremental His conduction, and prolongation of the Wenckebach cycle length. In LQT1 rabbits, dofetilide altered the His morphology and slowed His conduction, resulting in intra-His block, and additionally prolonged the ventricular refractoriness, leading to pseudo-AV block. The ventricular effective refractory period (VERP) in right ventricular apex and base was significantly longer in LQT2 than LQT1 (P Ͻ 0.05) or LMC (P Ͻ 0.01), with a greater VERP dispersion in LQT2 than LQT1 rabbits. Isoproterenol reduced the VERP dispersion in LQT2 rabbits by shortening the VERP in the base more than in the apex but had no effect on VERP in LQT1. EPS and optical mapping experiments demonstrated genotype-specific differences in AV conduction and ventricular refractoriness. The occurrence of infra-His blocks in LQT2 rabbits under isoflurane and intra-His block in LQT1 rabbits after dofetilide suggest differential regional sensitivities of the rabbit His-Purkinje system to drugs blocking IKr and IKs.long QT syndrome; His-Purkinje conduction; rapidly activating delayed-rectifier potassium current; slow delayed-rectifier potassium current; transgenic rabbit model; pharmacogenomics; ventricular effective refractory period dispersion; in vivo electrophysiological study THE INHERITED LONG-QT SYNDROME (LQTS) is a genetically heterogeneous arrhythmic disease characterized by impaired cardiac repolarization leading to QT prolongation, polymorphic ventricular tachycardia (pVT), and sudden cardiac death (SCD) (reviewed in Ref. 34). The most common forms of LQTS, type 1 and type 2 (LQT1 and LQT2), account for Ͼ90% of the genotyped cases and are due to loss-of-function mutations in KvLQT1 [␣-subunit of slow delayed-rectifier K ϩ current (I Ks )] (11) or HERG [␣-subunit of rapidly activating delayed-rectifier K ϩ current (I Kr )] (9), respectively. The known triggers for pVTs in LQTS vary f...

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“…We know of only one report of an extrastimulus-induced ͕1:1→2:1͖ flip, in a patient with 2:1 atrioventricular heart block. 48 Injection of a sufficiently premature atrial or ventricular extrastimulus during sinus rhythm resulted in infraHisian block of that beat. Following the resultant post-extra systolic ventricular pause, the next sinus beat conducted, but the next one did not, thus setting up a rhythm of 2:1 block.…”

Section: Cˆ1:1↔2:1‰ Amplitude Hysteresismentioning

confidence: 99%

Hysteresis and bistability in the direct transition from 1:1 to 2:1 rhythm in periodically driven single ventricular cells

Yehia¹,

Jeandupeux²,

Alonso³

et al. 1999

Chaos: An Interdisciplinary Journal of Nonlinear Science

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The transmembrane potential of a single quiescent cell isolated from rabbit ventricular muscle was recorded using a suction electrode in whole-cell recording mode. The cell was then driven with a periodic train of current pulses injected into the cell through the same recording electrode. When the interpulse interval or basic cycle length (BCL) was sufficiently long, 1:1 rhythm resulted, with each stimulus pulse producing an action potential. Gradual decrease in BCL invariably resulted in loss of 1:1 synchronization at some point. When the pulse amplitude was set to a fixed low level and BCL gradually decreased, N+1:N rhythms (N>/=2) reminiscent of clinically observed Wenckebach rhythms were seen. Further decrease in BCL then yielded a 2:1 rhythm. In contrast, when the pulse amplitude was set to a fixed high level, a period-doubled 2:2 rhythm resembling alternans rhythm was seen before a 2:1 rhythm occurred. With the pulse amplitude set to an intermediate level (i.e., to a level between those at which Wenckebach and alternans rhythms were seen), there was a direct transition from 1:1 to 2:1 rhythm as the BCL was decreased: Wenckebach and alternans rhythms were not seen. When at that point the BCL was increased, the transition back to 1:1 rhythm occurred at a longer BCL than that at which the {1:1-->2:1} transition had initially occurred, demonstrating hysteresis. With the BCL set to a value within the hysteresis range, injection of a single well-timed extrastimulus converted 1:1 rhythm into 2:1 rhythm or vice versa, providing incontrovertible evidence of bistability (the coexistence of two different periodic rhythms at a fixed set of stimulation parameters). Hysteresis between 1:1 and 2:1 rhythms was also seen when the stimulus amplitude, rather than the BCL, was changed. Simulations using numerical integration of an ionic model of a single ventricular cell formulated as a nonlinear system of differential equations provided results that were very similar to those found in the experiments. The steady-state action potential duration restitution curve, which is a plot of the duration of the action potential during 1:1 rhythm as a function of the recovery time or diastolic interval immediately preceding that action potential, was determined. Iteration of a finite-difference equation derived using the restitution curve predicted the direct {1:1<-->2:1} transition, as well as bistability, in both the experimental and modeling work. However, prediction of the action potential duration during 2:1 rhythm was not as accurate in the experiments as in the model. Finally, we point out a few implications of our findings for cardiac arrhythmias (e.g., Mobitz type II block, ischemic alternans). (c) 1999 American Institute of Physics.

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Two‐to‐One AV Block Associated with the Congenital Long QT Syndrome

Abstract: The His-Purkinje system of our LQTS patient displayed dynamic properties with a strong increase in refractoriness for short-long sequences and a decrease for long-short sequences that triggered intermittent 2:1 AV blocks.

Cited by 19 publications

References 12 publications

Homozygous SCN5A Mutation in Long-QT Syndrome With Functional Two-to-One Atrioventricular Block

Homozygous SCN5A Mutation in Long-QT Syndrome With Functional Two-to-One Atrioventricular Block

Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction

Hysteresis and bistability in the direct transition from 1:1 to 2:1 rhythm in periodically driven single ventricular cells

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