Long QT syndrome.
Ontology highlight
ABSTRACT:
SUBMITTER: Jackson H
PROVIDER: S-EPMC3153516 | biostudies-literature | 2011 Aug
REPOSITORIES: biostudies-literature
Publications
Long QT syndrome.
Jackson Heather H Huisman Lee-Anna LA Sanatani Shubhayan S Arbour Laura T LT
CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 20110411 11
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Project description:To date, KCNH2 mutations identified in LQT2 patients have been heavily studied by heterologous expression systems, allowing for pathogenicity evaluation of a certain hERG mutation by overexpressing mutant channels. However, they fall short in mimicking the full spectrum of electrophysiological changes and ion channel remodeling that occur in cardiomyocytes under physiological conditions in the context of LQT. Due to the marked differences in the lifespan, size, anatomy and physiology from humans, current zebrafish and rodent models cannot fully mimic the abnormal QT interval diseases 2. For instance, rodents exhibit an extremely higher heart rate and a much shorter action potential duration (APD) compared to humans. IKr is the predominant repolarizing current in human ventricles while inhibition of IKr in rodents has no significant effect on ventricular repolarization, making it infeasible to study LQT2 by genetic mouse model 3. Hence, there is a crucial need to construct an animal model capable of mimicking human inherited arrhythmia conditions. To address the above scientific question, we chose to create a miniature pig model. Given many physiological similarities with humans, and breeding and genome editing advantages (when compared to non-human primates), To explore the mechanism underlying mutation of KCNH2 caused LQT, we compared the transcriptomes of KCNH2-mut pigs and WT controls
2025-02-03 | GSE288082 | GEO
Project description:BackgroundIncreased variability of QT interval (QTV) has been linked to arrhythmias in animal experiments and multiple clinical situations. Congenital long QT syndrome (LQTS), a pure repolarization disease, may provide important information on the relationship between delayed repolarization and QTV.Methods and resultsTwenty-four-hour Holter monitor tracings from 78 genotyped congenital LQTS patients (52 females; 51 LQT1, 23 LQT2, 2 LQT5, 2 JLN, 27 symptomatic; age, 35.2±12.3 years) were evaluated with computer-assisted annotation of RR and QT intervals. Several models of RR-QT relationship were tested in all patients. A model assuming exponential decrease of past RR interval contributions to QT duration with 60-second time constant provided the best data fit. This model was used to calculate QTc and residual "intrinsic" QTV, which cannot be explained by heart rate change. The intrinsic QTV was higher in patients with long QTc (r=0.68; P<10(-4)), and in LQT2 than in LQT1/5 patients (5.65±1.28 vs 4.46±0.82; P<0.0002). Both QTc and intrinsic QTV were similar in symptomatic and asymptomatic patients (467±52 vs 459±53 ms and 5.10±1.19 vs 4.74±1.09, respectively).ConclusionsIn LQTS patients, QT interval adaptation to heart rate changes occurs with time constant ?60 seconds, similar to results reported in control subjects. Intrinsic QTV correlates with the degree of repolarization delay and might reflect action potential instability observed in animal models of LQTS.
| S-EPMC4845278 | biostudies-literature
Project description:BackgroundThe QT interval is a risk marker for cardiac events such as torsades de pointes. However, QT measurements obtained from a 12-lead ECG during clinic hours may not capture the full extent of a patient's daily QT range.ObjectiveThe purpose of this study was to evaluate the utility of 24-hour Holter ECG recording in patients with long QT syndrome (LQTS) to identify dynamic changes in the heart rate-corrected QT interval and to investigate methods of visualizing the resulting datasets.MethodsBeat-to-beat QTc (Bazett) intervals were automatically measured across 24-hour Holter recordings from 202 LQTS type 1, 89 type 2, and 14 type 3 genotyped patients and a reference group of 200 healthy individuals. We measured the percentage of beats with QTc greater than the gender-specific threshold (QTc ≥470 ms in women and QTc ≥450 ms in men). The percentage of beats with QTc prolongation was determined across the 24-hour recordings.ResultsBased on the median percentage of heartbeats per patient with QTc prolongation, LQTS type 1 patients showed more frequent QTc prolongation during the day (~3 PM) than they did at night (~3 AM): 97% vs 48%, P ~10(-4) for men, and 68% vs 30%, P ~10(-5) for women. LQTS type 2 patients showed less frequent QTc prolongation during the day compared to nighttime: 87% vs 100%, P ~10(-4) for men, and 62% vs 100%, P ~10(-3) for women.ConclusionIn patients with genotype-positive LQTS, significant differences exist in the degree of daytime and nocturnal QTc prolongation. Holter monitoring using the "QT clock" concept may provide an easy, fast, and accurate method for assessing the true personalized burden of QTc prolongation.
| S-EPMC4698188 | biostudies-literature
Project description:BackgroundFetal arrhythmias characteristic of long QT syndrome (LQTS) include torsades de pointes (TdP) and/or 2° atrioventricular block, but sinus bradycardia, defined as fetal heart rate<3% for gestational age, is most common. We hypothesized that prenatal rhythm phenotype might predict LQTS genotype and facilitate improved risk stratification and management.Method and resultsRecords of subjects exhibiting fetal LQTS arrhythmias were reviewed. Fetal echocardiograms, neonatal ECG, and genetic testing were evaluated. We studied 43 subjects exhibiting fetal LQTS arrhythmias: TdP±2° atrioventricular block (group 1, n=7), isolated 2° atrioventricular block (group 2, n=4), and sinus bradycardia (group 3, n=32). Mutations in known LQTS genes were found in 95% of subjects tested. SCN5A mutations occurred in 71% of group 1, whereas 91% of subjects with KCNQ1 mutations were in group 3. Small numbers of subjects with KCNH2 mutations (n=4) were scattered in all 3 groups. Age at presentation did not differ among groups, and most subjects (n=42) were live-born with gestational ages of 37.5±2.8 weeks (mean±SD). However, those with TdP were typically delivered earlier. Prenatal treatment in group 1 terminated (n=2) or improved (n=4) TdP. The neonatal heart rate-corrected QT interval (mean±SE) of group 1 (664.7±24.9) was longer than neonatal heart rate-corrected QT interval in both group 2 (491.2±27.6; P=0.004) and group 3 (483.1±13.7; P<0.001). Despite medical and pacemaker therapy, postnatal cardiac arrest (n=4) or sudden death (n=1) was common among subjects with fetal/neonatal TdP.ConclusionsRhythm phenotypes of fetal LQTS have genotype-suggestive features that, along with heart rate-corrected QT interval duration, may risk stratify perinatal management.
| S-EPMC4151528 | biostudies-literature
Project description:We report a case of torsades de pointes arrhythmia as the first manifestation of congenital Long QT syndrome in a 77-year-old man with family history of sudden unexplained death. This case illustrates the importance of vigilant clinical assessment and genetic counseling in families with sudden death in order to identify properly asymptomatic relatives at risk for cardiac events. It also demonstrates that Long QT syndrome can still manifest with potentially fatal arrhythmias late in life in previously asymptomatic elderly patients.
| S-EPMC6931632 | biostudies-literature
Project description:Long QT syndrome (LQTS) is a cardiovascular disorder characterized by an abnormality in cardiac repolarization leading to a prolonged QT interval and T-wave irregularities on the surface electrocardiogram. It is commonly associated with syncope, seizures, susceptibility to torsades de pointes, and risk for sudden death. LQTS is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. The availability of therapy for this lethal disease emphasizes the importance of early and accurate diagnosis. Additionally, understanding of the molecular mechanisms underlying LQTS could help to optimize genotype-specific treatments to prevent deaths in LQTS patients. In this review, we briefly summarize current knowledge regarding molecular underpinning of LQTS, in particular focusing on LQT1, LQT2, and LQT3, and discuss novel strategies to study ion channel dysfunction and drug-specific therapies in LQT1, LQT2, and LQT3 syndromes.
| S-EPMC8183884 | biostudies-literature
Project description:The prevalence of genetic arrhythmogenic diseases is unknown. For the long-QT syndrome (LQTS), figures ranging from 1:20 000 to 1:5000 were published, but none was based on actual data. Our objective was to define the prevalence of LQTS.In 18 maternity hospitals, an ECG was performed in 44 596 infants 15 to 25 days old (43 080 whites). In infants with a corrected QT interval (QTc) >450 ms, the ECG was repeated within 1 to 2 weeks. Genetic analysis, by screening 7 LQTS genes, was performed in 28 of 31 (90%) and in 14 of 28 infants (50%) with, respectively, a QTc >470 ms or between 461 and 470 ms. A QTc of 451 to 460, 461 to 470, and >470 ms was observed in 177 (0.41%), 28 (0.06%), and 31 infants (0.07%). Among genotyped infants, disease-causing mutations were found in 12 of 28 (43%) with a QTc >470 ms and in 4 of 14 (29%) with a QTc of 461 to 470 ms. One genotype-negative infant (QTc 482 ms) was diagnosed as affected by LQTS on clinical grounds. Among family members of genotype-positive infants, 51% were found to carry disease-causing mutations. In total, 17 of 43 080 white infants were affected by LQTS, demonstrating a prevalence of at least 1:2534 apparently healthy live births (95% confidence interval, 1:1583 to 1:4350).This study provides the first data-based estimate of the prevalence of LQTS among whites. On the basis of the nongenotyped infants with QTc between 451 and 470 ms, we advance the hypothesis that this prevalence might be close to 1:2000. ECG-guided molecular screening can identify most infants affected by LQTS and unmask affected relatives, thus allowing effective preventive measures.
| S-EPMC2784143 | biostudies-literature
Project description:Ion channels represent the molecular entities that give rise to the cardiac action potential, the fundamental cellular electrical event in the heart. The concerted function of these channels leads to normal cyclical excitation and resultant contraction of cardiac muscle. Research into cardiac ion channel regulation and mutations that underlie disease pathogenesis has greatly enhanced our knowledge of the causes and clinical management of cardiac arrhythmia. Here we review the molecular determinants, pathogenesis, and pharmacology of congenital Long QT Syndrome. We examine mechanisms of dysfunction associated with three critical cardiac currents that comprise the majority of congenital Long QT Syndrome cases: 1) IKs, the slow delayed rectifier current; 2) IKr, the rapid delayed rectifier current; and 3) INa, the voltage-dependent sodium current. Less common subtypes of congenital Long QT Syndrome affect other cardiac ionic currents that contribute to the dynamic nature of cardiac electrophysiology. Through the study of mutations that cause congenital Long QT Syndrome, the scientific community has advanced understanding of ion channel structure-function relationships, physiology, and pharmacological response to clinically employed and experimental pharmacological agents. Our understanding of congenital Long QT Syndrome continues to evolve rapidly and with great benefits: genotype-driven clinical management of the disease has improved patient care as precision medicine becomes even more a reality.
| S-EPMC5539372 | biostudies-literature
Project description:Long QT syndrome (LQTS) is a disorder of ventricular repolarization that predisposes affected individuals to lethal cardiac arrhythmias. To date, an appropriate animal model of inherited LQTS does not exist. The zebrafish is a powerful vertebrate model used to dissect molecular pathways of cardiovascular development and disease. Because fundamental electrical properties of the zebrafish heart are remarkably similar to those of the human heart, the zebrafish may be an appropriate model for studying human inherited arrhythmias. Here we describe the molecular, cellular, and electrophysiological basis of a zebrafish mutant characterized by ventricular asystole. Genetic mapping and direct sequencing identify the affected gene as kcnh2, which encodes the channel responsible for the rapidly activating delayed rectifier K(+) current (I(Kr)). We show that complete loss of functional I(Kr) in embryonic hearts leads to ventricular cell membrane depolarization, inability to generate action potentials (APs), and disrupted calcium release. A small hyperpolarizing current restores spontaneous APs, implying wild-type function of other ionic currents critical for AP generation. Heterozygous fish manifest overt cellular and electrocardiographic evidence for delayed ventricular repolarization. Our findings provide insight into the pathogenesis of homozygous kcnh2 mutations and expand the use of zebrafish mutants as a model system to study human arrhythmias.
| S-EPMC2040896 | biostudies-literature
Project description:BACKGROUND:Long QT syndrome (LQTS) is caused by the abnormal function of ion channels, which may also affect atrial electrophysiology and be associated with the risk of atrial fibrillation (AF). However, large-scale studies of AF risk among patients with LQTS and its relation to LQTS manifestations are lacking. We aimed to assess the risk of AF and its relationship to the LQTS genotype and the long-term prognosis in patients with LQTS. METHODS:Genotype-positive patients with LQTS (784 LQT1, 746 LQT2, and 233 LQT3) were compared with 2043 genotype-negative family members. Information on the occurrence of AF was based on physician-reported ECG-verified events. Multivariate Cox proportional hazards regression analyses were performed for ages 0 to 60 and after 60 years (reflecting an early and late-onset of AF) to assess the risk of incident AF by genotype and the relationship of AF to the risk of cardiac events defined as syncope, documented torsades de pointes, and aborted cardiac arrest or sudden cardiac death. RESULTS:In patients followed from birth to 60 years of age, patients with LQT3 had an increased risk of AF compared with genotype-negative family members (hazard ratio=6.62; 95% CI, 2.04-21.49; P<0.001), while neither LQT1 nor LQT2 demonstrated increased AF risk. After the age of 60 years, patients with LQT2 had significantly lower risk of AF compared with genotype-negative controls (hazard ratio=0.07; 95% CI, 0.01-0.53, P=0.011). AF was a significant predictor of cardiac events in patients with LQT3 through the age of 60 (hazard ratio=5.38; 95% CI, 1.17-24.82; P=0.031). CONCLUSIONS:Our data demonstrate an increased risk of early age AF in patients with LQT3 and also indicate a protective effect of the LQT2 genotype in it's association with a decreased risk of AF after the age of 60.
| S-EPMC6814383 | biostudies-literature