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The causes and circumstances surrounding death are understudied in patients with pulmonary arterial hypertension (PAH). We sought to determine the specific reasons and characteristics surrounding the death of patients with PAH. All deaths of patients with pulmonary hypertension (PH) followed in the Cleveland Clinic Pulmonary Vascular Program were prospectively reviewed by the PH team. A total of 84 patients with PAH (age 58 ± 14 yr; 73% females) who died between June 2008 and May 2012 were included. PH was determined to be the direct cause of death (right heart failure or sudden death) in 37 (44%) patients; PH contributed to but did not directly cause death in 37 (44%) patients; and the death was not related to PH in the remaining cases (n = 7; 8.3%). In three (3.6%) patients the final cause of death could not be adequately assessed. Most patients died in a healthcare environment and most received PH-specific therapies. In our cohort, 50% of all patients with PAH and 75.7% of those who died of right heart failure received parenteral prostanoid therapy. Less than half of patients had advanced healthcare directives. Most patients with PAH in our cohort died of their disease; however, right ventricular failure or sudden death was the sole cause of death in less than half of patients.

Accurate and regular risk assessment is important for evaluation and treatment of pulmonary arterial hypertension (PAH) patients, including those with functional class (FC) II symptoms, a population considered at low risk for disease progression. Risk assessment methods include subjective and objective evaluations. Multiparametric assessments include tools based on the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines (COMPERA and FPHR methods, respectively) and the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL; REVEAL 2.0 tool). To better understand risk status determination in FC II patients, we compared physician-reported risk assessments with objective multiparameter assessment tools. This retrospective chart analysis included PAH patients with FC II symptoms receiving monotherapy or dual therapy. Physicians were surveyed (via telephone) to obtain an assessment of patient risk using their typical methodology, which might have been informed by objective risk assessment. Patient risk was then calculated independently using COMPERA, FPHR and REVEAL 2.0 tools. Factors associated with incongruent risk assessment were identified. Of the 153 patients, 41%, 46%, and 13% were classified as low, intermediate, and high risk, respectively, by physicians. Concordance between physician gestalt and objective methods ranged from 43%-54%. Among patients considered as low risk by physician gestalt, 4%-28% were categorized as high risk using objective methods. The most common physician factor associated with incongruent risk assessment was less frequent echocardiography during follow-up (every 7-12 months vs. every 3 months; p = 0.01). More than half of FC II PAH patients were classified as intermediate/high risk using objective multiparameter assessments. Incorporating objective risk-assessment algorithms into clinical practice may better inform risk assessment and treatment strategies.

Objective To summarize knowledge and identify gaps in evidence regarding treatment of right ventricular dysfunction (RVD) in acute respiratory distress syndrome (ARDS). Data sources We conducted a comprehensive search of MEDLINE, Embase, CINAHL, Web of Science, and the Cochrane Central Register of Controlled Trials. Study selection Studies were included if they reported effects of treatments on right ventricular function, whether or not the intent was to modify right ventricular function. Data extraction Data extraction was performed independently and in duplicate by two authors. Data items included the study design, patient population, type of intervention, comparison group, and RV-specific outcomes. Data synthesis Of 1,430 studies screened, 51 studies reporting on 1,526 patients were included. By frequency, the included studies examined the following interventions: ventilator settings (29.4%), inhaled medications (33.3%), extracorporeal life support (13.7%), intravenous or oral medications (13.7%), and prone positioning (9.8%). The majority of the studies were non-randomized experimental studies (53%), with the next most common being case reports (16%). Only 5.9% of studies were RCTs. In total, 27% of studies were conducted with the goal of modifying RV function. Conclusions Given the prevalence of RVD in ARDS and its association with mortality, the dearth of research on this topic is concerning. This review highlights the need for prospective trials aimed at treating RV dysfunction in ARDS.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary arterial pressures that can lead to right heart failure and death. No cure exists for this disease, but therapeutic advancements have extended its median survival from 2 to 7 years. Mechanistic research in PAH has been limited by factors including that a) animal models do not fully recapitulate the disease or provide insights into its pathogenesis, and b) cellular material from PAH patients is primarily obtained from donor lungs during autopsy or transplantation, which reflect end-stage disease. Therefore, there is a need to identify tools that can elucidate the specific mechanisms of human disease in individual patients, a critical step to guide treatment decisions based on specific pathway abnormalities. Here we demonstrate a simple method to isolate and culture circulating endothelial cells (CECs) obtained at the time of right heart catheterization in PAH patients. We tested these CECs using transcriptomics and found that they have typical traits of PAH, including those involving key treatment pathways, i.e. nitric oxide, endothelin, prostacyclin and BMP/activin pathways. CECs show important gene expression changes in other central PAH disease pathways. In summary, we present a new cellular model for the ex-vivo mechanistic evaluation of critical PAH pathways that participate in the pathogenesis of the disease and may help personalized therapeutic decisions.

Pulmonary hypertension (PH) is defined as resting mean pulmonary artery pressure ≥25 mmHg measured by right heart catheterization. PH is a progressive, life-threatening disease with a variety of etiologies. Swift and accurate diagnosis of PH and appropriate classification in etiologic group will allow for earlier treatment and improved outcomes. A number of imaging tools are utilized in the evaluation of PH, such as chest X-ray, computed tomography (CT), ventilation/perfusion (V/Q) scan, and cardiac magnetic resonance imaging. Newer imaging tools such as dual-energy CT and single-photon emission computed tomography/computed tomography V/Q scanning have also emerged; however, their place in the diagnostic evaluation of PH remains to be determined. In general, each imaging technique provides incremental information, with varying degrees of sensitivity and specificity, which helps suspect the presence and identify the etiology of PH. The present study aims to provide a comprehensive review of the utility, advantages, and shortcomings of the imaging modalities that may be used to evaluate patients with PH.

Previous research has raised concerns regarding inconsistencies between reported and pre-specified outcomes in randomized controlled trials (RCTs) across various biomedical disciplines. However, studies examining whether similar discrepancies exist in RCTs focusing on gastrointestinal and liver diseases are limited. This study aimed to assess the extent of discrepancies between registered and published primary outcomes in RCTs featured in journals specializing in gastroenterology and hepatology. We retrospectively retrieved RCTs published between January 1, 2017 and December 31, 2021 in the top three journals from each quartile ranking of the 2020 Journal Citation Reports within the \"Gastroenterology and Hepatology\" subcategory. We extracted data on trial characteristics, registration details, and pre-specified versus published primary outcomes. Pre-specified primary outcomes were retrieved from the World Health Organization's International Clinical Trials Registry Platform. Only trials reporting specific primary outcomes were included in analyzing primary outcome discrepancies. We also assessed whether there was a potential reporting bias that deemed to favor statistically significant outcomes. Statistical analyses included chi-square tests, Fisher's exact tests, univariate analyses, and logistic regression. Of 362 articles identified, 312 (86.2%) were registered, and 79.8% of the registrations (249 out of 312) were prospective. Among the 285 trials reporting primary outcomes, 76 (26.7%) exhibited at least one discrepancy between registered and published primary outcomes. The most common discrepancies included different assessment times for the primary outcome (n = 32, 42.1%), omitting the registered primary outcome in publications (n = 21, 27.6%), and reporting the registered secondary outcomes as primary outcomes (n = 13, 17.1%). Univariate analyses revealed that primary outcome discrepancies were lower in the publication year 2020 compared to year 2021 (OR = 0.267, 95% CI: 0.101, 0.706, p = 0.008). Among the 76 studies with primary outcome discrepancies, 20 (26.3%) studies were retrospectively registered, and 32 (57.1%) of the prospectively registered trials with primary outcome discrepancies showed statistically significant results. However, no significant differences were found between journal quartiles regarding primary outcome consistency and potential reporting bias (p = 0.14 and p = 0.28, respectively). This study highlights the disparities between registered and published primary outcomes in RCTs within gastroenterology and hepatology journals. Attention to factors such as the timing of primary outcome assessments in published trials and the consistency between registered and published primary outcomes is crucial. Enhanced scrutiny from journal editors and peer reviewers during the review process is necessary to ensure the reliability of gastrointestinal and hepatic trials.

This review focuses on the advancements in the treatment of pulmonary hypertension (PH), especially after the Food and Drug Administration (FDA) approval of sotatercept and the advances in treatment recommendations after seven World Symposia on PH. PH, a complex and progressive condition defined hemodynamically by a mean pulmonary artery pressure >20 mmHg, encompasses multiple PH groups, each with distinct pathophysiological characteristics and treatment implications. Diagnosing PH can be challenging because symptoms like shortness of breath, fatigue, and chest pain are nonspecific. Contemporary treatment of pulmonary arterial hypertension aims to improve outcomes, symptoms, and overall quality of life, with a primary focus on preventing and treating right ventricular failure. Comprehensive risk stratification remains crucial, aiding in personalized therapy adjustments that improve patients’ outcomes. This review also touches upon the limited treatment options for other PH groups, like PH associated with left heart disease, parenchymal lung diseases, and chronic thromboembolic PH, underscoring the need for expanded therapeutic options. Despite advances, challenges remain: diagnostic delays, misdiagnosis, absence of head-to-head clinical trials, and the timing of introducing newer treatments such as sotatercept are discussed, emphasizing an integrated approach that transcends vasodilation to target underlying disease mechanisms. Future directions envision a comprehensive risk stratification incorporating right ventricular function and a mechanism-based treatment paradigm, encouraging a tailored therapeutic approach in PH management. Plain language summary Contemporary treatment of pulmonary hypertension Pulmonary hypertension is a condition characterized by high pressure in the vessels of the lung. During the last three decades, great progress has been made in the treatment of the disease. This review article describes the current treatment of pulmonary arterial hypertension, based on recommendations from the 7th World Symposium in Pulmonary Hypertension. It incorporates current knowledge on the use of a recently FDA approved medication, i.e. sotatercept, a medication with unique mechanism of action that directly acts on the disease process. It emphasizes the importance of risk stratification and early and aggressive treatment of the disease to improve outcomes. Furthermore it discusses the current treatment of different types of pulmonary hypertension, including pulmonary hypertension associated with left heart disease and parenchymal lung disease.

The prevalence and prognostic implications of hypoxemia either at rest or during six-minute walk test (6MWT) in patients with idiopathic or heritable pulmonary arterial hypertension (IPAH or HPAH) have not been systemically studied. We sought to determine the prevalence, phenotypic and prognostic implications of hypoxemia in patients with IPAH and HPAH. Patients with IPAH or HPAH were identified from the Cleveland Clinic Pulmonary Hypertension Registry. Pulse oximetry (SpO2) at rest and during 6MWT was used to define hypoxemia at rest or during activities when measurements were lower than 90%, respectively. A total of 292 patients (age 50.6 ± 18.0 years, 73% females) with IPAH (88%) and HPAH (12%) were included. Of them, 143 (49%) had SpO2 >90% at rest and during 6MWT, 89 (31%) subjects had hypoxemia during 6MWT and 60 (20%) had hypoxemia at rest. Patients with hypoxemia had older age, greater body mass index, higher prevalence of cardiovascular risk factors, worse functional capacity and pulmonary function tests but less severe pre-capillary pulmonary hypertension. Individuals with hypoxemia either at rest or during the initial 6MWT had worse long-term survival when compared to subjects without hypoxemia, even when adjusting for a great number of potential confounders. (HR: 2.5 (95% CI: 1.54-3.98)). Hypoxemia in patients with IPAH and HPAH is associated with more comorbidities, less severe pre-capillary pulmonary hypertension and worse survival.

Background: Pulmonary hypertension (PH) is a complex disorder associated with various underlying conditions, including cardiac and respiratory diseases. PH is classified into five groups based on etiology, disease mechanisms, hemodynamic data, and treatment options. Preliminary data suggest that sodium-glucose cotransport-2 inhibitors (SGLT2-I), known for their benefits in chronic kidney disease, heart failure, and type-2 diabetes mellitus, may have therapeutic implications in PH through their metabolic effects, which include reducing aerobic glycolysis, improving mitochondrial function, and enhancing fatty acid oxidation. Objective: This study aimed to evaluate the clinical effects of SGLT2-I in PH by analyzing a large multicenter database of medical records from the TriNetX Network. Design: The cohort included adult patients with PH diagnosed between January 1, 2012, and January 1, 2023, classified by PH group and treatment with SGLT2-I. Propensity score matching (PSM) was used to balance baseline characteristics between the SGLT2-I and non-SGLT2-I groups. Methods: The primary endpoint was a composite of all-cause mortality, RHF, and hospital admissions over 365 days. Secondary endpoints included the individual components of the primary endpoint, intubations, RHF incidence, IV diuretic use, and NT-Pro-BNP levels. PSM was used to adjust for baseline differences between cohorts. Results: A total of 771,490 patients with PH were identified, with 58,303 treated with SGLT2-I. After PSM, each cohort of treated and untreated patients included 58,302 patients. Patients treated with SGLT inhibitors had a significant reduction in the primary composite endpoint (HR 0.71, 95% CI: 0.707–0.729). Secondary outcomes, including all-cause mortality, hospitalization, and the number of intubations, were also significantly lower in patients treated with SGLT-2 inhibitors. Beneficial effects of SGLT2-I were observed across all PH groups. Conclusion: This study demonstrates that SGLT2-I may be clinically beneficial in patients with PH by reducing all-cause mortality, RHF, and hospital admissions. Our findings support the role of SGLT2-I as a therapeutic option in PH and provide support for future randomized controlled trials using this treatment.

Pulmonary arterial hypertension (PAH) is a disorder characterized by progressive remodeling of small pulmonary arteries, leading to increased pulmonary vascular resistance, right ventricular failure and premature death (1‐2). Over the past 30 years, significant advancements have been made in the treatment of PAH, including the recent approval of sotatercept, a first‐in‐class fusion protein that acts as a ligand trap for activins and growth differentiation factors, which are key players in the transforming growth factor β (TGF‐β) superfamily (3‐4). Sotatercept improves exercise capacity, as assessed by 6‐min walk distance and World Health Organization (WHO) functional class, reduces pulmonary vascular resistance and NT‐pro brain natriuretic peptide, and improves the simplified French risk score while extending the time to death or nonfatal clinical worsening (3). The 7th World Symposium in pulmonary hypertension recommends the addition of sotatercept as an option in PAH patients who have not achieved low risk despite combination therapy with at least an endothelin receptor antagonist and phosphodiesterase type‐5 inhibitor, in intermediate or high‐risk patients. The STELLAR study of sotatercept in PAH patients demonstrated the efficacy of this medication in patients receiving background therapy (3). In fact, 34% of the patients were on double and 60% of the patients on triple therapy. Interestingly 40% were on prostacyclin infusion therapy (3). Post‐hoc analysis of the stellar study showed a beneficial effect for those on double or triple background PAH therapy as well as those receiving prostacyclin infusion at baseline (1,5). It remains unclear if the addition of sotatercept to other PAH treatments may have unexpected complications. It is possible that by rebalancing the proliferative/antiproliferative effects in the pulmonary circulation, the effect of other treatments for PAH may become excessive, particularly when parenteral prostacyclin is used at high doses. This phenomenon may manifest with the typical characteristics of prostacyclin overdose, including enhanced side effects and high cardiac output heart failure. Hereby we describe a patient with PAH on triple PAH‐specific therapy, who after the initiation of sotatercept developed a large pericardial effusion and high cardiac output heart failure.