Pediatric Pediatric Pulmonary Arterial Hypertension Research Articles

Tadalafil Nanoemulsion Mists for Treatment of Pediatric Pulmonary Hypertension via Nebulization.

Oral tadalafil (TD) proved promising in treating pediatric pulmonary arterial hypertension (PAH). However, to ensure higher efficacy and reduce the systemic side effects, targeted delivery to the lungs through nebulization was proposed as an alternative approach. This poorly soluble drug was previously dissolved in nanoemulsions (NEs). However, the formulations could not resist aqueous dilution, which precluded its dilution with saline for nebulization. Thus, the current study aimed to modify the previous systems into dilutable TD-NEs and assess their suitability for a pulmonary application. In this regard, screening of various excipients was conducted to optimize the former systems; different formulations were selected and characterized in terms of physicochemical properties, nebulization performance, stability following sterilization, and biocompatibility. Results showed that the optimal system comprised of Capmul-MCM-EP:Labrafac-lipophile (1:1) (w/w) as oil, Labrasol:Poloxamer-407 (2:1) (w/w) as surfactant mixture (Smix) and water. The optimum formulation P2TD resisted aqueous dilution, exhibited reasonable drug loading (2.45 mg/mL) and globule size (25.04 nm), acceptable pH and viscosity for pulmonary administration, and could be aerosolized using a jet nebulizer. Moreover, P2TD demonstrated stability following sterilization and a favorable safety profile confirmed by both in-vitro and in-vivo toxicity studies. These favorable findings make P2TD promising for the treatment of pediatric PAH.

Factors determining change in treatment for ambulatory children with pulmonary arterial hypertension: Implications for monitoring.

While care models adapt to the COVID‐19 pandemic with virtual and hybrid visits, clinical factors associated with treatment changes among ambulatory pediatric pulmonary arterial hypertension (PAH) patients are not well characterized. To understand which data critically altered treatment recommendations, we conducted a retrospective review among ambulatory children with Group 1 PAH to determine optimal visit and diagnostic strategies. Changes in management included: unplanned new treatments, dose modifications of vasodilators or diuretics, unscheduled hospitalizations, or changes to activity recommendations, catheterization schedule, or other testing. Factors prompting management changes were classified as symptoms, exam findings, or diagnostic tests. Across 398 ambulatory visits by 48 patients, 38 patients (79%) at 88 visits (22%) required change in management, most commonly in targeted PH medication. Changes were driven by symptoms alone (15%), diagnostic testing alone (47%), exam only (2%), symptoms and exam (2%), combination of testing and symptoms or testing and exam (25%), and other reasons (9%). Patients with World Health Organization functional Class IV (odds ratio [OR] 9.04 vs. Class I, p = 0.014) or Class III (OR 2.08 vs. Class I, p = 0.050) were more likely to undergo change in management. However, among Class I patients, 18% of visits generated changes in management because of test findings. While multiple factors affect management in ambulatory pediatric PH, neither symptoms nor exam was sufficient for identifying patients warranting clinical change in management. Testing accounted for most changes. Thus, in‐person or hybrid surveillance including history, exam, and diagnostic testing remains essential for optimal management of pediatric PAH.

Pulmonary arterial banding in mice may be a suitable model for studies on ventricular mechanics in pediatric pulmonary arterial hypertension

BackgroundThe role of interventricular mechanics in pediatric pulmonary arterial hypertension (PAH) and its relation to right ventricular (RV) dysfunction has been largely overlooked. Here, we characterize the impact of maintained pressure overload in the RV–pulmonary artery (PA) axis on myocardial strain and left ventricular (LV) mechanics in pediatric PAH patients in comparison to a preclinical PA-banding (PAB) mouse model. We hypothesize that the PAB mouse model mimics important aspects of interventricular mechanics of pediatric PAH and may be beneficial as a surrogate model for some longitudinal and interventional studies not possible in children.MethodsBalanced steady-state free precession (bSSFP) cardiovascular magnetic resonance (CMR) images of 18 PAH and 17 healthy (control) pediatric subjects were retrospectively analyzed using CMR feature-tracking (FT) software to compute measurements of myocardial strain. Furthermore, myocardial tagged-CMR images were also analyzed for each subject using harmonic phase flow analysis to derive LV torsion rate. Within 48 h of CMR, PAH patients underwent right heart catheterization (RHC) for measurement of PA/RV pressures, and to compute RV end-systolic elastance (RV_Ees, a measure of load-independent contractility). Surgical PAB was performed on mice to induce RV pressure overload and myocardial remodeling. bSSFP-CMR, tagged CMR, and intra-cardiac catheterization were performed on 12 PAB and 9 control mice (Sham) 7 weeks after surgery with identical post-processing as in the aforementioned patient studies. RV_Ees was assessed via the single beat method.ResultsLV torsion rate was significantly reduced under hypertensive conditions in both PAB mice (p = 0.004) and pediatric PAH patients (p < 0.001). This decrease in LV torsion rate correlated significantly with a decrease in RV_Ees in PAB (r = 0.91, p = 0.05) and PAH subjects (r = 0.51, p = 0.04). In order to compare combined metrics of LV torsion rate and strain parameters principal component analysis (PCA) was used. PCA revealed grouping of PAH patients with PAB mice and control subjects with Sham mice. Similar to LV torsion rate, LV global peak circumferential, radial, and longitudinal strain were significantly (p < 0.05) reduced under hypertensive conditions in both PAB mice and children with PAH.ConclusionsThe PAB mouse model resembles PAH-associated myocardial mechanics and may provide a potential model to study mechanisms of RV/LV interdependency.

Longitudinal assessment of right atrial conduit fraction provides additional insight to predict adverse events in pediatric pulmonary hypertension

BackgroundRecent studies show adverse right atrial (RA) emptying pattern is prognostic for clinical worsening events in pediatric pulmonary arterial hypertension (PAH). No study has reported changes in RA emptying over time or evaluated whether serial measurements offer further prognostic information. MethodsProspective study of 32 children with idiopathic or heritable PAH undergoing echocardiogram at baseline and 1-year. RA conduit fraction percent (RA cF%) was measured as percentage of total diastolic RA area change prior to the electrical p wave. Clinical worsening was analyzed with a predefined composite adverse event outcome. ResultsLongitudinal subjects (median age 13.3 yr) had RA cF% 61% (IQR 32–68%) at baseline and 60% (IQR 35–73%) at 1-year (NS). 11 subjects had a qualifying event during median 21-month follow-up. Subjects with an event had 1-year RA cF% = 33% (IQR 20–40%) compared to 72% (IQR 63–75%) for those with no event (p < 0.001). Event rates were lowest for subjects with both echocardiograms showing RA cF% > 60% (0%), highest for subjects with neither (80%), and intermediate for those with one (38%, p = 0.003). ConclusionsChanges in RA cF% inform risk of adverse events in pediatric PAH. This finding supports the role of RA cF% as both a prognostic biomarker and potential treatment target.

Abstract 14979: Endostatin as a Predictor of Severity and Survival in Pediatric Congenital Heart Disease Associated Pulmonary Hypertension

Introduction: Pediatric pulmonary arterial hypertension (PAH) is a multifactorial pulmonary vascular disease with high mortality. Endostatin (ES), an angiogenic inhibitor, is associated with disease severity and mortality in adults with PAH and poor lung growth in children. Hypothesis: Increased ES is associated with worse disease severity and outcomes in pediatric PAH. Methods: Serum ES levels were measured in two cohorts of pediatric PAH (IPAH, FPAH and APAH) patients; the cross-sectional CCHMC PAH Biobank (PAHB, N=175) and a longitudinal cohort from Children’s Hospital of Colorado (CHC, N=61). Outcomes included medical therapy, functional and hemodynamic measures, and survival (death, transplant, palliative shunt). Adjusted logistic and linear regressions and Kaplan-Meier analysis were used to assess the relationship between ES and clinical outcomes. Results: In both cohorts, ES was significantly higher in PAH associated with congenital heart disease (APAH-CHD, PAHB n=70, p=0.002; CHC n=29, p=0.007) and was highest in those with a ventricular shunt (n=24, p=0.001). In APAH-CHD, ES was associated with a decreased 6MWD (-108m, -187- -30, p=0.01) and increased mean right atrial pressure (mRAP 1.8mmHg, 0.3-3.3, p=0.02). Longitudinally, in the APAH-CHD subgroup when adjusted for age, sex, and multiple time points, higher ES was associated with increased PVRi and mPAP (PVRi 2.5WU*m 2 , 0.7-4.3, p=0.007; mPAP 10mmHg, 4.5-15, p&lt;0.001). Kaplan-Meier analysis (Figure 1) demonstrated that ES was associated with worse outcomes in both cohorts, with an adjusted Cox proportional hazard ratio of 4.3 (1.13-16, p=0.03) in the PAHB. Conclusions: ES was associated with worse functional measures, pulmonary vascular hemodynamics, and survival in pediatric APAH-CHD. These observations suggest that serum ES could act as a pulmonary vascular specific biomarker to identify those who are at increased risk of developing PAH and predict poor outcomes in APAH-CHD.

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

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

A Review on Drug of Pediatric Pulmonary Arterial Hypertension (PAH), their Chemistry and Pharmaceutical Dosage Forms

Hypertension, specifically pulmonary hypertension, is a syndromethat can affect pediatric patients as well as adults. Pulmonary arterial hypertension (PAH) in pediatric patients, while rare, can be a lifethreateningcondition. There is no cure for PAH, only treatment options forchildren that are largely based on the results of adult studies. These therapies, however, can improve quality of life and survival. Treatment can be challenging because of the less approved medications and tolerable dosage forms for pediatric patients. Pediatric pulmonary arterial hypertension (PAH) shares common features of adult disease, but is associated with several additional disorders and challenges that require unique approaches. Current classes of medications primarily used to treat pediatric hypertension include phosphodiesterase inhibitors, endothelin receptor antagonists, and prostacyclins. Additional agents that may be utilized in selected pediatric patients include calcium channel blockers, anticoagulants, and inhalednitric oxide. Updates are provided on issues related to utility of the previous classification system to reflect pediatric-specific aetiologies and approaches to medical and interventional management of PAH. Also updates are provided about currently available drug substance and their details, pharmaceutical dosage forms and their details along with the mechanism of action, pharmacokinetics of the drug. These emerging data are improving the identification of appropriate targets for goal-oriented therapy inchildren. Such data will likely improve future advanced pharmaceutical dosage development and product design to enhance outcomes in pediatric PAH.&#x0D; Keywords: Pulmonary arterial hypertension, pediatric hypertension, PAH

Management of Pulmonary Arterial Hypertension in the Pediatric Patient.

Pediatric pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. Herein we review the diagnosis and classification for pediatric PAH and detail the current therapeutic options available for use in the pediatric PAH population. Classification and treatment of pediatric PAH is guided by adult criteria and treatment algorithms, yet the distribution of factors contributing to PAH in children differs significantly from that seen in adults. It is necessary to understand these differences in order to appropriately tailor therapy to the needs of the child or adolescent. An expanding array of targeted PAH drugs are now approved for use in adults, and many of these drugs are used "off-label" to treat children and adolescents with PAH. Use of these novel therapies has coincided with marked improvement in outcomes, suggesting significant benefit. However, because most of these drugs have not been studied in rigorous randomized, controlled trials in children, it is critical that physicians understand their mechanisms of action, potential benefits, and safety profiles. Pediatric PAH outcomes have improved substantially in the modern era, coinciding with the "off-label" use of targeted PAH drugs in children and adolescents. Ideally, care should be provided at centers with specialized expertise in the diagnosis and treatment of pediatric PAH by providers who understand the appropriate diagnostic algorithms, classification schemes, and treatment approaches.

DECREASED PULMONARY PULSE TRANSIT IS ASSOCIATED WITH PEDIATRIC PULMONARY ARTERIAL HYPERTENSION

Echocardiographic metrics may aid the management of pediatric pulmonary arterial hypertension (PAH). Reduced pulmonary pulse transit time (pPTT) has been proposed as a marker of PAH in adults. This study tested the hypothesis that decreased pPTT associates with pediatric PAH. A retrospective, case-

Effect of electrical dyssynchrony on left and right ventricular mechanics in children with pulmonary arterial hypertension

Electrical and right ventricular (RV) mechanical dyssynchrony has been previously described in pediatric pulmonary arterial hypertension (PAH), but less is known about the relationship between electrical dyssynchrony and biventricular function. In this study we applied cardiac magnetic resonance (CMR) imaging to evaluate biventricular size and function with a focus on left ventricular (LV) strain mechanics in pediatric PAH patients with and without electrical dyssynchrony. Fifty-six children with PAH and comprehensive CMR evaluation were stratified based on QRS duration z-score, with electrical dyssynchrony defined as z-score ≥2. Comprehensive biventricular volumetric, dyssynchrony, and strain analysis was performed. Nineteen PAH patients had or developed electrical dyssynchrony. Patients with electrical dyssynchrony had significantly reduced RV ejection fraction (35% vs 50%, p = 0.003) and greater end-diastolic (168 vs 112 ml/m2, p = 0.041) and end-systolic (119 vs 57, ml/m2, p = 0.026) volumes. Patients with electrical dyssynchrony had reduced RV longitudinal strain (-14% vs -19%, p = 0.007), LV circumferential strain measured at the free wall (-19% vs -22%, p = 0.047), and the LV longitudinal strain in the septal region (-10% vs -15%, p = 0.0268). LV mechanical intraventricular dyssynchrony was reduced in patients with electrical dyssynchrony at the LV free wall (43 vs 19 ms, p = 0.019). The electrical dyssynchrony is associated with the reduced LV strain, enlarged RV volumes, and reduced biventricular function in children with PAH. CMR assessment of biventricular mechanical function with respect to QRS duration may help to detect pathophysiologic processes associated with progressed PAH.

Physical Activity in Pediatric Pulmonary Arterial Hypertension Measured by Accelerometry. A Candidate Clinical Endpoint.

The development of evidence-based treatment guidelines for pediatric pulmonary arterial hypertension (PAH) is hampered by lack of pediatric clinical trials. Trial design is hampered by lack of a feasible clinical endpoint in this population. To evaluate the use of accelerometry for measuring physical activity (PA) in pediatric PAH and to investigate its correlation with clinical disease severity markers. We included children from the Dutch National Network for Pediatric Pulmonary Hypertension. Control patients were recruited from the outpatient cardiology clinic of the Beatrix Children's Hospital. Children were asked to wear the accelerometer for 7 days. Vector magnitude counts per minute (VM CPM) and time per day spent in different PA intensity levels were defined as accelerometer outcomes. VM CPM was lower in children with PAH (n = 29) than in controls (n = 60; 647 vs. 921; P < 0.001). Children with PAH spent less time in moderate and vigorous PA (13 vs. 29 min/d and 2 vs. 13 min/d, respectively; P < 0.001). Time spent in moderate and vigorous PA correlated inversely with World Health Organization functional class. Time spent in moderate PA correlated positively with 6-minute-walk distance. In post hoc analyses, VM CPM and time spent in moderate/vigorous combined and vigorous PA were associated with outcome (P ≤ 0.044). PA is markedly decreased in children with PAH. Accelerometer output correlated with clinical disease severity markers and may predict outcome. We showed an exciting potential of PA as a meaningful endpoint for clinical trials in pediatric PAH, although its clinical utility and prognostic value need to be further validated.

Clinical classification in pediatric pulmonary arterial hypertension associated with congenital heart disease.

Congenital heart disease (CHD) is a frequent cause of pediatric pulmonary arterial hypertension (PAH), with diverse etiology and outcome. We aimed to describe phenotypic heterogeneity in pediatric PAH associated with CHD (PAH-CHD), assess the applicability of the Nice CHD classification, and explore whether this classification accurately reflects patient/disease characteristics and survival. All children with CHD from a contemporary cohort of consecutive pediatric PAH patients followed in three major referral centers (Denver, New York, the Netherlands) were characterized and classified on the basis of the latest proposed clinical classification for PAH-CHD (World Symposium on Pulmonary Hypertension, Nice, 2013). According to this classification, 24% of 134 children were classified into group 1, 14% into group 2, 19% into group 3, and 30% into group 4; 11% could not be classified. Types of CHD and hemodynamic profile differed between groups, with the highest right atrial pressure in group 4 (P < 0.040). Group 3 children had Down syndrome less frequently (P = 0.011) but other (un)defined syndromes most frequently (P = 0.063) and received most intense PAH-targeted therapy (P = 0.003). With 15 deaths and one lung transplant (12%; median follow-up: 4.3 years), survival differences could not be demonstrated between the groups in the Nice CHD classification. Pediatric PAH-CHD is a heterogeneous condition frequently associated with extracardiac, developmental factors that are believed to affect disease development. The Nice CHD classification identifies groups with specific patient/disease characteristics. However, a substantial proportion of children could not be classified. Group 3 forms a distinct disease entity. Its prognostic value could not be determined because of the low number of events. The Nice CHD classification supports clinical characterization of PAH-CHD; however, further refinement is needed to classify all children with PAH-CHD.

Reliable and developmentally appropriate study end points are needed to achieve drug development for treatment of pediatric pulmonary arterial hypertension

To identify suitable end points and surrogates for pediatric pulmonary arterial hypertension (PAH) as the lack of developmentally appropriate end point and clinical trials contribute to the unmet medical need. Reviewed the efficacy end points and surrogates for all trials (1995 to 2013) that were submitted to the Food and Drug Administration (FDA) to support the approval of PAH therapy and conducted literature search. An increase in the 6 min walking distance (6MWD) was used as a primary end point in 8/9 adult PAH trials. This end point is not suitable for infants and young children because of performance limitations and lack of control data. One adult PAH trial used time to the first morbidity or mortality event as a primary end point, which could potentially be used in pediatric PAH trials. In the sildenafil pediatric PAH trial, the change in pulmonary vascular resistance index or mean pulmonary artery pressure was used as a surrogate for the 6MWD to assess exercise capacity. However, two deaths and three severe adverse events during the catheterizations made this an unacceptably high-risk surrogate. The INOmax persistent pulmonary hypertension of the newborn trial used a reduction in initiation of extracorporeal membrane oxygenation treatment as a primary end point, which is not feasible for other pediatric PAH trials. A Literature review revealed none of the existing noninvasive markers are fully validated as surrogates to assess PAH efficacy and long-term safety. For pediatric PAH trials, clinical end points are acceptable, and novel validated surrogates would be helpful. FDA seeks collaboration with academia, industry and parents to develop other suitable and possibly more efficient efficacy end points to facilitate pediatric PAH drug development.

Six-minute walking distance and decrease in oxygen saturation during the six-minute walk test in pediatric pulmonary arterial hypertension

ObjectiveTo investigate the prognostic value of the 6-minute walking distance (6-MWD), transcutaneous saturation (tcSO2) and heart rate (HR) obtained during the 6-minute walk test (6-MWT) in pediatric pulmonary arterial hypertension (PAH). MethodsThis was an observational study with forty-seven pediatric PAH patients, aged ≥7years, and diagnosed and followed at the national referral center for pediatric PAH in the Netherlands. All patients performed a comprehensive 6-minute walk test (6-MWT), which measures 6-MWD and tcSO2 and HR before (“baseline”), during (“exercise”) and 5min after (“recovery”) the walk test. ResultsThe 6-MWD expressed either in meters or in sex- and age-corrected z-scores, was associated with transplant-free survival, independently from sex, age, and the presence of a shunt-defect. Shorter 6-MWD correlated with higher WHO-FC and increased NT-pro-BNP. Absolute tcSO2 at exercise and tcSO2-decrease during 6-MWT were associated with transplant-free survival, independent from 6-MWD. Combining tcSO2-decrease with 6-MWD provided the strongest prognostic model. Patients with 6-MWD>352m (the median 6-MWD) had a better outcome than those with smaller 6-MWD. A large tcSO2-decrease during 6-MWT (>19% for patients with and >5% for patients without a shunt defect) identified patients with worse transplant-free survival both in patients with a 6-MWD above and below the median 6-MWD. ConclusionsThe 6-MWD is an independent predictor of prognosis in pediatric PAH, that reflects disease severity and clinically relevant exercise-tolerance and therefore qualifies as a treatment goal. The magnitude of tcSO2-decrease during 6-MWT, adjusted for the presence of a shunt, indicates an additional risk factor for prognosis in children with PAH.

Prognostic factors in pediatric pulmonary arterial hypertension: A systematic review and meta-analysis

BackgroundDespite the introduction of targeted therapies in pediatric pulmonary arterial hypertension (PAH), prognosis remains poor. For the definition of treatment strategies and guidelines, there is a high need for an evidence-based recapitulation of prognostic factors. The aim of this study was to identify and evaluate prognostic factors in pediatric PAH by a systematic review of the literature and to summarize the prognostic value of currently reported prognostic factors using meta-analysis. Methods and resultsMedline, EMBASE and Cochrane Library were searched on April 1st 2014 to identify original studies that described predictors of mortality or lung-transplantation exclusively in children with PAH. 1053 citations were identified, of which 25 were included for further analysis. Hazard ratios (HR) and 95% confidence intervals were extracted from the papers. For variables studied in at least three non-overlapping cohorts, a combined HR was calculated using random-effects meta-analysis. WHO functional class (WHO-FC, HR 2.7), (N-terminal pro-) brain natriuretic peptide ([NT-pro]BNP, HR 3.2), mean right atrial pressure (mRAP, HR 1.1), cardiac index (HR 0.7), indexed pulmonary vascular resistance (PVRi, HR 1.3) and acute vasodilator response (HR 0.3) were identified as significant prognostic factors (p≤0.001). ConclusionsThis systematic review combined with separate meta-analyses shows that WHO-FC, (NT-pro)BNP, mRAP, PVRi, cardiac index and acute vasodilator response are consistently reported prognostic factors for outcome in pediatric PAH. These variables are useful clinical tools to assess prognosis and should be incorporated in treatment strategies and guidelines for children with PAH.

Survival Differences in Pediatric Pulmonary Arterial Hypertension: Clues to a Better Understanding of Outcome and Optimal Treatment Strategies

In order to describe survival and treatment strategies in pediatric pulmonary arterial hypertension (PAH) in the current era of PAH-targeted drugs and to identify predictors of outcome, we studied uniformly defined contemporary patient cohorts at 3 major referral centers for pediatric PAH (New York [NY], Denver, and the Netherlands [NL]). In pediatric PAH, discrepancies exist in reported survival rates between North American and European patient cohorts, and robust data for long-term treatment effects are lacking. According to uniform inclusion criteria, 275 recently diagnosed consecutive pediatric PAH patients who visited the 3 referral centers between 2000 and 2010 were included. Unadjusted survival rates differed between the center cohorts (1-, 3-, and 5-year transplantation-free survival rates: 100%, 96%, and 90% for NY; 95%, 87%, and 78% for Denver; and 84%, 71%, and 62% for NL, respectively; p < 0.001). Based on World Health Organization (WHO) functional class and hemodynamic parameters, disease severity at diagnosis differed between the center cohorts. Adjustment for diagnosis, WHO functional class, indexed pulmonary vascular resistance, and pulmonary-to-systemic arterial pressure ratio resolved the observed survival differences. Treatment with PAH-targeted dual and triple therapy during the study period was associated with better survival than treatment with PAH-targeted monotherapy. Survival rates of pediatric PAH patients differed between 3 major referral centers. This could be explained by differences between the center cohorts in patients' diagnoses and measures of disease severity, which were identified as important predictors of outcome. In this study, treatment with PAH-targeted combination therapy during the study period was independently associated with improved survival.

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.

Evaluation of Circulating Proteins and Hemodynamics Towards Predicting Mortality in Children with Pulmonary Arterial Hypertension

BackgroundAlthough many predictors have been evaluated, a set of strong independent prognostic mortality indicators has not been established in children with pediatric pulmonary arterial hypertension (PAH). The aim of this study was to identify a combination of clinical and molecular predictors of survival in PAH.MethodsThis single-center, retrospective cohort study was performed from children with PAH between 2001 and 2008 at Children's Hospital Colorado. Blood samples from 83 patients (median age of 8.3 years-old) were obtained. We retrospectively analyzed 46 variables, which included 27 circulating proteins, 7 demographic variables and 12 hemodynamic and echocardiographic variables for establishing the best predictors of mortality. A data mining approach was utilized to evaluate predictor variables and to uncover complex data structures while performing variable selection in high dimensional problems.ResultsThirteen children (16%) died during follow-up (median; 3.1 years) and survival rates from time of sample collection at 1 year, 3 years and 5 years were 95%, 85% and 79%, respectively. A subset of potentially informative predictors were identified, the top four are listed here in order of importance: Tissue inhibitors of metalloproteinases-1 (TIMP-1), apolipoprotein-AI, RV/LV diastolic dimension ratio and age at diagnosis. In univariate analysis, TIMP-1 and apolipoprotein-AI had significant association with survival time (hazard ratio [95% confidence interval]: 1.25 [1.03, 1.51] and 0.70 [0.54–0.90], respectively). Patients grouped by TIMP-1 and apolipoprotein-AI values had significantly different survival risks (p<0.01).ConclusionImportant predictors of mortality were identified from a large number of circulating proteins and clinical markers in this cohort. If confirmed in other populations, measurement of a subset of these predictors could aid in management of pediatric PAH by identifying patients at risk for death. These findings also further support a role for the clinical utility of measuring circulating proteins.

A Randomized, Open-Label, 3-Way Crossover Study to Demonstrate Bioequivalence of Sildenafil Powder for Oral Suspension With Tablets Used Commercially and in Clinical Studies for the Treatment of Pulmonary Arterial Hypertension.

Sildenafil citrate (Revatio) is approved for pediatric pulmonary arterial hypertension (PAH) in the European Union. A new pediatric formulation, 10 mg/mL sildenafil citrate powder for oral suspension (POS), was developed for pediatric PAH patients. Bioequivalence among the POS suspension (20 mg), the Revatio 20-mg commercial tablet, and the sildenafil citrate 2 × 10-mg clinical trial tablets was assessed. In this randomized, open-label study, 42 healthy adult volunteers received the 3 different sildenafil treatments, each in a single 20-mg oral dose, using a 3-way crossover design. Blood samples were collected at predefined times and analyzed for sildenafil plasma concentrations. Natural log-transformed sildenafil pharmacokinetic parameters (Cmax , AUClast , and AUC∞ ) were evaluated for bioequivalence using a mixed-effects model. Results were used to estimate relative bioavailability and construct 90% confidence intervals (CIs). Bioequivalence was concluded if the 90% CIs for Cmax , AUClast , and AUC∞ were wholly contained within 80% to 125%. All 90% CIs for the ratios of adjusted geometric means of Cmax , AUClast , and AUC∞ were within 80% to 125%, the prespecified bioequivalence criteria. All 3 formulations were well tolerated. In conclusion, the POS suspension, the commercial 20-mg Revatio tablet, and the 10-mg sildenafil tablets were all bioequivalent to one another when given at the equal doses.

Effects of Oral Sildenafil Treatment on Exercise Capacity in Pediatric Pulmonary Arterial Hypertension (PAH)

PURPOSE: In the US, sildenafil is approved for adult but not pediatric PAH. The randomized, double-blind STARTS-1 study assessed the effect of sildenafil on cardiopulmonary exercise testing (CPET) in treatment-naïve pediatric PAH patients. Although peak oxygen consumption (pVO2) has been considered the “gold standard” CPET measurement, the ventilation to carbon dioxide output (VE/VCO2) slope also appears prognostic in various cardiopulmonary disorders including PAH (Oudiz Am J Cardiol 2010;105:1186-1191).