Incidence of chronic thromboembolic pulmonary hypertension after a first episode of pulmonary embolism

Study objective: To assess the incidence of chronic thromboembolic pulmonary hypertension (CTPH) after the first episode of objectively confirmed pulmonary embolism (PE). Design: Prospective cohort study in 12 Italian medical centers. Patients: Consecutive patients treated with oral anticoagulants for the first episode of PE, either idiopathic or associated with temporary risk factors, were followed up for at least 3 years. Patients were excluded from the study if they had a known persistent risk factor for venous thromboembolism (VTE). Interventions: At the follow-up visits, patients were evaluated for persistent dyspnea, either at rest or on exertion. All patients who were referred with dyspnea were assessed by transthoracic echocardiography, with evaluation of the systolic and mean pulmonary artery pressures. Patients with evidence of pulmonary hypertension on echocardiography underwent perfusion lung scans and pulmonary angiography to confirm the diagnosis of CTPH. Results: Overall, 259 patients were included in the study. PE was idiopathic in 135 patients, while it was associated with at least a temporary risk factor for VTE in 124 patients. After an average follow-up period of 46 months, 37 patients were found to have persistent dyspnea that was unexplained in 5 patients. Among these patients, a diagnosis of CTPH was confirmed in two patients with idiopathic PE (0.8% of the overall study population [95% confidence interval (CI), 0.0 to 1.9]; 1.5% of patients with idiopathic PE [95% CI, 0.0 to 3.6]). The diagnosis was made 14 and 22 months, respectively, after the acute PE. Conclusions: The incidence of CTPH observed in this study was about 1%. CTPH was observed in two patients with idiopathic PE

Modulation of PAR(1) signalling by benzimidazole compounds

BACKGROUND AND PURPOSE Recently, a small molecule (Q94) was reported to selectively block PAR1/Gaq interaction and signalling. Here, we describe the pharmacological properties of Q94 and two analogues that share its benzimidazole scaffold (Q109, Q89). Q109 presents a modest variation from Q94 in the substituent group at the 2-position, while Q89 has quite different groups at the 1- and 2-positions. EXPERIMENTAL APPROACH Using human microvascular endothelial cells, we examined intracellular Ca2+ mobilization and inositol 1,4,5-trisphosphate accumulation as well as isoprenaline- or forskolin-stimulated cAMP production in response to thrombin. KEY RESULTS Q89 (10 mu M) produced a leftward shift in the thrombin-mediated intracellular Ca2+ mobilization concentrationresponse curve while having no effect on the Emax. Both Q94 (10 mu M) and Q109 (10 mu M) reduced intracellular Ca2+ mobilization, leading to a decrease in Emax and an increase in EC50 values. Experiments utilizing receptor-specific activating peptides confirmed that Q94 and Q109 were selective for PAR1 as they did not alter the Ca2+ response mediated by a PAR2 activating peptide. Consistent with our Ca2+ results, micromolar concentrations of either Q94 or Q109 significantly reduced thrombin-induced inositol 1,4,5-trisphosphate production. Neither Q94 nor Q109 diminished the inhibitory effects of thrombin on cAMP production, indicating they inhibit signalling selectively through the Gq pathway. Our results also suggest the 1,2-disubstituted benzimidazole derivatives act as allosteric agonists of PAR1. CONCLUSIONS AND IMPLICATIONS The Q94 and Q109 benzimidazole derivatives represent a novel scaffold for the development of new PAR1 inhibitors and provide a starting point to develop dual signalling pathway-selective positive/negative modulators of PAR1