Natural history of chronic thromboembolic pulmonary disease with no or mild pulmonary hypertension.

BACKGROUND: We describe baseline characteristics, disease progression and mortality in chronic thromboembolic pulmonary disease patients as a function of mean pulmonary artery pressure (mPAP) according to new and previous definitions of pulmonary hypertension. METHODS: All patients diagnosed with chronic thromboembolic pulmonary disease between January, 2015 and December, 2019 were dichotomized according to initial mPAP: ≤ 20 mmHg ('normal') vs 21-24 mmHg ('mildly-elevated'). Baseline features were compared between the groups, and pairwise analysis performed to determine changes in clinical endpoints at 1-year, excluding those who underwent pulmonary endarterectomy or did not attend follow-up. Mortality was assessed for the whole cohort over the entire study period. RESULTS: One hundred thirteen patients were included; 57 had mPAP ≤ 20 mmHg and 56 had mPAP 21-24 mmHg. Normal mPAP patients had lower pulmonary vascular resistance (1.6 vs 2.5WU, p < 0.01) and right ventricular end-diastolic pressure (5.9 vs 7.8 mmHg, p < 0.01) at presentation. At 3 years, no major deterioration was seen in either group. No patients were treated with pulmonary artery vasodilators. Eight had undergone pulmonary endarterectomy. Over 37 months median follow-up, mortality was 7.0% in the normal mPAP group and 8.9% in the mildly-elevated mPAP group. Cause of death was malignancy in 62.5% of cases. CONCLUSIONS: Chronic thromboembolic pulmonary disease patients with mild pulmonary hypertension have statistically higher right ventricular end-diastolic pressure and pulmonary vascular resistance than those with mPAP ≤ 20 mmHg. Baseline characteristics were otherwise similar. Neither group displayed disease progression on non-invasive tests up to 3 years. Mortality over 37 months follow-up is 8%, and mainly attributable to malignancy. Further prospective study is required to validate these findings.

Supplementation with Iron in Pulmonary Arterial Hypertension. Two Randomized Crossover Trials.

Rationale: Iron deficiency, in the absence of anemia, is common in patients with idiopathic and heritable pulmonary arterial hypertension (PAH) and is associated with a worse clinical outcome. Oral iron absorption may be impeded by elevated circulating hepcidin concentrations. The safety and benefit of parenteral iron replacement in this patient population is unclear. Objectives: To evaluate the safety and efficacy of parenteral iron replacement in PAH. Methods: In two randomized, double-blind, placebo-controlled 12-week crossover studies, 39 patients in Europe received a single infusion of ferric carboxymaltose (Ferinject) (1,000 mg or 15 mg/kg if weight <66.7 kg) or saline as placebo, and 17 patients in China received iron dextran (Cosmofer) (20 mg iron/kg body weight) or saline placebo. All patients had idiopathic or heritable PAH and iron deficiency at entry as defined by a serum ferritin <37 µg/L or iron <10.3 µmol/L or transferrin saturations <16.4%. Results: Both iron treatments were well tolerated and improved iron status. Analyzed separately and combined, there was no effect on any measure of exercise capacity (using cardiopulmonary exercise testing or 6-minute walk test) or cardiopulmonary hemodynamics, as assessed by right heart catheterization, cardiac magnetic resonance, or plasma NT-proBNP (N-terminal-pro hormone brain natriuretic peptide) at 12 weeks. Conclusions: Iron repletion by administration of a slow-release iron preparation as a single infusion to patients with PAH with iron deficiency without overt anemia was well tolerated but provided no significant clinical benefit at 12 weeks. Clinical trial registered with ClinicalTrials.gov (NCT01447628).

Idiopathic pulmonary arterial hypertension and co-existing lung disease: is this a new phenotype?

Patients classified as idiopathic pulmonary arterial hypertension (defined as Group 1 on European Respiratory Society (ERS)/European Cardiac Society (ESC) criteria) may have evidence of minor co-existing lung disease on thoracic computed tomography. We hypothesised that these idiopathic pulmonary arterial hypertension patients (IPAH lung disease ) are a separate subgroup of idiopathic pulmonary arterial hypertension with different phenotype and outcome compared with idiopathic pulmonary arterial hypertension patients without co-existing lung disease (IPAH no lung disease ). Patients with 'IPAH lung disease ' have been eligible for all clinical trials of Group 1 patients because they have normal clinical examination and normal spirometry but we wondered whether they responded to treatment and had similar survival to patients with 'IPAH no lung disease '. We described the outcome of the cohort of patients with 'IPAH no lung disease ' in a previous paper. Here, we have compared incident 'IPAH lung disease ' patients with 'IPAH no lung disease ' patients diagnosed concurrently in all eight Pulmonary Hypertension centres in the UK and Ireland between 2001-2009. Compared with 'IPAH no lung disease ' (n = 355), 'IPAH lung disease ' patients (n = 137) were older, less obese, predominantly male, more likely to be current/ex-smokers and had lower six-minute walk distance, lower % predicted diffusion capacity for carbon monoxide, lower mean pulmonary arterial pressure and lower pulmonary vascular resistance index. After three months of pulmonary hypertension-targeted treatment, six-minute walk distance improved equally in 'IPAH lung disease ' and 'IPAH no lung disease '. However, survival of 'IPAH lung disease ' was lower than 'IPAH no lung disease ' (one year survival: 72% compared with 93%). This survival was significantly worse in 'IPAH lung disease ' even after adjusting for age, gender, smoking history, comorbidities and haemodynamics. 'IPAH lung disease ' patients had similar short-term improvement in six-minute walk distance with anti-pulmonary arterial hypertension therapy but worse survival compared with 'IPAH no lung disease ' patients. This suggests that 'IPAH lung disease ' are a separate phenotype and should not be lumped with 'IPAH no lung disease ' in clinical trials of Group 1 pulmonary arterial hypertension.

The outcome of reoperative pulmonary endarterectomy surgery.

OBJECTIVES: Pulmonary endarterectomy (PEA) is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension (PH). Despite excellent outcomes following PEA, a small proportion of patients have residual proximal disease or present with recurrent chronic thromboembolic PH and may benefit from further surgery. The aim of this study was to analyse outcomes following reoperative PEA at a high-volume national tertiary referral centre for the management of chronic thromboembolic PH. METHODS: This retrospective analysis was performed using our prospectively maintained PH database to identify all patients who underwent reoperative PEA surgery between the commencement of the programme in 1997 and January 2017, and the patients' data were collected for analysis. RESULTS: Twelve patients underwent reoperative PEA during the period of study. The mean interval between primary procedure and reoperative procedure was 6.3 years. Significant improvements were observed in pulmonary haemodynamics following reoperative PEA. Mean pulmonary arterial pressure decreased from 46.8 to 29.8 mmHg (P < 0.0001) and pulmonary vascular resistance decreased from 662 to 362 dyne·s·cm-5 (P = 0.0007). A significant functional improvement in the 6-min walking test distance was also observed, increasing from 327 to 460 m at 6 months postoperatively (P = 0.0018). Median length of hospital stay was 12 days. In-hospital mortality was 8.3% with 1-year survival of 83.3%. CONCLUSIONS: Reoperative PEA is technically possible and relatively safe, achieving good functional and physiological outcomes. Patients must be carefully selected by a multidisciplinary team, and surgery should be performed in experienced centres.

Outcome of pulmonary endarterectomy in symptomatic chronic thromboembolic disease.

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.

Unexplained iron deficiency in idiopathic and heritable pulmonary arterial hypertension.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: The prevalence of unexplained iron deficiency is significantly higher in idiopathic PAH than in CTEPH. This may be linked to interleukin-6.

Survival after pulmonary thromboendarterectomy: effect of residual pulmonary hypertension.

OBJECTIVE: Pulmonary endarterectomy is the treatment of choice for chronic thromboembolic pulmonary hypertension. In many patients hemodynamics are normalized early after surgical intervention. However, the effect of residual pulmonary hypertension on postoperative clinical status and survival is unknown. METHODS: Data were collected prospectively on all patients who underwent pulmonary endarterectomy in a continuous national series between 1997 and December 2007. Postoperatively, patients underwent scheduled reinvestigation, including functional testing and right heart catheterization, at 3 months after the operation. They were divided into 2 groups based on mean pulmonary artery pressure: group 1, less than 30 mm Hg; group 2, 30 mm Hg or greater. RESULTS: Three hundred fourteen patients underwent pulmonary endarterectomy, survived to hospital discharge, and completed the 3-month follow-up period. At 3 months after pulmonary endarterectomy, there was a significant reduction in mean pulmonary artery pressure for the whole cohort (48±12 to 26±10 mm Hg, P<.001). However, 31% of the patients had residual pulmonary hypertension. Group 1 patients enjoyed significantly better exercise capacity and improved symptoms compared with group 2 patients. In addition, there were significantly fewer patients receiving targeted medical therapy in group 1 versus group 2 (0% vs 25%, P<.001). Conditional survival after discharge from the hospital for the whole cohort was 90.0% at 5 years and was not different between groups (90.3% for group 1 vs 89.9% for group 2, P=.36). CONCLUSIONS: For patients undergoing pulmonary endarterectomy, survival after hospital discharge is excellent. Residual pulmonary hypertension significantly compromised symptom status and functional capacity but did not appear to adversely affect medium-term survival. The effect of targeted medical therapy in patients with residual pulmonary hypertension after pulmonary endarterectomy needs to be evaluated further.

Functional and haemodynamic outcome 1 year after pulmonary thromboendarterectomy.

OBJECTIVE: Chronic thromboembolic pulmonary hypertension (CTEPH) results in severe symptoms and impaired survival. Pulmonary thromboendarterectomy (PTE) is considered the gold standard treatment. Many units have reported excellent early results post PTE, but there is less information on whether benefit is sustained. We sought to determine the medium-term functional and haemodynamic outcome for patients following PTE and the longer-term survival after discharge from hospital. METHODS: Data were collected prospectively on all patients who underwent PTE in the UK between 1997 and June 2006. Patients were reassessed at 3 and 12 months after operation. Follow-up over time was assessed using repeated measures ANOVA, the Friedman test or Wilcoxon signed ranks test as appropriate. RESULTS: Two hundred and twenty-nine patients underwent PTE, survived to hospital discharge, and completed follow-up. At 3 months following operation, there was a significant reduction in mean pulmonary artery pressure (47+/-14 to 25+/-14mmHg, p<0.001), a significant increase in cardiac index (1.9+/-0.7 to 2.5+/-0.6l/minm(2), p<0.001) and a significant increase in 6-min walk distance (269+/-123 to 375+/-104m, p<0.001). At 12-month follow-up, the haemodynamic improvements were sustained and there was a further increase in 6-min walk distance (375+/-104 to 392+/-108m, p=0.004). NYHA class was significantly reduced at 3 months, with the improvement sustained at 12 months. Conditional survival following discharge from hospital was 92.5% at 5 years and 88.3% at 10 years. CONCLUSIONS: PTE is a very effective therapy for CTEPH. This is the first report from a continuous national series to fully characterise haemodynamic and functional outcome 1 year after PTE. Patients enjoy continued improvement in haemodynamic status that translates into better exercise capacity, reduced symptoms and excellent survival.

Role of NT-proBNP and 6MWD in chronic thromboembolic pulmonary hypertension.

BACKGROUND: This study aims to evaluate the role of NT-proBNP and six minute walking distance (6MWD) in the pre- and post-operative assessment of subjects undergoing pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Subjects undergoing PEA between August 2004 and July 2006 were assessed at baseline and 3 months post-operatively with resting haemodynamics, NT-proBNP and 6MWD. RESULTS: A number of 111 subjects underwent surgery, of which 102 were included. 15 subjects died before their 3 month assessment. Non-survivors had significantly worse preoperative NT-proBNP and 6MWD (4728 pg/mL vs 1863 pg/mL, p=0.001, 182.4 m vs 263.5 m, p=0.001). Taking pre-operative cut-off values of 1200 pg/mL for NT-proBNP and 345 m for 6MWD, both tests had high negative predictive value for predicting mortality (97.3% and 100%, respectively). Amongst survivors, peri-operative changes in NT-proBNP and 6MWD correlated with changes in total pulmonary resistance (TPR) (r=0.49, p<0.001 and r=-0.46, p<0.001). Post-operatively, both NT-proBNP and 6MWD also correlated with mPAP (r=0.65, p<0.001 and r=-0.50, p<0.001) and PVR (r=0.63, p<0.001 and r=-0.47, p<0.001). The ability of NT-proBNP to predict persistent pulmonary hypertension was significantly confounded by age, but not gender, BMI or renal function. CONCLUSIONS: Pre-operative evaluation with NT-proBNP and 6MWD helps risk-stratify patients prior to PEA. Post-operatively, both markers correlate with changes in disease burden and right ventricular function. These results suggest that both NT-proBNP and 6MWD offer effective 'bedside' tools for the long term follow up of patients with CTEPH.

Demographic features, BMPR2 status and outcomes in distal chronic thromboembolic pulmonary hypertension.

BACKGROUND: Although pulmonary endarterectomy (PEA) is potentially curative in chronic thromboembolic pulmonary hypertension (CTEPH), some patients have distally distributed disease that is not amenable to surgery. The aetiology and characteristics of this patient group are currently not well understood. OBJECTIVES: This study compares the baseline demographic features and outcomes in subjects with distal CTEPH, those with proximal CTEPH and those with idiopathic pulmonary arterial hypertension (IPAH) to determine whether these conditions represent separate entities or whether they exist along the same spectrum of disease. METHODS: The medical history, clinical characteristics, bone morphogenetic protein receptor type II (BMPR2) mutation status and outcomes of 96 subjects with IPAH, 35 with distal CTEPH and 68 with proximal CTEPH referred to a single specialist centre between 1994 and 2005 were reviewed. RESULTS: There were significant differences between the distal CTEPH, proximal CTEPH and IPAH groups in age (55.9 years vs 54.8 years vs 46.2 years, p<0.001), proportion who were male (43% vs 69% vs 29%, p<0.001), previous deep vein thrombosis (28.6% vs 30.9% vs 3.1%, p<0.001), positive BMPR2 status (0% vs 0% vs 15%, p = 0.018), mean pulmonary artery pressure (47.3 mm Hg vs 45.4 mm Hg vs 54.8 mm Hg, p<0.001) and total pulmonary resistance (12.9 WU vs 12.4 WU vs 18.1 WU, p<0.001). Patients with distal CTEPH and those with IPAH were managed similarly and had comparable survival characteristics (1 year survival 77% vs 86%; 3 year survival 53% vs 60%; p = 0.68). CONCLUSIONS: Patients with distal CTEPH share certain demographic features with patients with proximal CTEPH that not only indicate a common aetiology but also help to differentiate them from patients with IPAH. Despite more favourable haemodynamic parameters in those with distal CTEPH, patients in this group had a poor long-term outcome which was similar to that of patients with IPAH.