The diagnosis and management of long QT syndrome based on fetal echocardiography.
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ABSTRACT:
SUBMITTER: Blais BA
PROVIDER: S-EPMC5601325 | biostudies-literature | 2017 Sep
REPOSITORIES: biostudies-literature
Publications
The diagnosis and management of long QT syndrome based on fetal echocardiography.
Blais Benjamin A BA Satou Gary G Sklansky Mark S MS Madnawat Himani H Moore Jeremy P JP
HeartRhythm case reports 20170718 9
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Project description:A low baseline fetal heart rate at 20 weeks' gestation was detected in a fetus without cardiac structural anomalies. Fetal echocardiography and magnetocardiography were used to diagnose congenital long QT syndrome. It was confirmed in the neonate, and the same pathogenic variant in KCNQ1 was subsequently identified in the mother.
| S-EPMC10865115 | 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:ImportanceIntrauterine fetal death or stillbirth occurs in approximately 1 out of every 160 pregnancies and accounts for 50% of all perinatal deaths. Postmortem evaluation fails to elucidate an underlying cause in many cases. Long QT syndrome (LQTS) may contribute to this problem.ObjectiveTo determine the spectrum and prevalence of mutations in the 3 most common LQTS susceptible genes (KCNQ1, KCNH2, and SCN5A) for a cohort of unexplained cases.Design, setting, and patientsIn this case series, retrospective postmortem genetic testing was conducted on a convenience sample of 91 unexplained intrauterine fetal deaths (mean [SD] estimated gestational age at fetal death, 26.3 [8.7] weeks) that were collected from 2006-2012 by the Mayo Clinic, Rochester, Minnesota, or the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. More than 1300 ostensibly healthy individuals served as controls. In addition, publicly available exome databases were assessed for the general population frequency of identified genetic variants.Main outcomes and measuresComprehensive mutational analyses of KCNQ1 (KV7.1, LQTS type 1), KCNH2 (HERG/KV11.1, LQTS type 2), and SCN5A (NaV1.5, LQTS type 3) were performed using denaturing high-performance liquid chromatography and direct DNA sequencing on genomic DNA extracted from decedent tissue. Functional analyses of novel mutations were performed using heterologous expression and patch-clamp recording.ResultsThe 3 putative LQTS susceptibility missense mutations (KCNQ1, p.A283T; KCNQ1, p.R397W; and KCNH2 [1b], p.R25W), with a heterozygous frequency of less than 0.05% in more than 10 000 publicly available exomes and absent in more than 1000 ethnically similar control patients, were discovered in 3 intrauterine fetal deaths (3.3% [95% CI, 0.68%-9.3%]). Both KV7.1-A283T (16-week male) and KV7.1-R397W (16-week female) mutations were associated with marked KV7.1 loss-of-function consistent with in utero LQTS type 1, whereas the HERG1b-R25W mutation (33.2-week male) exhibited a loss of function consistent with in utero LQTS type 2. In addition, 5 intrauterine fetal deaths hosted SCN5A rare nonsynonymous genetic variants (p.T220I, p.R1193Q, involving 2 cases, and p.P2006A, involving 2 cases) that conferred in vitro electrophysiological characteristics consistent with potentially proarrhythmic phenotypes.Conclusions and relevanceIn this molecular genetic evaluation of 91 cases of intrauterine fetal death, missense mutations associated with LQTS susceptibility were discovered in 3 cases (3.3%) and overall, genetic variants leading to dysfunctional LQTS-associated ion channels in vitro were discovered in 8 cases (8.8%). These preliminary findings may provide insights into mechanisms of some cases of stillbirth.
| S-EPMC3852902 | biostudies-literature
Project description:A 32-week fetus with tachycardia and bradycardia, diagnosed with torsades de pointes, atrioventricular block, and sinus bradycardia due to a de novo KCNH2 mutation was successfully managed by a cardio-obstetrical team. Maternal/fetal pharmacogenomic testing resulted in appropriate drug dosing without toxicity and delivery of a term infant in sinus rhythm.
| S-EPMC10715977 | biostudies-literature
Project description:Congenital long QT syndrome (LQTS) is a genetically heterogeneous group of heritable disorders of myocardial repolarization linked by the shared clinical phenotype of QT prolongation on electrocardiogram and an increased risk of potentially life-threatening cardiac arrhythmias. At the molecular level, mutations in 15 distinct LQTS-susceptibility genes that encode ion channel pore-forming α-subunits and accessory β-subunits central to the electromechanical function of the heart have been implicated in its pathogenesis. Over the past 2 decades, our evolving understanding of the electrophysiological mechanisms by which specific genetic substrates perturb the cardiac action potential has translated into vastly improved approaches to the diagnosis, risk stratification, and treatment of patients with LQTS. In this review, we describe how our understanding of the molecular underpinnings of LQTS has yielded numerous clinically meaningful genotype-phenotype correlations and how these insights have translated into genotype- and phenotype-guided approaches to the clinical management of LQTS.
| S-EPMC3940076 | biostudies-literature
Project description:While published guidelines are useful in the care of patients with long-QT syndrome, it can be difficult to decide how to apply the guidelines to individual patients, particularly those with intermediate risk. We explored the diversity of opinion among 24 clinicians with expertise in long-QT syndrome. Experts from various regions and institutions were presented with 4 challenging clinical scenarios and asked to provide commentary emphasizing why they would make their treatment recommendations. All 24 authors were asked to vote on case-specific questions so as to demonstrate the degree of consensus or divergence of opinion. Of 24 authors, 23 voted and 1 abstained. Details of voting results with commentary are presented. There was consensus on several key points, particularly on the importance of the diagnostic evaluation and of β-blocker use. There was diversity of opinion about the appropriate use of other therapeutic measures in intermediate-risk individuals. Significant gaps in knowledge were identified.
| S-EPMC8301722 | biostudies-literature
Project description:BackgroundAmong all fetal heart block patients, > 50% cases are associated with maternal autoimmune diseases, and such patients should receive treatment. However, nearly half of fetal heart block cases involve a mother with negative results following autoimmune antibody screening. A few studies have reported long QT syndrome (LQTS) can also present as a severe fetal bradycardia, which does not respond to fetal treatment. Herein, we reported a rare case of an infant who presented with high-degree autoimmune-mediated fetal atrioventricular block (AVB) with LQTS induced by a novel KCNH2 variant. This case led us to review our prenatal therapeutic strategy.Case presentationA 1-year-old boy presented to our heart center having experienced syncope 5 times in the past year. He had previously presented with fetal bradycardia during the fetal stage from 27 + 3 gestational weeks. The fetal echocardiography demonstrated AVB (2:1 transmission). As the maternal autoimmune antibody results were positive, his mother had received dexamethasone treatment during pregnancy; subsequently, the fetal AVB had changed from 2:1 to 4:3 transmission with elevated ventricular beating rates. However, this patient was identified to have complete AVB after birth. The initial electrocardiogram and Holter measurements at hospital administration showed complete AVB, pleomorphic ventricular tachycardia, a prolonged QT interval (QT = 602 ms, corrected QT = 538 ms), and wide and deep inverted T-waves. Meanwhile, torsades de pointes could be observed in several transit ventricular tachycardias based on Holter monitoring review. Genetic testing revealed KCNH2 c.2483G > A variant-induced LQTS. An implantable cardioverter defibrillator device and permanent pacemaker were both considered as therapeutic alternations; his parents ultimately accepted the implantation of a permanent pacemaker.ConclusionsFor fetuses with autoimmune-mediated AVB, intrauterine treatment should still be pursued immediately. However, once the treatment outcomes are deemed unacceptable or unexpected, other genetic variant-related channelopathies should be highly suspected. If the fetus lacks a positive family history, fetal genetic testing should be recommended to improve the prognosis of such patients by introducing integrative therapeutic strategies between the prenatal and postnatal phases.
| S-EPMC10044358 | biostudies-literature
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