Arrhythmia phenotype during fetal life suggests long-QT syndrome genotype: risk stratification of perinatal long-QT syndrome

Abstract

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.

Keywords: arrhythmias, cardiac; atrioventricular block; fetal; long-QT syndrome; sinus bradycardia torsade de pointes.

Figure 1

Illustrative cardiac rhythms of Group 1 and Group 2 subjects. (A) Simultaneous atrial and ventricular M-Mode of established ‘TdP’ in a fetus with R1623Q mutation at 32 weeks of gestation. Although M-mode cannot definitively diagnose TdP, AV dissociation and the irregular tachycardia (arrows, top tracing) at a cycle length varying from 200-300 ms is highly suggestive of TdP. The atrial (bottom tracing, ‘a’) rhythm is regular (arrows) and the cycle length is 540 ms. (B) Ventricular (V) m-mode at initiation (red arrow) of ‘TdP’ in the same fetus. Based on the ‘V-V#x2019; interval of about 1000 ms, rhythm preceding the initiation of TdP is probably 2° AV block (C) Simultaneous ventricular and atrial M-Mode of established TdP in a fetus with KCNH2 mutation and at 34 weeks of gestation. The atrial (‘a’) cycle length is regular at a rate of 120 bpm (cycle length 500 ms) and the ventricular rhythm is irregular at a rate of 212 bpm (cycle length 284 ms, arrows, bottom tracing). (D). Simultaneous atrial and ventricular M-Mode of sinus bradycardia and intermittent 2° AV block in a 34 week fetus with KCNH2 mutation. Atrial contractions (“a”, bottom arrows) are regular at a cycle length of 517 ms. The AV relationship is initially 1:1, but there is ventricular silence between the 4^th and 5^th and 5^th and 6^th ventricular contractions while atrial contractions continue at the original rate. This identifies 2° AV block. (E) Pulsed Aortic (Ao) and mitral valve Doppler tracing of the same fetus during a period of sustained 2° AV block. The mitral “a” waves (white arrows) occur at a regular rate while only every other aortic outflow waveform is conducted. Together, these findings indentify 2° AV block.

Figure 1

Illustrative cardiac rhythms of Group 1 and Group 2 subjects. (A) Simultaneous atrial and ventricular M-Mode of established ‘TdP’ in a fetus with R1623Q mutation at 32 weeks of gestation. Although M-mode cannot definitively diagnose TdP, AV dissociation and the irregular tachycardia (arrows, top tracing) at a cycle length varying from 200-300 ms is highly suggestive of TdP. The atrial (bottom tracing, ‘a’) rhythm is regular (arrows) and the cycle length is 540 ms. (B) Ventricular (V) m-mode at initiation (red arrow) of ‘TdP’ in the same fetus. Based on the ‘V-V#x2019; interval of about 1000 ms, rhythm preceding the initiation of TdP is probably 2° AV block (C) Simultaneous ventricular and atrial M-Mode of established TdP in a fetus with KCNH2 mutation and at 34 weeks of gestation. The atrial (‘a’) cycle length is regular at a rate of 120 bpm (cycle length 500 ms) and the ventricular rhythm is irregular at a rate of 212 bpm (cycle length 284 ms, arrows, bottom tracing). (D). Simultaneous atrial and ventricular M-Mode of sinus bradycardia and intermittent 2° AV block in a 34 week fetus with KCNH2 mutation. Atrial contractions (“a”, bottom arrows) are regular at a cycle length of 517 ms. The AV relationship is initially 1:1, but there is ventricular silence between the 4^th and 5^th and 5^th and 6^th ventricular contractions while atrial contractions continue at the original rate. This identifies 2° AV block. (E) Pulsed Aortic (Ao) and mitral valve Doppler tracing of the same fetus during a period of sustained 2° AV block. The mitral “a” waves (white arrows) occur at a regular rate while only every other aortic outflow waveform is conducted. Together, these findings indentify 2° AV block.

Figure 1

Illustrative cardiac rhythms of Group 1 and Group 2 subjects. (A) Simultaneous atrial and ventricular M-Mode of established ‘TdP’ in a fetus with R1623Q mutation at 32 weeks of gestation. Although M-mode cannot definitively diagnose TdP, AV dissociation and the irregular tachycardia (arrows, top tracing) at a cycle length varying from 200-300 ms is highly suggestive of TdP. The atrial (bottom tracing, ‘a’) rhythm is regular (arrows) and the cycle length is 540 ms. (B) Ventricular (V) m-mode at initiation (red arrow) of ‘TdP’ in the same fetus. Based on the ‘V-V#x2019; interval of about 1000 ms, rhythm preceding the initiation of TdP is probably 2° AV block (C) Simultaneous ventricular and atrial M-Mode of established TdP in a fetus with KCNH2 mutation and at 34 weeks of gestation. The atrial (‘a’) cycle length is regular at a rate of 120 bpm (cycle length 500 ms) and the ventricular rhythm is irregular at a rate of 212 bpm (cycle length 284 ms, arrows, bottom tracing). (D). Simultaneous atrial and ventricular M-Mode of sinus bradycardia and intermittent 2° AV block in a 34 week fetus with KCNH2 mutation. Atrial contractions (“a”, bottom arrows) are regular at a cycle length of 517 ms. The AV relationship is initially 1:1, but there is ventricular silence between the 4^th and 5^th and 5^th and 6^th ventricular contractions while atrial contractions continue at the original rate. This identifies 2° AV block. (E) Pulsed Aortic (Ao) and mitral valve Doppler tracing of the same fetus during a period of sustained 2° AV block. The mitral “a” waves (white arrows) occur at a regular rate while only every other aortic outflow waveform is conducted. Together, these findings indentify 2° AV block.

Figure 1

Illustrative cardiac rhythms of Group 1 and Group 2 subjects. (A) Simultaneous atrial and ventricular M-Mode of established ‘TdP’ in a fetus with R1623Q mutation at 32 weeks of gestation. Although M-mode cannot definitively diagnose TdP, AV dissociation and the irregular tachycardia (arrows, top tracing) at a cycle length varying from 200-300 ms is highly suggestive of TdP. The atrial (bottom tracing, ‘a’) rhythm is regular (arrows) and the cycle length is 540 ms. (B) Ventricular (V) m-mode at initiation (red arrow) of ‘TdP’ in the same fetus. Based on the ‘V-V#x2019; interval of about 1000 ms, rhythm preceding the initiation of TdP is probably 2° AV block (C) Simultaneous ventricular and atrial M-Mode of established TdP in a fetus with KCNH2 mutation and at 34 weeks of gestation. The atrial (‘a’) cycle length is regular at a rate of 120 bpm (cycle length 500 ms) and the ventricular rhythm is irregular at a rate of 212 bpm (cycle length 284 ms, arrows, bottom tracing). (D). Simultaneous atrial and ventricular M-Mode of sinus bradycardia and intermittent 2° AV block in a 34 week fetus with KCNH2 mutation. Atrial contractions (“a”, bottom arrows) are regular at a cycle length of 517 ms. The AV relationship is initially 1:1, but there is ventricular silence between the 4^th and 5^th and 5^th and 6^th ventricular contractions while atrial contractions continue at the original rate. This identifies 2° AV block. (E) Pulsed Aortic (Ao) and mitral valve Doppler tracing of the same fetus during a period of sustained 2° AV block. The mitral “a” waves (white arrows) occur at a regular rate while only every other aortic outflow waveform is conducted. Together, these findings indentify 2° AV block.

Figure 1

Illustrative cardiac rhythms of Group 1 and Group 2 subjects. (A) Simultaneous atrial and ventricular M-Mode of established ‘TdP’ in a fetus with R1623Q mutation at 32 weeks of gestation. Although M-mode cannot definitively diagnose TdP, AV dissociation and the irregular tachycardia (arrows, top tracing) at a cycle length varying from 200-300 ms is highly suggestive of TdP. The atrial (bottom tracing, ‘a’) rhythm is regular (arrows) and the cycle length is 540 ms. (B) Ventricular (V) m-mode at initiation (red arrow) of ‘TdP’ in the same fetus. Based on the ‘V-V#x2019; interval of about 1000 ms, rhythm preceding the initiation of TdP is probably 2° AV block (C) Simultaneous ventricular and atrial M-Mode of established TdP in a fetus with KCNH2 mutation and at 34 weeks of gestation. The atrial (‘a’) cycle length is regular at a rate of 120 bpm (cycle length 500 ms) and the ventricular rhythm is irregular at a rate of 212 bpm (cycle length 284 ms, arrows, bottom tracing). (D). Simultaneous atrial and ventricular M-Mode of sinus bradycardia and intermittent 2° AV block in a 34 week fetus with KCNH2 mutation. Atrial contractions (“a”, bottom arrows) are regular at a cycle length of 517 ms. The AV relationship is initially 1:1, but there is ventricular silence between the 4^th and 5^th and 5^th and 6^th ventricular contractions while atrial contractions continue at the original rate. This identifies 2° AV block. (E) Pulsed Aortic (Ao) and mitral valve Doppler tracing of the same fetus during a period of sustained 2° AV block. The mitral “a” waves (white arrows) occur at a regular rate while only every other aortic outflow waveform is conducted. Together, these findings indentify 2° AV block.