Browsing by Author "Gerhardt, Felix"

Abstract Aims To systematically assess late outcomes of acute pulmonary embolism (PE) and to investigate the clinical implications of post-PE impairment (PPEI) fulfilling prospectively defined criteria. Methods and results A prospective multicentre observational cohort study was conducted in 17 large-volume centres across Germany. Adult consecutive patients with confirmed acute symptomatic PE were followed with a standardized assessment plan and pre-defined visits at 3, 12, and 24 months. The co-primary outcomes were (i) diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), and (ii) PPEI, a combination of persistent or worsening clinical, functional, biochemical, and imaging parameters during follow-up. A total of 1017 patients (45% women, median age 64 years) were included in the primary analysis. They were followed for a median duration of 732 days after PE diagnosis. The CTEPH was diagnosed in 16 (1.6%) patients, after a median of 129 days; the estimated 2-year cumulative incidence was 2.3% (1.2–4.4%). Overall, 880 patients were evaluable for PPEI; the 2-year cumulative incidence was 16.0% (95% confidence interval 12.8–20.8%). The PPEI helped to identify 15 of the 16 patients diagnosed with CTEPH during follow-up (hazard ratio for CTEPH vs. no CTEPH 393; 95% confidence interval 73–2119). Patients with PPEI had a higher risk of re-hospitalization and death as well as worse quality of life compared with those without PPEI. Conclusion In this prospective study, the cumulative 2-year incidence of CTEPH was 2.3%, but PPEI diagnosed by standardized criteria was frequent. Our findings support systematic follow-up of patients after acute PE and may help to optimize guideline recommendations and algorithms for post-PE care.

Objectives We tested the hypothesis whether selective blunting of platelet-derived growth factor (PDGF)-dependent vascular smooth muscle cell (VSMC) proliferation and migration is sufficient to prevent neointima formation after vascular injury. Background To prevent neointima formation and stent thrombosis after coronary interventions, it is essential to inhibit VSMC proliferation and migration without harming endothelial cell function. The role of PDGF-a potent mitogen and chemoattractant for VSMC that does not affect endothelial cells-for neointima formation remains controversial. Methods To decipher the signaling pathways that control PDGF beta receptor (beta PDGFR)-driven VSMC proliferation and migration, we characterized 2 panels of chimeric CSF1R/beta PDGFR mutants in which the binding sites for beta PDGFR-associated signaling molecules (Src, phosphatidylinositol 3-kinase [PI3K], GTPase activating protein of ras, SHP-2, phospholipase C gamma 1 [PLC gamma]) were individually mutated. Based on in vitro results, the importance of PDGF-initiated signals for neointima formation was investigated in genetically modified mice. Results Our results indicate that the chemotactic response to PDGF requires the activation of Src, PI3K, and PLC gamma, whereas PDGF-dependent cell cycle progression is exclusively mediated by PI3K and PLC gamma. These 2 signaling molecules contribute to signal relay of the beta PDGFR by differentially regulating cyclin D1 and p27(kip1). Blunting of beta PDGFR-induced PI3K and PLC gamma signaling by a combination mutant (F3) completely abolished the mitogenic and chemotactic response to PDGF. Disruption of PDGF-dependent PI3K and PLC gamma signaling in mice expressing the F3 receptor led to a profound reduction of neointima formation after balloon injury. Conclusions Signaling by the activated beta PDGFR, particularly through PI3K and PLC gamma, is crucial for neointima formation after vascular injury. Disruption of these specific signaling pathways is sufficient to attenuate pathogenic processes such as vascular remodeling in vivo. (J Am Coll Cardiol 2011;57:2527-38) (C) 2011 by the American College of Cardiology Foundation

Acute pulmonary embolism (PE) is a frequent cause of death and serious disability. The risk of PE-associated mortality and morbidity extends far beyond the acute phase of the disease. In earlier follow-up studies, as many as 30 % of the patients died during a follow-up period of up to 3 years, and up to 50 % of patients continued to complain of dyspnea and/or poor physical performance 6 months to 3 years after the index event. The most feared 'late sequela' of PE is chronic thromboembolic pulmonary hypertension (CTEPH), the true incidence of which remains obscure due to the large margin of error in the rates reported by mostly small, single-center studies. Moreover, the functional and hemodynamic changes corresponding to early, possibly reversible stages of CTEPH, have not been systematically investigated. The ongoing Follow-Up after acute pulmonary embolism (FOCUS) study will prospectively enroll and systematically follow, over a 2-year period and with a standardized comprehensive program of clinical, echocardiographic, functional and laboratory testing, a large multicenter prospective cohort of 1000 unselected patients (all-comers) with acute symptomatic PE. FOCUS will possess adequate power to provide answers to relevant remaining questions regarding the patients' long-term morbidity and mortality, and the temporal pattern of post-PE abnormalities. It will hopefully provide evidence for future guideline recommendations regarding the selection of patients for long-term follow-up after PE, the modalities which this follow-up should include, and the findings that should be interpreted as indicating progressive functional and hemodynamic post-PE impairment, or the development of CTEPH.