Complex and Novel Arrhythmias Precede Stillbirth in Fetuses With De Novo Long QT Syndrome

Abstract

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.

Keywords: atrioventricular block; heart rate; long QT syndrome; magnetocardiography; stillbirth.

Figures

Fig. 1.

Genotype composition of fetal LQTS cohort. Within the cohort of 39 subjects there were 6 deaths. All involved de novo variants. Four were de novo SCN5A variants.

Fig. 2.

Novel LQTS rhythm patterns. A) Transition from 2:1 to 3:1 AV block in fetus #35. A premature ventricular contraction (PVC; asterisk) occurs at the transition, followed by an aberrantly conducted beat and a relatively short QT interval that progressively lengthens. In 2:1 AV block the T-waves are notched, which is commonly seen in LQT2. In 3:1 AV block the QRS complexes change morphology and become narrower. B-C) Complex rhythm with TdP, PVCs, (B) periods of AV block in a 3:1 or 2:1 conduction ratio and (C) atrial flutter in fetus #37. Sinus beats (upward arrows) were relatively rare due to AV block, PVCs (asterisks), and the prevalence of TdP. P-waves are indicated by downward arrows. The T-waves (T) show a negative-positive biphasic morphology. TdP was usually initiated by a PVC. Atrial flutter (330 bpm) was seen approximately 25% of the time and occurred with and without the presence of TdP. D) QRS alternans in 2:1 AV block in fetus #31. The QRS complexes (arrows) are narrow and on time, but show marked beat-to-beat variation in amplitude and polarity. Normally, QRS alternans occurs during 1:1 AV conduction in a regular ABAB pattern and is characterized by modest variation in QRS amplitude and prominent variation in QRS morphology. E-G) TdP with a cycle length similar to that of sinus rhythm in fetuses #35, #28, and #31, respectively. The horizontal bars indicate the duration of the PP intervals. H) Transition from typical TdP to slow VT with a rate of 127 bpm in fetus #29.

Fig. 2.

Novel LQTS rhythm patterns. A) Transition from 2:1 to 3:1 AV block in fetus #35. A premature ventricular contraction (PVC; asterisk) occurs at the transition, followed by an aberrantly conducted beat and a relatively short QT interval that progressively lengthens. In 2:1 AV block the T-waves are notched, which is commonly seen in LQT2. In 3:1 AV block the QRS complexes change morphology and become narrower. B-C) Complex rhythm with TdP, PVCs, (B) periods of AV block in a 3:1 or 2:1 conduction ratio and (C) atrial flutter in fetus #37. Sinus beats (upward arrows) were relatively rare due to AV block, PVCs (asterisks), and the prevalence of TdP. P-waves are indicated by downward arrows. The T-waves (T) show a negative-positive biphasic morphology. TdP was usually initiated by a PVC. Atrial flutter (330 bpm) was seen approximately 25% of the time and occurred with and without the presence of TdP. D) QRS alternans in 2:1 AV block in fetus #31. The QRS complexes (arrows) are narrow and on time, but show marked beat-to-beat variation in amplitude and polarity. Normally, QRS alternans occurs during 1:1 AV conduction in a regular ABAB pattern and is characterized by modest variation in QRS amplitude and prominent variation in QRS morphology. E-G) TdP with a cycle length similar to that of sinus rhythm in fetuses #35, #28, and #31, respectively. The horizontal bars indicate the duration of the PP intervals. H) Transition from typical TdP to slow VT with a rate of 127 bpm in fetus #29.

Fig. 3.

Magnetic and mechanical alternans. A) QRS and T-wave alternans in fetus #32. B) Pulsed Doppler tracing from the same fetus showing mechanical alternans. Notice the prolonged diastolic relaxation with every other beat. The flow pattern can mimic PVCs, but is distinguished by its uniform cycle length.