Arrhythmia Phenotype During Fetal Life Suggests Long-QT Syndrome Genotype

Abstract

Background Fetal arrhythmias characteristic of long QT syndrome (LQTS) include torsades de pointes (TdP) and/or 2° atrioventricular block (AVB), 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 LQTS fetal arrhythmias were reviewed. Fetal echocardiograms, neonatal ECG, and genetic testing were evaluated. We studied 43 subjects exhibiting fetal LQTS arrhythmias: TdP ± 2° AVB (Group 1, n=7), isolated 2° AVB (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 while 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 wks (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 QTc (mean±SE) of Group 1 (664.7±24.9) was longer than neonatal QTc 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 which, along with QTc duration, may risk stratify perinatal management.

Third Trimester Fetal Heart Rate Predicts Phenotype and Mutation Burden in the Type 1 Long QT Syndrome

“…Regarding phenotype, our data reveal that the mean third trimester intrauterine heart rates of LQT1 fetuses correlate with neonatal heart rate, as well as show association with postnatal cardiac phenotype (QTc and arrhythmia). Importantly, although sinus bradycardia is often described as a rather benign manifestation, with a favorable outcome when treated with β-blockers, [13][14][15]25 it is evident from the present study that isolated sinus bradycardia may also be the presenting symptom of a most severe form of LQTS (ie, double mutation carriage), Figure 6. Mean third trimester heart rates, stratified by specific genotype, and phenotype indicated by marker shapes (minus sign, no symptoms; ×, arrhythmia symptoms), related to different cutoffs (horizontal lines) representing obstetric standard for bradycardia (<110 beats per minute), reduced fetal heart rate (110-120 beats per minute), and the discussed cut-off for long-QT syndrome (LQTS) suspicion (≤133 beats per minute, ie, mean noncarrier heart rate −2 SD).…”

“…15 In a later study on the same cohort, 21/32 fetal cases presenting with isolated sinus bradycardia (defined as fetal heart rate less than the third percentile for gestational age and absence of atrioventricular block or ventricular tachycardia) were reported to be of LQT1 genotype. 13 In this present study including 110 mutation carriers from 2 LQT1 founder populations, fetal heart rate manifestations were clearly genotype dependent, ranging from mild in single mutation carriers to pronounced in double mutation carriers. Even within the single-mutations group, carriers of the p.R518X nonsense mutation (associated with a 50% KCNQ1 function-loss in vitro 23 ) presented with a tendency toward milder heart rate reduction and QTc prolongation than carriers of the dominant negative p.Y111C mutation (associated with >75% KCNQ1 function-loss in vitro 24 ).…”

“…However, as fetal manifestations in LQTS have typically been described in cases presenting with fetal arrhythmia, it has not been established whether fetal heart rate in LQTS correlates with genotype per se. To date, the combined data on fetal heart rate in genotype ascertained LQTS is based on <50 mutation carriers, [13][14][15] leading to a paucity of genotype-specific data. Moreover, little is known about whether relative bradycardia in utero correlates to postnatal cardiac phenotype in LQTS.…”

“…There was a mean of 9±3 intrauterine heart rate recordings per fetus (range, 1-18) including a mean of 6±3 recordings during the third trimester and onwards (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. When considering all heart rates from week 29 onwards, including heart rates recorded at admission to the delivery ward, pedigree-based association analysis including all founder population cases (n=184) revealed that mean heart rates were lower per added mutation (no mutation, 142±6 beats per minute (n=74); single mutation, 133±8 beats per minute (n=97); double mutations, 111±6 beats per minute (n=13); P<0.0001).…”

“…25 With regards to fetal LQTS, little genotype-specific data have previously been presented, although several studies report intrauterine bradycardia in LQTS fetuses. [13][14][15]25,28,29 In the largest previous study on fetal LQTS (genotype ascertained fetuses: 23 LQT1/6 LQT2/6 LQT3), no genotype-specific hypotheses were tested because of the small sample size, however, the LQT1 subgroup was described as having predominantly sinus rhythm and a mild bradycardia. 15 In a later study on the same cohort, 21/32 fetal cases presenting with isolated sinus bradycardia (defined as fetal heart rate less than the third percentile for gestational age and absence of atrioventricular block or ventricular tachycardia) were reported to be of LQT1 genotype.…”