Circulating angiopoietins in idiopathic pulmonary arterial hypertension.

AIMS: To determine the diagnostic utility of circulating angiopoietin-1 (Ang-1) and its antagonist angiopoietin-2 (Ang-2) as potential biomarkers of disease severity or response to treatment in idiopathic pulmonary arterial hypertension (IPAH). Imbalances in angiogenic factors including vascular endothelial cell growth factor (VEGF) and the angiopoetin-Tie2 receptor system have been implicated in the pathogenesis of IPAH. METHODS AND RESULTS: Plasma Ang-1, Ang-2, soluble Tie2 (sTie2), and VEGF were determined by in-house immunoassays in two cohorts of IPAH patients: a retrospective cohort (n = 81) and a prospective cohort (n = 25). Ten patients with normal pulmonary artery pressures and 14 apparently healthy subjects served as controls. Plasma levels of all angiogenic factors were elevated in IPAH patients compared with controls (all P < 0.005). Angiopoietin-2, but not Ang-1, sTie2, and VEGF correlated with cardiac index (r = -0.53, P < 0.001), pulmonary vascular resistance (PVR) (r= 0.60, P < 0.001), and mixed venous oxygen saturation (SvO(2)) (r= -0.63, P < 0.001). In multivariate analysis, elevated Ang-2 was an independent risk factor of mortality (P = 0.004). The patients in the prospective cohort were studied longitudinally at baseline and 3 months after initiation of therapy. Changes in Ang-2 after initiation of therapy correlated with changes in mean right atrial pressure (r = 0.6, P = 0.008), PVR (r = 0.51, P = 0.04), and inversely related to changes in SvO(2) (r = -0.75, P < 0.001). Histological studies showed that the expression of Ang-2 mRNA and protein was up-regulated in plexiform lesions from IPAH lung tissue samples. CONCLUSION: Ang-2 may be involved in the pathogenesis of IPAH, and plasma Ang-2 might serve as a promising new biomarker of disease severity and response to treatment in patients with IPAH.

Osteopontin in patients with idiopathic pulmonary hypertension.

BACKGROUND: Osteopontin (OPN) is a pleiotropic cytokine that has been postulated to play a role in the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). OPN plasma levels may be related to disease severity and mortality in patients with PAH. METHODS: OPN plasma levels obtained during right-sided heart catheterization were assessed by a commercially available enzyme-linked immunosorbent assay and related to hemodynamics, exercise capacity, N-terminal pro-brain natriuretic peptide (NT-pro-BNP) level, uric acid level, C-reactive protein level, and survival in two cohorts of patients with IPAH: a 4-year retrospective cohort (n = 70) and a prospective cohort (n = 25) followed for 3 months after initiation of therapy. Forty apparently healthy individuals served as control subjects. RESULTS: Baseline OPN levels were elevated in patients with IPAH compared with healthy control subjects (50.2 ± 35.9 vs 23.7 ± 2.8 ng/mL, P < .0001). In the retrospective as well as in the prospective cohort, OPN levels correlated with mean right atrial pressure and NT-BNP. In the retrospective cohort, OPN levels also correlated with age (r = 0.3, P = .02), 6-min walking distance (r=-0.4, P = .05), and New York Heart Association class (r = 0.4, P = .001). Multivariate Cox analysis demonstrated that baseline OPN levels were independent predictors of mortality (P = .02). When patients were divided according to their baseline OPN values, being normal or elevated at baseline (below or above 34.5 ng/mL), proportional survival rates were 100% vs 80% after 1 year and 77% vs 51% after 3 years, respectively. CONCLUSION: Circulating OPN predicts survival in patients with IPAH and is associated with a higher New York Heart Association class. OPN, thus, may be useful as a biomarker in IPAH.

Outcome after cardiopulmonary resuscitation in patients with pulmonary arterial hypertension.

Patients with pulmonary arterial hypertension (PAH) often die from right heart failure or sudden cardiac death. Cardiopulmonary resuscitation (CPR) may be instituted in these patients but there are no data in the medical literature about the outcome of CPR in this group of patients. We conducted a retrospective multicenter international study on the frequency and results of CPR in patients with PAH. A total of 3,130 patients with PAH were treated between 1997 and 2000 in 17 referral centers in Europe and in the United States. During this period, 513 patients had circulatory arrest and CPR was attempted in 132 (26%) of these patients. Although 96% of the CPR attempts took place in hospitalized patients (74% in intensive care units or equally equipped facilities) and although there was only minimal delay between collapse and initiation of CPR, resuscitation efforts were primarily unsuccessful in 104 patients (79%). Only eight patients (6%) survived for more than 90 d; these patients had no residual neurologic deficit. Hemodynamics obtained within 3 mo before CPR did not show any significant differences between the survivors and nonsurvivors. Except for one patient, all long-term survivors had identifiable causes of circulatory arrest that were rapidly reversible. Our data indicate that CPR for circulatory arrest in patients with PAH is rarely successful unless the cause of the cardiopulmonary decompensation can be corrected.