Aim: Pulmonary arterial hypertension (PAH) covers a range of life-limiting illnesses characterised by increased pulmonary arterial pressures leading to right heart failure and death, if untreated. 15-25% of patients have a genetic mutation, the most common affecting bone morphogenetic protein receptor type 2 (BMPR2). The aim was to profile inflammatory cytokines in BMPR2-mutation positive and PAH patients without mutations and analyse their influence on survival. Methods and Results: Levels of cytokines and growth factors were measured in plasma samples from BMPR2-mutation positive patients (BMPR2mut, n=54), patients without any driving mutations (n=54), and healthy controls (n=56) recruited from the United Kingdom cohort. BMPR2-mutation positive patients and patients without mutations had high levels of interleukin-6, interleukin-8, tumour necrosis factor-alpha, and vascular endothelial growth factor-A compared to controls. Only BMPR2-mutation carrying patients had higher G-CSF levels compared to controls. VEGF-A levels were substantially higher in patients without mutations compared to the BMPR2mut group. Only interleukin-6 was a significant discriminator for mortality in the BMPR2mut cohort (cumulative survival with interleukin-6>1.6pg/ml at 3 years was 65% compared to 96% with interleukin-6<1.6pg/ml, P=0.0013). N-Terminal pro-B-Type natriuretic peptide levels did not discriminate for survival in our BMPR2mut cohort (cumulative survival for patients with an NT-proBNP>130ng/ml at 3 years was 76% compared to 84% for patients with an NT-proBNP<130ng/ml, P=0.37). NT-proBNP outperformed interleukin-6 in PAH without driving mutations. Conclusions: BMPR2-mutation positive and PAH patients without mutations have different inflammatory profiles. In our BMPR2-mutation positive cohort IL-6 was the strongest prognostic biomarker and NT-proBNP failed to discriminate for survival. This is the first instance of genotype directly affecting clinical care in pulmonary vascular disease.
IntroductionChronic thromboembolic disease (CTED) is a consequence of failure of thrombus resolution following pulmonary embolism. Thrombotic material becomes fibrosed, resulting in chronic vascular occlusion without pulmonary hypertension. The prevalence and incidence of the condition is unknown and the mechanisms behind exercise intolerance are poorly understood. Surgical management in selected cases may significantly improve symptoms and patient functioning.1 MethodsWe prospectively evaluated baseline characteristics of patients with CTED in a single referral centre between January 2015 and June 2016. Newly referred patients with suspected CTED underwent a standard assessment as delineated in international guidelines with a minimum of 2 imaging modalities, resting and exercise right heart catheterisation and additionally incremental cardiopulmonary exercise testing (CPET). All patients were assessed in a pulmonary endarterectomy (PEA) MDT.Results128 patients were diagnosed with CTEPH or CTED from our referral centre. 28 patients were referred with suspected CTED due to ECHO findings. Of these 21 patients were confirmed to have CTED at right heart catheterization and 16 underwent full investigation protocol and were analysed. Patients with CTED were younger than contemporary cohorts of CTEPH2 and were more likely to have a past medical history of VTE (94%). Patients with CTED had normal resting haemodynamics, preserved RV function at rest and normal NT-proBNP (Table1). After careful review of each patient’s investigations only 5 of the 21 patients with CTED were offered PEA.ConclusionsPatients with CTED represent a significant proportion of the new referrals to our specialist centre. Surgery is deemed an appropriate therapeutic approach in a small subset of patients with significant functional and symptomatic impairment. The natural history of CTED is unclear so any discussion of surgery needs to carefully consider surgical risk of death and morbidity against the potential for symptomatic improvement.Abstract P27 Table 1Baseline characteristics and results of invasive and non-invasive investigations.Gender M/F11 (69)/5 (31)Age [years] Median, IQR53, 46.6–61.5WHO class I/II/III2/9/5NT-proBNP [pg/ml] Mean ± SD76.87 ± 816MWT Median, IQR• Distance [m]• Δ SpO2 444, 366–5211.5, 1–3.75mPAP [mmHg] Median, IQR20.5, 18–23PVR [dyn·s·cm−5] Median, IQR158, 112–195.7PAWP [mmHg] Median, IQR10.5, 8–12CO [L/min] Median, IQR5.35, 4.1–5.8ReferencesTaboada D, et al. Outcome of pulmonary endarterctomy in symptomatic chronic thromboembolic disease. ERJ 2014;44(6):1635–45.Pepke-Zaba J, et al. Chronic Thromboembolic Pulmonary Hypertension (CTEPH): Results from and international prospective registry. Circulation 2011;124(18):1973–81.
IntroductionPatients with chronic thromboembolic disease (CTED) without pulmonary hypertension commonly present with dyspnoea and fatigue. These symptoms limit physical function and impair quality of life. As resting haemodynamics in these patients are normal or near normal, stress testing may be a useful investigation to clarify mechanisms of functional impairment.MethodsWe prospectively evaluated baseline characteristics of patients with CTED in a single referral centre between January 2015 and June 2016. Newly referred patients with suspected CTED underwent a standard assessment as delineated in international guidelines1 with a minimum of 2 imaging modalities, resting and exercise right heart catheterisation (RHC) and additionally incremental cardiopulmonary exercise testing (CPET). All patients were assessed in a pulmonary endarterectomy MDT.ResultsOf 21 patients with confirmed CTED, 16 have completed the full assessment protocol (median age 53, 47–62). 14 (87%) were in functional class II/III. All patients had normal right ventricular function on echocardiography. Airway obstruction was present in 7 patients (44.5%). In majority of patients peak VO2 and oxygen pulse were decreased and VE/VCO2 at anaerobic threshold (AT) was increased (Table 1). CPET revealed 3 types of exercise limitation: combined cardiovascular and ventilatory limitation (n = 12), ventilatory limitation (n = 2) and limitation due to other reasons (n = 2). Peak oxygen consumption correlated with the symptoms domain of CAMPHOR (pulmonary hypertension specific quality of life measure) (p = 0.0242, R 0.56), cardiac output increase on exercise (p = 0.03, R 0.569) and VE/VCO2 at anaerobic threshold (p = 0.012, R 0.608). Resting mPAP and PVR did not correlate with peak VO2 or symptoms.ConclusionsWe confirm the limited utility of resting measurements, including RHC in CTED for understanding exercise and functional limitation. CPET identified alternative causes for breathlessness and clarifies that patients with CTED are limited on exertion because of inability to increase cardiac output and hyperventilation.ReferenceGalie N, et al. ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. EHJ 2015;58(1):e129–e152.Abstract P29 Table 1Exercise intolerance in chronic thromboembolic diseaseGender M/F number(%)11 (69)/5 (31)Age [years] Median, IQR53, 46.6–61.5Camphor score Median, IQR• Symptoms• Activity• QoL9.5, 5–12.33, 1.8–6.85, 0.8–12mPAP [mmHg] Median, IQR20.5, 18–23PVR [dyn·s·cm- 5] Median, IQR158, 112–195.7PAWP [mmHg] Median, IQR10.5, 8–12Cardiac Output [L/min] Median, IQR5.35, 4.1–5.8Cardiac Output fold increase on exercise*2.4 ± 0.5mPAP on exercise [mmHg]*30, 25.8–32.8TPR on exercise [WU]2.6, 2.1–3.9Peak VO2 [%pred.] Mean ± SD90 ± 19.5VE/VCO2 at AT Median, IQR36, 31–44.9Peak O2 pulse [% pred.] Median, IQR84.5, 71–107* Exercise at 40% of peak workload achieved during incremental CPET
IntroductionRecent studies have demonstrated that metabolomic profiling can identify metabolites and pathways which may have importance in the pathobiology of pulmonary arterial hypertension. However, the plasma metabolome in chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic vascular occlusions without pulmonary hypertension (CTED) has not been well characterised.ObjectiveTo profile circulating metabolites in CTEPH and CTED and assess metabolite gradients across the pulmonary circulation.MethodsIn the patient group, multisite blood sampling was performed at the time of right heart catheterisation. Blood samples were collected from the superior vena cava, pulmonary artery and radial artery.Venous blood samples from patients were compared to healthy controls to identify the metabolites present and to assess the difference between health and disease. Additionally, in the disease group, transpulmonary gradients were assessed by analysis of fold change in metabolite concentration between paired samples from the pulmonary artery and radial artery.Untargeted, semi-quantitative metabolic profiling of plasma was performed using the Metabolon DiscoveryHD4™ platform (Metabolon, NC, USA), utilising 2 ultra-high performance liquid chromatography methods, coupled with tandem mass spectrometry. Kruskal-Wallis analysis was used to compare metabolites between disease and control, with false discovery rate correction for multiple testing.ResultsThe disease group included patients with a spectrum of chronic pulmonary vascular occlusions (Table 1). A total of 1375 metabolites were detected in 70 venous plasma samples analysed from 43 patients and 27 healthy controls. Amongst endogenous metabolites, 266 showed a significant difference between disease and control. In the disease group there were increases in acylcarnitine metabolites, long chain fatty acids, polyamines, glycogen metabolites and primary bile acid metabolites compared to healthy controls. There was a reduction in lysolipids, plasmalogens, aminosugars, branched chain amino acid metabolites, glutathione metabolites and a number of steroids (Table 1). Analysis of transpulmonary gradients revealed primarily a reduction in metabolite concentration across the pulmonary circulation. This included depletion of energy substrates, lysolipids, lysoplasmalogens and acylcholines.ConclusionsThis pilot study of circulating metabolites in patients with CTEPH, CTED and healthy controls reveals differences between health and disease in several biological pathways. Measurement of the transpulmonary gradient of metabolites indicated predominant clearance of circulating metabolites associated with energy metabolism and cell turnover. These findings require confirmation in a larger population.Abstract S135 Table 1Study population and changes in metabolite groups in venous blood of patients compared to healthy controlsChronic pulmonary vascular occlusions (n = 43)Controls (n = 27) Group demographicsAge (years)58 (22–77)44 (18–75)Sex (% male)6460 Patient groupProx...
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