@ERSpublicationsThe risk stratification strategy proposed by the current European PH guidelines allows accurate survival prediction http://ow.ly/KsWk30c46nK ABSTRACT The 2015 European pulmonary hypertension (PH) guidelines propose a risk stratification strategy for patients with pulmonary arterial hypertension (PAH). Low-, intermediate-and high-risk strata are defined by estimated 1-year mortality risks of <5%, 5-10% and >10%, respectively. This risk assessment strategy awaits validation.We analysed data from patients with newly diagnosed PAH enrolled into COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension), a European-based PH registry. An abbreviated version of the risk assessment strategy proposed by the European PH guidelines was applied, using the following variables: World Health Organization functional class, 6-min walking distance, brain natriuretic peptide or its N-terminal fragment, right atrial pressure, cardiac index and mixed venous oxygen saturation.Data from 1588 patients were analysed. Mortality rates were significantly different between the three risk strata ( p<0.001 for all comparisons). In the entire patient population, the observed mortality rates 1 year after diagnosis were 2.8% in the low-risk cohort (n=196), 9.9% in the intermediate-risk cohort (n=1116) and 21.2% in the high-risk cohort (n=276). In addition, the risk assessment strategy proved valid at follow-up and in major PAH subgroups.An abbreviated version of the risk assessment strategy proposed by the current European PH guidelines provides accurate mortality estimates in patients with PAH.
ObjectiveIn patients with pulmonary arterial hypertension (PAH), supportive therapies may be beneficial in addition to targeted medical treatment. Here, we evaluated the effectiveness and safety of oscillatory whole-body vibration (WBV) in patients on stable PAH therapy.MethodsTwenty-two patients with PAH (mean PAP≥25 mm Hg and pulmonary arterial wedge pressure (PAWP)≤15 mm Hg) who were in world health organization (WHO)-Functional Class II or III and on stable PAH therapy for≥3 months, were randomised to receive WBV (16 sessions of 1-hour duration within 4 weeks) or to a control group, that subsequently received WBV. Follow-up measures included the 6-min walking distance (6MWD), cardiopulmonary exercise testing (CPET), echocardiography, muscle-power, and health-related quality of life (HRQoL; SF-36 and LPH questionnaires).ResultsWhen compared to the control group, patients receiving WBV exhibited a significant improvement in the primary endpoint, the 6MWD (+35.4±10.9 vs −4.4±7.6 m), resulting in a net benefit of 39.7±7.8 m (p=0.004). WBV was also associated with substantial improvements in CPET variables, muscle power, and HRQoL. The combined analysis of all patients (n=22) indicated significant net improvements versus baseline in the 6MWD (+38.6 m), peakVO2 (+65.7 mL/min), anaerobic threshold (+40.9 mL VO2/min), muscle power (+4.4%), and HRQoL (SF-36 +9.7, LPH −11.5 points) (all p<0.05). WBV was well tolerated in all patients, and no procedure-related severe adverse events (SAEs) occurred.ConclusionsWBV substantially improves exercise capacity, physical performance, and HRQoL in patients with PAH who are on stable targeted therapy. This methodology may be utilised in structured training programmes, and may be feasible for continuous long-term physical exercise in these patients.Trial registration numberNCT01763112; Results.
Objective-Despite modern therapies, pulmonary arterial hypertension (PAH) harbors a high mortality. Vascular remodeling is a hallmark of the disease. Recent clinical studies revealed that antiremodeling approaches with tyrosine-kinase inhibitors such as imatinib are effective, but its applicability is limited by significant side effects. Although imatinib has multiple targets, expression analyses support a role for platelet-derived growth factor (PDGF) in the pathobiology of the disease. However, its precise role and downstream signaling events have not been established. Approach and Results-Patients with PAH exhibit enhanced expression and phosphorylation of β PDGF receptor (βPDGFR) in remodeled pulmonary arterioles, particularly at the binding sites for phophatidyl-inositol-3-kinase and PLCγ at tyrosine residues 751 and 1021, respectively. These signaling molecules were identified as critical downstream mediators of βPDGFR-mediated proliferation and migration of pulmonary arterial smooth muscle cells. We, therefore, investigated mice expressing a mutated βPDGFR that is unable to recruit phophatidyl-inositol-3-kinase and PLCγ (βPDGFR F3/F3 ). PDGF-dependent Erk1/2 and Akt phosphorylation, cyclin D1 induction, and proliferation, migration, and protection against apoptosis were abolished in βPDGFR F3/F3 pulmonary arterial smooth muscle cells. On exposure to chronic hypoxia, vascular remodeling of pulmonary arteries was blunted in βPDGFR F3/F3 mice compared with wild-type littermates. These alterations led to protection from hypoxia-induced PAH and right ventricular hypertrophy. Conclusions-By means of a genetic approach, our data provide definite evidence that the activated βPDGFR is a key contributor to pulmonary vascular remodeling and PAH. Selective disruption of PDGF-dependent phophatidyl-inositol-3-kinase and PLCγ activity is sufficient to abolish these pathogenic responses in vivo, identifying these signaling events as valuable targets for antiremodeling strategies in PAH. From the Klinik III für Innere Medizin, Herzzentrum der Universität zu Köln, Cologne, Germany (H.t.F., E.M.B., M.L., M.Z., A.K., M.V., E.C., T.K., S.B., S.R.); Center for Molecular Medicine Cologne (CMMC) (H.t.F., E.M.B., M.L., M.Z., A.K., M.V., E.C., S.B., S.R.), and Cologne Cardiovascular Research Center (CCRC) (H.t.F., A.K., S.B., S.R.), University of Cologne, Cologne, Germany; University of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany (W.J., K.M., R.T.S.); and Center for Cardiovascular Research, University of Hawaii, Honolulu (M.D.T. 10,11 Data from atherosclerosis and restenosis models support an important role of PDGF in vivo. 12,13 In the context of PAH, several studies reporting expression analyses and pharmacological interventions suggest a role for PDGF in experimental and human disease, [14][15][16][17][18][19][20] but its precise role and downstream signaling remain to be established.Inhibition of PDGFR signaling may be achieved by tyrosine kinase inhibitors, such as imatinib mesylate, which was developed for the...
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