Novel Liver Injury Phenotypes and Outcomes in Clinical Trial Participants with Pulmonary Hypertension.

RATIONALE: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) cause right ventricular dysfunction which can impact other solid organs. However, the profiles and consequences of hepatic injury due to PAH and CTEPH have not been well-studied. OBJECTIVES: We aimed to identify underlying patterns of liver injury in a cohort of PAH and CTEPH patients enrolled in 15 randomized clinical trials conducted between 1998 and 2014. METHODS: We used unsupervised machine learning to identify liver injury clusters in 13 trials and validated the findings in two additional trials. We then determined whether these liver injury clusters were associated with clinical outcomes or treatment effect heterogeneity. MEASUREMENTS AND MAIN RESULTS: Our training dataset included 4,219 patients and our validation dataset included 1,756 patients with serum total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and albumin data. Using k-means clustering, we identified phenotypes with no liver injury, hepatocellular injury, cholestatic injury, and combined injury patterns. Patients in the cholestatic injury liver cluster had the shortest time to clinical worsening and the highest risk of mortality. The cholestatic injury group also experienced the greatest placebo-corrected treatment effect on six-minute walk distance. Randomization to the experimental arm transitioned patients to a healthier liver status. CONCLUSIONS: Liver injury was associated with adverse outcomes in patients with PAH and CTEPH. Randomization to active treatment had beneficial effects on liver health compared to placebo. The role of liver disease (often subclinical) in determining outcomes warrants prospective studies.

Pulmonary arterial hypertension treatment: an individual participant data network meta-analysis.

BACKGROUND AND AIMS: Effective therapies that target three main signalling pathways are approved to treat pulmonary arterial hypertension (PAH). However, there are few large patient-level studies that compare the effectiveness of these pathways. The aim of this analysis was to compare the effectiveness of the treatment pathways in PAH and to assess treatment heterogeneity. METHODS: A network meta-analysis was performed using individual participant data of 6811 PAH patients from 20 Phase III randomized clinical trials of therapy for PAH that were submitted to the US Food and Drug Administration. Individual drugs were grouped by the following treatment pathways: endothelin, nitric oxide, and prostacyclin pathways. RESULTS: The mean (±standard deviation) age of the sample was 49.2 (±15.4) years; 78.4% were female, 59.7% had idiopathic PAH, and 36.5% were on background PAH therapy. After covariate adjustment, targeting the endothelin + nitric oxide pathway {ß: 43.7 m [95% confidence interval (CI): 32.9, 54.4]}, nitric oxide pathway [ß: 29.4 m (95% CI: 22.6, 36.3)], endothelin pathway [ß: 25.3 m (95% CI: 19.8, 30.8)], and prostacyclin pathway [oral/inhaled ß: 19.1 m (95% CI: 14.2, 24.0), intravenous/subcutaneous ß: 24.4 m (95% CI: 15.1, 33.7)] significantly increased 6 min walk distance at 12 or 16 weeks compared with placebo. Treatments also significantly reduced the likelihood of having clinical worsening events. There was significant heterogeneity of treatment effects by age, body mass index, hypertension, diabetes, and coronary artery disease. CONCLUSIONS: Drugs targeting the three traditional treatment pathways significantly improve outcomes in PAH, with significant treatment heterogeneity in patients with some comorbidities. Randomized clinical trials are warranted to identify the most effective treatment strategies in a personalized approach.

Extrapulmonary manifestations of pulmonary arterial hypertension.

INTRODUCTION: Extrapulmonary manifestations of pulmonary arterial hypertension (PAH) may play a critical pathobiological role and a deeper understanding will advance insight into mechanisms and novel therapeutic targets. This manuscript reviews our understanding of extrapulmonary manifestations of PAH. AREAS COVERED: A group of experts was assembled and a complimentary PubMed search performed (October 2023 - March 2024). Inflammation is observed throughout the central nervous system and attempts at manipulation are an encouraging step toward novel therapeutics. Retinal vascular imaging holds promise as a noninvasive method of detecting early disease and monitoring treatment responses. PAH patients have gut flora alterations and dysbiosis likely plays a role in systemic inflammation. Despite inconsistent observations, the roles of obesity, insulin resistance and dysregulated metabolism may be illuminated by deep phenotyping of body composition. Skeletal muscle dysfunction is perpetuated by metabolic dysfunction, inflammation, and hypoperfusion, but exercise training shows benefit. Renal, hepatic, and bone marrow abnormalities are observed in PAH and may represent both end-organ damage and disease modifiers. EXPERT OPINION: Insights into systemic manifestations of PAH will illuminate disease mechanisms and novel therapeutic targets. Additional study is needed to understand whether extrapulmonary manifestations are a cause or effect of PAH and how manipulation may affect outcomes.

Nonlinear associations between computed tomography-measures of adiposity and long pentraxin-3 in the Multi-Ethnic Study of Atherosclerosis.

Objective: Long pentraxin-3 (PTX-3) is an acute phase protein associated with cardiovascular disease, lung injury, and mortality. We evaluated the association between computed tomography (CT)-measurements of adipose tissue and plasma levels of PTX-3. Methods: We performed a cross-sectional analysis of community-dwelling adults enrolled in the multi-center Multiethnic Study of Atherosclerosis who underwent cardiac or abdominal CT and had available PTX-3 measurements. Results: There was a U-shaped association between pericardial adipose tissue volume (PAT), abdominal visceral adipose tissue area (VAT), hepatic attenuation, and PTX-3 levels, with extremes of adiposity associated with greater PTX-3 levels. Using multivariable-adjusted piecewise regression models, among participants with low PAT, every 1% increase in PAT volume was associated with a 13.8% decrease in PTX-3 (95% confidence interval [CI] -21.6 to -6.0); among participants with high PAT, every 1% increase in PAT volume was associated with a 6.0% increase in PTX-3 (95% CI -0.4 to 12.5). Results were similar for abdominal VAT and hepatic attenuation. Conclusions: In a cohort of community-dwelling adults, we demonstrated a "U-shaped" association between pericardial, abdominal visceral, and hepatic adiposity with PTX3 levels, suggesting that extreme adiposity is associated with greater circulating levels of PTX3. Further work is required to identify the mechanisms linking adiposity and PTX-3.

Electrocardiographic Abnormalities and Their Association with Outcomes in Randomized Clinical Trials of Pulmonary Arterial Hypertension.

Rationale: Pulmonary arterial hypertension (PAH) is a progressive disease with manifestations including right atrial enlargement, right ventricular dysfunction, dilation, and hypertrophy. Electrocardiography (ECG) is a noninvasive, inexpensive test that is routinely performed in clinical settings. Prior studies have described separate abnormal findings in the electrocardiograms of patients with PAH. However, the role of composite ECG findings reflective of right heart disease (RHD) for risk stratification, clinical trial enrichment, and management of patients with PAH has not been explored. Objectives: To describe a pattern of RHD on ECG in patients with PAH and to investigate the association of this pattern with clinical measures of disease severity and outcomes. Methods: We harmonized individual participant data from 18 phase III randomized clinical trials of therapies for PAH (1998-2013) submitted to the U.S. Food and Drug Administration. RHD was defined as the presence of right ventricular hypertrophy, right axis deviation, right atrial enlargement, or right bundle branch block on ECG. Random effects linear regression, multilevel ordinal regression (cumulative link model), and Cox proportional hazards models were used to assess the association of RHD by ECG with 6-minute walk distance (6MWD), World Health Organization (WHO) functional class, and clinical worsening after a priori adjustment for age, sex, body mass index, and PAH etiology. Effect modification of treatment and ECG abnormalities was assessed by including an interaction term. Results: A total of 4,439 patients had baseline ECG, and 68% of patients had evidence of RHD. RHD on ECG was associated with higher pulmonary vascular resistance (P < 0.001) and higher mean pulmonary artery pressures (P < 0.001). Patients with RHD on ECG had 10 meters shorter 6MWD (P = 0.005) and worse WHO functional class (P < 0.001) at baseline. RHD on baseline ECG was associated with increased risk of clinical worsening (hazard ratio, 1.42; 95% confidence interval; 1.21, 1.67; P < 0.001). Patients with RHD had greater treatment effect in terms of 6MWD, WHO functional class, and time to clinical worsening than those without (P for interaction = 0.03, 0.001, and 0.03, respectively). Conclusions: RHD by ECG may be associated with worse outcomes and potentially greater treatment effect. Electrocardiograms could be an inexpensive, widely available noninvasive method to enrich clinical trial populations in PAH.