Two-dimensional knowledge-based volumetric reconstruction of the right ventricle documents short-term improvement in pulmonary hypertension.

BACKGROUND: Data are scarce about short-term right ventricular changes in pulmonary hypertension. Two-dimensional knowledge-based reconstruction of the right ventricle with 2D echocardiography (2DKBR) has been shown to be a valid alternative to Cardiac MRI. PATIENTS AND METHODS: In this longitudinal study 25 pulmonary hypertension patients underwent 2DKBR of the right ventricle, assessment of NT-proBNP levels and functional class at baseline and after a mean follow-up of 6.1 months. Patients were followed up clinically for a further mean of 8.2 months. The majority of patients had connective tissue disease (CTD) associated pulmonary arterial hypertension (n=15) or chronic thromboembolic pulmonary hypertension (CTEPH; n=6). A total of 15 patients underwent an intervention, either new targeted therapy, escalation of targeted therapy or pulmonary endarterectomy. A total of 10 clinically stable patients were routinely followed up without any change in therapy. RESULTS: There were significant improvements in the right ventricular end-diastolic volume index (111±29 mL/m² vs 100±36 mL/m²; P=.038), end-systolic volume index (72±23 mL/m² vs 61±25 mL/m²; P=.001), and ejection fraction (35±10% vs 40±9%; P=.030). Changes in NT-proBNP levels correlated strongest with changes in end-systolic volume index (r=-.77; P=<.0001). Four patients experienced clinical worsening during extended follow-up, dilatation of the right ventricle was associated with clinical worsening. CONCLUSION: In a CTD and CTEPH dominated patient population significant reverse remodeling and improvement of ejection fraction occurred despite a short follow-up and was paralleled by significant changes in NT-proBNP levels. Further right ventricular dilatation was associated with worse clinical outcome. 2DKBR is a feasible substitute for Cardiac MRI to follow-up right ventricular indices in pulmonary hypertension.

Survival in portopulmonary hypertension: Outcomes of the United Kingdom National Pulmonary Arterial Hypertension Registry.

BACKGROUND: Portopulmonary hypertension (PoPH) is a rare condition associated with poor survival, and the effect of modern therapies that target pulmonary arterial hypertension (PAH) on long-term outcome is unknown. This study investigated the baseline characteristics and survival in the cohort of patients diagnosed with PoPH in the United Kingdom National Pulmonary Hypertension Service. METHODS: A retrospective review was conducted of all incident treatment-naïve patients with PoPH within the United Kingdom national registry diagnosed between January 2001 and December 2010. RESULTS: Patients with PoPH (n = 110) had survival rates of 85%, 60%, and 35% at 1, 3, and 5 years. The prevalence of PoPH was 0.85 cases/1 million. Mean age at diagnosis was 53 ± 12 years, with a balanced distribution in gender. Alcohol (n = 57) and hepatitis C (n = 10) were the most common causes of portal hypertension. Phosphodiesterase V inhibitors were the most frequently used targeted therapy, in 63.6% (n = 70) of patients, endothelin receptor antagonists were used in 10% (n = 11) and prostacyclin analogs in 12.7% (n = 14). Univariate and multivariate analysis of baseline characteristics did not demonstrate a significant influence of severity of portal hypertension or liver cirrhosis, World Health Organization Functional Class, cardiopulmonary hemodynamics, or year of diagnosis on survival. CONCLUSIONS: Survival of patients with PoPH remains poor despite targeted therapy and worse than patients with idiopathic PAH. The benefit of PAH therapies in PoPH on long-term morbidity and mortality outcomes needs further consideration and study.

Optical coherence tomography evaluation of pulmonary arterial vasculopathy in Systemic Sclerosis.

Our current understanding of the pathophysiology of pulmonary vascular disease is incomplete, since information about alterations of the pulmonary vasculature in pulmonary arterial hypertension (PAH) is primarily provided by autopsy or tissue specimens. The aim of this study was to compare the distal pulmonary vasculature of <2 mm in diameter in Systemic Sclerosis (SSc) patients with (n = 17) and without (n = 5) associated PAH using Optical Coherence Tomography during Right Heart catheterization. SSc-PAH patients showed significant thickening of Intima Media Thickening Area compared to patients without PAH (27 +/- 5.8% vs. 21 +/- 1.4%, p = 0.024). A good haemodynamic response to previous targeted PAH treatment was associated with a significantly greater number of small pulmonary artery side branches <300 µm per cm vessel (3.8 +/- 1.1 vs. 1.8 +/- 1.1; p = 0.010) and not associated with Intima Media thickening Area (26 +/- 5.4% vs. 28 +/- 6.7%; p = 0.6). Unexpected evidence of pulmonary artery thrombus formation was found in 19% of SSc-PAH patients. This is the first in-vivo study demonstrating a direct link between a structural abnormality of pulmonary arteries and a response to targeted treatment in PAH. Intravascular imaging may identify subgroups that may benefit from anticoagulation.

Characteristics and Survival of Anti-U1 RNP Antibody-Positive Patients With Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue diseases (CTDs). This study aimed to investigate the clinical and hemodynamic characteristics and survival of anti-U1 RNP-positive patients with CTD-associated PAH, with a focus on systemic sclerosis (SSc)-associated PAH. METHODS: We implemented a prospective database that included patients with CTD-associated PAH for whom there were clinical, autoantibody, and mortality data. We compared clinical and hemodynamic characteristics to anti-U1 RNP antibody status. We then assessed whether anti-U1 RNP antibodies could be a prognostic factor in CTD-associated PAH with a focus on SSc-associated PAH. RESULTS: We studied a total of 342 patients with CTD-associated PAH, of whom 36 (11%) were anti-U1 RNP antibody positive. Anti-U1 RNP-positive patients were younger and less functionally impaired than were anti-U1 RNP-negative patients in CTD- and SSc-associated PAH. Hemodynamic parameters were similar in anti-U1 RNP-positive and anti-U1 RNP-negative patients. In CTD-associated PAH, anti-U1 RNP positivity was associated with decreased mortality in univariable analysis (hazard ratio 0.34 [95% confidence interval 0.18-0.65], P < 0.001). In multivariable analysis, anti-U1 RNP positivity was also associated with decreased mortality (hazard ratio 0.44 [95% confidence interval 0.20-0.97], P = 0.043) independently of age, sex, functional parameters, lung involvement, and hemodynamic parameters. Results were similar in SSc-associated PAH, although the association between anti-U1 RNP positivity and survival did not reach significance in univariable (hazard ratio 0.47 [95% confidence interval 0.22-1.02], P = 0.055) and multivariable (hazard ratio 0.47 [95% confidence interval 0.20-1.11], P = 0.085) analyses. CONCLUSION: Anti-U1 RNP positivity was associated with distinct clinical characteristics and survival in CTD- and SSc-associated PAH. While hemodynamic parameters were similar in anti-U1 RNP-positive and anti-U1 RNP-negative patients, our results suggest that anti-U1 RNP positivity could be a factor protecting against mortality in CTD- and SSc-associated PAH.

Clinical characteristics, haemodynamics and treatment of pulmonary hypertension in sarcoidosis in a single centre, and meta-analysis of the published data.

Pulmonary hypertension (PH) in sarcoidosis is associated with bad outcomes. Although there is interest in using pulmonary vasodilators (PVs) for PH in sarcoidosis, there are few data to support their use. In this study, a retrospective review of a cohort of patients with PH and sarcoidosis was conducted, focusing on those treated with PVs, and a meta-analysis of published reports indexed in MEDLINE was performed. Twenty-four patients were found. The rate of mortality or transplantation rate was 41.2%. Median survival without transplantation was 5.3 years. More patients who died or underwent transplantation during follow-up had moderate or severe lung fibrosis (66.7% vs 15.4%), had right ventricular dysfunction (80% vs 7.7%), and were in World Health Organization class IV (66.7% vs 30.8%). Body surface areas were lower in patients with events, as was cardiac output. Mortality was not different between patients treated with PVs and those not treated (54.5% vs 38.5%, p = 0.44) despite the treated patients' having more right ventricular dysfunction and worse hemodynamics. In a Cox regression survival model, lower body surface area, right ventricular dysfunction, and the presence of moderate or severe lung fibrosis were predictors of worse outcomes, but not treatment with PVs. PV-treated patients (n = 11) showed improved 6-minute walk distances and decreased N-terminal pro-B-type natriuretic peptide levels during follow-up. There was a trend toward improvement in hemodynamic profile. Four studies plus the data from this study were included in the meta-analysis. Six-minute walk distance improved by 30.64 m after treatment. Hemodynamics improved, with a reduction in mean pulmonary arterial pressure of 8.03 mm Hg and a decrease in pulmonary vascular resistance of 4.23 Wood units. In conclusion, PH in sarcoidosis is associated with adverse outcomes, particularly when accompanied by right ventricular dysfunction and/or moderate or severe lung fibrosis. Treating selected patients can improve hemodynamics and functional parameters.

Borderline mean pulmonary artery pressure in patients with systemic sclerosis: transpulmonary gradient predicts risk of developing pulmonary hypertension.

OBJECTIVE: To determine whether patients with systemic sclerosis (SSc) and borderline mean pulmonary artery pressure (PAP) at cardiac catheterization are more likely to develop pulmonary hypertension (PH) than those in whom pulmonary pressure is normal. METHODS: Patients with SSc in whom PH and significant interstitial lung disease had been excluded at baseline were enrolled in our prospective cohort. Analysis of followup data identified patients who met prespecified criteria prompting repeat catheterization to reassess for possible PH. Using Kaplan-Meier, receiver operating characteristic, and Cox regression methods, we studied the development of PH and death. RESULTS: Of 228 patients in this study, 86 had borderline mean PAP (21-24 mm Hg) at baseline. Following prespecified criteria, 76 patients underwent repeat catheterization, and 29 of these developed PH. Two cases were related to disease of the left side of the heart. The average mean PAP increased from baseline (20.2 mm Hg) to followup (24.3 mm Hg) (P<0.05 by Student's t-test). Patients with borderline mean PAP were more likely to develop PH than patients with mean PAP≤20 mm Hg (P<0.001 by log rank test, hazard ratio [HR] 3.7). A transpulmonary gradient (TPG)≥11 mm Hg at baseline also predicted PH (P<0.001 by log rank test, HR 7.9). Incident development of pulmonary arterial hypertension (PAH) was not benign, with a mortality of 18% within 3 years. CONCLUSION: Our findings indicate that borderline mean PAP and an elevated TPG in patients with SSc predict progression to PH. These patients should be monitored closely for the development of PH. Our findings indicate that catheterization data are useful in patients considered at risk of PAH.

Improving the detection of pulmonary hypertension in systemic sclerosis using pulmonary function tests.

OBJECTIVE: To construct a readily applicable formula for selecting patients with systemic sclerosis (SSc) for right-sided heart catheterization (RHC) based on the results of their pulmonary function tests (PFTs). METHODS: The diagnostic value of PFT variables was quantified in 386 patients with SSc against data obtained from RHC. RESULTS: We derived the following formula using data from 257 patients: predicted mPAP = 136 - SpO2 - 0.25 × DLCO % predicted, where mPAP is the mean pulmonary artery pressure, SpO2 is the oxygen saturation as measured by pulse oximetry, and DLCO is the diffusing capacity for carbon monoxide. We validated the formula in the remaining 129 SSc patients. The area under the curve was 0.75 (95% confidence interval [95% CI] 0.67, 0.84). Using a predicted threshold of 25 mm Hg, the sensitivity was 90.1% (95% CI 82, 96) and the specificity was 29.2% (95% CI 17, 44). When used as a screening procedure in a typical scleroderma patient population, it is projected that those with an mPAP below 25 mm Hg are unlikely to have pulmonary hypertension (PH; prevalence 4.4%), those with a predicted mPAP of 25-35 mm Hg are at average risk of having PH (prevalence of 11.3%), and those with a formula-predicted mPAP above 35 mm Hg are likely to have PH (prevalence of 62.9%), thus justifying RHC. In patients with equivocal findings on echocardiography, a high formula-predicted mPAP is strongly associated with the presence of PH. CONCLUSION: We derived and validated an easily applied formula for determining pulmonary function in patients with SSc that identifies subgroups with a low, average, or high prevalence of PH. It provides information that is complementary to echocardiography and that should improve the selection of patients for RHC.

Clinical experience with bosentan and sitaxentan in connective tissue disease-associated pulmonary arterial hypertension.

OBJECTIVES: To report outcomes in patients with CTD-pulmonary arterial hypertension (CTD-PAH) in an observational cohort treated with bosentan or sitaxentan and determine whether differences would justify a randomized, controlled multicentre study in this subpopulation. METHODS: Patients with CTD-PAH, diagnosed by right-heart catheter studies, were assigned to either bosentan or sitaxentan based on physician choice. All patients were followed up with repeat assessments and data were collected for the local registry database. RESULTS: The bosentan- (n = 32) and sitaxentan- (n = 22) treated groups had comparable haemodynamic and prognostic measures at baseline. Repeat haemodynamic assessments showed reductions in pulmonary vascular resistance with bosentan (-99 dynes/s/cm(5), P < 0.01) and sitaxentan (-92 dynes/s/cm(5), P < 0.05). The 6-min walk distance improved at 3 months with sitaxentan (25 m, P < 0.05). N-terminal pro-B-type natriuretic peptide levels fell in the bosentan cohort at 6 months (-70 pmol/l, P < 0.05) and 1 year (-83 pmol/l, P < 0.01). Haemoglobin fell with both drugs (at 3 months -0.5 g/dl bosentan, P < 0.05 and -0.9 g/dl sitaxentan, P < 0.005). Calculations of the difference in treatment effect did not demonstrate superiority of either therapy. The 1-year estimated clinical worsening event rates were high: 41% sitaxentan, 62% bosentan (P = 0.142), with serious event rates of 27 and 14% (P = 0.263, log-rank test), respectively. Six patients discontinued bosentan because of transaminase elevation within the first year. Estimated 1-year survival was similar in both groups and 96% overall. CONCLUSION: Both sitaxentan and bosentan appear effective in CTD-PAH, but the apparent additional benefit of sitaxentan reported from the open-label Sitaxentan To Relieve ImpaireD Exercise-2X study was not confirmed in this observational cohort. Although survival has improved, event rates continue to be substantial and CTD-PAH remains a therapeutic challenge.

Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary arterial hypertension.

AIMS: The aims of this study were to evaluate the diagnostic value and to explore the prognostic value of N-terminal brain natriuretic peptide (N-TproBNP) in patients with systemic sclerosis (SSc) both with and without pulmonary arterial hypertension (PAH). METHODS AND RESULTS: N-TproBNP, six-minute walk distance (SMWD), haemodynamics (at right heart catheterization) or tricuspid gradient (by echocardiography), and survival were assessed in 109 patients with SSc. The study population included 68 individuals with PAH [mean pulmonary artery pressure (PAP) >25 mmHg and pulmonary capillary wedge pressure <15 mmHg] and 41 individuals without PAH. In patients with PAH, the prognostic value of baseline and change in WHO functional class, N-TproBNP levels, and SMWD were compared using Kaplan-Meier survival curves and Cox proportional hazard analysis. The mean duration of follow-up was 10 months (range 1-18 months). One year survival in patients with normal PAP was 100% when compared with 83.5% in those with SSc-PAH (P < 0.05). The patients without PAH had a mean N-TproBNP level of 139 pg/mL (SD 151); those with SSc-PAH had a significantly higher mean N-TproBNP level of 1474 pg/mL (SD 2642) (P = 0.0002). Among patients with PAH for every order of magnitude increase in N-TproBNP level there was a four-fold increased risk of death (P = 0.002 for baseline level and P = 0.006 for follow-up level). Baseline N-TproBNP levels were correlated positively with mean PAP (r = 0.62; P < 0.0001), pulmonary vascular resistance (PVR) (r = 0.81; P < 0.0001), and inversely with SMWD (r = -0.46; P < 0.0001). Among patients with SSc-PAH, 13 patients (19%) were in WHO functional classes II and had mean N-TproBNP levels of 325 pg/mL (SD 388). Fifty-three patients (78%) were in WHO classes III and IV and had significantly higher mean N-TproBNP levels of 1677 pg/mL (SD 2835) (P = 0.02). At an N-TproBNP level of 395 pg/mL, the sensitivity and specificity for predicting the presence of SSc-PAH were 56 and 95% respectively. CONCLUSION: Raised N-TproBNP levels are directly related to the severity of PAH. In screening programs, SSc patients with an N-TproBNP in excess of 395 pg/mL have a very high probability of having pulmonary hypertension. Baseline and serial changes in N-TproBNP levels are highly predictive of survival. A 10-fold increase in N-TproBNP level on therapy is associated with a greater than three-fold increase in mortality, and may indicate therapeutic failure.