Longitudinal Changes in Circulating Ketone Body Levels in Patients With Acute Heart Failure: A Post Hoc Analysis of the EMPA-Response-AHF Trial.

BACKGROUND: Ketone bodies are endogenous fuels produced by the liver under conditions of metabolic or neurohormonal stress. Circulating ketone bodies are increased in patients with chronic heart failure (HF), yet little is known about the effect of acute HF on ketosis. We tested the hypothesis that ketogenesis is increased in patients with acute decompensated HF. METHODS AND RESULTS: This was a post hoc analysis of 79 patients with acute HF included in the EMPA-RESPONSE-AHF trial, which compared sodium-dependent glucose-cotransporter protein 2 inhibitor treatment with empagliflozin for 30 days with placebo in patients with acute HF [NCT03200860]. Plasma concentrations of ketone bodies acetone, ß-hydroxybutyrate, and acetoacetate were measured at baseline and 5 different timepoints. Changes in ketone bodies over time were monitored using repeated measures analysis of variance. In the total cohort, median total ketone body concentration was 251 µmol/L (interquartile range, 178-377 µmol/L) at baseline, which gradually decreased to 202 µmol/L (interquartile range, 156-240 µmol/L) at day 30 (P = .041). Acetone decreased from 60 µmol/L (interquartile range, 34-94 µmol/L) at baseline to 30 µmol/L (interquartile range, 21-42 µmol/L) ( P < .001), whereas ß-hydroxybutyrate and acetoacetate remained stable over time. Higher acetone concentrations were correlated with higher N-terminal pro brain natriuretic peptide levels (r = 0.234; P = .039). Circulating ketone bodies did not differ between patients treated with empagliflozin or placebo throughout the study period. A higher acetone concentration at baseline was univariately associated with a greater risk of the composite end point, including in-hospital worsening HF, HF rehospitalizations, and all-cause mortality after 30 days. However, after adjustment for age and sex, acetone did not remain an independent predictor for the combined end point. CONCLUSIONS: Circulating ketone body concentrations, and acetone in particular, were significantly higher during an episode of acute decompensated HF compared with after stabilization. Treatment with empagliflozin did not affect ketone body concentrations in patients with acute HF.

GlycA, a novel pro-inflammatory glycoprotein biomarker is associated with mortality: results from the PREVEND study and meta-analysis.

BACKGROUND: Chronic diseases are associated with an inflammatory response. We determined the association of two inflammatory markers, GlycA and high-sensitivity C-reactive protein (hsCRP), with overall and cause-specific mortality in a cohort of men and women. METHODS: Cox regression analyses were used to examine associations of GlycA and hsCRP with all-cause, cancer and cardiovascular mortality in 5526 subjects (PREVEND cohort; average follow-up 12.6 years). RESULTS: GlycA was associated with all-cause mortality (n = 838), independent of clinical risk factors and hsCRP (hazard ratio 1.43 [95% confidence interval (CI): 1.09-1.87] for top versus bottom quartiles). For hsCRP, the association with all-cause mortality was nonsignificant after adjustment for GlycA. GlycA and hsCRP were associated with cancer mortality in men (n = 248), but not in women (n = 132). Neither GlycA nor hsCRP was independently associated with cardiovascular mortality (n = 201). In a meta-analysis of seven population-based studies, including 8153 deaths, the pooled multivariable-adjusted relative risk of GlycA for all-cause mortality was 1.74 (95% CI: 1.40-2.17) for top versus bottom quartiles. The association of GlycA with all-cause mortality was somewhat stronger than that of hsCRP. GlycA and hsCRP were not independently associated with cardiovascular mortality. The associations of GlycA and hsCRP with cancer mortality were present in men, but not in women. CONCLUSIONS: GlycA is significantly associated with all-cause mortality. GlycA and hsCRP were each not independently associated with cardiovascular mortality. The association of GlycA and hsCRP with cancer mortality appears to be driven by men.

Tumor Necrosis Factor-α is Inversely Related to Free Thyroxine in Euthyroid Subjects Without Diabetes.

Lower thyroid functional status within the euthyroid range may confer increased atherosclerosis susceptibility, as evidenced by increased intima media thickness and coronary artery calcification. Associations of lower thyroid functional status with pro-atherogenic (inflammatory) biomarkers may also extend into the euthyroid range. Here we established relationships of plasma tumor necrosis factor-α (TNF-α) with thyroid stimulating hormone (TSH) and free thyroxine (free T4) in euthyroid subjects with and without Type 2 diabetes mellitus (T2DM). Fasting TSH, free T4, and TNF-α were measured in 81 nondiabetic subjects and in 73 T2DM subjects with Type 2 diabetes mellitus (T2DM; insulin using subjects were excluded) with TSH and free T4 levels each within the institutional reference ranges. TSH was similar and free T4 was slightly higher in T2DM (p<0.016). Plasma TNF-α was increased in T2DM (p=0.007). In nondiabetic subjects, TNF-α was correlated inversely with free T4 (r=-0.254, p=0.022), whereas such a relationship was absent in T2DM subjects (r=0.058, p=0.63). Multivariable linear regression analysis showed that in nondiabetic subjects TNF-α remained inversely associated with free T4 after adjustment for age and sex (ß=-0.243, p=0.032) and additionally for thyroid autoantibodies (ß=-0.251, p=0.027), contrasting the lack of relationship in T2DM subjects (interaction: p=0.053). In T2DM subjects, TNF-α was also unrelated to free T4 taking account of possible confounders, as well as after exclusion of subjects using metformin or antihypertensive medication. In conclusion, higher levels of TNF-α relate to lower free T4. Low-normal thyroid function could influence pro-inflammatory pathways. This relationship appears to be disturbed in T2DM.

Plasma phospholipid transfer protein activity is inversely associated with betaine in diabetic and non-diabetic subjects.

BACKGROUND: The choline metabolite, betaine, plays a role in lipid metabolism, and may predict the development of cardiovascular disease and type 2 diabetes mellitus (T2DM). Phospholipid transfer protein (PLTP) and lecithin:cholesterol acyltransferase (LCAT) require phosphatidylcholine as substrate, raising the possibility that there is an intricate relationship of these protein factors with choline metabolism. Here we determined the relationships of PLTP and LCAT activity with betaine in subjects with and without T2DM. METHODS: Plasma betaine (nuclear magnetic resonance spectroscopy), PLTP activity (liposome-vesicle HDL system), LCAT activity (exogenous substrate assay) and (apo)lipoproteins were measured in 65 type 2 diabetic (T2DM) and in 55 non-diabetic subjects. RESULTS: PLTP and LCAT activity were elevated in T2DM (p < 0.05), whereas the difference in betaine was not significant. In age-, sex- and diabetes status-controlled correlation analysis, betaine was inversely correlated with triglycerides and positively with HDL cholesterol (p < 0.05 to 0.01). PLTP and LCAT activity were positively correlated with triglycerides and inversely with HDL cholesterol (p < 0.05 to 0.001). PLTP (r = -0.245, p = 0.006) and LCAT activity (r = -0.195, p = 0.035) were correlated inversely with betaine. The inverse association of PLTP activity with betaine remained significant after additional adjustment for body mass index and lipoprotein variables (ß = -0.179, p = 0.034), whereas its association with LCAT activity lost significance (ß = -0.056, p = 0.44). CONCLUSIONS: Betaine may influence lipoprotein metabolism via an effect on PLTP activity.

Higher Plasma ApoE Levels are Associated with Low-Normal Thyroid Function: Studies in Diabetic and Nondiabetic Subjects.

Low-normal thyroid function within the euthyroid range may confer higher plasma triglycerides, but relationships with plasma apolipoprotein (apo) E, which plays an important role in the metabolism of triglyceride-rich apoB-containing lipoproteins, are unknown. We determined relationships of plasma apoE with thyroid stimulating hormone (TSH) and free thyroxine (free T4) in euthyroid subjects with and without Type 2 diabetes mellitus (T2DM). TSH, free T4, lipids, and apoE were measured in fasting plasma from 72 T2DM subjects and 82 nondiabetic subjects. The APOE genotype was also determined. Free T4 was slightly higher in T2DM (p=0.030), but TSH levels were not different vs. nondiabetic subjects. The APOE genotype distribution was not different between the groups. None of the participants had the ε2/ε2 genotype. Plasma triglycerides were higher in T2DM (p=0.037). ApoB and apoE levels were not different between the groups. In all subjects combined, multivariable analysis showed that plasma triglycerides (p=0.039), non-high density lipoprotein (non-HDL) cholesterol (p=0.030), and apoE levels (p=0.002) were each independently and positively associated with TSH after adjustment for age, sex, T2DM and the presence of the APOE ε3 allele. Furthermore, the associations of TSH with apoE remained present after adjustment for either triglycerides, non-HDL cholesterol, or apoB (p=0.005 to 0.023). The presence of T2DM did not modify the relationships of TSH with these (apo) lipoprotein variables (p=0.11 to 0.36). In conclusion, low-normal thyroid function, as indicated by higher TSH levels within the euthyroid range, may influence the metabolism of triglyceride-rich lipoproteins by affecting apoE regulation.

Vascular risk factors, vascular disease, lipids and lipid targets in patients with familial dysbetalipoproteinemia: a European cross-sectional study.

BACKGROUND: Familial dysbetalipoproteinemia (FD), also known as type III hyperlipoproteinemia, is a genetic dyslipidemia characterized by elevated very low density lipoprotein (VLDL) and chylomicron remnant particles that confers increased risk of cardiovascular disease (CVD). The objective of this study was to evaluate the prevalence of vascular risk factors, CVD, lipid values, treatment and lipid targets in patients with FD across Europe. METHODS: This cross-sectional study was performed in 305 patients with FD from seven academic hospitals in four European countries. Information was collected from clinical records. RESULTS: Patients mean (±standard deviation) age was 60.9±14.4 years, 201 (66%) were male, 69 (23%) had diabetes mellitus (DM) and 87 (29%) had a prior history of CVD. Mean body mass index was 28.5±5.0 kg/m2. Lipid-lowering medication was used by 227 (74%) patients (27% usual dose (theoretical low-density lipoprotein cholesterol (LDL-C) reduction≤40%) and 46% intensive dose (theoretical LDL-C reduction>40%)). Non high-density lipoprotein cholesterol (non-HDL-C) levels below treatment target (<3.3 mmol/L) were present in 123 (40%) patients and 163 patients (53%) had LDL-C levels below target (<2.5 mmol/L). No significant determinants were found for having non-HDL-C levels below target, while a prior history of CVD (OR 1.90, 95%CI 1.05-3.47) and presence of DM (OR 2.00, 95%CI 1.08-3.70) were associated with having LDL-C levels below treatment target. CONCLUSION: The majority of FD patients had non-HDL-C levels above the treatment target of 3.3 mmol/L. Intensive dose lipid-lowering medication was used by only half of the patients, leaving them at increased cardiovascular risk.

Hepatic syndecan-1 changes associate with dyslipidemia after renal transplantation.

Syndecan-1 is a transmembrane heparan sulfate (HS) proteoglycan present on hepatocytes and involved in uptake of triglyceride-rich lipoproteins via its HS polysaccharide side chains. We hypothesized that altered hepatic syndecan-1 metabolism could be involved in dyslipidemia related to renal transplantation. In a rat renal transplantation model elevated plasma triglycerides were associated with fivefold increased expression of hepatic syndecan-1 mRNA (p < 0.01), but not protein. Expression of syndecan-1 sheddases (ADAM17, MMP9) and heparanase was significantly up-regulated after renal transplantation (all p < 0.05). Profiling of HS side chains revealed loss of hepatic HS upon renal transplantation accompanied by significant decreased functional capacity for VLDL binding (p = 0.02). In a human renal transplantation cohort (n = 510), plasma levels of shed syndecan-1 were measured. Multivariate analysis showed plasma syndecan-1 to be independently associated with triglycerides (p < 0.0001) and inversely with HDL cholesterol (p < 0.0001). Last, we show a physical association of syndecan-1 to HDL from renal transplant recipients (RTRs), but not to HDL from healthy controls. Our data suggest that after renal transplantation loss of hepatic HS together with increased syndecan-1 shedding hampers lipoprotein binding and uptake by the liver contributing to dyslipidemia. Our data open perspectives toward improvement of lipid profiles by targeted inhibition of syndecan-1 catabolism in renal transplantation.

A liquid chromatography tandem mass spectrometry assay for plasma renin activity using online solid-phase extraction.

BACKGROUND: The plasma renin activity (PRA) assay measures the ability of renin to generate angiotensin I (AngI) from angiotensinogen. It is used to monitor mineralocorticoid therapy and to screen hypertensive individuals for primary aldosteronism (PA). METHODS: Samples were incubated in the presence of protease inhibitors for 6.5 and 24 h. The reaction was stopped by the addition of 2% ammonium hydroxide. AngI was then quantified by liquid chromatography tandem mass spectrometry using online solid-phase extraction (XLC-MS/MS). RESULTS: This method requires a sample volume of 50 µL and has an inter-assay precision <14% across the working range. A 6.5-h incubation gave a lower limit of quantification (LLOQ) of 0.3 nmol/L/h and this can be reduced to 0.08 nmol/L/h using a 24-h incubation. Comparison to a radioimmunoassay revealed excellent correlation (r(2) = 0.98), but a 37% negative bias. We also found that renin is stable in whole blood for up to 24 h at room temperature. In contrast, storage at 4°C should be avoided as prorenin cryoactivation can affect the PRA result in some patient groups. CONCLUSIONS: We have developed and fully validated a semi-automated XLC-MS/MS method for the measurement of PRA. In addition, a reference range specific to this assay has been defined. We have also demonstrated that renin is stable for up to 24 h at room temperature. This will enable this assay to be extended to samples taken in primary care, potentially increasing the number of hypertensive patients who can be screened for PA.

Type 2 diabetes mellitus interacts with obesity and common variations in PLTP to affect plasma phospholipid transfer protein activity.

BACKGROUND: Phospholipid transfer protein (PLTP) is an emerging cardiometabolic risk marker that is important in high-density lipoprotein (HDL) and triglyceride metabolism. Plasma PLTP activity is elevated in type 2 diabetes mellitus, whereas glucose may regulate PLTP gene transcription in vitro. Of interest, common PLTP variations that predict cardiovascular disease have been identified recently. We investigated whether the diabetic state is able to amplify relationships between obesity and PLTP gene variations with circulating PLTP levels. SUBJECTS AND METHODS: Plasma PLTP activity (using a phospholipid vesicles-HDL system), PLTP gene score [number of PLTP activity-decreasing alleles based on two tagging polymorphisms (rs378114 and rs60- 65904)] and waist circumference were determined in two Dutch cohorts comprising 237 patients with type 2 diabetes and 78 control subjects. RESULTS: Patients with diabetes were more obese (P < 0.001 for prevalence of increased waist circumference) and had 13% higher plasma PLTP activity (P < 0.001). PLTP gene score was not different in diabetic and control subjects (P = 0.40). PLTP activity was highest in patients with diabetes with an enlarged waist and lowest in control subjects with a normal waist circumference (P < 0.001). Multiple linear regression analysis revealed a positive interaction between diabetes status and waist circumference on PLTP activity (ß = 0.200, P = 0.005). Furthermore, diabetes status (ß = -0.485, P = 0.046) or HbA1c (ß = -0.240, P = 0.035) interacted with PLTP gene score to affect PLTP activity. CONCLUSIONS: Type 2 diabetes and enlarged waist circumference interact to impact on plasma PLTP activity. Diabetes may also amplify the association between plasma PLTP activity and common PLTP gene variations. Our findings support the hypothesis that diabetes-environment and diabetes-gene interactions govern plasma PLTP activity.

Short term dietary sodium restriction decreases HDL cholesterol, apolipoprotein A-I and high molecular weight adiponectin in healthy young men: relationships with renal hemodynamics and RAAS activation.

BACKGROUND AND AIMS: We aimed to determine the effect of short-term dietary sodium restriction on plasma total cholesterol, LDL-C, HDL-C, triglycerides, apolipoprotein (apo) A-I, apo B and high molecular weight (HMW) adiponectin in non-obese, normotensive young men. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), plasma renin activity (PRA) and aldosterone were also measured. METHODS AND RESULTS: Sixty-five men, aged 23 ± 7 years, were randomly studied on a high sodium intake (HS, 228 ± 77 mmol Na+/24 h) and a low sodium intake (LS, 36 ± 27 mmol Na+/24 h), each period lasting 1 week. LS decreased GFR and ERPF and increased PRA and aldosterone (p < 0.0001 for all). LS also induced a decrease in HDL-C (3.8 ± 10.8%), apo A-I (3.7 ± 6.5%) and HMW-adiponectin (13.6 ± 40.5%) (p < 0.05 for all), but plasma total cholesterol, LDL-C, triglycerides and apo B did not significantly change. The changes in HDL-C and apo A-I were correlated negatively to the changes in effective renal plasma flow (p < 0.05), whereas the changes in HMW adiponectin were correlated negatively to the changes in PRA and aldosterone (p < 0.05 for both). CONCLUSION: Short term sodium restriction modestly decreases HDL-C, apo A-I and HMW-adiponectin in healthy men. Changes in GFR and ERPF and in the renin-angiotensin-aldosterone system as induced by LS may be involved in these responses.

Apolipoprotein B/A-I and total cholesterol/high-density lipoprotein cholesterol ratios both predict cardiovascular events in the general population independently of nonlipid risk factors, albuminuria and C-reactive protein.

BACKGROUND: the total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) and apolipoprotein (apo) B/A-I ratios predict major adverse cardiovascular events (MACEs). The extent to which these associations are modified by high-sensitivity C-reactive protein (hs-CRP) and albuminuria is largely unknown. We compared the strength of these ratios with first MACE in the general population and determined whether these associations remain when taking account of these risk markers. SUBJECTS AND METHODS: a prospective case-cohort study was performed among 6948 subjects (PREVEND cohort) without previous cardiovascular disease and who did not use lipid-lowering drugs initially. Fasting serum TC, low-density lipoprotein cholesterol (LDL-C), HDL-C, non-HDL-C, apoB, apoA-I, triglycerides, hs-CRP and albuminuria were measured at baseline. The composite endpoint was incident MACE. RESULTS: a total of 362 first cardiovascular events occurred during 7.9 years of follow-up. All pro- and anti-atherogenic measures of lipoproteins and apos predicted MACEs in age- and sex-adjusted Cox proportional hazard analyses (P = 0.018 to P < 0.001). The age- and sex-adjusted hazard ratio (HR) was 1.37 [95% confidence interval (CI), 1.26-1.48] for the apoB/apoA-I ratio and 1.24 (95% CI, 1.18-1.29) for the TC/HDL-C ratio (both P < 0.001). These relationships were essentially unaltered after additional adjustment for triglyceride levels. Pair-wise comparison revealed that these ratios were of similar importance in age- and sex-adjusted analysis (P = 0.397). The HRs of apoB/apoA-I (P < 0.001) and TC/HDL-C (P < 0.001) for risk of MACEs were only marginally attenuated by additional controlling for traditional risk factors (hypertension, diabetes, obesity and smoking), hs-CRP and albuminuria. CONCLUSIONS: first MACE is associated with both the fasting serum apoB/apoA-I ratio and the TC/HDL-C ratio in the general population, independently of triglycerides, hs-CRP and albuminuria.

Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol.

OBJECTIVES: The current literature provides little information on the frequency of mutations in the ATP-binding cassette transporter A1 (ABCA1) in patients with low high-density lipoprotein cholesterol (HDL) levels that are referred to the clinic. In 78 patients with low plasma levels of HDL cholesterol that were referred to our clinic, we routinely screened for ABCA1 gene mutations and studied the functionality of newly identified ABCA1 missense mutations. METHODS: The coding regions and exon-intron boundaries of the ABCA1 gene were sequenced in 78 subjects with HDL cholesterol levels below the 10th percentile for age and gender. Novel mutations were studied by assessing cholesterol efflux capacity (using apolipoprotein A-I as acceptor) after transient expression of ABCA1 variants in BHK cells. RESULTS: Sixteen out of 78 patients (21%) were found to carry 19 different ABCA1 gene variants (1 frameshift, 2 splice-site, 4 nonsense and 12 missense variation) of which 14 variations were novel. Of three patients with homozygous mutations and three patients having compound heterozygous mutations only one patient presented with the clinical characteristics of Tangier Disease (TD) in the presence of nearly complete HDL deficiency. Seven out of eight newly identified ABCA1 missense mutations were found to exhibit a statistically significant loss of cholesterol efflux capacity. CONCLUSION: This study shows that one out of five patients who are referred to our hospital because of low HDL cholesterol levels have a functional ABCA1 gene mutation. It is furthermore demonstrated that in vitro studies are needed to assess functionality of ABCA1 missense mutations.

Plasma lecithin: cholesterol acyltransferase activity modifies the inverse relationship of C-reactive protein with HDL cholesterol in nondiabetic men.

Lecithin:cholesterol acyltransferase (LCAT) is instrumental in high-density lipoprotein (HDL) maturation, but high LCAT levels do not predict low cardiovascular risk. LCAT may affect antioxidative or anti-inflammatory properties of HDL. We determined the relationship of plasma high-sensitivity C-reactive protein (CRP) with LCAT activity and evaluated whether LCAT activity modifies the decreasing effect of HDL cholesterol (HDL-C) on CRP, as an estimate of its anti-inflammatory properties. Plasma HDL-C, apolipoprotein (apo) A-I and LCAT activity (exogenous substrate method) were measured in 260 nondiabetic men without cardiovascular disease. CRP was correlated inversely with HDL-C and apo A-I, and positively with LCAT activity (P<0.01 to 0.001). Multivariate regression analysis demonstrated that age- and smoking-adjusted plasma CRP levels were associated negatively with HDL-C (beta=-0.224, P<0.001) and positively with LCAT activity (beta=0.119, P=0.034), as well as with the interaction between HDL-C and LCAT activity (beta=0.123, P=0.026). There was also an interaction between apo A-I and LCAT activity on CRP (beta=0.159, P=0.005). These relationships remained similar after adjustment for apo B-containing lipoproteins. In conclusion, the inverse relationship of HDL-C with CRP is attenuated by LCAT activity at higher HDL-C levels. It is hypothesized that LCAT could mitigate HDL's anti-inflammatory or antioxidative properties at higher HDL-C concentrations.

Apolipoprotein M predicts pre-beta-HDL formation: studies in type 2 diabetic and nondiabetic subjects.

OBJECTIVE: Studies in mice suggest that plasma apoM is lowered in hyperinsulinaemic diabetes and that apoM stimulates formation of pre-beta-HDL. Pre-beta-HDL is an acceptor of cellular cholesterol and may be critical for reverse cholesterol transport. Herein, we examined whether patients with type 2 diabetes have reduced plasma apoM and whether apoM is associated with pre-beta-HDL formation and cellular cholesterol efflux. DESIGN: In 78 patients with type 2 diabetes and 89 control subjects, we measured plasma apoM with ELISA, pre-beta-HDL and pre-beta-HDL formation, phospholipid transfer protein (PLTP) activity and the ability of plasma to promote cholesterol efflux from cultured fibroblasts. RESULTS: ApoM was approximately 9% lower in patients with type 2 diabetes compared to controls (0.025 +/- 0.006 vs. 0.027 +/- 0.007 g L(-1), P = 0.01). The difference in apoM was largely attributable to diabetes-associated obesity. ApoM was positively related to both HDL (r = 0.16; P = 0.04) and LDL cholesterol (r = 0.28; P = 0.0003). Pre-beta-HDL and pre-beta-HDL formation were not different between diabetic and control subjects. ApoM predicted pre-beta-HDL (r = 0.16; P = 0.04) and pre-beta-HDL formation (r = 0.19; P = 0.02), even independently of positive relationships with apoA-I, HDL-cholesterol and PLTP activity. Cellular cholesterol efflux to plasma was positively related to pre-beta-HDL and PLTP activity but not significantly to apoM. CONCLUSIONS: Plasma apoM is modestly reduced in type 2 diabetes. Pre-beta-HDL and pre-beta-HDL formation are positively associated with apoM, supporting the hypothesis that apoM plays a role in HDL remodelling in humans. Lower apoM may provide a mechanism to explain why pre-beta-HDL formation is not increased in type 2 diabetes despite elevated PLTP activity.

Antiproteinuric therapy decreases LDL-cholesterol as well as HDL-cholesterol in non-diabetic proteinuric patients: relationships with cholesteryl ester transfer protein mass and adiponectin.

OBJECTIVE: Dyslipidemia contributes to increased cardiovascular risk in nephrotic syndrome. We questioned whether reduction in proteinuria not only lowers low-density lipoprotein cholesterol (LDL-C), but also high-density lipoprotein cholesterol (HDL-C) and cholesteryl ester transfer protein (CETP) mass and whether changes in HDL-C were related to changes in plasma adiponectin. METHODS: Thirty-two non-diabetic proteinuric patients (12 on statin therapy), were followed during two double blind 6-week periods of placebo and treatment (low sodium + 100mg losartan + 25 mg hydrochlorothiazide). RESULTS: With placebo HDL-C was lower but LDL-C and CETP were not different in proteinuric patients compared with matched controls. LDL-C, HDL-C and CETP decreased upon proteinuria reduction. The decrease in LDL-C correlated with the drop in CETP and the degree of proteinuria reduction. HDL-C also decreased in proportion to proteinuria lowering. Individual changes in HDL-C were correlated with changes in adiponectin. CONCLUSION: LDL-C lowering upon robust reduction of proteinuria may be affected by changes in plasma CETP mass, but this treatment also decreases HDL-C in relation to the degree of proteinuria reduction. This adverse effect on HDL-C may in part be attributable to changes in adiponectin.