Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA).

BACKGROUND: For almost 30 years, anticoagulation has been recommended for patients with idiopathic pulmonary arterial hypertension (IPAH). Supporting evidence, however, is limited, and it is unclear whether this recommendation is still justified in the modern management era and whether it should be extended to patients with other forms of pulmonary arterial hypertension (PAH). METHODS AND RESULTS: We analyzed data from Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), an ongoing European pulmonary hypertension registry. Survival rates of patients with IPAH and other forms of PAH were compared by the use of anticoagulation. The sample consisted of 1283 consecutively enrolled patients with newly diagnosed PAH. Anticoagulation was used in 66% of 800 patients with IPAH and in 43% of 483 patients with other forms of PAH. In patients with IPAH, there was a significantly better 3-year survival (P=0.006) in patients on anticoagulation compared with patients who never received anticoagulation, albeit the patients in the anticoagulation group had more severe disease at baseline. The survival difference at 3 years remained statistically significant (P=0.017) in a matched-pair analysis of n=336 IPAH patients. The beneficial effect of anticoagulation on survival of IPAH patients was confirmed by Cox multivariable regression analysis (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94). In contrast, the use of anticoagulants was not associated with a survival benefit in patients with other forms of PAH. CONCLUSIONS: The present data suggest that the use of anticoagulation is associated with a survival benefit in patients with IPAH, supporting current treatment recommendations. The evidence remains inconclusive for other forms of PAH. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01347216.

Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis.

RATIONALE: Systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) portends worse outcome than other forms of PAH. Vasoconstrictive and vascular remodeling actions of endothelin (ET) 1 and angiotensin (Ang) II via endothelin receptor type A (ETAR) and Ang receptor type-1 (AT1R) activation are implicated in PAH pathogenesis. OBJECTIVES: We hypothesized that stimulating autoantibodies (Abs) targeting and activating AT1R and ETAR may contribute to SSc-PAH pathogenesis, and tested their functional and biomarker relevance. METHODS: Anti-AT1R and -ETAR Abs were detected by ELISA in different cohorts of patients and tested in vitro and in an animal model for their pathophysiological effects. MEASUREMENTS AND MAIN RESULTS: The Abs were significantly higher and more prevalent in patients with SSc-PAH (n = 81) and connective tissue disease-associated PAH (n = 110) compared with other forms of PAH/pulmonary hypertension (n = 106). High anti-AT1R and anti-ETAR Abs predicted development of SSc-PAH and SSc-PAH-related mortality in a prospective analysis. Both Abs increased endothelial cytosolic Ca(2+) concentrations in isolated perfused rat lungs, which could be blocked by respective specific receptor antagonists. Ab-mediated stimulation of intralobar pulmonary rat artery ring segments increased vasoconstrictive responses to Ang II and ET-1, and implicated cross-talk between both pathways demonstrated by reciprocal blockade with respective antagonists. Transfer of SSc-IgG containing both autoantibodies into healthy C57BL/6J mice led to more abundant vascular and airway α-smooth muscle actin expression and inflammatory pulmonary vasculopathy. CONCLUSIONS: Anti-AT1R and -ETAR Abs are more frequent in SSc-PAH/connective tissue disease-PAH compared with other forms of pulmonary hypertension, and serve as predictive and prognostic biomarkers in SSc-PAH. Both antibodies may contribute to SSc-PAH via increased vascular endothelial reactivity and induction of pulmonary vasculopathy.

Poor sleep quality is associated with exercise limitation in precapillary pulmonary hypertension.

BACKGROUND: Patients with precapillary pulmonary hypertension (PH) have been reported to suffer from poor sleep quality, however, if this is related to physical exercise performance has not yet been thoroughly investigated. METHODS: Clinically stable out-patients with idiopathic pulmonary arterial hypertension (IPAH, n = 52) and chronic thromboembolic PH (CTEPH, n = 64) in NYHA classes II and III were prospectively enrolled. 54 healthy volunteers matched for anthropometric variables served as a control group. The Pittsburgh Sleep Quality Index (PSQI) was used to rate subjective sleep quality. In the PH patients, six-minute walk tests (6MWT) were performed to assess exercise capacity. RESULTS: Poor sleep quality (i.e. a PSQI score > 5) occurred more frequently in PH (IPAH: n = 25 [48.1%], CTEPH: n = 39 [60.9%], controls: n = 10 [18.5%]; p < 0.01 when compared to controls). In addition, poor vs. good sleepers had significantly higher average NYHA class (IPAH: 2.6 ± 0.1 vs. 2.3 ± 0.1, CTEPH: 2.8 ± 0.1 vs. 2.3 ± 0.2; p < 0.01) and shorter 6MWT distances (IPAH: 338 ± 23 vs. 441 ± 29 m, CTEPH: 355 ± 15 vs. 413 ± 26 m; p < 0.05). CONCLUSIONS: Self-reported poor sleep quality is more common in PH than in healthy controls. Furthermore, it is related to reduced physical exercise capacity.

Assessment and prognostic relevance of right ventricular contractile reserve in patients with severe pulmonary hypertension.

BACKGROUND: This study sought to analyze a new approach to assess exercise-induced pulmonary artery systolic pressure (PASP) increase by means of stress Doppler echocardiography as a possible measure of right ventricular contractile reserve in patients with severe pulmonary hypertension and right heart failure. METHODS AND RESULTS: In this prospective study, patients with invasively diagnosed pulmonary arterial hypertension or inoperable chronic thromboembolic pulmonary hypertension and impaired right ventricular pump function despite a stable targeted pulmonary arterial hypertension medication underwent a broad panel of noninvasive assessments, including stress echocardiography and cardiopulmonary exercise testing. On the basis of the assumption that exercise-induced PASP is a measure of right ventricular contractile reserve, patients were classified into 2 groups according to an exercise-induced PASP increase above or below the median. Patients were followed up for 3.0 ± 1.8 years. Univariate and multivariate analyses were used for factors predicting survival. Of 124 patients, 66 were below the median exercise-induced PASP increase of 30 mm Hg (low PASP), and 58 patients were above the median (high PASP). These groups were not significantly different in terms of medication and resting hemodynamics. Low PASP was associated with a significantly lower 6-minute walking distance, peak o2 per kilogram, and 1-, 3-, and 4-year survival rates (92%, 69%, and 48%, respectively, versus 96%, 92%, and 89%). In the multivariate Cox model analysis adjusted for age and sex, PASP increase during exercise and peak o2 per kilogram remained independent prognostic markers (hazard ratio, 2.56 for peak o2 per kilogram and 2.84 for PASP increase). CONCLUSIONS: Exercise-induced PASP increase is of high clinical and prognostic relevance in pulmonary hypertension patients and may indicate right ventricular contractile reserve. Stress Doppler echocardiography may be a useful tool for prognostic assessment in pulmonary hypertension patients.

The prognostic significance of inspiratory capacity in pulmonary arterial hypertension.

BACKGROUND: Patients with pulmonary arterial hypertension (PAH) present with an altered inspiratory capacity (IC) reflecting dynamic hyperinflation (DH) that leads to mechanical constraints and excessive ventilatory demand, particularly during exercise, resulting in exertional dyspnea. OBJECTIVES: Assessment of the long-term consequences of altered IC and DH in PAH. METHODS: 50 patients with newly diagnosed PAH were prospectively recruited. All patients were assessed by means of right heart catheterization, 6-min walking distance (6MWD) test, lung function and cardiopulmonary exercise testing, including the assessment of IC. RESULTS: 37 patients with idiopathic PAH and 13 patients with conditions associated with PAH (29 female; mean age 51.6 ± 15.1 years; World Health Organization, WHO class, 2.7 ± 0.6) presented with a mean pulmonary arterial pressure of 42.8 ± 15.9 mm Hg and pulmonary vascular resistance (PVR) of 737.2 ± 592.8 dyn*s/cm(5). The mean IC at rest was 87.2 ± 17.3% pred. Kaplan-Meier analysis revealed that patients with an IC at rest >89% pred. had a significantly better 5-year survival than those with lower values (94.1 vs. 75.1%; log-rank p = 0.036). Univariate analysis identified IC at rest (% pred.) as a predictor of survival with a hazard ratio (HR) of 5.05 (95% confidence interval, CI, 0.97-26.24, p = 0.054). In multivariate analysis including PVR, WHO class, 6MWD and peak oxygen uptake as covariates, IC at rest remained an independent predictor of survival (HR: 8.06, 95% CI 0.92-70.34; p = 0.059). DH expressed as ΔIC or static hyperinflation expressed as IC/total lung capacity at rest revealed no prognostic significance. CONCLUSION: In patients with PAH, IC at rest is of prognostic significance at the time of diagnosis.

Economic evaluation of exercise training in patients with pulmonary hypertension.

PURPOSE: Exercise training as an add-on to medical therapy has been shown to improve exercise capacity, quality of life, and possibly prognosis in patients with pulmonary hypertension (PH). The purpose of this study was to analyze the impact of exercise training on healthcare costs in PH. METHODS: Estimated healthcare costs have been compared between patients with severe PH under optimized medical therapy only (control group) versus patients who received exercise training as an add-on to medical therapy (training group). Cost-analysis included a cost-estimation model of costs for baseline and follow-up visits and all PH-related healthcare events that occurred within the follow-up period. Time to clinical worsening and survival were assessed by clinical records, phone, and/or control visits. RESULTS: At baseline, the training (n = 58) and control group (n = 48) did not differ in age, gender, WHO-functional class, 6-min walking distance, hemodynamic parameters, or PH-targeted medication. During a follow-up of 24 ± 12 months, the training group had significantly better survival rates at 1 and 3 years and less worsening events (death, lung transplantation, hospitalization due to PH, new PAH-targeted medication) than the control group (15 vs. 25 events, p < 0.05), which also led to lower estimated healthcare costs of 657 within a period of 2 years. CONCLUSIONS: This is the first study to investigate the cost-effectiveness of exercise training in PH. Due to less worsening events within 2 years, healthcare costs were lower in patients performing exercise training as add-on to medical therapy than in patients with medical treatment only. Further prospective, randomized studies are needed to confirm these findings.

Reduced microRNA-150 is associated with poor survival in pulmonary arterial hypertension.

RATIONALE: MicroRNAs (miRNAs or miRs) are implicated in the pathogenesis of various cardiovascular diseases, including pulmonary arterial hypertension (PAH). OBJECTIVES: We sought to measure changes in plasma levels of miRNAs in patients with PAH and relate them to the severity of the disease. METHODS: A microarray screen was performed on total plasma RNA from eight patients with PAH and eight healthy control subjects. Quantitative polymerase chain reaction confirmed reduced miR-150 concentrations and was then used to measure miR-150 levels in (1) two separate cohorts of patients with PAH, from London (n = 145) and Sheffield (n = 30), respectively; (2) circulating microvesicles and blood cells; and (3) lungs from a monocrotaline rat model. MEASUREMENTS AND MAIN RESULTS: Fifty-eight miRNAs showed differences in plasma concentration and miR-150 the largest down-regulation in PAH. Receiver-operator-characteristic analysis showed both raw and normalized plasma miR-150 levels correlated with 2-year survival (P < 0.01) in patients with PAH. Cox regression analysis confirmed miR-150 levels as a significant predictor of survival. Age, baseline cardiac index, World Health Organization functional class, 6-minute walk distance, disease duration, and red cell distribution width also predicted survival. Entering these covariates in a multivariable model verified plasma miR-150 levels as an independent predictor of survival in PAH (hazard ratio, 0.533; P = 0.010). miR-150 levels also predicted survival in a second, independent PAH cohort. miR-150 levels were significantly reduced in circulating microvesicles from patients with PAH and the lungs of the monocrotaline rat. CONCLUSIONS: Reduced circulating miR-150 levels are associated with poor survival in PAH.

[Mental distress and wish for psychosomatic treatment of patients with pulmonary hypertension]. / Psychische Belastung und Psychosomatischer Behandlungswunsch von Patienten mit Pulmonaler Hypertonie.

BACKGROUND: The study investigated the level of mental distress in patients with pulmonary hypertension (PH) and assessed the use of and the wish for psychosomatic treatment. METHODS: A total sample of n=187 outpatients participated in the cross-sectional survey. The short form of the Patient Health Questionnaire (PHQ-D), the EuroQol (EQ-5D) and a questionnaire assessing the wish for psychosomatic treatment were applied. RESULTS: 50.6% of the patients exhibited depressive symptoms of varying degrees, 19.2% showed symptoms of major depression. 14.8% of the pa-tients reported panic attacks, and 7.1% demonstrated symptoms of a panic syndrome. Quality of life was low (EQ-5D VAS M=60). Experience with outpatient or inpatient psychotherapy was reported by 23.4% and 8.6% of the patients, respectively. 56.5% reported a wish for psychosomatic treatment. CONCLUSIONS: PH-Patients are more likely to suffer from mild or subthreshold depressive syndromes, but are very interested in psychosomatic treatment. The implementation of psychosomatic interventions into clinical practice would be desirable.

Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2 mutations.

BACKGROUND: Mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene can lead to idiopathic pulmonary arterial hypertension (IPAH). This study prospectively screened for BMPR2 mutations in a large cohort of PAH-patients and compared clinical features between BMPR2 mutation carriers and non-carriers. METHODS: Patients have been assessed by right heart catheterization and genetic testing. In all patients a detailed family history and pedigree analysis have been obtained. We compared age at diagnosis and hemodynamic parameters between carriers and non-carriers of BMPR2 mutations. In non-carriers with familial aggregation of PAH further genes/gene regions as the BMPR2 promoter region, the ACVRL1, Endoglin, and SMAD8 genes have been analysed. RESULTS: Of the 231 index patients 22 revealed a confirmed familial aggregation of the disease (HPAH), 209 patients had sporadic IPAH. In 49 patients (86.3% of patients with familial aggregation and 14.3% of sporadic IPAH) mutations of the BMPR2 gene have been identified. Twelve BMPR2 mutations and 3 unclassified sequence variants have not yet been described before. Mutation carriers were significantly younger at diagnosis than non-carriers (38.53 ± 12.38 vs. 45.78 ± 11.32 years, p < 0.001) and had a more severe hemodynamic compromise. No gene defects have been detected in 3 patients with HPAH. CONCLUSION: This study identified in a large prospectively assessed cohort of PAH- patients new BMPR2 mutations, which have not been described before and confirmed previous findings that mutation carriers are younger at diagnosis with a more severe hemodynamic compromise. Thus, screening for BMPR2 mutations may be clinically useful.

Long-term effects of intravenous iloprost in patients with idiopathic pulmonary arterial hypertension deteriorating on non-parenteral therapy.

BACKGROUND: The majority of patients with idiopathic pulmonary arterial hypertension (IPAH) in functional classes II and III are currently being treated with non-parenteral therapies, including endothelin receptor antagonists (ERA), phosphodiesterase (PDE)-5 inhibitors, inhaled iloprost or combinations of these substances. If these treatments fail, current guidelines recommend the addition of parenteral prostanoid therapy. There is, however, limited evidence for the efficacy of parenteral prostanoids when added to combinations of non-parenteral therapies. METHODS: In this retrospective, multicentre study we collected data from consecutive IPAH patients receiving intravenous iloprost in addition to optimized non-parenteral therapy between Jan 2002 and Dec 2009. Analyses included 6 min walk distance (6MWD), functional class, need for transplantation, and survival. RESULTS: During the observation period, 50 patients were treated with intravenous iloprost in addition to non-parenteral therapy; 44% of the patients were on dual combination therapy and 52% on triple combination. Three months after initiation of iloprost, functional class had improved in 24% of the patients and the median 6MWD had increased from 289 m to 298 m (n.s.). During the observation period, 22 patients (44%) died and 14 (28%) underwent lung transplantation. The probabilities of LuTx-free survival at 1, 3 and 5 years following iloprost initiation were 38%, 17% and 17%, respectively. A 6MWD < 300 m and persistent functional class IV at 3 months after initiation of intravenous iloprost were predictors of an adverse outcome. CONCLUSION: In essence, late initiation of intravenous iloprost in IPAH patients who previously failed to respond to non-parenteral therapies appears to be of limited efficacy in the majority patients. Alternative therapeutic options are currently not available, underlying the need for the development of new drugs.