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Cyrus A Kholdani,1 Wassim H Fares,2 Terence K Trow2 1Section of Pulmonary, Critical Care and Sleep Medicine, 2Yale Pulmonary Vascular Disease Program, Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA Abstract: Macitentan is the most recently approved dual endothelin-receptor antagonist (ERA) for the treatment of symptomatic pulmonary arterial hypertension. Compared to other available ERAs, it demonstrates superior receptor-binding properties, with consequently improved tissue penetration, and a longer duration of action allowing for once-daily dosing. It has a favorable adverse-effect profile, with notably no demonstrable increase in the risk of hepatotoxicity or peripheral edema, but like other ERAs, it is potentially limited by significant anemia. Phase I data have demonstrated a favorable drug–drug interaction profile and no need for dose adjustment with hepatic and renal impairment. In the pivotal SERAPHIN study, treatment of symptomatic pulmonary arterial hypertension patients with macitentan led to statistically significant improvements in functional class, exercise tolerance, and hemodynamic parameters, in addition to a reduction in morbidity in an event-driven long-term trial. Keywords: endothelin, endothelin receptor antagonists, macitentan, pulmonary arterial hypertension

Our study presents cases demonstrating the technique and safety of percutaneous occlusion of adult patients with partial anomalous pulmonary venous return (PAPVR). PAPVR is a rare condition that is traditionally treated surgically. Percutaneous interventions are rarely reported. Most patients with PAPVR present in youth and are surgical candidates. In nonsurgical candidates or those who prefer a percutaneous approach, there are little available data to guide therapy. Patients with PAPVR and indications for intervention were treated with percutaneous techniques to occlude anomalous venous return and relieve the hemodynamic effects of these anomalies. Several different percutaneous techniques were used, sometimes in tandem to achieve occlusion. Percutaneous closure was achieved successfully in 3 cases, with improvement in symptoms and in hemodynamic status. A total of 2 patients achieved positive remodeling in right chamber sizes. In conclusion, percutaneous occlusion of PAPVR is feasible, with a multitude of transcatheter options available. This represents a novel approach to the adult patient with PAPVR, specifically, those without a surgical option. Condensed Abstract: Partial anomalous pulmonary venous return is a rare congenital condition, which is traditionally treated surgically. Adult patients with congenital heart disease are potentially nonsurgical candidates and, as such, benefit from percutaneous approaches. Our study describes the safety and feasibility of percutaneous closure of partial anomalous pulmonary venous return and the positive impact on hemodynamic and chamber measures., Competing Interests: Declaration of competing interest Dr. Laham reports relations with Medtronic Coronary and Structural Heart Disease Management, Abbott, and Edwards Lifesciences Corporation that include consulting or advisory. The remaining authors have no competing interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Benchmarks of clinical management are essential for improving the quality of care. However, the lack of established quality metrics for pulmonary arterial hypertension (PAH) contributes to practice heterogeneity. We assessed our center's diagnostic practices, therapeutic practices, and risk-adjusted survival patterns over time for the purpose of establishing quality benchmarks. We analyzed the demographics, clinical characteristics, and diagnostic evaluation of 702 PAH patients enrolled between 1999 and 2019. We examined outcomes in this cohort, including an analysis of risk stratification, therapeutic practice patterns, hospitalizations, organ transplant, and survival. Initial diagnostic workup of incident PAH cases demonstrated excellent completion of echocardiographic (99%) and pulmonary function testing (91%), with improved completion of VQ scanning over the study time period (90% between 2015 and 2019). Right heart catheterization (RHC) was performed in all patients; RHC performed at our center was more likely to include complete hemodynamic data than those performed at referring institutions (55.4% and 30.4% respectively). The average number of PAH-specific medications prescribed increased over time; however, there was no significant increase in the use of parenteral therapy over time, even when stratified by the REVEAL risk score. Survival rates in the cohort were 94% at 1 year, 75% at 5 years, and 60% at 10 years, comparable to those of other PAH cohorts. Analysis of our well-characterized cohort of PAH patients reveals the extent to which guideline-directed diagnostic and therapeutic care is delivered at our specialty center, and the associated outcomes; these data may serve as a benchmark for continued improvements in quality of PAH care., Competing Interests: The authors declare no conflicts of interest., (© 2025 The Author(s). Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Background: Peak tricuspid regurgitant velocity (TRV) on transthoracic echocardiography (TTE) is a commonly obtained parameter and robust predictor of subsequent adverse clinical outcomes., Objectives: The purpose of this study was to determine the predictors and clinical significance of TRV progression., Methods: We retrospectively linked consecutive outpatient TTE reports from our institution to 2005 to 2017 Medicare claims. Individuals with prior tricuspid surgery, endocarditis, tricuspid stenosis, missing TRV values, TTEs performed during inpatient hospitalization, or <2 TTEs were excluded., Results: A total of 4,572 patients (mean age 67.8 ± 11.9 years, 50.4% female) received 13,273 TTEs over a median follow-up of 7.4 (IQR: 4.5-6.9) years. TRV increased by a mean of 0.23 (95% CI: 0.22 to 0.23 m/s/y, P < 0.001) (range, 0.01-0.80 m/s/y). Older age, depressed left ventricular ejection fraction, diabetes, hypertension, hyperlipidemia, atrial fibrillation, heart failure, and chronic kidney disease were associated with faster progression (all P < 0.05). Accounting for 23 demographic, clinical, and TTE variables, faster TRV progression was associated with a stepwise increased risk of all-cause mortality (TRV progression quartile 4 vs 1; adjusted HR: 2.17; 95% CI: 1.74-2.71; P < 0.001). Those with regression of TRV (n = 384 [8.4%]) had a lower mortality risk (adjusted HR: 0.40; 95% CI: 0.28-0.57; P < 0.001)., Conclusions: In this large, multidecade study of Medicare beneficiaries with serial TTEs performed in the outpatient setting, the mean rate of TRV progression was 0.23 m/s/y. Older age, left heart disease, and adverse metabolic features were associated with faster progression. Faster progression was associated with a graded risk for all-cause mortality.

We present the case of a 58-year-old man who presented with dyspnea, cough, and weight loss and was ultimately diagnosed with pulmonary amyloidosis and multiple myeloma. Diagnosis was achieved with a lung biopsy which showed AL amyloid deposits involving the interstitium, vessels, and airway. He was treated with cyclophosphamide, bortezomib, and dexamethasone but died prior to completing treatment. His case is unique for the amyloid deposition found in all three lung compartments with clear pathophysiologic manifestations of each compartment, and the rapid disease progression that led to respiratory failure and death., Competing Interests: RH reports receiving the following: indirect clinical trial research funding from Boehringer Ingelheim, Regeneron, and Galapagos; authorship fees from Dynamed and Wolters Kluwer; consulting fees from Teladoc, ImpactNetwork, Boehringer Ingelheim, and Paradigm Medical; advisory board meeting fees from Boehringer Ingelheim. PVL has received consulting fees from Gala Therapeutics, Intuitive Surgical, and Galvanize Therapeutics, unrelated to the current work. All other authors report no conflicts of interest., (© 2022 The Authors. Published by Elsevier Ltd.)

Background: Pulmonary vascular disease is associated with poor outcomes in individuals affected by interstitial lung disease. The pulmonary vessels can be quantified with noninvasive imaging, but whether radiographic indicators of vasculopathy are associated with early interstitial changes is not known., Research Question: Are pulmonary vascular volumes, quantified from CT scans, associated with interstitial lung abnormalities (ILA) in a community-based sample with a low burden of lung disease?, Study Design and Methods: In 2,386 participants of the Framingham Heart Study, we used CT imaging to calculate pulmonary vascular volumes, including the small vessel fraction (a surrogate of vascular pruning). We constructed multivariable logistic regression models to investigate associations of vascular volumes with ILA, progression of ILA, and restrictive pattern on spirometry. In secondary analyses, we additionally adjusted for diffusing capacity and emphysema, and performed a sensitivity analysis restricted to participants with normal FVC and diffusing capacity., Results: In adjusted models, we found that lower pulmonary vascular volumes on CT were associated with greater odds of ILA, antecedent ILA progression, and restrictive pattern on spirometry. For example, each SD lower small vessel fraction was associated with 1.81-fold greater odds of ILA (95% CI, 1.41-2.31; P < .0001), and 1.63-fold greater odds of restriction on spirometry (95% CI, 1.18-2.24; P = .003). Similar patterns were seen after adjustment for diffusing capacity for carbon monoxide, emphysema, and among participants with normal lung function., Interpretation: In this cohort of community-dwelling adults not selected on the basis of lung disease, more severe vascular pruning on CT was associated with greater odds of ILA, ILA progression, and restrictive pattern on spirometry. Pruning on CT may be an indicator of early pulmonary vasculopathy associated with interstitial lung disease., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary arterial hypertension (PAH) is a progressive, fatal disease. Current prognostic models are not ideal, and identifying more accurate prognostic variables is needed. The objective of this study was to evaluate the relative prognostic value of the right atrial pressure/pulmonary artery wedge pressure (RAP/PAWP) ratio in PAH patients. We hypothesized that the RAP/PAWP ratio is more predictive of survival than any of the other measured or calculated hemodynamic variables., Methods: We performed a secondary analysis of a PAH cohort (Cohort 1) and validated our results in a separate cohort (Cohort 2). Cohort 1 included primarily patients enrolled in prospective, short-term, randomized clinical trials and subsequently followed long term. Cohort 2 included patients prospectively enrolled in a PAH registry at a tertiary PAH referral center., Results: Cohort 1 (n = 847) and Cohort 2 (n = 697) had a mean age of 47 and 54 years, respectively. Most were female (78% and 73%, respectively), Caucasian (83% and 82%), with advanced functional class disease status (New York Heart Association Functional Class III/IV 85% and 68%) and with significantly elevated hemodynamics (mean RAP/PAWP ratio: 1.2 and 1.0; pulmonary vascular resistance: 13.5 and 9.4 Wood units). RAP/PAWP ratio indicated a 1-year hazard ratio of 1.44 (p = 0.0001) and 1.35, respectively (p < 0.0001), and was the most consistently predictive hemodynamic variable across the 2 cohorts. These results remain valid even when adjusted for other covariables in multivariable regression models., Conclusions: The RAP/PAWP ratio is a more specific predictor of survival than any other hemodynamic variable, and we recommend that it be used in clinical prognostication and PAH predictive models., (Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The right heart failure (RHF) syndrome is a pathophysiologically complex state commonly associated with dysfunction of the right ventricle (RV). The normal RV is suited for its purposes of distributing venous blood to the low-resistance pulmonary circulation. Myriad stresses imposed upon it, though, can ultimately result in its failure, with the threat of cardiovascular collapse being the most dreaded outcome. Decreased cardiac output with increased central venous pressures are hemodynamic hallmarks of this highly morbid condition. Proper management of RHF is predicated on the accurate assessment of the key hemodynamic and clinical components signaling the syndrome that is the result of the failing RV. Appropriate use of diagnostic tools is paramount for understanding the key components of RV function: the preload state of the RV, its contractility, and the afterload burden placed on it. In making these assessments, it remains crucial to understand the limitations of these tools when managing RHF in the intensive care unit. An understanding of each of these components allows for the understanding of the physiology and the clinical presentation which can guide the use of therapies appropriately tailored to manage the condition., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Right heart failure is a clinical syndrome of various causes that commonly involves failure of the right ventricle (RV). The hemodynamic hallmark of the syndrome is increasing central venous pressure and worsening cardiac output with a rising RV end-diastolic pressure. When dealing with RV failure, clinicians must assess and optimize the intravascular volume state, support RV contractility, and address any pathologic elevations of afterload so that systemic perfusion is preserved. Despite these measures, there may still be a need to offer rescue interventions to the failing RV in carefully selected patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Upon metamorphosis, amphibian tadpoles lose their tails through programmed cell death induced by thyroid hormone (T3). Before transformation, the tail functions as an essential locomotory organ. The binding protein for the stress neuropeptide corticotropin-releasing factor (CRF; CRF-BP) is strongly up-regulated in the tail of Xenopus tadpoles during spontaneous or T3-induced metamorphosis. This finding led us to investigate physiological roles for CRF and CRF-BP in tadpole tail. We found CRF, CRF-BP, and functional CRF1 receptor in tail and CRF and functional CRF1 receptors, but not CRF-BP, in the tail muscle-derived cell line XLT-15. CRF, acting via the CRF1 receptor, slowed spontaneous tail regression in explant culture and caused a reduction in caspase 3/7 activity. CRF increased, but stable CRF-BP overexpression decreased, [3H]thymidine incorporation in XLT-15 cells. Overexpression of CRF-BP in vivo accelerated the loss of tail muscle cells during spontaneous metamorphosis. Lastly, exposure of tail explants to hypoxia increased CRF and urocortin 1 but strongly decreased CRF-BP mRNA expression. We show that CRF is expressed in tadpole tail, is up-regulated by environmental stressors, and is cytoprotective. The inhibitory binding protein for CRF is regulated by hormones or by environmental stressors and can modulate CRF bioactivity.