Patent Ductus Arteriosus and Lung MRI Phenotype in Moderate and Severe Bronchopulmonary Dysplasia-Pulmonary Hypertension.

RATIONALE: A hemodynamically significant patent ductus arteriosus (hsPDA) in premature infants has been associated with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). However, these associations remain incompletely understood. OBJECTIVES: The aim was to assess the association between hsPDA duration with clinical outcomes, PH, and phenotypic differences on lung MRI. METHODS: This retrospective cohort study identified all infants with BPD <32 weeks gestation who also underwent a research lung MRI <48 weeks postmenstrual age (PMA) from 2014-2022. Clinical echocardiograms were reviewed for hsPDA, and categorized into no hsPDA, hsPDA 1-60 days, and hsPDA >60 days. Outcome variables included BPD severity, PH at 36 weeks PMA, PH after 36 weeks PMA in the absence of shunt (PH-PVD), tracheostomy or death, and lung phenotype by MRI via modified Ochiai score, indexed total lung volume (TLVI), and whole lung hyperdensity (WLH). Logistic regression and ANOVA analysis were used. MEASUREMENTS AND MAIN RESULTS: In total, 133 infants born at 26.2 ± 1.9 weeks and 776 ± 276g were reviewed (47 no hsPDA, 44 hsPDA 1-60 days, 42 hsPDA >60 days). hsPDA duration >60 days was associated with BPD severity (p<0.01), PH at 36 weeks PMA (aOR 9.7 [95% CI: 3.3-28.4]), PH-PVD (aOR 6.5 [95% CI: 2.3-18.3]), and tracheostomy or death (aOR 3.0 [95% CI: 1.0-8.8]). Duration of hsPDA > 60 days was associated with higher Ochiai score (p=0.03) and TLVI (p=0.01), but not WLH (p=0.91). CONCLUSIONS: In infants with moderate or severe BPD, prolonged exposure to hsPDA is associated with BPD severity, PH-PVD, and increased parenchymal lung disease by MRI.

Wireless Pulmonary Artery Pressure Monitor Implantation in a Patient with Duchenne Muscular Dystrophy.

Assessing heart failure progression in patients with Duchenne Muscular Dystrophy (DMD) is challenging given the multi-system nature of disease. Herein we describe the first case use of an implantable pulmonary artery pressure monitor and describe the potential clinical utility of this approach in patients with DMD.

Ventricular global function index is associated with clinical outcomes in pediatric pulmonary hypertension.

BACKGROUND: Multiple right ventricular (RV) metrics have prognostic value in pulmonary hypertension (PH). A cardiac magnetic resonance imaging (CMR) derived global ventricular function index (GFI) provided improved prediction of composite adverse outcome (CAO) in adults with atherosclerosis. GFI has not yet been explored in a PH population. We explored the feasibility of GFI as a predictor of CAO in a pediatric PH population. METHODS: Two center retrospective chart review identified pediatric PH patients undergoing CMR from Jan 2005-June 2021. GFI, defined as the ratio of the stroke volume to the sum of mean ventricular cavity and myocardial volume, was calculated for each patient. CAO was defined as death, lung transplant, Potts shunt, or parenteral prostacyclin initiation after CMR. Cox proportional hazards regression was used to estimate associations and assess model performance between CMR parameters and CAO. RESULTS: The cohort comprised 89 patients (54% female, 84% World Health Organization (WHO) Group 1; 70% WHO-FC ≤ 2; and 27% on parenteral prostacyclin). Median age at CMR was 12 years (IQR 8.1-17). Twenty-one (24%) patients experienced CAO during median follow up of 1.5 years. CAO cohort had higher indexed RV volumes (end systolic-145 vs 99 mL/m2, p = 0.003; end diastolic-89 vs 46 mL/m2, p = 0.004) and mass (37 vs 24 gm/m2, p = 0.003), but lower ejection fraction (EF) (42 vs 51%, p < 0.001) and GFI (40 vs 52%, p < 0.001). Higher indexed RV volumes (hazard ratios [HR] 1.01, CI 1.01-1.02), lower RV EF (HR 1.09, CI 1.05-1.12) and lower RV GFI (HR 1.09, CI 1.05-1.11) were associated with increased risk of CAO. In survival analysis, patients with RV GFI < 43% demonstrated decreased event-free survival and increased hazard of CAO compared to those with RV GFI ≥ 43%. In multivariable models, inclusion of GFI provided improved prediction of CAO compared to models incorporating ventricular volumes, mass or EF. CONCLUSIONS: RV GFI was associated with CAO in this cohort, and inclusion in multivariable models had increased predictive value compared to RVEF. GFI uses readily available CMR data without additional post-processing and may provide additional prognostic value in pediatric PH patients beyond traditional CMR markers.

Biomarkers of Pulmonary Hypertension Are Altered in Children with Down Syndrome and Pulmonary Hypertension.

OBJECTIVE: To evaluate the performance of pulmonary hypertension (PH) biomarkers in children with Down syndrome, an independent risk factor for PH, in whom biomarker performance may differ compared with other populations. STUDY DESIGN: Serum endostatin, interleukin (IL)-1 receptor 1 (ST2), galectin-3, N-terminal pro hormone B-natriuretic peptide (NT-proBNP), IL-6, and hepatoma-derived growth factor (HDGF) were measured in subjects with Down syndrome and PH (n = 29), subjects with Down syndrome and resolved PH (n = 13), subjects with Down syndrome without PH (n = 49), and subjects without Down syndrome with World Symposium on Pulmonary Hypertension group I pulmonary arterial hypertension (no Down syndrome PH group; n = 173). Each biomarker was assessed to discriminate PH in Down syndrome. A classification tree was created to distinguish PH from resolved PH and no PH in children with Down syndrome. RESULTS: Endostatin, galectin-3, HDGF, and ST2 were elevated in subjects with Down syndrome regardless of PH status. Not all markers differed between subjects with Down syndrome and PH and subjects with Down syndrome and resolved PH. NT-proBNP and IL-6 levels were similar in the Down syndrome with PH group and the no Down syndrome PH group. A classification tree identified NT-proBNP and galectin-3 as the best markers for sequentially distinguishing PH, resolved PH, and no PH in subjects with Down syndrome. CONCLUSIONS: Proteomic markers are used to improve the diagnosis and prognosis of PH but, as demonstrated here, can be altered in genetically unique populations such as individuals with Down syndrome. This further suggests that clinical biomarkers should be evaluated in unique groups with the development of population-specific nomograms.

Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab.

Overactivated complement is a high-risk feature in hematopoietic stem cell transplant (HSCT) recipients with transplant-associated thrombotic microangiopathy (TA-TMA), and untreated patients have dismal outcomes. We present our experience with 64 pediatric HSCT recipients who had high-risk TA-TMA (hrTA-TMA) and multiorgan injury treated with the complement blocker eculizumab. We demonstrate significant improvement to 66% in 1-year post-HSCT survival in treated patients from our previously reported untreated cohort with same hrTA-TMA features that had 1-year post-HSCT survival of 16.7%. Responding patients benefited from a brief but intensive course of eculizumab using pharmacokinetic/pharmacodynamic-guided dosing, requiring a median of 11 doses of eculizumab (interquartile range [IQR] 7-20). Treatment was discontinued because TA-TMA resolved at a median of 66 days (IQR 41-110). Subjects with higher complement activation measured by elevated blood sC5b-9 at the start of treatment were less likely to respond (odds ratio, 0.15; P = .0014) and required more doses of eculizumab (r = 0.43; P = .0004). Patients with intestinal bleeding had the fastest eculizumab clearance, required the highest number of eculizumab doses (20 vs 9; P = .0015), and had lower 1-year survival (44% vs 78%; P = .01). Over 70% of survivors had proteinuria on long-term follow-up. The best glomerular filtration rate (GFR) recovery in survivors was a median 20% lower (IQR, 7.3%-40.3%) than their pre-HSCT GFR. In summary, complement blockade with eculizumab is an effective therapeutic strategy for hrTA-TMA, but some patients with severe disease lacked a complete response, prompting us to propose early intervention and search for additional targetable endothelial injury pathways.

Transcatheter pulmonary valve-in-valve implantation within the expandable Inspiris Resilia® bioprosthetic valve.

Transcatheter pulmonary valve implantation (TPVI) is a common intervention for patients with repaired congenital heart disease. A key issue relates to the presence of an appropriately sized implantation zone for the transcatheter valve. We report the first case, to our knowledge, of TPVI within the newly engineered Inspiris Resilia® bioprosthetic valve, intentionally designed with a balloon-expandable valve ring (a.k.a. VFit zone) for prospective valve implantation.

Bronchopulmonary dysplasia from chest radiographs to magnetic resonance imaging and computed tomography: adding value.

Bronchopulmonary dysplasia (BPD) is a common long-term complication of preterm birth. The chest radiograph appearance and survivability have evolved since the first description of BPD in 1967 because of improved ventilation and clinical strategies and the introduction of surfactant in the early 1990s. Contemporary imaging care is evolving with the recognition that comorbidities of tracheobronchomalacia and pulmonary hypertension have a great influence on outcomes and can be noninvasively evaluated with CT and MRI techniques, which provide a detailed evaluation of the lungs, trachea and to a lesser degree the heart. However, echocardiography remains the primary modality to evaluate and screen for pulmonary hypertension. This review is intended to highlight the important findings that chest radiograph, CT and MRI can contribute to precision diagnosis, phenotyping and prognosis resulting in optimal management and therapeutics.

Impact of mechanical circulatory support on pediatric heart transplant candidates with elevated pulmonary vascular resistance.

With the new era of increasing use of mechanical circulatory support (MCS) in children, seemingly more patients with elevated pulmonary vascular resistance (PVR) are having positive outcomes. The purpose of this study was to define the effect of MCS on pediatric patients listed for heart transplant with an elevated PVR. The United Network for Organ Sharing (UNOS) database was used to identify patients aged 0-18 at the time of listing for heart transplant between 2010 and 2019 who had PVR documented (n = 2081). Patients were divided into MCS (LVAD, RVAD, BiVAD, and TAH) and No MCS groups, then divided by PVR (PVR) at the time of listing: <3, 3-6, and >6 Wood units (WU). MCS was used in 20% overall (n = 426); 57% of those with PVR <3, 27% with PVR 3-6, and 16% with PVR >6. MCS, PVR <3 patients had a higher chance of positive waitlist outcome than all No MCS groups (vs. PVR <3, P = .049; vs. PVR 3-6, P = .004; vs. PVR >6, P < .001). MCS, PVR 3-6 patients had a higher chance of positive waitlist outcome than all No MCS groups (vs. PVR <3, P = .048; vs. PVR 3-6, P = .009; vs. PVR >6, P < .001). MCS, PVR >6 patients had a higher chance of positive waitlist outcome than No MCS, PVR >6 patients (P = .012). Within the No MCS group, patients with a PVR >6 had a higher incidence of negative waitlist outcome compared to PVR <3 (17% vs. 10%, P = .002); this was not the case in the MCS group (5% vs. 6%, P = .693). More patients in the MCS group were ventilator dependent (15% vs. 9%, P < .001) at the time of listing and less likely to have a functional status >50% (43% vs. 73%, P < .001). No significant differences in post-transplant survival were found in pairwise comparisons of MCS and No MCS PVR subgroups. Patients supported with MCS had a significantly higher chance of a positive waitlist outcome than those without such support regardless of PVR status. This was most pronounced with a PVR greater than 6 WU. MCS compared to No MCS patients had better waitlist survival and equivalent post-transplant survival. MCS patients, despite being more ill, had better overall survival regardless of PVR.

Prognostic Value of Change in Cardiac Index After Prostacyclin Initiation in Pediatric Pulmonary Hypertension.

Invasive hemodynamic assessment remains the gold standard for the diagnosis of pediatric pulmonary hypertension and for longitudinal assessment of response to therapy. This analysis sought to describe the changes in hemodynamic variables after initiation of prostacyclin therapy and determine which changes bear predictive power of adverse clinical outcomes. A retrospective chart review of established patients at Cincinnati Children's Hospital with pulmonary arterial hypertension (PAH) who required prostacyclin therapy between 2004 and 2018 was performed. The baseline hemodynamic parameters at diagnosis as well as change in those parameters between initial catheterization and post-prostacyclin initiation catheterization were independent variables. Cox proportional hazard regression and recursive partitioning analysis were used to characterize which hemodynamic factors predicted the composite adverse outcome (CAO) defined as death, lung transplantation, or reverse Pott's shunt surgery. During the study period, 29 patients met inclusion criteria in which there were 7 CAOs: 4 deaths, 3 lung transplants, and 2 reverse Pott's shunts. Median time between catheterizations was 86 days and between the initiation of prostacyclin therapy and the second catheterization was 54 days. Cox regression revealed that only baseline pulmonary artery pressure (> 51 mmHg) and a failure to increase cardiac index illustrated statistically significant hazard for occurrence of the CAO (p < 0.01). These criteria significantly dichotomized the population in a Kaplan-Meier analysis into likelihoods of experiencing the CAO. While controlling for other hemodynamic variables, the absence of augmentation of cardiac index after the initiation of prostacyclin therapy is a valuable prognostic indicator of adverse PAH outcomes in pediatrics.

Cost-Utility of Sildenafil for Persistent Pulmonary Hypertension of the Newborn.

OBJECTIVE: While advanced therapies for severe persistent pulmonary hypertension of the newborn (PPHN) such as inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation (ECMO) are standard treatments in high-income countries, these therapies are often unavailable in resource-limited settings such as middle-income countries. However, there are small clinical trials illustrating the efficacy of sildenafil at reducing mortality in PPHN. This analysis sought to determine the cost-utility of enteral sildenafil for the treatment of severe PPHN. STUDY DESIGN: A Markov-state transition model was constructed for the two clinical approaches to compare costs, clinical outcomes, and quality of life: (1) "conventional," (2) "sildenafil." The impact of sildenafil was modeled as a relative risk modifier of the conventional strategy's mortality risk. Transitional probabilities, costs, and utility metrics were extracted from the literature. Sensitivity analyses for each model input as well as 100-patient Monte Carlo simulations were used to test the durability of the model conclusion. RESULTS: The sildenafil strategy was cost-effective for upper but not lower middle-income countries with an incremental cost-effectiveness ratio of $2,339 per quality-adjusted life year. This conclusion was durable across a wide-range of model assumptions; the sildenafil strategy only failed to meet criteria for cost-effectiveness when sildenafil therapy had a mortality relative risk efficacy of >0.89, if life expectancy in that country is <40 years, or if the lifetime forecasted costs of a survivor's life was quite high. CONCLUSION: Enteral sildenafil is a cost-effective intervention for severe PPHN for upper middle-income countries where ECMO and iNO are not available. KEY POINTS: · PPHN is a common life-threatening condition in newborns.. · Sildenafil improves survival of PPHN.. · Sildenafil is cost-effective for upper-middle income countries..

Elevated Interleukin-6 Levels Predict Clinical Worsening in Pediatric Pulmonary Arterial Hypertension.

OBJECTIVE: To assess whether circulating interleukin-6 (IL-6) is associated with measures of disease severity and clinical worsening in pediatric pulmonary arterial hypertension (PAH). STUDY DESIGN: IL-6 was measured by enzyme-linked immunosorbent assay in serum samples from a cross-sectional cohort from the National Heart, Lung, and Blood Institute Pulmonary Arterial Hypertension Biobank (n = 175) and a longitudinal cohort from Children's Hospital Colorado (CHC) (n = 61). Associations between IL-6, disease severity, and outcomes were studied with regression and Kaplan-Meier analysis. RESULTS: In analyses adjusted for age and sex, each log-unit greater IL-6 was significantly associated in the Pulmonary Arterial Hypertension Biobank cohort with greater pulmonary vascular resistance indices, lower odds of having idiopathic PAH or treatment with prostacyclin, and greater odds of having PAH associated with a repaired congenital shunt. In the CHC cohort, each log-unit greater IL-6 was significantly associated with greater mean pulmonary arterial pressure over time. Kaplan-Meier analysis in the CHC cohort revealed that IL-6 was significantly associated with clinical worsening (a composite score of mortality, transplant, or palliative surgery) (P = .037). CONCLUSIONS: IL-6 was significantly associated with worse hemodynamics at baseline and over time and may be associated with clinical worsening. IL-6 may provide a less-invasive method for disease monitoring and prognosis in pediatric PAH as well as a potential therapeutic target.

Pediatric pulmonary hypertension: insulin-like growth factor-binding protein 2 is a novel marker associated with disease severity and survival.

BACKGROUND: Insulin-like growth factors (IGFs), and their binding proteins (IGFBPs), play a significant role in cardiovascular function and may influence the pathobiology of PAH. We determined the diagnostic and prognostic value of IGF1 and IGFBP2 in pediatric PAH. METHODS: Serum was analyzed by ELISA for IGF1 and IGFBP2 in pediatric PAH subjects from the NHLBI PAH Biobank (PAHB, n = 175) and a cohort of asthmatic subjects (n = 46, age 0-21 years) as a chronic pediatric pulmonary disease control. Biomarkers were analyzed with demographic and clinical variables for PAH severity. RESULTS: Serum IGF1 was significantly lower in PAH compared to controls, while IGFBP2 was elevated in PAH subjects compared to controls. In the PAHB, IGF1 was negatively associated with mPAP and PVR, while IGFBP2 was positively associated with PVR and negatively associated with cardiac output and 6-min walk distance. Higher IGFBP2 levels were associated with use of prostacyclin therapy. IGFBP2 was associated with death, transplant, or palliative shunt with a Cox proportional hazard ratio of 8.8 (p < 0.001) but not IGF1 (p = 0.13). CONCLUSIONS: Circulating IGFBP2 is a novel marker for pediatric PAH, which is associated with worse functional status, and survival. IGF axis dysregulation may be an important mechanistic target in pediatric pulmonary arterial hypertension. IMPACT: Pediatric pulmonary hypertension is a severe disease, with poorly understood pathobiology. There are few studies looking at the pathobiology of pulmonary hypertension only in children. The IGF axis is dysregulated in pediatric pulmonary arterial hypertension. IGF axis dysregulation, with increased IGFBP2, is associated with worse clinical outcomes in pediatric pulmonary artery hypertension. IGF axis dysregulation gives new insight into the disease process and may be a mechanistic or therapeutic target.

Pharmacokinetics of Oral Treprostinil in Children With Pulmonary Arterial Hypertension.

As part of a clinical trial, this study examined the pharmacokinetics (PK) of oral treprostinil (TRE) in children with pulmonary arterial hypertension. The trial consisted of the following 3 cohorts: transition from parenteral (cohort 1) or inhaled (cohort 2) TRE, or de novo addition (cohort 3). Oral TRE was dosed 3 times daily. PK samples were obtained before an oral TRE dose, and at 2, 4, 6, and 8 hours thereafter. The PK parameters were calculated using noncompartmental analysis. Thirty-two children (n = 10 in cohorts 1 and 2, n = 12 in cohort 3) were enrolled; the median age was 12 years (range 7-17 years), and the median weight was 42.2 kg (range 19.3-78 kg). The median oral TRE dose for all subjects was 3.8 mg (5.9, 3.5, and 4.0 mg for cohorts 1, 2, and 3, respectively). The TRE concentration versus time profile demonstrated a peak concentration at a median of 3.8 hours with wide variability. In cohort 1, oral dosing led to higher peak (5.9 ng/mL) and lower trough (1 ng/mL) concentrations than parenteral (peak 5.4 ng/mL and trough 4.2 ng/mL), but a lower mean concentration (3.61 vs. 4.46 ng/mL), likely due to variable metabolism and noncomparable dosing. Both the area under the curve and average concentration were linearly correlated with oral TRE dose and dose normalized to body weight, but not with weight or age alone. In pediatric patients, an increased oral TRE dose or dose frequency may be required to minimize PK variability and achieve greater correlation with parenteral dosing.

Cardiovascular magnetic resonance imaging derived septal curvature in neonates with bronchopulmonary dysplasia associated pulmonary hypertension.

BACKGROUND: Bronchopulmonary dysplasia (BPD) associated with pulmonary hypertension (PH) is a significant source of morbidity and mortality in premature infants. Recent advances have allowed the use of cardiovascular magnetic resonance (CMR) in the assessment of respiratory and cardiac disease in infants with BPD. In adults and older pediatric patients, decreased CMR interventricular septal curvature correlates with increased mean pulmonary artery pressure and pulmonary vascular resistance. The current study sought to determine the relationship of CMR derived septal curvature in neonates with BPD and BPD-PH with a need for PH therapy. METHODS: Forty moderate or severe BPD and 12 mild BPD or control infants were imaged without contrast between 38 and 47 weeks post-menstrual age on a neonatal-sized, neonatal intensive care unit-sited 1.5 T CMR scanner. CMR indices including eccentricity index (CMR-EI) and septal curvature were measured and compared to BPD severity and clinical outcomes including hospital length of stay (LOS), duration of respiratory support, respiratory support level at discharge and PH therapy. RESULTS: CMR-EI was directly associated and septal curvature was inversely associated with BPD severity. In a univariate analysis, CMR-EI and septal curvature were associated with increased hospital LOS, duration of respiratory support, respiratory support at hospital discharge, and need for PH therapy. In multivariable analysis CMR-EI was associated with hospital LOS and duration of respiratory support and septal curvature was associated with respiratory support at hospital discharge. Septal curvature was the only clinical or CMR variable associated with need for PH therapy (R2 = 0.66, p = 0.0014) in multivariable analysis demonstrating improved discrimination beyond CMR-EI. CONCLUSIONS: CMR derived septal curvature correlates significantly with clinical outcomes including hospital LOS, duration of respiratory support, respiratory support level at hospital discharge, and PH therapy in neonates with BPD and BPD-PH. Further, CMR derived septal curvature demonstrated improved discrimination of need for PH therapy and respiratory support at discharge compared to clinical variables and other CMR indices, supporting septal curvature as a non-invasive marker of PH in this population with potential to guide management strategies.

Pulmonary venous Doppler patterns and midterm outcomes in fetuses with left-sided obstructive lesions and restrictive atrial septum.

OBJECTIVE: To compare length of stay of the initial neonatal hospitalization and mortality across multiple stages of surgical palliation for infants with left-sided obstructive lesions and severely restrictive or intact atrial septum (I/RAS). METHODS: Retrospective cohort study of patients prenatally diagnosed with left-sided obstructive lesions and I/RAS, defined by fetal pulmonary venous Dopplers. RESULTS: We identified 76 fetal patients with 59 live born intending to pursue intervention. Those with I/RAS had longer durations of mechanical ventilation (P = .031) but no difference in intensive care unit or total length of stay. Survival to discharge from neonatal hospitalization was 41.7% in the I/RAS group and 80.7% in the unrestrictive group (P = .001). There was a higher proportion of deaths between stage 1 and stage 2 in the I/RAS group - 5/9 (55.6%) vs 9/50 (18%) in the unrestrictive group (P = .027). Beyond stage 2 palliation there was trend toward a difference in overall mortality (66.7% in I/RAS vs 35.7% in unrestrictive, P = .05) but no statistically significant difference in transplant-free survival (33.3% in I/RAS vs 53.5% in unrestrictive, P = .11). CONCLUSION: The survival disadvantage conferred by prenatally diagnosed severe atrial septal restriction is most pronounced in the neonatal and early infancy period, with no detectable difference in late midterm transplant-free survival in our cohort.

Team-based approach to identify cardiac toxicity in critically ill hematopoietic stem cell transplant recipients.

INTRODUCTION: We observed pulmonary hypertension (PH), pericardial effusions, and left ventricular systolic dysfunction (LVSD) in multiple critically ill hematopoietic stem cell transplant (HSCT) recipients. We implemented routine structured echocardiography screening for HSCT recipients admitted to the pediatric intensive care unit (PICU) using a standardized multidisciplinary process. METHODS: HSCT recipients admitted to the PICU with respiratory distress, hypoxia, shock, and complications related to transplant-associated thrombotic microangiopathy were screened on admission and every 1-2 weeks thereafter. Echocardiography findings requiring intervention and/or further screening included elevated right ventricular pressure, LVSD, and moderate to large pericardial effusions. All echocardiograms were compared to the patient's routine pretransplant echocardiogram. RESULTS: Seventy HSCT recipients required echocardiography screening over a 3-year period. Echo abnormalities requiring intervention and/or further screening were found in 35 (50%) patients. Twenty-four (34%) patients were noted to have elevated right ventricular pressure; 14 (20%) were at risk for PH, while 10 (14%) had PH. All patients with PH were treated with pulmonary vasodilators. LVSD was noted in 22 (31%) patients; 15/22 (68%) received inotropic support. Moderate to large pericardial effusions were present in nine (13%) patients, with six needing pericardial drain placement. DISCUSSION: Echocardiographic abnormalities are common in critically ill HSCT recipients. Utilization of echocardiogram screening may allow for early detection and timely intervention for cardiac complications in this high-risk cohort.

Variable Eculizumab Clearance Requires Pharmacodynamic Monitoring to Optimize Therapy for Thrombotic Microangiopathy after Hematopoietic Stem Cell Transplantation.

Thrombotic microangiopathy (TMA) after hematopoietic stem cell transplantation (HSCT) associated with terminal complement activation, as measured by elevated plasma terminal complement (sC5b-9) concentrations, has a very high mortality. The complement inhibitor eculizumab may be a therapeutic option for HSCT-associated TMA. We examined the pharmacokinetics and pharmacodynamics (PK/PD) of eculizumab in children and young adult HSCT recipients with TMA and activated complement to determine drug dosing requirements for future efficacy trials. We analyzed prospectively collected laboratory samples and clinical data from 18 HSCT recipients with high-risk TMA presenting with complement activation who were treated with eculizumab. We measured eculizumab serum concentrations, total hemolytic complement activity, and plasma sC5b-9 concentrations. Population PK/PD analyses correlated eculizumab concentrations with complement blockade and clinical response and determined interindividual differences in PK parameters. We also compared transplant survival in patients treated with eculizumab (n = 18) with patients with the same high-risk TMA features who did not receive any targeted therapy during a separate prospective observational study (n = 11). In the PK analysis, we found significant interpatient variability in eculizumab clearance, ranging from 16 to 237 mL/hr/70 kg in the induction phase. The degree of complement activation measured by sC5b-9 concentrations at the start of therapy, in addition to actual body weight, was a significant determinant of eculizumab clearance and disease response. Sixty-one percent of treated patients had complete resolution of TMA and were able to safely discontinue eculizumab without disease recurrence. Overall survival was significantly higher in treated subjects compared with untreated patients (56% versus 9%, P = .003). Complement blocking therapy is associated with improved survival in HSCT patients with high-risk TMA who historically have dismal outcomes, but eculizumab pharmacokinetics in HSCT recipients differ significantly from reports in other diseases like atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria. Our eculizumab dosing algorithm, including pr-treatment plasma sC5b-9 concentrations, patient's actual body weight, and the first eculizumab dose (mg), accurately determined eculizumab concentration-time profiles for HSCT recipients with high-risk TMA. This algorithm may guide eculizumab treatment and ensure that future efficacy studies use the most clinically appropriate and cost-efficient dosing schedules.

Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder.

An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including lncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific lncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides lncRNA genes, also a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. We suggest that lung-transcribed 16q24.1 lncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development.

Changes in Ventricular Geometry Predict Severity of Right Ventricular Hypertension.

Changes in ventricular geometry are often seen in patients with right ventricular hypertension secondary to pulmonary hypertension (PH). Progressive systolic bowing of the inter-ventricular septum occurs with increasing right ventricular pressure (RVp) and can be quantified with the left ventricular end-systolic eccentricity index (LVEI). Only limited data exist in children to evaluate the relationship between the LVEI and invasive RVp. We sought to assess the correlation between the LVEI and an invasively measured peak systolic RVp to aortic pressure (pAo) ratio. Medical records of patients undergoing echocardiography within 30 days of right and left heart catheterization for evaluation of PH between February 2009 and March 2014 were retrospectively reviewed. Forty-six studies in 29 subjects (median age 3.8 years, 46 % female), with a median time from echocardiogram to catheterization of -1.0 days, were included for analysis. The mean LVEI was 1.6 ± 0.5, and mean RVp/pAo ratio was 0.68 ± 0.26. There was a significant positive correlation (r = 0.76, p < 0.001) between LVEI and RVp/pAo ratio. ROC analysis demonstrated an area under the curve = 0.91 for prediction of RVp/pAo >0.50 by the LVEI. An LVEI >1.48 had a sensitivity of 76 % and specificity of 100 % in predicting RVp/pAo >0.50, while an LVEI >1.24 had a sensitivity of 88 % and specificity of 83 %. Echocardiographically derived LVEI is strongly correlated with invasively determined RVp/pAo ratio. In combination with other noninvasive measures of RVp, LVEI may help minimize the need for invasive patient evaluation.