Molecular biology and the prolonged QT syndromes

Towbin, Jeffrey A.; Vatta, Matteo

doi:10.1016/s0002-9343(00)00715-4

Cited by 94 publications

(55 citation statements)

References 89 publications

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“…3,17,18 The incidence of aLQTS is unknown, but the syndrome most likely is more unrecognized than rare. 19 According to estimates, 20 3000 to 4000 patients die each year of sudden cardiac death caused by long QT syndromes, highlighting the importance of developing strategies for early identification and prevention of the syndromes.…”

Section: Acquired Long Qt Syndrome: Frequency Onset and Risk Factormentioning

confidence: 99%

Acquired Long QT Syndrome: Frequency, Onset, and Risk Factors in Intensive Care Patients

Kozik

Wung

2012

Critical Care Nurse

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Background Acquired long QT syndrome is a reversible condition that can lead to torsades de pointes and sudden cardiac death. Objective To determine the frequency, onset, frequency of medications, and risk factors for the syndrome in intensive care patients. Methods In a retrospective chart review of 88 subjects, hourly corrected QT intervals calculated by using the Bazett formula were collected. Acquired long QT syndrome was defined as a corrected QT of 500 milliseconds or longer or an increase in corrected QT of 60 milliseconds or greater from baseline level. Risk factors and medications administered were collected from patients’ medical records. Results The syndrome occurred in 46 patients (52%); mean time of onset was 7.4 hours (SD, 9.4) from time of admission. Among the 88 patients, 52 (59%) received a known QTc-prolonging medication. Among the 46 with the syndrome, 23 (50%) received a known QT-prolonging medication. No other risk factor studied was significantly predictive of the syndrome. Conclusions Acquired long QT syndrome occurs in patients not treated with a known QT-prolonging medication, indicating the importance of frequent QT monitoring of all intensive care patients.

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Section: Acquired Long Qt Syndrome: Frequency Onset and Risk Factormentioning

confidence: 99%

Acquired Long QT Syndrome: Frequency, Onset, and Risk Factors in Intensive Care Patients

Kozik

Wung

2012

Critical Care Nurse

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“…1,2 Genetic investigations demonstrate that mutations in ␣ subunits of cardiac potassium and sodium channels account for Ϸ75% of congenital LQTS (LQT1, LQT2, and LQT3) and that Ϸ1% of LQTS are due to mutations involving ankyrin-B, potassium channel ␤ subunits, or voltage-dependent L-type calcium channel ␣ 1C subunit (LQT4, LQT5, LQT6, LQT7, and Clinical Perspective p 2112 LQT8). [3][4][5][6][7][8][9] Thus far, all known LQTS susceptibility genes encode cardiac ion channels (either ␣ pore-forming subunits or auxiliary ␤ subunits) except LQT4, caused by ANK2-encoded ankyrin-B.…”

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confidence: 99%

Mutant Caveolin-3 Induces Persistent Late Sodium Current and Is Associated With Long-QT Syndrome

et al. 2006

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Background-Congenital long-QT syndrome (LQTS) is a primary arrhythmogenic syndrome stemming from perturbed cardiac repolarization. LQTS, which affects Ϸ1 in 3000 persons, is 1 of the most common causes of autopsy-negative sudden death in the young. Since the sentinel discovery of cardiac channel gene mutations in LQTS in 1995, hundreds of mutations in 8 LQTS susceptibility genes have been identified. All 8 LQTS genotypes represent primary cardiac channel defects (ie, ion channelopathy) except LQT4, which is a functional channelopathy because of mutations in ankyrin-B. Approximately 25% of LQTS remains unexplained pathogenetically. We have pursued a "final common pathway" hypothesis to elicit novel LQTS-susceptibility genes. With the recent observation that the LQT3-associated, SCN5A-encoded cardiac sodium channel localizes in caveolae, which are known membrane microdomains whose major component in the striated muscle is caveolin-3, we hypothesized that mutations in caveolin-3 may represent a novel pathogenetic mechanism for LQTS. Methods and Results-Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, we performed open reading frame/splice site mutational analysis on CAV3 in 905 unrelated patients referred for LQTS genetic testing. CAV3 mutations were engineered by site-directed mutagenesis and the molecular phenotype determined by transient heterologous expression into cell lines that stably express the cardiac sodium channel hNa v 1.5. We identified 4 novel mutations in CAV3-encoded caveolin-3 that were absent in Ͼ1000 control alleles. Electrophysiological analysis of sodium current in HEK293 cells stably expressing hNa v 1.5 and transiently transfected with wild-type and mutant caveolin-3 demonstrated that mutant caveolin-3 results in a 2-to 3-fold increase in late sodium current compared with wild-type caveolin-3. Our observations are similar to the increased late sodium current associated with LQT3-associated SCN5A mutations. Conclusions-The present study reports the first CAV3 mutations in subjects with LQTS, and we provide functional data demonstrating a gain-of-function increase in late sodium current. (Circulation. 2006;114:2104-2112.)

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“…These arrhythmias are likely to be caused by aberrant function of ion channels leading to abnormal electrical properties of the heart. Mutations in genes encoding ion channels have emerged in the last decade as the basis for a variety of inherited arrhythmias, including long QT syndrome types 1-3 and 5-7, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (1). However, 30-45% of cases with arrhythmia cannot be explained by mutation of currently identified genes (2-4, ʈ).…”

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confidence: 99%

A cardiac arrhythmia syndrome caused by loss of ankyrin-B function

Mohler

Splawski

Napolitano

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

296

285

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220-kDa ankyrin-B is required for coordinated assembly of Na͞Ca exchanger, Na͞K ATPase, and inositol trisphosphate (InsP3) receptor at transverse-tubule͞sarcoplasmic reticulum sites in cardiomyocytes. A loss-of-function mutation of ankyrin-B identified in an extended kindred causes a dominantly inherited cardiac arrhythmia, initially described as type 4 long QT syndrome. Here we report the identification of eight unrelated probands harboring ankyrin-B loss-of-function mutations, including four previously undescribed mutations, whose clinical features distinguish the cardiac phenotype associated with loss of ankyrin-B activity from classic long QT syndromes. Humans with ankyrin-B mutations display varying degrees of cardiac dysfunction including bradycardia, sinus arrhythmia, idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk of sudden death. However, a prolonged rate-corrected QT interval was not a consistent feature, indicating that ankyrin-B dysfunction represents a clinical entity distinct from classic long QT syndromes. The mutations are localized in the ankyrin-B regulatory domain, which distinguishes function of ankyrin-B from ankyrin-G in cardiomyocytes. All mutations abolish ability of ankyrin-B to restore abnormal Ca 2؉ dynamics and abnormal localization and expression of Na͞Ca exchanger, Na͞K ATPase, and InsP3R in ankyrin-B ؉/؊ cardiomyocytes. This study, considered together with the first description of ankyrin-B mutation associated with cardiac dysfunction, supports a previously undescribed paradigm for human disease due to abnormal coordination of multiple functionally related ion channels and transporters, in this case the Na͞K ATPase, Na͞Ca exchanger, and InsP3 receptor.

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Molecular biology and the prolonged QT syndromes

Cited by 94 publications

References 89 publications

Acquired Long QT Syndrome: Frequency, Onset, and Risk Factors in Intensive Care Patients

Acquired Long QT Syndrome: Frequency, Onset, and Risk Factors in Intensive Care Patients

Mutant Caveolin-3 Induces Persistent Late Sodium Current and Is Associated With Long-QT Syndrome

A cardiac arrhythmia syndrome caused by loss of ankyrin-B function

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