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Heart (British Cardiac Society) Mar 2022Congenital long QT syndrome (LQTS) is characterised by heart rate corrected QT interval prolongation and life-threatening arrhythmias, leading to syncope and sudden... (Review)
Review
Congenital long QT syndrome (LQTS) is characterised by heart rate corrected QT interval prolongation and life-threatening arrhythmias, leading to syncope and sudden death. Variations in genes encoding for cardiac ion channels, accessory ion channel subunits or proteins modulating the function of the ion channel have been identified as disease-causing mutations in up to 75% of all LQTS cases. Based on the underlying genetic defect, LQTS has been subdivided into different subtypes. Growing insights into the genetic background and pathophysiology of LQTS has led to the identification of genotype-phenotype relationships for the most common genetic subtypes, the recognition of genetic and non-genetic modifiers of phenotype, optimisation of risk stratification algorithms and the discovery of gene-specific therapies in LQTS. Nevertheless, despite these great advancements in the LQTS field, large gaps in knowledge still exist. For example, up to 25% of LQTS cases still remain genotype elusive, which hampers proper identification of family members at risk, and it is still largely unknown what determines the large variability in disease severity, where even within one family an identical mutation causes malignant arrhythmias in some carriers, while in other carriers, the disease is clinically silent. In this review, we summarise the current evidence available on the diagnosis, clinical management and therapeutic strategies in LQTS. We also discuss new scientific developments and areas of research, which are expected to increase our understanding of the complex genetic architecture in genotype-negative patients, lead to improved risk stratification in asymptomatic mutation carriers and more targeted (gene-specific and even mutation-specific) therapies.
Topics: Arrhythmias, Cardiac; Electrocardiography; Genetic Testing; Genotype; Humans; Ion Channels; Long QT Syndrome; Mutation; Phenotype
PubMed: 34039680
DOI: 10.1136/heartjnl-2020-318259 -
Pediatric Cardiology Oct 2019Long QT syndrome (LQTS) is an inherited primary arrhythmia syndrome that may present with malignant arrhythmia and, rarely, risk of sudden death. The clinical symptoms... (Review)
Review
Long QT syndrome (LQTS) is an inherited primary arrhythmia syndrome that may present with malignant arrhythmia and, rarely, risk of sudden death. The clinical symptoms include palpitations, syncope, and anoxic seizures secondary to ventricular arrhythmia, classically torsade de pointes. This predisposition to malignant arrhythmia is from a cardiac ion channelopathy that results in delayed repolarization of the cardiomyocyte action potential. The QT interval on the surface electrocardiogram is a summation of the individual cellular ventricular action potential durations, and hence is a surrogate marker of the abnormal cellular membrane repolarization. Severely affected phenotypes administered current standard of care therapies may not be fully protected from the occurrence of cardiac arrhythmias. There are 17 different subtypes of LQTS associated with monogenic mutations of 15 autosomal dominant genes. It is now possible to model the various LQTS phenotypes through the generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes. RNA interference can silence or suppress the expression of mutant genes. Thus, RNA interference can be a potential therapeutic intervention that may be employed in LQTS to knock out mutant mRNAs which code for the defective proteins. CRISPR/Cas9 is a genome editing technology that offers great potential in elucidating gene function and a potential therapeutic strategy for monogenic disease. Further studies are required to determine whether CRISPR/Cas9 can be employed as an efficacious and safe rescue of the LQTS phenotype. Current progress has raised opportunities to generate in vitro human cardiomyocyte models for drug screening and to explore gene therapy through genome editing.
Topics: Electrocardiography; Heart Ventricles; Humans; Induced Pluripotent Stem Cells; Long QT Syndrome; Mutation; Myocytes, Cardiac
PubMed: 31440766
DOI: 10.1007/s00246-019-02151-x -
JACC. Clinical Electrophysiology May 2022Congenital long QT syndrome (LQTS) encompasses a group of heritable conditions that are associated with cardiac repolarization dysfunction. Since its initial description... (Review)
Review
Congenital long QT syndrome (LQTS) encompasses a group of heritable conditions that are associated with cardiac repolarization dysfunction. Since its initial description in 1957, our understanding of LQTS has increased dramatically. The prevalence of LQTS is estimated to be ∼1:2,000, with a slight female predominance. The diagnosis of LQTS is based on clinical, electrocardiogram, and genetic factors. Risk stratification of patients with LQTS aims to identify those who are at increased risk of cardiac arrest or sudden cardiac death. Factors including age, sex, QTc interval, and genetic background all contribute to current risk stratification paradigms. The management of LQTS involves conservative measures such as the avoidance of QT-prolonging drugs, pharmacologic measures with nonselective β-blockers, and interventional approaches such as device therapy or left cardiac sympathetic denervation. In general, most forms of exercise are considered safe in adequately treated patients, and implantable cardioverter-defibrillator therapy is reserved for those at the highest risk. This review summarizes our current understanding of LQTS and provides clinicians with a practical approach to diagnosis and management.
Topics: Death, Sudden, Cardiac; Defibrillators, Implantable; Electrocardiography; Female; Heart; Humans; Long QT Syndrome; Male
PubMed: 35589186
DOI: 10.1016/j.jacep.2022.02.017 -
Circulation. Arrhythmia and... Aug 2012
Review
Topics: Adrenergic beta-Antagonists; Animals; DNA Mutational Analysis; Defibrillators, Implantable; Electric Countershock; Genetic Predisposition to Disease; Genetic Testing; Genetic Therapy; Humans; Long QT Syndrome; Mutation; Phenotype; Prevalence; Sympathectomy
PubMed: 22895603
DOI: 10.1161/CIRCEP.111.962019 -
Acta Clinica Croatica Dec 2021Congenital long QT syndrome (LQTS) is a disorder of myocardial repolarization defined by a prolonged QT interval on electrocardiogram (ECG) that can cause ventricular... (Review)
Review
Congenital long QT syndrome (LQTS) is a disorder of myocardial repolarization defined by a prolonged QT interval on electrocardiogram (ECG) that can cause ventricular arrhythmias and lead to sudden cardiac death. LQTS was first described in 1957 and since then its genetic etiology has been researched in many studies, but it is still not fully understood. Depending on the type of monogenic mutation, LQTS is currently divided into 17 subtypes, with LQT1, LQT2, and LQT3 being the most common forms. Based on the results of a prospective study, it is suggested that the real prevalence of congenital LQTS is around 1:2000. Clinical manifestations of congenital LQTS include LQTS-attributable syncope, aborted cardiac arrest, and sudden cardiac death. Many patients with congenital LQTS will remain asymptomatic for life. The initial diagnostic evaluation of congenital LQTS includes obtaining detailed personal and multi-generation family history, physical examination, series of 12-lead ECG recordings, and calculation of the LQTS diagnostic score, called Schwartz score. Patients are also advised to undertake 24-hour ambulatory monitoring, treadmill/cycle stress testing, and LQTS genetic testing for definitive confirmation of the diagnosis. Currently available treatment options include lifestyle modifications, medication therapy with emphasis on beta-blockers, device therapy and surgical therapy, with beta-blockers being the first-line treatment option, both in symptomatic and asymptomatic patients.
Topics: Arrhythmias, Cardiac; Death, Sudden, Cardiac; Electrocardiography; Genotype; Humans; Long QT Syndrome; Prospective Studies
PubMed: 35734489
DOI: 10.20471/acc.2021.60.04.22 -
Human Mutation Aug 2012Discriminating between rare benign and pathogenic variation is a key challenge in clinical genetics, particularly as increasing numbers of nonsynonymous...
Discriminating between rare benign and pathogenic variation is a key challenge in clinical genetics, particularly as increasing numbers of nonsynonymous single-nucleotide polymorphisms (SNPs) are identified in resequencing studies. Here, we describe an approach for the functional annotation of nonsynonymous variants that identifies functionally important, disease-causing residues across protein families using multiple sequence alignment. We applied the methodology to long QT syndrome (LQT) genes, which cause sudden death, and their paralogues, which largely cause neurological disease. This approach accurately classified known LQT disease-causing variants (positive predictive value = 98.4%) with a better performance than established bioinformatic methods. The analysis also identified 1078 new putative disease loci, which we incorporated along with known variants into a comprehensive and freely accessible long QT resource (http://cardiodb.org/Paralogue_Annotation/), based on newly created Locus Reference Genomic sequences (http://www.lrg-sequence.org/). We propose that paralogous annotation is widely applicable for Mendelian human disease genes.
Topics: Chromosome Mapping; Computational Biology; Humans; Long QT Syndrome; NAV1.5 Voltage-Gated Sodium Channel
PubMed: 22581653
DOI: 10.1002/humu.22114 -
Postgraduate Medical Journal Jul 2021Many drug therapies are associated with prolongation of the QT interval. This may increase the risk of Torsades de Pointes (TdP), a potentially life-threatening cardiac... (Review)
Review
Many drug therapies are associated with prolongation of the QT interval. This may increase the risk of Torsades de Pointes (TdP), a potentially life-threatening cardiac arrhythmia. As the QT interval varies with a change in heart rate, various formulae can adjust for this, producing a 'corrected QT' (QTc) value. Normal QTc intervals are typically <450 ms for men and <460 ms for women. For every 10 ms increase, there is a ~5% increase in the risk of arrhythmic events. When prescribing drugs associated with QT prolongation, three key factors should be considered: patient-related risk factors (eg, female sex, age >65 years, uncorrected electrolyte disturbances); the potential risk and degree of QT prolongation associated with the proposed drug; and co-prescribed medicines that could increase the risk of QT prolongation. To support clinicians, who are likely to prescribe such medicines in their daily practice, we developed a simple algorithm to help guide clinical management in patients who are at risk of QT prolongation/TdP, those exposed to QT-prolonging medication or have QT prolongation.
Topics: Humans; Long QT Syndrome; Patient Care Management; Practice Patterns, Physicians'; Risk Adjustment; Torsades de Pointes
PubMed: 33122341
DOI: 10.1136/postgradmedj-2020-138661 -
Medicina (Kaunas, Lithuania) Nov 2022Long QT syndrome (LQTS) is majorly an autosomal dominantly inherited electrical dysfunction, but there are exceptions (Jervell and Lange-Nielsen syndrome is inherited in... (Review)
Review
Long QT syndrome (LQTS) is majorly an autosomal dominantly inherited electrical dysfunction, but there are exceptions (Jervell and Lange-Nielsen syndrome is inherited in an autosomal recessive pattern). This disorder prolongs ventricular repolarization and increases the risk of ventricular arrhythmias, syncope, and even sudden cardiac death. The risk of fatal events is reduced during pregnancy, but dramatically increases during the 9 months after delivery, especially in patients with LQT2. In women with LQTS, treatment with β-blockers at appropriate doses is recommended throughout pregnancy and the high-risk postnatal period. In this review, we summarize the management of LQTS during pregnancy and beyond.
Topics: Pregnancy; Humans; Female; Long QT Syndrome; Arrhythmias, Cardiac; Adrenergic beta-Antagonists
PubMed: 36422233
DOI: 10.3390/medicina58111694 -
British Journal of Clinical Pharmacology Mar 2016Torsades de pointes (TdP) is a characteristic polymorphic ventricular arrhythmia associated with delayed ventricular repolarization as evidenced on the surface... (Review)
Review
Torsades de pointes (TdP) is a characteristic polymorphic ventricular arrhythmia associated with delayed ventricular repolarization as evidenced on the surface electrocardiogram by QT interval prolongation. It typically occurs in self-limiting bursts, causing dizziness and syncope, but may occasionally progress to ventricular fibrillation and sudden death. Acquired long QT syndromes are mainly caused by cardiac disease, electrolyte abnormalities or exposure to drugs that block rectifying potassium channels, especially IKr. Management of TdP or marked QT prolongation includes removal or correction of precipitants, including discontinuation of culprit drugs and institution of cardiac monitoring. Electrolyte abnormalities and hypoxia should be corrected, with potassium concentrations maintained in the high normal range. Immediate treatment of TdP is by intravenous administration of magnesium sulphate, terminating prolonged episodes using electrical cardioversion. In refractory cases of recurrent TdP, the arrhythmia can be suppressed by increasing the underlying heart rate using isoproterenol (isoprenaline) or transvenous pacing. Other interventions are rarely needed, but there are case reports of successful use of lidocaine or phenytoin. Anti-arrhythmic drugs that prolong ventricular repolarization should be avoided. Some episodes of TdP could be avoided by careful prescribing of QT prolonging drugs, including an individualized assessment of risks and benefits before use, performing baseline and periodic electrocardiograms and measurement of electrolytes, especially during acute illnesses, using the lowest effective dose for the shortest possible time and avoiding potential drug interactions. These steps are particularly important in those with underlying repolarization abnormalities and those who have previously experienced drug-induced TdP.
Topics: Anti-Arrhythmia Agents; Disease Management; Humans; Long QT Syndrome; Torsades de Pointes
PubMed: 26183037
DOI: 10.1111/bcp.12726 -
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