Long-Term Follow-Up of Patients With Short QT Syndrome

Giustetto, Carla; Schimpf, Rainer; Mazzanti, Andrea; Scrocco, Chiara; Maury, Philippe; Anttonen, Olli; Probst, Vincent; Blanc, Jean Jacques; Sbragia, Pascal; Dalmasso, Paola; Borggrefe, Martin; Gaïta, Fiorenzo

doi:10.1016/j.jacc.2011.03.038

Cited by 279 publications

(221 citation statements)

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“…35 It is noteworthy that although we postulate that the loss-of-function of the cardiac potassium channels could induce transmission distortion and contribute to female predominance in LQTS, a marked male predominance, up to 80%, has been observed among patients with a short QT syndrome. 36,37 This syndrome is caused by gain-of-function variants in the same channels where loss-of-function variants lead to LQTS, but only in a limited number of cases. It is tempting to suggest a possible role for channel dysfunction in this male predominance, but this must be tempered by the fact that most of the genetic background of this syndrome has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction

et al. 2015

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Transmission distortion of disease-causing alleles in long QT syndrome (LQTS) has been reported, suggesting a potential role of KCNQ1 and KCNH2 in reproduction. This study sought to investigate parental transmission in LQTS families according to ethnicity, gene loci (LQT1-3: KCNQ1, KCNH2, and SCN5A) or severity of channel dysfunction. We studied 3782 genotyped members from 679 European and Japanese LQTS families (2748 carriers). We determined grandparental and parental origins of variant alleles in 1903 children and 624 grandchildren, and the grandparental origin of normal alleles in healthy children from 44 three-generation control families. LQTS alleles were more of maternal than paternal origin (61 vs 39%, Po0.001). The ratio of maternally transmitted alleles in LQT1 (66%) was higher than in LQT2 (56%, Po0.001) and LQT3 (57%, P = 0.03). Unlike the Mendelian distribution of grandparental alleles seen in control families, variant grandparental LQT1 and LQT2 alleles in grandchildren showed an excess of maternally transmitted grandmother alleles. For LQT1, maternal transmission differs according to the variant level of dysfunction with 68% of maternal transmission for dominant negative or unknown functional consequence variants vs 58% for non-dominant negative and variants leading to haploinsufficiency, Po0.01; however, for LQT2 or LQT3 this association was not significant. An excess of disease-causing alleles of maternal origin, most pronounced in LQT1, was consistently found across ethnic groups. This observation does not seem to be linked to an imbalance in transmission of the LQTS subtype-specific grandparental allele, but to the potential degree of potassium channel dysfunction.

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Section: Discussionmentioning

confidence: 99%

Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction

et al. 2015

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“…Fifteen patients with diagnosis of SQTS 11 were included in the study (Table 1). None had structural heart disease.…”

Section: Short Qt Syndrome Patientsmentioning

confidence: 99%

New echocardiographic insights in short QT syndrome: More than a channelopathy?

et al. 2015

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BACKGROUND Short QT syndrome (SQTS) is a congenital ion channel disease characterized by an increased risk of sudden cardiac death. Little is known about the possibility that accelerated repolarization alters mechanical function in SQTS.OBJECTIVES The study investigated the presence of left ventricular dysfunction and mechanical dispersion, assessed by tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE), and their correlation with QT interval duration and genetics.METHODS Fifteen SQTS patients (7 with HERG and 3 with KCNQ1 mutation) were studied. Electrocardiographic and echocardiographic parameters were compared with age-and sex-matched healthy controls.RESULTS When compared to the control group, SQTS patients showed reduced left ventricular contraction (global longitudinal strain: À16.0% Ϯ 3.4% vs À22.6% Ϯ 1.7%, P o .001; myocardial performance index 0.59 Ϯ 0.17 vs 0.34 Ϯ 0.08, P o .001) and a higher incidence of ejection fraction o55% (odds ratio 11, 95% confidence interval 1.045-374, P ¼ .04). Mechanical dispersion assessed by TDI (P o .01) and STE (P o .001) was higher in the SQTS group than in controls; each parameter showed a significant inverse correlation with QT interval but not with QT dispersion.CONCLUSION This study showed that in SQTS systolic function may also be affected. SQTS patients presented a significant dispersion of myocardial contraction. TDI and STE could become part of the evaluation of this rare disease.

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“…However, the higher use of hydroquinidine in patients with HERG mutations (7 of 7 patients with HERG mutations vs 4 of 8 patients without HERG mutations; P ¼ .05) could have leveled off the results, especially considering that the hydroquinidine effect is more relevant in patients with HERG mutations. 3 Further investigation is needed to confirm this hypothesis. To the Editor-Higher incidence of esophageal lesions after atrial fibrillation ablation related to the use of esophageal temperature probes…”

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Reply to the Editor—Altered in vivo systolic function in the short QT syndrome anticipated in silico

et al. 2015

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A recent article by Frea et al 1 in HeartRhythm provides new evidence for altered systolic function in patients with the short QT syndrome (SQTS). They studied 15 patients with the SQTS (7 with the hERG mutation-linked SQT1 variant, 3 with KCNQ1 mutation-linked SQT2 variant, and 5 without known mutations) by using tissue Doppler imaging and speckle tracking electrocardiography to reveal reduced left ventricular contraction and increased mechanical dispersion in the SQTS group as compared with healthy controls. 1 A longer myocardial performance index was seen in patients with the SQTS, but without significant alterations in isovolumetric contraction and relaxation times, implying that this results from reduced ejection time. Over half of the patients with the SQTS also displayed pathological values of global longitudinal shortening, which correlated positively with corrected QT interval shortening. 1 Mechanical dispersion affected the final stage of contraction in patients with the SQTS. 1 In 2013, we published a simulation study in which the functional effects of SQTS K þ channel mutations were incorporated into human ventricular electromechanical models. 2 The incorporation of the SQT1 N588K hERG mutation profoundly reduced the intracellular calcium transient, leading to greatly reduced active force. The SQT3 D172N Kir2.1 mutation, which predominantly influences late repolarization, produced a more modest effect. 2 Once stretch-activated channels (SACs) were incorporated into the base model, the effects of the SQT mutations on the Ca 2þ transient and force generation were reduced and reduced further if SAC Ca 2þ permeability was incorporated. 2 Under simulated action potential clamp, shorter action potentials led to a reduced sarcoplasmic reticulum Ca 2þ content and Ca 2þ transients in the control model, implicating abbreviated repolarization itself as a driver of altered contractility; the mitigating effects of SAC incorporation correlated with changes in Na þ homeostasis and sodium-calcium exchange (NCX) activity. 2 The extent to which mechanisms demonstrated in our "proof-ofconcept" simulations, made in the absence of any compensatory remodeling, apply to the modest but significant systolic dysfunction in patients with the SQTS 1 remains to be established. However, given the important findings of Frea et al, 1 further investigation of altered mechanical function in the SQTS is now warranted. Reply to the Editor-Altered in vivo systolic function in the short QT syndrome anticipated in silicoOur group recently demonstrated an in vivo association between short QT syndrome (SQTS) and a slight but significant systolic dysfunction. 1 Hancox and colleagues 2 partially anticipated this report showing an interesting correlation between SQTS channel mutations (mostly HERG mutation) and shortening of action potential with an in vitro reduction in Ca 2þ transient and force generation. These 2 studies seem to suggest that the association between SQTS and systolic impairment may be explained by 3 mechanisms: a greater...

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Long-Term Follow-Up of Patients With Short QT Syndrome

Abstract: SQTS carries a high risk of sudden death in all age groups. Symptomatic patients have a high risk of recurrent arrhythmic events. HQ is effective in preventing ventricular tachyarrhythmia induction and arrhythmic events during long-term follow-up.

Cited by 279 publications

References 24 publications

Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction

Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction

New echocardiographic insights in short QT syndrome: More than a channelopathy?

Reply to the Editor—Altered in vivo systolic function in the short QT syndrome anticipated in silico

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