Ionic Mechanisms of Acquired QT Prolongation and Torsades de Pointes in Rabbits With Chronic Complete Atrioventricular Block

Tsuji, Yukiomi; Opthof, Tobias; Yasui, Kohichiroh; Inden, Yasuya; Takemura, Haruki; Niwa, Noriko; Zhu, Lu; Lee, Jong-Kook; Honjo, Haruo; Kamiya, Kaichiro; Kodama, Itsuo

doi:10.1161/01.cir.0000031160.86313.24

Cited by 82 publications

(75 citation statements)

References 21 publications

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“…These findings were based on canine and rabbit models of chronic complete AV block that showed reduction in I Kr and I Ks , and altered L-type Ca 2+ current, with other currents (inward Na + current, transient outward K + current and inward rectifier K + current) remaining normal (15,16,18). The antiarrhythmic drugs, dofetilide and azimilide, produced similar electrophysiological and proarrhythmic effects on canine hearts (19).…”

Section: Mechanism Of Tdp In Complete Av Blockmentioning

confidence: 91%

“…Mechanistically, it has been reported that during bradyarrhythmias, downregulation of the repolarizing currents -rapid and slow delayed rectifier K + currents (I Kr and I Ks , respectively) -results in QT interval prolongation and TdP (15)(16)(17)(18). These findings were based on canine and rabbit models of chronic complete AV block that showed reduction in I Kr and I Ks , and altered L-type Ca 2+ current, with other currents (inward Na + current, transient outward K + current and inward rectifier K + current) remaining normal (15,16,18).…”

Section: Mechanism Of Tdp In Complete Av Blockmentioning

confidence: 99%

See 1 more Smart Citation

Torsades de pointes during complete atrioventricular block: Genetic factors and electrocardiogram correlates

Subbiah

Gollob

Gula

et al. 2010

Canadian Journal of Cardiology

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V entricular arrhythmias have been reported in the setting of complete atrioventricular (AV) block since 1918 (1). In 1966, Dessertenne (2) described such an arrhythmia as torsades de pointes (TdP), a polymorphic ventricular tachycardia preceded by QT interval prolongation, now known to be caused by congenital or acquired long QT syndrome (LQTS) (3).Bradyarrhythmias caused by high-grade AV block are common. It is, however, infrequent that bradyarrhythmias are associated with QT interval prolongation and TdP phenomena (4-6). In patients with bradycardia-induced TdP, a number of electrocardiogram (ECG) parameters during bradycardia correlate with increased risk of TdP, including the QT interval (4-6), T wave morphology and T peak to T end (T p -T e ) (6). Although ECG parameters can be reasonable predictors of TdP in bradyarrhythmias (4-6), there are limited data on cellular or genetic mechanisms of bradycardia-induced TdP (7,8).We hypothesized that patients with bradycardia-mediated QT arrhythmia may have latent congenital LQTS or a vulnerable genetic polymorphism. In the setting of AV block, reduced repolarization reserve may be 'unmasked' in patients, manifesting as QT interval prolongation and TdP. Such an occult form of LQTS has previously been reported among patients with undiagnosed congenital LQTS who develop marked QT interval prolongation and TdP when exposed to QT-prolonging drugs (9,10). Moreover, the development of TdP in the setting of AV block may identify ion channel mutations that have a propensity to cause TdP and sudden cardiac death. INtRodUCtIoN: Atrioventricular (AV) block is infrequently associated with QT prolongation and torsades de pointes (TdP). It was hypothesized that patients with AV block-mediated QT-related arrhythmia may have latent congenital long QT syndrome or a vulnerable genetic polymorphism. Methods: Eleven patients with complete AV block and TdP were prospectively identified. Patients underwent assessment, resting electrocardiography and telemetry at baseline, during AV block and pre-TdP. Genetic testing of KCNH2, KCNQ1, KCNE1, KCNE2 and SCN5A was performed. Thirty-three patients with AV block without TdP were included for comparison. ResULts: Genetic variants were identified in 36% of patients with AV block and TdP. Patients with AV block who developed TdP had significantly longer mean (± SD) corrected QT intervals (440±93 ms versus 376±40 ms, P=0.048) and T peak to T end (T p -T e ) intervals (147±25 ms versus 94±25 ms, P=0.0001) than patients with AV block alone. In patients with a genetic variant, there was a significant increase in T p -T e intervals at baseline, in AV block and pre-TdP compared with those who were genotype negative. A personal or family history of syncope or sudden death was more likely observed in patients with a genetic variant. CoNCLUsIoNs: TdP in the setting of AV block may be a marker of an underlying genetic predisposition to reduced repolarization reserve. The T p -T e interval at baseline, in AV block and pre-TdP may predict a genetic mutation ...

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Section: Mechanism Of Tdp In Complete Av Blockmentioning

confidence: 91%

Section: Mechanism Of Tdp In Complete Av Blockmentioning

confidence: 99%

Torsades de pointes during complete atrioventricular block: Genetic factors and electrocardiogram correlates

Subbiah

Gollob

Gula

et al. 2010

Canadian Journal of Cardiology

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“…Interestingly, Brooksby et al (5) have shown that the electrical remodeling related to cardiac hypertrophy was restricted to a decrease in I K1 current density with no difference in the resting potential level of cardiomyocytes from control and spontaneously hypertensive rats. The fewer electrophysiological studies available in the literature related to volume-overload induced cardiac hypertrophy showed a decrease in I K (50,56) but an increase in I K1 without any change in I to (56).…”

mentioning

confidence: 87%

Basal and IGF-I-dependent regulation of potassium channels by MAP kinases and PI3-kinase during eccentric cardiac hypertrophy

Teos¹,

Zhao²,

Alvin³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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The potassium channels IK and IK1, responsible for the action potential repolarization and resting potential respectively, are altered during cardiac hypertrophy. The activation of insulin-like growth factor-I (IGF-I) during hypertrophy may affect channel activity. The aim was to examine the modulatory effects of IGF-I on IK and IK1 through mitogenactivated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways during hypertrophy. With the use of specific inhibitors for ERK1/2 (PD98059), p38 MAPK (SB203580) and PI3K/Akt (LY294002), Western blot and whole cell patch-clamp were conducted on sham and aorto-caval shunt-induced hypertrophy adult rat myocytes. Basal activation levels of MAPKs and Akt were increased during hypertrophy. Acute IGF-I (10 Ϫ8 M) enhanced basal activation levels of these kinases in normal hearts but only those of Akt in hypertrophied ones. IK and IK1 activities were lowered by IGF-I. Inhibition of ERK1/2, p38 MAPK, or Akt reduced basal IK activity by 70, 32, or 50%, respectively, in normal cardiomyocytes vs. 53, 34, or 52% in hypertrophied ones. However, basal activity of IK1 was reduced by 45, 48, or 45% in the former vs. 63, 43, or 24% in the latter. The inhibition of either MAPKs or Akt alleviated IGF-I effects on IK and IK1. We conclude that basal IK and IK1 are positively maintained by steady-state Akt and ERK activities.

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“…Moreover, several similarities have been found between experimental models of atrioventricular block-induced torsades de pointes and specific forms of human congenital long QT syndrome. Frequent episodes of spontaneous torsades de pointes during day and night, abnormal QTU complex, and reduction of both IKr and IKs in a rabbit atrioventricular block model (Tsuji , 2002) closely resemble the clinical characteristics of the malignant form of human congenital long QT syndrome caused by double mutation of HERG and KCNQ1. An enhanced susceptibility to acquired torsades de pointes, the adrenergic dependence of torsades de pointes, the typical T-wave patterns during prolonged QT intervals and the reduction of IKs in dog with chronic atrio-ventricular block closely resemble the clinical characteristics of the LQT1 or LQT5 form of human congenital long QT syndrome.…”

Section: Genetic Bases Of Atrio-ventricular Block-induced Torsades Dementioning

confidence: 65%

“…This association has been extensively evaluated in animal studies. Tsuji et al reported the results obtained in a rabbit model with atrio-ventricular block induced by injection of formaldehyde into the atrio-ventricular node (Tsuji, 2002). These rabbits received ventricular pacing support after atrio-ventricular block induction.…”

Section: Electrical Remodelling During Atrio-ventricular Blockmentioning

confidence: 99%

Atrio-Ventricular Block-Induced Torsades de Pointes: An Update

Chevalier¹,

Scridon²

2011

Aspects of Pacemakers - Functions and Interactions in Cardiac and Non-Cardiac Indications

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Ionic Mechanisms of Acquired QT Prolongation and Torsades de Pointes in Rabbits With Chronic Complete Atrioventricular Block

Cited by 82 publications

References 21 publications

Torsades de pointes during complete atrioventricular block: Genetic factors and electrocardiogram correlates

Torsades de pointes during complete atrioventricular block: Genetic factors and electrocardiogram correlates

Basal and IGF-I-dependent regulation of potassium channels by MAP kinases and PI3-kinase during eccentric cardiac hypertrophy

Atrio-Ventricular Block-Induced Torsades de Pointes: An Update

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