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Dual combination therapy with a phosphodiesterase-5 inhibitor (PDE5i) and endothelin receptor antagonist is recommended for most patients with intermediate-risk pulmonary arterial hypertension (PAH). The RESPITE and REPLACE studies suggest that switching from a PDE5i to a soluble guanylate cyclase (sGC) activator may provide clinical improvement in this situation. The optimal approach to escalation or transition of therapy in this or other scenarios is not well defined. We developed an expert consensus statement on the transition to sGC and other treatment escalations and transitions in PAH using a modified Delphi process. The Delphi process used a panel of 20 physicians with expertise in PAH. Panelists answered three questionnaires on the management of treatment escalations and transitions in PAH. The initial questionnaire included open-ended questions. Later questionnaires consolidated the responses into statements that panelists rated on a Likert scale from -5 (strongly disagree) to +5 (strongly agree) to determine consensus. The Delphi process produced several consensus recommendations. Escalation should be considered for patients who are at high risk or not achieving treatment goals, by adding an agent from a new class, switching from oral to parenteral prostacyclins, or increasing the dose. Switching to a new class or within a class should be considered if tolerability or other considerations unrelated to efficacy are affecting adherence. Switching from a PDE5i to an SGC activator may benefit patients with intermediate risk who are not improving on their present therapy. These consensus-based recommendations may be helpful to clinicians and beneficial for patients when evidence-based guidance is unavailable.

Rationale: Single-center studies demonstrated that methamphetamine use is associated with pulmonary arterial hypertension (Meth-APAH). We used the Pulmonary Hypertension Association Registry to evaluate the national distribution of Meth-APAH and to compare its impact on patient-reported and clinical outcomes relative to idiopathic PAH.Objectives: To determine if patients with Meth-APAH differ from those with idiopathic PAH in demographics, regional distribution in the United States, hemodynamics, health-related quality of life, PAH-specific treatment, and health care use.Methods: The Pulmonary Hypertension Association Registry is a U.S.-based prospective cohort of patients new to care at a Pulmonary Hypertension Care Center. The registry collects baseline demographics, clinical parameters, and repeated measures of health-related quality of life, World Health Organization functional class, 6-minute walk distance, therapy, and health care use. Repeated measures of functional class, health-related quality of life, type of therapy, emergency department visits, and hospitalizations were compared using generalized estimating equations.Results: Of 541 participants included, 118 had Meth-APAH; 83% of Meth-APAH arose in the western United States. The Meth-APAH group was younger and had a poorer socioeconomic status and lower cardiac index than the idiopathic PAH group, despite no difference in mean pulmonary artery pressure or pulmonary vascular resistance. The Meth-APAH group had a more advanced functional class in longitudinal models (0.22 points greater; 95% confidence interval [CI], 0.07 to 0.37) and worse PAH-specific (emPHasis-10) health-related quality of life (-5.4; 95% CI, -8.1 to -2.8). There was no difference in dual combination therapy; however, participants with Meth-APAH were less likely to be initiated on triple therapy (odds ratio [OR], 0.43; 95% CI, 0.24 to 0.77) or parenteral therapy (OR, 0.10; 95% CI, 0.04 to 0.24). Participants with Meth-APAH were more likely to seek care in the emergency department (incidence rate ratio, 2.30; 95% CI, 1.71 to 3.11) and more likely to be hospitalized (incidence rate ratio, 1.42; 95% CI, 1.10 to 1.83).Conclusions: Meth-APAH represents a unique clinical phenotype of PAH, most common in the western United States. It accounts for a notable proportion of PAH in expert centers. Assessment for methamphetamine use is necessary in patients with PAH.

BackgroundRight ventricular (RV) adaptation to acute and chronic pulmonary hypertensive syndromes is a significant determinant of short- and long-term outcomes. Although remarkable progress has been made in the understanding of RV function and failure since the meeting of the NIH Working Group on Cellular and Molecular Mechanisms of Right Heart Failure in 2005, significant gaps remain at many levels in the understanding of cellular and molecular mechanisms of RV responses to pressure and volume overload, in the validation of diagnostic modalities, and in the development of evidence-based therapies.MethodsA multidisciplinary working group of 20 international experts from the American Thoracic Society Assemblies on Pulmonary Circulation and Critical Care, as well as external content experts, reviewed the literature, identified important knowledge gaps, and provided recommendations.ResultsThis document reviews the knowledge in the field of RV failure, identifies and prioritizes the most pertinent research gaps, and provides a prioritized pathway for addressing these preclinical and clinical questions. The group identified knowledge gaps and research opportunities in three major topic areas: 1) optimizing the methodology to assess RV function in acute and chronic conditions in preclinical models, human studies, and clinical trials; 2) analyzing advanced RV hemodynamic parameters at rest and in response to exercise; and 3) deciphering the underlying molecular and pathogenic mechanisms of RV function and failure in diverse pulmonary hypertension syndromes.ConclusionsThis statement provides a roadmap to further advance the state of knowledge, with the ultimate goal of developing RV-targeted therapies for patients with RV failure of any etiology.

Background: The Epistaxis Severity Score (ESS) is the gold-standard patient-reported outcome measure for evaluating nosebleed severity in patients with hereditary hemorrhagic telangiectasia (HHT). To date, the ESS has been assessed only for content validity and concurrent validity. Objective: We evaluate the internal consistency and test–retest reliability of the ESS. Materials and Methods: After receiving institutional review board approval, we sent an online survey battery, including the ESS survey, to 305 (39% male) English-speaking HHT patients ≥18 years old at a single center. Of those, 140 (46%) patients completed the battery, and 110/140 (79%) reported epistaxis. Cronbach's alpha and correlation analyses were used to evaluate internal consistency. For the test–retest reliability evaluation, we recruited 69 HHT patients during HHT clinic to complete 2 self-administered ESS surveys 2 weeks apart. Participants also completed a modified Clinical Global Impression-Improvement scale with readministration of the ESS survey. We calculated the intraclass correlation coefficient in a 2-way mixed model with absolute agreement. Results: The ESS survey demonstrated low internal consistency (Cronbach's alpha = 0.495), suggesting that it measured multiple unrelated concepts. Factor analysis revealed 3 latent factors with moderate intercorrelation, suggesting the presence of 3 related but distinct constructs underlying the ESS. However, the ESS demonstrated excellent test–retest reliability (intraclass correlation coefficient = 0.955; 95% CI, 0.91-0.98). Conclusion: Although the ESS demonstrates high test–retest reliability, it may not adequately assess different dimensions of nosebleed severity. Additional correlated survey questions and sub-scores may be needed to increase internal consistency to accurately measure each component of epistaxis severity. It is necessary to acknowledge epistaxis severity from different dimensions and to consider evaluating individual ESS items separately for a comprehensive understanding. [ABSTRACT FROM AUTHOR]

Background: Studies evaluating health-related quality of life (HRQOL) in patients with hereditary hemorrhagic telangiectasia (HHT) have expanded rapidly in the past decade. These studies have evaluated QOL aspects ranging from the general QOL for patients living with HHT to intervention-specific outcomes. However, few tools have been fully validated across the spectrum of disease manifestations and interventions in HHT. Objective: In this scoping review, we aim to map the literature on HHT-QOL metrics, identify gaps, inform future QOL research, and facilitate future metric development. Methods: We analyzed articles in English that assessed at least 1 measure of general HRQOL, including physical health, mental health, social health, or intervention-specific QOL in patients with HHT. Searches across 2 bibliographic databases (PubMed and Scopus) yielded 186 articles after duplicates were removed. Sixty-three studies met eligibility criteria: 22 prospective studies (34.9%), 20 retrospective studies (31.7%), 12 cross-sectional studies (17.5%), 6 randomized controlled trials or secondary analyses of a randomized controlled trials (9.5%), 2 qualitative studies (3.2%), and 1 case-control study (1.6%). Two additional studies—1 prospective and 1 cross-sectional study—were identified at the October 2022 14th International HHT Conference and included, making a total of 65 studies. Results: The 65 eligible studies used 30 QOL instruments. Twenty studies characterized baseline HRQOL, and 45 studies evaluated QOL before and after treatment. Of those 45 studies, 37 evaluated HRQOL before and after therapies targeting epistaxis and nasal symptoms, 4 targeted therapies for liver arteriovenous malformations and high-output heart failure, 3 evaluated therapies for both epistaxis and gastrointestinal bleeding, and 1 evaluated treatment targeting gastrointestinal bleeding alone. Conclusions: Comparison of results across studies remains challenging given the heterogeneity in outcomes measures. Further development of HHT-specific patient-reported outcomes instruments that capture the global illness experience of HHT is needed. [ABSTRACT FROM AUTHOR]

Objective: Patients with connective tissue disease–associated pulmonary arterial hypertension (CTD‐PAH) experience worse survival and derive less benefit from pulmonary vasodilator therapies than patients with idiopathic PAH (IPAH). We sought to identify differential metabolism in patients with CTD‐PAH versus patients with IPAH that might underlie these observed clinical differences. Methods: Adult participants with CTD‐PAH (n = 141) and IPAH (n = 165) from the Pulmonary Vascular Disease Phenomics (PVDOMICS) study were included. Detailed clinical phenotyping was performed at cohort enrollment, including broad‐based global metabolomic profiling of plasma samples. Participants were followed prospectively for ascertainment of outcomes. Supervised and unsupervised machine learning algorithms and regression models were used to compare CTD‐PAH versus IPAH metabolomic profiles and to measure metabolite‐phenotype associations and interactions. Gradients across the pulmonary circulation were assessed using paired mixed venous and wedged samples in a subset of 115 participants. Results: Metabolomic profiles distinguished CTD‐PAH from IPAH, with patients with CTD‐PAH demonstrating aberrant lipid metabolism with lower circulating levels of sex steroid hormones and higher free fatty acids (FAs) and FA intermediates. Acylcholines were taken up by the right ventricular–pulmonary vascular (RV‐PV) circulation, particularly in CTD‐PAH, while free FAs and acylcarnitines were released. In both PAH subtypes, dysregulated lipid metabolites, among others, were associated with hemodynamic and RV measurements and with transplant‐free survival. Conclusions: CTD‐PAH is characterized by aberrant lipid metabolism that may signal shifted metabolic substrate utilization. Abnormalities in RV‐PV FA metabolism may imply a reduced capacity for mitochondrial beta oxidation within the diseased pulmonary circulation. [ABSTRACT FROM AUTHOR]

ObjectivePulmonary arterial hypertension (PAH) affects up to 15% of patients with connective tissue diseases (CTDs). Previous recommendations developed as part of larger efforts in PAH did not include detailed recommendations for patients with CTD-associated PAH. Therefore, we sought to develop recommendations for screening and early detection of CTD-associated PAH.MethodsWe performed a systematic review of the literature on the screening and diagnosis of PAH in CTD. Using the RAND/University of California, Los Angeles consensus methodology, we developed case scenarios followed by 2 stages of voting. First, international experts from a variety of specialties voted anonymously on the appropriateness of each case scenario. The experts then met face-to-face to discuss and resolve discrepant votes to arrive at consensus recommendations.ResultsThe key recommendation stated that all patients with systemic sclerosis (SSc) should be screened for PAH. In addition, patients with mixed connective tissue disease or other CTDs with scleroderma features (scleroderma spectrum disorders) should be screened for PAH. It was recommended that screening pulmonary function tests (PFTs) with single-breath diffusing capacity for carbon monoxide, transthoracic echocardiogram, and measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) be performed in all patients with SSc and scleroderma spectrum disorders. In patients with SSc and scleroderma spectrum disorders, transthoracic echocardiogram and PFTs should be performed annually. The full screening panel (transthoracic echocardiogram, PFTs, and measurement of NT-proBNP) should be performed as soon as any new signs or symptoms are present.ConclusionWe provide consensus-based, evidence-driven recommendations for screening and early detection of CTD-associated PAH. It is our hope that these recommendations will lead to earlier detection of CTD-associated PAH and ultimately improve patient outcomes.