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Aims: In long QT syndrome (LQTS), primary prevention improves outcome; thus, early identification is key. The most common LQTS phenotype is a foetal heart rate (FHR) < 3rd percentile for gestational age (GA) but the effects of cohort, genotype, variant, and maternal β-blocker therapy on FHR are unknown. We assessed the influence of these factors on FHR in pregnancies with familial LQTS and developed a FHR/GA threshold for LQTS., Methods and Results: In an international cohort of pregnancies in which one parent had LQTS, LQTS genotype, familial variant, and maternal β-blocker effects on FHR were assessed. We developed a testing algorithm for LQTS using FHR and GA as continuous predictors. Data included 1966 FHRs at 7-42 weeks' GA from 267 pregnancies/164 LQTS families [220 LQTS type 1 (LQT1), 35 LQTS type 2 (LQT2), and 12 LQTS type 3 (LQT3)]. The FHRs were significantly lower in LQT1 and LQT2 but not LQT3 or LQTS negative. The LQT1 variants with non-nonsense and severe function loss (current density or β-adrenergic response) had lower FHR. Maternal β-blockers potentiated bradycardia in LQT1 and LQT2 but did not affect FHR in LQTS negative. A FHR/GA threshold predicted LQT1 and LQT2 with 74.9% accuracy, 71% sensitivity, and 81% specificity., Conclusion: Genotype, LQT1 variant, and maternal β-blocker therapy affect FHR. A predictive threshold of FHR/GA significantly improves the accuracy, sensitivity, and specificity for LQT1 and LQT2, above the infant's a priori 50% probability. We speculate this model may be useful in screening for LQTS in perinatal subjects without a known LQTS family history., Competing Interests: Conflict of interest: M.J.A. is a consultant for Abbott, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Invitae, Medtronic, Tenaya Therapeutics, and UpToDate. M.J.A. and Mayo Clinic are involved in equity/intellectual property/royalty relationships with AliveCor, Anumana, ARMGO Pharma, Pfizer, and Thryv Therapeutics. A.A.M.W. is a consultant for Thryv Therapeutics with minor financial interest. S.P.E. is involved with Spaulding Research with minor financial interest., (Published by Oxford University Press on behalf of the European Society of Cardiology 2023.)

Background: Long QT syndrome (LQTS) is a leading cause of sudden cardiac death in early life and has been implicated in ≈10% of sudden infant deaths and unexplained stillbirths. The purpose of our study was to use fetal magnetocardiography to characterize the electrophysiology and rhythm phenotypes of fetuses with de novo and inherited LQTS variants and identify risk factors for sudden death before birth., Methods: We reviewed the fetal magnetocardiography database from the University of Wisconsin Biomagnetism Laboratory for fetuses with confirmed LQTS. We assessed waveform intervals, heart rate, and rhythm, including the signature LQTS rhythms: functional 2° atrioventricular block, T-wave alternans, and torsade de pointes (TdP)., Results: Thirty-nine fetuses had pathogenic variants in LQTS genes: 27 carried the family variant, 11 had de novo variants, and 1 was indeterminate. De novo variants, especially de novo SCN5A variants, were strongly associated with a severe rhythm phenotype and perinatal death: 9 (82%) showed signature LQTS rhythms, 6 (55%) showed TdP, 5 (45%) were stillborn, and 1 (9%) died in infancy. Those that died exhibited novel fetal rhythms, including atrioventricular block with 3:1 conduction ratio, QRS alternans in 2:1 atrioventricular block, long-cycle length TdP, and slow monomorphic ventricular tachycardia. Premature ventricular contractions were also strongly associated with TdP and perinatal death. Fetuses with familial variants showed a lower incidence of signature LQTS rhythm (6/27=22%), including TdP (3/27=11%). All were live born., Conclusions: The malignancy of de novo LQTS variants was remarkably high and demonstrate that these mutations are a significant cause of stillbirth. Their ability to manifest rhythms not known to be associated with LQTS increases the difficulty of echocardiographic diagnosis and decreases the likelihood that a resultant fetal loss is attributed to LQTS. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03047161.

Background: Most fetal deaths are unexplained. Long QT syndrome is a genetic disorder of cardiac ion channels. Affected individuals, including fetuses, are predisposed to sudden death. We sought to determine the risk of fetal death in familial long QT syndrome, in which the mother or father carries the long QT syndrome genotype. In addition, we assessed whether risk differed if the long QT syndrome genotype was inherited from the mother or father., Objective: This was a retrospective review of pregnancies in families with the 3 most common heterozygous pathogenic long QT syndrome genotypes in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3), which occur in approximately 1 in 2000 individuals. The purpose of our study was to compare pregnancy and birth outcomes in familial long QT syndrome with the normal population and between maternal and paternal carriers of the long QT syndrome genotype. We hypothesized that fetal death before (miscarriage) and after (stillbirths) 20 weeks gestation would be increased in familial long QT syndrome compared with the normal population and that the parent of origin would not affect birth outcomes., Study Design: Our study was a multicenter observational case series of 148 pregnancies from 103 families (80 mothers, 23 fathers) with familial long QT syndrome (60 with LQT1, 29 with LQT2, 14 with LQT3) who were recruited from 11 international centers with expertise in hereditary heart rhythm diseases, pediatric and/or adult electrophysiology, and high-risk pregnancies. Clinical databases from these sites were reviewed for long QT syndrome that occurred in men or women of childbearing age (18-40 years). Pregnancy outcomes (livebirth, stillbirth, and miscarriage), birthweights, and gestational age at delivery were compared among long QT syndrome genotypes and between maternal vs paternal long QT syndrome-affected status with the use of logistic regression analysis., Results: Most offspring (80%; 118/148) were liveborn at term; 66% of offspring (73/110) had long QT syndrome. Newborn infants of mothers with long QT syndrome were delivered earlier and, when the data were controlled for gestational age, weighed less than newborn infants of long QT syndrome fathers. Fetal arrhythmias were observed rarely, but stillbirths (fetal death at >20 weeks gestation) were 8 times more frequent in long QT syndrome (4% vs approximately 0.5%); miscarriages (fetal death at ≤20 weeks gestation) were 2 times that of the general population (16% vs 8%). The likelihood of fetal death was significantly greater with maternal vs paternal long QT syndrome (24.4% vs 3.4%; P=.036). Only 10% of all fetal deaths underwent postmortem long QT syndrome testing; 2 of 3 cases were positive for the family long QT syndrome genotype., Conclusion: This is the first report to demonstrate that mothers with long QT syndrome are at increased risk of fetal death and to uncover a previously unreported cause of stillbirth. Our results suggest that maternal effects of long QT syndrome channelopathy may cause placental or myometrial dysfunction that confers increased susceptibility to fetal death and growth restriction in newborn survivors, regardless of long QT syndrome status., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Long-QT syndrome (LQTS), an inherited cardiac repolarization disorder, is an important cause of fetal and neonatal mortality. Detecting LQTS prenatally is challenging. A fetal heart rate (FHR) less than third percentile for gestational age is specific for LQTS, but the sensitivity is only ≈50%. Left ventricular isovolumetric relaxation time (LVIRT) was evaluated as a potential diagnostic marker for fetal LQTS., Methods and Results: LV isovolumetric contraction time, LV ejection time, LVIRT, cycle length, and FHR were measured using pulsed Doppler waveforms in fetuses. Time intervals were expressed as percentages of cycle length, and the LV myocardial performance index was calculated. Single measurements were stratified by gestational age and compared between LQTS fetuses and controls. Receiver-operator curves were performed for FHR and normalized LVIRT (N-LVIRT). A linear mixed-effect model including multiple measurements was used to analyze trends in FHR, N-LVIRT, and LV myocardial performance index. There were 33 LQTS fetuses and 469 controls included. In LQTS fetuses, the LVIRT was prolonged in all gestational age groups ( P <0.001), as was the N-LVIRT. The best cutoff to diagnose LQTS was N-LVIRT ≥11.3 at ≤20 weeks (92% sensitivity, 70% specificity). Simultaneous analysis of N-LVIRT and FHR improved the sensitivity and specificity for LQTS (area under the curve=0.96; 95% confidence interval, 0.82-1.00 at 21-30 weeks). N-LVIRT, LV myocardial performance index, and FHR trends differed significantly between LQTS fetuses and controls through gestation., Conclusions: The LVIRT is prolonged in LQTS fetuses. Findings of a prolonged N-LVIRT and sinus bradycardia can improve the prenatal detection of fetal LQTS., (© 2018 American Heart Association, Inc.)

Introduction: Fetal magnetocardiography (fMCG), the magnetic analog of ECG, has provided invaluable insight into the mechanisms of fetal arrhythmias. In the past 15years, we have evaluated over 300 fetuses with arrhythmia by fMCG. We review the unique characteristics and natural history of the long QT syndrome (LQTS) rhythms., Methods: We reviewed the fMCGs of subjects referred with suspected LQTS based on either a positive family history or echo diagnosis of the LQTS rhythms (sinus bradycardia, ventricular tachycardia, or 2:1 AV conduction) to the Biomagnetism laboratory in the Department of Medical Physics, UW-Madison. We recorded fMCGs using a 37-channel (Magnes, 4D Neuroimaging, Inc., San Diego, CA) superconducting quantum interference device (SQUID) biomagnetometer, housed in a magnetically-shielded room for 1200-6000s. Signal processing was used to remove maternal interference. Cardiac intervals (R-R, p, QRS, QT) were measured and compared to published normals. We correlated fetal heart rate (FHR) patterns and effects of fetal movement on FHR and rhythm using actocardiography., Results: Thirty-nine fetuses were studied at a mean of 28 (19-38) weeks of gestation. All had structurally normal hearts. One was on amiodarone for suspected supraventricular tachycardia and hydrops. Five had serial fMCGs. Isolated sinus bradycardia with a QTc >490ms was found in 35: 33 had a KCNQ1 mutation There was one false positive and one false negative LQTS diagnosis. Four fetuses had torsades de pointes (TdP) and 3 had periods of 2:1 conduction and either KCNH2 or SCN5A mutations. TdP was rarely initiated with a preceding long-short pattern and did not degenerate into ventricular fibrillation. One fetus with TdP died in utero, 2 with fetal TdP had postnatal cardiac arrest., Conclusion: Fetal LQTS is diagnosed by an fMCG QTc >490ms with an 89% sensitivity and specificity. TdP are seen with uncharacterized, KCNH2 or SCN5A R1623q mutations. Fetal TdP occurs when QTc ≥620ms. Identifying fetal LQTS and defining its rhythms by fMCG risk stratifies postnatal management., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose of Review: The purpose of this study is to update the perinatal cardiologist and obstetrical care provider on the presentation and management of the fetus with long QT syndrome (LQTS)., Recent Findings: LQTS is a known cause of sudden death in childhood, adolescence and young adulthood that presents during fetal life, but is often not recognized. Torsades de pointes (TdP) ±2° atrioventricular block (AVB) are not always attributed to LQTS, although the most common LQTS rhythm, a fetal heart rate of less than third percentile for gestational age (GA), is not recognized as abnormal because it does not meet the standard obstetrical criteria for bradycardia. Early recognition and appropriate treatment can be life saving for the fetus and unsuspecting LQTS family members. Fetal rhythm phenotype and postnatal QTc can predict postnatal rhythm and suggest genotype: bradycardic fetuses usually have KCNQ1 mutation, while those with TdP and/or a postnatal QTc more than 500 ms have SCN5A, KCNH2 or uncharacterized mutations., Summary: The fetus with repeated heart rates of less than third percentile of GA and those with TdP ±2° AVB are likely to manifest the same rhythm after birth and have an LQTS mutation.

Background: The electrophysiology of long QT syndrome (LQTS) in utero is virtually unstudied. Our goal here was to evaluate the efficacy of fetal magnetocardiography (fMCG) for diagnosis and prognosis of fetuses at risk of LQTS., Methods and Results: We reviewed the pre/postnatal medical records of 30 fetuses referred for fMCG because of a family history of LQTS (n=17); neonatal/childhood sudden cardiac death (n=3), or presentation of prenatal LQTS rhythms (n=12): 2° atrioventricular block, ventricular tachycardia, heart rate < 3(rd) percentile. We evaluated heart rate and reactivity, cardiac time intervals, T-wave characteristics, and initiation/termination of Torsade de Pointes, and compared these with neonatal ECG findings. After birth, subjects were tested for LQTS mutations. Based on accepted clinical criteria, 21 subjects (70%; 9 KCNQ1, 5 KCNH2, 2 SCN5A, 2 other, 3 untested) had LQTS. Using a threshold of corrected QT= 490 ms, fMCG accurately identified LQTS fetuses with 89% (24/27) sensitivity and 89% (8/9) specificity in 36 sessions. Four fetuses (2 KCNH2 and 2 SCN5A), all with corrected QT ≥ 620 ms, had frequent episodes of Torsade de Pointes, which were present 22-79% of the time. Although some episodes initiated with a long-short sequence, most initiations showed QRS aberrancy and a notable lack of pause dependency. T-wave alternans was strongly associated with severe LQTS phenotype., Conclusions: Corrected QT prolongation (≥490 ms) assessed by fMCG accurately identified LQTS in utero; extreme corrected QT prolongation (≥620 ms) predicted Torsade de Pointes. FMCG can play a critical role in the diagnosis and management of fetuses at risk of LQTS.

Background: Fetal 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 Results: Records 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., Conclusions: Rhythm phenotypes of fetal LQTS have genotype-suggestive features that, along with heart rate-corrected QT interval duration, may risk stratify perinatal management.

Background: Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on 2 unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause., Methods and Results: We ascertained 2 unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents. The 2 parent-child trios were investigated with the use of exome sequencing to search for de novo genetic variants. We then performed follow-up candidate gene screening on an independent cohort of 82 subjects with congenital long-QT syndrome without an identified genetic cause. Biochemical studies were performed to determine the functional consequences of mutations discovered in 2 genes encoding calmodulin. We discovered 3 heterozygous de novo mutations in either CALM1 or CALM2, 2 of the 3 human genes encoding calmodulin, in the 2 probands and in 2 additional subjects with recurrent cardiac arrest. All mutation carriers were infants who exhibited life-threatening ventricular arrhythmias combined variably with epilepsy and delayed neurodevelopment. Mutations altered residues in or adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain. Recombinant mutant calmodulins exhibited several-fold reductions in calcium binding affinity., Conclusions: Human calmodulin mutations disrupt calcium ion binding to the protein and are associated with a life-threatening condition in early infancy. Defects in calmodulin function will disrupt important calcium signaling events in heart, affecting membrane ion channels, a plausible molecular mechanism for potentially deadly disturbances in heart rhythm during infancy.

Background: Fetal long QT syndrome (LQTS) is associated with complex arrhythmias including torsades de pointes and 2° atrioventricular block. Sinus bradycardia has also been associated with fetal LQTS, but little is known of this rhythm manifestation. Our purpose was to characterize the fetal heart rate (FHR)/gestational age (GA) profile of fetal LQTS., Methods and Results: We ascertained fetal LQTS subjects by family history (Group 1) or fetal arrhythmia referral (Group 2). We compared FHR in LQTS subjects versus normal fetuses. To identify FHR predictors of LQTS, we calculated a bradycardia index as % of LQTS FHR recordings either ≤110 beats per minute (obstetric standard) or ≤3(rd) percentile for GA. Among 42 LQTS subjects, 26 were in Group 1 and 16 in Group 2. There were 536 normal fetuses. The bradycardia index was only 15% for FHR ≤110 beats per minute, but 66% for FHR ≤3rd percentile for GA. Ten fetuses with complex arrhythmias also had severe and sustained sinus bradycardia throughout gestation. Identifying a fetal proband in Group 2 resulted in LQTS diagnosis in 9 unsuspected members of 6 families., Conclusions: FHR varies by GA in both normal and LQTS fetuses. Postnatal evaluation of neonates with FHR ≤3(rd) percentile for GA may improve ascertainment of LQTS in fetuses, neonates, and undiagnosed family members.

Background: Congenital long-QT syndrome (LQTS) may present during fetal development and can be life-threatening. The molecular mechanism for the unusual early onset of LQTS during fetal development is unknown., Objective: We sought to elucidate the molecular basis for severe fetal LQTS presenting at 19 weeks' gestation, the earliest known presentation of this disease., Methods: Fetal magnetocardiography was used to demonstrated torsades de pointes and a prolonged rate-corrected QT interval. In vitro electrophysiological studies were performed to determine functional consequences of a novel SCN5A mutation found in the fetus., Results: The fetus presented with episodes of ventricular ectopy progressing to incessant ventricular tachycardia and hydrops fetalis. Genetic analysis disclosed a novel, de novo heterozygous mutation (L409P) and a homozygous common variant (R558 in SCN5A). In vitro electrophysiological studies demonstrated that the mutation in combination with R558 caused significant depolarized shifts in the voltage dependence of inactivation and activation, faster recovery from inactivation, and a 7-fold higher level of persistent current. When the mutation was engineered in a fetal-expressed SCN5A splice isoform, channel dysfunction was markedly potentiated. Also, R558 alone in the fetal splice isoform evoked a large persistent current, and hence both alleles were dysfunctional., Conclusion: We report the earliest confirmed diagnosis of symptomatic LQTS and present evidence that mutant cardiac sodium channel dysfunction is potentiated by a developmentally regulated alternative splicing event in SCN5A. Our findings provide a plausible mechanism for the unusual severity and early onset of cardiac arrhythmia in fetal LQTS., (Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims In long QT syndrome (LQTS), primary prevention improves outcome; thus, early identification is key. The most common LQTS phenotype is a foetal heart rate (FHR) < 3rd percentile for gestational age (GA) but the effects of cohort, genotype, variant, and maternal β-blocker therapy on FHR are unknown. We assessed the influence of these factors on FHR in pregnancies with familial LQTS and developed a FHR/GA threshold for LQTS. Methods and results In an international cohort of pregnancies in which one parent had LQTS, LQTS genotype, familial variant, and maternal β-blocker effects on FHR were assessed. We developed a testing algorithm for LQTS using FHR and GA as continuous predictors. Data included 1966 FHRs at 7–42 weeks' GA from 267 pregnancies/164 LQTS families [220 LQTS type 1 (LQT1), 35 LQTS type 2 (LQT2), and 12 LQTS type 3 (LQT3)]. The FHRs were significantly lower in LQT1 and LQT2 but not LQT3 or LQTS negative. The LQT1 variants with non-nonsense and severe function loss (current density or β-adrenergic response) had lower FHR. Maternal β-blockers potentiated bradycardia in LQT1 and LQT2 but did not affect FHR in LQTS negative. A FHR/GA threshold predicted LQT1 and LQT2 with 74.9% accuracy, 71% sensitivity, and 81% specificity. Conclusion Genotype, LQT1 variant, and maternal β-blocker therapy affect FHR. A predictive threshold of FHR/GA significantly improves the accuracy, sensitivity, and specificity for LQT1 and LQT2, above the infant's a priori 50% probability. We speculate this model may be useful in screening for LQTS in perinatal subjects without a known LQTS family history. [ABSTRACT FROM AUTHOR]

Background: Repeated fetal heart rates (FHR) < 3rd percentile for gestational age (GA) with 1:1 atrioventricular conduction (sinus bradycardia) can be a marker for long QT syndrome. We hypothesized that other inherited arrhythmia syndromes might present with fetal sinus bradycardia. Methods: We reviewed pregnancies referred with sinus bradycardia to the Colorado Fetal Care Center between 2013 and 2023. FHR/GA data, family history, medication exposure, normalized isovolumic contraction times (n-IVRT), postnatal genetic testing, and ECGs at 4–6 weeks after birth were reviewed. Results: Twenty-nine bradycardic subjects were evaluated by fetal echocardiography. Five were lost to follow-up, one refused genetic testing, and one had negative genetic testing for any inherited arrhythmia. Six had non-genetic causes of fetal bradycardia with normal prenatal n-IVRT and postnatal QTc. Thirteen carried pathogenic variants in RYR2 (n = 2), HCN4 (n = 2), KCNQ1 (6), and other LQTS genes (n = 4). The postnatal QTc was <470 ms in subjects with RYR2, HCN4, and two of those with KCNQ1 mutations, and >470 ms in subjects with CALM 2, KCNH2, SCN5A, and four of those with KCNQ1 mutations. LQTS and RYR2 mutations were associated with prolonged n-IVRT, but HCN4 was not. Two fetuses died in utero with variants of uncertain significance (CACNA1 and KCNE1). Cascade testing uncovered six affected but undiagnosed parents and confirmed familial inheritance in five. Conclusion: In addition to heralding LQTS, repeated FHR < 3rd percentile for GA is a risk factor for other inherited arrhythmia syndromes. These findings suggest that genetic testing should be offered to infants with a history of FHR < 3rd percentile for GA even if the postnatal ECG demonstrates a normal QTc interval. [ABSTRACT FROM AUTHOR]

Aims Detection and careful stratification of fetal heart rate (FHR) is extremely important in all pregnancies. The most lethal cardiac rhythm disturbances occur during apparently normal pregnancies where FHR and rhythm are regular and within normal or low-normal ranges. These hidden depolarization and repolarization abnormalities, associated with genetic ion channelopathies cannot be detected by echocardiography, andmay be responsible for up to 10% of unexplained fetal demise, prompting a need for newer and better fetal diagnostic techniques. Other manifest fetal arrhythmias such as premature beats, tachycardia, and bradycardia are commonly recognized. Methods Heart rhythm diagnosis in obstetrical practice is usually made by M-mode and pulsed Doppler fetal echocardiography, but not all fetal cardiac time intervals are captured by echocardiographic methods. Results and Conclusions This article reviews different types of fetal arrhythmias, their presentation and treatment strategies, and gives an overview of the present and future diagnostic techniques. [ABSTRACT FROM AUTHOR]

This article discusses a study which evaluated the role of Doppler echocardiography in the successful management of fetal arrhythmias. The diagnosis of arrhythmia by Doppler echocardiography is based on the atrioventricular relationship and the atrial and ventricular rates. Data from the procedure will distinguish fetuses that can be conservatively managed from those that would benefit in-utero pharmacotherapy.