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Rachel Hopper, MD

  • Rachel Knight Hopper

Specialties

Cardiology

Work and Education

Professional Education

University of Michigan Medical School, Ann Arbor, MI, 5/11/2007

Residency

Boston Childrens Hospital Pediatric Residency, Boston, MA, 06/30/2010

Fellowship

Stanford University Pediatric Cardiology Fellowship, Palo Alto, CA, 6/30/2013

Stanford University Pediatric Cardiology Fellowship, Palo Alto, CA, 6/30/2014

Board Certifications

Pediatric Cardiology, American Board of Pediatrics

Pediatrics, American Board of Pediatrics

All Publications

Younger age at initiation of subcutaneous treprostinil is associated with better response in pediatric Group 1 pulmonary arterial hypertension. Pulmonary circulation Kochanski, J. J., Feinstein, J. A., Ogawa, M., Ritter, V., Hopper, R. K., Adamson, G. T. 2024; 14 (1): e12328

Abstract

Children with severe Group 1 pulmonary arterial hypertension (PAH) have an unpredictable response to subcutaneous treprostinil (TRE) therapy, which may be influenced by age, disease severity, or other unknown variables at time of initiation. In this retrospective single-center cohort study, we hypothesized that younger age at TRE initiation, early hemodynamic response (a decrease in pulmonary vascular resistance by 30% at follow-up catheterization), and less severe baseline hemodynamics (Rp:Rs < 1.1) would each be associated with better clinical outcomes. In 40 pediatric patients with Group I PAH aged 17 days-18 years treated with subcutaneous TRE, younger age (cut-off of 6-years of age, AUC 0.824) at TRE initiation was associated with superior 5-year freedom from adverse events (94% vs. 39%, p=0.002), better WHO functional class (I or II: 88% vs. 39% p=0.003), and better echocardiographic indices of right ventricular function at most recent follow-up. Neither early hemodynamic response nor less severe baseline hemodynamics were associated with better outcomes. Patients who did not have a significant early hemodynamic response to TRE by first follow-up catheterization were unlikely to show subsequent improvement in PVRi (1/8, 13%). These findings may help clinicians counsel families and guide clinical decision making regarding the timing of advanced therapies.

View details for DOI 10.1002/pul2.12328

View details for PubMedID 38348195

View details for PubMedCentralID PMC10860541

Pulmonary Vasodilator Therapy in Pediatric Patients on Ventricular Assist Device Support: A Single-Center Experience and Proposal for Use. ASAIO journal (American Society for Artificial Internal Organs : 1992) Schramm, J. E., Dykes, J. C., Hopper, R. K., Feinstein, J. A., Rosenthal, D. N., Kameny, R. J. 2023

Abstract

Pediatric precapillary pulmonary hypertension can develop in response to systemic atrial hypertension. Systemic atrial decompression following ventricular assist device (VAD) implantation may not sufficiently lower pulmonary vascular resistance (PVR) to consider heart transplant candidacy. Prostacyclins have been used in adult VAD patients with success, but pediatric data on safety and efficacy in this population are limited. We sought to describe our center's experience to show its safety and to present our current protocol for perioperative use. We reviewed our use of prostacyclin therapy in pediatric patients on VAD support with high PVR from 2016 to 2021. Of the 17 patients who met inclusion, 12 survived to transplant and 1 is alive with VAD in situ. All patients survived posttransplant. With continuous intravenous (IV) epoprostenol or treprostinil therapy, there were no bleeding complications or worsening of end-organ function. A significant reduction was observed in vasoactive inotropic scores by 49% in the first 24 hours post-prostacyclin initiation. The proportion of patients surviving to transplant in this high-risk cohort is favorable. In conclusion, prostacyclins may be safe to use in patients with elevated PVR as part of their VAD and transplant course and may provide a transplant option in those otherwise not candidates.

View details for DOI 10.1097/MAT.0000000000002023

View details for PubMedID 37556563

Measurement of Physical Activity by Actigraphy in Infants and Young Children with Pulmonary Arterial Hypertension. The Journal of pediatrics Avitabile, C. M., Yung, D., Handler, S., Hopper, R. K., Fineman, J., Freire, G., Varghese, N., Mullen, M., Krishnan, U. S., Austin, E., Silveira, L., Ivy, D. D. 2023: 113639

Abstract

OBJECTIVE: To evaluate the feasibility, tolerability, and adherence with wearable actigraphy devices among infants and children with pulmonary arterial hypertension (PAH).STUDY DESIGN: This multi-center, 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 (CPM), activity intensity, heart rate, and heart rate variability (HRV) 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=0.20; FitBit 13 [10, 13.8] in PAH vs. 12 [8, 14] in control, p=0.87). Complete data were obtained in 81% of eligible ActiGraph participants and 72% of FitBit participants. PAH participants demonstrated fewer steps, lower vector magnitude CPM, more sedentary activity, and less intense physical activity at all levels compared with control participants. No statistically significant differences in HRV were demonstrated between the two groups.CONCLUSIONS: Measurement of physical activity and other endpoints using wearable actigraphy devices was feasible in young children with PAH. Larger studies should determine associations between physical activity and disease severity in young PAH patients to identify relevant endpoints for pediatric clinical trials.

View details for DOI 10.1016/j.jpeds.2023.113639

View details for PubMedID 37517653

Editorial: Advances in the care of the pediatric pulmonary hypertension patient: from the neonate to the adolescent-young adult patient. Frontiers in pediatrics Avitabile, C. M., Hopper, R. K., Handler, S. S., Bates, A. 2023; 11: 1220070

View details for DOI 10.3389/fped.2023.1220070

View details for PubMedID 37303755

View details for PubMedCentralID PMC10248507

International practice heterogeneity in pre-transplant management of pulmonary hypertension related to pediatric left heart disease. Pediatric transplantation Hopper, R. K., van der Have, O., Hollander, S. A., Dipchand, A. I., Perez de Sa, V., Feinstein, J. A., Tran-Lundmark, K. 2023: e14461

Abstract

BACKGROUND: Elevated pulmonary vascular resistance (PVR) in the setting of left heart failure may contribute to poor outcomes after pediatric heart transplant (HTx), but peri-transplant management is variable.METHODS: We sought to characterize international practice by surveying physicians at pediatric HTx centers.RESULTS: We received 49 complete responses from 39 centers in 16 countries. Most respondents are pediatric cardiologists (90%), practice at centers offering heart (86%) and lung (55%) transplant, and perform pre-HTx acute vasoreactivity testing (AVT, 88%) in patients with elevated PVR. Half (51%) reported defining a PVR cutoff for HTx eligibility as 6WUm2 (56%) post-AVT (84%). The highest post-AVT PVR ever accepted for HTx ranged from 3-14.4 (median 6) WUm2 . To treat elevated pre-transplant PVR, phosphodiesterase type 5 inhibitors are most common (65%) followed by oxygen (31%), nitric oxide (14%), endothelin receptor antagonists (11%), and prostacyclins (6%). Nearly a third (31%) do not routinely use pulmonary vasodilators without implantation of a left ventricular assist device (LVAD). Case scenarios highlight treatment variability: in a restrictive cardiomyopathy scenario, HTx listing with post-transplant vasodilator therapy was favored, whereas in a Shone's complex patient with fixed PVR, LVADpulmonary vasodilators followed by repeat catheterization was most common. Management of dilated cardiomyopathy with reactive PVR was variable. Most continue vasodilator therapy until HTx (16%), PVR normalizes (16%) or 6months.CONCLUSIONS: Management of elevated PVR in children awaiting HTx is heterogenous. Evidence-based guidelines are needed to allow for longitudinal determination of optimal outcomes and standardized care.

View details for DOI 10.1111/petr.14461

View details for PubMedID 36593638

Role of left atrial hypertension in pulmonary hypertension associated with bronchopulmonary dysplasia Frontiers in Pediatrics Sullivan, R. T., Tandel, M. D., Bhombal, S., Adamson, G. T., Boothroyd, D. B., Tracy, M., Moy, A., Hopper, R. K. 2022: 1012136

Abstract

Left atrial hypertension (LAH) may contribute to pulmonary hypertension (PH) in premature infants with bronchopulmonary dysplasia (BPD). Primary causes of LAH in infants with BPD include left ventricular diastolic dysfunction or hemodynamically significant left to right shunt. The incidence of LAH, which is definitively diagnosed by cardiac catheterization, and its contribution to PH is unknown in patients with BPD-PH. We report the prevalence of LAH in an institutional cohort with BPD-PH with careful examination of hemodynamic contributors and impact on patient outcomes. This single-center, retrospective cohort study examined children <2 years of age with BPD-PH who underwent cardiac catheterization at Lucile Packard Children's Hospital Stanford. Patients with unrepaired simple shunt congenital heart disease (CHD) and pulmonary vein stenosis (only 1 or 2 vessel disease) were included. Patients with complex CHD were excluded. From April 2010 to December 2021, 34 patients with BPD-PH underwent cardiac catheterization. We define LAH as pulmonary capillary wedge pressure (PCWP) or left atrial pressure (LAP) of at least 10 mmHg. In this cohort, median PCWP was 8 mmHg, with LAH present in 32% (n = 11) of the total cohort. A majority (88%, n = 30) of the cohort had severe BPD. Most patients had some form of underlying CHD and/or pulmonary vein stenosis: 62% (n = 21) with an atrial septal defect or patent foramen ovale, 62% (n = 21) with patent ductus arteriosus, 12% (n = 4) with ventricular septal defect, and 12% (n = 4) with pulmonary vein stenosis. Using an unadjusted logistic regression model, baseline requirement for positive pressure ventilation at time of cardiac catheterization was associated with increased risk for LAH (odds ratio 8.44, 95% CI 1.46-48.85, p = 0.02). Small for gestational age birthweight, sildenafil use, and CHD were not associated with increased risk for LAH. LAH was associated with increased risk for the composite outcome of tracheostomy and/or death, with a hazard ratio of 6.32 (95% CI 1.72, 22.96; p = 0.005). While the etiology of BPD-PH is multifactorial, LAH is associated with PH in some cases and may play a role in clinical management and patient outcomes.

View details for DOI 10.3389/fped.2022.1012136

View details for PubMedCentralID PMC9615143

Pulmonary Hypertension in Children with Down Syndrome: Results from the Pediatric Pulmonary Hypertension Network Registry. The Journal of pediatrics Hopper, R. K., Abman, S. H., Elia, E. G., Avitabile, C. M., Yung, D., Mullen, M. P., Austin, E. D., Bates, A., Handler, S. S., Feinstein, J. A., Ivy, D. D., Kinsella, J. P., Mandl, K. D., Raj, J. U., Sleeper, L. A., Pediatric Pulmonary Hypertension Network Investigators 2022

Abstract

OBJECTIVE: To characterize distinct comorbidities, outcomes, and treatment patterns in children with Down syndrome and pulmonary hypertension) in a large, multicenter pediatric pulmonary hypertension registry.STUDY DESIGN: We analyzed data from the Pediatric Pulmonary Hypertension Network (PPHNet) Registry, comparing demographic and clinical characteristics of children with and without Down syndrome. We examined factors associated with pulmonary hypertension resolution and a composite outcome of pulmonary hypertension severity in the cohort with Down syndrome.RESULTS: Of 1475 pediatric patients with pulmonary hypertension, 158 (11%) had Down syndrome. Median age of pulmonary hypertension diagnosis in patients with Down syndrome was 0.49 years (IQR 0.21, 1.77), similar to non-Down syndrome. There was no difference in rates of cardiac catheterization and prescribed pulmonary hypertension medications in children with or without Down syndrome. Comorbidities in Down syndrome included congenital heart disease (95%, repaired in 68%), sleep apnea (56%), prematurity (49%), recurrent respiratory exacerbations (35%), gastroesophageal reflux (38%), and aspiration (31%). pulmonary hypertension resolved in 43% after 3 years, associated with pulmonary hypertension diagnosis age <6 months (54% vs 29%, p=0.002) and pre-tricuspid shunt (65% vs 38%, p=0.02). Five-year transplant-free survival was 88% (95% CI: 80-97%). Tracheostomy (HR 3.29, 95% CI 1.61-6.69) and reflux medication use (HR 2.08, 95% CI 1.11-3.90) were independently associated with for a composite outcome of severe pulmonary hypertension.CONCLUSIONS: Despite high rates of cardiac and respiratory comorbidities that influence pulmonary hypertension severity, children with Down syndrome-associated pulmonary hypertension generally have survival rates similar to children with non-Down syndrome-associated pulmonary hypertension. Pulmonary hypertension resolution is common, but reduced among children with complicated respiratory comorbidities.

View details for DOI 10.1016/j.jpeds.2022.08.027

View details for PubMedID 36027975

Subcutaneous Treprostinil Improves Surgical Candidacy for Next Stage Palliation in Single Ventricle Patients With High-Risk Hemodynamics. Seminars in thoracic and cardiovascular surgery Sullivan, R. T., Handler, S. S., Feinstein, J. A., Ogawa, M., Liu, E., Ma, M., Hopper, R. K., Norris, J., Hollander, S. A., Chen, S. 2022

Abstract

Single ventricle (SV) patients with pulmonary vascular disease (SV-PVD) are considered poor surgical candidates for Glenn or Fontan palliation. Given limited options for Stage 1 (S1) and Stage 2 (S2) SV patients with SV-PVD, we report on the use of subcutaneous treprostinil (TRE) to treat SV-PVD in this population. This single-center, retrospective cohort study examined SV patients who were not candidates for subsequent surgical palliation due to SV-PVD and were treated with TRE. The primary outcome was ability to progress to the next surgical stage; secondary outcomes included changes in hemodynamics after TRE initiation. Between 3/2014 and 8/2021, 17 SV patients received TRE for SV-PVD: 11 after S1 and 6 after S2 (median PVR 4.1 [IQR 3.2-4.8] WU*m2, and 5.0 [IQR 1.5-6.1] WU*m2, respectively). Nine of eleven (82%) S1 progressed to S2, and 2 (18%) underwent heart transplant (HTx). Three of six (50%) S2 progressed to Fontan, 1 underwent HTx and 2 are awaiting Fontan on TRE. TRE significantly decreased PVR in S1 patients with median post-treatment PVR of 2.0 (IQR 1.5-2.6) WU*m2. TRE can allow for further surgical palliation in select pre-Fontan patients with SV-PVD, obviating the need for HTx. Improvement in PVR was significant in S1 patients and persisted beyond discontinuation of therapy for most patients.

View details for DOI 10.1053/j.semtcvs.2022.07.011

View details for PubMedID 35931345

Revisiting Arginine Therapy for Sickle Cell Acute Vaso-occlusive Painful Crisis. American journal of respiratory and critical care medicine Hopper, R. K., Gladwin, M. T. 2022

View details for DOI 10.1164/rccm.202204-0673ED

View details for PubMedID 35549664

Cardiac Catheterization and Hemodynamics in a Multicenter Cohort of Children with Pulmonary Hypertension. Annals of the American Thoracic Society Rosenzweig, E. B., Bates, A., Mullen, M. P., Abman, S. H., Austin, E. D., Everett, A., Fineman, J., Feinstein, J., Hopper, R. K., Kinsella, J. P., Krishnan, U. S., Lu, M., Mandl, K. D., Raj, J. U., Varghese, N., Yung, D., Handler, S. S., Sleeper, L. A., Pediatric Pulmonary Hypertension Network 1800

Abstract

RATIONALE: Hemodynamic assessments direct care among children with pulmonary hypertension (PH), yet the use of cardiac catheterization is highly variable, which could impact patient care and research. Objective We analyzed hemodynamic findings from right (RHC) and left heart catheterization (LHC), acute vasodilator testing (AVT) and the safety of catheterization in children with World Symposium on Pulmonary Hypertension(WSPH) Group 1 and 3 subtypes in a large multicenter North American cohort.METHODS: Of 1475 children enrolled in the Pediatric PH Network registry (2014 -2020), there were 1383 Group 1 and 3 patients, of whom 671 (48.5%) had a RHC performed at diagnosis and were included for analysis.RESULTS: Compared to those without a diagnostic RHC, these children were older, less likely to be an infant or preterm, more often female, treated with targeted PH medications at diagnosis and had advanced WHO functional class. Catheterization was performed without a difference in complication rates between WSPH Groups. PCWP was well-correlated with LVEDP and left atrial pressures. AVT using 3 different methods were comparable; positive AVT was observed in 8.0-11.8% of subjects and did not differ between WSPH Groups 1 and 3 or associated with freedom from the composite endpoint of lung transplantation or death during follow-up.CONCLUSIONS: In a large pediatric PH cohort, diagnostic RHC + LHC in WSPH Group 1 and 3 patients were performed safely at experienced pediatric PH Centers. Hemodynamic differences were noted between Group 1 and 3 subjects. Higher mean PAP and PAPm:SAPm ratio were associated with a higher risk of death/transplantation. Findings suggest overall safety and potential value of RHC as a standard diagnostic approach to guide PH management in children.

View details for DOI 10.1513/AnnalsATS.202108-998OC

View details for PubMedID 35049414

A case of acquired von Willebrand disease in severe pediatric pulmonary hypertension contributing to bleeding following reverse Potts shunt. Pulmonary Circulation Sullivan, R. T., Lo, C., Martin, E., Kameny, R. J., Hopper, R. K. 2022; 12 (e12042)

View details for DOI 10.1002/pul2.12042

A case of acquired von Willebrand disease in severe pediatric pulmonary hypertension contributing to bleeding following reverse Potts shunt. Pulmonary circulation Sullivan, R. T., Lo, C., Martin, E., Kameny, R. J., Hopper, R. K. 2022; 12 (1): e12042

Abstract

The reverse Potts shunt is increasingly used as a palliative measure for end-stage pulmonary arterial hypertension (PAH) as a means to offload the right ventricle and improve functional status. This case report describes a child who developed significant hemothorax after reverse Potts shunt that required surgical exploration, blood product administration, and prolonged intensive care hospitalization. Despite lack of preoperative bleeding symptoms, testing revealed acquired von Willebrand disease (aVWD), with subsequent resolution of bleeding. Alterations in von Willebrand factor, including aVWD, have been reported in children with severe PAH but have not previously been associated with bleeding after reverse Potts shunt procedure. As bleeding is a recognized postoperative morbidity in PAH patients undergoing reverse Potts shunt, we highlight a potential role for preoperative testing for aVWD as perioperative factor replacement therapy may improve postoperative outcomes.

View details for DOI 10.1002/pul2.12042

View details for PubMedID 35506098

View details for PubMedCentralID PMC9052962

Characterisation of Pediatric Pulmonary Hypertensive Vascular Disease from the PPHNet Registry. The European respiratory journal Abman, S. H., Mullen, M. P., Sleeper, L. A., Austin, E. D., Rosenzweig, E. B., Kinsella, J. P., Ivy, D., Hopper, R. K., Usha Raj, J., Fineman, J., Keller, R. L., Bates, A., Krishnan, U. S., Avitabile, C. M., Davidson, A., Natter, M. D., Mandl, K. D., Pediatric Pulmonary Hypertension Network 2021

Abstract

BACKGROUND: There are limited data about the range of diseases, natural history, age-appropriate endpoints and optimal care for children with pulmonary hypertension (PH), including the need for developing high quality patient registries of children with diverse forms of PH to enhance care and research.OBJECTIVE: To characterise the distribution and clinical features of diseases associated with pediatric PH, including natural history, evaluation, therapeutic interventions and outcomes, as defined by the WSPH Classification.METHODS: 1475 patients were enrolled into a multisite registry across the Pediatric Pulmonary Hypertension Network (PPHNet), comprised of 8 interdisciplinary PH programs.RESULTS: WSPH Groups 1 (PAH) and 3 (lung disease) were the most common primary classifications (45% and 49% of subjects, respectively). The most common Group 3 conditions were BPD and CDH. Group 1 disease was predominantly associated with congenital heart disease (60%) and idiopathic (23% of Group 1 cases). In comparison with Group 1, Group 3 subjects had better disease resolution (HR=3.1, p<0.001), tended to be younger at diagnosis (0.3 (0.0,0.6) versus 1.6 (0.1,6.9) years (median (IQR); p<0.001), and were more often male (57% versus. 45%, p<0.001). Down syndrome (DS), the most common genetic syndrome in the registry, constituted 11% of the entire PH cohort.CONCLUSIONS: We find a striking proportion of pediatric PH patients with Group 3 disorders, reflecting the growing recognition of PH in diverse developmental lung diseases. Greater precision of clinical phenotyping based on disease-specific characterization may further enhance care and research of pediatric PH.

View details for DOI 10.1183/13993003.03337-2020

View details for PubMedID 34140292

Pulmonary Arterial Hypertension: Diagnosis, Treatment, and Novel Advances. American journal of respiratory and critical care medicine Maron, B. A., Abman, S. H., Elliott, C. G., Frantz, R. P., Hopper, R. K., Horn, E. M., Nicolls, M. R., Shlobin, O. A., Shah, S. J., Kovacs, G. n., Olschewski, H. n., Rosenzweig, E. B. 2021

Abstract

The diagnosis and management of pulmonary arterial hypertension (PAH) includes several advances, such as broader recognition of extra-pulmonary vascular organ system involvement, validated point-of-care clinical assessment tools, and a focus on early-initiation of multiple pharmacotherapeutics in appropriate patients. Indeed, a principal goal in PAH today is early diagnosis for prompt initiation of treatment to achieve minimal symptom burden, optimize the patient's biochemical, hemodynamic, and functional profile, and limit adverse events. To accomplish this end, clinicians must be familiar with novel risk factors and the revised hemodynamic definition for PAH. Fresh insights into the role of developmental biology (i.e., perinatal health) may also be useful for predicting incident PAH in early adulthood. Emergent or underutilized approaches to PAH management include a novel TGF- ligand trap pharmacotherapy, remote pulmonary artery pressure monitoring, next-generation imaging using inert gas-based magnetic resonance and other technologies, right atrial pacing, and pulmonary artery denervation. These and other PAH state-of-the-art advances are summarized here for the wider pulmonary medicine community.

View details for DOI 10.1164/rccm.202012-4317SO

View details for PubMedID 33861689

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. n., Chen, S. n., 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 13mmHg, 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): 105560
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 (513 vs 1237mm Hg, P < .01), alveolar-arterial gradient (42230 vs 32727mm Hg, P < .01), and PaO2 to FiO2 ratio (8210 vs 19915mm 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): 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 26.32.3 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

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

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-+
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)
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

Death or resolution: the "natural history" of pulmonary hypertension in bronchopulmonary dysplasia JOURNAL OF PERINATOLOGY Altit, G., Bhombal, S., Hopper, R. K., Tacy, T. A., Feinstein, J. 2019; 39 (3): 41525
Time versus treatment: interpreting longitudinal data analysis of treprostinil Reply JOURNAL OF PEDIATRICS Hopper, R. K., Rogers, R., Lawrence, K. M., Hedrick, H. L. 2019; 206: 305-306
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 9.15.1years) and 79 healthy adult controls (mean age 59.710.7years) 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 (4618 vs. 9034; p<0.001), peak systolic (S) signal velocity (10.03.5 vs. 11.73.5; p<0.001), and ratio of peak diastolic (D)-to-atrial (A) signal velocity (1.40.5 vs. 0.40.3; 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 (43.733.9 vs. 47.742.1; p=0.04) and diastolic (D)-to-atrial (A) signal velocity (1.20.5 vs. 1.50.5; p=0.01) but not systolic (S) signals (0.140.05 vs. 0.140.05; 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 born32 weeks estimated gestational age (GA). Cox regression was used for survival analysis.RESULTS: Sixty-one patients with PH (26.51.5 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 1.0927 vs 0.8320 %, p=0.0002). At follow-up (mean 250186 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. n., Ogawa, M. n., Sakarovitch, C. n., Hopper, R. K., Adamson, G. T., Hanna, B. n., Ivy, D. D., Miller-Reed, K. n., Yung, D. n., McCarthy, E. n., Siehr-Handler, S. L., Feinstein, J. A. 2019; 73 (6): 38393

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 ngkgmin with a range of 8-146 ngkgmin. 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 172days. BNP levels declined after 1.40.2days of treatment and again after 5.20.6days. After 60.8days 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 DOI 10.1016/j.jpedsurg.2018.10.039

View details for PubMedID 30442461

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

View details for DOI 10.1177/2045894019857533

View details for PubMedID 31144586

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. n., 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 18years) 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

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: 4449
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): 78283

View details for PubMedID 30095716

Settling the Score in Pulmonary Hypertension?* PEDIATRIC CRITICAL CARE MEDICINE Hopper, R. K., Cornfield, D. N. 2018; 19 (8): 78283
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): 3067
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. n., Raj, J. U., Abman, S. H. 2018; 197: 1722

View details for PubMedID 29628412

Codependence of Bone Morphogenetic Protein Receptor 2 and Transforming Growth Factor- in Elastic Fiber Assembly and Its Perturbation in Pulmonary Arterial Hypertension. Arteriosclerosis, thrombosis, and vascular biology Tojais, N. F., Cao, A. n., Lai, Y. J., Wang, L. n., Chen, P. I., Alcazar, M. A., de Jesus Perez, V. n., Hopper, R. K., Rhodes, C. J., Bill, M. A., Sakai, L. Y., Rabinovitch, M. n. 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-1 (TGF1). Thus, we considered whether BMPs like TGF1 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, TGF1 increased elastin mRNA, but the elevation in elastin protein was dependent on BMPR2; TGF1 and BMP4, via BMPR2, increased extracellular accumulation of fibrillin-1. Both BMP4- and TGF1-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 TGF1 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 TGF1. 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 TGF1- and BMP4-mediated elastic fiber assembly and is of pathophysiologic significance in PAH.

View details for PubMedID 28619995

Evaluation and Management of Pulmonary Hypertension in Children with Bronchopulmonary Dysplasia. The Journal of pediatrics Krishnan, U. n., Feinstein, J. A., Adatia, I. n., Austin, E. D., Mullen, M. P., Hopper, R. K., Hanna, B. n., Romer, L. n., Keller, R. L., Fineman, J. n., Steinhorn, R. n., Kinsella, J. P., Ivy, D. D., Rosenzweig, E. B., Raj, U. n., Humpl, T. n., Abman, S. H. 2017; 188: 2434.e1

View details for PubMedID 28645441

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 DOI 10.1016/j.chest.2016.01.007

View details for PubMedID 26836930

View details for PubMedCentralID PMC6026244

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 (SM22) 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, SMA, SM22, calponin, phospho-vimentin and Slug. The transition was associated with spindle SM-like morphology, and the increase in SMA 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: 312-4

View details for DOI 10.1016/j.jpeds.2015.11.050

View details for PubMedID 26703869

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 -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) areassociated 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, PGC1 and TFAM, regulators of mitochondrial biogenesis, and mitochondrial DNA. Decreasing PAEC BMPR2 by siRNA during reoxygenation represses p53, PGC1, NRF2, TFAM, mitochondrial membrane potential, and ATP and induces mitochondrial DNA deletion and apoptosis. Reducing PAEC BMPR2 in normoxia increases p53, PGC1, 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

View details for PubMedCentralID PMC3177856

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

View details for PubMedCentralID PMC1415274