Raimon Ferré

Reversal of atherogenic lipoprotein profile in HIV-1 infected patients with lipodystrophy after replacing protease inhibitors by nevirapine

BackgroundThe widespread use of protease inhibitors (PI) has been associated with abnormalities in the lipid profile of HIV-1-infected patients. Treatment simplification approaches in which PI are replaced by nevirapine (NVP) have been shown to improve PI-related toxicity. ObjectiveTo assess the impact on plasma lipids of replacing the PI by NVP in HIV-1 infected patients with lipodystrophy. MethodsWe studied 34 patients with lipodystrophy who had been the first to be enrolled in a prospective, randomized trial of continuing current treatment, or replacing PI with NVP. Sixteen patients replaced their PI with NVP and 18 continued their current PI-containing treatment. Total, low density lipoprotein (LDL), very low density lipoprotein (VLDL), intermediate density lipoprotein and high density lipoprotein (HDL) cholesterol and triglyceride levels, the size and particle number of LDL were determined at baseline and after 24 weeks, by nucleic magnetic resonance spectroscopy. FindingsAfter 24 weeks of replacing the PI with NVP, we observed a reduction of total cholesterol (P = 0.028), LDL-cholesterol (P = 0.001), the number of circulating LDL particles (P = 0.003) and the VLDL-1 triglyceride level (P = 0.032). A concomitant significant increase was observed in both HDL-cholesterol level (P = 0.002) and HDL particle size (P < 0.001). No significant changes were observed in the group that continued taking the PI. ConclusionsThe replacement of PI by NVP improved the lipid profile both by reducing the number and lipid content of atherogenic LDL particles, and increasing the protective HDL fraction. Although total triglyceride levels remained unchanged, a reduction in the VLDL-1 fraction contributes to the reduction of LDL particles. These changes are expected to reduce the risk of cardiovascular disease in HIV-1-infected patients on highly active antiretroviral therapy.

Efavirenz induces a striking and generalized increase of HDL-cholesterol in HIV-infected patients

This study analyses in depth lipid and lipoprotein changes in 20 HIV-infected patients on an efavirenz-containing regimen, either as initial therapy or as a substitute for a protease inhibitor. Total plasma lipids and the distribution of subclasses of lipoproteins were analysed at baseline and after 48 weeks by nuclear magnetic resonance spectroscopy, and showed a mean increase of 20% in HDL-cholesterol in both regimens. Up to 85% of patients significantly improved their atherogenic index (LDL/HDL ratio).

Fatty acid-binding protein 4 is associated with endothelial dysfunction in patients with type 2 diabetes

OBJECTIVE Adipocyte fatty acid-binding protein (FABP4) plasma levels are higher in type 2 diabetes (T2D). Endothelial dysfunction is also common in T2D. We have investigated the relationship between circulating FABP4 levels and endothelial function in diabetic patients. METHODS In 257 patients (105 diabetic and 152 non-diabetic) at increased risk of cardiovascular disease, we measured circulating FABP4, reactive hyperemia index (RHI) by peripheral artery tonometry, intima-media thickness, and biomarkers of inflammation, oxidation and endothelial function. RESULTS In T2D subjects, FABP4 was negatively associated with endothelial function, as measured by RHI (r=-0.226, P=0.05). In a stepwise multivariate linear regression model, FABP4 was a predictor of RHI in T2D patients (P=0.04). CONCLUSION Circulating levels of FABP4 are inversely associated with endothelial function in T2D patients, as measured by RHI. We suggest a direct effect of plasma FABP4 on the vascular endothelium in those with T2D.

FABP4 plasma levels are increased in familial combined hyperlipidemia

The lipid profile of familial combined hyperlipidemia (FCHL) shares some characteristics with atherogenic dyslipidemia seen in diabetes, metabolic syndrome, and obesity. Adipocyte fatty acid-binding protein 4 (FABP4) appears to be a determinant of atherogenic dyslipidemia. We examined relationships between FABP4 plasma concentrations, dyslipidemia, and metabolic variables in patients with FCHL. We studied 273 unrelated FCHL patients and 118 control subjects. FABP4 was higher in FCHL than controls, with mean levels of 21.8 (10.1) microg/l and 19.2 (9.2) microg/l, respectively (adjusted P= 0.012). In FCHL, FABP4 correlated to body mass index (BMI), waist circumference, insulin levels, and homeostasis model assessment (HOMA) index (all P< 0.05), but not to lipid levels, whereas in obese patients, FABP4 correlated to triglyceride levels (r = 0.303, P= 0.014) and very low density lipoprotein size (r = 0.502, P = 0.001), as determined by nuclear magnetic resonance. Associations of FABP4 with BMI and waist circumference, but not with insulin levels, persisted in this subgroup. Plasma FABP4 does not influence the lipid phenotype of FCHL. In a small subgroup of obese FCHL, FABP4 levels were associated with triglyceride-rich lipoproteins independent of insulin resistance. These results support a hyperlipidemic mechanism of FCHL different from similar metabolic conditions where fat mass is strongly related to FABP4 and hypertriglyceridemia.

High-density lipoprotein cholesterol and apolipoprotein A1 levels strongly influence the reactivity of small peripheral arteries.

OBJECTIVE Reactive hyperaemia after shear stress is a surrogate marker of endothelial function. However, the mechanisms controlling the dilation capacity of small peripheral resistance arteries are not well characterised. We evaluated reactive hyperaemia by peripheral artery tonometry (PAT) in the acral arteries and studied their clinical and biochemical determinants. METHODS Eight hundred sixteen subjects at intermediate to high cardiovascular risk were recruited. The reactive hyperaemia index (RHI) of small digital arteries was measured by PAT. Clinical history data, anthropometry and biochemical parameters were also analysed. We studied the associations between clinical and biochemical factors and small artery RHI. RESULTS HDL cholesterol and apolipoprotein A1 levels were strongly and directly correlated with an increased dilation response. Metabolic syndrome components, such as increased waist circumference, hypertriglyceridaemia and smoking, were inversely associated with RHI as were serum markers of inflammation. The predictors of small peripheral artery RHI were HDL cholesterol, which had a protective effect, and smoking, which had a negative impact. CONCLUSION HDL cholesterol and apolipoprotein A1 levels had a strong, positive correlation with small artery reactive hyperaemia, whereas smoking, waist circumference and triglyceride levels were inversely associated. HDL cholesterol was the main determinant of RHI in small peripheral resistance arteries.

Nuclear Magnetic Resonance Lipoprotein Subclasses and the APOE Genotype Influence Carotid Atherosclerosis in Patients with Systemic Lupus Erythematosus

Objective. Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis. Since the conventional lipid profile (total plasma cholesterol, triglycerides, low and high density lipoprotein cholesterol) is not consistently altered in SLE, we hypothesized that investigation of lipoprotein subclasses would improve prediction of risk of atherosclerosis in these patients. Methods. As a quantitative index of atherosclerosis, we measured the carotid intima-media thickness (IMT) in 68 patients with SLE and related the atherosclerosis to a detailed lipoprotein profile generated using nuclear magnetic resonance (NMR). We measured the cholesterol transported by the pool of remnant lipoproteins (RLPc) and evaluated the modulatory effect of the APOE genotype on the lipoprotein subclass profile and atherosclerosis associated with SLE. Results. Circulating lipoprotein remnant particles [RLPc and intermediate density lipoprotein (IDL)] were positively correlated with IMT, and among them, the indicator that explained 20.2% of the variability in carotid atherosclerosis measured in these patients was IDL, as assessed by NMR. Carriers of the APOE2 allele were at increased risk due to a significant accumulation of IDL particles. Conclusion. Lipoprotein subclasses are more associated with subclinical atherosclerosis in patients with SLE than the lipid variables that are routinely measured. The IDL fraction, which is significantly modulated by the APOE genotype, is the most strongly, significantly, and positively correlated with IMT.

Circulating PCSK9 in patients with type 2 diabetes and related metabolic disorders

BACKGROUND PCSK9 is a pivotal molecule in the regulation of lipid metabolism. Previous studies have suggested that PCSK9 expression and its function in LDL receptor regulation could be altered in the context of diabetes. The aim was to assess PCSK9 plasma levels in patients with type 2 diabetes (T2DM) and other related metabolic disorders as well as its relation to the metabolomic profile generated by nuclear magnetic resonance (NMR) and glucose homeostasis. METHODS There were recruited a total of 457 patients suffering from T2DM and other metabolic disorders (metabolic syndrome (MetS), obesity and atherogenic dyslipidaemia (AD) and other disorders). Anamnesis, anthropometry and physical examinations were conducted, and vascular and abdominal adiposity imaging were carried out. Biochemical studies were performed to determine PCSK9 plasma levels 6 weeks after lipid lowering drug wash-out in treated patients. A complete metabolomic lipid profile was also generated by NMR. The rs505151 and rs11591147 genetic variants of PCSK9 gene were identified in patients. RESULTS The results showed that PCSK9 levels are increased in patients with T2DM and MetS (14% and 13%; p<0.005, respectively). Circulating PCSK9 levels were correlated with an atherogenic lipid profile and with insulin resistance parameters. PCSK9 levels were also positively associated with AD, as defined by lipoprotein particle number and size. The rs11591147 genetic variant resulted in lower levels of circulating PCSK9 and LDL cholesterol (LDL-C). CONCLUSIONS PCSK9 plasma levels are increased in T2DM and MetS patients and are associated with LDL-C and other parameters of AD and glucose metabolism.

Increasing long-chain n-3PUFA consumption improves small peripheral artery function in patients at intermediate–high cardiovascular risk

Dietary long-chain n-3 polyunsaturated fatty acids (LCn-3PUFA) improve endothelial function in medium-large-sized arteries, but effects on small peripheral arteries, responsible for most arterial resistance, are little known. We investigated the effects of increasing LCn-3PUFA intake with the usual diet on small artery reactive hyperemia index (saRHI). Within a clinical trial evaluating the effects of 1 year of intensive lifestyle intervention versus standard care on cardiovascular markers in subjects at risk, we selected 108 participants regardless of treatment allocation (n=47 standard care; n=61 intensive intervention) with complete baseline and follow-up information on dietary, clinical, saRHI and biochemical data, including biomarkers of inflammation and endothelial activation. At the end of follow-up, saRHI increased across tertiles of change in dietary LCn-3PUFA. Subjects in the top tertile (increased LCn-3PUFA intake) increased serum ApoA1 and decreased hs-CRP, serum TNF-α, sICAM-1, sVCAM-1 and oxLDL from baseline. After pooling data, in unadjusted models, changes in saRHI significantly correlated to changes in LCn-3PUFA intake and ApoA1 (directly) and changes in systolic blood pressure, waist circumference, TNF-α, sVCAM-1 and sE-selectin (inversely). In a multivariate model, changes in dietary LCn-3PUFA were significantly associated with changes in saRHI [B=0.08 (95% confidence interval=0.083-0.291) for an increase by 100 mg/day]. Systolic blood pressure was inversely associated with saRHI changes [B=-0.203 (-0.441 to -0.029) for a 9-mmHg increase]. We conclude that increased dietary consumption of LCn-3PUFA might be a cost-effective strategy to improve peripheral vasoactivity.

Small artery dilation and endothelial markers in cardiovascular risk patients

Eur J Clin Invest 2012; 42 (1): 34–41

Two novel single nucleotide polymorphisms in the promoter of the cellular retinoic acid binding protein II gene (CRABP-II).

The cellular retinoic acid binding protein-II (CRABP-II) is an intracellular protein involved in the transmission of the vitamin A-derived signal which regulates genes responsible for lipid metabolism and adipocyte differentiation. Cellular Retinoic Acid Binding Protein-II gene (CRABP-II) (GDB 134819) is located on chromosome 1q21-23 and this region has been linked with related disorders such as Familial Combined Hyperlipidemia (FCHL), type 2 Diabetes Mellitus, and Lipodystrophy. In this context we hypothesized that CRABP-II is an interesting protein and aimed to provide genetic markers for future studies. In order to do that, we screened the promoter and the entire coding regions for mutations in 53 patients diagnosed with FCHL and 89 normolipidemic controls. Two new single nucleotide polymorphisms (SNPs) were identified in the promoter region a C to A change at position -515 and a T to C substitution at position -394, the latter creating a binding site for SP1. The change -515C > A was identified in a FCHL patient whereas the -394T > C was found in 3 FCHL patients and 4 normolipidemic subjects. This report provides two new polymorphisms in CRABP-II, which can be used as genetic markers for future studies of association or linkage with diseases, particularly those associated with the metabolic syndrome.