Enhanced chronic inflammation and increased branched chain amino acids in adrenal disorders: a cross-sectional study.

CONTEXT: Patients with adrenal hormone excess demonstrate increased cardiovascular risk and mortality. OBJECTIVE: We aimed to determine the impact of adrenal disorders on the inflammation marker GlycA, total branched-chain amino acids (BCAA), ketone bodies and the gut microbiome-derived metabolites trimethylamine N-oxide (TMAO) and betaine. METHODS: We conducted a single-center cross-sectional study of patients with nonfunctioning adenomas (NFA), mild autonomous cortisol secretion (MACS), primary aldosteronism (PA), Cushing syndrome (CS), pheochromocytoma/paragangliomas (PPGL), other benign or malignant adrenal masses, and adrenocortical carcinoma (ACC) between January 2015 and July 2022 (n=802). Referent subjects included participants of the PREVEND (Prevention of Renal and Vascular End-stage Disease) study (n=5241). GlycA, BCAA, ketone bodies, TMAO, and betaine were measured using nuclear magnetic resonance spectroscopy. Multivariable logistic analyses were adjusted for age, sex, BMI, smoking, hypertension, diabetes mellitus and statin therapy. RESULTS: In age-and sex-adjusted comparison to referent subjects, increased GlycA was noted in all patient categories, increased BCAA in NFA, MACS, CS, PA and ACC, increased TMAO in patients with other malignant adrenal masses, increased betaine in NFA and MACS, and increased ketone bodies in NFA, CS and ACC. Essentially similar findings were observed in fully adjusted analysis and after exclusion of subjects with diabetes and cardiovascular disease. CONCLUSION: Patients with functioning and non-functioning adrenal masses demonstrated increased GlycA and BCAA, biomarkers associated with adverse cardiometabolic disorders and mortality. Patients with NFA demonstrated an adverse metabolic profile similar to patients with MACS and CS.

Cell-free, high-density lipoprotein-specific phospholipid efflux assay predicts incident cardiovascular disease.

BACKGROUNDCellular cholesterol efflux capacity (CEC) is a better predictor of cardiovascular disease (CVD) events than HDL-cholesterol (HDL-C) but is not suitable as a routine clinical assay.METHODSWe developed an HDL-specific phospholipid efflux (HDL-SPE) assay to assess HDL functionality based on whole plasma HDL apolipoprotein-mediated solubilization of fluorescent phosphatidylethanolamine from artificial lipid donor particles. We first assessed the association of HDL-SPE with prevalent coronary artery disease (CAD): study I included NIH severe-CAD (n = 50) and non-CAD (n = 50) participants, who were frequency matched for sex, BMI, type 2 diabetes mellitus, and smoking; study II included Japanese CAD (n = 70) and non-CAD (n = 154) participants. We also examined the association of HDL-SPE with incident CVD events in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study comparing 340 patients with 340 controls individually matched for age, sex, smoking, and HDL-C levels.RESULTSReceiver operating characteristic curves revealed stronger associations of HDL-SPE with prevalent CAD. The AUCs in study I were as follows: HDL-SPE, 0.68; apolipoprotein A-I (apoA-I), 0.62; HDL-C, 0.63; and CEC, 0.52. The AUCs in study II were as follows: HDL-SPE, 0.83; apoA-I, 0.64; and HDL-C, 0.53. Also longitudinally, HDL-SPE was significantly associated with incident CVD events independent of traditional risk factors with ORs below 0.2 per SD increment in the PREVEND study (P < 0.001).CONCLUSIONHDL-SPE could serve as a routine clinical assay for improving CVD risk assessment and drug discovery.TRIAL REGISTRATIONClinicalTrials.gov NCT01621594.FUNDINGNHLBI Intramural Research Program, NIH (HL006095-06).

Adiposity and the development of dyslipidemia in APOE ε2 homozygous subjects: A longitudinal analysis in two population-based cohorts.

BACKGROUND AND AIMS: Familial dysbetalipoproteinemia (FD), characterized by remnant lipoprotein accumulation and premature cardiovascular disease, occurs in homozygous carriers of the APOE ε2 allele, but genetic predisposition alone does not suffice for the clinical phenotype. Cross-sectional studies suggest that a second metabolic hit - notably adiposity or insulin resistance - is required, but the association between these risk factors and development of FD has not been studied prospectively. METHODS: For this study, we evaluated 18,987 subjects from two large prospective Dutch population-based cohorts (PREVEND and Rotterdam Study) of whom 118 were homozygous APOE ε2 carriers. Of these, 69 subjects were available for prospective analyses. Dyslipidemia - likely to be FD - was defined as fasting triglyceride (TG) levels >3 mmol/L in untreated subjects or use of lipid lowering medication. The effect of weight, body mass index (BMI), waist circumference, type 2 diabetes mellitus and non-TG metabolic syndrome on development of dyslipidemia was investigated. RESULTS: Eleven of the 69 ε2ε2 subjects (16%) developed dyslipidemia - likely FD - during follow-up. Age-, sex- and cohort-adjusted risk factors for the development of FD were BMI (OR 1.19; 95%CI 1.04-1.39), waist circumference (OR 1.26 95%CI 1.01-1.61) and presence of non-TG metabolic syndrome (OR 4.39; 95%CI 1.04-18.4) at baseline. Change in adiposity during follow-up was not associated with development of dyslipidemia. CONCLUSIONS: Adiposity increases the risk of developing an FD-like lipid phenotype in homozygous APOE ε2 subjects. These results stress the importance of healthy body weight in subjects at risk of developing FD.

GlycA, a novel proinflammatory glycoprotein biomarker, and high-sensitivity C-reactive protein are inversely associated with sodium intake after controlling for adiposity: the Prevention of Renal and Vascular End-Stage Disease study.

BACKGROUND: The extent to which dietary sodium intake may confer alterations in the inflammatory status is unclear. GlycA is a novel proton nuclear magnetic resonance spectroscopy-measured biomarker of systemic inflammation, which is associated with the development of cardiovascular disease and diabetes. OBJECTIVE: We determined associations of the inflammatory markers GlycA and high-sensitivity C-reactive protein (hsCRP) with 24-h sodium excretion. DESIGN: A cross-sectional, population-based study was performed in 3935 subjects who were not using an antihypertensive medication, lipid-lowering drugs, or a glucose-lowering treatment. Urinary sodium excretion was calculated as the mean of two 24-h urine excretions. Linear regression models were used, with 24-h sodium excretion as an independent variable and GlycA or ln hsCRP as a dependent variable. RESULTS: The mean ± SD sodium excretion was 143.0 ± 53.4 mmol/24 h. The GlycA concentration was 343.6 ± 58.7 µmol/L, and the geometric mean of the hsCRP concentration was 1.20 mg/L (95% CI: 1.16, 1.25 mg/L). In age- and sex-adjusted analyses, GlycA and ln hsCRP were not significantly associated with 24-h sodium excretion [B: 1.23 (95% CI: -0.67, 3.13; P = 0.21) and 0.03 (95% CI: -0.004, 0.07; P = 0.08), respectively, per 1-SD increase]. After additional adjustment for body mass index (BMI), both GlycA (B: -2.76; 95% CI: -4.65, -0.86; P = 0.004) and ln hsCRP (B: -0.07; 95% CI: -0.11, -0.04; P < 0.001) were inversely associated with 24-h sodium excretion. These associations were similar if adjustment was performed for waist circumference instead of BMI or if additional adjustment was performed for relevant clinical and laboratory variables and were particularly present in men. CONCLUSIONS: The proinflammatory biomarkers GlycA and hsCRP are inversely related to higher 24-h sodium excretion when taking into account the variation in adiposity. These inverse relations remain present after taking into account other covariates.

Atorvastatin affects low density lipoprotein and non-high density lipoprotein cholesterol relations with apolipoprotein B in type 2 diabetes mellitus: modification by triglycerides and cholesteryl ester transfer protein.

OBJECTIVES: Non-HDL-cholesterol (non-HDL-C) and apolipoprotein (apo) B are proposed as treatment targets. The extent to which statin therapy affects relationships of LDL-C and non-HDL-C with apoB was examined in type 2 diabetes. METHODS: Analyses were performed in 217 hypertriglyceridaemic type 2 diabetic patients (Diabetes Atorvastatin Lipid Intervention (DALI) cohort). 61 patients randomized to placebo, 70 to 10 mg atorvastatin daily and 65 - 80 mg atorvastin daily completed follow-up. RESULTS: Baseline fasting LDL-C of 2.42 mmol/l and non-HDL-C of 3.69 mmol/l corresponded to the apoB guideline target of 0.90 g/l. During atorvastatin (10 and 80 mg daily), the LDL-C target was achieved most frequently, and lower LDL-C (2.38 and 2.29 mmol/l) and non-HDL-C (3.24 and 3.19 mmol/l) concentrations corresponded to this apoB goal. Decreases in LDL-C during atorvastatin treatment were negatively related (p < 0.001), but decreases in non-HDL-C were positively related to changes in triglycerides (p < 0.001), independently from decreases in apoB (p < 0.001 for all). Decreases in LDL-C and non-HDL-C were positively associated with decreases in cholesteryl ester transfer protein mass (p < 0.001). CONCLUSIONS: During atorvastatin lower LDL-C and non-HDL-C levels correspond to the apoB guideline target, which would favour its use as treatment target.