N W Morrell

Bosentan in inoperable chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a devastating disease in which the pulmonary vasculature becomes obstructed by organised fibrotic material, presumed to be the consequence of incomplete resolution of pulmonary emboli. The ensuing increased pulmonary vascular resistance and right ventricular dysfunction results in severe exercise limitation, symptomatic right heart failure, and markedly impaired survival. Recent studies suggest that the frequency of this condition is higher than previously appreciated, occurring in up 3.8% of patients following acute pulmonary embolism after 2 years.1 The treatment of choice is pulmonary endarterectomy (PEA), a potentially curative surgical procedure in which the fibrotic material is removed from …

Phosphodiesterase type 5 and high altitude pulmonary hypertension

Background: This study explored phosphodiesterase type 5 (PDE5) inhibition as a strategy for treating high altitude pulmonary arterial hypertension (HAPH). Methods: 689 subjects (313 men) of mean (SD) age 44 (0.6) years living above 2500 m were screened for HAPH by medical examination and electrocardiography, and 188 (27%) met the criteria for right ventricular hypertrophy. 44 underwent cardiac catheterisation and 29 (66%) had a resting mean pulmonary artery pressure (PAP) above 25 mm Hg. 22 patients with a raised mean PAP were randomised to receive sildenafil (25 or 100 mg) or matching placebo taken 8 hourly for 12 weeks. Results: At 3 months, patients on sildenafil 25 mg 8 hourly (n = 9) had a significantly (p = 0.018) lower mean PAP (−6.9 mm Hg) at the end of the dosing interval than those on placebo (n = 8) (95% CI −12.4 to −1.3). The treatment effect for sildenafil 100 mg 8 hourly (n = 5) compared with placebo was −6.4 mm Hg (95% CI −12.9 to 0.1). Both doses improved 6 minute walk distance, the lower dose by 45.4 m (95% CI 11.5 to 79.4; p = 0.011) and the higher dose by 40.0 m (95% CI 0.2 to 79.8; p = 0.049). Sildenafil was well tolerated. Necroscopic lung specimens from three subjects with HAPH showed abundant PDE5 in the muscular coat of remodelled pulmonary arterioles. Conclusions: PDE5 is an attractive drug target for the treatment of HAPH and a larger study of the long term effects of PDE5 inhibition in HAPH is warranted.

NPR-A–Deficient Mice Show Increased Susceptibility to Hypoxia-Induced Pulmonary Hypertension

BACKGROUND Mice in which the gene encoding NPR-A, a guanylyl cyclase-linked natriuretic peptide receptor, has been disrupted were used to examine the contribution of natriuretic peptides to maintaining pulmonary vascular homeostasis in normal- and low-oxygen environments. METHODS AND RESULTS Wild-type (+/+), heterozygous (+/-), and homozygous null mutants (-/-) were studied. The response of the pulmonary vasculature to atrial, B-type, and C-type natriuretic peptides (ANP, BNP, and CNP) during acute hypoxia was studied in isolated perfused lungs. Right ventricular systolic pressure (RVSP), RV weight, and pulmonary vascular remodeling were measured in each genotype exposed to normal air and after 7 and 21 days in a hypoxic atmosphere (10% O2). ANP and BNP (300 ng) reduced pulmonary artery pressure during acute hypoxia-induced pulmonary vasoconstriction in +/+ mice, but this effect was attenuated in +/- and absent in -/- mice. CNP (600 ng) had little effect in all 3 genotypes. RVSP and RV weight were similar in the 3 genotypes housed in a normal-O2 environment. Seven and 21 days of hypoxia produced a pronounced and significantly greater increase in RVSP and RV weight in -/- mice compared with +/+ or +/- mice and more rapid muscularization of distal pulmonary arterioles. CONCLUSIONS ANP and BNP do not contribute to maintaining normal pulmonary artery pressure but play an important role in attenuating the pulmonary vascular response to hypoxia. NPR-A mediates the vasorelaxant effect of ANP in pulmonary vasculature.

Evidence for the Involvement of Type I Interferon in Pulmonary Arterial Hypertension

Rationale: Evidence is increasing of a link between interferon (IFN) and pulmonary arterial hypertension (PAH). Conditions with chronically elevated endogenous IFNs such as systemic sclerosis are strongly associated with PAH. Furthermore, therapeutic use of type I IFN is associated with PAH. This was recognized at the 2013 World Symposium on Pulmonary Hypertension where the urgent need for research into this was highlighted. Objective: To explore the role of type I IFN in PAH. Methods and Results: Cells were cultured using standard approaches. Cytokines were measured by ELISA. Gene and protein expression were measured using reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemistry. The role of type I IFN in PAH in vivo was determined using type I IFN receptor knockout (IFNAR1−/−) mice. Human lung cells responded to types I and II but not III IFN correlating with relevant receptor expression. Type I, II, and III IFN levels were elevated in serum of patients with systemic sclerosis associated PAH. Serum interferon &ggr; inducible protein 10 (IP10; CXCL10) and endothelin 1 were raised and strongly correlated together. IP10 correlated positively with pulmonary hemodynamics and serum brain natriuretic peptide and negatively with 6-minute walk test and cardiac index. Endothelial cells grown out of the blood of PAH patients were more sensitive to the effects of type I IFN than cells from healthy donors. PAH lung demonstrated increased IFNAR1 protein levels. IFNAR1−/− mice were protected from the effects of hypoxia on the right heart, vascular remodeling, and raised serum endothelin 1 levels. Conclusions: These data indicate that type I IFN, via an action of IFNAR1, mediates PAH.

Right ventricular dysfunction in chronic thromboembolic obstruction of the pulmonary artery: a pressure-volume study using the conductance catheter

Pressure-volume loops describe dynamic ventricular performance, relevant to patients with and at risk of pulmonary hypertension. We used conductance catheter-derived pressure-volume loops to measure right ventricular (RV) mechanics in patients with chronic thromboembolic pulmonary arterial obstruction at different stages of pathological adaptation. Resting conductance catheterization was performed in 24 patients: 10 with chronic thromboembolic pulmonary hypertension (CTEPH), 7 with chronic thromboembolic disease without pulmonary hypertension (CTED), and 7 controls. To assess the validity of conductance measurements, RV volumes were compared in a subset of 8 patients with contemporaneous cardiac magnetic resonance (CMR). Control, CTED, and CTEPH groups showed different pressure-volume loop morphology, most notable during systolic ejection. Prolonged diastolic relaxation was seen in patients with CTED and CTEPH [tau = 56.2 ± 6.7 (controls) vs. 69.7 ± 10.0 (CTED) vs. 67.9 ± 6.2 ms (CTEPH), P = 0.02]. Control and CTED groups had lower afterload (Ea) and contractility (Ees) compared with the CTEPH group (Ea = 0.30 ± 0.10 vs. 0.52 ± 0.24 vs. 1.92 ± 0.70 mmHg/ml, respectively, P < 0.001) (Ees = 0.44 ± 0.20 vs. 0.59 ± 0.15 vs. 1.13 ± 0.43 mmHg/ml, P < 0.01) with more efficient ventriculoarterial coupling (Ees/Ea = 1.46 ± 0.30 vs. 1.27 ± 0.36 vs. 0.60 ± 0.18, respectively, P < 0.001). Stroke volume assessed by CMR and conductance showed closest agreement (mean bias +9 ml, 95% CI -1 to +19 ml) compared with end-diastolic volume (+48 ml, -16 to 111 ml) and end-systolic volume (+37 ml, -21 to 94 ml). RV conductance catheterization detects novel alteration in pressure-volume loop morphology and delayed RV relaxation in CTED, which distinguish this group from controls. The observed agreement in stroke volume assessed by CMR and conductance suggests RV mechanics are usefully measured by conductance catheter in chronic thromboembolic obstruction.

Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension.

Our aim is to assess the safety and potential clinical benefit of intravenous iron (Ferinject) infusion in iron deficient patients with idiopathic pulmonary arterial hypertension (IPAH). Iron deficiency in the absence of anemia (1) is common in patients with IPAH; (2) is associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis; and (3) correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by reduced absorption due to elevated hepcidin levels. The safety and benefits of parenteral iron replacement in IPAH are unknown. Supplementation of Iron in Pulmonary Hypertension (SIPHON) is a Phase II, multicenter, double-blind, randomized, placebo-controlled, crossover clinical trial of iron in IPAH. At least 60 patients will be randomized to intravenous ferric carboxymaltose (Ferinject) or saline placebo with a crossover point after 12 weeks of treatment. The primary outcome will be the change in resting pulmonary vascular resistance from baseline at 12 weeks, measured by cardiac catheterization. Secondary measures include resting and exercise hemodynamics and exercise performance from serial bicycle incremental and endurance cardiopulmonary exercise tests. Other secondary measurements include serum iron indices, 6-Minute Walk Distance, WHO functional class, quality of life score, N-terminal pro-brain natriuretic peptide (NT-proBNP), and cardiac anatomy and function from cardiac magnetic resonance. We propose that intravenous iron replacement will improve hemodynamics and clinical outcomes in IPAH. If the data supports a potentially useful therapeutic effect and suggest this drug is safe, the study will be used to power a Phase III study to address efficacy.

New insights into the pathogenesis and treatment of primary pulmonary hypertension

Primary pulmonary hypertension (PPH) is defined clinically by a sustained elevation of pulmonary arterial pressure (>25 mm Hg at rest or >30 mm Hg during exercise) without a demonstrable cause. Symptoms of PPH are largely non-specific but may include worsening shortness of breath, chest pain, syncope, fatigue, and peripheral oedema. It is a rare disorder with an estimated incidence of 2–3 per million per year.1 PPH shows a female bias with a F:M ratio of 2.3:1. The median age at diagnosis is 36 years but it may occur at any age. PPH is a progressive, often fatal, disease with mean survival from diagnosis of 2.8 years.2 The precise molecular mechanisms underlying PPH have hitherto remained elusive. Clues to the aetiology of the disease have been suggested by environmental stimuli associated with the development of severe pulmonary hypertension, pathologically indistinguishable from PPH. The association with appetite suppressants, in particular the fenfluramine/dexfenfluramine group,3 suggested a role of re-uptake inhibition of serotonin.4 Severe PPH may also follow HIV-1 infection, and PPH is associated with autoimmune thyroid disease and the presence of circulating anti-Ku and antinuclear antibodies.1 Pathologically, PPH is characterised by the obliteration of precapillary pulmonary arteries leading to right ventricular failure. Histologically, small pulmonary arteries show increased wall thickness, distal extension of smooth muscle into normally non-muscular vessels, the formation of a neointima, and plexiform lesions. The nature of the cell type responsible for the intimal obliteration of small pulmonary arteries in PPH has been the subject of considerable debate.5-7 The intimal lesions comprise myofibroblast-like cells, and the expression of endothelium specific markers is confined to cells lining the vascular lumen.5 8 Further debate surrounds the composition of the plexiform lesion,9 although substantial evidence exists for regarding this lesion as a proliferation of endothelial cells supported by a …

Ventriculo‐arterial coupling detects occult RV dysfunction in chronic thromboembolic pulmonary vascular disease

Chronic thromboembolic disease (CTED) is suboptimally defined by a mean pulmonary artery pressure (mPAP) <25 mmHg at rest in patients that remain symptomatic from chronic pulmonary artery thrombi. To improve identification of right ventricular (RV) pathology in patients with thromboembolic obstruction, we hypothesized that the RV ventriculo‐arterial (Ees/Ea) coupling ratio at maximal stroke work (Ees/Eamax sw) derived from an animal model of pulmonary obstruction may be used to identify occult RV dysfunction (low Ees/Ea) or residual RV energetic reserve (high Ees/Ea). Eighteen open chested pigs had conductance catheter RV pressure‐volume (PV)‐loops recorded during PA snare to determine Ees/Eamax sw. This was then applied to 10 patients with chronic thromboembolic pulmonary hypertension (CTEPH) and ten patients with CTED, also assessed by RV conductance catheter and cardiopulmonary exercise testing. All patients were then restratified by Ees/Ea. The animal model determined an Ees/Eamax sw = 0.68 ± 0.23 threshold, either side of which cardiac output and RV stroke work fell. Two patients with CTED were identified with an Ees/Ea well below 0.68 suggesting occult RV dysfunction whilst three patients with CTEPH demonstrated Ees/Ea ≥ 0.68 suggesting residual RV energetic reserve. Ees/Ea > 0.68 and Ees/Ea < 0.68 subgroups demonstrated constant RV stroke work but lower stroke volume (87.7 ± 22.1 vs. 60.1 ± 16.3 mL respectively, P = 0.006) and higher end‐systolic pressure (36.7 ± 11.6 vs. 68.1 ± 16.7 mmHg respectively, P < 0.001). Lower Ees/Ea in CTED also correlated with reduced exercise ventilatory efficiency. Low Ees/Ea aligns with features of RV maladaptation in CTED both at rest and on exercise. Characterization of Ees/Ea in CTED may allow for better identification of occult RV dysfunction.

Nebulised iloprost in pulmonary arterial hypertension due to eisenmengers syndrome

Eisenmengers syndrome (ES) is a slow progressive disorder characterised by pulmonary arterial hypertension (PAH) leading to right heart compromise. Systemic application of pulmonary vasodilator therapy is complicated by the risk of increased right to left shunt and paradoxical embolism. Nebulised iloprost is an established treatment in PAH leading to functional and symptomatic improvement with the advantage of pulmonary selectivity. We report 10 patients (9 female, 1, male, age 40 [26-58] years) with ES due to ASD (n 5), VSD (n 4), and atrioventicular canal defect (n 1), who were started on nebulised iloprost treatment in a single centre setting. All patients were in NYHA class III and received additional therapy with oxygen, anticoagulation, and diuretics. Iloprost was administered using an ultrasonic nebuliser (Multisonic compact ) in increasing dose up to 140 mcg / 24 hours. 3 patients stopped treatment due to severe side effects, bronchoconstriction in bronchial asthma, and non-compliance. In 7 patients treatment lead to symptomatic improvement in exercise capacity, dyspnoea and fluid retention. In 5 patients who completed a 7 months follow up, 6 minute walk distance (6MWD) significantly improved by 28% from baseline (p 0.002) without deterioration of oxygenation at rest and during exercise (figure, table). Nebulised Iloprost might be a treatment option in PAH in ES that enables symptomatic and functional benefit without worsening hypoxemia.

S143 Evidence that Type I interferon drives pulmonary arterial hypertension

Rationale There is increasing evidence of a link between interferon (IFN) and pulmonary arterial hypertension (PAH). Conditions such as HIV and Systemic sclerosis (SSc) where endogenous IFN levels are chronically elevated are strongly associated with PAH. Furthermore, therapeutic use of type I IFN is now known to cause PAH and increase the systemic release of endothelin (ET)-1 in some patients. The link between IFN therapy and PAH was formally recognised at the 5-yearly World Symposium on Pulmonary Hypertension (Nice, Feb 2013). Our group has identified the mitogen ET-1 and the archetypal interferon stimulated gene - interferon gamma inducible protein 10 (IP10) as candidate mediators for IFN induced PAH. Using a comprehensive approach incorporating human pulmonary vascular cells in vitro , genetically modified mice in vivo and clinical samples with patient data we sought to explore the role of type I IFN in PAH. Methods Primary cells were cultured and responses measured using standard approaches. Serum cytokine and ET-1 levels were measured by ELISA. The role of type I IFN in PAH in vivo was determined using type I IFN receptor knock out (IFNAR1 -/-) mice and the chronic hypoxia model of PAH. Results Human pulmonary artery smooth muscle cells expressed the type I IFN receptor and released ET-1 (Fig. 1a) and IP10 in response to IFNα. In patients with SSc associated PAH, serum IP10 and ET-1 levels were raised and correlated positively together (Fig. 1b). In addition IP10 correlated strongly with pulmonary haemodynamics and 6 minute walk distance (Fig. 1b). Finally, IFN was found to mediate PAH in vivo since mice lacking a functioning type I IFN receptor were protected from hypoxia induced PAH (Fig. 1c). Abstract S143 Figure 1. A— ET-1 release from human pulmonary artery smooth muscle cells. Data expressed as mean ± SEM from n = 5 experiments. Statistical significance determined by one-way ANOVA * p<0.05. B — Pearson Correlation between serum levels of IP10 and ET-1 (* p<0.05) and IP10 and 6 minute walk test (* p<0.05) in 28 patients with Systemic Sclerosis associated PAH. C — Mice lacking a functional type I IFN receptor (lFNAR1-/-) exposed to hypoxia (10% O2) or normoxia compared to wild type (C57Bl/6J) mice. Data presented as mean ± SEM for n = 4–15 mice. Right ventricular hypertrophy assessed as ratio of right ventricular (RV) mass to body weight (BW) (RV/BW). Statistical significance determined by one-way ANOVA followed by Bonferronis multiple comparison post-test (###p<0.0001 for normoxic vs. hypoxic conditions) and (*p<0.05 for lFNAR-/- vs. C57Bl/6J mice). Discussion and Conclusions These novel data reveal a clear pathological role for type I IFN in PAH and provide crucial insight into the mechanisms underpinning pulmonary vascular toxicity associated with type I IFN therapies. Furthermore, endogenous IFN elevated in autoimmune disease or viral infection, are now implicated in PAH. We conclude that type I IFN, via an action of IFNAR1 and potentially through ET-1 and IP10, mediates PAH and may represent a novel therapeutic target.