Kids Mod PAH trial: A multicenter trial comparing mono- versus duo-therapy for initial treatment of pediatric pulmonary hypertension.

Pulmonary hypertension (PH) is a significant health problem that contributes to high morbidity and mortality in diverse cardiac, pulmonary, and systemic diseases in children. Evidence-based advances in PH care have been challenged by a paucity of quality endpoints for assessing clinical course and the lack of robust clinical trial data to guide pharmacologic therapies in children. While the landmark adult AMBITION trial demonstrated the benefit of up-front combination PH therapy with ambrisentan and tadalafil, it remains unknown whether upfront combination therapy leads to more rapid and sustained clinical benefits in children with various categories of PH. In this article, we describe the inception of the Kids Mod PAH Trial, a multicenter Phase III trial, to address whether upfront combination therapy (sildenafil and bosentan vs. sildenafil alone) improves PH outcomes in children, recognizing that marked differences between the etiology and therapeutic response between adults and children exist. The primary endpoint of this study is WHO functional class (FC) 12 months after initiation of study drug therapy. In addition to the primary outcome, secondary endpoints are being assessed, including a composite measure of time to clinical worsening, WHO FC at 24 months, echocardiographic assessment of PH and quantitative assessment of right ventricular function, 6-min walk distance, and NT-proBNP levels. Exploratory endpoints include selected biomarkers, actigraphy, and assessments of quality of life. This study is designed to pave the way for additional clinical trials by establishing a robust infrastructure through the development of a PPHNet Clinical Trials Network.

Measurement of Physical Activity by Actigraphy in Infants and Young Children with Pulmonary Arterial Hypertension.

OBJECTIVE: To evaluate the feasibility, tolerability, and adherence with wearable actigraphy devices among infants and children with pulmonary arterial hypertension (PAH). STUDY DESIGN: This multicenter, prospective, observational study included children ages 0-6 years with and without PAH. Participants wore the ActiGraph wGT3X-BT on the hip and FitBit Inspire on the wrist during waking hours for 14 days. Steps, vector magnitude counts per minute, activity intensity, heart rate, and heart rate variability were compared between groups. RESULTS: Forty-seven participants (18 PAH, 29 control) were enrolled from 10 North American sites. PAH patients were mostly functional class II (n = 16, 89%) and treated with oral medications at the time of enrollment. The number of wear days was not significantly different between the groups (ActiGraph: 10 [95% CI: 5.5, 12.2] in PAH vs 8 [4, 12] in control, P = .20; FitBit 13 [10, 13.8] in PAH vs 12 [8, 14] in control, P = .87). Complete data were obtained in 81% of eligible ActiGraph participants and 72% of FitBit participants. PAH participants demonstrated fewer steps, lower vector magnitude counts per minute, more sedentary activity, and less intense physical activity at all levels compared with control participants. No statistically significant differences in heart rate variability were demonstrated between the 2 groups. CONCLUSIONS: Measurement of physical activity and other end points using wearable actigraphy devices was feasible in young children with PAH. Larger studies should determine associations between physical activity and disease severity in young patients with PAH to identify relevant end points for pediatric clinical trials.

Impact of Socioeconomic Status, Race and Ethnicity, and Geography on Prenatal Detection of Hypoplastic Left Heart Syndrome and Transposition of the Great Arteries.

BACKGROUND: Prenatal detection (PND) has benefits for infants with hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA), but associations between sociodemographic and geographic factors with PND have not been sufficiently explored. This study evaluated whether socioeconomic quartile (SEQ), public insurance, race and ethnicity, rural residence, and distance of residence (distance and driving time from a cardiac surgical center) are associated with the PND or timing of PND, with a secondary aim to analyze differences between the United States and Canada. METHODS: In this retrospective cohort study, fetuses and infants <2 months of age with HLHS or TGA admitted between 2012 and 2016 to participating Fetal Heart Society Research Collaborative institutions in the United States and Canada were included. SEQ, rural residence, and distance of residence were derived using maternal census tract from the maternal address at first visit. Subjects were assigned a SEQ z score using the neighborhood summary score or Canadian Chan index and separated into quartiles. Insurance type and self-reported race and ethnicity were obtained from medical charts. We evaluated associations among SEQ, insurance type, race and ethnicity, rural residence, and distance of residence with PND of HLHS and TGA (aggregate and individually) using bivariate analysis with adjusted associations for confounding variables and cluster analysis for centers. RESULTS: Data on 1862 subjects (HLHS: n=1171, 92% PND; TGA: n=691, 58% PND) were submitted by 21 centers (19 in the United States). In the United States, lower SEQ was associated with lower PND in HLHS and TGA, with the strongest association in the lower SEQ of pregnancies with fetal TGA (quartile 1, 0.78 [95% CI, 0.64-0.85], quartile 2, 0.77 [95% CI, 0.64-0.93], quartile 3, 0.83 [95% CI, 0.69-1.00], quartile 4, reference). Hispanic ethnicity (relative risk, 0.85 [95% CI, 0.72-0.99]) and rural residence (relative risk, 0.78 [95% CI, 0.64-0.95]) were also associated with lower PND in TGA. Lower SEQ was associated with later PND overall; in the United States, rural residence and public insurance were also associated with later PND. CONCLUSIONS: We demonstrate that lower SEQ, Hispanic ethnicity, and rural residence are associated with decreased PND for TGA, with lower SEQ also being associated with decreased PND for HLHS. Future work to increase PND should be considered in these specific populations.

Risk Factors for Mortality and Circulatory Outcome Among Neonates Prenatally Diagnosed With Ebstein Anomaly or Tricuspid Valve Dysplasia: A Multicenter Study.

Background In a recent multicenter study of perinatal outcome in fetuses with Ebstein anomaly or tricuspid valve dysplasia, we found that one third of live-born patients died before hospital discharge. We sought to further describe postnatal management strategies and to define risk factors for neonatal mortality and circulatory outcome at discharge. Methods and Results This 23-center, retrospective study from 2005 to 2011 included 243 fetuses with Ebstein anomaly or tricuspid valve dysplasia. Among live-born patients, clinical and echocardiographic factors were evaluated for association with neonatal mortality and palliated versus biventricular circulation at discharge. Of 176 live-born patients, 7 received comfort care, 11 died <24 hours after birth, and 4 had insufficient data. Among 154 remaining patients, 38 (25%) did not survive to discharge. Nearly half (46%) underwent intervention. Mortality differed by procedure; no deaths occurred in patients who underwent right ventricular exclusion. At discharge, 56% of the cohort had a biventricular circulation (13% following intervention) and 19% were palliated. Lower tricuspid regurgitation jet velocity (odds ratio [OR], 2.3 [1.1-5.0], 95% CI, per m/s; P=0.025) and lack of antegrade flow across the pulmonary valve (OR, 4.5 [1.3-14.2]; P=0.015) were associated with neonatal mortality by multivariable logistic regression. These variables, along with smaller pulmonary valve dimension, were also associated with a palliated outcome. Conclusions Among neonates with Ebstein anomaly or tricuspid valve dysplasia diagnosed in utero, a variety of management strategies were used across centers, with poor outcomes overall. High-risk patients with low tricuspid regurgitation jet velocity and no antegrade pulmonary blood flow should be considered for right ventricular exclusion to optimize their chance of survival.

Correction: Endostatin and ST2 are predictors of pulmonary hypertension disease course in infants.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Endostatin and ST2 are predictors of pulmonary hypertension disease course in infants.

INTRODUCTION: Pulmonary hypertension (PH) is a common comorbidity of cardiopulmonary disease. Endostatin, an inhibitor of angiogenesis, is elevated in neonates with lung disease. ST2 is a heart failure biomarker correlated with PH in adults. We hypothesized that these biomarkers may be useful in diagnosing PH and categorizing its severity in infants. METHODS: Endostatin, ST2, and NT-proBNP plasma concentrations from 26 infants with PH and 21 control infants without PH were correlated with echocardiographic and clinical features using regression models over time. RESULTS: Endostatin, ST2, and NT-proBNP concentrations were elevated in PH participants versus controls (p < 0.0001). Endostatin was associated with right ventricular dysfunction (p = 0.014), septal flattening (p = 0.047), and pericardial effusion (p < 0.0001). ST2 concentrations predicted right to left patent ductus arteriosus flow (p = 0.009). NT-proBNP was not associated with PH features. CONCLUSIONS: Endostatin and ST2 concentrations were associated with echocardiographic markers of worse PH in infants and may be better predictors than existing clinical standards.

Home Monitoring for Fetal Heart Rhythm During Anti-Ro Pregnancies.

BACKGROUND: Fetal atrioventricular block (AVB) occurs in 2% to 4% of anti-Ro antibody-positive pregnancies and can develop in <24 h. Only rarely has standard fetal heart rate surveillance detected AVB in time for effective treatment. OBJECTIVES: Outcome of anti-Ro pregnancies was surveilled with twice-daily home fetal heart rate and rhythm monitoring (FHRM) and surveillance echocardiography. METHODS: Anti-Ro pregnant women were recruited from 16 international centers in a prospective observational study. Between 18 and 26 weeks' gestation, mothers checked FHRM twice daily with a commercially available Doppler monitor and underwent weekly or biweekly surveillance fetal echocardiograms. If FHRM was abnormal, a diagnostic echocardiogram was performed. Cardiac cycle length and atrioventricular interval were measured, and cardiac function was assessed on all echocardiograms. After 26 weeks, home FHRM and echocardiograms were discontinued, and mothers were monitored during routine obstetrical visits. Postnatal electrocardiograms were performed. RESULTS: Most mothers (273 of 315, 87%) completed the monitoring protocol, generating 1,752 fetal echocardiograms. Abnormal FHRM was detected in 21 mothers (6.7%) who sought medical attention >12 h (n = 7), 3 to 12 h (n = 9), or <3 h (n = 5) after abnormal FHRM. Eighteen fetuses had benign rhythms, and 3 had second- or third-degree AVB. Treatment of second-degree AVB <12 h after abnormal FHRM restored sinus rhythm. Four fetuses had first-degree AVB diagnosed by echocardiography; none progressed to second-degree AVB. No AVB was missed by home FHRM or developed after FHRM. CONCLUSIONS: Home FHRM confirms the rapid progression of normal rhythm to AVB and can define a window of time for successful therapy. (Prospective Maternal Surveillance of SSA [Sjögren Syndrome A] Positive Pregnancies Using a Hand-held Fetal Heart Rate Monitor; NCT02920346).

Transthoracic Echocardiographic Assessment of Coronary Flow in the Diagnosis of Right Ventricular-Dependent Coronary Circulation in Pulmonary Atresia with Intact Ventricular Septum.

Right ventricular-dependent coronary circulation (RVDCC) is associated with pulmonary atresia with intact ventricular septum and is defined by two or more epicardial coronary arteries with atresia or severe stenosis resulting in the dependency of coronary supply by retrograde flow. The hypothesis of this study is that coronary Doppler flow patterns on echocardiography can be used to distinguish patients with RVDCC. Between 2007 and 2016, we reviewed 16 patients with pulmonary atresia or critical pulmonary stenosis. Patients were divided into two groups, those with RVDCC (determined by angiography or pathology evaluation) and those without. Echocardiographic evaluation of the coronary arteries included 2-dimensional measurements and pulse wave Doppler flow pattern in 3 epicardial coronary arteries. Velocity-time integral (VTI) and maximal velocity (Vmax) were measured and compared between the two groups. Three coronary flow patterns were demonstrated: (1) all antegrade flow, (2) antegrade to retrograde VTI flow ratio > 1, and (3) antegrade to retrograde VTI flow ratio ≤ 1. Of the 7 patients with RVDCC, 6 (86%) had evidence of flow pattern 3 in ≥ 2 of the 3 coronary arteries in contrast to 0 (0%) of the non-RVDCC patients (p = 0.001). Higher retrograde Vmax was associated with RVDCC (p < 0.001) and coronary artery dilatation with Z-score ≥ + 3 was also associated with RVDCC (p = 0.02). Echocardiographic evaluation of the coronaries can be useful in identifying RVDCC. More retrograde flow in at least two coronary arteries is strongly suggestive of RVDCC. Dilatation of the coronary arteries is also supportive evidence.

Closure of a secundum atrial septal defect in two infants with chronic lung disease using the Gore HELEX Septal Occluder.

Children with a secundum atrial septal defect are usually asymptomatic and are referred for elective closure after 3-4 years of age; however, in premature infants with chronic lung disease, bronchopulmonary dysplasia, or pulmonary hypertension, increased pulmonary blood flow secondary to a left-to-right atrial shunt, may exacerbate their condition. Closure of the atrial septal defect in these patients can result in significant clinical improvement. We report the cases of two premature infants with chronic lung disease, who underwent atrial septal defect closure with the Gore HELEX Septal Occluder and discuss the technical aspects of using the device in these patients and their clinical outcomes.

Echocardiographic evaluation of coronary arteries in congenital heart disease.

Among populations of patients with the congenital heart disease, there is considerable diversity in the anatomy of the coronary arteries. Understanding these anatomical differences is vitally important in directing interventions and surgical repair. In this report, the authors describe the echocardiographic evaluation of the variants of coronary artery anatomy in the following lesions: transposition of the great arteries, congenitally corrected transposition of the great arteries, double-inlet left ventricle, common arterial trunk, tetralogy of Fallot, and double-outlet right ventricle.

Surveillance of fetal arrhythmias in the outpatient setting: current limitations and call for action.

Surveillance of fetal arrhythmias in the outpatient setting remains limited by lack of monitoring modalities. Despite technological advances made in the field of obstetrics, existing devices are not currently suitable to monitor fetal arrhythmias. In this report, the author describes the current and developing fetal heart rate monitoring technologies including the recent introduction of hand-held Doppler monitors for outpatient surveillance of fetal arrhythmias.

Outcomes and Predictors of Perinatal Mortality in Fetuses With Ebstein Anomaly or Tricuspid Valve Dysplasia in the Current Era: A Multicenter Study.

BACKGROUND: Ebstein anomaly and tricuspid valve dysplasia are rare congenital tricuspid valve malformations associated with high perinatal mortality. The literature consists of small, single-center case series spanning several decades. We performed a multicenter study to assess the outcomes and factors associated with mortality after fetal diagnosis in the current era. METHODS AND RESULTS: Fetuses diagnosed with Ebstein anomaly and tricuspid valve dysplasia from 2005 to 2011 were included from 23 centers. The primary outcome was perinatal mortality, defined as fetal demise or death before neonatal discharge. Of 243 fetuses diagnosed at a mean gestational age of 27±6 weeks, there were 11 lost to follow-up (5%), 15 terminations (6%), and 41 demises (17%). In the live-born cohort of 176 live-born patients, 56 (32%) died before discharge, yielding an overall perinatal mortality of 45%. Independent predictors of mortality at the time of diagnosis were gestational age <32 weeks (odds ratio, 8.6; 95% confidence interval, 3.5-21.0; P<0.001), tricuspid valve annulus diameter z-score (odds ratio, 1.3; 95% confidence interval, 1.1-1.5; P<0.001), pulmonary regurgitation (odds ratio, 2.9; 95% confidence interval, 1.4-6.2; P<0.001), and a pericardial effusion (odds ratio, 2.5; 95% confidence interval, 1.1-6.0; P=0.04). Nonsurvivors were more likely to have pulmonary regurgitation at any gestational age (61% versus 34%; P<0.001), and lower gestational age and weight at birth (35 versus 37 weeks; 2.5 versus 3.0 kg; both P<0.001). CONCLUSION: In this large, contemporary series of fetuses with Ebstein anomaly and tricuspid valve dysplasia, perinatal mortality remained high. Fetuses with pulmonary regurgitation, indicating circular shunt physiology, are a high-risk cohort and may benefit from more innovative therapeutic approaches to improve survival.

Impact of prenatal haemodynamic and functional abnormalities in Ebstein's anomaly on survival.

Predicting outcomes of foetuses with Ebstein's anomaly and tricuspid valve dysplasia continues to be challenging. Limited data exist on the prognostic significance of prenatal haemodynamic and functional parameters in this population. Our aim was to investigate the prognostic significance of haemodynamic and ventricular functional parameters in addition to associated morphometric parameters in patients with Ebstein's anomaly. We reviewed medical records of foetuses with Ebstein's anomaly and tricuspid valve dysplasia at All Children's Hospital Johns Hopkins Medicine and Johns Hopkins University between 2005 and 2012. The main outcome was survival past 30 days from birth; participants who died in utero or <30 days after birth were considered non-survivors. There were 13 survivors and seven non-survivors. We found that participants with abnormal right ventricular function predicted by low tricuspid regurgitation velocity (<2.3 m/second) (p=0.012) and low estimated right ventricular pressure (<24 mmHg) (p=0.029), a low (<7) cardiovascular profile score (p=0.029) and high (>0.53) cardiothoracic ratio (p=0.008) at the first foetal echocardiogram were less likely to survive. In addition, participants with a fossa ovalis/atrial septal length ratio <0.36 at the last foetal echocardiogram (p=0.051) were more likely to die, albeit of borderline statistical significance. Low tricuspid regurgitation velocity and low right ventricular estimated pressure, or a low cardiovascular profile score could be potential prognostic factors for Ebstein's anomaly and tricuspid valve dysplasia. However, future larger prospective studies are needed to confirm these initial findings.

Foetal echocardiography of transposition of the great arteries and common arterial trunk.

Advances in foetal echocardiography allow detection of conotruncal anomalies such as transposition of the great arteries and common arterial trunk. Early detection of these anomalies is important for appropriate delivery planning, family counselling, and management. This manuscript will review the anatomic considerations, differential diagnosis, and foetal echocardiographic features of each of these malformations and review the importance of prenatal diagnosis and family counselling.

Long-term management of patients with hypoplastic left heart syndrome: the diagnostic approach at All Children's Hospital.

Improved survival in children with hypoplastic left heart syndrome has created a sub-population of children and young adults who are living with functionally univentricular physiology. Routine surveillance with comprehensive screening for structural cardiac disease, functional cardiac disease, arrhythmias, thromboembolic disease, and associated dysfunction of end organs is important. Future directives will better define the plans of care for routine surveillance in patients with hypoplastic left heart syndrome.

Hybrid procedure for obstructive neonatal left ventricular tumors.

We report the use of the hybrid procedure (bilateral pulmonary artery banding, ductal stenting followed by balloon atrial septostomy) in the first week of life for the treatment of two neonates with large left ventricular fibromas resulting in univentricular physiology. At 6 months of age, second-stage palliation was accomplished and the 2 patients are growing well with normal developmental milestones and no atrial or ventricular ectopy at 30 months. Hybrid strategy offers a less invasive, initial intervention and the options of typical second-stage univentricular palliation, conversion to biventricular physiology in cases of tumor regression, planned surgical resection, or transplantation.

Overt expression of AP-1 reduces alpha myosin heavy chain expression and contributes to heart failure from chronic volume overload.

Reduced expression of alpha-MHC plays a significant role in cardiac contractile dysfunction from hemodynamic overload. Previously, Pur proteins and YY1 have been shown to play a role in alpha-MHC repression during heart failure induced by pressure overload and by spontaneous hypertension, respectively. This was not observed in volume-overload-induced heart failure, suggesting additional regulatory mechanisms for alpha-MHC repression. The present study was performed to identify volume overload responsive transcription factors involved in alpha-MHC gene regulation. DNA binding activity of several transcription factors was evaluated in a functionally characterized rat model of heart failure induced by aorto-caval shunt. After 10 weeks of shunt, severe LV dilatation and reduced LV function were accompanied by increased expression of ANF and beta-MHC, and decreased expression of alpha-MHC. This was associated with dramatic (10-fold) activation of AP-1 together with increased expression of c-fos and c-jun. AP-1 activation was not observed following 4 weeks of shunt when cardiac function was preserved. In cultured cardiomyocytes, induction of AP-1 by PMA attenuated alpha-MHC mRNA by 60%. Transient transfection assays mapped PMA responsive sequence to -582 to -588 bp of alpha-MHC promoter. Deletion or mutation of these nucleotides had minimal effect on basal promoter activity but played a dominant role in PMA-mediated repression of alpha-MHC promoter activity. Over-expression of c-fos and c-jun in cardiomyocytes inhibited alpha-MHC promoter activity in a concentration dependent manner. Data suggest a repressive role of AP-1 in alpha-MHC expression and its possible involvement in the transition from compensatory hypertrophy to heart failure in chronic volume overload.

Edad de presentaciòn de menarquia y su relaciòn con el estado nutricional en la poblaciòn rural de Tisaleo Tungurahua

La menarquia es el inicio de la menstruaciòn causado por un incremento gradual en la secreciòn de hormona gonadotròfica, se conoce la incidencia de factores ètnico-geogràficos, nutricionales y hàbitos de vida como determinantes de la apariciòn de la menarquia. En este estudio se analizò la edad de presentaciòn de menarquia en un grupo de adolescentes de 10 a 18 años (n=87) en el que se obtuvo positividad en 22 personas de acuerdo a la edad en que fue encuestado. La media fue de 13 años con un rango entre los 11 a los 15 años. El mayor porcentaje se encontrò a los 14 años (45.45 por ciento) y en orden de frecuencia 13,12,11 y 15. Tambièn se corroboran los datos de peso y talla encontràndose que los casos que presentan menarquia siempre se encuentran por encima de la media de estos datos obtenidos en la muestra total...