-
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 -
Circulation Feb 2020Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition...
BACKGROUND
Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely tested in patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required.
METHODS
Utilizing an evidence-based framework, 3 gene curation teams blinded to each other's work scored the level of evidence for 17 genes reported to cause LQTS. A Clinical Domain Channelopathy Working Group provided a final classification of these genes for causation of LQTS after assessment of the evidence scored by the independent curation teams.
RESULTS
Of 17 genes reported as being causative for LQTS, 9 () were classified as having limited or disputed evidence as LQTS-causative genes. Only 3 genes () were curated as definitive genes for typical LQTS. Another 4 genes () were found to have strong or definitive evidence for causality in LQTS with atypical features, including neonatal atrioventricular block. The remaining gene () had moderate level evidence for causing LQTS.
CONCLUSIONS
More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine.
Topics: Atrioventricular Block; Evidence-Based Medicine; Female; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Humans; Long QT Syndrome; Male; Multicenter Studies as Topic
PubMed: 31983240
DOI: 10.1161/CIRCULATIONAHA.119.043132 -
Journal of Clinical Medicine Research May 2018Drug induced long QT syndrome is quite common in daily clinical practice but its impact is unknown.
BACKGROUND
Drug induced long QT syndrome is quite common in daily clinical practice but its impact is unknown.
METHODS
PubMed and EMBASE databases (until May 2, 2017) were searched to identify studies reporting drug induced long QT syndrome and followed the PRISMA guidelines. The main outcomes measured in these studies were QTc prolongation, ventricular arrhythmias, torsade de pointes (TdP) and death.
RESULTS
Out of 176 non-duplicate reports, 36 studies satisfied inclusion criteria and provided data on patients exposed to drugs that can potentially cause long QT. Totally, 14,756 patients were exposed and 930 patients (6.3%) were found to have QTc prolongation. The number of males was 6,400 and females were 5,723 patients. The mean age of the patients was 43.8 ± 9.36 years. Ventricular arrhythmias were found in 379 patients (2.6%), 26 patients were found to have premature atrial contractions (PACs) and premature ventricular contractions (PVCs). TdP was found in 49 patients (0.33 %), sudden cardiac death (SCD) was found in five patients and 586 patients were found to have all-cause mortality.
CONCLUSIONS
Around 6% of patients have risk of QT prolongation when exposed but only 0.3% developed TdP and 2.6% developed ventricular arrhythmias. Risk of developing arrhythmias is higher with concomitant use of multiple QT prolonging drugs.
PubMed: 29581800
DOI: 10.14740/jocmr3338w -
Frontiers in Genetics 2019Short QT syndrome (SQTS) is a rare syndrome and affects different types of genes. However, data on differences of clinical profile and outcome of different SQTS types...
BACKGROUND
Short QT syndrome (SQTS) is a rare syndrome and affects different types of genes. However, data on differences of clinical profile and outcome of different SQTS types are sparse.
METHODS
We conducted a pooled analysis of 110 SQTS patients. Patients have been diagnosed between 2000 and 2017 at our institution (n = 12) and revealed using a literature review (n = 98). 29 studies were identified by analysing systematic data bases (PubMed, Web of Science, Cochrane Libary, Cinahl).
RESULTS
67 patients with genotype positive SQTS origin and 43 patients with genotype negative origin were found. A significant difference is documented between the sex with a higher predominance of male in genotype negative SQTS patients and predominance of females in genotype positive SQTS patients (male 52% versus 84%, female 45% versus 14%; p = 0.0016). No relevant difference of their median age (genotype positive 27 ± 19 versus genotype negative 29 ± 15; p = 0.48) was found. Asymptomatic patients and patients reporting symptoms such as syncope, sudden cardiac death, atrial flutter and ventricular fibrillation documented in both groups were similar except atrial fibrillation (genotype positive 19% versus genotype negative 0%; p = 0.0055). The QTc interval was not significantly different in both groups (genotype positive 315 ± 32 versus genotype negative 320 ± 19; p = 0.30). The treatments (medical treatment and ICD implantation) in both groups were comparable. Electrophysiology studies were not significantly higher documented in patients with genotype positive and negative origin (24% versus 9%; p = 0.075). Events at follow up such as VT, VF, and SCD were not higher presented in patients with genotype positive (13% versus 9%) (p = 0.25). 54% of genotype positive SQTS patients showed SQTS 1 followed by STQS 2 (21%) and SQTS 3 (10%).
CONCLUSIONS
The long-term risk of a malignant arrhythmic event is not higher in patients with genotype positive. However, patients with genotype positive present themselves more often with AF with a female predominance. Also, other events at follow up such as syncope, atrial flutter and palpitation were not significantly higher (9% versus 0%; p = 0.079).
PubMed: 32010184
DOI: 10.3389/fgene.2019.01312 -
Fetal Diagnosis and Therapy 2013This systematic review evaluated the existence of risk factors for the fetal manifestation of long QT syndrome (LQTS). (Review)
Review
OBJECTIVE
This systematic review evaluated the existence of risk factors for the fetal manifestation of long QT syndrome (LQTS).
METHODS
Prenatal cardiac findings suggestive of fetal LQTS were studied using 30 English literature reports extracted from the Pubmed database (1979 to December 2011) using the search terms 'long QT syndrome', 'fetal arrhythmia' and 'congenital heart disease'.
RESULTS
LQTS accounted for 15-17% of fetal bradycardias <110 bpm among fetuses with a normally structured heart. Of the patients with significant prenatal findings of LQTS, 17-35% exhibited a reduced baseline fetal heart rate (FHR) of 110-120 bpm on electronic cardiotocography. Other prenatal signs were sinus or intermittent bradycardia <110 bpm arising from atrioventricular block, tachyarrhythmias, pleural effusion and hydrops. More than 30% of Japanese infants with LQTS born at or after the mid-1980s exhibited the above-mentioned in utero signs.
CONCLUSIONS
Fetal factors including a slightly reduced baseline FHR of 110-120 bpm, bradycardia <110 bpm, tachyarrhythmias or clinical signs of heart failure, such as pleural effusion and hydrops, were associated with a higher frequency of LQTS. The use of these signs may help to increase the perinatal diagnosis of LQTS.
Topics: Cardiotocography; Echocardiography; Female; Fetal Diseases; Humans; Incidence; Long QT Syndrome; Pregnancy; Prenatal Diagnosis; Risk Factors
PubMed: 22776830
DOI: 10.1159/000339150 -
Value in Health : the Journal of the... Jul 2015Recent improvements in the identification of the genetic basis of long QT syndrome (LQTS) have led to significant changes in the diagnosis and management of this... (Review)
Review
BACKGROUND
Recent improvements in the identification of the genetic basis of long QT syndrome (LQTS) have led to significant changes in the diagnosis and management of this life-threatening condition. Genetic and electrocardiogram (ECG) tests are the most relevant examples among testing strategies for LQTS, yet their cost-effectiveness remains controversial.
OBJECTIVE
The aim of this work was to review the available evidence on the cost-effectiveness of genetic and ECG testing strategies for the diagnosis of LQTS.
METHODS
We performed a systematic review of the literature on the cost-effectiveness of genetic and ECG screening strategies for the early detection of LQTS using MEDLINE, EMBASE, and CRD databases between 2000 and 2013. A weighted version of Drummond checklist was instrumental in further assessing the quality of the included studies.
RESULTS
We identified four eligible articles. Among them, genetic testing in the early detection of LQTS was cost-effective compared with no testing in symptomatic cases and not cost-effective when compared with watchful waiting in asymptomatic first-degree relatives of patients with established LQTS although it reached cost-effectiveness in higher risk subgroups, whereas ECG testing in neonates was highly cost-effective when compared with any screening strategy.
CONCLUSIONS
LQTS profiling and patients' stratification have the potential to improve the disease management. Because of the limited current knowledge in this field, the present review recommends to perform further cost-effectiveness evaluations of the genetic and ECG screening alternatives, especially within European health care systems, which are still not available in the literature on genetic testing.
Topics: Age Factors; Comparative Effectiveness Research; Cost-Benefit Analysis; Electrocardiography; Genetic Predisposition to Disease; Genetic Testing; Health Care Costs; Heart Rate; Humans; Infant, Newborn; Long QT Syndrome; Models, Economic; Phenotype; Predictive Value of Tests; Young Adult
PubMed: 26297099
DOI: 10.1016/j.jval.2015.03.1788 -
Journal of the American Heart... Jul 2022Background Diagnosis is particularly challenging in concealed or asymptomatic long QT syndrome (LQTS). Provocative testing, unmasking the characterization of LQTS, is a... (Meta-Analysis)
Meta-Analysis Review
Background Diagnosis is particularly challenging in concealed or asymptomatic long QT syndrome (LQTS). Provocative testing, unmasking the characterization of LQTS, is a promising alternative method for the diagnosis of LQTS, but without uniform standards. Methods and Results A comprehensive search was conducted in PubMed, Embase, and the Cochrane Library through October 14, 2021. The fixed effects model was used to assess the effect of the provocative testing on QTc interval. A total of 22 studies with 1137 patients with LQTS were included. At baseline, QTc interval was 40 ms longer in patients with LQTS than in controls (mean difference [MD], 40.54 [95% CI, 37.43-43.65]; <0.001). Compared with the control group, patients with LQTS had 28 ms longer ΔQTc upon standing (MD, 28.82 [95% CI, 23.05-34.58]; <0.001), nearly 30 ms longer both at peak exercise (MD, 27.31 [95% CI, 21.51-33.11]; <0.001) and recovery 4 to 5 minutes (MD, 29.85 [95% CI, 24.36-35.35]; <0.001). With epinephrine infusion, QTc interval was prolonged both in controls and patients with QTS, most obviously in LQT1 (MD, 68.26 [95% CI, 58.91-77.60]; <0.001) and LQT2 (MD, 60.17 [95% CI, 50.18-70.16]; <0.001). Subgroup analysis showed QTc interval response to abrupt stand testing and exercise testing varied between LQT1, LQT2, and LQT3, named Type Ⅰ, Type Ⅱ, and Type Ⅲ. Conclusions QTc trend Type Ⅰ and Type Ⅲ during abrupt stand testing and exercise testing can be used to propose a prospective evaluation of LQT1 and LQT3, respectively. Type Ⅱ QTc trend combined epinephrine infusion testing could distinguish LQT2 from control. A preliminary diagnostic workflow was proposed but deserves further evaluation.
Topics: Electrocardiography; Epinephrine; Exercise Test; Genotype; Humans; Long QT Syndrome
PubMed: 35861842
DOI: 10.1161/JAHA.122.025246 -
Cureus Sep 2021Long QT syndrome (LQTS) is one of the most common inherited cardiac channelopathies with a prevalence of 1:2000. The condition can be congenital or acquired with 15... (Review)
Review
Long QT syndrome (LQTS) is one of the most common inherited cardiac channelopathies with a prevalence of 1:2000. The condition can be congenital or acquired with 15 recognized genotypes; the most common subtypes are LQTS 1, 2, and 3 making up to 85%-90% of the cases. LQTS is characterized by delayed ventricular cardiomyocyte repolarization manifesting on the surface electrocardiogram (EKG) by a prolonged corrected QT (QTc) interval. The mainstay of treatment for this condition involves in part or combination medical therapy via β-blockers as first-line (or other anti-arrhythmic), left cardiac sympathectomy, or implantable cardiac defibrillator placement. Given the high rate of adverse cardiac events (ACE) or sudden cardiac death (SCD) in this population of patients with this disease, this review seeks to highlight the genotype-specific treatment consensus in β-blocker therapy of the most common subtypes. A database search of PubMed, PMC, and Medline was conducted to ascertain the most recent data in the last five years on the management of LQTS types 1-3 and the role of β-blockers in reducing ACE in these types. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were adhered to in the study selection, and selected studies focused on humans, written in the English Language, and within the last five years of LQTS subtypes 1, 2, and 3. Eleven relevant studies were selected after considering inclusion criteria, exclusion criteria, and quality appraisal within the last five years, focusing on β-blocker selection directed based on the subtypes of LQTS. Two meta-analyses, one cohort study, and eight reviews provided significant data that non-selective β-blockers unequivocally are of benefit in these LQTS types. Summary of findings suggested nadolol followed by propranolol yields the best results in LQTS 1, while nadolol would yield the best effect in LQTS 2 and 3.
PubMed: 34646680
DOI: 10.7759/cureus.17632 -
Annals of Noninvasive Electrocardiology... Jan 2023QTc prolongation is key in diagnosing long QT syndrome (LQTS), however 25%-50% with congenital LQTS (cLQTS) demonstrate a normal resting QTc. T wave morphology (TWM) can... (Review)
Review
INTRODUCTION
QTc prolongation is key in diagnosing long QT syndrome (LQTS), however 25%-50% with congenital LQTS (cLQTS) demonstrate a normal resting QTc. T wave morphology (TWM) can distinguish cLQTS subtypes but its role in acquired LQTS (aLQTS) is unclear.
METHODS
Electronic databases were searched using the terms "LQTS," "long QT syndrome," "QTc prolongation," "prolonged QT," and "T wave," "T wave morphology," "T wave pattern," "T wave biomarkers." Whole text articles assessing TWM, independent of QTc, were included.
RESULTS
Seventeen studies met criteria. TWM measurements included T-wave amplitude, duration, magnitude, Tpeak-Tend, QTpeak, left and right slope, center of gravity (COG), sigmoidal and polynomial classifiers, repolarizing integral, morphology combination score (MCS) and principal component analysis (PCA); and vectorcardiographic biomarkers. cLQTS were distinguished from controls by sigmoidal and polynomial classifiers, MCS, QTpeak, Tpeak-Tend, left slope; and COG x axis. MCS detected aLQTS more significantly than QTc. Flatness, asymmetry and notching, J-Tpeak; and Tpeak-Tend correlated with QTc in aLQTS. Multichannel block in aLQTS was identified by early repolarization (ERD ) and late repolarization (LRD ), with ERD reflecting hERG-specific blockade. Cardiac events were predicted in cLQTS by T wave flatness, notching, and inversion in leads II and V , left slope in lead V ; and COG last 25% in lead I. T wave right slope in lead I and T-roundness achieved this in aLQTS.
CONCLUSION
Numerous TWM biomarkers which supplement QTc assessment were identified. Their diagnostic capabilities include differentiation of genotypes, identification of concealed LQTS, differentiating aLQTS from cLQTS; and determining multichannel versus hERG channel blockade.
Topics: Humans; Electrocardiography; Long QT Syndrome; Genotype; Biomarkers
PubMed: 36345173
DOI: 10.1111/anec.13015 -
Frontiers in Cardiovascular Medicine 2022Mutations in the gene-encoding for the major Ca channel of the heart-may exhibit a variety of clinical manifestations. These include typical or atypical Timothy...
Geno- and phenotypic characteristics and clinical outcomes of gene mutation associated Timothy syndrome, "cardiac only" Timothy syndrome and isolated long QT syndrome 8: A systematic review.
BACKGROUND
Mutations in the gene-encoding for the major Ca channel of the heart-may exhibit a variety of clinical manifestations. These include typical or atypical Timothy syndromes (TS) which are associated with multiple organ manifestations, and cardiac involvement in form of malignant arrhythmias, QTc prolongation, or AV block. "Cardiac only" Timothy syndrome (COTS) shows no extracardiac manifestation, whereas some gene mutations are associated with QTc prolongation alone (isolated long QT syndrome 8, LQT8).
METHODS
A systematic search of the literature reporting cases of gene mutation associated syndromes, including TS, COTS and isolated LQT8 major databases published from 2004 through 2019 was performed. Detailed patient-level phenotypic and genotypic characteristics, as well as long-term outcome measures were collected and compared between pre-specified patient groups, defined both on phenotype and genotype.
RESULTS
A total of 59 TS, 6 COTS, and 20 isolated LQT8 index cases were identified. Apart of syndactyly or baldness, there were no major differences regarding clinical manifestations or outcome measures between TS subtypes, either defining TS subtypes on the genotype or based on the phenotype. Both subtypes were characterized by an extreme degree of QTc prolongation (median ≥600 ms) which were reflected in high major adverse cardiac event rate. On the other hand, there were marked differences between TS, COTS, and isolated LQT8. Timothy syndrome was characterized by a much earlier disease onset, much more pronounced QTc prolongation and much higher mortality rate than COTS or isolated LQT8. Similar differences were observed comparing exon 8/8A vs. non-exon 8/8A mutation carriers. TS showed a high degree of genetic homogeneity, as the p.Gly406Arg mutation either in exon 8 or exon 8A alone was responsible for 70% of the cases.
CONCLUSIONS
Clinical phenotypes associated with mutations in the gene show important clinical differences. Timothy syndrome is associated with the most severe clinical phenotype and with the highest risk of morbidity and mortality. However, distinguishing TS subtypes, in any form, are not supported by our data.
SYSTEMATIC REVIEW REGISTRATION
[https://www.crd.york.ac.uk/prospero/], identifier [CRD42020184737].
PubMed: 36523353
DOI: 10.3389/fcvm.2022.1021009