Persistent Atrial Fibrillation Is Associated With Reduced Risk of Torsades de Pointes in Patients With Drug-Induced Long QT Syndrome

Darbar, Dawood; Kimbrough, John; Jawaid, Asif; McCray, Robert; Ritchie, Marylyn D.; Roden, Dan M.

doi:10.1016/j.jacc.2007.09.066

Cited by 43 publications

(32 citation statements)

References 35 publications

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“…The serum [K + ] in rabbits after 4 weeks on a low-K + diet decreased by approximately 50% compared with the control rabbits (low K + , 2.4 mM; control, 4.69 mM), and the hypokalemic rabbits displayed a prolonged QT interval (low K + , 0.36 seconds; control, 0.27 seconds). Hypokalemia is defined as a serum K + level less than 3.5 mM (30), and the condition has been associated with the occurrence of cardiac arrhythmic events such as Torsades de pointes (30)(31)(32). In hypokalemic patients, serum [K + ] of 2.1 and 2.8 mM were reported (31).…”

Section: Discussionmentioning

confidence: 99%

Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines

Guo¹,

Massaeli²,

Xu³

et al. 2009

J. Clin. Invest.

137

190

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Although the modulation of ion channel gating by hormones and drugs has been extensively studied, much less is known about how cell surface ion channel expression levels are regulated. Here, we demonstrate that the cell surface density of both the heterologously expressed K + channel encoded by the human ether-a-gogo-related gene (HERG) and its native counterpart, the rapidly activating delayed rectifier K + channel (I Kr IntroductionThe amplitude of ion channel currents is determined by a combination of channel gating (open versus closed times) and channel density in the plasma membrane. Whereas ion channel gating is known to be modulated by various means, such as hormones and drugs, much less is known about how the density of WT ion channels in the plasma membrane is regulated.The human ether-a-go-go-related gene (HERG) encodes the pore-forming subunits of the rapidly activating delayed rectifier K + channel (I Kr ) in the heart (1, 2). Mutations in HERG reduce I Kr and cause type 2 long QT syndrome (LQT2), a disorder that predisposes individuals to life-threatening arrhythmias (3). In addition, the HERG channel is a common target for diverse classes of drugs that induce acquired long QT syndrome (LQTS; ref. 4). Whereas drugs usually reduce HERG channel current (I HERG ) by blocking the channel, LQTS-causing HERG mutations often decrease I HERG by disrupting forward trafficking of the channel, thereby reducing expression levels of HERG at the plasma membrane (5). However, little is presently known about how the plasma membrane density of WT HERG channels is regulated under either physiological or pathophysiological conditions. Disorders of extracellular K + concentration ([K + ] o ) are the most common electrolyte abnormality found in clinical practice and can be life threatening. For example, abrupt, insulin-induced shifts of K + from the extracellular compartment into cells, abnormal K + losses caused by digestive or kidney disorders, and the use of certain diuretics are common causes of low [K + ] o (hypokalemia). It is also

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Section: Discussionmentioning

confidence: 99%

Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines

Guo¹,

Massaeli²,

Xu³

et al. 2009

J. Clin. Invest.

137

190

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“…9 In a recently published case-control study, Darbar and colleagues compared patients with drug-associated QT prolongation only with individuals with QT prolongation and TdP. 29 The comparison demonstrated that while on drug both groups of patients showed increased QTend-QTpeak intervals the increase in the latter group was significantly higher.…”

Section: Discussionmentioning

confidence: 99%

Assessment of the Ion Channel-blocking Profile of the Novel Combined Ion Channel Blocker AZD1305 and Its Proarrhythmic Potential Versus Dofetilide in the Methoxamine-sensitized Rabbit In Vivo

Carlsson

Andersson

Linhardt

et al. 2009

Journal of Cardiovascular Pharmacology

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AZD1305 is a novel antiarrhythmic agent under clinical evaluation for management of atrial fibrillation. This study assessed its ion channel-blocking potency by the whole cell patch-clamp technique in vitro and its proarrhythmic liability in anesthetized methoxamine-sensitized rabbits in comparison with dofetilide. AZD1305 predominantly blocked the hERG, the L-type calcium and the hNav1.5 currents in a concentration-dependent manner. In vivo AZD1305 increased the QT interval (from 145 +/- 8 to 196 +/- 18 ms, P < 0.01) without inducing ventricular extrasystoles or torsades de pointes (TdP). In contrast, dofetilide prolonged the QT interval from 161 +/- 3 to 256 +/- 15 ms (P < 0.001) and caused TdP in 12/17 rabbits (P < 0.01 vs. AZD1305). During AZD1305 and dofetilide infusion, the QTend-peak interval maximally increased by 14 +/- 4 and 30 +/- 6 ms (P < 0.05 vs. AZD1305) and the beat-by-beat QT interval variability (quantified as the short-term variability, STV) changed from 2 +/- 0.8 to 2 +/- 0.3 ms (NS) and from 2 +/- 0.2 to 12 +/- 1.1 ms (P < 0.001), respectively. Following dofetilide-induced TdP, 6 rabbits each were injected with saline or AZD1305. In contrast to saline, AZD1305 abbreviated the QT interval (from 275 +/- 25 to 216 +/- 9 ms, P < 0.05), reduced the STV to 1 +/- 0.1 ms (P < 0.001) and suppressed TdP in all 6 rabbits (P < 0.01 vs. saline). In conclusion, AZD1305 can be characterised as a combined ion channel blocker that delays repolarization without increasing beat-by-beat variability of repolarization (BVR) or inducing TdP whereas selective IKr blockade by dofetilide prolongs the QT interval and eventually increases BVR resulting in TdP.

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“…the mean QTc intervals were shorter during AF than in sinus rhythm (considering the limitations of Bazett's QTc estimation for irregular rhythms 18 ), although it is important to note that heart rate was substantially higher during AF than during sinus rhythm (Table 1). A good adaptation of the QTc interval to increased heart rates has been described as a characteristic feature of LQT-3 subtypes.…”

Section: Family Screeningmentioning

confidence: 99%

A mutation in the sodium channel is responsible for the association of long QT syndrome and familial atrial fibrillation

et al. 2008

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Persistent Atrial Fibrillation Is Associated With Reduced Risk of Torsades de Pointes in Patients With Drug-Induced Long QT Syndrome

Abstract: This study strongly suggests that despite ongoing rate irregularity, AF reduces the likelihood of developing TdP after the administration of drugs that prolong cardiac repolarization.

Cited by 43 publications

References 35 publications

Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines

Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines

Assessment of the Ion Channel-blocking Profile of the Novel Combined Ion Channel Blocker AZD1305 and Its Proarrhythmic Potential Versus Dofetilide in the Methoxamine-sensitized Rabbit In Vivo

A mutation in the sodium channel is responsible for the association of long QT syndrome and familial atrial fibrillation

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