Mutations in Conserved Amino Acids in the KCNQ1 Channel and Risk of Cardiac Events in Type‐1 Long‐QT Syndrome
ABSTRACT Background: Type-1 long-QT syndrome (LQT1) is caused by mutations in the KCNQ1 gene. The purpose of this study was to investigate whether KCNQ1 mutations in highly conserved amino acid residues within the voltage-gated potassium channel family are associated with an increased risk of cardiac events.Methods and Results: The study population involved 492 LQT1 patients with 54 missense mutations in the transmembrane region of the KCNQ1 channel. The amino acid sequences of the transmembrane region of 38 human voltage-gated potassium channels were aligned. An adjusted Shannon entropy score for each amino acid residue was calculated ranging from 0 (no conservation) to 1.0 (full conservation). Cox analysis was used to identify independent factors associated with the first cardiac event (syncope, aborted cardiac arrest, or death). Patients were subcategorized into tertiles by their adjusted Shannon entropy scores. The lowest tertile (score 0–0.469; n = 146) was used as a reference group; patients with intermediate tertile scores (0.470–0.665; n = 150) had no increased risk of cardiac events (HR = 1.19, P = 0.42) or aborted cardiac arrest/sudden cardiac death (HR = 1.58, P = 0.26), and those with the highest tertile scores (>0.665; n = 196) showed significantly increased risk of cardiac events (HR = 3.32, P <0.001) and aborted cardiac arrest/sudden cardiac death (HR = 2.62, P = 0.04). The increased risk in patients with the highest conservation scores was independent of QTc, gender, age, and beta-blocker therapy.Conclusions: Mutations in highly conserved amino acid residues in the KCNQ1 gene are associated with a significant risk of cardiac events independent of QTc, gender, and beta-blocker therapy.
SourceAvailable from: Douglas L. Jones[Show abstract] [Hide abstract]
ABSTRACT: Beta-blockers are the standard of care for the treatment of long QT syndrome (LQTS), and have been shown to reduce recurrent syncope and mortality in patients with type 1 LQTS (LQT1). Although beta-blockers have minimal effect on the resting corrected QT interval, their effect on the dynamics of the non-corrected QT interval is unknown, and may provide insight into their protective effects. Twenty-three patients from eight families with genetically distinct mutations for LQT1 performed exercise stress testing before and after beta-blockade. One hundred and fifty-two QT, QTc, and Tpeak-Tend intervals were measured before starting beta-blockers and compared with those at matched identical cycle lengths following beta-blockade. Beta-blockers demonstrated heart-rate-dependent effects on the QT and QTc intervals. In the slowest heart rate tertile (<90 b.p.m.), beta-blockade increased the QT and QTc intervals (QT: 405 vs. 409 ms; P = 0.06; QTc: 459 vs. 464 ms; P = 0.06). In the fastest heart rate tertile (>100 b.p.m.), the use of beta-blocker was associated with a reduction in both the QT and QTc intervals (QT: 367 vs. 358 ms; P < 0.0001; QTc: 500 vs. 486 ms; P < 0.0001). The Tpeak-Tend interval showed minimal change at slower heart rates (<90 b.p.m.) (93 vs. 87 ms; P = 0.09) and at faster heart rates (>100 b.p.m.) (87 vs. 84 ms; P = NS) following beta-blockade. Beta-blockers have heart-rate-dependent effects on the QT and QTc intervals in LQTS. They appear to increase the QT and QTc intervals at slower heart rates and shorten them at faster heart rates during exercise.Europace 05/2014; 16(12). DOI:10.1093/europace/euu086 · 3.05 Impact Factor
Article: GENETICS OF LONG QT SYNDROME.[Show abstract] [Hide abstract]
ABSTRACT: 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.Methodist DeBakey cardiovascular journal 01/2014; 10(1):29-33. DOI:10.14797/mdcj-10-1-29
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ABSTRACT: Background: Mutations in SCN5A can result in both long QT type 3 (LQT3) and Brugada syndrome (BrS), and a few mutations have been found to have an overlapping phenotype. Long QT syndrome is characterized by prolonged QT interval, and a prerequisite for a BrS diagnosis is ST elevation in the right precordial leads of the electrocardiogram. Methods and Results: In a Danish family suffering from long QT syndrome, a novel missense mutation in SCN5A, changing a leucine residue into a glutamine residue at position 1786 (L1786Q), was found to be present in heterozygous form co-segregating with prolonged QT interval. The proband presented with an aborted cardiac arrest, and his mother died suddenly and unexpectedly at the age of 65. Flecainide treatment revealed coved ST elevation in all mutation carriers. Electrophysiological investigations of the mutant in HEK293 cells indicated a reduced peak current, a negative shift in inactivation properties and a positive shift in activation properties, compatible with BrS. Furthermore, the sustained (INa,late) tetrodotoxin-sensitive sodium current was found to be drastically increased, explaining the association between the mutation and LQT syndrome. Conclusions: The L1786Q mutation is associated with a combined LQT3 and concealed BrS phenotype explained by gating characteristics of the mutated ion channel protein. Hence, sodium channel blockade should be considered in clinical evaluation of apparent LQT3 patients.Circulation Journal 03/2014; 78(5). DOI:10.1253/circj.CJ-13-1167 · 3.69 Impact Factor