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Journal of the American College of... Feb 2023
Topics: Humans; Expert Testimony; Long QT Syndrome; Electrocardiography
PubMed: 36725177
DOI: 10.1016/j.jacc.2022.11.037 -
Annals of Noninvasive Electrocardiology... Nov 2017Since its initial description by Jervell and Lange-Nielsen in 1957, the congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. A... (Review)
Review
Since its initial description by Jervell and Lange-Nielsen in 1957, the congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. A prolonged QT interval in the surface electrocardiogram is the sine qua non of the LQTS and is a surrogate measure of the ventricular action potential duration (APD). Congenital as well as acquired alterations in certain cardiac ion channels can affect their currents in such a way as to increase the APD and hence the QT interval. The inhomogeneous lengthening of the APD across the ventricular wall results in dispersion of APD. This together with the tendency of prolonged APD to be associated with oscillations at the plateau level, termed early afterdepolarizations (EADs), provides the substrate of ventricular tachyarrhythmia associated with LQTS, usually referred to as torsade de pointes (TdP) VT. This review will discuss the genetic, molecular, and phenotype characteristics of congenital LQTS as well as current management strategies and future directions in the field.
Topics: Adrenergic beta-Antagonists; Electrocardiography; Humans; Long QT Syndrome; Torsades de Pointes
PubMed: 28670758
DOI: 10.1111/anec.12481 -
Sports Health 2016The congenital long QT syndrome (LQTS) is an inherited channelopathy known for its electrocardiographic manifestations of QT prolongation and its hallmark arrhythmia,... (Review)
Review
CONTEXT
The congenital long QT syndrome (LQTS) is an inherited channelopathy known for its electrocardiographic manifestations of QT prolongation and its hallmark arrhythmia, torsades de pointes (TdP). TdP can lead to syncope or sudden death and is often precipitated by triggers such as physical exertion or emotional stress. Given that athletes may be at particular risk for adverse outcomes, those suspected of having LQTS should be evaluated, risk stratified, treated, and receive appropriate counseling by providers with sufficient expertise according to the latest guidelines.
EVIDENCE ACQUISITION
The following keywords were used to query MEDLINE and PubMed through 2016: LQTS, LQT1, LQT2, LQT3, long QT, long QTc, prolonged QT, prolonged QTc, QT interval, QTc interval, channelopathy, channelopathies, athletes, torsades de pointes, and sudden cardiac death. Selected articles within this primary search, in addition to relevant references from those articles, were reviewed for relevant information and data. Articles with pertinent information regarding pathophysiology, evaluation, diagnosis, genetic testing, treatment, and guidelines for athletes were included, particularly those published in the prior 2 decades.
STUDY DESIGN
Clinical review.
LEVEL OF EVIDENCE
Level 3.
RESULTS
Diagnosis of LQTS involves eliciting the patient's family history, clinical history, and evaluation of electrocardiographic findings. Genetic testing for common mutations can confirm suspected cases. β-Blockers represent the mainstay of treatment, though interventions such as implantable cardioverter-defibrillator placement or left cardiac sympathetic denervation may be required. Properly evaluated and treated athletes with LQTS have a low risk of cardiac events.
CONCLUSION
Detection and management of LQTS in the athletic population is crucial given the possibility of adverse outcomes with the stress of athletic participation. Preparticipation screening examinations should include a thorough clinical and family history. Screening electrocardiograms may display key findings consistent with LQTS while genetic testing can confirm the diagnosis. Formerly considered a strict contraindication to athletic participation, LQTS is now an increasingly manageable entity with proper evaluation and treatment by qualified and experienced providers.
Topics: Athletes; Death, Sudden, Cardiac; Defibrillators, Implantable; Electrocardiography; Health Knowledge, Attitudes, Practice; Humans; Long QT Syndrome; Practice Guidelines as Topic; Risk Assessment; Sports Medicine; Torsades de Pointes
PubMed: 27480102
DOI: 10.1177/1941738116660294 -
Clinical and Experimental Pharmacology... Dec 2017Ageing is associated with increased prevalences of both atrial and ventricular arrhythmias, reflecting disruption of the normal sequence of ion channel activation and... (Review)
Review
Ageing is associated with increased prevalences of both atrial and ventricular arrhythmias, reflecting disruption of the normal sequence of ion channel activation and inactivation generating the propagated cardiac action potential. Experimental models with specific ion channel genetic modifications have helped clarify the interacting functional roles of ion channels and how their dysregulation contributes to arrhythmogenic processes at the cellular and systems level. They have also investigated interactions between these ion channel abnormalities and age-related processes in producing arrhythmic tendency. Previous reviews have explored the relationships between age and loss-of-function Na 1.5 mutations in producing arrhythmogenicity. The present review now explores complementary relationships arising from gain-of-function Na 1.5 mutations associated with long QT3 (LQTS3). LQTS3 patients show increased risks of life-threatening ventricular arrhythmias, particularly after 40 years of age, consistent with such interactions between the ion channel abnormailities and ageing. In turn clinical evidence suggests that ageing is accompanied by structural, particularly fibrotic, as well as electrophysiological change. These abnormalities may result from biochemical changes producing low-grade inflammation resulting from increased production of reactive oxygen species and superoxide. Experimental studies offer further insights into the underlying mechanisms underlying these phenotypes. Thus, studies in genetically modified murine models for LQTS implicated action potential recovery processes in arrhythmogenesis resulting from functional ion channel abnormalities. In addition, ageing wild type (WT) murine models demonstrated both ion channel alterations and fibrotic changes with ageing. Murine models then suggested evidence for interactions between ageing and ion channel mutations and provided insights into potential arrhythmic mechanisms inviting future exploration.
Topics: Action Potentials; Age Factors; Aging; Animals; Genetic Predisposition to Disease; Heart Rate; Humans; Incidence; Kinetics; Long QT Syndrome; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Phenotype; Risk Factors
PubMed: 28024120
DOI: 10.1111/1440-1681.12721 -
Circulation Journal : Official Journal... 2014Congenital long QT syndrome (LQTS) is an inherited arrhythmia syndrome characterized by a prolonged QT interval on the 12-lead ECG, torsades de pointes and a higher... (Review)
Review
Congenital long QT syndrome (LQTS) is an inherited arrhythmia syndrome characterized by a prolonged QT interval on the 12-lead ECG, torsades de pointes and a higher chance of sudden cardiac death. LQTS segregates in a Mendelian fashion, which includes Romano-Ward syndrome with an autosomal dominant pattern as well as a rare autosomal recessive pattern (Jervell and Lange-Nielsen syndrome). Since 1957 when Jervell and Lange-Nielsen reported the first familial LQTS with congenital deafness, progress in understanding the genetic and electrophysiological mechanisms of LQTS has tremendously improved diagnostic methods and treatments. In the meantime, it has become evident that LQTS may not always be explained by a single gene mutation, but seems to follow a more complex genetic model intertwined with genetic common polymorphisms that have a mild to moderate effect on disease expression. In this review, we summarize the characteristics of LQTS (mainly LQT1-3) and briefly describe the most recent advances in LQTS clinical diagnostics as well as genetics.
Topics: Adrenergic beta-Antagonists; Autonomic Denervation; Combined Modality Therapy; Death, Sudden, Cardiac; Defibrillators, Implantable; Electrocardiography; Genes, Dominant; Genes, Recessive; Genetic Heterogeneity; Genotype; Humans; Ion Channels; Long QT Syndrome; Multifactorial Inheritance; Phenotype; Potassium; Romano-Ward Syndrome; Syncope
PubMed: 25274057
DOI: 10.1253/circj.cj-14-0905 -
JACC. Clinical Electrophysiology Mar 2022
Topics: Heart; Humans; Long QT Syndrome; Sympathectomy
PubMed: 35331423
DOI: 10.1016/j.jacep.2021.11.004 -
Journal of the American Heart... Sep 2022Background Diagnosis of congenital long-QT syndrome (LQTS) is complicated by phenotypic ambiguity, with a frequent normal-to-borderline resting QT interval. A 3-step...
Background Diagnosis of congenital long-QT syndrome (LQTS) is complicated by phenotypic ambiguity, with a frequent normal-to-borderline resting QT interval. A 3-step algorithm based on exercise response of the corrected QT interval (QTc) was previously developed to diagnose patients with LQTS and predict subtype. This study evaluated the 3-step algorithm in a population that is more representative of the general population with LQTS with milder phenotypes and establishes sex-specific cutoffs beyond the resting QTc. Methods and Results We identified 208 LQTS likely pathogenic or pathogenic or variant carriers in the Canadian NLQTS (National Long-QT Syndrome) Registry and 215 unaffected controls from the HiRO (Hearts in Rhythm Organization) Registry. Exercise treadmill tests were analyzed across the 5 stages of the Bruce protocol. The predictive value of exercise ECG characteristics was analyzed using receiver operating characteristic curve analysis to identify optimal cutoff values. A total of 78% of male carriers and 74% of female carriers had a resting QTc value in the normal-to-borderline range. The 4-minute recovery QTc demonstrated the best predictive value for carrier status in both sexes, with better LQTS ascertainment in female patients (area under the curve, 0.90 versus 0.82), with greater sensitivity and specificity. The optimal cutoff value for the 4-minute recovery period was 440 milliseconds for male patients and 450 milliseconds for female patients. The 1-minute recovery QTc had the best predictive value in female patients for differentiating LQTS1 versus LQTS2 (area under the curve, 0.82), and the peak exercise QTc had a marginally better predictive value in male patients for subtype with (area under the curve, 0.71). The optimal cutoff value for the 1-minute recovery period was 435 milliseconds for male patients and 455 milliseconds for femal patients. Conclusions The 3-step QT exercise algorithm is a valid tool for the diagnosis of LQTS in a general population with more frequent ambiguity in phenotype. The algorithm is a simple and reliable method for the identification and prediction of the 2 major genotypes of LQTS.
Topics: Canada; Exercise Test; Female; Humans; KCNQ1 Potassium Channel; Long QT Syndrome; Male; Sex Characteristics
PubMed: 36102233
DOI: 10.1161/JAHA.121.025108 -
Journal of the American College of... Feb 2023Long QT syndrome (LQTS) predisposes individuals to arrhythmic syncope or seizure, sudden cardiac arrest, or sudden cardiac death (SCD). Increased physician and public...
BACKGROUND
Long QT syndrome (LQTS) predisposes individuals to arrhythmic syncope or seizure, sudden cardiac arrest, or sudden cardiac death (SCD). Increased physician and public awareness of LQTS-associated warning signs and an increase in electrocardiographic screening programs may contribute to overdiagnosis of LQTS.
OBJECTIVES
This study sought to identify the diagnostic miscues underlying the continued overdiagnosis of LQTS.
METHODS
Electronic medical records were reviewed for patients who arrived with an outside diagnosis of LQTS but were dismissed as having normal findings subsequently. Data were abstracted for details on referral, clinical history, and both cardiologic and genetic test results.
RESULTS
Overall, 290 of 1,841 (16%) patients with original diagnosis of LQTS (174 [60%] female; mean age at first Mayo Clinic evaluation, 22 ± 14 years; mean QTc interval, 427 ± 25 milliseconds) were dismissed as having normal findings. The main cause of LQTS misdiagnosis or overdiagnosis was a prolonged QTc interval secondary to vasovagal syncope (n = 87; 30%), followed by a seemingly positive genetic test result for a variant in 1 of the main LQTS genes (n = 68; 23%) that was ultimately deemed not to be of clinical significance. Furthermore, patients received misdiagnoses because of a positive family history of SCD that was deemed unrelated to LQTS (n = 46; 16%), isolated/transient QT prolongation (n = 44; 15%), or misinterpretation of the QTc interval as a result of inclusion of the U-wave (n = 40, 14%).
CONCLUSIONS
Knowing the 5 main determinants of discordance between a previously rendered diagnosis of LQTS and full diagnostic reversal or removal (vasovagal syncope, "pseudo"-positive genetic test result in LQTS-causative genes, family history of SCD, transient QT prolongation, and misinterpretation of the QTc interval) increases awareness and provides critical guidance to reduce this burden of overdiagnosed LQTS.
Topics: Female; Male; Humans; Syncope, Vasovagal; Long QT Syndrome; Death, Sudden, Cardiac; Heart Arrest; Phenotype; Electrocardiography
PubMed: 36725176
DOI: 10.1016/j.jacc.2022.11.036 -
Current Problems in Cardiology Oct 2013Congenital long QT syndrome (LQTS) is a genetically heterogeneous group of heritable disorders of myocardial repolarization linked by the shared clinical phenotype of QT... (Review)
Review
Congenital long QT syndrome (LQTS) is a genetically heterogeneous group of heritable disorders of myocardial repolarization linked by the shared clinical phenotype of QT prolongation on electrocardiogram and an increased risk of potentially life-threatening cardiac arrhythmias. At the molecular level, mutations in 15 distinct LQTS-susceptibility genes that encode ion channel pore-forming α-subunits and accessory β-subunits central to the electromechanical function of the heart have been implicated in its pathogenesis. Over the past 2 decades, our evolving understanding of the electrophysiological mechanisms by which specific genetic substrates perturb the cardiac action potential has translated into vastly improved approaches to the diagnosis, risk stratification, and treatment of patients with LQTS. In this review, we describe how our understanding of the molecular underpinnings of LQTS has yielded numerous clinically meaningful genotype-phenotype correlations and how these insights have translated into genotype- and phenotype-guided approaches to the clinical management of LQTS.
Topics: Algorithms; Electrocardiography; Evidence-Based Medicine; Genetic Predisposition to Disease; Genetic Testing; Genotype; Humans; Long QT Syndrome; Mutation; Phenotype; Risk Assessment
PubMed: 24093767
DOI: 10.1016/j.cpcardiol.2013.08.001 -
Journal of the American Heart... Dec 2023It has been postulated that long QT syndrome (LQTS) can cause fetal loss through putative adverse effects of the channelopathy on placenta and myometrial function. The...
BACKGROUND
It has been postulated that long QT syndrome (LQTS) can cause fetal loss through putative adverse effects of the channelopathy on placenta and myometrial function. The authors aimed to describe the fetal death rate in a population of pregnant women with long QT syndrome and investigate whether women with more severe phenotype had worse fetal outcomes.
METHODS AND RESULTS
The authors retrospectively evaluated fetal outcomes of 64 pregnancies from 23 women with long QT syndrome followed during pregnancy in a tertiary pregnancy and heart disease program. Thirteen of 64 pregnancies (20%) resulted in a fetal loss, 12 miscarriages (19%), and 1 stillbirth (1.6%). Baseline maternal characteristics, including age and use of β-blockers, did not differ between women who experienced a fetal death or not. Maternal corrected QT interval (QTc) was significantly longer in pregnancies that resulted in fetal death compared with live births (median, 518 ms [interquartile range (IQR), 482-519 ms] versus 479 ms [IQR, 454-496 ms], <0.001). Mothers treated with β-blockers had babies born at term with lower birth weight compared with untreated women (2973±298 g versus 3470±338 g, =0.002). In addition, the birth weight of babies born at term to treated women with QTc >500 ms was significantly lower compared with women with QTc <500 ms (2783±283 g versus 3084±256 g, =0.029).
CONCLUSIONS
Women with long QT syndrome with more severe phenotypes have a higher incidence of fetal death. Maternal QTc is longer in pregnancies that result in fetal loss, and the birth weight of babies born to patients taking β-blockers with a QTc >500 ms is lower, suggesting that patients with more marked phenotype may experience worse fetal outcomes.
Topics: Humans; Female; Pregnancy; Birth Weight; Retrospective Studies; Long QT Syndrome; Fetal Death; Phenotype; Adrenergic beta-Antagonists; Electrocardiography
PubMed: 38014677
DOI: 10.1161/JAHA.122.029407