Robyn J. Barst

Pulmonary arterial hypertension: a comparison between children and adults

The characteristics of pulmonary arterial hypertension (PAH), including pathology, symptoms, diagnosis and treatment are reviewed in children and adults. The histopathology seen in adults is also observed in children, although children have more medial hypertrophy at presentation. Both populations have vascular and endothelial dysfunction. Several unique disease states are present in children, as lung growth abnormalities contribute to pulmonary hypertension. Although both children and adults present at diagnosis with elevations in pulmonary vascular resistance and pulmonary artery pressure, children have less heart failure. Dyspnoea on exertion is the most frequent symptom in children and adults with PAH, but heart failure with oedema occurs more frequently in adults. However, in idiopathic PAH, syncope is more common in children. Haemodynamic assessment remains the gold standard for diagnosis, but the definition of vasoreactivity in adults may not apply to young children. Targeted PAH therapies approved for adults are associated with clinically meaningful effects in paediatric observational studies; children now survive as long as adults with current treatment guidelines. In conclusion, there are more similarities than differences in the characteristics of PAH in children and adults, resulting in guidelines recommending similar diagnostic and therapeutic algorithms in children (based on expert opinion) and adults (evidence-based).

Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia

Primary pulmonary hypertension (PPH) is a rare but severe and progressive disease characterised by obstructive lesions of small pulmonary arteries. Patients with PPH often have mutations in the bone morphogenetic protein receptor type II (BMPR2) gene, whereas some carry mutations in the activin receptor-like kinase 1 (ALK‐1) gene, generally associated with hereditary haemorrhagic telangiectasia (HHT) type 2, a vascular dysplasia affecting multiple organs. The aim of this study was to determine whether members of families with PPH and confirmed or probable HHT had ALK‐1 mutations. ALK‐1 and BMPR2 mutation analysis was performed on deoxyribonucleic acid from affected members of four families with PPH and confirmed or suspected HHT. ALK‐1 mutations were identified in all four families and three novel mutations found in exon 10, leading to truncated proteins. In the fourth family, a missense mutation, previously reported in four independent HHT families, was detected in exon 8. Analysis of the BMPR2 gene revealed no exonic mutations in the probands with both PPH and HHT. The present data bring to 10 the number of reported families with primary pulmonary hypertension and hereditary haemorrhagic telangiectasia type 2, representing 16% of the 61 families with known activin receptor-like kinase 1 mutations. Such mutations might predispose to primary pulmonary hypertension, and specialists should be aware of the potential link between these two disorders.

PET Imaging May Provide a Novel Biomarker and Understanding of Right Ventricular Dysfunction in Patients With Idiopathic Pulmonary Arterial Hypertension

Background— The clinical course in pulmonary arterial hypertension (PAH) is variable, and there is limited information on the determinants and progression of right ventricular (RV) dysfunction. The objective is to develop PET metabolic imaging of the RV as a noninvasive tool in patients with PAH. Methods and Results— We performed PET scanning in 16 patients with idiopathic PAH (age, 41±14 years, 82% women) using 13N-NH3 for perfusion imaging and 18F-fluorodeoxyglucose for metabolic imaging. The myocardium was divided into 6 regions of interest (3 left ventricular [LV], 3 RV), and time-activity curves were generated. A 2- compartment model was used to calculate myocardial blood flow (MBF), and Patlak analysis was used to calculate the rate of myocardial glucose uptake (MGU). All patients underwent cardiac catheterization, cardiac MRI, and cardiopulmonary exercise testing with gas exchange. MBF, MGU, and the ratio of RV/LV MGU were correlated to clinical parameters. Pulmonary artery (PA) pressure was 79±19/30±8 mm Hg (mean, 48±10 mm Hg). MBF was 0.84±0.33 mL/g per minute for the LV and 0.45±0.14 mL/g per minute for the RV. Mean MGU was 136±72 nmol/g per minute for the LV and 96±69 nmol/g per minute for the RV. The ratio of RV/LV MGU correlated significantly with PA systolic (r=0.75, P=0.0085) and mean (r=0.87, P=0.001) pressure and marginally with maximum oxygen consumption (r=−0.59, P=0.05). RV free wall MGU also correlated well with mean PA pressure (r=0.66, P=0.03). Conclusions— PET scanning with 13N-NH3 and 18F-fluorodeoxyglucose is a feasible modality for quantifying RV blood flow and metabolism in patients with idiopathic PAH.

Positron Emission Tomography Imaging May Provide a Novel Biomarker and Understanding of Right Ventricular Dysfunction in Patients with Idiopathic Pulmonary Arterial Hypertension

Background— The clinical course in pulmonary arterial hypertension (PAH) is variable, and there is limited information on the determinants and progression of right ventricular (RV) dysfunction. The objective is to develop PET metabolic imaging of the RV as a noninvasive tool in patients with PAH. Methods and Results— We performed PET scanning in 16 patients with idiopathic PAH (age, 41±14 years, 82% women) using 13N-NH3 for perfusion imaging and 18F-fluorodeoxyglucose for metabolic imaging. The myocardium was divided into 6 regions of interest (3 left ventricular [LV], 3 RV), and time-activity curves were generated. A 2- compartment model was used to calculate myocardial blood flow (MBF), and Patlak analysis was used to calculate the rate of myocardial glucose uptake (MGU). All patients underwent cardiac catheterization, cardiac MRI, and cardiopulmonary exercise testing with gas exchange. MBF, MGU, and the ratio of RV/LV MGU were correlated to clinical parameters. Pulmonary artery (PA) pressure was 79±19/30±8 mm Hg (mean, 48±10 mm Hg). MBF was 0.84±0.33 mL/g per minute for the LV and 0.45±0.14 mL/g per minute for the RV. Mean MGU was 136±72 nmol/g per minute for the LV and 96±69 nmol/g per minute for the RV. The ratio of RV/LV MGU correlated significantly with PA systolic (r=0.75, P=0.0085) and mean (r=0.87, P=0.001) pressure and marginally with maximum oxygen consumption (r=−0.59, P=0.05). RV free wall MGU also correlated well with mean PA pressure (r=0.66, P=0.03). Conclusions— PET scanning with 13N-NH3 and 18F-fluorodeoxyglucose is a feasible modality for quantifying RV blood flow and metabolism in patients with idiopathic PAH.

Clinical trials in neonates and children: Report of the pulmonary hypertension academic research consortium pediatric advisory committee.

Drug trials in neonates and children with pulmonary hypertensive vascular disease pose unique but not insurmountable challenges. Childhood is defined by growth and development. Both may influence disease and outcomes of drug trials. The developing pulmonary vascular bed and airways may be subjected to maldevelopment, maladaptation, growth arrest, or dysregulation that influence the disease phenotype. Drug therapy is influenced by developmental changes in renal and hepatic blood flow, as well as in metabolic systems such as cytochrome P450. Drugs may affect children differently from adults, with different clearance, therapeutic levels and toxicities. Toxicity may not be manifested until the child reaches physical, endocrine and neurodevelopmental maturity. Adverse effects may be revealed in the next generation, should the development of ova or spermatozoa be affected. Consideration of safe, age-appropriate tablets and liquid formulations is an obvious but often neglected prerequisite to any pediatric drug trial. In designing a clinical trial, precise phenotyping and genotyping of disease is required to ensure appropriate and accurate inclusion and exclusion criteria. We need to explore physiologically based pharmacokinetic modeling and simulations together with statistical techniques to reduce sample size requirements. Clinical endpoints such as exercise capacity, using traditional classifications and testing cannot be applied routinely to children. Many lack the necessary neurodevelopmental skills and equipment may not be appropriate for use in children. Selection of endpoints appropriate to encompass the developmental spectrum from neonate to adolescent is particularly challenging. One possible solution is the development of composite outcome scores that include age and a developmentally specific functional classification, growth and development scores, exercise data, biomarkers and hemodynamics with repeated evaluation throughout the period of growth and development. In addition, although potentially costly, we recommend long-term continuation of blinded dose ranging after completion of the short-term, double-blind, placebo-controlled trial for side-effect surveillance, which should include neurodevelopmental and peripubertal monitoring. The search for robust evidence to guide safe therapy of children and neonates with pulmonary hypertensive vascular disease is a crucial and necessary goal.

Sitaxsentan, a selective endothelin-A receptor antagonist for the treatment of pulmonary arterial hypertension

Sitaxsentan, a highly selective endothelin-A (ETA) receptor antagonist (6500-fold more selective for ETA receptors than endothelin-B (ETB) receptors), may benefit patients with pulmonary artery hypertension (PAH) by blocking the vasoconstrictor effects of ETA receptors while maintaining the vasodilator/clearance functions of ETB receptors. In its first randomised, placebo-controlled study, Sitaxsentan to Relieve Impaired Exercise-1 (STRIDE-1), sitaxsentan improved exercise capacity assessed by 6 min walk, New York Heart Association functional class, cardiac index and pulmonary vascular resistance in New York Heart Association class II, III and IV patients with idiopathic PAH, PAH related to connective tissue disease or PAH related to congenital heart disease. In STRIDE-1, doses of 100 and 300 mg/day p.o. were evaluated. Although both doses showed equivalent efficacy, the lower dose had a more tolerable safety profile. Additional studies are ongoing to assess the relative safety and efficacy of 50 and 100 mg/day doses, both in de novo patients and in patients previously treated with the ETA/ETB receptor antagonist bosentan. Long-term comparative studies are necessary to determine whether there is a clinically meaningful difference between selective ETA receptor antagonism and ETA/ETB receptor antagonism.

Novel loci interacting epistatically with bone morphogenetic protein receptor 2 cause familial pulmonary arterial hypertension

BACKGROUND Familial pulmonary arterial hypertension (FPAH) is a rare, autosomal-dominant, inherited disease with low penetrance. Mutations in the bone morphogenetic protein receptor 2 (BMPR2) have been identified in at least 70% of FPAH patients. However, the lifetime penetrance of these BMPR2 mutations is 10% to 20%, suggesting that genetic and/or environmental modifiers are required for disease expression. Our goal in this study was to identify genetic loci that may influence FPAH expression in BMPR2 mutation carriers. METHODS We performed a genome-wide linkage scan in 15 FPAH families segregating for BMPR2 mutations. We used a dense single-nucleotide polymorphism (SNP) array and a novel multi-scan linkage procedure that provides increased power and precision for the localization of linked loci. RESULTS We observed linkage evidence in four regions: 3q22 ([median log of the odds (LOD) = 3.43]), 3p12 (median LOD) = 2.35), 2p22 (median LOD = 2.21), and 13q21 (median LOD = 2.09). When used in conjunction with the non-parametric bootstrap, our approach yields high-resolution to identify candidate gene regions containing putative BMPR2-interacting genes. Imputation of the disease model by LOD-score maximization indicates that the 3q22 locus alone predicts most FPAH cases in BMPR2 mutation carriers, providing strong evidence that BMPR2 and the 3q22 locus interact epistatically. CONCLUSIONS Our findings suggest that genotypes at loci in the newly identified regions, especially at 3q22, could improve FPAH risk prediction in FPAH families. We also suggest other targets for therapeutic intervention.