Safety and Efficacy of Flecainide in Subjects with Long QT‐3 Syndrome (ΔKPQ Mutation): A Randomized, Double‐Blind, Placebo‐Controlled Clinical Trial

Moss, Arthur J.; Windle, John R.; Hall, William J.; Zaręba, Wojciech; Robinson, Jennifer L.; McNitt, Scott; Severski, B S Patricia; Rosero, Spencer; Daubert, James P.; Qi, Ming; Cieciorka, R N Michael; Manalan, Allan S.

doi:10.1111/j.1542-474x.2005.00077.x

Cited by 140 publications

(87 citation statements)

References 18 publications

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“…The overlapping phenotype (LQT3 and BrS) has been previously reported for 1795insD (10,11), ΔKPQ (13,14), ΔK1500 (15), and E1784K (13). In contrast, a carrier of T1304M did not show ST elevation during a flecainide test (13).…”

Section: Spectrum Of Scn5a Dysfunction In Lqt3 Associated With Brs Anmentioning

confidence: 90%

“…However, these agents, especially class IC drugs, also unmask or exacerbate ST elevation in BrS. Despite this apparent divergence of Na channel blocker action, some LQT3 patients display ST elevation characteristic of BrS spontaneously (10)(11)(12) or during class IC drug therapy (13,14). The results of the present study indicate that the BrS/LQT3 overlap is not likely to reflect coinherited genetic variations, gender, or ethnicity and thus implicate the biophysical properties of specific mutant channels as the primary mediator of this mixed phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…The overlap between the LQT3 and BrS phenotypes has also been reported in other SCN5A mutations such as ΔKPQ (13,14), E1784K (13), and ΔK1500 (15), raising a concern about the safety of class IC drug therapy in LQT3 patients (13) and questions about the underlying mechanisms. However, phenotypic variability in LQT3…”

Section: Introductionmentioning

confidence: 99%

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The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome

et al. 2008

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Phenotypic overlap of type 3 long QT syndrome (LQT3) with Brugada syndrome (BrS) is observed in some carriers of mutations in the Na channel SCN5A. While this overlap is important for patient management, the clinical features, prevalence, and mechanisms underlying such overlap have not been fully elucidated. To investigate the basis for this overlap, we genotyped a cohort of 44 LQT3 families of multiple ethnicities from 7 referral centers and found a high prevalence of the E1784K mutation in SCN5A. Of 41 E1784K carriers, 93% had LQT3, 22% had BrS, and 39% had sinus node dysfunction. Heterologously expressed E1784K channels showed a 15.0-mV negative shift in the voltage dependence of Na channel inactivation and a 7.5-fold increase in flecainide affinity for resting-state channels, properties also seen with other LQT3 mutations associated with a mixed clinical phenotype. Furthermore, these properties were absent in Na channels harboring the T1304M mutation, which is associated with LQT3 without a mixed clinical phenotype. These results suggest that a negative shift of steady-state Na channel inactivation and enhanced tonic block by class IC drugs represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and BrS and further indicate that class IC drugs should be avoided in patients with Na channels displaying these behaviors.

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Section: Spectrum Of Scn5a Dysfunction In Lqt3 Associated With Brs Anmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome

et al. 2008

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“…Given the electrophysiological consequence of an lQt3-causing sCn5a mutation, late sodium current blockers including mexiletine, flecainide, or ranolazine may represent gene-specific therapeutic options for lQt3. 14,15 however, the response to sodium channel blockers is mutation-specific, and while there has been clear evidence of the benefit of mexiletine in some lQt3 patients, others have shown no benefit. in general, when the Qtc is > 500 ms, lQt2 females and lQt3 males are at higher risk for a cardiac event.…”

Section: The Major Lqts Genotypesmentioning

confidence: 99%

Genetics of Long QT Syndrome

Tester¹,

Ackerman

2014

Methodist DeBakey Cardiovascular Journal

168

112

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Long QT syndrome (LQTS) is a potentially life-threatening cardiac arrhythmia characterized by delayed myocardial repolarization that produces QT prolongation and increased risk for torsades des pointes (TdP)-triggered syncope, seizures, and sudden cardiac death (SCD) in an otherwise healthy young individual with a structurally normal heart. Currently, there are three major LQTS genes (KCNQ1, KCNH2, and SCN5A) that account for approximately 75% of the disorder. For the major LQTS genotypes, genotype-phenotype correlations have yielded gene-specific arrhythmogenic triggers, electrocardiogram (ECG) patterns, response to therapies, and intragenic and increasingly mutation-specific risk stratification. The 10 minor LQTS-susceptibility genes collectively account for less than 5% of LQTS cases. In addition, three atypical LQTS or multisystem syndromic disorders that have been associated with QT prolongation have been described, including ankyrin-B syndrome, Anderson-Tawil syndrome (ATS), and Timothy syndrome (TS). Genetic testing for LQTS is recommended in patients with either a strong clinical index of suspicion or persistent QT prolongation despite their asymptomatic state. However, genetic test results must be interpreted carefully.

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“…81 Other examples of beneficial drug effects include reports suggesting that quinidine may ameliorate the ECG phenotype and arrhythmic risk of patients with Brugada syndrome via quinidine-induced I to blockade 82,83 and may effectively treat (by I Kr blockade) the gain-of-function mutation in I Kr associated with 1 form of the congenital short-QT syndrome, 84 as well as the use of mexiletine or flecainide as a treatment for congenital LQT3. [85][86][87] …”

Section: Future Strategiesmentioning

confidence: 99%