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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 -
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 -
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 -
Europace : European Pacing,... Aug 2023Sudden cardiac death (SCD) is responsible for several millions of deaths every year and remains a major health problem. To reduce this burden, diagnosing and... (Review)
Review
Sudden cardiac death (SCD) is responsible for several millions of deaths every year and remains a major health problem. To reduce this burden, diagnosing and identification of high-risk individuals and disease-specific risk stratification are essential. Treatment strategies include treatment of the underlying disease with lifestyle advice and drugs and decisions to implant a primary prevention implantable cardioverter-defibrillator (ICD) and perform ablation of the ventricles and novel treatment modalities such as left cardiac sympathetic denervation in rare specific primary electric diseases such as long QT syndrome and catecholaminergic polymorphic ventricular tachycardia. This review summarizes the current knowledge on SCD risk according to underlying heart disease and discusses the future of SCD prevention.
Topics: Humans; Death, Sudden, Cardiac; Long QT Syndrome; Heart Diseases; Defibrillators, Implantable; Risk Assessment
PubMed: 37622576
DOI: 10.1093/europace/euad203 -
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 -
Europace : European Pacing,... Apr 2022Risk stratification of patients with long QT syndrome (LQTS) represents a difficult task. In 2018, we proposed a granular estimate of the baseline 5-year risk of...
AIMS
Risk stratification of patients with long QT syndrome (LQTS) represents a difficult task. In 2018, we proposed a granular estimate of the baseline 5-year risk of life-threatening arrhythmias (LAE) for patients with LQTS, based on the genotype (long QT syndrome Type 1, long QT syndrome Type 2, and long QT syndrome Type 3) and the duration of the QTc interval. We sought to externally validate a novel risk score model (1-2-3-LQTS-Risk model) in a geographically diverse cohort from the USA and to evaluate its performance and assess potential clinical implication of this novel model.
METHODS AND RESULTS
The prognostic model (1-2-3-LQTS-Risk model) was derived using data from a prospective, single-centre longitudinal cohort study published in 2018 (discovery cohort) and was validated using an independent cohort of 1689 patients enrolled in the International LQTS Registry (Rochester NY, USA). The validation study revealed a C-index of 0.69 [95% confidence interval (CI): 0.61-0.77] in the validation cohort, when compared with C-index of 0.79 (95% CI: 0.70-0.88) in the discovery cohort. Adopting a 5-year risk ≥5%, as suggested by the ROC curve analysis as the most balanced threshold for implantable cardioverter-defibrillator (ICD) implantation, would result in a number needed to treat (NNT) of nine (NNT = 9; 95% CI: 6.3-13.6).
CONCLUSION
The 1-2-3-LQTS-Risk model, the first validated 5-year risk score model for patients with LQTS, can be used to aid clinicians to identify patients at the highest risk of LAE who could benefit most from an ICD implant and avoid unnecessary implants.
Topics: Arrhythmias, Cardiac; Death, Sudden, Cardiac; Electrocardiography; Humans; Long QT Syndrome; Longitudinal Studies; Prospective Studies; Risk Factors
PubMed: 34505884
DOI: 10.1093/europace/euab238 -
Journal of Cardiovascular... Jan 2023
Topics: Humans; Torsades de Pointes; Electrocardiography; Long QT Syndrome
PubMed: 36335630
DOI: 10.1111/jce.15736 -
Psychopharmacology Jan 2023While meta-analyses of clinical trials found that lurasidone and partial dopamine agonists (brexpiprazole and aripiprazole) were the antipsychotics less likely to cause...
RATIONALE
While meta-analyses of clinical trials found that lurasidone and partial dopamine agonists (brexpiprazole and aripiprazole) were the antipsychotics less likely to cause QTc prolongation, and sertindole, amisulpride, and ziprasidone were the most frequently associated with this adverse drug reaction; no real-world studies have investigated this risk between the different antipsychotics.
OBJECTIVES AND METHODS
Using data recorded from 1967 to 2019 in VigiBase®, the World Health Organization's Global Individual Case Safety Reports database, we performed disproportionality analysis to investigate the risk of reporting QT prolongation between 20 antipsychotics.
RESULTS
Sertindole had the highest risk of reporting QT prolongation, followed by ziprasidone and amisulpride. Lurasidone was associated with the lowest risk. First-generation antipsychotics were associated with a greater QT prolongation reporting risk (ROR, 1.21; 95%CI, 1.10-1.33) than second-generation antipsychotics. A positive correlation was found between the risk of reporting QT prolongation and affinity for hERG channel (R = 0.14, slope = Pearson coefficient = 0.41, p value = 0.1945).
CONCLUSIONS
This large study in a real-world setting suggests that sertindole and ziprasidone were the antipsychotics drugs associated with the highest risk of QT prolongation reporting. Our results suggest that lurasidone is less associated with QT interval prolongation reports. Our study also suggests that antipsychotics with the higher hERG affinity are more associated with to QT prolongations reports.
Topics: Humans; Antipsychotic Agents; Amisulpride; Lurasidone Hydrochloride; Pharmacovigilance; Long QT Syndrome
PubMed: 36515735
DOI: 10.1007/s00213-022-06293-4 -
Circulation Sep 2021Polymorphic ventricular tachyarrhythmias are highly lethal arrhythmias. Several types of polymorphic ventricular tachycardia have similar electrocardiographic... (Review)
Review
Polymorphic ventricular tachyarrhythmias are highly lethal arrhythmias. Several types of polymorphic ventricular tachycardia have similar electrocardiographic characteristics but have different modes of therapy. In fact, medications considered the treatment of choice for one form of polymorphic ventricular tachycardia, are contraindicated for the other. Yet confusion about terminology, and thus diagnosis and therapy, continues. We present an in-depth review of the different forms of polymorphic ventricular tachycardia and propose a practical step-by-step approach for distinguishing these malignant arrhythmias.
Topics: Arrhythmias, Cardiac; Electrocardiography; Emergency Treatment; Humans; Long QT Syndrome; Tachycardia, Ventricular
PubMed: 34491774
DOI: 10.1161/CIRCULATIONAHA.121.055783