Effects of cohort, genotype, variant, and maternal β-blocker treatment on foetal heart rate predictors of inherited long QT syndrome.

Alexander M Kaizer, Annika Winbo, Sally-Ann B Clur, Susan P Etheridge, Michael J Ackerman, Hitoshi Horigome, Ulrike Herberg, Federica Dagradi, Carla Spazzolini, Stacy A S Killen, Annette Wacker-Gussmann, Arthur A M Wilde, Elena Sinkovskaya, Alfred Abuhamad, Margherita Torchio, Chai-Ann Ng, Annika Rydberg, Peter J Schwartz, Bettina F Cuneo

Journal: Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 2023;25(11):euad319

PMID: 37975542

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Abstract

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.

Published by Oxford University Press on behalf of the European Society of Cardiology 2023.

Address: Biostatistics and Informatics, Colorado School of Public Health, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA.; Department of Clinical Sciences, Pediatrics, Umeå University, Umea, Sweden.; Department of Physiology, University of Auckland, Auckland, New Zealand.; Department of Pediatric Cardiology, Emma Children's Hospital, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Department of Cardiology, University Medical Center, Amsterdam, The Netherlands.; Department of Pediatrics, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT, USA.; Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Mayo Clinic, Rochester, MN, USA.; Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN, USA.; Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.; Windland Smith Rice Genetic Heart Rhythm Clinic and Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN, USA.; Department of Pediatrics, Section of Cardiology, Tsukuba University, Tsukuba, Japan.; Department of Pediatric Cardiology, RWTH University Hospital Aachen, Aachen, Germany.; Department of Pediatric Cardiology, University Hospital Bonn, Bonn, Germany.; Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Via Pier Lombardo 22, 2015 Milan, Italy.; Department of Pediatrics, Division of Cardiology, Vanderbilt University Medical Center, Nashville, TN, USA.; Department of Congenital Heart Disease and Paediatric Cardiology, German Heart Center, Munich, Germany.; Department of Cardiology, University Medical Center, Amsterdam, The Netherlands.; Department of Cardiology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.; Department of Cardiology, Amseterdam University Medical Center, Amsterdam, The Netherlands.; Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Eastern Virginia Medical School, Norfolk, VA, USA.; Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.; The School of Clinical Medicine, UNSW Sydney, Darlinghurst, New South Wales, Australia.; Department of Clinical Sciences, Pediatrics, Umeå University, Umea, Sweden.; Department of Cardiology, University Medical Center, Amsterdam, The Netherlands.; Department of Pediatrics, Section of Cardiology, University of Denver School of Medicine, 13123 16th Ave, Box 100, Aurora, CO 80045, USA.

DOI: 10.1093/europace/euad319

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MeSH Terms: Infant, Female, Pregnancy, Humans, Heart Rate, Fetal, Long QT Syndrome, Genotype, Adrenergic beta-Antagonists, Phenotype, Electrocardiography