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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 pulmonary arterial hypertension who achieve a six-minute walk distance of 380-440 m may have improved prognosis. Using the randomized controlled trial of macitentan in pulmonary arterial hypertension (SERAPHIN), the association between six-minute walk distance and long-term outcomes was explored. Patients with six-minute walk distance data at Month 6 were dichotomized as above or below the median six-minute walk distance (400 m) and assessed for future risk of pulmonary arterial hypertension-related death or hospitalization and all-cause death. Additionally, six-minute walk distance values at baseline, Month 6 and the change from baseline to Month 6 were categorized by quartiles. All associations were analyzed by the Kaplan-Meier method using a log-rank test and Cox regression models. Patients with a six-minute walk distance >400 m vs. ≤400 m at Month 6 have a reduced risk of pulmonary arterial hypertension-related death or hospitalization (hazard ratio 0.48; 95% confidence interval 0.33-0.69). The risk was also lower for patients with higher quartiles of six-minute walk distance at baseline or Month 6 (baseline: hazard ratio [Q4 (>430 m) vs. Q1 (≤300 m)] 0.23; 95% confidence interval 0.15-0.36; Month 6: hazard ratio [Q4 (>455 m) vs. Q1 (≤348 m)] 0.33; 95% confidence interval 0.19-0.55). In contrast, six-minute walk distance changes at Month 6 were not associated with the risk of pulmonary arterial hypertension-related death or hospitalization (p = 0.477). These findings were consistent when adjusted for known confounders. Similar results were observed for the risk of all-cause death up to end of study. Patients with pulmonary arterial hypertension walking >400 m had better long-term prognosis. Although changes in six-minute walk distance were not associated with long-term outcomes, assessing absolute six-minute walk distance values remains important in the clinical management of patients with pulmonary arterial hypertension.

Small, open-label studies suggest that combinations of existing therapies may be effective for pulmonary arterial hypertension (PAH). To evaluate the safety and efficacy of adding inhaled iloprost, a prostacyclin analog, to the endothelin receptor antagonist bosentan in patients with PAH. In a randomized, multicenter, double-blind trial, inhaled iloprost (5 mug) or placebo was added to stable monotherapy with bosentan for 12 wk. Efficacy endpoints included change from baseline in 6-min-walk distance (6-MWD), modified New York Heart Association (NYHA) functional class, hemodynamic parameters, and time to clinical worsening. A total of 67 patients with PAH (55% idiopathic PAH, 45% associated PAH, 94% NYHA class III, and mean baseline 6-MWD of 335 m) were randomized. At Week 12, patients receiving iloprost had a mean increase in 6-MWD of 30 m (p = 0.001); placebo patients had a mean 6-MWD increase of 4 m (p = 0.69), with a placebo-adjusted difference of +26 m (p = 0.051). NYHA status improved by one class in 34% of iloprost versus 6% of placebo patients (p = 0.002). Iloprost delayed the time to clinical worsening (p = 0.0219). Improvements were noted in postinhalation placebo-adjusted change in mean pulmonary artery pressure (-8 mm Hg; p < 0.001) and pulmonary vascular resistance (-254 dyn x s x cm(-5); p < 0.001). Combination therapy was well tolerated. Within the limitations of a relatively small sample size, results of this study demonstrate that the addition of inhaled iloprost in patients with PAH with reduced exercise capacity on bosentan monotherapy is safe and efficacious.

Many potential therapeutic options are now available for patients with pulmonary arterial hypertension. Interest has emerged in using therapies in various combinations. Retrospective experience has suggested that this approach is common and can be efficacious. Data are emerging supporting the benefit of combination therapy; however, limitations and questions remain about this strategy. This report reviewed the rationale for combination therapy and summarized the results from clinical trials.

Aberrant kinase signaling that involves platelet-derived growth factor receptor (PDGFR) α/β, colony stimulating factor 1 receptor (CSF1R), and stem cell factor receptor (c-KIT) pathways may be responsible for vascular remodeling in pulmonary arterial hypertension. Targeting these specific pathways may potentially reverse the pathological inflammation, cellular proliferation, and fibrosis associated with pulmonary arterial hypertension progression. Seralutinib (formerly known as GB002) is a novel, potent, clinical stage inhibitor of PDGFRα/β, CSF1R, and c-KIT delivered via inhalation that is being developed for patients with pulmonary arterial hypertension. Here, we report on an ongoing Phase 2 randomized, double-blind, placebo-controlled trial (NCT04456998) evaluating the efficacy and safety of seralutinib in subjects with World Health Organization Group 1 Pulmonary Hypertension who are classified as Functional Class II or III. A total of 80 subjects will be enrolled and randomized to receive either study drug or placebo for 24 weeks followed by an optional 72-week open-label extension study. The primary endpoint is the change from baseline to Week 24 in pulmonary vascular resistance by right heart catheterization. The secondary endpoint is the change in distance from baseline to Week 24 achieved in the 6-min walk test. A computerized tomography sub-study will examine the effect of seralutinib on pulmonary vascular remodelling. A separate heart rate monitoring sub-study will examine the effect of seralutinib on cardiac effort during the 6-min walk test.

Background Without aggressive treatment, pulmonary arterial hypertension (PAH) has a 5-year mortality of approximately 40%. A patient’s response to vasodilators at diagnosis impacts the therapeutic options and prognosis. We hypothesized that analyzing perfusion images acquired before and during vasodilation could identify characteristic differences between PAH and control subjects. Methods We studied 5 controls and 4 subjects with PAH using HRCT and 13 NN PET imaging of pulmonary perfusion and ventilation. The total spatial heterogeneity of perfusion (CV 2 Qtotal ) and its components in the vertical (CV 2 Qvgrad ) and cranio-caudal (CV 2 Qzgrad ) directions, and the residual heterogeneity (CV 2 Qr ), were assessed at baseline and while breathing oxygen and nitric oxide (O 2  + iNO). The length scale spectrum of CV 2 Qr was determined from 10 to 110 mm, and the response of regional perfusion to O 2  + iNO was calculated as the mean of absolute differences. Vertical gradients in perfusion (Q vgrad ) were derived from perfusion images, and ventilation-perfusion distributions from images of 13 NN washout kinetics. Results O 2  + iNO significantly enhanced perfusion distribution differences between PAH and controls, allowing differentiation of PAH subjects from controls. During O 2  + iNO, CV 2 Qvgrad was significantly higher in controls than in PAH (0.08 (0.055–0.10) vs. 6.7 × 10 –3 (2 × 10 –4 –0.02), p < 0.001) with a considerable gap between groups. Q vgrad and CV 2 Qtotal showed smaller differences: − 7.3 vs. − 2.5, p = 0.002, and 0.12 vs. 0.06, p = 0.01. CV 2 Qvgrad had the largest effect size among the primary parameters during O 2  + iNO. CV 2 Qr , and its length scale spectrum were similar in PAH and controls. Ventilation-perfusion distributions showed a trend towards a difference between PAH and controls at baseline, but it was not statistically significant. Conclusions Perfusion imaging during O2 + iNO showed a significant difference in the heterogeneity associated with the vertical gradient in perfusion, distinguishing in this small cohort study PAH subjects from controls.

Various erythropoietic abnormalities are highly prevalent among patients with pulmonary arterial hypertension (PAH) and associated with worse disease severity. Given the poorly understood yet important roles of dysregulated erythropoiesis and iron metabolism in PAH, we sought to further characterize the hematologic and iron profiles in PAH and their relationship to PAH severity. We recruited 67 patients with PAH and 13 healthy controls. Hemodynamics attained within 1 year of blood sample collection were available for 36 patients. Multiple hematologic, iron, and inflammatory parameters were evaluated for their association with hemodynamics. The subset with hemodynamic data consisted of 29 females (81%). The most common etiologies were idiopathic PAH (47%) and connective tissue disease‐related PAH (33%). 19 (53%) had functional class 3 or 4 symptomatology, and 12 (33%) were on triple pulmonary vasodilator therapy. Immature reticulocyte fraction (IRF) had significant positive correlations with mean pulmonary artery (PA) pressure (mPAP) (0.59, p < 0.001), pulmonary vascular resistance (0.52, p = 0.001), and right atrial pressure (0.46, p = 0.005), and significant negative correlations with cardiac index (−0.43, p = 0.009), PA compliance (PAC) (−0.60, p < 0.001), stroke volume index (SVI) (−0.57, p < 0.001), and mixed venous oxygen saturation (−0.51, p = 0.003). IRF correlated with markers of iron deficiency (ID) and erythropoiesis. On multivariable linear regression, IRF was associated with elevated mPAP and reduced SVI and PAC independent of EPO levels, transferrin saturation, and soluble transferrin receptor levels. We identified IRF as a novel and potent biomarker of PAH hemodynamic severity, possibly related to its associations with erythropoiesis, ID, and tissue hypoxia.

Pulmonary hypertension is defined as a mean pulmonary artery pressure ≥25mmHg and is a recently recognized complication of chronic kidney disease and end-stage renal disease. There is significant epidemiological overlap with kidney disease and the underlying causes of World Health Organization group 1–4 pulmonary hypertension (pulmonary arteriopathy, left heart disease, chronic pulmonary disease, and chronic thromboembolic disease, respectively). In addition, an entity of ‘unexplained pulmonary hypertension,’ group 5, in patients with chronic kidney disease and end-stage renal disease has emerged, with prevalence estimates of 30–50%. The pathogenesis of pulmonary hypertension in this population is due to alterations in endothelial function, increased cardiac output, and myocardial dysfunction leading to elevated left heart filling pressure, with recent data suggesting that left heart dysfunction may account for the vast majority of pulmonary hypertension in patients with kidney disease. Pulmonary hypertension is an independent predictor of increased mortality in patients on dialysis and those undergoing kidney transplantation. This review summarizes what is known about the epidemiology, pathogenesis, transplantation outcomes, mortality, and treatment of pulmonary hypertension in patients with chronic kidney disease and end-stage renal disease.

The Pulmonary Arterial Hypertension‐Quality Enhancement Research Initiative Extension Program was designed to support physicians’ adherence to pulmonary arterial hypertension (PAH) guidelines. Guidelines were followed in >95% of patients with functional class (FC) II/III, but for only 28.6% of FC IV patients (Month 36). Low adherence was driven by FC IV patients’ preference to avoid parenteral treatment.

Background Pulmonary thromboendarterectomy (PTE) is an effective treatment for chronic thromboembolic pulmonary hypertension (CTEPH), but is a technically challenging operation for cardiothoracic surgeons. Starting a new program allows an opportunity to define a learning curve for PTE. Methods A retrospective case review was performed of 134 consecutive PTEs performed from 1998 to 2016 at a single institution. Outcomes were compared using either a two-tailed t-test for continuous variables or a chi-squared test for categorical variables according to experience of the program by terciles (T). Results The 30-day mortality was 3.7%. The mean length of hospital stay, length of ICU stay, and duration on a ventilator were 12.6 days, 4.6 days, and 2.0 days, respectively. The mean decrease in systolic pulmonary artery pressure (sPAP) was 41.3 mmHg. Patients with Jamieson type 2 disease had a greater change in mean sPAP than those with type 3 disease ( p  = 0.039). The mean cardiopulmonary bypass time was 180 min (T1–198 min, T3–159 min, p  = <0.001), and the mean circulatory arrest time was 37 min (T1-44 min, T3-31 min, p  < 0.001). Plotting circulatory arrest times as a running sum compared to the mean demonstrated 2 inflection points, the first at 22 cases and the second at 95 cases. Conclusions PTE is a challenging procedure to learn, and good outcomes are a result of a multi-disciplinary effort to optimize case selection, operative performance, and postoperative care. Approximately 20 cases are needed to become proficient in PTE, and nearly 100 cases are required for more efficient clearing of obstructed pulmonary arteries.