Chronic thromboembolic disease is characterised by persistent pulmonary thromboembolic occlusions without pulmonary hypertension. Early surgical treatment with pulmonary endarterectomy may improve ...symptoms and prevent disease progression. We sought to assess the outcome of pulmonary endarterectomy in symptomatic patients with chronic thromboembolic disease. Patients with symptomatic chronic thromboembolic disease and a mean pulmonary artery pressure <25 mmHg at baseline with right heart catheterisation and treated with pulmonary endarterectomy between January 2000 and July 2013 were identified. Patients were reassessed at 6 months and at 1 year following surgery. A total of 42 patients underwent surgery and the median length of stay in hospital was 11 days. There was no in-hospital mortality but complications occurred in 40% of patients. At 1 year, following surgery, 95% of the patients remained alive. There was a significant symptomatic improvement with 95% of patients in the New York Heart Association functional classes I or II at 6 months. There was a significant improvement in quality of life assessed by the Cambridge pulmonary hypertension outcome review questionnaire. In this carefully selected cohort of chronic thromboembolic disease patients, pulmonary endarterectomy resulted in significant improvement in symptoms and quality of life. Appropriate patient selection is paramount given the known surgical morbidity and mortality, and surgery should only be performed in expert centres.
Inflammation is a feature of pulmonary arterial hypertension (PAH), and increased circulating levels of cytokines are reported in patients with PAH. However, to date, no information exists on the ...significance of elevated cytokines or their potential as biomarkers. We sought to determine the levels of a range of cytokines in PAH and to examine their impact on survival and relationship to hemodynamic indexes.
We measured levels of serum cytokines (tumor necrosis factor-alpha, interferon-gamma and interleukin-1beta, -2, -4, -5, -6, -8, -10, -12p70, and -13) using ELISAs in idiopathic and heritable PAH patients (n=60). Concurrent clinical data included hemodynamics, 6-minute walk distance, and survival time from sampling to death or transplantation. Healthy volunteers served as control subjects (n=21). PAH patients had significantly higher levels of interleukin-1beta, -2, -4, -6, -8, -10, and -12p70 and tumor necrosis factor-alpha compared with healthy control subjects. Kaplan-Meier analysis showed that levels of interleukin-6, 8, 10, and 12p70 predicted survival in patients. For example, 5-year survival with interleukin-6 levels of >9 pg/mL was 30% compared with 63% for patients with levels < or = 9 pg/mL (P=0.008). In this PAH cohort, cytokine levels were superior to traditional markers of prognosis such as 6-minute walk distance and hemodynamics.
This study illustrates dysregulation of a broad range of inflammatory mediators in idiopathic and familial PAH and demonstrates that cytokine levels have a previously unrecognized impact on patient survival. They may prove to be useful biomarkers and provide insight into the contribution of inflammation in PAH.
Background: There are currently no licensed medical therapies for inoperable chronic thromboembolic pulmonary hypertension (CTEPH).
Methods: In this double-blind, placebo-controlled pilot study, 19 ...subjects with inoperable CTEPH were randomly assigned to sildenafil
or placebo for 12 weeks. The primary end point was change in 6-min walking distance (6MWD). Secondary end points included
changes in World Health Organization (WHO) class, cardiopulmonary hemodynamics, quality of life (QOL) scores, and N-terminal
pro brain natriuretic peptide (NT-proBNP). All subjects were transferred to open-label sildenafil at the end of the study
and offered repeat assessment at 12 months.
Results: There were no significant differences between the two groups with respect to change in exercise capacity. However significant
improvements were seen in WHO class and pulmonary vascular resistance (PVR). Seventeen subjects were eligible for reassessment
at 12 months and demonstrated significant improvements in 6MWD, activity and symptom components of QOL, cardiac index, PVR,
and NT-proBNP.
Conclusions: Although this pilot study was insufficiently powered to test the primary end point, it did suggest beneficial effects in
favor of sildenafil in several secondary end points at both 3 months and 12 months. Further larger-scale trials of sildenafil
in inoperable CTEPH are required to confirm these findings and potentially increase the treatment options available for this
devastating disease.
Trial registration: The study protocol was registered with the UK National Research Register database (publication ID N0542136603).
inoperable
pulmonary endarterectomy
pulmonary hypertension
sildenafil
thromboembolism
Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone ...morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.
While traffic and air pollution exposure is associated with increased mortality in numerous diseases, its association with disease severity and outcomes in pulmonary arterial hypertension (PAH) ...remains unknown.Exposure to particulate matter with a 50% cut-off aerodynamic diameter ≤2.5 μm (PM
), nitrogen dioxide (NO
) and indirect measures of traffic-related air pollution (distance to main road and length of roads within buffer zones surrounding residential addresses) were estimated for 301 patients with idiopathic/heritable PAH recruited in the UK National Cohort Study of Idiopathic and Heritable PAH. Associations with transplant-free survival and pulmonary haemodynamic severity at baseline were assessed, adjusting for confounding variables defined
Higher estimated exposure to PM
was associated with higher risk of death or lung transplant (unadjusted hazard ratio (HR) 2.68 (95% CI 1.11-6.47) per 3 μg·m
; p=0.028). This association remained similar when adjusted for potential confounding variables (HR 4.38 (95% CI 1.44-13.36) per 3 μg·m
; p=0.009). No associations were found between NO
exposure or other traffic pollution indicators and transplant-free survival. Conversely, indirect measures of exposure to traffic-related air pollution within the 500-1000 m buffer zones correlated with the European Society of Cardiology/European Respiratory Society risk categories as well as pulmonary haemodynamics at baseline. This association was strongest for pulmonary vascular resistance.In idiopathic/heritable PAH, indirect measures of exposure to traffic-related air pollution were associated with disease severity at baseline, whereas higher PM
exposure may independently predict shorter transplant-free survival.
Anaemia is common in left heart failure and is associated with a poorer outcome. Many patients with pulmonary arterial hypertension (PAH) are anaemic or iron-deficient. This study was performed to ...investigate the prevalence of iron deficiency in PAH and to identify possible causes.
All patients with idiopathic or heritable PAH diagnosed in 1995-2008 were identified. Controls were selected from patients with chronic thromboembolic pulmonary hypertension (CTEPH). Full blood counts were examined and any abnormality was investigated. Patients were excluded if they had a cause for iron deficiency. The prevalence study was based on 85 patients with idiopathic PAH and 120 with CTEPH. A separate group of 20 patients with idiopathic PAH and 24 with CTEPH with matching haemodynamics were prospectively investigated for serum factors affecting iron metabolism.
The prevalence study identified a point prevalence of unexplained iron deficiency of 50% in premenopausal women with idiopathic PAH compared with 8% in premenopausal women with CTEPH (p=0.002); 14% in postmenopausal women with idiopathic PAH compared with 6% in postmenopausal women with CTEPH (p=0.16); 28% in men with idiopathic PAH men compared with 2% in men with CTEPH (p=0.002); and 60% in patients with heritable PAH. The serum study showed that patients with idiopathic PAH had lower serum iron and transferrin saturations than those with CTEPH. Interleukin-6 levels correlated with iron levels (r=-0.6, p=0.006) and transferrin saturations (r=-0.68, p=0.001) in idiopathic PAH but not in CTEPH.
The prevalence of unexplained iron deficiency is significantly higher in idiopathic PAH than in CTEPH. This may be linked to interleukin-6.
Beyond their role as innate immune effectors, natural killer (NK) cells are emerging as important regulators of angiogenesis and vascular remodeling. Pulmonary arterial hypertension (PAH) is ...characterized by severe pulmonary vascular remodeling and has long been associated with immune dysfunction. Despite this association, a role for NK cells in disease pathology has not yet been described.
Analysis of whole blood lymphocytes and isolated NK cells from PAH patients revealed an expansion of the functionally defective CD56(-)/CD16(+) NK subset that was not observed in patients with chronic thromboembolic pulmonary hypertension. NK cells from PAH patients also displayed decreased levels of the activating receptor NKp46 and the killer immunoglobulin-like receptors 2DL1/S1 and 3DL1, reduced secretion of the cytokine macrophage inflammatory protein-1β, and a significant impairment in cytolytic function associated with decreased killer immunoglobulin-like receptor 3DL1 expression. Genotyping patients (n=222) and controls (n=191) for killer immunoglobulin-like receptor gene polymorphisms did not explain these observations. Rather, we show that NK cells from PAH patients exhibit increased responsiveness to transforming growth factor-β, which specifically downregulates disease-associated killer immunoglobulin-like receptors. NK cell number and cytotoxicity were similarly decreased in the monocrotaline rat and chronic hypoxia mouse models of PAH, accompanied by reduced production of interferon-γ in NK cells from hypoxic mice. NK cells from PAH patients also produced elevated quantities of matrix metalloproteinase 9, consistent with a capacity to influence vascular remodeling.
Our work is the first to identify an impairment of NK cells in PAH and suggests a novel and substantive role for innate immunity in the pathobiology of this disease.
The 6 minutes walk test (6MWT) is often shown to be the best predictor of mortality in pulmonary hypertension (PH) probably because it challenges the failing heart to deliver adequate cardiac output. ...We hypothesised that the 6MWT elicits maximal cardiac output as measured during a maximal cardiopulmonary exercise testing (CPET).
18 patients with chronic thromboembolic pulmonary hypertension (n = 12) or pulmonary arterial hypertension (n = 6) and 10 healthy subjects performed a 6MWT and CPET with measurements of cardiac output (non invasive rebreathing device) before and directly after exercise. Heart rate was measured during 6MWT with a cardiofrequence meter.
Cardiac output and heart rate measured at the end of the 6MWT were linearly related to 6MW distance (mean±SD: 490±87 m). Patients with a high NT-pro-BNP achieve a maximum cardiac output during the 6MWT, while in normal subjects and in patients with a low-normal NT-proBNP, cardiac output at the end of a 6MWT was lower than achieved at maximum exercise during a CPET. In both cases, heart rate is the major determinant of exercise-induced increase in cardiac output. However, stroke volume increased during CPET in healthy subjects, not in PH patients.
Maximal cardiac output is elicited by 6MWT in PH patients with failing right ventricle. Cardiac output increase is dependent on chronotropic response in patients with PH.
Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy, ...and heart failure. PAH can be associated with other diseases (APAH: connective tissue diseases, congenital heart disease, and others) but often the etiology is idiopathic (IPAH). Mutations in bone morphogenetic protein receptor 2 (BMPR2) are the cause of most heritable cases but the vast majority of other cases are genetically undefined.
To identify new risk genes, we utilized an international consortium of 4241 PAH cases with exome or genome sequencing data from the National Biological Sample and Data Repository for PAH, Columbia University Irving Medical Center, and the UK NIHR BioResource - Rare Diseases Study. The strength of this combined cohort is a doubling of the number of IPAH cases compared to either national cohort alone. We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 1647 IPAH cases and 18,819 controls. We also analyzed de novo variants in 124 pediatric trios enriched for IPAH and APAH-CHD.
Seven genes with rare deleterious variants were associated with IPAH with false discovery rate smaller than 0.1: three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (fibulin 2, FBLN2; platelet-derived growth factor D, PDGFD). The new genes were identified based solely on rare deleterious missense variants, a variant type that could not be adequately assessed in either cohort alone. The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most variants occur in conserved protein domains. For pediatric PAH, predicted deleterious de novo variants exhibited a significant burden compared to the background mutation rate (2.45×, p = 2.5e-5). At least eight novel pediatric candidate genes carrying de novo variants have plausible roles in lung/heart development.
Rare variant analysis of a large international consortium identified two new candidate genes-FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling. Trio analysis predicted that ~ 15% of pediatric IPAH may be explained by de novo variants.
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