Genotype Predicts Outcomes in Fetuses and Neonates With Severe Congenital Long QT Syndrome

Jeremy P Moore; Roberto G Gallotti; Kevin M Shannon; J Martijn Bos; Elham Sadeghi; Janette F Strasburger; Ronald T Wakai; Hitoshi Horigome; Sally-Ann Clur; Allison C Hill; Maully J Shah; Shashank Behere; Georgia Sarquella-Brugada; Richard Czosek; Susan P Etheridge; Peter Fischbach; Prince J Kannankeril; Kara Motonaga; Andrew P Landstrom; Matthew Williams; Akash Patel; Federica Dagradi; Reina B Tan; Elizabeth Stephenson; Mani Ram Krishna; Christina Y Miyake; Michelle E Lee; Shubhayan Sanatani; Seshadri Balaji; Ming-Lon Young; Saad Siddiqui; Peter J Schwartz; Kalyanam Shivkumar; Michael J Ackerman

doi:10.1016/j.jacep.2020.06.001

Genotype Predicts Outcomes in Fetuses and Neonates With Severe Congenital Long QT Syndrome

JACC Clin Electrophysiol. 2020 Nov;6(12):1561-1570. doi: 10.1016/j.jacep.2020.06.001. Epub 2020 Aug 26.

Authors

Jeremy P Moore¹, Roberto G Gallotti², Kevin M Shannon², J Martijn Bos³, Elham Sadeghi⁴, Janette F Strasburger⁴, Ronald T Wakai⁵, Hitoshi Horigome⁶, Sally-Ann Clur⁷, Allison C Hill⁸, Maully J Shah⁹, Shashank Behere⁹, Georgia Sarquella-Brugada¹⁰, Richard Czosek¹¹, Susan P Etheridge¹², Peter Fischbach¹³, Prince J Kannankeril¹⁴, Kara Motonaga¹⁵, Andrew P Landstrom¹⁶, Matthew Williams¹⁷, Akash Patel¹⁸, Federica Dagradi¹⁹, Reina B Tan²⁰, Elizabeth Stephenson²¹, Mani Ram Krishna²², Christina Y Miyake²³, Michelle E Lee²³, Shubhayan Sanatani²⁴, Seshadri Balaji²⁵, Ming-Lon Young²⁶, Saad Siddiqui²⁷, Peter J Schwartz²⁸, Kalyanam Shivkumar², Michael J Ackerman³

Affiliations

¹ Division of Pediatric Cardiology, University of California Los Angeles (UCLA) Medical Center, Los Angeles, California, USA; UCLA Cardiac Arrhythmia Center and Ahmanson Adult Congenital Heart Disease Center, UCLA Health System, Los Angeles, California, USA. Electronic address: jpmoore@mednet.ucla.edu.
² Division of Pediatric Cardiology, University of California Los Angeles (UCLA) Medical Center, Los Angeles, California, USA; UCLA Cardiac Arrhythmia Center and Ahmanson Adult Congenital Heart Disease Center, UCLA Health System, Los Angeles, California, USA.
³ Department of Cardiovascular Medicine (Division of Heart Rhythm Services), Mayo Clinic, Rochester, Minnesota, USA; Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
⁴ Department of Pediatrics, Medical College of Wisconsin, Herma Heart Institute, Milwaukee, Wisconsin, USA.
⁵ Biomagnetism Laboratory, Department of Medical Physics, University of Wisconsin, Madison, Wisconsin, USA.
⁶ Department of Pediatrics, Tsukuba University, Ibaraki, Japan.
⁷ Department of Pediatric Cardiology, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, the Netherlands.
⁸ Division of Cardiology, Children's Hospital Los Angeles, Los Angeles, California, USA.
⁹ Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹⁰ Arrhythmia, Inherited Cardiac Diseases Unit, Hospital Sant Joan de Déu, Barcelona, Spain; Medical Sciences Department, School of Medicine, University of Girona, Girona, Spain.
¹¹ The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
¹² Primary Children's Hospital, University of Utah School of Medicine, Salt Lake City, Utah, USA.
¹³ Division of Pediatric Cardiology, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia, USA.
¹⁴ Monroe Carrell Children's Hospital, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
¹⁵ Division of Pediatric Cardiology, Stanford University, Palo Alto, California, USA.
¹⁶ Department of Pediatrics, Division of Cardiology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina, USA.
¹⁷ Division of Cardiology, Rady Children's Hospital, University of California San Diego, San Diego, California, USA.
¹⁸ Division of Pediatric Cardiology, University of California San Francisco Benioff Children's Hospital, University of California, San Francisco, California, USA.
¹⁹ Center for Cardiac Arrhythmias of Genetic Origin, Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Auxologico Italiano, Milan, Italy.
²⁰ Division of Pediatric Cardiology, New York University Langone School of Medicine, New York, New York, USA.
²¹ Labbatt Family Heart Centre, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
²² Amrita Institute of Medical Science, Kochi, India.
²³ Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, USA.
²⁴ Division of Cardiology, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
²⁵ Division of Pediatric Cardiology, Oregon Health and Science University, Portland, Oregon, USA.
²⁶ Joe DiMaggio Children's Hospital Heart Institute, Memorial Healthcare System, Hollywood, Florida, USA.
²⁷ The Heart Institute for Children, Advocate Children's Hospital, Oak Lawn, Illinois, USA.
²⁸ Center for Cardiac Arrhythmias of Genetic Origin, Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Auxologico Italiano, Milan, Italy; Department of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy; Molecular Cardiology Laboratory, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.

Abstract

Objectives: This study sought to determine the relationship between long QT syndrome (LQTS) subtype (LTQ1, LTQ2, LTQ3) and postnatal cardiac events (CEs).

Background: LQTS presenting with 2:1 atrioventricular block or torsades de pointes in the fetus and/or neonate has been associated with risk for major CEs, but overall outcomes and predictors remain unknown.

Methods: A retrospective study involving 25 international centers evaluated the course of fetuses/newborns diagnosed with congenital LQTS and either 2:1 atrioventricular block or torsades de pointes. The primary outcomes were age at first CE after dismissal from the newborn hospitalization and death and/or cardiac transplantation during follow-up. CE was defined as aborted cardiac arrest, appropriate shock from implantable cardioverter-defibrillator, or sudden cardiac death.

Results: A total of 84 fetuses and/or neonates were identified with LQTS (12 as LQT1, 35 as LQT2, 37 as LQT3). Median gestational age at delivery was 37 weeks (interquartile range: 35 to 39 weeks) and age at hospital discharge was 3 weeks (interquartile range: 2 to 5 weeks). Fetal demise occurred in 2 and pre-discharge death in 1. Over a median of 5.2 years, there were 1 LQT1, 3 LQT2, and 23 LQT3 CEs (13 aborted cardiac arrests, 5 sudden cardiac deaths, and 9 appropriate shocks). One patient with LQT1 and 11 patients with LQT3 died or received cardiac transplant during follow-up. The only multivariate predictor of post-discharge CEs was LQT3 status (LQT3 vs. LQT2: hazard ratio: 8.4; 95% confidence interval: 2.6 to 38.9; p < 0.001), and LQT3, relative to LQT2, genotype predicted death and/or cardiac transplant (p < 0.001).

Conclusions: In this large multicenter study, fetuses and/or neonates with LQT3 but not those with LQT1 or LQT2 presenting with severe arrhythmias were at high risk of not only frequent, but lethal CEs.

Keywords: atrioventricular block; cardiac sympathetic denervation; fetal arrhythmia; fetus; genetic testing; implantable cardioverter-defibrillator; long QT syndrome; magnetocardiography; sudden cardiac death; torsades de pointes.

Published by Elsevier Inc.

Publication types

Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aftercare*
Electrocardiography
Fetus
Genotype
Humans
Infant, Newborn
Long QT Syndrome* / complications
Long QT Syndrome* / genetics
Patient Discharge
Retrospective Studies

Abstract

Publication types

MeSH terms

Grants and funding