Serial tissue Doppler imaging in the evaluation of bronchopulmonary dysplasia-associated pulmonary hypertension among extremely preterm infants: a prospective observational study.

Objectives: To evaluate serial tissue Doppler cardiac imaging (TDI) in the evolution of bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) among extremely preterm infants. Design: Prospective observational study. Setting: Single-center, tertiary-level neonatal intensive care unit. Patients: Infant born <28 weeks gestation. Main outcome measures: Utility of TDI in the early diagnosis and prediction of BPD-PH and optimal timing for screening of BPD-PH. Results: A total of 79 infants were included. Of them, 17 (23%) had BPD-PH. The mean gestational age was 25.9 ± 1.1 weeks, and mean birth weight was 830 ± 174 g. The BPD-PH group had a high incidence of hemodynamically significant patent ductus arteriosus (83% vs. 56%, p < 0.018), longer oxygen days (96.16 ± 68.09 vs. 59.35 ± 52.1, p < 0.008), and prolonged hospital stay (133.8 ± 45.9 vs. 106.5 ± 37.9 days, p < 0.005). The left ventricular eccentricity index (0.99 ± 0.1 vs. 1.1 ± 0.7, p < 0.01) and the ratio of acceleration time to right ventricular ejection time showed a statistically significant trend from 33 weeks (0.24 ± 0.05 vs. 0.28 ± 0.05, p < 0.05). At 33 weeks, the BPD-PH group showed prolonged isovolumetric contraction time (27.84 ± 5.5 vs. 22.77 ± 4, p < 0.001), prolonged isovolumetric relaxation time (40.3 ± 7.1 vs. 34.9 ± 5.3, p < 0.003), and abnormal myocardial performance index (0.39 ± 0.05 vs. 0.32 ± 0.03, p < 0.001). These differences persisted at 36 weeks after conceptional gestational age. Conclusions: TDI parameters are sensitive in the early evolution of BPD-PH. Diagnostic accuracy can be increased by combining the TDI parameters with conventional echocardiographic parameters. BPD-PH can be recognizable as early as 33-34 weeks of gestation.

Successful pharmacological management of a child with compound heterozygous familial hypercholesterolemia and review of the recent literature.

Severe familial hypercholesterolemia (SFH) is characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) and severe early-onset cardiovascular disease if left untreated. We report on the decade-long therapeutic journey of a 15-year-old boy with SFH due to a severe compound heterozygous genotype. He presented at the age of 5 years with widespread xanthomas and LDL-C of 17.4 mmol/L. He was diagnosed with SFH, initially treated with colestyramine that was subsequently combined with simvastatin. At the age of 12 years, he was diagnosed to have supravalvular aortic stenosis and ezetimibe/atorvastatin was introduced in place of colestyramine/simvastatin. At the age of 14 years, he received triple therapy with evolocumab, initially at the recommended dose of 420 mg monthly and then reduced to 140 mg biweekly. Currently at the age of 15 years, he is on atorvastatin 40 mg ON, ezetimibe 10 mg OM, and evolocumab 140 mg biweekly, achieving LDL-C levels of 2.4 mmol/L. Genetic testing identified compound heterozygous mutations in the LDL receptor genes [c.(940 + 1_941-1) (1845 + 1_1846-1)dup] and exon 12, nucleotide c.1747 C > T, amino acid p.(His583Tyr). Medical management without lipoprotein apheresis can achieve target LDL-C in children with SFH. Our patient, who developed supravalvular aortic stenosis at the age of 12 years, needed early aggressive treatment when SFH guidelines and newer drugs for young children were unavailable. Our patient demonstrated that 140 mg biweekly of evolocumab has the same cholesterol-lowering effect as the recommended 420 mg monthly dose.

Readiness for Hospital Discharge, Stress, and Coping in Mothers of Children Undergoing Cardiac Surgeries: A Single-Center Prospective Study.

OBJECTIVES: To examine the relationship between stress, coping, and discharge readiness in mothers of children undergoing congenital heart surgeries. DESIGN: Quantitative descriptive study at three time points: pre surgery (time point I), day of hospital discharge (time point II) and 2 weeks following discharge (time point III). SETTING: Tertiary care pediatric hospital in Singapore. PARTICIPANTS: One hundred mothers whose children had undergone congenital heart surgeries. MEASUREMENTS AND MAIN RESULTS: Data collection included self-reported questionnaires of the Pediatric Inventory for Parents and the Coping Health Inventory for Parents across three time points. Readiness for Hospital Discharge Scale was administered at hospital discharge (time point II). The utilization of health services and support was reported at post discharge (time point III). One-hundred mothers participated in this study between May 2016 and July 2017. Their mean age was 35.8 years (SD = 7.0), and the mean age of their children was 3.7 years (SD = 4.6). There was significant reduction in mean stress difficulty (Pediatric Inventory for Parents) of mothers (F = 4.58; p = 0.013) from time point I to III. No significant changes were found in the overall mean coping score (Coping Health Inventory for Parents) of mothers across time. The mean overall score for the readiness for discharge (Readiness for Hospital Discharge Scale) of mothers at hospital discharge was 207.34 (SD = 29.22). Coping through family integration subscale and communication stress predicted discharge readiness of mothers (adjusted R = 0.11; p = 0.034). Mothers who reported higher overall stress (Pediatric Inventory for Parents) 2 weeks post discharge were more likely to call a friend or family member, visit the emergency department, or have their child readmitted to hospital following hospital discharge. CONCLUSIONS: We identified coping by family integration and communication-related stress as predictors of readiness for discharge. Strategies targeted at communication and family integration for discharge preparation may improve caregivers' readiness for hospital discharge.

The Impact of Pre-operative Nutritional Status on Outcomes Following Congenital Heart Surgery.

Aims and Objectives: Malnutrition is common in children with congenital heart disease and may contribute to adverse outcomes. This study evaluates the impact of pre-operative nutritional status on outcomes after congenital heart surgery. Methods: We conducted a retrospective cohort study enrolling children under 10 years old who underwent congenital heart surgery at a tertiary children's hospital from 2012 to 2016. Patients who had patent ductus arteriosus ligation only, genetic syndromes, or global developmental delay were excluded. Outcome measures included 30-day mortality, intensive care unit (ICU) length of stay (LOS), hospital LOS, duration of mechanical ventilation, and number of inotropes used post-operatively. We performed univariate/multivariable logistic regression analysis, adjusting for age, cyanotic cardiac lesion, co-morbidity, and Risk Adjustment for Congenital Heart Surgery (RACHS-1) score. Results: Three hundred two children of median age 16.2 [interquartile range (IQR) 3.1, 51.4)] months were included. The most common cardiac lesions were ventricular septal defect (27.8%), atrial septal defect (17.9%), and Tetralogy of Fallot (16.6%). Median weight-for-age z-score (WAZ) was -1.46 (IQR -2.29, -0.61), height-for-age z-score (HAZ) was -0.94 (IQR -2.10, -0.10), and body mass index (BMI)-for-age z-score (BAZ) was -1.11 (IQR -2.19, -0.30). In multivariable analysis, there was an increased risk of 30-day mortality for WAZ ≤-2 vs. WAZ >-2 [adjusted odds ratio (aOR): 4.01, 95% CI: 1.22, 13.13; p = 0.022]. For HAZ ≤-2 vs. HAZ > -2, there was increased risk of hospital LOS ≥ 7 days (aOR: 2.08, 95% CI: 1.12, 3.89; p = 0.021), mechanical ventilation ≥48 h (aOR: 2.63, 95% CI: 1.32, 5.24; p = 0.006) and of requiring ≥3 inotropes post-operatively (aOR: 3.00, 95% CI: 1.37, 6.59; p = 0.006). Conclusion: In children undergoing congenital heart surgery, WAZ ≤ -2 is associated with higher 30-day mortality, while HAZ ≤ -2 is associated with longer durations of hospital LOS and mechanical ventilation, and increased risk of use of 3 or more inotropes post-operatively. Future studies are necessary to develop safe and efficacious peri-operative nutritional interventions, particularly in patients with WAZ and HAZ ≤ -2.

The Impact of Time to Rate Control of Junctional Ectopic Tachycardia After Congenital Heart Surgery.

BACKGROUND: Junctional ectopic tachycardia (JET) after congenital heart disease (CHD) surgery is often self-limiting but is associated with increased risk of morbidity and mortality. Contributing factors and impact of time to achieve rate control of JET are poorly described. METHODS: From January 2010 to June 2015, a retrospective, single-center cohort study was performed of children who developed JET after CHD surgery . We classified the cohort into two groups: patients who achieved rate control of JET in ≤24 hours and in >24 hours. We examined factors associated with time to rate control and compared clinical outcomes (mortality, duration of mechanical ventilation, length of intensive care unit [ICU], and hospital stay) between the two groups. RESULTS: Our cohort included 27 children, with a median age of 3 (interquartile range: 0.7-38] months. The most common CHD lesions were ventricular septal defect (n = 10, 37%), tetralogy of Fallot (n = 7, 25.9%), and transposition of the great arteries (n = 4, 14.8%). In all, 15 (55.6%) and 12 (44.4%) patients achieved rate control of JET in ≤24 hours and >24 hours, respectively. There was a difference in median mechanical ventilation time (97 [21-145) vs 311 [100-676] hours; P = .013) and ICU stay (5.0 [2.0-8.0] vs 15.5 [5.5-32.8] days, P = .023) between the patients who achieved faster rate control than those who didn't. There was no difference in length of hospital stay and mortality between the groups. CONCLUSION: Our study demonstrated that time to achieve rate control of JET was associated with increased duration of mechanical ventilation and ICU stay.

Re-trafficking of hERG reverses long QT syndrome 2 phenotype in human iPS-derived cardiomyocytes.

AIMS: Long QT syndrome 2 (LQTS2) caused by missense mutations in hERG channel is clinically associated with abnormally prolonged ventricular repolarization and sudden cardiac deaths. Modelling monogenic arrhythmogenic diseases using human-induced pluripotent stem cells (hiPSCs) offers unprecedented mechanistic insights into disease pathogenesis. We utilized LQTS2-hiPSC-derived cardiomyocytes (CMs) to elucidate pathological changes and to demonstrate reversal of LQTS2 phenotype in a therapeutic intervention using a pharmacological agent, (N-[N-(N-acetyl-l-leucyl)-l-leucyl]-l-norleucine) (ALLN). METHODS AND RESULTS: We generated LQTS2-specific CMs (A561V missense mutation in KCNH2) from iPSCs using the virus-free reprogramming method. These CMs recapitulate dysfunction of hERG potassium channel with diminished IKr currents, prolonged repolarization durations, and elevated arrhythmogenesis due to reduced membrane localization of glycosylated/mature hERG. Dysregulated expression of folding chaperones and processing proteasomes coupled with sequestered hERG in the endoplasmic reticulum confirmed trafficking-induced disease manifestation. Treatment with ALLN, not only increased membrane localization of mature hERG but also reduced repolarization, increased IKr currents and reduced arrhythmogenic events. Diverged from biophysical interference of hERG channel, our results show that modulation of chaperone proteins could be therapeutic in LQTS2 treatment. CONCLUSION: Our in vitro study shows an alternative approach to rescue diseased LQTS2 phenotype via corrective re-trafficking therapy using a small chemical molecule, such as ALLN. This potentially novel approach may have ramifications in other clinically relevant trafficking disorders.

Late complications following tetralogy of Fallot repair: the need for long-term follow-up.

INTRODUCTION: We report a series of operated tetralogy of Fallot (TOF) patients focusing on complications and outcomes. MATERIALS AND METHODS: Data from TOF patients seen at our centre's adult congenital heart disease clinic was analysed. RESULTS: There were 21 patients: the mean age was 32.2 +/- 12.4 years; the age at first operation was 9.0 +/- 7.9 years; the mean postoperative follow-up duration was 23.5 +/- 12.1 years; and the current New York Heart Association (NYHA) status: I, 82%; II, 4%; III, 14%. Fourteen patients had complete operative notes. All these patients underwent total TOF correction; 2 had staged aortopulmonary shunt with total correction at a mean of 3.2 years later, pulmonary artery patch augmentation in 8 patients and pulmonary valvotomy in 8 patients. Three patients required pulmonary valve homograft replacement for severe pulmonary regurgitation (PR) at 13, 28 and 36 years after the initial corrective operation. CURRENT INVESTIGATIONS: RBBB on ECG (91%), QRS duration 137 +/- 29 ms. Echocardiography showed dilated right ventricular end-diastolic (RVED) diameters (3.2 +/- 0.8 cm); severe PR (67%), residual right ventricular outflow tract obstruction (RVOTO) (42%) and VSD patch leakage (9%). Cardiac magnetic resonance (CMR) (8 patients) showed dilated RVED volumes 252.6 +/- 93.8 mL, indexed RV volume 165.7 +/- 34.8 mL; RV systolic function was preserved in most patients with a RV ejection fraction of 49.5 +/- 5.7%. One patient had atrial tachycardia and another had frequent non-sustained ventricular tachycardia that required radiofrequency ablation. CONCLUSION: Patients with TOF who had full corrective surgery during childhood are now surviving into adulthood. Many challenges arising from complications in the postoperative period remain. It is imperative that adult TOF patients should have regular followup to monitor development and subsequent management of these complications.