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.

Novel Liver Injury Phenotypes and Outcomes in Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are disorders of the pulmonary vasculature that cause right ventricular dysfunction. Systemic consequences of right ventricular dysfunction include damage to other solid organs, such as the liver. However, the profiles and consequences of hepatic injury due to PAH and CTEPH have not been well-studied. Methods: 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 2012. 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. Results: Our training dataset included 4,219 patients and our validation dataset included 1,756 patients with complete liver laboratory panels (serum total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and albumin). Using k-means clustering paired with factor analysis, we identified four unique liver phenotypes (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 highest chance of worsening World Health Organization functional class. Randomization to the experimental arm was associated with a transition to healthier liver clusters compared to randomization to the control arm. The cholestatic injury group experienced the greatest placebo-corrected treatment benefit in terms of six-minute walk distance. Conclusions: Liver injury patterns were associated with adverse outcomes in patients with PAH and CTEPH. Randomization to active treatment of pulmonary hypertension in these clinical trials had beneficial effects on liver health compared to placebo. The independent role of liver disease (often subclinical) in determining outcomes warrants prospective studies of the clinical utility of liver phenotyping for PAH prognosis and contribution to clinical disease.

CKD, plasma lipids, and common carotid intima-media thickness: results from the multi-ethnic study of atherosclerosis.

BACKGROUND AND OBJECTIVES: Altered levels of atherogenic lipoproteins have been shown to be common in mild kidney dysfunction. This study sought to determine the associations between plasma lipids (including LDL particle distribution) and subclinical atherosclerosis measured by the common carotid intima-media thickness (IMT) across levels of estimated GFR (eGFR) and to assess whether inflammation modifies these associations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Cross-sectional analyses of 6572 participants in the Multi-Ethnic Study of Atherosclerosis enrolled from 2000 to 2002 were performed. RESULTS: CKD, defined as eGFR <60 ml/min per 1.73 m(2), was present in 853 individuals (13.0%). Associations of total cholesterol and LDL cholesterol (LDL-C) with IMT were J shaped, particularly among participants with CKD (P value for interaction, P=0.01). HDL cholesterol (HDL-C) and small-dense LDL-C were consistently and linearly associated with IMT across levels of eGFR. The results showed differences in IMT of -21.41 (95% confidence interval, -41.00, -1.57) in eGFR ≥60 and -58.49 (-126.61, 9.63) in eGFR <60 per unit difference in log-transformed HDL-C, and 4.83 (3.16, 6.50) in eGFR ≥60 and 7.48 (1.45, 13.50) in eGFR <60 per 100 nmol/L difference in small-dense LDL. Among participants with CKD, inflammation significantly modified the associations of total cholesterol and LDL-C with IMT (P values for interaction, P<0.01 and P<0.001, respectively). CONCLUSIONS: Compared with total cholesterol and LDL-C, abnormalities in HDL-C and small-dense LDL-C are more strongly and consistently associated with subclinical atherosclerosis in CKD. Inflammation modifies the association between total cholesterol and LDL-C with IMT.