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Among over 1100 patients with pulmonary arterial hypertension who received selexipag, an oral selective IP prostacyclin-receptor agonist, or placebo, the risk of the composite end point of death or complication was lower with selexipag than with placebo at 1.3 years of follow-up. Pulmonary arterial hypertension is a severe disease with a poor prognosis despite available treatment options. 1 Current recommendations support the use of a combination of therapies that target the endothelin, nitric-oxide, and prostacyclin pathways. 2 , 3 Despite the benefits of intravenous prostacyclin therapy, 2 , 4 many patients with pulmonary arterial hypertension die without ever receiving this treatment. 5 , 6 The burden and risks related to the administration of prostacyclin therapy are probably contributing factors. 7 Selexipag is an oral selective IP prostacyclin-receptor agonist that is structurally distinct from prostacyclin. 8 – 11 In a placebo-controlled, phase 2 trial involving patients who were already receiving treatment for pulmonary . . .

In an event-driven trial, macitentan (an endothelin-receptor antagonist) at a dose of 3 or 10 mg was compared with placebo in patients with symptomatic pulmonary arterial hypertension. At a median of 115 weeks, both macitentan doses were associated with reduced morbidity and mortality. Pulmonary arterial hypertension, a severe disease characterized by a sustained elevation of pulmonary vascular resistance, ultimately leads to right heart failure and death. 1 Disease progression occurs despite the availability of drugs that are specific for the disorder. 2 Endothelin-receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclin and its analogues have been approved for the treatment of pulmonary arterial hypertension and adopted clinically on the basis of short-term trials (12 to 16 weeks) that have shown improvements in exercise capacity as measured by the distance walked in 6 minutes. 3 – 10 However, current guidelines suggest that the primary end point in phase 3 . . .

Patients with previously untreated pulmonary arterial hypertension who were randomly assigned to combination therapy with ambrisentan and tadalafil had a significantly lower risk of a composite clinical failure outcome at 20 months than did the pooled monotherapy group. Regardless of the initiating trigger, pulmonary arterial hypertension results in the altered synthesis of a variety of vasoactive substances derived from the endothelium. 1 Current therapies for pulmonary arterial hypertension 2 target abnormalities in one of three intracellular pathways with signaling dysfunction: the prostacyclin, nitric oxide, or endothelin pathway. 1 However, no single class of drug is consistently effective in treating all patients, which suggests that no single pathway plays a dominant pathogenic role. 3 , 4 Combination therapy with agents that target several different pathways may potentially increase the overall therapeutic effect on the mechanisms of this disease 5 and provide additional clinical benefits. 6 – . . .

Background Previous studies indicate that patients with pulmonary arterial hypertension (PAH) carrying a mutation in the bone morphogenetic protein receptor type 2 ( BMPR2 ) gene, develop the disease 10 years earlier than non-carriers, and have a more severe hemodynamic compromise at diagnosis. A recent report has suggested that this may only be the case for females and that patients with missense mutations in BMPR2 gene have more severe disease than patients with truncating mutations. Methods We reviewed data from all patients with PAH considered as idiopathic and patients with a family history of PAH, who underwent genetic counselling in the French PAH network between January, 1 st 2004 and April, 1 st 2010. We compared clinical, functional, and hemodynamic characteristics between carriers and non-carriers of a BMPR2 mutation, according to gender or BMPR2 mutation type. Results PAH patients carrying a BMPR2 mutation (n = 115) were significantly younger at diagnosis than non-carriers (n = 267) (35.8 ± 15.4 and 47.5 ± 16.2 respectively, p < 0.0001). The presence of a BMPR2 mutation was associated with a younger age at diagnosis in females (36.4 ± 14.9 in BMPR2 mutation carriers and 47.4 ± 15.8 in non-carriers, p < 0.0001), and males (34.6 ± 16.8 in BMPR2 mutation carriers and 47.8 ± 17.1 in non-carriers, p < 0.0001). BMPR2 mutation carriers had a more severe hemodynamic compromise at diagnosis, but this was not influenced by gender. No differences in survival and time to death or lung transplantation were found in male and female PAH patients carrying a BMPR2 mutation. No differences were observed in clinical outcomes according to the type of BMPR2 mutations (missense, truncating, large rearrangement or splice defect). Conclusion When compared to non-carriers, BMPR2 mutation carriers from the French PAH network are younger at diagnosis and present with a more severe hemodynamic compromise, irrespective of gender. Moreover, BMPR2 mutation type had no influence on clinical phenotypes in our patient population.

Background Involvement of inflammation in pulmonary hypertension (PH) has previously been demonstrated and recently, immune-modulating dendritic cells (DCs) infiltrating arterial lesions in patients suffering from idiopathic pulmonary arterial hypertension (IPAH) and in experimental monocrotaline-induced PH have been reported. Occurrence of perivascular inflammatory cells could be linked to local increase of oxidative stress (OS), as it has been shown for systemic atherosclerosis. The impact of OS on vascular remodeling in PH is still to be determined. We hypothesized, that augmented blood-flow could increase OS and might thereby contribute to DC/inflammatory cell-recruitment and smooth-muscle-cell-proliferation. Methods We applied a monocrotaline-induced PH-model and combined it with permanent flow-challenge. Thirty Sprague-Dawley rats were assigned to following groups: control, monocrotaline-exposure (MCT), monocrotaline-exposure/pneumonectomy (MCT/PE). Results Hemodynamic exploration demonstrated most severe effects in MCT/PE, corresponding in histology to exuberant medial and adventitial remodeling of pulmonary muscular arteries, and intimal remodeling of smaller arterioles; lung-tissue PCR evidenced increased expression of DCs-specific fascin, CD68, proinflammatory cytokines (IL-6, RANTES, fractalkine) in MCT/PE and to a lesser extent in MCT. Major OS enzyme NOX-4 was maximal in MCT/PE. Antioxidative stress enzymes Mn-SOD and glutathion-peroxidase-1 were significantly elevated, while HO-1 showed maximal expression in MCT with significant decrease in MCT/PE. Catalase was decreased in MCT and MCT/PE. Expression of NOX-4, but also of MN-SOD in MCT/PE was mainly attributed to a highly increased number of interstitial and perivascular CXCR4/SDF1 pathway-recruited mast-cells. Stress markers malonedialdehyde and nitrotyrosine were produced in endothelial cells, medial smooth muscle and perivascular leucocytes of hypertensive vasculature. Immunolabeling for OX62, CD68 and actin revealed adventitial and medial DC- and monocyte-infiltration; in MCT/PE, medial smooth muscle cells were admixed with CD68 + /vimentin + cells. Conclusion Our experimental findings support a new concept of immunologic responses to increased OS in MCT/PE-induced PAH, possibly linking recruitment of dendritic cells and OS-producing mast-cells to characteristic vasculopathy.

Mean pulmonary artery pressure (MPAP) and systolic pulmonary artery pressure (SPAP) are used interchangeably to define pulmonary hypertension (PH). We tested the hypothesis that the measurement of MPAP and SPAP is redundant in resting humans over a wide pressure range. Prospective, observational study. Catheterization laboratory in a university hospital. This study involved 31 patients, as follows: primary PH, nine patients; chronic pulmonary thromboembolism, seven patients; venous PH, six patients; and control subjects with normal pulmonary artery pressure, nine patients. None. High-fidelity pulmonary artery pressures were obtained when patients were at rest. Over the wide MPAP range that was under study (10 to 78 mm Hg), MPAP and SPAP were strongly related (r2 = 0.98). Regression analysis performed on the first 16 subjects (test sample) allowed us to propose a formula (MPAP = 0.61 SPAP + 2 mm Hg), the accuracy of which was confirmed in the remaining 15 subjects (validation sample bias, 0 ± 2 mm Hg). If PH was defined by an SPAP in excess of 30 or 40 mm Hg, this corresponded to an MPAP in excess of 20 or 26 mm Hg. If PH was defined by an MPAP of > 25 mm Hg, this corresponded to an SPAP of > 38 mm Hg. In resting humans, MPAP can be accurately predicted from SPAP over a wide pressure range. The new formula may help to refine the threshold pressure values used in the diagnosis of PH. Further studies are needed to test the hypothesis that our formula may allow the noninvasive prediction of MPAP from Doppler-derived SPAP values.

Pulmonary arterial hypertension, which is characterized by vascular proliferation and remodeling of small pulmonary vessels, leads to a progressive increase in pulmonary vascular resistance and, ultimately, to right ventricular failure and death. Despite recent major improvements in therapy, no current treatments cure this devastating condition. This article discusses recent progress in developing treatments that prolong patients' lives and improve their quality of life. Pulmonary arterial hypertension is characterized by vascular proliferation and remodeling of small vessels and leads to a progressive increase in pulmonary vascular resistance. Pulmonary arterial hypertension is a disease of the small pulmonary arteries that is characterized by vascular proliferation and remodeling. 1 , 2 It results in a progressive increase in pulmonary vascular resistance and, ultimately, right ventricular failure and death. A diagnosis of primary (or idiopathic) pulmonary hypertension is made when no known risk factor is identified. 3 , 4 The diagnostic classification of pulmonary arterial hypertension is described in Table 1. 3 Despite recent major improvements in symptomatic treatments, no current treatment cures this devastating condition. 1 , 2 , 5 – 9 However, during the past 20 years, treatment options for patients with the disease have evolved to help . . .

In this trial, 261 patients with chronic thromboembolic pulmonary hypertension were assigned to placebo or to the soluble guanylate cyclase stimulator riociguat. At 16 weeks, riociguat had significantly improved the 6-minute walk distance and pulmonary vascular resistance. Chronic thromboembolic pulmonary hypertension is characterized by obstruction of the pulmonary vasculature by residual organized thrombi, 1 leading to increased pulmonary vascular resistance, progressive pulmonary hypertension, and right ventricular failure. 2 , 3 Patients with chronic thromboembolic pulmonary hypertension have a poor prognosis unless they receive treatment early. 4 Pulmonary endarterectomy is the standard treatment for chronic thromboembolic pulmonary hypertension and is the only potentially curative treatment. 5 However, surgery is not an option for all patients; some patients are ineligible for surgery owing to the occlusion of distal vessels or coexisting conditions, some decline surgery, and some do not have access to expert surgical . . .

Florent Soubrier and colleagues identify biallelic mutations in EIF2AK4 as a major cause of pulmonary veno-occlusive disease, a rare form of pulmonary hypertension. EIF2AK4 encodes a serine-threonine kinase, and the disease-causing mutations are predicted to result in loss of protein function. Pulmonary veno-occlusive disease (PVOD) is a rare and devastating cause of pulmonary hypertension that is characterized histologically by widespread fibrous intimal proliferation of septal veins and preseptal venules and is frequently associated with pulmonary capillary dilatation and proliferation 1 , 2 . PVOD is categorized into a separate pulmonary arterial hypertension–related group in the current classification of pulmonary hypertension 3 . PVOD presents either sporadically or as familial cases with a seemingly recessive mode of transmission 4 . Using whole-exome sequencing, we detected recessive mutations in EIF2AK4 (also called GCN2 ) that cosegregated with PVOD in all 13 families studied. We also found biallelic EIF2AK4 mutations in 5 of 20 histologically confirmed sporadic cases of PVOD. All mutations, either in a homozygous or compound-heterozygous state, disrupted the function of the gene. These findings point to EIF2AK4 as the major gene that is linked to PVOD development and contribute toward an understanding of the complex genetic architecture of pulmonary hypertension.

Currently, five classes of drug are approved for the treatment of pulmonary arterial hypertension (PAH): phosphodiesterase 5 inhibitors (PDE5i); endothelin receptor antagonists; prostacyclin analogs; the IP receptor agonist selexipag; and the soluble guanylate cyclase (sGC) stimulator riociguat. For patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), riociguat is currently the only approved pharmacotherapy. Despite the development of evidence-based guidelines on appropriate use of specific drugs, in clinical practice patients are often prescribed PAH-targeted therapies off label or at inadequate doses. PDE5i are the most often prescribed class of drugs as initial therapy, either alone or in combination with other drug classes. However, a proportion of patients receiving PAH therapies do not reach or maintain treatment goals. As PDE5i and riociguat target different molecules in the nitric oxide-sGC-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway, for patients with PAH without an initial or sustained response to PDE5i, there is a biological rationale for switching to riociguat. However, robust data from randomized controlled trials on the safety and efficacy of switching are lacking, as is formal guidance for clinicians. Here we review studies of sequential combination therapy, and trial data and case studies that have investigated switching between PAH-approved therapies, particularly from PDE5i to riociguat in patients with PAH with an insufficient response to PDE5i, and in patients with CTEPH who were receiving off-label treatment. These studies summarize the current evidence and practical real-life experience on the concept of switching treatments.