Computed tomographic findings in TBX4 mutation: a common cause of severe pulmonary artery hypertension in children.

BACKGROUND: Mutations in the T-Box 4 (TBX4) gene are a lesser-known cause of heritable pulmonary arterial hypertension (PAH). Patients with heritable PAH typically have worse outcomes when compared with patients with idiopathic PAH, yet little is known about the phenotypical presentation of this mutation. OBJECTIVE: This article reviews the pattern of chest CT findings in pediatric patients with PAH and TBX4 mutations and compares their radiographic presentation with those of age-matched patients with PAH but without TBX4 mutations. MATERIALS AND METHODS: A retrospective chart review of the pulmonary arterial hypertension database was performed. Pediatric patients with PAH-confirmed TBX4 mutations and an available high CT were included. Fifteen (9 females) patients met the inclusion criteria. Fourteen (8 females) age-matched controls with diagnosed PAH but without TBX4 mutations were also evaluated. The median age at diagnosis was 7.4 years (range: 0.1-16.4 years). Demographic information and clinical outcomes were collected. CTs of the chest were reviewed for multiple airway, parenchymal, and structural abnormalities (16 imaging findings in total). Chi-square tests were used to compare the prevalence of each imaging finding in the TBX4 cohort compared to the control group. RESULTS: Patients with TBX-4 mutations had increased presence of peripheral or subpleural irregularity (73% vs 0%, P < 0.01), cystic lucencies (67% vs 7%, P < 0.01), and linear or reticular opacity (53% vs 0%, P < 0.01) compared to the control group. Ground glass opacities, bronchiectasis, and centrilobular nodules were not significantly different between the two patient groups (P > 0.05). CONCLUSION: TBX4 mutations have distinct imaging phenotypes in pediatric patients with PAH. Compared to patients without this mutation, patients with TBX-4 genes typically present with peripheral or subpleural irregularity, cystic lucencies, and linear or reticular opacity.

Kids Mod PAH trial: A multicenter trial comparing mono- versus duo-therapy for initial treatment of pediatric pulmonary hypertension.

Pulmonary hypertension (PH) is a significant health problem that contributes to high morbidity and mortality in diverse cardiac, pulmonary, and systemic diseases in children. Evidence-based advances in PH care have been challenged by a paucity of quality endpoints for assessing clinical course and the lack of robust clinical trial data to guide pharmacologic therapies in children. While the landmark adult AMBITION trial demonstrated the benefit of up-front combination PH therapy with ambrisentan and tadalafil, it remains unknown whether upfront combination therapy leads to more rapid and sustained clinical benefits in children with various categories of PH. In this article, we describe the inception of the Kids Mod PAH Trial, a multicenter Phase III trial, to address whether upfront combination therapy (sildenafil and bosentan vs. sildenafil alone) improves PH outcomes in children, recognizing that marked differences between the etiology and therapeutic response between adults and children exist. The primary endpoint of this study is WHO functional class (FC) 12 months after initiation of study drug therapy. In addition to the primary outcome, secondary endpoints are being assessed, including a composite measure of time to clinical worsening, WHO FC at 24 months, echocardiographic assessment of PH and quantitative assessment of right ventricular function, 6-min walk distance, and NT-proBNP levels. Exploratory endpoints include selected biomarkers, actigraphy, and assessments of quality of life. This study is designed to pave the way for additional clinical trials by establishing a robust infrastructure through the development of a PPHNet Clinical Trials Network.

Computational platform for doctor-artificial intelligence cooperation in pulmonary arterial hypertension prognostication: a pilot study.

Background: Pulmonary arterial hypertension (PAH) is a heterogeneous and complex pulmonary vascular disease associated with substantial morbidity. Machine-learning algorithms (used in many PAH risk calculators) can combine established parameters with thousands of circulating biomarkers to optimise PAH prognostication, but these approaches do not offer the clinician insight into what parameters drove the prognosis. The approach proposed in this study diverges from other contemporary phenotyping methods by identifying patient-specific parameters driving clinical risk. Methods: We trained a random forest algorithm to predict 4-year survival risk in a cohort of 167 adult PAH patients evaluated at Stanford University, with 20% withheld for (internal) validation. Another cohort of 38 patients from Sheffield University were used as a secondary (external) validation. Shapley values, borrowed from game theory, were computed to rank the input parameters based on their importance to the predicted risk score for the entire trained random forest model (global importance) and for an individual patient (local importance). Results: Between the internal and external validation cohorts, the random forest model predicted 4-year risk of death/transplant with sensitivity and specificity of 71.0-100% and 81.0-89.0%, respectively. The model reinforced the importance of established prognostic markers, but also identified novel inflammatory biomarkers that predict risk in some PAH patients. Conclusion: These results stress the need for advancing individualised phenotyping strategies that integrate clinical and biochemical data with outcome. The computational platform presented in this study offers a critical step towards personalised medicine in which a clinician can interpret an algorithm's assessment of an individual patient.

Chest computed tomography findings of ground-glass nodules with enhancing central vessel/nodule in pediatric patients with BMPR2 mutations and plexogenic arteriopathy.

BACKGROUND: Germline mutation in bone morphogenetic protein type II (BMPR2) is the most common cause of idiopathic/heritable pulmonary hypertension in pediatric patients. Despite the discovery of this gene there are no known descriptions of the CT or CT angiography findings in these children. OBJECTIVE: To correlate the clinical presentation, pathology and chest CT findings in pediatric patients with pulmonary hypertension caused by mutations in the BMPR2 gene. MATERIALS AND METHODS: We performed a search to identify pediatric patients with a BMPR2 mutation and CT or CT angiography with the clinical history of pulmonary hypertension. Three pediatric radiologists reviewed the children's CT imaging findings and ranked the dominant findings in order of prevalence via consensus. RESULTS: We identified three children with pulmonary hypertension and confirmed germline BMPR2 mutations, two of whom had undergone lung biopsy. We then correlated the imaging findings with histopathology and clinical course. CONCLUSION: All of our patients with BMPR2 mutations demonstrated a distinct CT pattern of ground-glass nodules with a prominent central enhancing vessel/nodule. These findings correlated well with the pathological findings of plexogenic arteriopathy.

Proteomics discovery of pulmonary hypertension biomarkers: Insulin-like growth factor binding proteins are associated with disease severity.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by sustained elevations of pulmonary artery pressure. To date, we lack circulating, diagnostic, and prognostic markers that correlate to clinical and functional parameters. In this study, we performed mass spectrometry-based proteomics analysis to identify circulating biomarkers of PAH. Plasma samples from patients with idiopathic pulmonary arterial hypertension (IPAH, N = 9) and matched normal controls (N = 9) were digested with trypsin and analyzed using data-dependent acquisition on an Orbitrap mass spectrometer. A total of 826 (false discovery rate [FDR] 0.047) and 461 (FDR 0.087) proteins were identified across all plasma samples obtained from IPAH and control subjects, respectively. Of these, 153 proteins showed >2 folds change (p < 0.05) between groups. Circulating levels of carbonic anhydrase 2 (CA2), plasma kallikrein (KLKB1), and the insulin-like growth factor binding proteins (IGFBP1-7) were quantified by immunoassay in an independent verification cohort (N = 36 PAH and N = 35 controls). CA2 and KLKB1 were significantly different in PAH versus control but were not associated with any functional or hemodynamic measurements. Whereas, IGFBP1 and 2 were associated with higher pulmonary vascular resistance, IGFBP2, 4, and 7 with decreased 6-min walk distance (6MWD), and IGFBP1, 2, 4, and 7 with worse survival. This plasma proteomic discovery analysis suggests the IGF axis may serve as important new biomarkers for PAH and play an important role in PAH pathogenesis.

Cellular sources of interleukin-6 and associations with clinical phenotypes and outcomes in pulmonary arterial hypertension.

The pro-inflammatory cytokine interleukin (IL)-6 has been associated with outcomes in small pulmonary arterial hypertension (PAH) cohorts composed largely of patients with severe idiopathic PAH (IPAH). It is unclear whether IL-6 is a marker of critical illness or a mechanistic biomarker of pulmonary vascular remodelling. We hypothesised that IL-6 is produced by pulmonary vascular cells and sought to explore IL-6 associations with phenotypes and outcomes across diverse subtypes in a large PAH cohort.IL-6 protein and gene expression levels were measured in cultured pulmonary artery smooth muscle cells (PASMCs) and endothelial cells (PAECs) from PAH patients and healthy controls. Serum IL-6 was measured in 2017 well-characterised PAH subjects representing each PAH subgroup. Relationships between IL-6 levels, clinical variables, and mortality were analysed using regression models.Significantly higher IL-6 protein and gene expression levels were produced by PASMCs than by PAECs in PAH (p<0.001), while there was no difference in IL-6 between cell types in controls. Serum IL-6 was highest in PAH related to portal hypertension and connective tissue diseases (CTD-PAH). In multivariable modelling, serum IL-6 was associated with survival in the overall cohort (hazard ratio 1.22, 95% CI 1.08-1.38; p<0.01) and in IPAH, but not in CTD-PAH. IL-6 remained associated with survival in low-risk subgroups of subjects with mild disease.IL-6 is released from PASMCs, and circulating IL-6 is associated with specific clinical phenotypes and outcomes in various PAH subgroups, including subjects with less severe disease. IL-6 is a mechanistic biomarker, and thus a potential therapeutic target, in certain PAH subgroups.

Adverse drug event rates in pediatric pulmonary hypertension: a comparison of real-world data sources.

OBJECTIVE: Real-world data (RWD) are increasingly used for pharmacoepidemiology and regulatory innovation. Our objective was to compare adverse drug event (ADE) rates determined from two RWD sources, electronic health records and administrative claims data, among children treated with drugs for pulmonary hypertension. MATERIALS AND METHODS: Textual mentions of medications and signs/symptoms that may represent ADEs were identified in clinical notes using natural language processing. Diagnostic codes for the same signs/symptoms were identified in our electronic data warehouse for the patients with textual evidence of taking pulmonary hypertension-targeted drugs. We compared rates of ADEs identified in clinical notes to those identified from diagnostic code data. In addition, we compared putative ADE rates from clinical notes to those from a healthcare claims dataset from a large, national insurer. RESULTS: Analysis of clinical notes identified up to 7-fold higher ADE rates than those ascertained from diagnostic codes. However, certain ADEs (eg, hearing loss) were more often identified in diagnostic code data. Similar results were found when ADE rates ascertained from clinical notes and national claims data were compared. DISCUSSION: While administrative claims and clinical notes are both increasingly used for RWD-based pharmacovigilance, ADE rates substantially differ depending on data source. CONCLUSION: Pharmacovigilance based on RWD may lead to discrepant results depending on the data source analyzed. Further work is needed to confirm the validity of identified ADEs, to distinguish them from disease effects, and to understand tradeoffs in sensitivity and specificity between data sources.

Comprehensive Noninvasive Evaluation of Right Ventricle-Pulmonary Circulation Axis in Pediatric Patients with Pulmonary Hypertension.

PURPOSE OF REVIEW: The purpose of this review is to detail the advanced echocardiographic studies that evaluated outcomes in pediatric PH using these advanced imaging techniques: (1) right heart size and function (using 2D and 3D echocardiography), (2) myocardial mechanics, and (3) right ventricular (RV) to pulmonary arterial coupling. RECENT FINDINGS: Advanced echocardiographic imaging tools in pediatric PH include RV/left ventricular ratio, 3D echocardiographic assessment of RV volumes and ejection fraction, right atrial and RV strain, and RV-pulmonary arterial coupling ratio that allow for evaluation of clinical outcomes in this patient population. The right atrial to RV axis provides insights to RV diastolic function that has been poorly understood in pediatrics. The RV-pulmonary arterial coupling ratio helps us understand the mechanics of the RV response to afterload. The advanced imaging tools provide clinical outcome evaluation in pediatric PH patients and provide insight into the RA-RV axis and the RV-pulmonary circulatory unit.

Left ventricular torsion rate and the relation to right ventricular function in pediatric pulmonary arterial hypertension.

The right ventricle and left ventricle are physically coupled through the interventricular septum. Therefore, changes in the geometry and mechanics of one ventricle can directly affect the function of the other. In treatment of pediatric pulmonary arterial hypertension, the left ventricle is often overlooked, with clinical focus primarily on improving right ventricular function. Pediatric pulmonary arterial hypertension represents a disease distinct from adult pulmonary arterial hypertension based on etiology and survival rates. We aimed to assess left ventricular torsion rate in pediatric pulmonary arterial hypertension and its role in right ventricular dysfunction. Cardiac magnetic resonance images with tissue tagging were prospectively acquired for 18 pediatric pulmonary arterial hypertension (WHO class I) patients and 17 control subjects with no known cardiopulmonary disease. The pulmonary arterial hypertension cohort underwent cardiac magnetic resonance within 48 hours of clinically indicated right heart catheterization. Using right heart catheterization data, we computed single beat estimation of right ventricular end-systolic elastance (as a measure of right ventricular contractility) and ventricular vascular coupling ratio (end-systolic elastance/arterial afterload). Left ventricular torsion rate was quantified from harmonic phase analysis of tagged cardiac magnetic resonance images. Ventricular and pulmonary pressures and pulmonary vascular resistance were derived from right heart catheterization data. Right ventricular ejection fraction and interventricular septum curvature were derived from cardiac magnetic resonance. Left ventricular torsion rate was significantly reduced in pulmonary arterial hypertension patients compared to control subjects (1.40 ± 0.61° vs. 3.02 ± 1.47°, P < 0.001). A decrease in left ventricular torsion rate was significantly correlated with a decrease in right ventricular contractility (end-systolic elastance) ( r = 0.61, P = 0.007), and an increase in right ventricular systolic pressure in pulmonary arterial hypertension kids ( r = -0.54, P = 0.021). In both pulmonary arterial hypertension and control subjects, left ventricular torsion rate correlated with right ventricular ejection fraction (controls r = 0.45, P = 0.034) (pulmonary arterial hypertension r = 0.57, P = 0.032). In the pulmonary arterial hypertension group, interventricular septum curvature demonstrated a strong direct relationship with right ventricular systolic pressure ( r = 0.7, P = 0.001) and inversely with left ventricular torsion rate ( r = -0.57, P = 0.013). Left ventricular torsion rate showed a direct relationship with ventricular vascular coupling ratio ( r = 0.54, P = 0.021), and an inverse relationship with mean pulmonary arterial pressure ( r = -0.60, P = 0.008), and pulmonary vascular resistance ( r = -0.47, P = 0.049). We conclude that in pediatric pulmonary arterial hypertension, reduced right ventricular contractility is associated with decreased left ventricular torsion rate.

Treatment initiation in paediatric pulmonary hypertension: insights from a multinational registry.

Different treatment options for pulmonary hypertension have emerged in recent years, and evidence-based management strategies have improved quality of life and survival in adults. In children with pulmonary vascular disease, therapeutic algorithms are not so clearly defined; this study determined current treatment initiation in children with pulmonary hypertension in participating centres of a registry. Through the multinational Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension registry, patient demographics, diagnosis, and treatment as judged and executed by the local physician were collected. Inclusion criteria were >3 months and <18 years of age and diagnostic cardiac catheterisation consistent with pulmonary hypertension (mean pulmonary arterial pressure ⩾25 mmHg, pulmonary vascular resistance index ⩾3 Wood units×m2, and mean pulmonary capillary wedge pressure ⩽12 mmHg). At diagnostic catheterisation, 217/244 patients (88.9%) were treatment naïve for pulmonary hypertension-targeted therapy. Targeted therapy was initiated after catheterisation in 170 (78.3%) treatment-naïve patients. A total of 19 patients received supportive therapy, 28 patients were not started on therapy, and 26 patients (10.7%) were on targeted treatment before catheterisation. Among treatment-naïve subjects, treatment was initiated with one targeted drug (n=112, 51.6%), dual therapy (n=39, 18%) or triple-therapy (n=5, 2.3%), and calcium channel blockers with one targeted medication in one patient (0.5%). Phosphodiesterase inhibitors type 5 were used frequently; some patients with pulmonary hypertension related to lung disease received targeted therapy. There is a diverse therapeutic approach for children with pulmonary hypertension with a need of better-defined treatment algorithms based on paediatric consensus for different aetiologies including the best possible diagnostic workup.

Effectiveness and safety of inhaled treprostinil for the treatment of pulmonary arterial hypertension in children.

The introduction of prostanoid therapy has revolutionized the treatment of pulmonary arterial hypertension (PAH). However, continuous intravenous prostacyclin infusion poses significant risks and challenges, particularly in children. Inhaled treprostinil has been shown to be safe and efficacious in adults. This study describes the safety and efficacy of inhaled treprostinil in children with PAH. A retrospective analysis of 29 children treated with inhaled treprostinil for ≥6 weeks was performed. Effects of inhaled treprostinil on exercise capacity, functional class, and echocardiographic and hemodynamic data were evaluated. Adverse events were documented. Patients received 3 to 9 breaths (6 µg/breath) of inhaled treprostinil 4 times/day. All were receiving background PAH therapy; 12 had previously received parenteral prostanoid. Inhaled treprostinil was discontinued in 4 patients because of symptoms including cough and bronchospasm (n = 3) and progression of PAH (n = 1). Mild side effects including cough (n = 9) and sore throat (n = 6) did not require discontinuation of therapy. World Health Organization functional class improved in 19 and was unchanged in 10; exercise capacity significantly improved with the 6-minute walk distance, improving on follow-up from 455.7 ± 71.5 to 498 ± 70 m (p = 0.01) and peak oxygen consumption increasing from 25.5 ± 10.2 to 27.4 ± 10 (p = 0.04). In conclusion, inhaled treprostinil was associated with improvement in exercise capacity and World Health Organization functional class when added to background targeted PAH therapy in children and had an acceptable safety profile. Based on these early data, further study of inhaled treprostinil appears warranted in pediatric patients with PAH.

Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Exposure to bosentan was lower in paediatric pulmonary arterial hypertension (PAH) patients treated with the marketed adult formulation at a dose of about 2 mg kg(-1) when compared with adult PAH patients. * In healthy adult subjects, bosentan pharmacokinetics are less than dose-proportional at doses of >or=500 mg. WHAT THIS STUDY ADDS: * The pharmacokinetics of a new paediatric bosentan formulation were characterized in paediatric PAH patients. * The level of exposure to bosentan as observed in adult PAH patients cannot be reached in paediatric patients with b.i.d. dosing. * In paediatric PAH patients, nondose-proportional pharmacokinetics of bosentan occur at lower doses when compared with healthy adult subjects. AIM: To show equivalent bosentan exposure in paediatric patients with pulmonary arterial hypertension (PAH) when compared with a cohort of historical controls of adult PAH patients using a newly developed paediatric formulation. METHODS: Thirty-six paediatric PAH patients were enrolled in this multicentre, prospective, open-label, noncontrolled study and treated for 4 weeks with bosentan 2 mg kg(-1) b.i.d. and then for 8 weeks with 4 mg kg(-1) b.i.d. Blood samples were taken for pharmacokinetic purposes. Exploratory efficacy measurements included World Health Organization (WHO) functional class and parent's and clinician's Global Clinical Impression scales. RESULTS: Comparing children with a historical group of adults, the geometric mean ratio (90% confidence interval) of the area under the plasma concentration-time curve was 0.54 (0.37, 0.78), i.e. children had lower exposure to bosentan than adults. Bosentan concentrations following doses of 2 and 4 mg kg(-1) were similar. Improvements in WHO functional class and the Global Clinical Impression scales occurred mainly in bosentan-naive patients, whereas the rare worsenings occurred in patients already on bosentan prior to study initiation. The paediatric formulation was well accepted and bosentan well tolerated in this study. No cases of elevated liver enzymes or anaemia were reported. CONCLUSIONS: Exposure to bosentan, as shown comparing the results from this study with those from a study in adults, was different in paediatric and adult PAH patients. Since FUTURE-1 and past studies suggest a favourable benefit-risk profile for bosentan at 2 mg kg(-1) b.i.d., this dose is recommended for children with PAH. The new paediatric formulation was well tolerated.

Importance of the clinical recognition of Loeys-Dietz syndrome in the neonatal period.

We describe 5 patients who presented with musculoskeletal abnormalities in the neonatal period. All patients were initially suspected to have Larsen syndrome or Beals syndrome but were subsequently diagnosed with a TGFBR2 mutation diagnostic of Loeys-Dietz syndrome. Patients had progressive aortic enlargement, which necessitated surgical intervention for 3 patients and resulted in the death of 1 patient. Delay in diagnosis of Loeys-Dietz syndrome may be associated with adverse prognosis.

Perioperative complications in children with pulmonary hypertension undergoing noncardiac surgery or cardiac catheterization.

BACKGROUND: Pulmonary arterial hypertension (PAH) can lead to significant cardiac dysfunction and is considered to be associated with an increased risk of perioperative cardiovascular complications. METHODS: We reviewed the medical records of children with PAH who underwent anesthesia or sedation for noncardiac surgical procedures or cardiac catheterizations from 1999 to 2004. The incidence, type, and associated factors of complications occurring intraoperatively through 48 h postoperatively were examined. RESULTS: Two hundred fifty-six procedures were performed in 156 patients (median age 4.0 yr). PAH etiology was 56% idiopathic (primary), 21% congenital heart disease, 14% chronic lung disease, 4% chronic airway obstruction, and 4% chronic liver disease. Baseline pulmonary artery pressure was subsystemic in 68% patients, systemic in 19%, and suprasystemic in 13%. The anesthetic techniques were 22% sedation, 58% general inhaled, 20% general IV. Minor complications occurred in eight patients (5.1% of patients, 3.1% of procedures). Major complications, including cardiac arrest and pulmonary hypertensive crisis, occurred in seven patients during cardiac catheterization procedures (4.5% of patients, 5.0% of cardiac catheterization procedures, 2.7% of all procedures). There were two deaths associated with pulmonary hypertensive crisis (1.3% of patients, 0.8% of procedures). Baseline suprasystemic PAH was a significant predictor of major complications by multivariate logistic regression analysis (OR = 8.1, P = 0.02). Complications were not significantly associated with age, etiology of PAH, type of anesthetic, or airway management. CONCLUSION: Children with suprasystemic PAH have a significant risk of major perioperative complications, including cardiac arrest and pulmonary hypertensive crisis.

Stress and strain in rat pulmonary artery material during a biaxial bubble test.

A biaxial bubble test has been designed to ascertain the mechanical properties of rat pulmonary arteries. The analytical procedure used to estimate stress and strain from the resulting test data is presented along with some analytical results. The bubble test was performed by loading a flat piece of rat pulmonary artery into a test fixture beneath a circular opening; the material was subsequently pressurized from below, producing a "bubble" of deformed material. Due to the anisotropy of the rat pulmonary artery, the resulting bubble was ellipsoidal in shape. Test results were recorded in the form of side-view images taken from various angles at incremental values of pressure. Average strains were estimated with the use of image analysis to measure changes in the bubble perimeter during inflation. Formulations for isotropic materials were applied to estimate stresses based on the anisotropic geometry of the bubbles produced during testing; some results of this preliminary analysis are presented here. Results from this analysis show differences in mechanical properties of the rat pulmonary artery from those of healthy versus hypertensive rats.