Haemodynamic characterisation and heart catheterisation complications in children with pulmonary hypertension: Insights from the Global TOPP Registry (tracking outcomes and practice in paediatric pulmonary hypertension).

BACKGROUND: The TOPP Registry has been designed to provide epidemiologic, diagnostic, clinical, and outcome data on children with pulmonary hypertension (PH) confirmed by heart catheterisation (HC). This study aims to identify important characteristics of the haemodynamic profile at diagnosis and HC complications of paediatric patients presenting with PH. METHODS AND RESULTS: HC data sets underwent a blinded review for confirmation of PH (defined as mean pulmonary arterial pressure ≥ 25 mmHg, pulmonary capillary wedge pressure ≤ 12 mmHg and pulmonary vascular resistance index [PVRI] of >3 WU × m(2)). Of 568 patients enrolled, 472 who fulfilled the inclusion criteria and had sufficient data from HC were analysed. A total of 908 diagnostic and follow-up HCs were performed and complications occurred in 5.9% of all HCs including five (0.6%) deaths. General anaesthesia (GA) was used in 53%, and conscious sedation in 47%. Complications at diagnosis were more likely to occur if GA was used (p=0.04) and with higher functional class (p=0.02). Mean cardiac index (CI) was within normal limits at diagnosis when analysed for the entire group (3.7 L/min/m(2); 95% confidence interval 3.4-4.1), as was right atrial pressure despite a severely increased PVRI (16.6 WU × m(2,) 95% confidence interval 15.6-17.76). However, 24% of the patients had a CI of <2.5L/min/m(2) at diagnosis. A progressive increase in PVRI and decrease in CI was observed with age (p<0.001). CONCLUSION: In TOPP, haemodynamic assessment was remarkable for preserved CI in the majority of patients despite severely elevated PVRI. HC-related complication incidence was 5.9%, and was associated with GA and higher functional class.

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).

A dosing/cross-development study of the multikinase inhibitor sorafenib in patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) and cancer share elements of pathophysiology. This provides an opportunity for the cross-development of anticancer agents that can be used in improving PAH care. The adaptation of new drugs across these disease populations warrants a structured approach. This study was a 16-week, phase Ib, single-center, open-label trial of the multikinase/angiogenesis inhibitor sorafenib. In order to assess the safety of sorafenib in PAH, patients with advanced but stable disease on parenteral prostanoids (with or without oral sildenafil) were initiated on treatment at the lowest active dosage administered to cancer patients: 200 mg daily. Patients underwent weekly clinical evaluations and monthly functional testing and dose escalations to a final dosage of 400 mg twice daily. Among 12 patients (10 of them women), sorafenib was well tolerated at 200 mg twice daily. The most common adverse events were moderate skin reactions on the hands and feet and alopecia. Our conclusion was therefore that this is a tolerable dosing regimen for testing the therapeutic activity of sorafenib in PAH patients.

Guidelines for the prevention of central venous catheter-related blood stream infections with prostanoid therapy for pulmonary arterial hypertension.

Intravenous prostanoids are the backbone of therapy for advanced pulmonary arterial hypertension (PAH) and have improved long-term outcome and quality of life. Currently, two prostanoids are approved by the US Food and Drug administration for parenteral administration: epoprostenol (Flolan) and treprostinil (Remodulin). Chronic intravenous therapy presents considerable challenges for patients and caregivers who must learn sterile preparation of the medication, operation of the pump, and care of the central venous catheter. Patients are routinely counseled and advised regarding the risks of CR-BSIs and catheter care before central line insertion. Central line infections as well as bacteremia are well documented risks of chronic intravenous therapy and may significantly contribute to morbidity and mortality. Recent reports have suggested a possible increase in CR-BSI; therefore, the Scientific Leadership Council of the Pulmonary Hypertension Association decided to provide guidelines for good clinical practice regarding catheter care. Although data exits regarding patients with central venous catheters and the risk of blood stream infections in patients with cancer or other disorders, there is little data regarding the special needs of patients with pulmonary arterial hypertension requiring central venous access. These guidelines are extrapolated from the diverse body of literature regarding central venous catheter care.

Delivery of intravenous treprostinil at low infusion rates using a miniaturized infusion pump in patients with pulmonary arterial hypertension.

PURPOSE: Treprostinil is approved for the treatment of pulmonary arterial hypertension (PAH) via continuous intravenous (IV) infusion. Treprostinil's anti-platelet aggregation characteristics and stability at room temperature may allow for low infusion rates (0.1-0.2 mL/hr) using a miniaturized infusion pump. METHODS: A 12-week, multi-center, open-label study in 12 adult PAH patients, evaluated the feasibility and safety of low-flow IV treprostinil administration via the 407C miniaturized pump. Patients receiving IV treprostinil at a stable dose were transitioned from their current CADD-Legacy pump to the 407C and were assessed for adverse events including catheter occlusions, pump alarms, and efficacy (six minute walk distance (6MWD), Borg Dyspnea Score (BDS), NYHA functional class, and PAH signs/symptoms). All patients were also maintained on therapeutic doses of warfarin, heparin or low molecular weight heparin throughout the study. RESULTS: Baseline mean (+/-SD) 6MWD was 477 +/- 76 m (n = 9) with mean BDS of 2.1 +/- 1.2 (n = 9). Week 12 mean 6MWD and BDS were 500 +/- 92 m and 2.3 +/- 1.7, respectively (n = 9). Four patients discontinued the study prematurely (3 AEs and 1 consent withdrawn). Adverse events included headache, flushing, and nausea. Pump complications occurred in 5 of 12 patients, and although no catheter occlusions occurred in any patient during the 12-week study, further study is needed regarding pump complications. CONCLUSION: This study demonstrates that treprostinil can be administered intravenously at infusion rates as low as 0.1 mL/hr for 12 weeks without catheter occlusions. Further studies are warranted because the potential for adverse events is of some concern.

Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil.

Pulmonary arterial hypertension (PAH) is fatal if untreated. Intravenous epoprostenol improves exercise capacity and haemodynamics in PAH, and increases survival in idiopathic PAH (IPAH). To evaluate the effects of subcutaneous (SC) treprostinil, a longer-acting prostacyclin analogue, followed by the addition of other PAH therapies if needed, 860 PAH patients treated with SC treprostinil for up to 4 yrs were followed. Survival is reported as Kaplan-Meier estimates. For 332 IPAH patients with baseline haemodynamics, observed survival is also compared with predicted survival using the National Institute of Health formula. Out of the 860 patients, 199 (23%) discontinued due to adverse events, 136 (16%) died, 117 (14%) discontinued due to deterioration, 29 (3%) withdrew consent and 11 (1%) underwent transplantation. In total, 97 patients (11%) switched from SC treprostinil to an alternative prostacyclin analogue; bosentan was added in 105 patients (12%) and sildenafil in 25 (3%). In conclusion, survival was 87-68% over 1-4 yrs for all 860 patients and 88-70% over 1-4 yrs with subcutaneous treprostinil monotherapy. For the idiopathic pulmonary arterial hypertension subset with baseline haemodynamics (n = 332), survival was 91-72% over 1-4 yrs. In contrast, predicted survival was 69-38% over 1-4 yrs. The safety profile for long-term subcutaneous treprostinil was consistent with previous short-term trials with no unexpected adverse events.

A study of aspirin and clopidogrel in idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is characterised by in situ thrombosis and increased thromboxane (Tx) A2 synthesis; however, there are no studies of antiplatelet therapy in IPAH. The aim of the current study was to determine the biochemical effects of aspirin (ASA) and clopidogrel on platelet function and eicosanoid metabolism in patients with IPAH. A randomised, double-blind, placebo-controlled crossover study of ASA 81 mg once daily and clopidogrel 75 mg once daily was performed. Plasma P-selectin levels and aggregometry were measured after exposure to adenosine diphosphate, arachidonic acid and collagen. Serum levels of TxB2 and urinary metabolites of TxA2 and prostaglandin I2 (Tx-M and PGI-M, respectively) were assessed. A total of 19 IPAH patients were enrolled, of whom nine were being treated with continuous intravenous epoprostenol. ASA and clopidogrel significantly reduced platelet aggregation to arachidonic acid and adenosine diphosphate, respectively. ASA significantly decreased serum TxB2, urinary Tx-M levels and the Tx-M/PGI-M ratio, whereas clopidogrel had no effect on eicosanoid levels. Neither drug significantly lowered plasma P-selectin levels. Epoprostenol use did not affect the results. In conclusion, aspirin and clopidogrel inhibited platelet aggregation, and aspirin reduced thromboxane metabolite production without affecting prostaglandin I2 metabolite synthesis. Further clinical trials of aspirin in patients with idiopathic pulmonary arterial hypertension should be performed.

Survival in patients with class III idiopathic pulmonary arterial hypertension treated with first line oral bosentan compared with an historical cohort of patients started on intravenous epoprostenol.

BACKGROUND: The oral dual endothelin receptor antagonist bosentan improves exercise capacity and delays clinical worsening in patients with pulmonary arterial hypertension, but its use could delay starting intravenous epoprostenol, a life saving treatment. METHODS: Survival in patients with functional class III idiopathic pulmonary arterial hypertension (PAH) treated with bosentan in clinical trials was compared with historical data from similar patients treated with epoprostenol in the clinic. Statistical methods were used to adjust for possible underlying differences between the two groups. RESULTS: Baseline factors for the 139 patients treated with bosentan and the 346 treated with epoprostenol suggested that the epoprostenol cohort had more severe disease-that is, a lower cardiac index (2.01 v 2.39 l/min/m2) and higher pressures and resistance. Kaplan-Meier survival estimates after 1 and 2 years were 97% and 91%, respectively, in the bosentan cohort and 91% and 84% in the epoprostenol cohort. Cox regression analyses adjusting for differences in baseline factors showed a greater probability of death in the epoprostenol cohort (hazard ratio 2.2 (95% confidence interval 1.2 to 4.0) in the model adjusted for haemodynamics). Alternative regression analyses and analyses to adjust for different data collection dates gave consistently similar results. When matched cohorts of 83 patients each were selected, survival estimates were similar. In the bosentan cohort 87% and 75% of patients followed for 1 and 2 years, respectively, remained on monotherapy. CONCLUSIONS: No evidence was found to suggest that initial treatment with oral bosentan, followed by or with the addition of other treatment if needed, adversely affected the long term outcome compared with initial intravenous epoprostenol in patients with class III idiopathic PAH.

The 6-min walk test (6MW) as an efficacy endpoint in pulmonary arterial hypertension clinical trials: demonstration of a ceiling effect.

BACKGROUND: PAH trials traditionally use 6MW as the primary endpoint. Concerns regarding a "ceiling effect" masking efficacy have led to exclusion of patients with milder disease from most trials (BL 6MW>450 m). STRIDE I evaluated the selective endothelin A receptor antagonist, sitaxsentan (SITAX), in a 12-week randomized, double-blind, trial (178 patients) employing placebo (PBO), 100 mg or 300 mg SITAX orally once daily in PAH and included patients with NYHA class II, congenital heart disease and a BL 6MW>450 m, groups often excluded from previous trials. METHODS: We analyzed 6MW effects For All Pts (intention-to treat) and those meeting Traditional enrollment criteria, defined as patients with NYHA class III or IV and 6MW< or =450 m at BL with idiopathic PAH or PAH related to connective tissue disease. The 100 mg and 300 mg SITAX arms are pooled based on similar treatment effects on 6MW. CONCLUSION: Existence of a "ceiling effect" is supported by these data. The magnitude of the treatment effect and statistical power when using 6MW as the endpoint. Comparisons between PAH trials that do not adjust for the effects of differing enrollment criteria require caution.

Survival with first-line bosentan in patients with primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is a progressive disease with high mortality. Administration of i.v. epoprostenol has demonstrated improved exercise tolerance, haemodynamics, and survival. The orally active, dual endothelin receptor antagonist bosentan improves exercise endurance, haemodynamics, and functional class over the short term. To determine the effect of first-line bosentan therapy on survival, this study followed 169 patients with PPH treated with bosentan in two placebo-controlled trials and their extensions. Data on survival and alternative treatments were collected from September 1999 (start of the first placebo-controlled study) to December 31, 2002. Observed survival up to 36 months was reported as Kaplan-Meier estimates and compared with predicted survival as determined for each patient by the National Institutes of Health Registry formula. Kaplan-Meier survival estimates were 96% at 12 months and 89% at 24 months. In contrast, predicted survival was 69% and 57%, respectively. In addition, at the end of 12 and 24 months, 85% and 70% of patients, respectively, remained alive and on bosentan monotherapy. Factors that predicted a worse outcome included World Health Organization Functional Class IV and 6-min walk distance below the median (358 m) at baseline. First-line bosentan therapy was found to improve survival in patients with advanced primary pulmonary hypertension.

Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2.

The efficacy and safety of combining bosentan, an orally active dual endothelin receptor antagonist and epoprostenol, a continuously infused prostaglandin, in the treatment of pulmonary arterial hypertension (PAH) was investigated. In this double-blind, placebo-controlled prospective study, 33 patients with PAH started epoprostenol treatment (2 ng.kg(-1)min(-1) starting dose, up to 14+/-2 ng.kg(-1)min(-1) at week 16) and were randomised for 16 weeks in a 2:1 ratio to bosentan (62.5 mg b.i.d for 4 weeks then 125 mg b.i.d) or placebo. Haemodynamics, exercise capacity and functional class improved in both groups at week 16. In the combination treatment group, there was a trend for a greater (although nonsignificant) improvement in all measured haemodynamic parameters. There were four withdrawals in the bosentan/epoprostenol group (two deaths due to cardiopulmonary failure, one clinical worsening, and one adverse event) and one withdrawal in the placebo/epoprostenol group (adverse event). This study showed a trend but no statistical significance towards haemodynamics or clinical improvement due to the combination of bosentan and epoprostenol therapy in patients with pulmonary arterial hypertension. Several cases of early and late major complications were reported. Additional information is needed to evaluate the risk/benefit ratio of combined bosentan-epoprostenol therapy in pulmonary arterial hypertension.

BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease.

The aim of the present study was to determine if patients with both pulmonary arterial hypertension (PAH), due to pulmonary vascular obstructive disease, and congenital heart defects (CHD), have mutations in the gene encoding bone morphogenetic protein receptor (BMPR)-2. The BMPR2 gene was screened in two cohorts: 40 adults and 66 children with PAH/CHD. CHDs were patent ductus arteriosus, atrial and ventricular septal defects, partial anomalous pulmonary venous return, transposition of the great arteries, atrioventicular canal, and rare lesions with systemic-to-pulmonary shunts. Six novel missense BMPR2 mutations were found in three out of four adults with complete type C atrioventricular canals and in three children. One child had an atrial septal defect and patent ductus arteriosus; one had an atrial septal defect, patent ductus arteriosus and partial anomalous pulmonary venous return; and one had an aortopulmonary window and a ventricular septal defect. Bone morphogenetic protein receptor 2 mutations were found in 6% of a mixed cohort of adults and children with pulmonary arterial hypertension/congenital heart defects. The current findings compliment recent reports in mouse models implicating members of the bone morphogenetic protein/transforming growth factor-beta pathway inducing cardiac anomalies analogous to human atrioventricular canals, septal defects and conotruncal congenital heart defects. The small number of patients studied and the ascertainment bias inherent in selecting for pulmonary arterial hypertension require further investigation.

Fatal pulmonary arterial hypertension associated with phenylpropanolamine exposure.

Exogenous substances such as the appetite suppressant fenfluramine are known to be causally related to the development of pulmonary arterial hypertension (PAH). In these cases, the clinical course as well as the pulmonary vascular disease pathologically is indistinguishable from idiopathic PAH. Other exogenous substances, such as amphetamines, cocaine, and meta-amphetamines, have been considered to be potential risk factors for inducing PAH. SOPHIA (the study of pulmonary hypertension in America), in addition to confirming previous reports of a causal association between the appetite suppressant fenfluramine and PAH, unexpectedly found a significantly increased risk for the development of PAH with exposure to over-the-counter antiobesity agents containing phenylpropanolamine. The first case is reported of fatal PAH in a child heavily treated with cold remedies containing phenylpropanolamine, which, in addition to the results of SOPHIA, strengthens the hypothesis that phenylpropanolamine is a risk factor for the development of PAH.

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.

Pulmonary arterial hypertension in children.

For physicians to admit that a group of patients remains for whom no cure is available in modern medicine is intellectually unsatisfying. Pulmonary arterial hypertension is a rare condition. Because the symptoms are nonspecific and the physical finding can be subtle, the disease is often diagnosed in its later stages. The natural history of pulmonary arterial hypertension is usually progressive and fatal. At the 1998 Primary Pulmonary Hypertension World Symposium, clinical scientists from around the world gathered to review and discuss the future of pulmonary arterial hypertension. Bringing together experts from a variety of disciplines provided the opportunity for a better understanding of the pathology, pathobiology, risk factors, genetics, diagnosis and treatment for pulmonary arterial hypertension. Remarkable progress has been made in the field of pulmonary arterial hypertension over the past several decades. The pathology is now better defined and significant advances have occurred in understanding the pathobiological mechanisms. Risk factors have been identified and the genetics have been characterised. Advances in technology allow earlier diagnosis as well as better assessment of disease severity. Therapeutic modalities such as new drugs, e.g. epoprostenol, treprostinil and bosentan, and surgical interventions, e.g. transplantation and blade septostomy, which were unavailable several decades ago, have had a significant impact on prognosis and outcome. Thus, despite the inability to really cure pulmonary arterial hypertension, therapeutic advances over the past two decades have resulted in significant improvements in the outcome for children with various forms of pulmonary arterial hypertension. This review of pulmonary arterial hypertension will highlight the key features of pulmonary hypertension in infants and children and the current understanding of pulmonary arterial hypertension with specific recommendations for current practice and future directions.

BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives.

This study investigated whether patients developing pulmonary arterial hypertension (PAH) after exposure to the appetite suppressants fenfluramine and dexfenfluramine have mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene, as reported in primary pulmonary hypertension. BMPR2 was examined for mutations in 33 unrelated patients with sporadic PAH, and in two sisters with PAH, all of whom had taken fenfluramine derivatives, as well as in 130 normal controls. The PAH patients also underwent cardiac catheterisation and body mass determinations. Three BMPR2 mutations predicting changes in the primary structure of the BMPR-II protein were found in three of the 33 unrelated patients (9%), and a fourth mutation was found in the two sisters. No BMPR2 mutations were identified in the 130 normal controls. This difference in frequency was statistically significant. Moreover, the mutation-positive patients had a somewhat shorter duration of fenfluramine exposure before illness than the mutation-negative patients, a difference that was statistically significant when the two sisters were included in the analysis. In conclusion, the present authors have detected bone morphogenetic protein receptor 2 mutations that appear to be rare in the general population but may combine with exposure to fenfluramine derivatives to greatly increase the risk of developing severe pulmonary arterial hypertension.

Increased levels of prostaglandin D(2) suggest macrophage activation in patients with primary pulmonary hypertension.

STUDY OBJECTIVE: TXA(2) (thromboxane A(2)) is a lipid mediator believed to be produced primarily by platelets in normal subjects, although macrophages are capable of synthesis. There is increased production of TXA(2) in patients with primary pulmonary hypertension (PPH), which may reflect augmented production by macrophages. The objective of this study was to determine if macrophages are activated in PPH and whether they contribute to the increased production of TXA(2). STUDY TYPE: Case control. SETTING: University hospital. METHODS: We measured the urinary metabolites of three mediators that predominantly derive from different cell types in vivo: (1) TX-M (platelets and macrophages), a TXA(2) metabolite; (2) prostaglandin D(2) (PGD(2)) metabolite (PGD-M); and (3) N-methylhistamine (mast cells), a histamine metabolite, in 12 patients with PPH and 11 normal subjects. RESULTS: The mean (+/- SEM) excretion of both TX-M and PGD-M at baseline was increased in PPH patients, compared to normal subjects (460 +/- 50 pg/mg creatinine vs 236 +/- 16 pg/mg creatinine [p = 0.0006], and 1,390 +/- 221 pg/mg creatinine vs 637 +/- 65 pg/mg creatinine [p = 0.005], respectively). N-methylhistamine excretion was not increased compared to normal subjects. There was a poor correlation between excretion of TX-M and PGD-M (r = 0.36) and between excretion of PGD-M and methylhistamine (r = 0.09) in individual patients. CONCLUSION: In patients with PPH, increased levels of PGD-M, without increased synthesis of N-methylhistamine, suggest that macrophages are activated. The lack of correlation between urinary metabolite levels of TXA(2) and PGD(2) implies that macrophages do not contribute substantially to elevated TXA(2) production in patients with PPH. They may, however, have a role in the pathogenesis and/or maintenance of PPH, which warrants further investigation.

Medical therapy of pulmonary hypertension. An overview of treatment and goals.

Therapeutic medical advances over the past two decades have resulted in significant improvements in the outcome for patients with various forms of pulmonary arterial hypertension. As the current understanding of the pathology and pathobiology of pulmonary arterial hypertension has moved forward, rationale for additional therapeutic modalities with novel therapeutic agents has led to increased clinical investigations. A brief overview of the pathology and pathobiology is presented as background for an introduction to the current medical therapy for pulmonary arterial hypertension as well as the goals for future treatment.