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Background: Ideally, vasodilator therapies for pulmonary arterial hypertension (PAH) should have a favorable impact on markers of vascular dysfunction, in addition to their known effects on hemodynamics, cardiac function, and patient's physical capacity. Methods:We analyzed circulating (plasma) markers of endothelial and platelet activation/dysfunction (enzyme-linked immunoassays) in the specific setting of advanced PAH associated with congenital heart disease, during the course of sildenafil and tadalafil therapies. Thirty-one patients were enrolled (age 10-54 years), most of them with chronic hypoxemia and elevated hematocrit. Drugs were administered orally for 6 months (sildenafil [n = 16], 20 mg t.i.d.; tadalafil [n = 15], single daily dose of 40 mg). Measurements were performed at baseline, and 90 and 180 days.Results: Compared to controls, patients had elevated baseline β-thromboglobulin (β-TG, P = .002), P-selectin (P = .027), tissue-type plasminogen activator (t-PA, P = .009), and von Willebrand factor antigen (VWF:Ag, P = .010). Thrombomodulin was importantly reduced (TM, P < .001), while soluble CD40 Ligand was not changed (P = .320). Tadalafil administration was associated with improvement of β-TG (P = .004), t-PA (P = .003) and TM (P = .046) levels, while P-selectin was improved by sildenafil treatment only (P = .034). VWF:Ag improved transiently in the sildenafil group (P = .019). Both therapies were associated with improvement of the physical capacity (functional class and distance walked during the 6-minute test, P < .05), hematocrit and hemoglobin level (P < .05), and health-related quality of life (physical and mental components, P < .05). Conclusion:In PAH associated with congenital heart disease, phosphodiesterase 5 inhibitors seem to have beneficial actions at microcirculatory level, beyond the proposed effects as vasodilators. K E Y W O R D Sbiomarkers, congenital heart disease, endothelial dysfunction, phosphodiesterase 5 inhibitors, platelets, pulmonary hypertension | 247 CLAVÉ et al.

Background and Objective. Inflammation is central in the pathogenesis of pulmonary hypertension. We investigated how serum cytokines correlate with clinical features, hemodynamics, and lung histology in young patients with pulmonary hypertension associated with congenital cardiac shunts. Design. Prospective, observational study. Methods and Results. Patients (n = 44) were aged 2.6 to 37.6 months. Group I patients (n = 31) were characterized by pulmonary congestion and higher pulmonary blood flow compared to group II (p = 0.022), with no need for preoperative cardiac catheterization. Group II patients (n = 13) had no congestive features. At catheterization, they had elevated pulmonary vascular resistance (5.7 [4.4–7.4] Wood units·m2, geometric mean with 95% CI). Cytokines were measured by chemiluminescence. Macrophage migration inhibitory factor (MIF) was found to be inversely related to pulmonary blood flow (r = −0.33, p = 0.026) and was higher in group II (high pulmonary vascular resistance) compared to group I (high pulmonary blood flow) (p = 0.017). In contrast, RANTES chemokine (regulated on activation, normal T cell expressed and secreted) was characteristically elevated in Group I (p = 0.022). Interleukin 16 was also negatively related to pulmonary blood flow (r S = −0.33, p = 0.029) and was higher in patients with obstructive vasculopathy at intraoperative lung biopsy (p = 0.021). Conclusion. Cytokines seem to be important and differentially regulated in subpopulations of young patients with cardiac shunts.

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In patients with Eisenmenger syndrome, life expectancy is usually longer than in patients with other forms of pulmonary arterial hypertension (PAH). We conducted a cohort study in which patients were followed over a long period of time in an attempt to identify potential predictors of clinical outcomes. Sixty-seven treatment-naïve patients were enrolled (age range = 12–60 years; median age = 33 years). Baseline demographic, diagnostic, and functional parameters, plasma levels of endothelial dysfunction markers, and treatment-related data were tested for possible correlations with event-free survival. Patients were started on oral PAH drugs at the beginning of follow-up (n = 23), during follow-up (n = 33), or remained untreated (n = 11). The duration of follow-up was 0.54–9.89 years (median = 7.13 years), with an overall survival rate of 82% and an event-free survival rate of 70%. The estimated mean for event-free survival time was 7.71 years (95% confidence interval [CI] = 6.86–8.55 years). Of the 16 variables that were analyzed, the duration of exposure to PAH drugs was identified as an independent protective factor (hazard ratio [HR] = 0.25 for quartiles, 95% CI = 0.14–0.47, P < 0.001). The initial functional class (HR = 3.07; 95% CI = 1.01–9.34; P = 0.048), the severity of right ventricular dysfunction (HR = 2.51 [mild, moderate or severe dysfunction]; 95% CI = 1.22–5.19; P = 0.013) and plasma von Willebrand factor concentration (HR = 1.74 for quartiles; 95% CI = 1.07–2.83; P = 0.026) were identified as risk factors. The length of exposure to oral PAH therapies influences survival favorably in Eisenmenger patients. This may be of interest for communities where access to medications is restricted.

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Background: Patients with pulmonary arterial hypertension (PAH) associated with the Eisenmeger syndrome (ES) frequently have decreased platelet counts and aggregation. This is probably due to chronic endogenous platelet activation and consumption associated with hypoxemia and blood hyperviscosity, with "exhausted" platelets present in circulation. When platelets are analyzed in vitro, decreased response to aggregation inducing agents is generally observed. Purpose: Since phosphodiesterase-5 inhibitors (PDE-5Is) are frequently used in the management of PAH, we investigated, the effects of sildenafil and tadalafil on in vitro platelet aggregation (PA) in adults with ES. Methods: Twenty-three naïve patients aged 28 (22-47) years (median and interquartile range) were randomly assigned to oral treatment with sildenafil (20mg t.i.d., N=11) or tadalafil (single daily dose of 40mg, N=12). Baseline spO 2 , Ht, Hb level and platelet count were 87% (80-92%), 52% (49-60%), 17 (16-20)g/dL and 205 (158-248) x 10 3 pl/μL, respectively. Data were collected at baseline, 90 and 180 days of treatment. Whole blood PA was analyzed by the impedance method. Results are expressed as percent normal. Results: Treatment with PDE-5Is resulted in decrease Ht and Hb level (p<0.001), but no change in platelet count. When patients analyzed as a whole (N=23), ADP-induced PA was 44% (23-91%), 54% (23-87%) and 71% (42-124%) respectively at baseline, 90 and 180 days (p=0.029). Collagen-induced PA was 55% (23-138%), 96% (67-162%) and 146% (62-187%), respectively (p=0.041). When treatment groups were investigated separately at 180 days, collagen-induced PA was 2.7 (1.1-11.1) times baseline in sildenafil-treated patients, and 1.8 (0.6-4.2) times baseline in the tadalafil group. ADP-induced PA was 2.2 (1.3-4.8) times baseline in the sildenafil , but 1.0 (0.7-3.6) time baseline for tadalafil. Conclusion: In ES patients, PDE-5Is therapy is associated with improvement of PA. This may be due to decelerated endogenous platelet activation associated with hemodynamic improvement. However, particularly for sildenafil, some patients may become transiently at a higher risk of thrombotic events, as PA increases far above normal levels.