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Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit. A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure. In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).

Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.

In translational models of pulmonary arterial hypertension (PAH), spironolactone improves cardiopulmonary hemodynamics by attenuating the adverse effects of hyperaldosteronism on endothelin type-B receptor function in pulmonary endothelial cells. This observation suggests that coupling spironolactone with inhibition of endothelin type-A receptor–mediated pulmonary vasoconstriction may be a useful treatment strategy for patients with PAH. We examined clinical data from patients randomized to placebo or the selective endothelin type-A receptor antagonist ambrisentan (10 mg/day) and in whom spironolactone use was reported during ARIES-1 and -2, which were randomized, double-blind, placebo-controlled trials assessing the effect of ambrisentan for 12 weeks on clinical outcome in PAH. From patients randomized to placebo (n = 132) or ambrisentan (n = 67), we identified concurrent spironolactone use in 21 (15.9%) and 10 (14.9%) patients, respectively. Compared with patients treated with ambrisentan alone (n = 57), therapy with ambrisentan + spironolactone improved change in 6-minute walk distance by 94% at week 12 (mean ± SE, +38.2 ± 8.1 vs +74.2 ± 27.4 m, p = 0.11), improved plasma B-type natriuretic peptide concentration by 1.7-fold (p = 0.08), and resulted in a 90% relative increase in the number of patients improving ≥1 World Health Organization functional class (p = 0.08). Progressive illness, PAH-associated hospitalizations, or death occurred as an end point for 5.3% of ambrisentan-treated patients; however, no patient treated with ambrisentan + spironolactone reached any of these end points. In conclusion, these pilot data suggest that coupling spironolactone and endothelin type-A receptor antagonism may be clinically beneficial in PAH. Prospective clinical trials are required to further characterize our findings.

Pulmonary arterial hypertension (PAH), which is a subset of pulmonary hypertension, is a group of diseases distinguished by vascular remodeling of the small pulmonary arteries with associated elevated pulmonary arterial pressure and right ventricular failure. This progressive and sometimes fatal disease occurs as an idiopathic disease or as a component of other disease states. Estimates of the incidence of PAH have varied from 5 to 52 cases/1 million population. Symptoms begin with shortness of breath with exertion and progress to dyspnea with normal activities and, finally, dyspnea at rest. Untreated patients with PAH have a 1-, 3-, and 5-year survival rate of 68%, 48%, and 34%, respectively. Treated, the survival rates improve to 91% to 97% after 1 year and 84% to 91% after 2 years. The current definition of PAH consists of 3 specific hemodynamic assessments confirmed by right heart catheterization findings. One of several important pathophysiologic mechanisms involved in PAH is pulmonary vascular remodeling, which is caused by endothelial and smooth muscle cell hyperproliferation. This is coincident with overexpression of the vasoconstrictor endothelin-1 and a reduction in the vasodilators nitric oxide and prostacyclin, which further impedes proper vasomotor tone, among other effects. Prostacyclin therapies augment the decreased prostacyclin levels in patients with PAH. The currently approved prostacyclins for the treatment of PAH include epoprostenol, iloprost, and treprostinil. Among the 3 medications, the delivery options include intravenous infusion, subcutaneous infusion, and inhaled formulations. Epoprostenol has been shown to have a positive effect on survival in patients with PAH. All prostacyclins have demonstrated improvements in functional class, exercise tolerance, and hemodynamics in patients with PAH. Intravenously and subcutaneously administered formulations of prostacyclins require continuous infusion pump administration, which presents clinical challenges for both the patient and the care provider. Dosing must be individualized and also presents a clinical challenge. Inhaled formulations seem efficacious in moderately symptomatic patients with PAH and might be appropriate when combined with an oral medication. Combination therapies are commonly used in clinical practice, with the decision to do so based on randomized controlled trial data and case study evidence. The present report provides an overview of PAH, the scientific rationale for treatment with prostacyclin therapy, and the benefits and risks of prostacyclin therapy, both as monotherapy and combined with other medications approved for the treatment of PAH.

Iron–sulfur (Fe‐S) clusters are essential for mitochondrial metabolism, but their regulation in pulmonary hypertension (PH) remains enigmatic. We demonstrate that alterations of the miR‐210‐ISCU1/2 axis cause Fe‐S deficiencies in vivo and promote PH. In pulmonary vascular cells and particularly endothelium, hypoxic induction of miR‐210 and repression of the miR‐210 targets ISCU1/2 down‐regulated Fe‐S levels. In mouse and human vascular and endothelial tissue affected by PH, miR‐210 was elevated accompanied by decreased ISCU1/2 and Fe‐S integrity. In mice, miR‐210 repressed ISCU1/2 and promoted PH. Mice deficient in miR‐210, via genetic/pharmacologic means or via an endothelial‐specific manner, displayed increased ISCU1/2 and were resistant to Fe‐S‐dependent pathophenotypes and PH. Similar to hypoxia or miR‐210 overexpression, ISCU1/2 knockdown also promoted PH. Finally, cardiopulmonary exercise testing of a woman with homozygous ISCU mutations revealed exercise‐induced pulmonary vascular dysfunction. Thus, driven by acquired (hypoxia) or genetic causes, the miR‐210‐ISCU1/2 regulatory axis is a pathogenic lynchpin causing Fe‐S deficiency and PH. These findings carry broad translational implications for defining the metabolic origins of PH and potentially other metabolic diseases sharing similar underpinnings. Synopsis Hypoxia‐inducible miR‐210 down‐regulates its targets ISCU1/2 to regulate pulmonary vascular and endothelial levels of Fe‐S clusters upon acquired injury or mutations. A patient with ISCU loss‐of‐function mutation presents with pulmonary vasculopathy. In mouse and human pulmonary vascular and endothelial tissue affected by PH, hypoxic induction of miR‐210 and repression of its targets ISCU1/2, down‐regulates iron‐sulfur levels. Using genetic and pharmacologic methods to perform gain‐of‐function and loss‐of‐function analyses of miR‐210 and ISCU1/2 in the pulmonary vasculature of mice, the miR‐210‐ISCU1/2 axis is shown to be necessary and sufficient for induction of hypoxic PH. Cardiopulmonary exercise testing of a woman with ISCU mutations revealed exercise‐induced pulmonary vascular dysfunction. Graphical Abstract Hypoxia‐inducible miR‐210 down‐regulates its targets ISCU1/2 to regulate pulmonary vascular and endothelial levels of Fe‐S clusters upon acquired injury or mutations. A patient with ISCU loss‐of‐function mutation presents with pulmonary vasculopathy.

The impact of patient positioning on PCWP measurement and PH classification is underexplored. This study evaluates the differences in hemodynamic assessments between supine and upright RHC. We conducted a retrospective analysis of a single‐center iCPET registry, comparing sequential hemodynamic measurements in the supine and upright positions in 1307 patients. Compared to upright RHC, supine RHC showed consistently higher mean PAP (21 ± 8.5 mmHg vs. 16 ± 8 mmHg) and PCWP (12 ± 4.7 mmHg vs. 6.4 ± 4.9 mmHg). The differences in mPAP and PCWP measurements between supine and upright RHC persisted regardless of sex, age, BMI, or severity of chronic lung disease. Supine RHC diagnosed significantly more cases of HFpEF (21.8% vs. 5.7%) and isolated postcapillary PH (10.9% vs. 1.8%), primarily due to the overestimation of PCWP. Upright RHC had a higher specificity for detecting elevated PCWP (>15 mmHg) in patients with PCWP/CO>2 (98.27% vs. 84.61%) and demonstrated a stronger association with PCWP/CO>2 (OR 9.11, 95% CI 5–16) compared to supine RHC (p = 0.058). PCWP measured in the supine position is higher compared to upright assessment and probably results in increased diagnosis of postcapillary PH.

Pulmonary hypertension includes heterogeneous diagnoses with distinct hemodynamic pathophysiologic features. Identifying elevated pulmonary vascular resistance (PVR) is critical for appropriate treatment. We reviewed data from patients seen at referral pulmonary hypertension clinics who had undergone echocardiography and right-side cardiac catheterization within 1 year. We derived equations to estimate PVR using the ratio of estimated pulmonary artery (PA) systolic pressure (PASPDoppler) to right ventricular outflow tract velocity time integral (VTI). We validated these equations in a separate sample and compared them with a published model based on the ratio of the transtricuspid flow velocity to right ventricular outflow tract VTI (model 1, Abbas et al 2003). The derived models were as follows: PVR = 1.2 × (PASP/right ventricular outflow tract VTI) (model 2) and PVR = (PASP/right ventricular outflow tract VTI) + 3 if notch present (model 3). The cohort included 217 patients with mean PA pressure of 45.3 ± 11.9 mm Hg, PVR of 7.3 ± 5.0 WU, and PA wedge pressure of 14.8 ± 8.1 mm Hg. Just >1/3 had a PA wedge pressure >15 mm Hg (35.5%) and 82.0% had PVR >3 WU. Model 1 systematically underestimated catheterization estimated PVR, especially for those with high PVR. The derived models demonstrated no systematic bias. Model 3 correlated best with PVR (r = 0.80 vs r = 0.73 and r = 0.77 for models 1 and 2, respectively). Model 3 had superior discriminatory power for PVR >3 WU (area under the curve 0.946) and PVR >5 WU (area under the curve 0.924), although all models discriminated well. Model 3-estimated PVR >3 was 98.3% sensitive and 61.1% specific for PVR >3 WU (positive predictive value 93%; negative predictive value 88%). In conclusion, we present an equation to estimate the PVR, using the ratio of PASPDoppler to right ventricular outflow tract VTI and a constant designating presence of right ventricular outflow tract VTI midsystolic notching, which provides superior agreement with catheterization estimates of PVR across a wide range of values.

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.

Pulmonary arterial hypertension (PAH) is a rare and progressive disease that continues to remain highly morbid despite multiple advances in medical therapies. There remains a persistent and desperate need to identify novel methods of treating and, ideally, reversing the pathologic vasculopathy that results in PAH development and progression. Sotatercept is a first-in-class fusion protein that is believed to primarily inhibit activin signaling resulting in decreased cell proliferation and differentiation, though the exact mechanism remains uncertain. Here, we review the currently available PAH therapies, data highlighting the importance of transforming growth factor-β (TGF-β) superfamily signaling in the development of PAH, and the published and on-going clinical trials evaluating sotatercept in the treatment of PAH. We will also discuss preclinical data supporting the potential use of the fusion protein KER-012 in the inhibition of aberrant TGF-β superfamily signaling to ameliorate the obstructive vasculopathy of PAH.