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2.  Simulations of Congenital Septal Defect Closure and Reactivity Testing in Patient-Specific Models of the Pediatric Pulmonary Vasculature: A 3D Numerical Study With Fluid-Structure Interaction 
Clinical imaging methods are highly effective in the diagnosis of vascular pathologies, but they do not currently provide enough detail to shed light on the cause or progression of such diseases, and would be hard pressed to foresee the outcome of surgical interventions. Greater detail of and prediction capabilities for vascular hemodynamics and arterial mechanics are obtained here through the coupling of clinical imaging methods with computational techniques. Three-dimensional, patient-specific geometric reconstructions of the pediatric proximal pulmonary vasculature were obtained from x-ray angiogram images and meshed for use with commercial computational software. Two such models from hypertensive patients, one with multiple septal defects, the other who underwent vascular reactivity testing, were each completed with two sets of suitable fluid and structural initial and boundary conditions and used to obtain detailed transient simulations of artery wall motion and hemodynamics in both clinically measured and predicted configurations. The simulation of septal defect closure, in which input flow and proximal vascular stiffness were decreased, exhibited substantial decreases in proximal velocity, wall shear stress (WSS), and pressure in the post-op state. The simulation of vascular reactivity, in which distal vascular resistance and proximal vascular stiffness were decreased, displayed negligible changes in velocity and WSS but a significant drop in proximal pressure in the reactive state. This new patient-specific technique provides much greater detail regarding the function of the pulmonary circuit than can be obtained with current medical imaging methods alone, and holds promise for enabling surgical planning.
doi:10.1115/1.2206202
PMCID: PMC4050970  PMID: 16813447
pulmonary hypertension; arterial biomechanics; hemodynamics; computational fluid mechanics; fluid-structure interaction
3.  Acute Pulmonary Vasodilator Testing With Inhaled Treprostinil in Children With Pulmonary Arterial Hypertension 
Pediatric cardiology  2012;34(4):1006-1012.
Acute pulmonary vasodilator testing (AVT) is essential to determining the initial therapy for children with pulmonary arterial hypertension (PAH). This study aimed to report the initial experience with inhaled treprostinil used for AVT in children with PAH and to evaluate the hemodynamic change after inhaled treprostinil compared with inhaled nitric oxide. This prospective cohort study was designed for 13 children who underwent AVT with inhaled treprostinil or oxygen plus inhaled nitric oxide (iNO) during catheterization. Inhaled treprostinil was delivered during cardiac catheterization by adapting the Optineb ultrasonic nebulizer via either a flow-inflating bag or the manual mode of the anesthesia system. The median age of the patients was 10 years (range 4–17 years). The etiologies of PAH included idiopathic PAH and associated PAH. All the patients tolerated inhaled treprostinil without marked clinical worsening and received six or nine breaths (36 or 54 µg) of treprostinil. The median of the total treprostinil doses was 1.53 µg/kg (range 0.71–2.89 µg/kg). Inhaled treprostinil was administrated via an endotracheal tube (n = 8), anesthesia mask (n = 3), or laryngeal mask airway (n = 2). Inhaled nitric oxide (iNO) and inhaled treprostinil significantly decreased the mean pulmonary artery pressure and the pulmonary vascular resistance index compared with baseline. Three adverse events were reported after inhaled treprostinil, including cough and mild to moderate hypotension with higher doses. All adverse events resolved without any intervention. This study report is the first to describe the use of inhaled treprostinil for AVT in children with PAH. In this small pediatric cohort, inhaled treprostinil was effectively delivered and well tolerated and may be useful for AVT.
doi:10.1007/s00246-012-0597-9
PMCID: PMC3608847  PMID: 23184020
Acute pulmonary vasodilator testing; Children; Iloprost; Inhaled treprostinil; Nitric oxide; Pulmonary arterial hypertension
4.  PORTOPULMONARY HYPERTENSION IN PEDIATRIC PATIENTS 
The Journal of Pediatrics  2005;147(1):20-26.
Objectives
To investigate the clinical presentation, manifestations, and response to therapy of portopulmonary hypertension (PPHTN) in pediatric patients.
Study design
This study was a retrospective chart review describing the evaluation and course of 7 patients with PPHTN.
Results
Causes of portal hypertension (HTN) included biliary atresia (3 cases), cavernous transformation of the portal vein (2 cases), and primary sclerosing cholangitis and cryptogenic cirrhosis (1 case each). The median interval from the diagnosis of portal HTN to PPHTN was 12.1 years. Four patients presented with a new heart murmur, 4 presented with syncope, and 3 presented with dyspnea. Although electrocardiograms (ECGs) and chest x-rays were normal in 3 and 2 patients, respectively, echocardiograms diagnosed pulmonary HTN in all 7 patients. Five patients had cardiac catheterizations; the average mean pulmonary artery pressure was 65 ± 20 mm Hg. Response to therapy was variable, and 4 patients died. Postmortem lung tissue examination revealed plexiform lesions and pulmonary arteriopathy.
Conclusions
Because symptoms are subtle and may be overlooked, pediatric patients with portal HTN who develop a new heart murmur, dyspnea, syncope, or who are being evaluated for liver transplantation require evaluation for PPHTN. ECG and chest x-ray are insensitive screens for PPHTN. An echocardiogram and cardiology evaluation is essential for the diagnosis.
doi:10.1016/j.jpeds.2005.02.019
PMCID: PMC3326402  PMID: 16027687
5.  Biomarkers for Pediatric Pulmonary Arterial Hypertension – A Call to Collaborate 
Therapeutic approaches in pediatric pulmonary arterial hypertension (PAH) are based primarily on clinician experience, in contrast to the evidence-based approach in adults with pulmonary hypertension. There is a clear and present need for non-invasive and objective biomarkers to guide the accurate diagnosis, treatment, and prognosis of this disease in children. The multifaceted spectrum of disease, clinical presentation, and association with other diseases makes this a formidable challenge. However, as more progress is being made in the understanding and management of adult PAH, the potential to apply this knowledge to children has never been greater. This review explores the state of the art with regard to non-invasive biomarkers in PAH, with an eye toward those adult PAH biomarkers potentially suitable for application in pediatric PAH.
doi:10.3389/fped.2014.00007
PMCID: PMC3910125  PMID: 24551834
pulmonary arterial hypertension; pediatric; biomarkers; imaging; magnetic resonance; echocardiography; right ventricle
6.  Ventilatory efficiency slope correlates with functional capacity, outcomes, and disease severity in pediatric patients with pulmonary hypertension☆,☆☆,★ 
International journal of cardiology  2013;169(6):445-448.
Background
Cardiopulmonary exercise testing is widely used in a variety of cardiovascular conditions. Ventilatory efficiency slope can be derived from submaximal exercise testing. The present study sought to evaluate the relationship between ventilatory efficiency slope and functional capacity, outcomes, and disease severity in pediatric patients with pulmonary hypertension.
Methods
Seventy six children and young adults with a diagnosis of pulmonary hypertension (PH) performed 258 cardiopulmonary exercise tests from 2001 to 2011. Each individual PH test was matched to a control test. Ventilatory efficiency slope was compared to traditional measures of functional capacity and disease severity including WHO functional classification, peak oxygen consumption, and invasive measures of pulmonary arterial pressures and pulmonary vascular resistance.
Results
Ventilatory efficiency slope was significantly higher in patients with pulmonary arterial hypertension, with an estimated increase of 7.2 for each increase in WHO class (p < 0.0001), compared with normal control subjects (38.9 vs. 30.9, p<0.001). Ventilatory efficiency slope correlated strongly with invasive measures of disease severity including pulmonary vascular resistance index (r =0.61), pulmonary artery pressure (r =0.58), mean pulmonary artery pressure/mean aortic pressure ratio (r =0.52), and peak VO2 (r=−0.58). Ventilatory efficiency slope in 12 patients with poor outcomes (9 death, 3 lung transplant), was significantly elevated compared to patients who did not (51.1 vs. 37.9, p<0.001).
Conclusions
Ventilatory efficiency slope correlates well with invasive and noninvasive markers of disease severity including peak VO2, WHO functional class, and catheterization variables in pediatric patients with PH. Ventilatory efficiency slope may be a useful noninvasive marker for disease severity.
doi:10.1016/j.ijcard.2013.10.012
PMCID: PMC3909671  PMID: 24144928
Ventilatory efficiency slope; VE/VCO2 slope; Pulmonary hypertension; Cardiopulmonary exercise testing; Pediatric
7.  Long-term Outcomes in Children with Pulmonary Arterial Hypertension Treated with Bosentan in Real World Clinical Settings 
The American journal of cardiology  2010;106(9):1332-1338.
Treatment algorithms in pediatric PAH are derived from clinical trials in adult populations, and from clinical practice, but experience in children is limited. In this retrospective cohort study, we analyzed outcomes in a previously identified cohort of 86 consecutive children with pulmonary arterial hypertension (PAH) treated with bosentan as part of their treatment regimen. All children with idiopathic PAH (IPAH) or heritable PAH, and PAH associated with congenital heart disease (PAH-CHD) or connective tissue disease (PAH-CTD) who started bosentan treatment between May 2001 and April 2003 in two tertiary pediatric referral centers were followed with data collection ending August 2006. 86 children (37 males; 49 females) aged 11±5 years with IPAH/HPAH (n=36), PAH-CHD (n=48) or PAH-CTD (n=2) received bosentan as monotherapy (n=42) or as add-on to pre-existing continuous intravenous epoprostenol or subcutaneous treprostinil (n=44). Median observation period was 39 months (range 2–60). 34 patients (40%) received at least one additional PAH-specific therapy during follow-up. At end of data collection, 25 patients (29%) remained on bosentan, 43 (50%) had stopped bosentan, 11 (13%) had died while on bosentan, and 7 were lost to follow-up. At 4 years, the Kaplan-Meier estimate of disease progression in patients while on bosentan was 54% (7 patients at risk) with a survival estimate of 82% (16 patients at risk). Risk factors significantly associated with survival were WHO FC and indexed PVR. In conclusion, outcome in children with PAH managed with current treatment regimens, appears favorable. However, despite current therapy options, disease progression remains a concern.
doi:10.1016/j.amjcard.2010.06.064
PMCID: PMC2966874  PMID: 21029834
Bosentan; pulmonary arterial hypertension; pediatrics; prostacyclin
8.  Sildenafil Increases Systemic Saturation and Reduces Pulmonary Artery Pressure in Patients with Failing Fontan Physiology 
Congenital heart disease  2009;4(2):107-111.
Objective
The purpose of this study was to investigate the effect of sildenafil in patients with failing Fontan physiology.
Design
A retrospective chart review was performed to compare history and available data in patients with Fontan circulations before and after starting sildenafil. The paired and unpaired Student’s t-tests were used for statistical analyses.
Patients
Six patients at our institution with Fontan physiology, persistent symptoms of cyanosis or effusion, and poor hemodynamics as measured in the catheterization laboratory were placed on sildenafil. One patient was not included in the analysis because of insufficient length of treatment. All patients had symptoms of failing Fontan hemodynamics with either persistent cyanosis or effusions. In this group, the mean pulmonary artery pressure was greater than 15 mm Hg (17.4 ± 1.5 mm Hg) with mean estimated pulmonary vascular resistance of 3.5 ± 1.0 Wood units × m2 prior to starting sildenafil.
Results
Sildenafil significantly increased the systemic arterial oxyhemoglobin saturation in this group (82.8 ± 7.3% pre-treatment vs. 91.0 ± 5.5% post-treatment, P = .017). In the four out of five patients who have had follow-up catheterizations, there was a significant decrease in pulmonary artery pressure (17.4 ± 1.5 mm Hg pre-treatment vs. 13.8 ± 2.1 mm Hg post-treatment, P = .018) and in estimated pulmonary vascular resistance pre- and post-sildenafil treatment (3.5 ± 1.0 Wood units × m2 pre-treatment vs. 2.0 ± 0.4 Wood units × m2 post-treatment, P = .031).
Conclusions
Sildenafil may be a useful adjunct to therapy in patients with failing Fontan physiology likely through its function as a pulmonary vasodilator.
doi:10.1111/j.1747-0803.2008.00237.x
PMCID: PMC3159127  PMID: 21866231
Single Ventricle; Fontan; Sildenafil; Pulmonary Vascular Resistance
9.  Closed-Hub Systems with Protected Connections and the Reduction of Risk of Catheter-Related Bloodstream Infection in Pediatric Patients Receiving Intravenous Prostanoid Therapy for Pulmonary Hypertension 
BACKGROUND
Intravenous prostanoids (epoprostenol and treprostinil) are effective therapies for pulmonary arterial hypertension but carry a risk of catheter-related bloodstream infection (CR-BSI). Prevention of CR-BSI during long-term use of indwelling central venous catheters is important.
OBJECTIVE
To evaluate whether using a closed-hub system and waterproofing catheter hub connections reduces the rate of CR-BSI per 1,000 catheter-days.
DESIGN
Single-center open observational study (January 2003–December 2008).
PATIENTS
Pediatric patients with pulmonary arterial hypertension who received intravenous prostanoids.
METHODS
In July 2007, CR-BSI preventive measures were implemented, including the use of a closed-hub system and the waterproofing of catheter hub connections during showering. Rates of CR-BSI before and after implementing preventive measures were compared with respect to medication administered and type of bacterial infection.
RESULTS
Fifty patients received intravenous prostanoid therapy for a total of 41,840 catheter-days. The rate of CR-BSI during the study period was 0.51 infections per 1,000 catheter-days for epoprostenol and 1.38 infections per 1,000 catheter-days for treprostinil, which differed significantly (P < .01). CR-BSIs caused by gram-negative pathogens occurred more frequently with treprostinil than with epoprostenol (0.91 infections per 1,000 catheter-days vs 0.08 infections per 1,000 catheter-days; P < .01). Patients treated with treprostinil after the implemented changes had a significant decrease in CR-BSI rate (1.95 infections per 1,000 catheter-days vs 0.19 infections per 1,000 catheter-days; P < .01).
CONCLUSION
The closed-hub system and the maintenance of dry catheter hub connections significantly reduced the incidence of CR-BSI (particularly infections caused by gram-negative pathogens) in patients receiving intravenous treprostinil.
doi:10.1086/605320
PMCID: PMC3117306  PMID: 19637961
10.  Clinical Safety, Pharmacokinetics, and Efficacy of Ambrisentan Therapy in Children With Pulmonary Arterial Hypertension 
Pediatric pulmonology  2012;48(1):27-34.
Summary
Recent trials in adult PAH revealed the efficacy of ambrisentan. However, in children with PAH, the clinical safety and pharmacokinetics of ambrisentan has not been well studied. Our aim was to investigate the clinical safety, pharmacokinetics, tolerability, and efficacy of endothelin receptor antagonist therapy with ambrisentan in children with pulmonary arterial hypertension (PAH). This retrospective cohort study provides clinical data from pediatric patients with PAH receiving ambrisentan as add-on therapy or transition from bosentan. Safety included evaluation of adverse events including aminotransferase abnormalities. The clinical impact was evaluated by improvement from baseline in clinical variables. A total of 38 pediatric patients with PAH received ambrisentan. Fifteen of 38 patients were switched from bosentan to ambrisentan. The remaining 23 children were treated with ambrisentan as an add-on therapy due to disease progression. In both transition and add-on cases, mean pulmonary artery pressure significantly improved (transition; 55 ± 18 vs. 45 ± 20 mmHg, n = 13, P = 0.04, add-on; 52 ± 17 vs. 45 ± 19 mmHg, n = 13, P = 0.03) during the follow-up. World Health Organization functional class improved in 31% of patients, but one patient required an atrial septostomy due to disease progression during the follow-up period (median, range; 20, 4–44 months). Five patients (13%) discontinued ambrisentan due to severe headache, lack of clinical efficacy, or near syncope. Ten patients (26%) had side effects associated with ambrisentan treatment, including nasal congestion, headache, and flushing. However, no patients had aminotransferase abnormalities and there were no deaths after initiation of ambrisentan during follow-up. Pharmacokinetics were evaluated in sixteen children treated with ambrisentan from 2.5 mg to 10.0 mg; the mean peak plasma concentration was 738 ± 452 ng/ml, mean time to peak plasma concentration was 3.2 ± 2.1 hours, and mean area under the curve plasma concentration was 6657 ± 4246 ng·hour/ml. In conclusion, initial experience with ambrisentan in children suggests that treatment is safe with similar pharmacokinetics to those in adults and may improve PAH in some children.
doi:10.1002/ppul.22555
PMCID: PMC3412194  PMID: 22511577
endothelin receptor antagonists; safety; tolerability; World Health Organization
11.  The Hemodynamic Response to Dexmedetomidine Loading Dose in Children With and Without Pulmonary Hypertension 
Anesthesia and analgesia  2013;117(4):10.1213/ANE.0b013e3182a15aa6.
BACKGROUND
Dexmedetomidine, an α-2 receptor agonist, is widely used in children with cardiac disease. Significant hemodynamic responses, including systemic and pulmonary vasoconstriction, have been reported after dexmedetomidine administration. Our primary goal of this prospective, observational study was to quantify the effects of dexmedetomidine initial loading doses on mean pulmonary artery pressure (PAP) in children with and without pulmonary hypertension.
METHODS
Subjects were children undergoing cardiac catheterization for either routine surveillance after cardiac transplantation (n = 21) or pulmonary hypertension studies (n = 21). After anesthetic induction with sevoflurane and tracheal intubation, sevoflurane was discontinued and anesthesia was maintained with midazolam 0.1 mg/kg IV (or 0.5 mg/kg orally preoperatively) and remifentanil IV infusion 0.5 to 0.8 μg/kg/min. Ventilation was mechanically controlled to maintain Pco2 35 to 40 mm Hg. When end-tidal sevoflurane was 0% and fraction of inspired oxygen (Fio2) was 0.21, baseline heart rate, mean arterial blood pressure, PAP, right atrial pressure, pulmonary artery occlusion pressure, right ventricular end-diastolic pressure, cardiac output, and arterial blood gases were measured, and indexed systemic vascular resistance, indexed pulmonary vascular resistance, and cardiac index were calculated. Each subject then received a 10-minute infusion of dexmedetomidine of 1 μg/kg, 0.75 μg/kg, or 0.5 μg/kg. Measurements and calculations were repeated at the conclusion of the infusion.
RESULTS
Most hemodynamic responses were similar in children with and without pulmonary hypertension. Heart rate decreased significantly, and mean arterial blood pressure and indexed systemic vascular resistance increased significantly. Cardiac index did not change. A small, statistically significant increase in PAP was observed in transplant patients but not in subjects with pulmonary hypertension. Changes in indexed pulmonary vascular resistance were not significant.
CONCLUSION
Dexmedetomidine initial loading doses were associated with significant systemic vasoconstriction and hypertension, but a similar response was not observed in the pulmonary vasculature, even in children with pulmonary hypertension. Dexmedetomidine does not appear to be contraindicated in children with pulmonary hypertension.
doi:10.1213/ANE.0b013e3182a15aa6
PMCID: PMC3830564  PMID: 23960035
12.  Food and Drug Administration (FDA) Postmarket Reported Side Effects and Adverse Events Associated with Pulmonary Hypertension Therapy in Pediatric Patients 
Pediatric cardiology  2013;34(7):1628-1636.
Because most medications for pediatric pulmonary hypertension (PH) are used off label and based on adult trials, little information is available on pediatric-specific adverse events (AEs). Although drug manufacturers are required to submit postmarket AE reports to the Food and Drug Administration (FDA), this information is rarely transmitted to practitioners. In the setting of a recent FDA warning for sildenafil, the authors sought to give a better description of the AEs associated with current therapies in pediatric PH. In January 2010, a written request was made to the Food and Drug Administration for AE records of commonly used PH medications. Reports were screened for pediatric patients, analyzed in terms of AEs, and compared with the medical literature. Arbitrarily, AEs that could be attributed to concomitant medications were not attributed to the PH medication in question. Adverse events occurring in more than 5 % of events for each drug were assumed to be associated with the targeted PH medication. Between November 1997 and December 2009, 588 pediatric AE reports (death in 257 cases) were reported for the three most commonly used therapies: bosentan, epoprostenol, and sildenafil. Many of the AEs were similar to those reported previously. However, 27 AEs not previously reported in the literature (e.g., pulmonary hemorrhage, hemoptysis, and pneumonia) were found. The FDA postmarket records for PH medications in pediatric patients show a significant number of AEs. The discovery of AEs not previously reported will better inform those caring for these complex and critically ill children, and the large number of deaths suggest they may be underreported in current literature.
doi:10.1007/s00246-013-0688-2
PMCID: PMC3783558  PMID: 23532466
Adverse drug events; Pediatrics; Pulmonary; hypertension
13.  Wall shear stress measured by phase contrast cardiovascular magnetic resonance in children and adolescents with pulmonary arterial hypertension 
Background
Pulmonary arterial hypertension (PAH) is a devastating disease with significant morbidity and mortality. At the macroscopic level, disease progression is observed as a complex interplay between mean pulmonary artery pressure, pulmonary vascular resistance, pulmonary vascular stiffness, arterial size, and flow. Wall shear stress (WSS) is known to mediate or be dependent on a number of these factors. Given that WSS is known to promote architectural vessel remodeling, it is imperative that the changes of this factor be quantified in the presence of PAH.
Methods
In this study, we analyzed phase contrast imaging of the right pulmonary artery derived from cardiovascular magnetic resonance to quantify the local, temporal and circumferentially averaged WSS of a PAH population and a pediatric control population. In addition, information about flow and relative area change were derived.
Results
Although the normotensive and PAH shear waveform exhibited a WSS profile which is uniform in magnitude and direction along the vessel circumference at systole, time-averaged WSS (2.2 ± 1.6 vs. 6.6 ± 3.4 dynes/cm2, P = 0.018) and systolic WSS (8.2 ± 5.0 v. 20.0 ± 9.1 dynes/cm2, P = 0.018) was significantly depressed in the PAH population as compared to the controls. BSA-indexed PA diameter was significantly larger in the PAH population (1.5 ± 0.4 vs. 0.7 ± 0.1 cm/m2, P = 0.003).
Conclusions
In the presence of preserved flow rates through a large PAH pulmonary artery, WSS is significantly decreased. This may have implications for proximal pulmonary artery remodeling and cellular function in the progression of PAH.
doi:10.1186/1532-429X-15-81
PMCID: PMC3848825  PMID: 24034144
Vessel size; Pulmonary hypertension; Wall shear stress; Cardiovascular magnetic resonance
14.  Children with pulmonary arterial hypertension and prostanoid therapy: Long-term hemodynamics 
BACKGROUND
Pediatric patients with severe pulmonary arterial hypertension (PAH) are treated with intravenous epoprostenol or intravenous or subcutaneous treprostinil. Little is known about longitudinal hemodynamics and outcomes of epoprostenol, treprostinil, and transitions from epoprostenol to treprostinil.
METHODS
This was retrospective study of 77 pediatric patients (47 idiopathic PAH, 24 congenital heart disease-PAH) receiving epoprostenol or treprostinil from 1992 to 2010 at 2 centers. Outcomes were defined as living vs dead/transplant.
RESULTS
Mean age at baseline was 7.7 ± 5.2 years, with follow-up of 4.3 ± 3.4 years. Thirty-seven patients were treated with epoprostenol, 20 with treprostinil, and 20 were transitioned from epoprostenol to treprostinil. Mean pulmonary-to-systemic vascular resistance ratio (Rp/Rs) for epoprostenol was 1.0 ± 0.4, 0.8 ± 0.4, 0.8 ± 0.4, 1.0 ± 0.4, and 1.2 ± 0.4, respectively, at baseline, 1, 2, 3, and 4 years. For treprostinil, Rp/Rs was 0.9 ± 0.3, 0.7 ± 0.3, 0.5 ± 0.2, (p < 0.01 vs baseline), and 1.1 ± 0.2, respectively, at baseline, 1, 2, and 3 to 4 years, respectively. There were similar changes in mean pulmonary artery pressure and pulmonary vascular resistance index. The Rp/Rs 1 year after epoprostenol to treprostinil transition increased from 0.6 to 0.8 (n = 7). Changes not statistically significant unless noted. Eight patients died or received a transplant within 2 years of baseline; compared with the rest of the cohort, mean baseline Rp/Rs, right atrial pressure, and pulmonary vascular resistance index were significantly worse in this group. Thirty-nine patients remain on prostanoids, 17 are off, 16 died, and 5 received heart-lung transplant. Kaplan-Meier 5-year transplant-free survival was 70% (95% confidence interval, 56%-80%).
CONCLUSION
There was improvement in Rp/Rs on both therapies at 1 to 2 years that was not sustained. The 5-year transplant-free survival was better than in similar adult studies.
doi:10.1016/j.healun.2013.01.1055
PMCID: PMC3760159  PMID: 23453572
pediatric patients; pulmonary arterial hypertension; epoprostenol; treprostinil; hemodynamics
15.  Development of Occlusive Neointimal Lesions in Distal Pulmonary Arteries of Endothelin B Receptor–Deficient Rats: A New Model of Severe Pulmonary Arterial Hypertension 
Circulation  2005;111(22):2988-2996.
Background
Human pulmonary arterial hypertension (PAH) is characterized by proliferation of vascular smooth muscle and, in its more severe form, by the development of occlusive neointimal lesions. However, few animal models of pulmonary neointimal proliferation exist, thereby limiting a complete understanding of the pathobiology of PAH. Recent studies of the endothelin (ET) system demonstrate that deficiency of the ETB receptor predisposes adult rats to acute and chronic hypoxic PAH, yet these animals fail to develop neointimal lesions. Herein, we determined and thereafter showed that exposure of ETB receptor–deficient rats to the endothelial toxin monocrotaline (MCT) leads to the development of neointimal lesions that share hallmarks of human PAH.
Methods and Results
The pulmonary hemodynamic and morphometric effects of 60 mg/kg MCT in control (MCT+/+) and ETB receptor–deficient (MCTsl/sl) rats at 6 weeks of age were assessed. MCTsl/sl rats developed more severe PAH, characterized by elevated pulmonary artery pressure, diminished cardiac output, and right ventricular hypertrophy. In MCTsl/sl rats, morphometric evaluation revealed the presence of neointimal lesions within small distal pulmonary arteries, increased medial wall thickness, and decreased arterial-to-alveolar ratio. In keeping with this, barium angiography revealed diminished distal pulmonary vasculature of MCTsl/sl rat lungs. Cells within neointimal lesions expressed smooth muscle and endothelial cell markers. Moreover, cells within neointimal lesions exhibited increased levels of proliferation and were located in a tissue microenvironment enriched with vascular endothelial growth factor, tenascin-C, and activated matrix metalloproteinase-9, factors already implicated in human PAH. Finally, assessment of steady state mRNA showed that whereas expression of ETB receptors was decreased in MCTsl/sl rat lungs, ETA receptor expression increased.
Conclusions
Deficiency of the ETB receptor markedly accelerates the progression of PAH in rats treated with MCT and enhances the appearance of cellular and molecular markers associated with the pathobiology of PAH. Collectively, these results suggest an overall antiproliferative effect of the ETB receptor in pulmonary vascular homeostasis.
doi:10.1161/CIRCULATIONAHA.104.491456
PMCID: PMC1934986  PMID: 15927975
arteriosclerosis; endothelin; metalloproteinases; nitric oxide; pediatrics
16.  Plasma proteomics of differential outcome to long-term therapy in children with idiopathic pulmonary arterial hypertension 
Proteomics. Clinical applications  2012;6(5-6):257-267.
Purpose
The prognosis for children with IPAH unresponsive to therapy is poor. We investigated the plasma proteome for a molecular basis of good versus poor outcome to long-term vasodilator therapy.
Experimental design
Plasma was collected at baseline or shortly after therapy initiation and following chronic vasodilator therapy, then divided into those with good outcome (n = 8), and those with a poor outcome (n = 7). To identify proteins unique to either outcome, we used differential gel electrophoresis and mass spectrometry. Results were confirmed by commercial enzyme-linked immunosorbent assay.
Results
Before and after therapy, SAA-4 was 4-fold lower in those with good outcome compared to those with poor outcome, while serum paraoxonase/arylesterase-1 was increased 2-fold in those with good outcome versus poor outcome. After therapy, haptoglobin and hemopexin were 1.45- and 1.8-fold lower, respectively, in those with a good versus poor outcome. Among those with a good outcome, SAP was 1.3-fold lower prior to therapy.
Conclusions and clinical relevance
SAP and SAA-4 regulate circulating mononuclear phagocytes. As such, they may contribute to the differential response to chronic vasodilator therapy in the context of inflammation in IPAH.
doi:10.1002/prca.201100078
PMCID: PMC3569520  PMID: 22653875
Inflammation; Pulmonary hypertension; Vasodilators
17.  Endothelin-1, the Unfolded Protein Response, and Persistent Inflammation 
Endothelin-1 is a potent vasoactive peptide that occurs in chronically high levels in humans with pulmonary hypertension and in animal models of the disease. Recently, the unfolded protein response was implicated in a variety of diseases, including pulmonary hypertension. In addition, evidence is increasing for pathological, persistent inflammation in the pathobiology of this disease. We investigated whether endothelin-1 might engage the unfolded protein response and thus link inflammation and the production of hyaluronic acid by pulmonary artery smooth muscle cells. Using immunoblot, real-time PCR, immunofluorescence, and luciferase assays, we found that endothelin-1 induces both a transcriptional and posttranslational activation of the three major arms of the unfolded protein response. The pharmacologic blockade of endothelin A receptors, but not endothelin B receptors, attenuated the observed release, as did a pharmacologic blockade of extracellular signal–regulated kinases 1 and 2 (ERK-1/2) signaling. Using short hairpin RNA and ELISA, we observed that the release by pulmonary artery smooth muscle cells of inflammatory modulators, including hyaluronic acid, is associated with endothelin-1–induced ERK-1/2 phosphorylation and the unfolded protein response. Furthermore, the synthesis of hyaluronic acid induced by endothelin-1 is permissive for persistent THP-1 monocyte binding. These results suggest that endothelin-1, in part because it induces the unfolded protein response in pulmonary artery smooth muscle cells, triggers proinflammatory processes that likely contribute to vascular remodeling in pulmonary hypertension.
doi:10.1165/rcmb.2010-0506OC
PMCID: PMC3262656  PMID: 21778413
unfolded protein response; endothelin; pulmonary artery smooth muscle; hyaluronic acid; inflammation
18.  Advancing clinical trial design in pulmonary hypertension 
Pulmonary Circulation  2013;3(1):217-225.
In pulmonary hypertension, as in many other diseases, there is a need for a smarter approach to evaluating new treatments. The traditional randomized controlled trial has served medical science well, but constrains the development of treatments for rare diseases. A workshop was established to consider alternative clinical trial designs in pulmonary hypertension and here discusses their merits, limitations and challenges to implementation of novel approaches.
doi:10.4103/2045-8932.109933
PMCID: PMC3641733  PMID: 23662200
pulmonary arterial hypertension; clinical trial design; adaptive designs; modeling and simulation; Bayesian modeling; group sequential designs; population enrichment
19.  Circulating Cytokines and Growth Factors in Pediatric Pulmonary Hypertension 
Mediators of Inflammation  2012;2012:143428.
Background. Management of pediatric pulmonary hypertension (PH) remains challenging. We have assessed a panel of circulating proteins in children with PH to investigate their value as predictive and/or prognostic biomarkers. From these determinations, we aim to develop a practical, noninvasive tool to aid in the management of pediatric PH. Methods. Twelve cytokines and growth factors putatively associated with lung or vascular disease were examined in plasma specimens from 70 children with PH using multiplex protein array technology. Associations between hemodynamics, adverse events, and protein markers were evaluated. Results. Epidermal growth factor (EGF) and IL-6 were associated with important hemodynamics. Of the twelve proteins, VEGF and IL-6 were significantly, univariately associated with the occurrence of an adverse event, with odds ratios (95% confidence intervals) of 0.56 (0.33–0.98) and 1.69 (1.03–2.77), respectively. When hemodynamic predictors were combined with protein markers, the ability to predict adverse outcomes within the following year significantly increased. Conclusions. Specific circulating proteins are associated with hemodynamic variables in pediatric PH. If confirmed in additional cohorts, measurement of these proteins could aid patient care and design of clinical trials by identifying patients at risk for adverse events. These findings also further support a role for inflammation in pediatric PH.
doi:10.1155/2012/143428
PMCID: PMC3536060  PMID: 23316102
20.  Clinical features of paediatric pulmonary hypertension: a registry study 
Lancet  2012;379(9815):537-546.
Summary
Background
Paediatric pulmonary hypertension, is an important cause of morbidity and mortality, and is insufficiently characterised in children. The Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP) registry is a global, prospective study designed to provide information about demographics, treatment, and outcomes in paediatric pulmonary hypertension.
Methods
Consecutive patients aged 18 years or younger at diagnosis with pulmonary hypertension and increased pulmonary vascular resistance were enrolled in TOPP at 31 centres in 19 countries from Jan 31, 2008, to Feb 15, 2010. Patient and disease characteristics, including age at diagnosis and at enrolment, sex, ethnicity, presenting symptoms, pulmonary hypertension classification, comorbid disorders, medical and family history, haemodynamic indices, and functional class were recorded. Follow-up was decided by the patients’ physicians according to the individual’s health-care needs.
Findings
362 of 456 consecutive patients had confirmed pulmonary hypertension (defined as mean pulmonary artery pressure ≥25 mm Hg, pulmonary capillary wedge pressure ≤12 mm Hg, and pulmonary vascular resistance index ≥3 WU/m32). 317 (88%) patients had pulmonary arterial hypertension (PAH), which was idiopathic [IPAH] or familial [FPAH] in 182 (57%), and associated with other disorders in 135 (43%), of which 115 (85%) cases were associated with congenital heart disease. 42 patients (12%) had pulmonary hypertension associated with respiratory disease or hypoxaemia, with bronchopulmonary dysplasia most frequent. Finally, only three patients had either chronic thromboembolic pulmonary hypertension or miscellaneous causes of pulmonary hypertension. Chromosomal anomalies, mainly trisomy 21, were reported in 47 (13%) of patients with confirmed disease. Median age at diagnosis was 7 years (IQR 3–12); 59% (268 of 456) were female. Although dyspnoea and fatigue were the most frequent symptoms, syncope occurred in 31% (57 of 182) of patients with IPAH or FPAH and in 18% (eight of 45) of those with repaired congenital heart disease; no children with unrepaired congenital systemic-to-pulmonary shunts had syncope. Despite severe pulmonary hypertension, functional class was I or II in 230 of 362 (64%) patients, which is consistent with preserved right-heart function.
Interpretation
TOPP identifies important clinical features specific to the care of paediatric pulmonary hypertension, which draw attention to the need for paediatric data rather than extrapolation from adult studies.
Funding
Actelion Pharmaceuticals.
doi:10.1016/S0140-6736(11)61621-8
PMCID: PMC3426911  PMID: 22240409
21.  Computational Simulation of the Pulmonary Arteries and its Role in the Study of Pediatric Pulmonary Hypertension 
Progress in pediatric cardiology  2010;30(1-2):63-69.
The hemodynamic state of the pulmonary arteries is challenging to routinely measure in children due to the vascular circuit's position in the lungs. The resulting relative scarcity of quantitative clinical diagnostic and prognostic information impairs management of diseases such as pulmonary hypertension, or high blood pressure of the pulmonary circuit, and invites new techniques of measurement. Here we examine recent applications of macro-scale computational mechanics methods for fluids and solids – traditionally used by engineers in the design and virtual testing of complex metal and composite structures – applied to study the pulmonary vasculature, both in healthy and diseased states. In four subject areas, we briefly outline advances in computational methodology and provide examples of clinical relevance.
doi:10.1016/j.ppedcard.2010.09.008
PMCID: PMC3076725  PMID: 21499523
22.  Assessment of Pulmonary Hypertension in the Pediatric Catheterization Laboratory 
Objectives
To assess protocols, demographics, and hemodynamics in pediatric patients undergoing catheterization for pulmonary hypertension (PH).
Background
Pediatric specific data is limited on PH.
Methods
Review of the Mid-Atlantic Group of Interventional Cardiology (MAGIC) collaboration PH registry dataset.
Results
Between November 2003 and October 2008, seven institutions submitted data from 177 initial catheterizations in pediatric patients with suspected PH. Pulmonary arterial hypertension associated with congenital heart disease (APAH-CHD) (n = 61, 34%) was more common than idiopathic PAH (IPAH) (n = 36, 20%). IPAH patients were older with higher mean pulmonary arterial pressures (mPAP) (P < 0.01). Oxygen lowered mPAP in patients with IPAH (P < 0.01) and associated PAH not related to congenital heart disease (APAH-non CHD) (P < 0.01). A synergistic effect was seen with inhaled Nitric Oxide (iNO) (P < 0.01). Overall 9/30 (29%) patients with IPAH and 8/48 (16%) patients with APAH-non CHD were reactive to vasodilator testing. Oxygen lowered pulmonary vascular resistance index (PVRI) in patients with APAH-CHD (P < 0.01). There was no additive effect with iNO but a subset of patients required iNO to lower PVRI below 5 WU·m2. General anesthesia (GA) lowered systemic arterial pressure (P < 0.01) with no difference between GA and procedural sedation on mPAP or PVRI. Adverse events were rare (n = 7) with no procedural deaths.
Conclusions
Pediatric patients with PH demonstrate a higher incidence of APAH-CHD and neonatal specific disorders compared to adults. Pediatric PH patients may demonstrate baseline mPAP < 40 mm Hg but > 50% systemic illustrating the difficulty in applying adult criteria to children with PH. Catheterization in children with PH is relatively safe.
doi:10.1002/ccd.22693
PMCID: PMC3116922  PMID: 20549685
pulmonary hypertension; pediatric; cardiac catheterization; hemodynamics; vasoreactivity
23.  Pulmonary Vascular Input Impedance is a Combined Measure of Pulmonary Vascular Resistance and Stiffness and Predicts Clinical Outcomes Better than PVR Alone in Pediatric Patients with Pulmonary Hypertension 
American heart journal  2007;155(1):166-174.
Background
Pulmonary vascular resistance (PVR) is the current standard for evaluating reactivity in children with pulmonary arterial hypertension (PAH). However, PVR measures only the mean component of right ventricular afterload and neglects pulsatile effects. We recently developed and validated an method to measure pulmonary vascular input impedance, which revealed excellent correlation between the zero-harmonic impedance value and PVR, and suggested a correlation between higher harmonic impedance values and pulmonary vascular stiffness (PVS). Here we show that input impedance can be measured routinely and easily in the catheterization laboratory, that impedance provides PVR and PVS from a single measurement, and that impedance is a better predictor of disease outcomes compared to PVR.
Methods
Pressure and velocity waveforms within the main PA were measured during right-heart catheterization of patients with normal PA hemodynamics (n=14) and those with PAH undergoing reactivity evaluation (49 subjects; 95 conditions). A correction factor needed to transform velocity into flow was obtained by calibrating against cardiac output. Input impedance was obtained off-line by dividing Fourier-transformed pressure and flow waveforms.
Results
Exceptional correlation was found between the indexed zero harmonic of impedance and indexed PVR (y=1.095·x+1.381, R2=0.9620). Additionally, the modulus sum of the first two harmonics of impedance was found to best correlate with indexed pulse pressure over stroke volume (PP/SV) (y=13.39·x-0.8058, R2=0.7962). Amongst a subset of PAH patients (n=25), cumulative logistic regression between outcomes to total indexed impedance was better (RL2=0.4012) than between outcomes and indexed PVR (RL2=0.3131).
Conclusions
Input impedance can be consistently and easily obtained from PW Doppler and a single catheter pressure measurement, provides comprehensive characterization of the main components of RV afterload, and better predicts patient outcomes compared to PVR alone.
doi:10.1016/j.ahj.2007.08.014
PMCID: PMC3139982  PMID: 18082509
hypertension; pulmonary; pulmonary heart disease; pediatrics; echocardiography; hemodynamics
24.  Weaning and Discontinuation of Epoprostenol in Children With Idiopathic Pulmonary Arterial Hypertension Receiving Concomitant Bosentan 
In 7 of 8 children with idiopathic pulmonary arterial hypertension treated with intravenous epoprostenol for > 1 year, concomitant use of bosentan allowed a reduction of epoprostenol and decreased its associated side effects without deterioration of clinical and hemodynamic parameters. In 3 children with normal or near-normal pulmonary artery pressure on epoprostenol, the addition of bosentan allowed discontinuation of epoprostenol and stabilization of hemodynamics for up to 1 year.
doi:10.1016/j.amjcard.2003.12.031
PMCID: PMC3138203  PMID: 15050507
25.  Performance of Cavopulmonary Palliation at Elevated Altitude 
Circulation  2008;118(14 Suppl):S177-S181.
Background
Outcomes of patients undergoing cavopulmonary palliation for single ventricle physiology may be impacted by living at altitude, as the passive pulmonary circulation is dependent on the resistance of the pulmonary vascular bed. The objective of this study is to identify risk factors for failure of cavopulmonary palliation at elevated altitude.
Methods and Results
Between January 1995 and March 2007, 122 consecutive patients living at a mean altitude of 1600 m (range 305 to 2570) underwent a bidirectional Glenn (BDG). There was one in-hospital mortality and 7 late deaths. 52 have proceeded to the Fontan procedure. Survival after BDG was 92.4% at 5 years. Freedom from palliation failure, defined as death, transplant, BDG/Fontan takedown, or revision was 81% at 5 years. At a mean follow-up of 39.8 months, 90 patients (75%) were in New York Heart Association class I. Patients with failing cavopulmonary circulation had higher pre-BDG pulmonary artery pressure (PAP) (18.3±6.1 mm Hg versus 14.8±5.1 mm Hg, P=0.016) and higher pre-BDG transpulmonary gradient (TPG) (11.2±6.2 mm Hg versus 7.7±4.3 mm Hg, P=0.014). Post-BDG, patients with palliation failure had increased PAP (15.0±5.7 mm Hg versus 10.8±2.8 mm Hg, P=0.008) and indexed pulmonary vascular resistance (PVRI) (2.43±1.0 Wood U · m2 versus 1.52±0.9 Wood U · m2, P=0.007).
Conclusions
The majority of patients at moderate altitude have favorable outcomes after BDG or Fontan palliation. Risk factors for palliation failure at elevated altitude include PAP >15 mm Hg, TPG >8 mm Hg, and PVRI >2.5 Wood U · m2.
doi:10.1161/CIRCULATIONAHA.107.751784
PMCID: PMC3129266  PMID: 18824752
Fontan procedure; single ventricle; altitude

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