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Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations.

ABSTRACT: Patients with long QT syndrome (LQTS) who harbor multiple mutations (i.e. ? 2 mutations in ? 1 LQTS-susceptibility gene) may experience increased risk for life-threatening cardiac events.The present study was designed to compare the clinical course of LQTS patients with multiple mutations to those with a single mutation.The risk for life-threatening cardiac events (comprising aborted cardiac arrest, implantable defibrillator shock, or sudden cardiac death) from birth through age 40 years, by the presence of multiple vs. single mutations, was assessed among 403 patients from the LQTS Registry.Patients with multiple mutations (n=57) exhibited a longer QTc at enrollment compared with those with a single mutation (mean ± SD: 506 ± 72 vs. 480 ± 56 msec, respectively; P=0.003) and had a higher rate of life threatening cardiac events during follow-up (23% vs. 11%, respectively; p=0.031). Consistently, multivariate analysis demonstrated that patients with multiple mutations had a 2.3-fold (P=0.015) increased risk for life threatening cardiac events as compared to patients with a single mutation. The presence of multiple mutations in a single LQTS gene was associated with a 3.2-fold increased risk for life threatening cardiac events (P=0.010) whereas the risk associated with multiple mutation status involving >1 LQTS gene was not significantly different from the risk associated with a single mutation (HR 1.7, P=0.26).LQTS patients with multiple mutations have a greater risk for life-threatening cardiac events as compared to patients with a single mutation.

SUBMITTER: Mullally J

PROVIDER: S-EPMC3690288 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations.

Mullally Jamie J Goldenberg Ilan I Moss Arthur J AJ Lopes Coeli M CM Ackerman Michael J MJ Zareba Wojciech W McNitt Scott S Robinson Jennifer L JL Benhorin Jesaia J Kaufman Elizabeth S ES Towbin Jeffrey A JA Barsheshet Alon A

Heart rhythm 20121119 3

<h4>Background</h4>Patients with long QT syndrome (LQTS) who harbor multiple mutations (i.e. ≥ 2 mutations in ≥ 1 LQTS-susceptibility gene) may experience increased risk for life-threatening cardiac events.<h4>Objectives</h4>The present study was designed to compare the clinical course of LQTS patients with multiple mutations to those with a single mutation.<h4>Methods</h4>The risk for life-threatening cardiac events (comprising aborted cardiac arrest, implantable defibrillator shock, or sudden ...[more]

PMID: 23174487

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Project description:ImportanceLong QT syndrome (LQTS) is caused by several ion channel genes, yet risk of arrhythmic events is not determined solely by the responsible gene pathogenic variants. Female sex after adolescence is associated with a higher risk of arrhythmic events in individuals with congenital LQTS, but the association between sex and genotype-based risk of LQTS is still unclear.ObjectiveTo examine the association between sex and location of the LQTS-related pathogenic variant as it pertains to the risk of life-threatening arrhythmias.Design, setting, and participantsThis retrospective observational study enrolled 1124 genotype-positive patients from 11 Japanese institutions from March 1, 2006, to February 28, 2013. Patients had LQTS type 1 (LQT1), type 2 (LQT2), and type 3 (LQT3) (616 probands and 508 family members), with KCNQ1 (n = 521), KCNH2 (n = 487) and SCN5A (n = 116) genes. Clinical characteristics such as age at the time of diagnosis, sex, family history, cardiac events, and several electrocardiographic measures were collected. Statistical analysis was conducted from January 18 to October 10, 2018.Main outcomes and measuresSex difference in the genotype-specific risk of congenital LQTS.ResultsAmong the 1124 patients (663 females and 461 males; mean [SD] age, 20 [15] years) no sex difference was observed in risk for arrhythmic events among those younger than 15 years; in contrast, female sex was associated with a higher risk for LQT1 and LQT2 among those older than 15 years. In patients with LQT1, the pathogenic variant of the membrane-spanning site was associated with higher risk of arrhythmic events than was the pathogenic variant of the C-terminus of KCNQ1 (HR, 1.60; 95% CI, 1.19-2.17; P = .002), although this site-specific difference in the incidence of arrhythmic events was observed in female patients only. In patients with LQT2, those with S5-pore-S6 pathogenic variants in KCNH2 had a higher risk of arrhythmic events than did those with others (HR, 1.88; 95% CI, 1.44-2.44; P < .001). This site-specific difference in incidence, however, was observed in both sexes. Regardless of the QTc interval, however, female sex itself was associated with a significantly higher risk of arrhythmic events in patients with LQT2 after puberty (106 of 192 [55.2%] vs 19 of 94 [20.2%]; P < .001). In patients with LQT3, pathogenic variants in the S5-pore-S6 segment of the Nav1.5 channel were associated with lethal arrhythmic events compared with others (HR, 4.2; 95% CI, 2.09-8.36; P < .001), but no sex difference was seen.Conclusions and relevanceIn this retrospective analysis, pathogenic variants in the pore areas of the channels were associated with higher risk of arrhythmic events than were other variants in each genotype, while sex-associated differences were observed in patients with LQT1 and LQT2 but not in those with LQT3. The findings of this study suggest that risk for cardiac events in LQTS varies according to genotype, variant site, age, and sex.

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Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations.

Publications

Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations.

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