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.

Bosentan in the treatment of pulmonary arterial hypertension with the focus on the mildly symptomatic patient.

Pulmonary arterial hypertension (PAH) is a progressive disease with poor survival outcomes. Bosentan is an oral endothelin-1 receptor antagonist (ERA) that has been shown in a large randomized placebo-controlled trial (BREATHE-1) to be effective at improving exercise tolerance in patients with PAH in functional class III and IV. Further studies have been conducted showing: benefit in smaller subgroups of PAH, eg, congenital heart disease, efficacy in combination with other PAH therapies, eg, sildenafil, improved long-term survival compared with historical controls. More recently, controlled trials of new ERAs have included patients with milder symptoms; those in functional class II. Analysis of the functional class II data is often limited by small numbers. These trials have generally shown a similar treatment effect to bosentan, but there are no controlled trials directly comparing these new ERAs. The EARLY trial exclusively enrolled functional class II patients and assessed hemodynamics at 6 months. Though significant, the reduction in pulmonary vascular resistance is merely a surrogate marker for the intended aim of delaying disease progression. Significant adverse effects associated with bosentan include edema, anemia and transaminase elevation. These may preclude a long duration of treatment. Further studies are required to determine optimum treatment strategy in mild disease.

Dietary intervention with oil rich fish reduces platelet-monocyte aggregation in man.

BACKGROUND: Dietary intake of fish rich in omega-3 fatty acids is associated with a reduction in cardiovascular events. The mechanisms for this are uncertain and previous studies investigating effects on platelet function have produced inconsistent results. Platelet-monocyte aggregation is a sensitive marker of platelet activation and may contribute to the initiation and progression of atherothrombosis. This study assessed the effect of dietary intervention with oily fish on platelet-monocyte aggregation in healthy subjects. METHODS: Fourteen subjects had their diet supplemented with 500 g of oil-rich fish per week for 4 weeks. A control group of 14 subjects received no dietary intervention over a 4-week period. Platelet-monocyte aggregates were assessed with flow cytometry. RESULTS: Dietary intervention with fish led to an increase in omega-3 fatty acids in plasma phospholipids (14.2+/-3.4% versus 5.8+/-1.3%, P<0.001). In contrast to the control group, platelet-monocyte aggregates were reduced by 35% following dietary intervention with oily fish (16.0+/-9.0% versus 24.8+/-10.9%, P<0.01), and returned to basal levels 4 weeks after discontinuation of supplementation. There was an inverse correlation between platelet-monocyte aggregation and plasma omega-3 fatty acid concentrations (r=-0.421, P=0.006). There were no changes in the plasma markers of platelet activation, soluble P-selectin or soluble CD40 ligand. CONCLUSIONS: We have demonstrated, for the first time, that dietary intervention with oil-rich fish reduces platelet-monocyte aggregation in man. Our results suggest that reduced platelet activation provides a potential mechanism through which fish oils confer their cardiovascular preventative benefits.