Increased serum PCSK9 in patients with idiopathic pulmonary arterial hypertension: insights from inflammatory cytokines.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important and major player in the pathophysiology of hypercholesterolemia and atherosclerosis. Recently, PCSK9 has been implicated in the pathogenesis of inflammatory diseases. Whether PCSK9 is involved in idiopathic pulmonary arterial hypertension (IPAH) remains unclear. This study aimed to investigate the relationship between PCSK9 and IPAH. Serum PCSK9, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 ß (IL-1ß), and monocyte chemotactic protein-1 (MCP-1) were measured by enzyme linked immunosorbent assay. Transthoracic echocardiography was performed among 40 IPAH patients and 20 control subjects. Hemodynamic data were collected via right heart catheterization in patients with IPAH. Serum PCSK9, TNF-α, IL-6, IL-1ß, and MCP-1 levels were significantly higher in IPAH patients than in control subjects (p < 0.001). Among enrolled IPAH patients, PCSK9 levels were higher in WHO-FC III/IV patients compared with those in WHO-FC I/II (p < 0.05), and were positively correlated with TNF-α, IL-6, MCP-1, N-Terminal pro-brain natriuretic peptide, pulmonary arterial systolic pressure (r = 0.653, p < 0.001), pulmonary arterial diastolic pressure (r = 0.466, p = 0.002), mean pulmonary arterial pressure (mPAP, r = 0.730, <0.001), pulmonary vascular resistance (r = 0.488, p = 0.001), and right ventricle diameter (r = 0.563, p < 0.001). In multiple regression analysis, mPAP was strongly associated with serum PCSK9 (ß = 0.694, p < 0.001), independent of other variables. Receiver operating characteristic curve analysis showed the optimal cutoff value of serum PCSK9 concentration for predicting IPAH was 90.67 ng/ml, with a sensitivity of 90.0% and a specificity of 85.0%. In conclusion, IPAH patients had elevated serum PCSK9 levels which correlated the presence and severity of pulmonary hypertension. PCSK9 may be a novel potential therapeutic target.

Small balloon strategy associated with low pacemaker implantation rate after self-expanding transcatheter valve implantation.

BACKGROUND: This study aims to investigate whether small balloon aortic valvuloplasty (BAV) reduces the need for permanent pacemaker implantation (PPMI) after transcatheter aortic valve implantation (TAVI). METHODS: This was a retrospective analysis using data from our local TAVI database. Small BAV was defined as a small balloon size (=18 mm) pre-dilatation. Normal BAV was defined as a balloon size >18 mm. The primary endpoint was the incidence of new PPMI. RESULTS: Of 99 consecutive TAVI patients, five patients were excluded due to pre-existing permanent pacemaker. Patients in the small BAV group (n=57) had a significantly lower PPMI rate compared with the normal BAV group (n=37) (3.5% vs. 18.9%, P=0.026). Moderate or severe aortic valve regurgitation post-procedure was similar between the small BAV and normal BAV groups (5.3% vs. 8.1%, P=0.480); likewise, the mean aortic gradient post-procedure did not differ significantly (11.5±5.2 mmHg vs. 12.2±7.3 mmHg, 1 mmHg=0.133 kPa, P=0.580) between the groups. Device success rates were also similar (94.7% vs. 91.8%, P=0.680). In multivariable analysis, small BAV (P=0.027), the ratio of prosthesis diameter to annulus diameter (P=0.048), and mean aortic gradient by echo in the basement (P=0.021) were independent predictors of PPMI. CONCLUSIONS: The small BAV strategy is associated with a low rate of permanent pacemaker implantation after transcatheter self-expanding valve implantation in this single-center observational study.

Serum High-Density Lipoprotein Cholesterol is Significantly Associated with the Presence and Severity of Pulmonary Arterial Hypertension: A Retrospective Cross-Sectional Study.

INTRODUCTION: To explore the relationship between serum high-density lipoprotein cholesterol (HDL-C) levels and the presence and severity of pulmonary arterial hypertension (PAH). METHODS: A total of 177 patients with PAH and 103 patients without pulmonary hypertension (PH) were enrolled in this study. All patients underwent right heart catheterization (RHC) for diagnosing and assessing the severity of PAH. Demographics, comorbidities, and laboratory data including serum HDL-C levels were collected. RESULTS: Plasma HDL-C levels in patients with PAH were significantly lower compared with patients without PH (1.08 ± 0.36 vs 1.49 ± 0.36, p < 0.001). HDL-C levels positively correlated with cardiac output (r = 0.360, p < 0.001), cardiac index (r = 0.337, p < 0.001), and mixed venous oxygen saturation (r = 0.426, p < 0.001), and negatively with mean pulmonary arterial pressure (r = - 0.529, p < 0.001), right atrial pressure (r = - 0.421, p < 0.001), and pulmonary vascular resistance (r = - 0.583, p < 0.001). Multivariate logistic regression analysis indicated that HDL-C was a significant independent predictor of PAH (OR 0.042, 95% CI 0.006-0.304, p = 0.002). The receiver operating characteristic curve analysis showed that the optimal cutoff value of the serum HDL-C concentration for predicting PAH was 1.32 mmol/L, with a sensitivity of 83.6% and a specificity of 72.8% (area under the curve 0.803, 95% confidence interval 0.750-0.856, p < 0.001). CONCLUSIONS: Serum HDL-C is a simple biomarker that might be used for prediction and assessment of PAH in Chinese Han ethnicity, and the mechanism underlying the association needs further study.

Multicenter Comparison of Percutaneous and Surgical Pulmonary Valve Replacement in Large RVOT.

BACKGROUND: A percutaneous approach for pulmonary valve replacement (PVR) is a feasible alternative to surgical PVR in selected patients with severe pulmonary regurgitation after repair of tetralogy of Fallot. However, large right ventricular outflow tract (diameter ≥ 25 mm) remains challenging. METHODS: This retrospective multicenter study enrolled consecutive patients with large right ventricular outflow tract who underwent percutaneous PVR (Venus P-valve, Venus MedTech Inc, Hangzhou, China) (n = 35) or surgical PVR (homograft valve; n = 30) between May 2014 and April 2017. Patients were followed up at 1, 3, 6, and 12 months, and yearly thereafter. Main study outcomes were pulmonary valve function and right ventricular function at discharge and midterm follow-up. RESULTS: PVR was successful in all patients. Percutaneous compared with surgical PVR group had: similarly distributed baseline characteristics; shorter hospitalization, intensive care unit stay, and endotracheal intubation duration; lower cost; lower pulmonary valve gradient before discharge; lower pulmonary valve regurgitant grade (mean difference, -0.63; 95% CI -1.11 to -0.20, P = .022), pulmonary valve gradient (mean difference, -5.7 mm Hg; 95% CI -9.4 to -2.2 mm Hg, P = .005), and right ventricular end-diastolic volume index (mean difference, -9.5 mL/m2; 95% CI -16.9 to -3.1 mL/m2, P = .022); and greater right ventricular ejection fraction (mean difference, 5.4%; 95% CI 2.4%-8.3%, P = .002) at median 36 months follow-up, without deaths in either group. CONCLUSIONS: Percutaneous PVR using Venus P-valve appeared to be a safe, efficacious and minimally invasive alternative to surgical PVR in selected patients with large right ventricular outflow tract yielding better right ventricular and pulmonary valve function at midterm follow-up.

Riociguat for the treatment of pulmonary hypertension: Chinese subgroup analyses and comparison.

OBJECTIVE: PATENT-1 and CHEST-1 were pivotal, international phase III trials assessing riociguat for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Here we compare Chinese patients from these studies with the overall populations, and report the clinical effect and safety of riociguat in Chinese patients with PAH and CTEPH. METHODS: PATENT-1 was a 12-week, randomised, double-blind, placebo-controlled trial of riociguat (maximum 2.5 mg three times daily or 1.5 mg three times daily (exploratory) in patients with PAH. CHEST-1 was a 16-week, randomised, double-blind, placebo-controlled trial of riociguat (maximum 2.5 mg three times daily) in patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy. The primary endpoint in each study was change from baseline to study end in 6 min walking distance (6MWD). Secondary endpoints included pulmonary vascular resistance (PVR), N-terminal prohormone of brain natriuretic peptide, WHO functional class (FC), and time to clinical worsening. RESULTS: Chinese patients in PATENT-1 (n=77) and CHEST-1 (n=32) were younger and had better baseline 6MWD and WHO FC versus the overall population. Riociguat increased 6MWD versus placebo in Chinese patients in PATENT-1 and CHEST-1, with a greater increase observed in CHEST-1 (least-squares mean differences +46 m and +102 m in PATENT-1 and CHEST-1, respectively). Riociguat also improved several secondary endpoints in both studies, and was well tolerated. CONCLUSIONS: Chinese patients displayed differences in baseline characteristics versus the overall populations in PATENT-1 and CHEST-1. Riociguat improved 6MWD, PVR, WHO FC, and other clinical outcomes in Chinese patients with PAH or CTEPH. TRIAL REGISTRATION NUMBER: PATENT-1: NCT00810693, Results; CHEST-1 NCT00855465, Results.

BMPR2 mutation is a potential predisposing genetic risk factor for congenital heart disease associated pulmonary vascular disease.

BACKGROUND: Pulmonary arterial hypertension (PAH) frequently arises in patients with congenital heart disease (CHD) and can lead to pulmonary vascular disease (PVD). The present study was initiated to distinguish the predisposing effect of bone morphogenetic protein receptor 2 (BMPR2) in CHD by comparing the different mutation features of BMPR2 between CHD patients with or without PVD. METHODS AND RESULTS: 294 CHD-PVD and 161 CHD without PVD patients were enrolled. PAH was diagnosed by heart catheterization at rest after CHD was first recognized by echocardiography. PVD was defined as a pulmonary vascular resistance (PVR) more than 3 Wood units. BMPR2 gene was screened by direct sequencing. A total of 24 mutations were identified, accounting for 22 of the 294 patients with CHD-PVD (7.5%) and 2 of the 161 CHD patients without PVD (1.2%, P=0.004). Female/male CHD-PVD patient ratio was 1.6:1, while in the BMPR2 mutation carriers female patients were more dominant (4.5:1, P=0.042). A significant higher BMPR2 mutation rate (12.6%) was found in repaired CHD-PVD (P=0.010). BMPR2 mutations in CHD-PVD patients were identified in different clinical phenotypes. Missense mutation of BMPR2 is the dominant mutation type. CONCLUSION: Genetic predisposing factor may be an important component in the process of development of PVD in CHD patients. Female, repaired patients are more likely to be detected with genetic mutations.

[Efficacy and safety of ambrisentan therapy in Chinese patients with pulmonary hypertension].

OBJECTIVE: To explore the efficacy, safety and tolerance of ambrisentan, a high-selective endothelin receptor antagonist, in Chinese patients with pulmonary hypertension (PH). METHODS: Twenty-eight PH patients (Group 1+Group 4) came from Shanghai East Hospital, Zhongshan Hospital of Fudan University and Fifth People's Hospital of Shanghai were recruited into this open-label, prospective multi-center trial between August 2012 and February 2013. They received 2.5-5.0 mg ambrisentan once daily for 12 weeks. The primary endpoint was the change in exercise capacity showed by six-minute walk distance (6MWD) from baseline to 12 weeks. Secondary endpoints included the changes in World Health Organization (WHO) function class, N-terminal brain natriuretic peptide (NT-proBNP) and liver function test results. RESULTS: There were 9 males and 19 females with an average age of (35 ± 17) years. The value of 6MWD increased from (372 ± 86) m at baseline to (443 ± 96) m (P = 0.000) after 12 weeks. WHO functional class improved after a 12-week therapy compared to the baseline level (P = 0.000). NT-proBNP decreased from a median of 732 ng/L at baseline to 329 ng/L after 12 weeks (P = 0.046). The baseline liver function test was normal. And liver function test didn't significantly change after a 12-week therapy. CONCLUSION: Ambrisentan therapy is well-tolerated and it improves the exercise capacity and WHO function class in Chinese PH patients.

Circulating ghrelin was negatively correlated with pulmonary arterial pressure in atrial septal defect patients.

BACKGROUND: Ghrelin was found to attenuate the magnitude of pulmonary arterial hypertension and pulmonary vascular remodeling in rats. The objective of this study was to explore the fasting plasma ghrelin level and the relationships between ghrelin and pulmonary arterial pressure (PAP) in atrial septal defect (ASD) patients with pulmonary arterial hypertension (PAH). METHODS: Fasting plasma ghrelin, obestatin, and insulin levels were measured by enzyme linked immunosorbent assay (ELISA) method in ASD patients with or without PAH according to the manufacturer's instructions. Insulin resistance was calculated by the homeostasis model of assessment for insulin resistance (HOMA-IR) approach, calculated as fasting insulin (microunits/ml)× fasting blood glucose (mmol/L)/22.5. Comparisons between the parameters of patients with PAH and those of patients with normal PAP were performed with an unpaired Student's t test. The relationships between ghrelin and various clinical parameters were examined by bivariate correlations and multiple regression analysis. RESULTS: We found that the fasting plasma ghrelin level and the ratio of ghrelin to obestatin were significantly lower in the PAH group compared with the control group ((582.4±12.8) pg/ml vs. (1045.2±95.5) pg/ml, P < 0.05 and 30.5±4.9 vs. 70.0±9.7, P < 0.01). The fasting plasma obestatin level was higher in the PAH group compared with the control group, but the difference between them was not significant ((23.2±3.1) pg/ml vs. (16.3±1.6) pg/ml, P > 0.05). In a multiple regression model analysis, only mean PAP was an independent predictor of ghrelin and the ratio of ghrelin to obestatin (standardized coefficient = -0.737, P < 0.001 and standardized coefficient = -0.588, P = 0.006, respectively). CONCLUSION: Ghrelin is negatively correlated with mean PAP and this suggests that circulating ghrelin might predict the severity of pulmonary hypertension in ASD patients with PAH.

[Initial experience of treating patients with severe mitral regurgitation with transcatheter mitral valve edge-to-edge repair in China].

OBJECTIVE: To evaluate the safety and efficacy and summarize the initial experience of transcatheter mitral valve repair (TMVR) for treating Chinese patients with severe mitral regurgitation. METHODS: In May 2012, TMVR using MitraClip system was applied in 3 patients with severe mitral regurgitation. One patient suffered from with mitral valve prolapse and two with functional mitral regurgitation. The efficacy and complications of the procedure were analyzed. RESULTS: TMVR procedure was successful in all 3 cases. NYHA classification improved by 1 grade in 2 patients and 2 grades in one patient. The mean operation time was (105 ± 38) minutes and X-ray exposure time was (10 ± 4) minutes. Mean aortic pressure was increased from (62 ± 18) mm Hg (1 mm Hg = 0.133 kPa) to (75 ± 14) mm Hg, and mean left atrial pressure was significantly reduced from (15 ± 10) mm Hg to (9 ± 5) mm Hg immediately after the deployment of MitraClip. Three days after the procedure, left ventricular diastolic dimension decreased from (63 ± 11) mm to (59 ± 10) mm, left atrial dimension declined from (59 ± 11) mm to (51 ± 8) mm, and NT-ProBNP was reduced from (4292 ± 1137) mmol/L to (1187 ± 489) mmol/L. No complications occurred in all three cases. CONCLUSIONS: Our initial experience showed that TMVR using MitraClip system is safe and effective for patients with severe mitral regurgitation. However, the long term benefit of the procedure should be validated through follow up.

Plasma N-terminal pro-brain natriuretic peptide levels are positively correlated with pulmonary arterial pressure in atrial septal defect patients.

N-terminal pro-brain natriuretic peptide (NT-proBNP), a pro-hormone secreted by the myocardium in response to various stimuli, was found to be correlated with several hemodynamic parameters in pulmonary hypertension associated with systemic sclerosis. We investigated plasma NT-proBNP levels and the relationships between NT-proBNP and several hemodynamic parameters in atrial septal defect (ASD) patients with or without pulmonary arterial hypertension (PAH). We found that plasma NT-proBNP level was significantly higher in PAH group compared with the control group (5495.4±388.4 pg/ml vs 4005.1±260.5 pg/ml, P<0.05). In a multiple regression model analysis, only mean pulmonary arterial pressure was an independent predictor of NT-proBNP (standardized coefficient=0.663, P=0.002). In the PAH group, only right atrial systolic pressure was found to be positively correlated with NT-proBNP, whereas other parameters were not found to be correlated with NT-proBNP. Our data suggests that NT-proBNP might also be a predictor of the severity of pulmonary hypertension in the ASD patients.

[Clinical analysis of 150 patients with idiopathic pulmonary arterial hypertension].

OBJECTIVE: To explore the demographic characteristics and clinical features of patients with idiopathic pulmonary arterial hypertension (IPAH) in China. METHODS: Between March 2007 and September 2010, IPAH diagnosis was confirmed by right heart catheterization in 150 adult patients from 31 clinical centers in China. Clinical and hemodynamic data were analyzed and patients were divided into WHO functional class I/II and WHO functional class III/IV group. RESULTS: The mean age of 150 patients were 36 ± 13 years with female patient/male patient ratio of 2:1, and mean BMI was (21.3 ± 3.5) kg/m(2). Fatigue (n = 123, 82.0%) and dyspnea (n = 112, 74.7%) are the most common symptoms. Accentuated pulmonic second sound (P(2)) was detected in 92.0% (n = 138) of patients during physical examination, which was also the most common sign. About 49.0% (n = 73) patients were WHO functional class I/II patients and 46.0% (n = 68) patients were WHO functional class III/IV patients. Six minutes walking distance (6MWD) and Borg dyspnea score was (337 ± 101) m and 2.0 (2.0, 4.0), respectively. Right ventricular hypertrophy was suggested by ECG in 93.1% (n = 140) patients. Right atrial pressure was (10 ± 6) mm Hg, mean pulmonary artery pressure was (61 ± 16) mm Hg, cardiac index was (2.3 ± 0.8) L×min(-1)×m(-2) and pulmonary vascular resistance (1484 ± 699) dyn×s(-1)×cm(-5) in this cohort. 6 MWD (305 m ± 89 m vs. 377 m ± 88 m) was significantly shorter while Borg dyspnea score [3.0 (3.0, 5.0) vs. 2.0 (2.0, 3.0)] was significantly higher in WHO functional class III/IV patients than in WHO functional class I/II patients. Similarly hemodynamic parameters were also worse in WHO functional class III/IV patients than in WHO functional class I/II patients (all P < 0.05). CONCLUSION: Idiopathic pulmonary arterial hypertension patients in this cohort affect mostly young adults, dominated by female gender and lower body mass index. Fatigue and dyspnea are the most common symptoms and accentuated pulmonic second sound (P(2)) is the most common sign. IPAH patients are often displaying severe functional and hemodynamic disturbance at first visit to hospitals. Dyspnea and hemodynamic impairment are related to 6MWD and WHO functional class.

Oral sildenafil therapy for Chinese patients with pulmonary arterial hypertension: a multicenter study.

The impact of sildenafil on pulmonary arterial hypertension (PAH) in Chinese patients has been less investigated. A prospective, open-label, uncontrolled and multicenter study, therefore, was carried out to address this issue. Ninety patients with multicause-induced PAH received oral sildenafil (75 mg/day) for 12 weeks. The 6-minute walk test (SMWT) and cardiac catheterization were performed at the beginning and the end of the 12 weeks. The primary endpoint was the changes in exercise capacity assessed by the SMWT; the secondary endpoint included assessment of functional class, evaluation of cardiopulmonary hemodynamics, and clinical worsening. Drug safety and tolerability were also examined. The results showed that there was a significant improvement in SMWT distances (342 ± 93 m vs 403 ± 88 m, P < .0001), Borg dyspnea score (2.9 ± 2.6 vs 2.4 ± 2.0, P = .0046), World Health Organization functional class, and cardiopulmonary hemodynamics (mean pulmonary artery pressure, P < .0001; cardiac index, P < .0001; pulmonary vascular resistance, P < .0001) after 12 weeks of oral sidenafil therapy. Almost all enrolled patients did not experience significant clinical worsening. This study confirms and extends the findings of previous studies relating to effects of sildenafil on PAH, suggesting that oral sildenafil is safe and effective for the treatment of adult patients with PAH in the Chinese population.

[Preliminary study on the efficacy and safety of oral sildenafil in pulmonary arterial hypertension in China].

OBJECTIVE: Sildenafil has been shown to be effective in pulmonary arterial hypertension (PAH). However, the impact of sildenafil on PAH has been under-investigated in China. The aim of the present study was to evaluate the efficacy and safety of oral sildenafil in PAH patients in China. METHODS: In this prospective, open-label and multi-center study, 90 patients were recruited from 14 centers to receive oral sildenafil (75 mg/d) for 12 weeks. They underwent a six-minute walk test (SMWT) and cardiac catheterization at the beginning and the end of 12 weeks. The primary endpoint was the changes in exercise capacity as assessed by SMWT. And the secondary endpoints included assessment of functional class, evaluation of cardiopulmonary hemodynamics and clinical deterioration (defined as death, transplantation and re-hospitalization for PAH). Drug safety and tolerability were also examined. RESULTS: There were 19 males and 71 females with an average age of 32.5 ± 12.1 years old (range: 18 - 61). Their etiologies were idiopathic (n = 15), related with congenital heart disease (n = 60), or related with connective tissue disease (n = 9) and chronic thromboembolic pulmonary hypertension (n = 6). Oral sildenafil significantly increased the SMWT distances [(342 ± 93) m vs. (403 ± 88) m, P < 0.001]. There was also remarkable improvement in Borg dyspnea score (2.9 ± 2.6 vs. 2.4 ± 2.0, P = 0.005). Furthermore, significant improvements in World Healthy Organization (WHO) functional class and cardiopulmonary hemodynamics were also found (mean pulmonary artery pressure, P < 0.001; cardiac index, P < 0.001; pulmonary vascular resistance, P < 0.001). Side effects were mild and consistent with other reports. CONCLUSION: This study confirms and extends previous studies. Oral sildenafil is both safe and effective for the treatment of adult PAH patients in China.

[Initial experience of transcatheter aortic valve implantation].

OBJECTIVE: To evaluate the safety and efficacy and summarize the initial experience of transcatheter aortic valve implantation (TAVI) for treating patients with severe aortic stenosis. METHODS: From October 2010 to May 2011, TAVI using 18 F Corevalve system was applied in 3 patients with severe calcified aortic valve stenosis at high risk for surgery. The efficacy and complications of the procedure were analyzed and the procedure experiences were summarized. RESULTS: TAVI procedure was successful in all 3 cases. The mean operation time was (109.0 ± 22.6) minutes and X-ray exposure time was (24.0 ± 9.5) minutes. The peak pressure gradients after surgery were significantly reduced [from (84 ± 15) mm Hg (1 mm Hg = 0.133 kPa) to (6 ± 3) mm Hg]. A trivial to mild paravalvular leak was observed in all patients post procedure. Case 1 was free from perioperative complications. Case 2 experienced a transient complete left bundle branch block. Case 3 developed 3 degree atrioventricular block and implanted with a permanent cardiac pacemaker, cardiac tamponade which was relieved through conservative treatment, including pericardial puncture and drainage and acute kidney injury. CONCLUSIONS: Our initial experience showed that TAVI using the 18 F Corevalve system is safe and effective for patients with severe calcified aortic valve stenosis at high-risk for surgery, though the procedure may cause some complications. Strict patient selection and proficient surgical techniques may reduce the incidence of complications.

Efficacy, safety and tolerability of bosentan in Chinese patients with pulmonary arterial hypertension.

BACKGROUND: Bosentan has an established role in the management of pulmonary arterial hypertension (PAH). This clinical trial assessed the benefits of bosentan in the Chinese population. METHODS: We investigated the efficacy and safety of bosentan in 92 Chinese citizens (mean +/- standard deviation age, 29.0 +/- 3.8 years) with PAH for a minimum of 12 weeks. All received bosentan (62.5 mg twice daily) for 4 weeks; then, patients who weighed <40 kg received 62.5 mg bosentan twice daily and patients who weighed >40 kg received 125 mg twice daily. All patients were eligible to continue bosentan beyond 12 weeks. The primary end point was a change in exercise capacity from baseline to 12 and 24 weeks. Secondary end points included a change in World Health Organization (WHO) functional class and changes in cardiopulmonary hemodynamics. RESULTS: At baseline, 66 patients (72%) were in WHO functional class III; presentation was 37 (40%) with idiopathic PAH (iPAH), 34 (37%) with PAH related to congenital heart disease (CHD), and 21 (23%) with PAH related to connective tissue disease (CTD). Exercise capacity increased to 67.8 m after 12 weeks and 92.6 m after 24 weeks (p < 0.001). After 24 weeks, WHO functional class decreased (-0.8 +/- 0.6; p < 0.001), mean pulmonary artery pressure and pulmonary vascular resistance decreased (p < 0.01), and cardiac output increased (p < 0.001). Twelve patients (13%) experienced at least 1 adverse event. CONCLUSIONS: Bosentan improved exercise capacity, functional class, and cardiopulmonary hemodynamics in this patient cohort and was well tolerated.