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European Heart Journal Nov 2023
Topics: Humans; Spondylosis; Long QT Syndrome
PubMed: 37740436
DOI: 10.1093/eurheartj/ehad608 -
Cardiology 2022The physiological QT prolongation in athletes is expected to widen the gray zone between physiology and pathology of QT, increasing the diagnostic challenges encountered... (Review)
Review
BACKGROUND
The physiological QT prolongation in athletes is expected to widen the gray zone between physiology and pathology of QT, increasing the diagnostic challenges encountered in athletes with QT prolongation.
SUMMARY
According to international recommendations for electrocardiogram in athletes, further evaluation for long QT syndrome (LQTS) is indicated in male athletes with corrected QT (QTc) ≥470 ms and in female athletes with QTc ≥480 ms. Apart from QTc ≥500 ms, diagnostic challenges arise in borderline cases of QTc prolongation, where further clinical investigations are needed to be performed to clarify whether LQTS exists. Clinical diagnostic investigations, including exercise testing, are more readily available, convenient, and easily interpretable, as well as less costly than genetic testing for LQTS. The main findings on exercise testing that are suggestive of LQTS can be the paradoxical prolongation of QTc during exercise and QTc ≥480 ms at fourth min of recovery.
KEY MESSAGES
Exercise testing appears to have an important role in the diagnostic evaluation of athletes with prolonged QT interval, when genetic testing is not available.
Topics: Male; Female; Humans; Long QT Syndrome; Electrocardiography; Exercise Test; Athletes; Exercise
PubMed: 35947943
DOI: 10.1159/000526385 -
Herzschrittmachertherapie &... Jun 2021Congenital long QT syndrome (LQTS) is a genetic disorder characterized by a prolonged QT interval in the surface electrocardiogram (ECG) that predisposes affected... (Review)
Review
Congenital long QT syndrome (LQTS) is a genetic disorder characterized by a prolonged QT interval in the surface electrocardiogram (ECG) that predisposes affected individuals to arrhythmic syncope, ventricular torsades-de-pointes, and sudden cardiac death at a young age. Investigations of large patient cohorts revealed sex-related differences in the LQTS phenotype. Adult women with LQTS are at higher risk for cardiac arrhythmias than are adult men with LQTS. Sex hormones are thought to play the primary role for these gender differences. Clinical experience and translational studies indicated that females with LQTS have a lower risk for cardiac arrhythmias during pregnancy and elevated risk in the postpartum period due to contrasting effects of estradiol and progesterone, as well as postpartum hormones on the action potential and arrhythmia substrate. However, this pro- or anti-arrhythmic potential of hormones varies depending on the underlying genotype, partly since sex hormones have distinct effects on different (affected) cardiac ion channels. Thus, a comprehensive evaluation of women with LQTS prior to and during pregnancy, during labor, and in the postpartum period with consideration of the patient's disease- and gene-specific risk factors is essential to providing precision management in this patient group. This review discusses the current understanding of hormonal influences in LQTS and provides practical guidance for the optimal management of LQTS patients during pregnancy, delivery, and the postpartum period.
Topics: Adult; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Electrocardiography; Female; Humans; Long QT Syndrome; Male; Postpartum Period; Pregnancy; Torsades de Pointes
PubMed: 33782754
DOI: 10.1007/s00399-021-00757-4 -
Clinical Pharmacology and Therapeutics Jul 2024
Topics: Humans; Long QT Syndrome; Electrocardiography
PubMed: 38879890
DOI: 10.1002/cpt.3294 -
Annals of Noninvasive Electrocardiology... Sep 2023Congenital Long QT Syndrome (LQTS) is a hereditary arrhythmic disorder. We aimed to assess the performance of current genetic variant annotation scores among LQTS...
BACKGROUND
Congenital Long QT Syndrome (LQTS) is a hereditary arrhythmic disorder. We aimed to assess the performance of current genetic variant annotation scores among LQTS patients and their predictive impact.
METHODS
We evaluated 2025 patients with unique mutations for LQT1-LQT3. A patient-specific score was calculated for each of four established genetic variant annotation algorithms: CADD, SIFT, REVEL, and PolyPhen-2. The scores were tested for the identification of LQTS and their predictive performance for cardiac events (CE) and life-threatening events (LTE) and then compared with the predictive performance of LQTS categorization based on mutation location/function. Score performance was tested using Harrell's C-index.
RESULTS
A total of 917 subjects were classified as LQT1, 838 as LQT2, and 270 as LQT3. The identification of a pathogenic variant occurred in 99% with CADD, 92% with SIFT, 100% with REVEL, and 86% with PolyPhen-2. However, none of the genetic scores correlated with the risk of CE (Harrell's C-index: CADD = 0.50, SIFT = 0.51, REVEL = 0.50, and PolyPhen-2 = 0.52) or LTE (Harrell's C-index: CADD = 0.50, SIFT = 0.53, REVEL = 0.54, and PolyPhen-2 = 0.52). In contrast, high-risk mutation categorization based on location/function was a powerful independent predictor of CE (HR = 1.88; p < .001) and LTE (HR = 1.89, p < .001).
CONCLUSION
In congenital LQTS patients, well-established algorithms (CADD, SIFT, REVEL, and PolyPhen-2) were able to identify the majority of the causal variants as pathogenic. However, the scores did not predict clinical outcomes. These results indicate that mutation location/functional assays are essential for accurate interpretation of the risk associated with LQTS mutations.
Topics: Humans; Genotype; Electrocardiography; Long QT Syndrome
PubMed: 37571804
DOI: 10.1111/anec.13080 -
Heart Rhythm Aug 2023Long QT syndrome type 2 (LQT2) is a genetic disorder caused by mutations in the KCNH2 gene, also known as the human ether-a-go-go-related gene (HERG). More than 30% of... (Review)
Review
Long QT syndrome type 2 (LQT2) is a genetic disorder caused by mutations in the KCNH2 gene, also known as the human ether-a-go-go-related gene (HERG). More than 30% of HERG mutations result in a premature termination codon that triggers a process called nonsense-mediated messenger RNA (mRNA) decay (NMD), where the mRNA transcript is degraded. NMD is a quality control mechanism that removes faulty mRNA to prevent the translation of truncated proteins. Recent advances in antisense oligonucleotide (ASO) technology in the field of cystic fibrosis (CF) have yielded significant progress, including the ASO-mediated comprehensive characterization of key NMD factors and exon-skipping therapy. These advances have contributed to our understanding of the role of premature termination codon-containing mutations in disease phenotypes and have also led to the development of potentially useful therapeutic strategies. Historically, studies of CF have provided valuable insights for the research on LQT2, particularly concerning increasing the expression of HERG. In this article, we outline the current state of knowledge regarding ASO, NMD, and HERG and discuss the introduction of ASO technology in the CF to elucidate the pathogenic mechanisms through targeting NMD. We also discuss the potential clinical therapeutic benefits and limitations of ASO for the management of LQT2. By drawing on lessons learned from CF research, we explore the potential translational values of these advances into LQT2 studies.
Topics: Humans; Codon, Nonsense; Oligonucleotides, Antisense; Ether-A-Go-Go Potassium Channels; Cystic Fibrosis; Long QT Syndrome; Mutation; Nonsense Mediated mRNA Decay; RNA, Messenger
PubMed: 37121422
DOI: 10.1016/j.hrthm.2023.04.021 -
Heart Rhythm Aug 2023
Topics: Humans; Arrhythmias, Cardiac; Long QT Syndrome; Electrocardiography
PubMed: 37149206
DOI: 10.1016/j.hrthm.2023.05.003 -
Pediatric Cardiology Dec 2022The objective of this study is to determine the prevalence of an abnormal electrocardiogram showing a prolonged QTc greater than 450 ms in infants with unilateral or...
The objective of this study is to determine the prevalence of an abnormal electrocardiogram showing a prolonged QTc greater than 450 ms in infants with unilateral or bilateral sensorineural hearing loss. We conducted a prospective study of healthy term infants (≥37 weeks gestational age) who failed their newborn auditory brainstem response hearing screen, were seen by an audiologist and diagnosed as having sensorineural hearing loss during follow-up to 1 year of age. In infants with a diagnosis of hearing loss, we collected a detailed family history and performed an ECG between 2 and 6 months of age. We obtained follow-up for 1 year by calling the parent requesting the hearing and cardiac status of their child. Two of the 40 infants with sensorineural hearing loss (5%) had a QTc greater than 450 ms. Both had mild bilateral hearing loss and genetic testing did not identify a known mutation for long QT syndrome. The remaining 38 infants had QTc intervals of ≤ 450 ms. One patient diagnosed with bilateral severe sensorineural hearing loss had a normal ECG (QTc = 417 ms). Several months after the ECG was performed, the infant's mother contacted the study cardiologist after she learned that the infant's maternal grandmother was diagnosed with a cardiomyopathy and arrhythmias. Genetic testing was recommended even though the child was asymptomatic and was positive for a pathogenic mutation in the KCNQ1 gene. We speculate that molecular genetic testing in infants with hearing loss may become the standard of care rather than targeted electrocardiograms.Clinical Trial Registration NCT02082431 https://www.clinicaltrials.gov/ct2/show/NCT02692521?cond=NCT02692521&rank=1 .
Topics: Infant; Infant, Newborn; Child; Female; Humans; Prospective Studies; KCNQ1 Potassium Channel; Long QT Syndrome; Hearing Loss; Hearing Loss, Sensorineural; Registries
PubMed: 35661239
DOI: 10.1007/s00246-022-02939-4 -
BMC Cardiovascular Disorders Aug 2023Long QT syndrome (LQTS) is one of the primary causes of sudden cardiac death (SCD) in youth. Studies have identified mutations in ion channel genes as key players in the...
OBJECTIVES
Long QT syndrome (LQTS) is one of the primary causes of sudden cardiac death (SCD) in youth. Studies have identified mutations in ion channel genes as key players in the pathogenesis of LQTS. However, the specific etiology in individual families remains unknown.
METHODS
Three unrelated Chinese pedigrees diagnosed with LQTS or Jervell and Lange-Nielsen syndrome (JLNS) were recruited clinically. Whole exome sequencing (WES) was performed and further validated by multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing.
RESULTS
All of the probands in our study experienced syncope episodes and featured typically prolonged QTc-intervals. Two probands also presented with congenital hearing loss and iron-deficiency anemia and thus were diagnosed with JLNS. A total of five different variants in KCNQ1, encoding a subunit of the voltage-gated potassium channel, were identified in 3 probands. The heterozygous variants, KCNQ1 c.749T > C was responsible for LQTS in Case 1, transmitting in an autosomal dominant pattern. Two patterns of compound heterozygous variants were responsible for JLNS, including a large deletion causing loss of the exon 16 and missense variant c.1663 C > T in Case 2, and splicing variant c.605-2 A > G and frame-shift variant c.1265del in Case 3. To our knowledge, the compound heterozygous mutations containing a large deletion and missense variant were first reported in patients with JLNS.
CONCLUSION
Our study expanded the LQTS genetic spectrum, thus favoring disease screening and diagnosis, personalized treatment, and genetic consultation.
Topics: Adolescent; Humans; Jervell-Lange Nielsen Syndrome; KCNQ1 Potassium Channel; Long QT Syndrome; Mutation; Exons; Mutation, Missense; Pedigree
PubMed: 37568094
DOI: 10.1186/s12872-023-03417-2 -
Asian Cardiovascular & Thoracic Annals Mar 2021Congenital long-QT syndrome represents the most common cardiac channelopathy and manifests as potentially lethal ventricular arrhythmias. Prevention strategies include...
BACKGROUND
Congenital long-QT syndrome represents the most common cardiac channelopathy and manifests as potentially lethal ventricular arrhythmias. Prevention strategies include beta-blockade pharmacotherapy, implantable cardioverter-defibrillators, and left cardiac sympathetic denervation, which can increase the threshold for ventricular fibrillation. Herein, we report our experience with video-assisted thoracoscopic left cardiac sympathetic denervation.
METHODS
We performed a retrospective review of the electronic medical records of all patients with congenital long-QT syndrome who underwent video-assisted thoracoscopic left cardiac sympathetic denervation at our institution.
RESULTS
From September 2009 to May 2016, 6 patients with a mean age of 30.5 years (range 20-47 years) underwent video-assisted thoracoscopic left cardiac sympathetic denervation for medically refractory long-QT syndrome. All patients had an uneventful recovery and were discharged 1-3 days after the operation. At a median follow-up of 14 months (range 12-60 months), 4 patients had no cardiac events while 2 experienced 1 episode of arrhythmic syncope and 1 episode of appropriate implantable cardioverter-defibrillator shock. Following surgery, the mean annual cardiac events in the study cohort decreased from 2.13 to 0.33 ( = 0.004) and the mean corrected QT interval reduced from 560 ms to 491 ms ( = 0.006).
CONCLUSIONS
Video-assisted thoracoscopic left cardiac sympathetic denervation is a safe and effective therapy in patients with congenital long-QT syndrome who continue to suffer from recurrent life-threatening arrhythmias or frequent implantable cardioverter-defibrillator discharges despite maximum tolerated doses of beta blockers.
Topics: Adult; Female; Heart; Humans; Long QT Syndrome; Male; Middle Aged; Retrospective Studies; Sympathectomy; Thoracic Surgery, Video-Assisted; Treatment Outcome; Young Adult
PubMed: 33115260
DOI: 10.1177/0218492320971492