Effect of In utero Non-steroidal anti-inflammatory drug therapy for severe ebstein anomaly or tricuspid valve dysplasia (NSAID therapy for fetal ebstein anomaly)

Abstract: Ebstein anomaly (EA) and tricuspid valve dysplasia (TVD) are rare congenital malformations associated with nearly 50% mortality when diagnosed in utero. The diseases often produce severe tricuspid regurgitation (TR) in the fetus and in some cases, pulmonary regurgitation (PR) and circular shunting ensue. Since the ductus arteriosus (DA) plays a critical role in the circular shunt and may be constricted by transplacental non-steroidal anti-inflammatory drugs (NSAIDs), we sought to assess the effect of NSAIDs on fetuses with EA/TVD. We reviewed mothers of singleton fetuses with EA/TVD and PR, indicative of circular shunting, who were offered NSAIDs at multiple centers from 2010-2018. Initial dosing consisted of indomethacin, followed by ibuprofen in most cases. Twenty-one patients at 10 centers were offered therapy 4 at a median gestational age (GA) of 30.0 weeks (range: 20.9-34.9). Most (15/21=71%) mothers received NSAIDs, and 12/15 (80%) achieved DA constriction after a median of 2.0 days (1.0-6.0). All fetuses with DA constriction had improved PR; 92% had improved Doppler patterns. Median GA at pregnancy outcome was 36.1 weeks (30.7-39.0) in fetuses with DA constriction vs. 33 weeks (23.3-37.3) in fetuses who did not receive NSAIDs or achieve DA constriction (p=0.040). Eleven of 12 patients (92%) with DA constriction survived to live-birth, whereas 4/9 patients (44%) who did not receive NSAIDs or achieve DA constriction survived (p=0.046). In conclusion, our findings demonstrate the proof of concept that NSAIDs mitigate circular shunt physiology by DA constriction and improve PR among fetuses with severe EA/TVD. Although the early results are encouraging, further investigation is necessary to determine safety and efficacy.

Effect of In Utero Non-Steroidal Anti-Inflammatory Drug Therapy for Severe Ebstein Anomaly or Tricuspid Valve Dysplasia (NSAID Therapy for Fetal Ebstein anomaly).

Ebstein anomaly (EA) and tricuspid valve dysplasia (TVD) are rare congenital malformations associated with nearly 50% mortality when diagnosed in utero. The diseases often produce severe tricuspid regurgitation (TR) in the fetus and in some cases, pulmonary regurgitation (PR) and circular shunting ensue. Since the ductus arteriosus (DA) plays a critical role in the circular shunt and may be constricted by transplacental nonsteroidal anti-inflammatory drugs (NSAIDs), we sought to assess the effect of NSAIDs on fetuses with EA/TVD. We reviewed mothers of singleton fetuses with EA/TVD and PR, indicative of circular shunting, who were offered NSAIDs at multiple centers from 2010 to 2018. Initial dosing consisted of indomethacin, followed by ibuprofen in most cases. Twenty-one patients at 10 centers were offered therapy at a median gestational age (GA) of 30.0 weeks (range: 20.9 to 34.9). Most (15/21 = 71%) mothers received NSAIDs, and 12 of 15 (80%) achieved DA constriction after a median of 2.0 days (1.0 to 6.0). All fetuses with DA constriction had improved PR; 92% had improved Doppler patterns. Median GA at pregnancy outcome (live-birth or fetal demise) was 36.1 weeks (30.7 to 39.0) in fetuses with DA constriction versus 33 weeks (23.3 to 37.3) in fetuses who did not receive NSAIDs or achieve DA constriction (p = 0.040). Eleven of 12 patients (92%) with DA constriction survived to live-birth, whereas 4 of 9 patients (44%) who did not receive NSAIDs or achieve DA constriction survived (p = 0.046). In conclusion, our findings demonstrate the proof of concept that NSAIDs mitigate circular shunt physiology by DA constriction and improve PR among fetuses with severe EA/TVD. Although the early results are encouraging, further investigation is necessary to determine safety and efficacy.

Measures of dyssynchrony in the left ventricle of healthy children and young patients with dilated cardiomyopathy.

BACKGROUND: Doppler tissue imaging may help identify children with dyssynchrony who could benefit from resynchronization therapy. However, few studies have quantified dyssynchrony measures in children; no study has investigated the relationship among age, heart rate, and dyssynchrony measures in children; and no study has quantified cross-correlation delay in children. The aim of this study was to test the hypotheses that measures of left ventricular dyssynchrony would correlate with age, primarily because of the correlation between heart rate and age, and that children with cardiomyopathy would have left ventricular dyssynchrony. METHODS: Sixty healthy children and 11 children with dilated cardiomyopathy were prospectively enrolled. Seven dyssynchrony measures were quantified: septal-to-lateral delay, peak velocity difference, the standard deviations of times to peak in 12 segments in systole and diastole, and cross-correlation delay in systole, diastole, and the whole cycle. RESULTS: The seven dyssynchrony measures were either not correlated with age or only weakly correlated with age after correcting for heart rate using Bazett's formula. Septal-to-lateral delay, peak velocity difference, and the standard deviation of times to peak in 12 segments in systole showed dyssynchrony in 57% to 85% of normal controls, compared with 20% for cross-correlation delay in the whole cycle and 3% for the standard deviation of times to peak in 12 segments in diastole. Cross-correlation delay in systole, cross-correlation delay in diastole, cross-correlation delay in the whole cycle, and the standard deviation of times to peak in 12 segments in diastole were elevated in children with dilated cardiomyopathy compared with controls. CONCLUSIONS: Echocardiographic dyssynchrony measures should be corrected for heart rate using Bazett's formula in children. Time-to-peak Doppler tissue imaging dyssynchrony measures classify many healthy children as having abnormalities with the timing of left ventricular contraction, which suggests that the methodology is not accurate in children. In preliminary studies, cross-correlation dyssynchrony measures show elevated systolic and diastolic measures of dyssynchrony in children with dilated cardiomyopathy compared with controls, which deserves further investigation to help identify children who may benefit from resynchronization therapy.

A juvenile murine heart failure model of pressure overload.

Persistent pressure overload can cause cardiac hypertrophy and progressive heart failure (HF). The authors developed a pressure-overload HF model of juvenile mice to study the cardiac response to pressure overload that may be applicable to clinical processes in children. Severe thoracic aortic banding (sTAB) was performed using a 28-gauge needle for 40 juvenile (age, 3 weeks) and 47 adult (age, 6 weeks) C57BL/6 male mice. To monitor the structural and functional changes, M-mode echocardiography was performed for conscious mice that had undergone sTAB and sham operation. Cardiac hypertrophy, dilation, and HF occurred in both juvenile and adult mice after sTAB. Compared with adults, juvenile HF is characterized by greater impairment of ventricular contractility and less hypertrophy. In addition, juvenile mice had significantly higher rates of survival than adult mice during the early postoperative weeks. Consistent with clinical HF seen in children, juvenile banded mice demonstrated a lower growth rate than either adult banded mice or juvenile control mice that had sham operations. The authors first developed a juvenile murine model of pressure-overload HF. Learning the unique characteristics of pressure-overload HF in juveniles should aid in understanding age-specific pathologic changes for HF development in children.