Genetically Defined Therapy of Inherited Long-QT Syndrome

Compton, Steve; Lux, Robert L.; Ramsey, Matthew R.; Strelich, Katie R.; Sanguinetti, Michael C.; Green, Larry S.; Keating, Mark T.; Mason, Jay W.

doi:10.1161/01.cir.94.5.1018

Cited by 263 publications

(43 citation statements)

References 35 publications

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“…25,26 In oocytes bathed by Kϩ concentrations ranging from 0.5 to 20 mmol/L, HERG current amplitude varied as a linear function of [Kϩ]e. 27 Unlike most other Kϩ currents, the magnitude of outward HERG current is paradoxically reduced on removal of extracellular Kϩ, thus explaining the increased action potential and prolonged ventricular repolarization in hypokalemic patients. In addition, an increase in serum potassium corrects or reduces part of the abnormalities of repolarization in patients with chromosome 7-linked LQT, 28 which was the case in our patients. Yang et al showed that the IKr blocking effects of quinidine and dofetilide, 2 antiarrhythmic agents, are increased by low extracellular potassium concentration.…”

Section: Discussionsupporting

confidence: 71%

C-terminal HERG Mutations

et al. 1999

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Background —The long-QT syndrome (LQTS) is a genetically heterogeneous disease in which 4 genes encoding ion-channel subunits have been identified. Most of the mutations have been determined in the transmembrane domains of the cardiac potassium channel genes KCNQ1 and HERG . In this study, we investigated the 3′ part of HERG for mutations. Methods and Results —New specific primers allowed the amplification of the 3′ part of HERG , the identification of 2 missense mutations, S818L and V822 M, in the putative cyclic nucleotide binding domain, and a 1-bp insertion, 3108+1G. Hypokalemia was a triggering factor for torsade de pointes in 2 of the probands of these families. Lastly, in a large family, a maternally inherited G to A transition was found in the splicing donor consensus site of HERG , 2592+1G-A, and a paternally inherited mutation, A341E, was identified in KCNQ1 . The 2 more severely affected sisters bore both mutations. Conclusions —The discovery of mutations in the C-terminal part of HERG emphasizes that this region plays a significant role in cardiac repolarization. Clinical data suggests that these mutations may be less malignant than mutations occurring in the pore region, but they can become clinically significant in cases of hypokalemia. The first description of 2 patients with double heterozygosity associated with a dramatic malignant phenotype implies that genetic analysis of severely affected young patients should include an investigation for >1 mutation in the LQT genes.

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Section: Discussionsupporting

confidence: 71%

C-terminal HERG Mutations

et al. 1999

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“…These findings correlate with earlier studies that focused on HERG current density, showing that I Kr current paradoxically increased when extracellular K + concentration was increased (Sanguinetti & Jurkiewicz, 1992). One group administered spironolactone to eight LQT2 patients for four weeks, and observed a decrease in QT interval, (Etheridge et al, 2003) while another treated seven subjects with potassium supplementation and had similar findings (Compton et al, 1996). Such approaches may be considered in LQT2 patients.…”

Section: Therapeutic Approachessupporting

confidence: 86%

Phenotypic Correlation of Genetic Mutations with Ventricular Arrhythmias

Krishnan¹,

Chen²,

McDonald³

2012

Cardiac Arrhythmias - New Considerations

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“…Potassium channel activators, such as nicorandil or pinacidil, have been shown to reverse epinephrine-induced QT prolongation and suppress ventricular arrhythmias (36,37). In LQT2, shortterm, exogenously administered potassium was reported to correct QT abnormalities in affected patients (38), presumably by enhancing IKr in the outward direction across the cell membrane. Recently, long-term oral potassium administration was shown to improve repolarization abnormalities in LQT2 patients (39).…”

Section: Therapeutic Considerationsmentioning

confidence: 99%