Rachel Knight Hopper

All Publications

• Pharmacokinetics of Oral Treprostinil in Children with Pulmonary Arterial Hypertension. Journal of cardiovascular pharmacology Hopper, R. K., Ivy, D. D., Yung, D., Mullen, M. P., Hanna, B. D., Kirkpatrick, E., Hirsch, R., Austin, E. D., Fineman, J., Solum, D., Deng, C. Q., Feinstein, J. A. 2020

  Abstract

  As part of a clinical trial, this study examined the pharmacokinetics (PK) of oral treprostinil in children with pulmonary arterial hypertension (PAH). The trial consisted of 3 cohorts: transition from parenteral (Cohort 1) or inhaled (Cohort 2) treprostinil, or de novo addition (Cohort 3). Oral treprostinil was dosed 3 times daily (TID). PK samples were obtained prior to an oral treprostinil 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; median age was 12 years (range 7 to 17 years) and median weight was 42.2 kg (range 19.3 to 78 kg). Median oral treprostinil dose for all subjects was 3.8 mg (5.9, 3.5, and 4.0 mg for Cohorts 1, 2, and 3, respectively). The treprostinil concentration vs. 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 compared with parenteral (peak 5.4, 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 to oral treprostinil dose and dose normalized to body weight, but not weight or age alone. In pediatric patients, increased oral treprostinil dose or dose frequency may be required to minimize PK variability and achieve greater correlation with parenteral dosing.

  View details for DOI 10.1097/FJC.0000000000000842

  View details for PubMedID 32398473

• Treprostinil improves hemodynamics and symptoms in children with mild pulmonary hypertension awaiting heart transplantation. Pediatric transplantation Hollander, S. A., Ogawa, M. T., Hopper, R. K., Liu, E., Chen, S., Rosenthal, D. N., Feinstein, J. A. 2020: e13742

  Abstract

  Treprostinil, a prostacyclin analog, is a safe and effective therapy for children with PAH; however, the use of this agent in children with mild PVR elevations related to HF, including those with SV congenital heart disease awaiting HT, is understudied. We describe the hemodynamic and symptomatic changes in pediatric patients awaiting HT treated with treprostinil.Single-center retrospective review of all patients was listed for HT who received treprostinil during the listing period. Changes in hemodynamic and functional indices between the baseline catheterization (prior to drug initiation), and prior to HT, and patient outcomes were analyzed.Among 16/17 (94%) who survived to HT, 8 (50%) were female, and 10 (63%) had SV physiology. The median age at drug initiation was 9 (IQR: 1, 14) years. The median duration of therapy prior to HT was 253 (IQR: 148, 504) days. Treprostinil significantly decreased PVR (3.8 vs 3.1 WU, P = .03), while mLA or mPCW pressure did not change (11 vs 13 mm Hg, P = .9). HF symptoms improved in 9/15 (60%) patients without VAD support prior to drug initiation, including 4/10 (40%) who did not receive a VAD any point while awaiting HT.Treprostinil may be used safely in patients with mild PAH awaiting HT, including those with SV disease. PVR falls without substantial increases in mLA/mPCW pressure. HF symptoms improve in some patients.

  View details for DOI 10.1111/petr.13742

  View details for PubMedID 32428328

• Pulmonary lung Doppler signals: normative data in a pediatric population compared with adults JOURNAL OF CLINICAL MONITORING AND COMPUTING Burstein, D. S., Hopper, R. K., McCarthy, E. K., Hall, K., Schatzberger, R., Palti, Y., Feinstein, J. A. 2019; 33 (6): 1055–60

  View details for DOI 10.1007/s10877-019-00258-3

  View details for Web of Science ID 000493607300013

• Inhaled Nitric Oxide Is Associated with Improved Oxygenation in a Subpopulation of Infants with Congenital Diaphragmatic Hernia and Pulmonary Hypertension. The Journal of pediatrics Lawrence, K. M., Monos, S., Adams, S., Herkert, L., Peranteau, W. H., Munson, D. A., Hopper, R. K., Avitabile, C. M., Rintoul, N. E., Hedrick, H. L. 2019

  Abstract

  OBJECTIVES: To determine which patients with congenital diaphragmatic hernia (CDH) and pulmonary hypertension (PH) benefit from inhaled nitric oxide (iNO) treatment by comparing characteristics and outcomes of iNO responders to nonresponders.STUDY DESIGN: We performed a retrospective chart review of infants with CDH treated at our center between 2011 and 2016. In a subset of patients, iNO was initiated for hypoxemia or echocardiographic evidence of extrapulmonary right to left shunting. Initial post-treatment blood gases were reviewed, and patients were classified as responders (increased PaO2 >20mm Hg) or nonresponders. Baseline characteristics, echocardiograms and outcomes were compared between groups with Fisher exact tests and Mann-Whitney t tests, as appropriate.RESULTS: During the study period, 95 of 131 patients with CDH (73%) were treated with iNO. All patients with pretreatment echocardiograms (n=90) had echocardiographic evidence of PH. Thirty-eight (40%) patients met treatment response criteria. Responders had significant improvements in PaO2 (51±3 vs 123±7mm Hg, P < .01), alveolar-arterial gradient (422±30 vs 327±27mm Hg, P < .01), and PaO2 to FiO2 ratio (82±10 vs 199±15mm Hg, P < .01). Nonresponders were more likely to have left ventricular systolic dysfunction (27% vs 8%, P=.03) on echocardiogram. Responders were less likely to require extracorporeal membrane support (50 vs 24%, P=.02).CONCLUSIONS: iNO treatment is associated with improved oxygenation and reduced need for ECMO in a subpopulation of patients with CDH with PH and normal left ventricular systolic function.

  View details for DOI 10.1016/j.jpeds.2019.09.052

  View details for PubMedID 31706636

• Diminished right ventricular function at diagnosis of pulmonary hypertension is associated with mortality in bronchopulmonary dysplasia PULMONARY CIRCULATION Altit, G., Bhombal, S., Feinstein, J., Hopper, R. K., Tacy, T. A. 2019; 9 (3)

  View details for DOI 10.1177/2045894019878598

  View details for Web of Science ID 000490128900001

• Histopathologic and Genetic Features of Alveolar Capillary Dysplasia with Atypical Late Presentation and Prolonged Survival JOURNAL OF PEDIATRICS Edwards, J. J., Murali, C., Pogoriler, J., Frank, D. B., Handler, S. S., Deardorff, M. A., Hopper, R. K. 2019; 210: 214-+

  View details for DOI 10.1016/j.jpeds.2019.01.047

  View details for Web of Science ID 000472497600039

• EXPRESS: Oral Treprostinil in Transition or as Add-on Therapy in Pediatric Pulmonary Arterial Hypertension. Pulmonary circulation Ivy, D. D., Feinstein, J., Yung, D., Mullen, M., Kirkpatrick, E. C., Hirsch, R., Austin, E., Fineman, J., Truong, U., Solum, D., Deng, C. Q., Hopper, R. K. 2019: 2045894019856471

  View details for DOI 10.1177/2045894019856471

  View details for PubMedID 31215336

• Pulmonary lung Doppler signals: normative data in a pediatric population compared with adults. Journal of clinical monitoring and computing Burstein, D. S., Hopper, R. K., McCarthy, E. K., Hall, K., Schatzberger, R., Palti, Y., Feinstein, J. A. 2019

  Abstract

  Lung Doppler signals (LDS) acquired via transthoracic echocardiography is a novel technology previously reported in adults for use in detecting pulmonary hypertension. The aim of this study was to characterize LDS in healthy children to establish normative pediatric LDS data, and compare the pediatric data to the previously published healthy adult LDS. In this prospective, two-center study, LDS were acquired in children without cardiopulmonary disease using a 2MHz transthoracic pulsed Doppler transducer. The data were processed to obtain Doppler velocity patterns corresponding to phases of the cardiac cycle. Signals were analyzed using a parametric Doppler signal-processing package and performance evaluation of the trained classifiers was performed using cross validation method. Pediatric signals were then compared to a retrospective cohort of healthy adults. Eighty-six healthy pediatric subjects (mean age 9.1±5.1years) and 79 healthy adult controls (mean age 59.7±10.7years) were included. The normative LDS velocity profiles were defined for pediatric subjects and then compared to adults; the highest discriminating LDS parameters between healthy children and adults were acceleration of atrial (A) signal contraction (46±18 vs. 90±34; p<0.001), peak systolic (S) signal velocity (10.0±3.5 vs. 11.7±3.5; p<0.001), and ratio of peak diastolic (D)-to-atrial (A) signal velocity (1.4±0.5 vs. 0.4±0.3; p<0.001). The sensitivity and specificity of this LDS based method to discern between healthy children and adult subjects was 98.6% and 97.4%, respectively. Subgroup analyses between younger (2-8years) and older (9-18years) pediatric LDS yielded significant differences between atrial (A) acceleration (43.7±33.9 vs. 47.7±42.1; p=0.04) and diastolic (D)-to-atrial (A) signal velocity (1.2±0.5 vs. 1.5±0.5; p=0.01) but not systolic (S) signals (0.14±0.05 vs. 0.14±0.05; p=0.97). In this study, we defined the normal LDS profile for healthy children and have demonstrated differences in LDS between children and adults. Specifically, healthy children had lower atrial contraction power, differences in ventricular compliance and increased chronotropic response. Further studies are warranted to investigate the application of this technology, for example as a tool to aid in the detection of pulmonary hypertension in children.

  View details for PubMedID 30661196

• Death or resolution: the "natural history" of pulmonary hypertension in bronchopulmonary dysplasia. Journal of perinatology : official journal of the California Perinatal Association Altit, G., Bhombal, S., Hopper, R. K., Tacy, T. A., Feinstein, J. 2019

  Abstract

  OBJECTIVES: The primary objective was to describe the early "natural history" of pulmonary hypertension (PH) in the premature population. The secondary objective was to describe factors associated with poor outcomes in the premature population with PH at 36 weeks post-menstrual age (PMA).STUDY DESIGN: Retrospective chart review of patients followed at our institution from 2000 to 2017 with echocardiographic (ECHO) evidence of PH at 36 weeks PMA, and born≤32 weeks estimated gestational age (GA). Cox regression was used for survival analysis.RESULTS: Sixty-one patients with PH (26.5±1.5 weeks at birth) were included. All PH patients had bronchopulmonary dysplasia (BPD), with 89% considered severe; 38% were small for gestational age. Necrotizing enterocolitis requiring surgery was common (25%). Use of post-natal steroids (HR 11.02, p=0.01) and increased severity of PH (HR 1.05, p<0.001) were associated with mortality. Pulmonary vein stenosis (PVS) was documented in 26% of the PH cohort, but not associated with increased mortality. ECHO estimation of pulmonary artery pressure (PAP) was available in 84%. PAP was higher in those who died (sPAP/sBP ratio 1.09±27 vs 0.83±20 %, p=0.0002). At follow-up (mean 250±186 weeks PMA), 72% of the PH cohort was alive. Most survivors (66%) had resolution of their PH on their most recent ECHO; 31% remained on PH therapy.CONCLUSION: PH resolved in most survivors in this study population. Mortality in those with BPD-PH was associated with male sex, post-natal steroid use, and increased severity of PH, but not with PVS.

  View details for PubMedID 30617286

• Subcutaneous and Intravenous Treprostinil Pharmacokinetics in Children With Pulmonary Vascular Disease. Journal of cardiovascular pharmacology Hall, K., Ogawa, M., Sakarovitch, C., Hopper, R. K., Adamson, G. T., Hanna, B., Ivy, D. D., Miller-Reed, K., Yung, D., McCarthy, E., Siehr-Handler, S. L., Feinstein, J. A. 2019; 73 (6): 383–93

  Abstract

  This study evaluated the pharmacokinetics of intravenous (IV) and subcutaneous (SC) treprostinil in pediatric patients with pulmonary vascular disease, and compared them with existing adult data from a similar cohort. Blood samples were collected from pediatric patients receiving steady-state IV or SC treprostinil and were assessed for plasma treprostinil concentration using liquid chromatography and tandem mass spectrometry. Forty participants, 15 receiving IV and 25 receiving SC treprostinil, were included in the analysis. Age ranged from 0.1 to 15.6 years. The median dose of treprostinil was 45.5 ng·kg·min with a range of 8-146 ng·kg·min. There was a linear relationship between treprostinil dose and plasma concentration with an R of 0.57. On average, there were higher blood concentrations per given dose of IV treprostinil compared with those per given dose of SC, but the difference was not significant. Compared with adult data, the slope of the pediatric data was similar, but the y-intercept was significantly lower. Additionally, the concentration per dose ratio was significantly higher in adults compared with children. Pediatric patients have significantly lower average blood concentrations of treprostinil per given dose compared with adults, and higher, but not significantly so, blood concentrations when treprostinil is administered IV as compared with SC administration.

  View details for DOI 10.1097/FJC.0000000000000674

  View details for PubMedID 31162247

• Use of prostaglandin E1 to treat pulmonary hypertension in congenital diaphragmatic hernia. Journal of pediatric surgery Lawrence, K. M., Berger, K., Herkert, L., Franciscovich, C., O'Dea, C. L., Waqar, L. N., Partridge, E., Hanna, B. D., Peranteau, W. H., Avitabile, C. M., Hopper, R. K., Rintoul, N. E., Hedrick, H. L. 2019; 54 (1): 55–59

  Abstract

  Prostaglandin E1 (PGE) has been used to maintain ductus arteriosus patency and unload the suprasystemic right ventricle (RV) in neonates with congenital diaphragmatic hernia (CDH) and severe pulmonary hypertension (PH). Here we evaluate the PH response in neonates with CDH and severe PH treated with PGE.We performed a retrospective chart review of CDH infants treated at our center between 2011 and 2016. In a subset, PGE was initiated for echocardiographic evidence of severe PH, metabolic acidosis, or hypoxemia. To assess PH response, we evaluated laboratory data, including B-type natriuretic peptide (BNP) and echocardiograms before and after PGE treatment. Categorical and continuous data were analyzed with Fisher's exact tests and Mann-Whitney t-tests, respectively.Fifty-seven infants were treated with PGE a mean 17 ± 2 days. BNP levels declined after 1.4 ± 0.2 days of treatment and again after 5.2 ± 0.6 days. After 6 ± 0.8 days of treatment, echocardiographic estimates of severe PH by tricuspid regurgitation jet velocity, ductus arteriosus direction, and ventricular septum position also improved significantly. Treatment was not associated with postductal hypoxemia or systemic hypoperfusion.In patients with CDH and severe PH, PGE is well tolerated and associated with improved BNP and echocardiographic indices of PH, suggesting successful unloading of the RV.Treatment study.Level III.

  View details for PubMedID 30442461

• Patent Ductus Arteriosus and the Effects of Its Late Closure in Preterm Infants with Severe Bronchopulmonary Dysplasia. Neonatology Ansems, S. M., Kirpalani, H., Mercer-Rosa, L., Wang, Y., Hopper, R. K., Fraga, M. V., Jensen, E. A. 2019: 1–8

  Abstract

  The natural history and optimal management of a patent ductus arteriosus (PDA) among infants with established severe bronchopulmonary dysplasia (sBPD) remains uncertain.To describe the characteristics of PDA present at ≥36 weeks' postmenstrual age (PMA) and the effects of late surgical PDA closure in a referral cohort of very preterm infants with sBPD.This retrospective cohort study was performed in a tertiary neonatal intensive care unit. Study infants were born at <32 weeks' gestation between 2010 and 2016, diagnosed with sBPD, and had an echocardiographic PDA at ≥36 weeks' PMA. We reviewed echocardiograms performed closest to 3 time points (≥36 weeks' PMA, hospital discharge, and 1 year of age) and assessed clinical outcomes among infants with versus without late PDA treatment.Among 329 infants with sBPD, 59 had a PDA at ≥36 weeks' PMA. Most PDAs were small (n = 33) and shunted left to right (n = 53). The PDA closed spontaneously prior to discharge in 5 of 21 infants who did not undergo surgical closure and decreased in size in 3. The PDA spontaneously closed by 1 year of age in 6 out of 12 infants with an open duct at discharge. PDA surgery (n = 23) at ≥36 weeks' PMA was not associated with increased risk for the composite outcome of tracheostomy, systemic vasodilator at discharge, or death after adjusting for potential confounders (OR 3.2, 95% CI 0.81-13.0).The majority of conservatively treated late PDAs closed spontaneously or decreased in size.PDA surgery was not associated with severe adverse clinical outcomes.

  View details for DOI 10.1159/000500269

  View details for PubMedID 31269508

• Racial and Ethnic Differences in Pediatric Pulmonary Hypertension: An Analysis of the Pediatric Pulmonary Hypertension Network Registry. The Journal of pediatrics Ong, M. S., Abman, S., Austin, E. D., Feinstein, J. A., Hopper, R. K., Krishnan, U. S., Mullen, M. P., Natter, M. D., Raj, J. U., Rosenzweig, E. B., Mandl, K. D. 2019

  Abstract

  To investigate racial and ethnic differences in pulmonary hypertension subtypes and survival differences in a pediatric population.This was a retrospective analysis of a cohort of patients with pulmonary hypertension (aged ≤18 years) enrolled in the Pediatric Pulmonary Hypertension Network registry between 2014 and 2018, comprising patients at eight Pediatric Centers throughout North America (n = 1417).Among children diagnosed after the neonatal period, pulmonary arterial hypertension was more prevalent among Asians (OR, 1.83; 95% CI, 1.21-2.79; P = .0045), lung disease-associated pulmonary hypertension among blacks (OR, 2.09; 95% CI, 1.48-2.95; P < .0001), idiopathic pulmonary arterial hypertension among whites (OR, 1.58; 95% CI, 1.06-2.41; P = .0289), and pulmonary veno-occlusive disease among Hispanics (OR, 6.11; 95% CI, 1.34-31.3; P = .0184). Among neonates, persistent pulmonary hypertension of the newborn (OR, 4.07; 95% CI, 1.54-10.0; P = .0029) and bronchopulmonary dysplasia (OR, 8.11; 95% CI, 3.28-19.8; P < .0001) were more prevalent among blacks, and congenital diaphragmatic hernia was more prevalent among whites (OR, 2.29; 95% CI, 1.25-4.18; P = .0070). An increased mortality risk was observed among blacks (HR, 1.99; 95% CI, 1.03-3.84; P = .0396), driven primarily by the heightened mortality risk among those with lung disease-associated pulmonary hypertension (HR, 2.84; 95% CI, 1.15-7.04; P = .0241).We found significant racial variability in the prevalence of pulmonary hypertension subtypes and survival outcomes among children with pulmonary hypertension. Given the substantial burden of this disease, further studies to validate phenotypic differences and to understand the underlying causes of survival disparities between racial and ethnic groups are warranted.

  View details for DOI 10.1016/j.jpeds.2019.04.046

  View details for PubMedID 31176455

• Diminished right ventricular function at diagnosis of pulmonary hypertension is associated with mortality in bronchopulmonary dysplasia. Pulmonary circulation Altit, G., Bhombal, S., Feinstein, J., Hopper, R. K., Tacy, T. A. 2019; 9 (3): 2045894019878598

  Abstract

  Pulmonary vascular disease and resultant pulmonary hypertension (PH) have been increasingly recognized in the preterm population, particularly among patients with bronchopulmonary dysplasia (BPD). Limited data exist on the impact of PH severity and right ventricular (RV) dysfunction at PH diagnosis on outcome. The purpose of this study was to evaluate if echocardiography measures of cardiac dysfunction and PH severity in BPD-PH were associated with mortality. The study is a retrospective analysis of the echocardiography at three months or less from time of PH diagnosis. Survival analysis using a univariate Cox proportional hazard model is presented and expressed using hazard ratios (HR). We included 52 patients with BPD and PH of which 16 (31%) died at follow-up. Average gestational age at birth was 26.3 ± 2.3 weeks. Echocardiography was performed at a median of 43.3 weeks (IQR: 39.0-54.7). The median time between PH diagnosis and death was 117 days (range: 49-262 days). Multiple measures of PH severity and RV performance were associated with mortality (sPAP/sBP: HR 1.02, eccentricity index: HR 2.02, tricuspid annular plane systolic excursion Z-score: HR 0.65, fractional area change: HR 0.88, peak longitudinal strain: HR 1.22). Hence, PH severity and underlying RV dysfunction at PH diagnosis were associated with mortality in BPD-PH patients. While absolute estimation of pulmonary pressures is not feasible in every screening echocardiography, thorough evaluation of RV function and other markers of PH may allow to discriminate the most at-risk population and should be considered as standard add-ons to the current screening at 36 weeks.

  View details for DOI 10.1177/2045894019878598

  View details for PubMedID 31662848

  View details for PubMedCentralID PMC6792284

• EXPRESS: Acute Vasoreactivity Testing in Pediatric Idiopathic Pulmonary Arterial Hypertension: an international Survey on Current Practice. Pulmonary circulation Caicedo, L., Hopper, R. K., Garcia, H., Ivy, D. D., Haag, D., Fineman, J., Humpi, T., Al-Tamimi, O., Feinstein, J., Berger, R. M., Berman-Rosenzweig, E., Kashour, T., Diaz, G. F., Mendoza, A., Bobhate, P., Handler, S., Lopes, A. A., Barwad, P., Kumar Rahit, M., Krishnan, U., Adatia, I. T., Moledina, S., Abman, S., Cerro Marin, M. J. 2019: 2045894019857533

  View details for DOI 10.1177/2045894019857533

  View details for PubMedID 31144586

• Reply. The Journal of pediatrics Hopper, R. K., Rogers, R., Lawrence, K. M., Hedrick, H. L. 2018

  View details for PubMedID 30559025

• Pulmonary Vein Stenosis: Outcomes in Children with Congenital Heart Disease and Prematurity. Seminars in thoracic and cardiovascular surgery DiLorenzo, M. P., Santo, A., Rome, J. J., Zhang, H., Faerber, J. A., Mercer-Rosa, L., Hopper, R. K. 2018

  Abstract

  OBJECTIVES: Pulmonary vein stenosis (PVS) is a rare condition that has been linked to prematurity and congenital heart disease (CHD). Despite these associations, treatment options are limited and outcomes are guarded. We investigated differences in PVS outcomes based on the presence of CHD and prematurity, and risk factors for mortality or lung transplantation in PVS.METHODS: Single center retrospective cohort study of patients diagnosed with PVS between January 2005 and May 2016, identified by ICD codes with chart validation. Cox proportional hazard models assessed risk factors for the composite outcome of mortality or lung transplantation.RESULTS: Ninety-three patients with PVS were identified: 65 (70%) had significant CHD, 32 (34%) were premature, and 14 (15%) were premature with CHD. Sixty-five (70%) underwent a PVS intervention and 42 (46%) underwent ≥2 interventions. Twenty-five (27%) subjects died or underwent lung transplant 5.8 months (Interquartile range (IQR) 1.1, 15.3) after diagnosis. There was no difference in age at diagnosis or mortality based on presence of CHD or prematurity. PVS diagnosis before age 6 months and greater than one pulmonary vein affected at diagnosis were associated with higher mortality (HR 3.4 (95% CI 1.5, 7.5), p=0.003, and HR 2.1 per additional vein affected (95% CI 1.3, 3.4), p=0.004, respectively).CONCLUSIONS: Survival in children with PVS is poor, independent of underlying CHD or prematurity. Younger age and greater number of veins affected at diagnosis are risk factors for worse outcome. Understanding causal mechanisms and development of treatment strategies are necessary to improve outcomes.

  View details for PubMedID 30278272

• Treprostinil Improves Persistent Pulmonary Hypertension Associated with Congenital Diaphragmatic Hernia JOURNAL OF PEDIATRICS Lawrence, K. M., Hedrick, H. L., Monk, H. M., Herkert, L., Waqar, L. N., Hanna, B. D., Peranteau, W. H., Rintoul, N. E., Hopper, R. K. 2018; 200: 44–49

  View details for DOI 10.1016/j.jpeds.2018.04.052

  View details for Web of Science ID 000442390400011

• Settling the Score in Pulmonary Hypertension? Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Hopper, R. K., Cornfield, D. N. 2018; 19 (8): 782–83

  View details for PubMedID 30095716

• Right ventricular function mirrors clinical improvement with use of prostacyclin analogues in pediatric pulmonary hypertension PULMONARY CIRCULATION Hopper, R. K., Wang, Y., DeMatteo, V., Santo, A., Kawut, S. M., Elci, O. U., Hanna, B. D., Mercer-Rosa, L. 2018; 8 (2): 2045894018759247

  Abstract

  Pulmonary hypertension (PH) causes significant morbidity and mortality in children due to right ventricular (RV) failure. We sought to determine the effect of prostacyclin analogues on RV function assessed by echocardiography in children with PH. We conducted a retrospective cohort study of children with PH treated with a prostacyclin analogue (epoprostenol or treprostinil) between January 2001 and August 2015 at our center. Data were collected before initiation of treatment (baseline) and at 1-3 and 6-12 months after. Protocolized echocardiogram measurements including tricuspid annular plane systolic excursion (TAPSE) and RV global longitudinal strain were made with blinding to clinical information. Forty-nine individuals (65% female), aged 0-29 years at the time of prostacyclin initiation were included. Disease types included pulmonary arterial hypertension (idiopathic [35%], heritable [2%], and congenital heart disease-associated [18%]), developmental lung disease (43%), and chronic thromboembolic PH (2%). Participants received intravenous (IV) epoprostenol (14%) and IV/subcutaneous (SQ) (67%) or inhaled (18%) treprostinil. Over the study period, prostacyclin analogues were associated with improvement in TAPSE ( P = 0.007), RV strain ( P < 0.001), and qualitative RV function ( P = 0.037) by echocardiogram, and BNP ( P < 0.001), functional class ( P = 0.047) and 6-min walk distance ( P = 0.001). TAPSE and strain improved at early follow up ( P = 0.05 and P = 0.002, respectively) despite minimal RV pressure change. In children with PH, prostacyclin analogues are associated with an early and sustained improvement in RV function measured as TAPSE and strain as well as clinical markers of PH severity. RV strain may be a sensitive marker of RV function in this population.

  View details for PubMedID 29480089

  View details for PubMedCentralID PMC5843105

• Central line replacement following infection does not improve reinfection rates in pediatric pulmonary hypertension patients receiving intravenous prostanoid therapy PULMONARY CIRCULATION McCarthy, E. K., Ogawa, M. T., Hopper, R. K., Feinstein, J. A., Gans, H. A. 2018; 8 (1): 2045893218754886

  Abstract

  Treatment of pediatric pulmonary hypertension (PH) with IV prostanoids has greatly improved outcomes but requires a central line, posing inherent infection risk. This study examines the types of infections, infection rates, and importantly the effect of line management strategies on reinfection in children receiving IV prostanoids for PH. This study is a retrospective review of all pediatric PH patients receiving intravenous epoprostenol (EPO) or treprostinil (TRE) at one academic tertiary care center between 2000 and 2014. No patients declined participation in the study or were otherwise excluded. Infectious complications were characterized by organism(s), infection rates, time to next infection, and line management decisions (salvage vs. replace). Of the 40 patients followed, 13 sustained 38 infections involving 49 pathogens, with a predominance of gram-positive (GP) organisms (n = 35). The pooled infection rate was 1.06 per 1000 prostanoid days with no difference between EPO and TRE. No significant difference in reinfection rate was observed when comparing line salvage to replacement, regardless of organism type. Both overall and organism-type comparisons suggest longer time between line infections following line salvage compared with line replacement (732 vs. 410 days overall; 793 vs. 363 days for GP; 611 vs. 581 days for gram-negative [GN]; P > 0.05 for all comparisons). Central line replacement following blood stream infections in pediatric PH patients does not improve subsequent infection rates or time to next infection, and may lead to unnecessary risks associated with line replacement, including potential loss of vascular access. A revised approach to central line infections in pediatric PH is proposed.

  View details for PubMedID 29309237

  View details for PubMedCentralID PMC5826011

• Subcutaneous treprostinil in pediatric patients with failing single-ventricle physiology JOURNAL OF HEART AND LUNG TRANSPLANTATION Handler, S. S., Ogawa, M. T., Hopper, R. K., Sakarovitch, C., Feinstein, J. A. 2018; 37 (2): 306–7

  View details for Web of Science ID 000424293900022

• The Left Ventricle in Congenital Diaphragmatic Hernia: Implications for the Management of Pulmonary Hypertension. The Journal of pediatrics Kinsella, J. P., Steinhorn, R. H., Mullen, M. P., Hopper, R. K., Keller, R. L., Ivy, D. D., Austin, E. D., Krishnan, U. S., Rosenzweig, E. B., Fineman, J. R., Everett, A. D., Hanna, B. D., Humpl, T., Raj, J. U., Abman, S. H. 2018; 197: 17–22

  View details for PubMedID 29628412

• Evaluation and Management of Pulmonary Hypertension in Children with Bronchopulmonary Dysplasia. The Journal of pediatrics Krishnan, U., Feinstein, J. A., Adatia, I., Austin, E. D., Mullen, M. P., Hopper, R. K., Hanna, B., Romer, L., Keller, R. L., Fineman, J., Steinhorn, R., Kinsella, J. P., Ivy, D. D., Rosenzweig, E. B., Raj, U., Humpl, T., Abman, S. H. 2017; 188: 24–34.e1

  View details for PubMedID 28645441

• Codependence of Bone Morphogenetic Protein Receptor 2 and Transforming Growth Factor-β in Elastic Fiber Assembly and Its Perturbation in Pulmonary Arterial Hypertension. Arteriosclerosis, thrombosis, and vascular biology Tojais, N. F., Cao, A., Lai, Y. J., Wang, L., Chen, P. I., Alcazar, M. A., de Jesus Perez, V., Hopper, R. K., Rhodes, C. J., Bill, M. A., Sakai, L. Y., Rabinovitch, M. 2017

  Abstract

  We determined in patients with pulmonary arterial (PA) hypertension (PAH) whether in addition to increased production of elastase by PA smooth muscle cells previously reported, PA elastic fibers are susceptible to degradation because of their abnormal assembly.Fibrillin-1 and elastin are the major components of elastic fibers, and fibrillin-1 binds bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-β1 (TGFβ1). Thus, we considered whether BMPs like TGFβ1 contribute to elastic fiber assembly and whether this process is perturbed in PAH particularly when the BMP receptor, BMPR2, is mutant. We also assessed whether in mice with Bmpr2/1a compound heterozygosity, elastic fibers are susceptible to degradation. In PA smooth muscle cell and adventitial fibroblasts, TGFβ1 increased elastin mRNA, but the elevation in elastin protein was dependent on BMPR2; TGFβ1 and BMP4, via BMPR2, increased extracellular accumulation of fibrillin-1. Both BMP4- and TGFβ1-stimulated elastic fiber assemblies were impaired in idiopathic (I) PAH-PA adventitial fibroblast versus control cells, particularly those with hereditary (H) PAH and a BMPR2 mutation. This was related to profound reductions in elastin and fibrillin-1 mRNA. Elastin protein was increased in IPAH PA adventitial fibroblast by TGFβ1 but only minimally so in BMPR2 mutant cells. Fibrillin-1 protein increased only modestly in IPAH or HPAH PA adventitial fibroblast stimulated with BMP4 or TGFβ1. In Bmpr2/1a heterozygote mice, reduced PA fibrillin-1 was associated with elastic fiber susceptibility to degradation and more severe pulmonary hypertension.Disrupting BMPR2 impairs TGFβ1- and BMP4-mediated elastic fiber assembly and is of pathophysiologic significance in PAH.

  View details for PubMedID 28619995

• In Pulmonary Arterial Hypertension, Reduced BMPR2 Promotes Endothelial-to-Mesenchymal Transition via HMGA1 and Its Target Slug CIRCULATION Hopper, R. K., Moonen, J. A., Diebold, I., Cao, A., Rhodes, C. J., Tojais, N. F., Hennigs, J. K., Gu, M., Wang, L., Rabinovitch, M. 2016; 133 (18): 1783-?

  Abstract

  -We previously reported high-throughput RNA sequencing analyses that identified heightened expression of the chromatin architectural factor High Mobility Group AT-hook 1 (HMGA1) in pulmonary arterial (PA) endothelial cells (ECs) from idiopathic PA hypertension (IPAH) patients compared to controls. Since HMGA1 promotes epithelial to mesenchymal transition in cancer, we hypothesized that increased HMGA1 could induce transition of PAECs to a smooth muscle (SM)-like mesenchymal phenotype (EndMT), explaining both dysregulation of PAEC function and possible cellular contribution to the occlusive remodeling that characterizes advanced IPAH.-We documented increased HMGA1 in PAECs cultured from IPAH vs. donor control lungs. Confocal microscopy of lung explants localized the increase in HMGA1 consistently to PA endothelium, and identified many cells double-positive for HMGA1 and smooth muscle 22 alpha (SM22α) in occlusive and plexogenic lesions. Since decreased expression and function of bone morphogenetic protein receptor (BMPR)2 is observed in PAH, we reduced BMPR2 by siRNA in control PAECs and documented an increase in HMGA1 protein. Consistent with transition of PAECs by HMGA1, we detected reduced PECAM-1 (CD31) and increased EndMT markers, αSMA, SM22α, calponin, phospho-vimentin and Slug. The transition was associated with spindle SM-like morphology, and the increase in αSMA was largely reversed by joint knockdown of BMPR2 and HMGA1 or Slug. Pulmonary ECs from mice with EC-specific loss of BMPR2 showed similar gene and protein changes.-Increased HMGA1 in PAECs resulting from dysfunctional BMPR2 signaling can transition endothelium to SM-like cells associated with PAH.

  View details for DOI 10.1161/CIRCULATIONAHA.115.020617

  View details for Web of Science ID 000375604400008

  View details for PubMedID 27045138

• Recommendations for the Use of Inhaled Nitric Oxide Therapy in Premature Newborns with Severe Pulmonary Hypertension. The Journal of pediatrics Kinsella, J. P., Steinhorn, R. H., Krishnan, U. S., Feinstein, J. A., Adatia, I., Austin, E. D., Rosenzweig, E. B., Everett, A. D., Fineman, J. R., Hanna, B. D., Hopper, R. K., Humpl, T., Ivy, D. D., Keller, R. L., Mullen, M. P., Raj, J. U., Wessel, D. L., Abman, S. H. 2016; 170: 312–14

  View details for PubMedID 26703869

• Persistent Challenges in Pediatric Pulmonary Hypertension. Chest Hopper, R. K., Abman, S. H., Ivy, D. D. 2016; 150 (1): 226–36

  Abstract

  Pulmonary hypertension and related pulmonary vascular diseases cause significant morbidities and high mortality and present many unique challenges toward improving outcomes in neonates, infants, and children. Differences between pediatric and adult disease are reflected in controversies regarding etiologies, classification, epidemiology, diagnostic evaluations, and therapeutic interventions. This brief review highlights several key topics reflecting recent advances in the field and identifies persistent gaps in our understanding of clinical pediatric pulmonary hypertension.

  View details for PubMedID 26836930

  View details for PubMedCentralID PMC6026244

• RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Rhodes, C. J., Im, H., Cao, A., Hennigs, J. K., Wang, L., Sa, S., Chen, P., Nickel, N. P., Miyagawa, K., Hopper, R. K., Tojais, N. F., Li, C. G., Gu, M., Spiekerkoetter, E., Xian, Z., Chen, R., Zhao, M., Kaschwich, M., del Rosario, P. A., Bernstein, D., Zamanian, R. T., Wu, J. C., Snyder, M. P., Rabinovitch, M. 2015; 192 (3): 356-366

  Abstract

  Pulmonary arterial hypertension is characterized by endothelial dysregulation, but global changes in gene expression have not been related to perturbations in function.RNA sequencing was utilized to discriminate changes in transcriptomes of endothelial cells cultured from lungs of patients with idiopathic pulmonary arterial hypertension vs. controls and to assess the functional significance of major differentially expressed transcripts.The endothelial transcriptomes from seven control and six idiopathic pulmonary arterial hypertension patients' lungs were analyzed. Differentially expressed genes were related to BMPR2 signaling. Those downregulated were assessed for function in cultured cells, and in a transgenic mouse.Fold-differences in ten genes were significant (p<0.05), four increased and six decreased in patients vs.No patient was mutant for BMPR2. However, knockdown of BMPR2 by siRNA in control pulmonary arterial endothelial cells recapitulated six/ten patient-related gene changes, including decreased collagen IV (COL4A1, COL4A2) and ephrinA1 (EFNA1). Reduction of BMPR2 regulated transcripts was related to decreased β-catenin. Reducing COL4A1, COL4A2 and EFNA1 by siRNA inhibited pulmonary endothelial adhesion, migration and tube formation. In mice null for the EFNA1 receptor, EphA2, vs. controls, VEGF receptor blockade and hypoxia caused more severe pulmonary hypertension, judged by elevated right ventricular systolic pressure, right ventricular hypertrophy and loss of small arteries.The novel relationship between BMPR2 dysfunction and reduced expression of endothelial COL4 and EFNA1 may underlie vulnerability to injury in pulmonary arterial hypertension.

  View details for DOI 10.1164/rccm.201408-1528OC

  View details for PubMedID 26030479

• BMPR2 Preserves Mitochondrial Function and DNA during Reoxygenation to Promote Endothelial Cell Survival and Reverse Pulmonary Hypertension CELL METABOLISM Diebold, I., Hennigs, J. K., Miyagawa, K., Li, C. G., Nickel, N. P., Kaschwich, M., Cao, A., Wang, L., Reddy, S., Chen, P., Nakahira, K., Alcazar, M. A., Hopper, R. K., Ji, L., Feldman, B. J., Rabinovitch, M. 2015; 21 (4): 596-608

  Abstract

  Mitochondrial dysfunction, inflammation, and mutant bone morphogenetic protein receptor 2 (BMPR2) are associated with pulmonary arterial hypertension (PAH), an incurable disease characterized by pulmonary arterial (PA) endothelial cell (EC) apoptosis, decreased microvessels, and occlusive vascular remodeling. We hypothesized that reduced BMPR2 induces PAEC mitochondrial dysfunction, promoting a pro-inflammatory or pro-apoptotic state. Mice with EC deletion of BMPR2 develop hypoxia-induced pulmonary hypertension that, in contrast to non-transgenic littermates, does not reverse upon reoxygenation and is associated with reduced PA microvessels and lung EC p53, PGC1α and TFAM, regulators of mitochondrial biogenesis, and mitochondrial DNA. Decreasing PAEC BMPR2 by siRNA during reoxygenation represses p53, PGC1α, NRF2, TFAM, mitochondrial membrane potential, and ATP and induces mitochondrial DNA deletion and apoptosis. Reducing PAEC BMPR2 in normoxia increases p53, PGC1α, TFAM, mitochondrial membrane potential, ATP production, and glycolysis, and induces mitochondrial fission and a pro-inflammatory state. These features are recapitulated in PAECs from PAH patients with mutant BMPR2.

  View details for DOI 10.1016/j.cmet.2015.03.010

  View details for Web of Science ID 000352500800014

  View details for PubMedID 25863249

• Neonatal Pulmonary Arterial Hypertension and Noonan Syndrome: Two Fatal Cases with a Specific RAF1 Mutation AMERICAN JOURNAL OF MEDICAL GENETICS PART A Hopper, R. K., Feinstein, J. A., Manning, M. A., Benitz, W., Hudgins, L. 2015; 167A (4): 882-885

  Abstract

  Mutations in RAF1 are associated with Noonan syndrome and hypertrophic cardiomyopathy. We present two infants with Noonan syndrome and an identical RAF1 mutation, p.Ser257Leu (c.770C>T), who developed severe pulmonary arterial hypertension (PAH) that proved to be fatal. The RAF1 gene encodes Raf-1 kinase, part of the Ras/mitogen-activated kinase (MAPK) signaling pathway, which has been linked to the development of PAH. This specific mutation has been associated with dephosphorylation of a critical serine residue and constitutive activation of the Raf-1 kinase. These two cases suggest that abnormal activation of the Ras/MAPK pathway may play a significant role in the development of pulmonary vascular disease in the subset of patients with Noonan syndrome and a specific RAF1 mutation. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37024

  View details for Web of Science ID 000352019000035

• FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. journal of clinical investigation Spiekerkoetter, E., Tian, X., Cai, J., Hopper, R. K., Sudheendra, D., Li, C. G., El-Bizri, N., Sawada, H., Haghighat, R., Chan, R., Haghighat, L., de Jesus Perez, V., Wang, L., Reddy, S., Zhao, M., Bernstein, D., Solow-Cordero, D. E., Beachy, P. A., Wandless, T. J., ten Dijke, P., Rabinovitch, M. 2013; 123 (8): 3600-3613

  Abstract

  Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs and bioactive compounds for induction of BMPR2 signaling. The best response was achieved with FK506 (tacrolimus), via a dual mechanism of action as a calcineurin inhibitor that also binds FK-binding protein-12 (FKBP12), a repressor of BMP signaling. FK506 released FKBP12 from type I receptors activin receptor-like kinase 1 (ALK1), ALK2, and ALK3 and activated downstream SMAD1/5 and MAPK signaling and ID1 gene regulation in a manner superior to the calcineurin inhibitor cyclosporine and the FKBP12 ligand rapamycin. In pulmonary artery endothelial cells (ECs) from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling. In mice with conditional Bmpr2 deletion in ECs, low-dose FK506 prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin. Low-dose FK506 also reversed severe PAH in rats with medial hypertrophy following monocrotaline and in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. Our studies indicate that low-dose FK506 could be useful in the treatment of PAH.

  View details for DOI 10.1172/JCI65592

  View details for PubMedID 23867624

• FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. journal of clinical investigation Spiekerkoetter, E., Tian, X., Cai, J., Hopper, R. K., Sudheendra, D., Li, C. G., El-Bizri, N., Sawada, H., Haghighat, R., Chan, R., Haghighat, L., de Jesus Perez, V., Wang, L., Reddy, S., Zhao, M., Bernstein, D., Solow-Cordero, D. E., Beachy, P. A., Wandless, T. J., ten Dijke, P., Rabinovitch, M. 2013; 123 (8): 3600-3613

  Abstract

  Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs and bioactive compounds for induction of BMPR2 signaling. The best response was achieved with FK506 (tacrolimus), via a dual mechanism of action as a calcineurin inhibitor that also binds FK-binding protein-12 (FKBP12), a repressor of BMP signaling. FK506 released FKBP12 from type I receptors activin receptor-like kinase 1 (ALK1), ALK2, and ALK3 and activated downstream SMAD1/5 and MAPK signaling and ID1 gene regulation in a manner superior to the calcineurin inhibitor cyclosporine and the FKBP12 ligand rapamycin. In pulmonary artery endothelial cells (ECs) from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling. In mice with conditional Bmpr2 deletion in ECs, low-dose FK506 prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin. Low-dose FK506 also reversed severe PAH in rats with medial hypertrophy following monocrotaline and in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. Our studies indicate that low-dose FK506 could be useful in the treatment of PAH.

  View details for DOI 10.1172/JCI65592

  View details for PubMedID 23867624

• Use of P-32 To Study Dynamics of the Mitochondrial Phosphoproteome JOURNAL OF PROTEOME RESEARCH Aponte, A. M., Phillips, D., Hopper, R. K., Johnson, D. T., Harris, R. A., Blinova, K., Boja, E. S., French, S., Balaban, R. S. 2009; 8 (6): 2679-2695

  Abstract

  Protein phosphorylation is a well-characterized regulatory mechanism in the cytosol, but remains poorly defined in the mitochondrion. In this study, we characterized the use of (32)P-labeling to monitor the turnover of protein phosphorylation in the heart and liver mitochondria matrix. The (32)P labeling technique was compared and contrasted to Phos-tag protein phosphorylation fluorescent stain and 2D isoelectric focusing. Of the 64 proteins identified by MS spectroscopy in the Phos-Tag gels, over 20 proteins were correlated with (32)P labeling. The high sensitivity of (32)P incorporation detected proteins well below the mass spectrometry and even 2D gel protein detection limits. Phosphate-chase experiments revealed both turnover and phosphate associated protein pool size alterations dependent on initial incubation conditions. Extensive weak phosphate/phosphate metabolite interactions were observed using nondisruptive native gels, providing a novel approach to screen for potential allosteric interactions of phosphate metabolites with matrix proteins. We confirmed the phosphate associations in Complexes V and I due to their critical role in oxidative phosphorylation and to validate the 2D methods. These complexes were isolated by immunocapture, after (32)P labeling in the intact mitochondria, and revealed (32)P-incorporation for the alpha, beta, gamma, OSCP, and d subunits in Complex V and the 75, 51, 42, 23, and 13a kDa subunits in Complex I. These results demonstrate that a dynamic and extensive mitochondrial matrix phosphoproteome exists in heart and liver.

  View details for DOI 10.1021/pr800913j

  View details for Web of Science ID 000266719400008

  View details for PubMedID 19351177

• Mitochondrial matrix phosphoproteome: Effect of extra mitochondrial calcium BIOCHEMISTRY Hopper, R. K., Carroll, S., Aponte, A. M., Johnson, D. T., French, S., Shen, R. F., Witzmann, F. A., Harris, R. A., Balaban, R. S. 2006; 45 (8): 2524-2536

  Abstract

  Post-translational modification of mitochondrial proteins by phosphorylation or dephosphorylation plays an essential role in numerous cell signaling pathways involved in regulating energy metabolism and in mitochondrion-induced apoptosis. Here we present a phosphoproteomic screen of the mitochondrial matrix proteins and begin to establish the protein phosphorylations acutely associated with calcium ions (Ca(2+)) signaling in porcine heart mitochondria. Forty-five phosphorylated proteins were detected by gel electrophoresis-mass spectrometry of Pro-Q Diamond staining, while many more Pro-Q Diamond-stained proteins evaded mass spectrometry detection. Time-dependent (32)P incorporation in intact mitochondria confirmed the extensive matrix protein phosphoryation and revealed the dynamic nature of this process. Classes of proteins that were detected included all of the mitochondrial respiratory chain complexes, as well as enzymes involved in intermediary metabolism, such as pyruvate dehydrogenase (PDH), citrate synthase, and acyl-CoA dehydrogenases. These data demonstrate that the phosphoproteome of the mitochondrial matrix is extensive and dynamic. Ca(2+) has previously been shown to activate various dehydrogenases, promote the generation of reactive oxygen species (ROS), and initiate apoptosis via cytochrome c release. To evaluate the Ca(2+) signaling network, the effects of a Ca(2+) challenge sufficient to release cytochrome c were evaluated on the mitochondrial phosphoproteome. Novel Ca(2+)-induced dephosphorylation was observed in manganese superoxide dismutase (MnSOD) as well as the previously characterized PDH. A Ca(2+) dose-dependent dephosphorylation of MnSOD was associated with an approximately 2-fold maximum increase in activity; neither the dephosphorylation nor activity changes were induced by ROS production in the absence of Ca(2+). These data demonstrate the use of a phosphoproteome screen in determining mitochondrial signaling pathways and reveal new pathways for Ca(2+) modification of mitochondrial function at the level of MnSOD.

  View details for DOI 10.1021/bi052475e

  View details for Web of Science ID 000235792300008

  View details for PubMedID 16489745