Patrizia Brizzi

Reduction of Albumin Excretion Rate in Normotensive Microalbuminuric Type 2 Diabetic Patients During Long-Term Simvastatin Treatment

OBJECTIVE To study the long-term effects of simvastatin on urinary albumin excretion rate (AER) in normotensive microalbuminuric type 2 diabetic patients with hypercholesterolemia. RESEARCH DESIGN AND METHODS A total of 19 normotensive microalbuminuric hypercholesterolemic type 2 diabetic patients entered a double-blind crossover study for 2 years, receiving either simvastatin (20 mg/day) or placebo (each treatment for 1 year). RESULTS Simvastatin significantly decreased plasma cholesterol (total and LDL) after 52 weeks of treatment. A concomitant significant decrease of AER (25% from basal) with no significant changes in creatinine clearance was observed during the same period. CONCLUSIONS Our data are in keeping with the hypothesis that simvastatin might be used as an additional means to preserve renal function in microalbuminuric hypercholesterolemic type 2 diabetic patients.

Lipoprotein metabolism during normal pregnancy

OBJECTIVE We sought to investigate the changes in circulating serum lipids and lipoproteins, including lipoprotein (a), and low-density lipoprotein size in women during normal pregnancy. STUDY DESIGN Twenty-two women (mean age, 31 +/- 5 years; 13 primiparous subjects) were studied during uncomplicated pregnancy with normal outcome. Twenty-four nulliparous women of similar age (31 +/- 4 years) were studied as control subjects. RESULTS Serum triglycerides and total and low-density lipoprotein cholesterol increased significantly during pregnancy in all women. Women with changes in low-density lipoprotein during the second and third trimesters showed a more marked increase in serum triglycerides, and this effect was slightly more evident in the multiparous subjects. No other differences were evident between primiparous and multiparous women apart from high-density lipoprotein cholesterol levels, which were slightly decreased in the latter subjects. CONCLUSIONS Our results show that during normal pregnancy, the increase in plasma triglycerides may lead to the appearance of the atherogenic dense low-density lipoproteins in a subgroup of women. We suggest that the observed changes in low-density lipoprotein patterns during pregnancy might be used to identify those women who later in life will have these atherogenic small and dense low-density lipoproteins.

Plasma lipid composition and LDL oxidation.

Abstract Low-density lipoprotein (LDL) oxidation in vivo depends on lipid composition and on plasma antioxidant status. The aim of our study was to investigate the relationship between plasma lipid composition and LDL oxidation and, in particular, to explore whether LDL-cholesterol/triglycerides ratio (LDL-C/TG) and LDL-cholesterol/high-density lipoprotein (HDL)-cholesterol ratio (LDL-C/HDL-C) can be used as predictive parameters of LDL oxidation in vivo. In 87 volunteers over a wide range of age plasma lipids and LDL oxidation were studied. Blood was collected after 12 h overnight fast. LDL oxidation was estimated by the level of conjugated diene (BDC) in the lipid fraction isolated from plasma after gradient ultracentrifugation. The results were expressed as μmol/l (BDC/l) to evaluate the level of oxidized LDL, and as nmol of BDC for mg of LDL-cholesterol (BDC/LDL-C) for the evaluation of LDL oxidation degree. BDC/l correlated significantly with age, total and LDL-C, apolipoprotein B and TG, while BDC/LDL-C negatively correlated with total cholesterol, apolipoprotein B, LDL/TG and LDL/HDL ratios. Age of subjects significantly correlated with total and LDL-C and apolipoprotein B. TG have a significant inverse correlation with HDL-C. Our results support the hypothesis that among the several factors involved in LDL oxidation the most important determinants are LDL/TG. Plasma triglycerides appear to be very important even when circulating cholesterol levels are within normal limits. Moreover, we found that the LDL/HDL ratio is also very important with regard to the putative protective role of HDL against LDL oxidation in vivo. In conclusion, plasma lipid parameters must be evaluated not only for their absolute values but also for their mutual ratios as expression of plasma lipid homeostasis. Both LDL/TG and LDL/HDL ratios can be used as predictive parameters of in vivo LDL oxidation.

Raised serum apolipoprotein (a) in active diabetic retinopathy

SummaryProgressive capillary occlusion often leads to severe retinopathy within 15–20 years of the onset of Type 1 (insulin-dependent) diabetes mellitus. Lipoprotein (a), a complex formed by apolipoprotein (a), apo B-100 and lipids, is considered an independent, genetically determined, predictor of cardiovascular disease. It may have antifibrinolytic properties in view of its similarity to plasminogen. To test the hypothesis that circulating lipoprotein (a) is associated with the process that leads to clinically active diabetic retinopathy, we measured the circulating levels of apolipoprotein (a) (which are strictly correlated with those of lipoprotein (a)) in two groups of patients with Type 1 diabetes of at least 15 years duration: 25 with active retinopathy and 27 without clinically detectable retinal lesions. Thirty-eight healthy subjects of the same age and sex served as controls. Serum apolipoprotein (a) was higher in the patients with active retinopathy (36(2-193) U/dl, geometric mean and range) than in those without clinically detectable retinal lesion (17(1–160)) and the control subjects (14(0–115)), p < 0.01 in both cases. The distribution of apolipoprotein (a) levels was skewed to the left, as expected, in the patients without clinically evident retinal lesions and the control groups, but there was a bimodal trend of distribution among those with active retinopathy. The levels of glycated haemoglobin were similar in the two groups of diabetic patients, and no significant differences were found for total and HDL cholesterol, triglycerides or apolipoproteins A1 and B between them and the control subjects. These preliminary results suggest that serum apolipoprotein (a) is elevated in patients with active retinopathy. The role of this lipoprotein as a predictor or a pathogenic effector of diabetic retinopathy, or both deserves further investigation.

Autoantibodies against oxidized low-density lipoprotein (ox-LDL) and LDL oxidation status

Abstract Oxidized low-density lipoproteins (ox-LDLs) and their autoantibodies (OLAB) are involved in the development of atherosclerosis in animal models, but their role in humans is still not clear. For this reason we studied 54 patients with β-thalassemia major (TM), as a model of chronically low circulating LDLs with a high level of oxidation; 44 patients with primary hypercholesterolemia, as model of chronically high circulating LDLs; 24 type 2 diabetic mellitus patients (T2DM) before and after 3 months of atorvastatin treatment (20 mg/day), as a model of acute changes in circulating LDLs; and 41 normolipidemic subjects as a control group. ox-LDLs were measured by the determination of baseline diene concentration in the plasma LDL lipidic fraction after 12 hours fasting and were expressed as the amount of conjugated dienes/liter (BDC/l) or BDC/LDL-cholesterol (LDL-C), which indicate respectively LDL oxidation degree and status. OLABwere determined using an enzyme immunoassay and related to LDL oxidation degree (BDC/l). In TM, BDC/l was lower, while BDC/LDL-C was significantly higher, compared to both hypercholesterolemia and normolipidemic subjects. Patients with hypercholesterolemia had higher BDC/l, but lower BDC/LDL-C and OLAB/BDC-l, than normolipidemic subjects. In T2DM patients at diet, BDC/LDL-C and OLAB/BDC-l were lower than in normolipidemic subjects. After 3 months of atorvastatin treatment, BDC/LDL-C and OLAB/BDC-l ratios increased. When all patients were evaluated together, a significant inverse correlation was evident between OLABand either LDL or BDC/l. Our findings suggest that a relationship between OLABtiter and oxidation indices (BDC/l and BDC/LDL-C) does exist and we may speculate that an increase in OLAB/BDC-l ratio might be protective against the risk of atherosclerosis.

Plasma lipids and lipoprotein changes after biliopancreatic diversion for morbid obesity

Background: The reduction in plasma cholesterol with increase in large and lower dense LDL (pattern A) obtained by statins is usually associated with a prompt reduction in cardiovascular risk, but after bariatric surgery for morbid obesity a delay of some years is observed. No data regarding LDL pattern are available in obese subjects after biliopancreatic surgery. Objective: To evaluate the modifications in LDL composition and LDL density after biliopancreatic surgery. Subjects: 29 patients (17 type 2 diabetics (type 2) and 12 non-diabetics (ND)) with BMI <35, who failed previous attempts to decrease weight by diet, were studied before and 6 months after biliopancreatic diversion for morbid obesity. Measurements: In all subjects, besides fasting circulating lipids, glucose and insulin, LDL and VLDL composition were determined and LDL density was evaluated as well. Results: After surgery we observed a significant reduction of all circulating lipids, including apolipoprotein (Apo) B. The decrease was more marked for total cholesterol (–41%) than for triglycerides (–28%), without a significant difference between type 2 and ND. After surgery, LDL presented a marked decrease in the percentage of cholesterol (from 36 to 32%) with a marked increase in the percentage of triglycerides (from 13 to 18%), without appreciable modification of ApoB. After surgery, 1 patient changed from pattern B to A, while 2 patients previously pattern A became pattern B. Also a decrease in HDL and ApoAI was evident in all the subjects with an increase in the VLDL-1. Conclusions: Our data indicate that after biliopancreatic diversion, the plasma lipid profile improves along with improvement of plasma glucose and insulin sensitivity, but the LDLs become richer in triglycerides. It is possible that the greater atherogenicity of these LDLs is compensated by an improvement in the general metabolic condition.

Effect of ovarian stimulation on plasma lipid and apolipoprotein concentrations in a population of infertile women undergoing IVF/embryo transfer

Twenty consecutive infertile women (mean age +/- SD, 36.9 +/- 5.4 years) undergoing ovarian stimulation with recombinant follicle stimulating hormone (rFSH) were recruited. Serial measurements of plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoprotein A1 (ApoA1), apolipoprotein B (Apo-B), lipoprotein(a) (Lp(a)), oestradiol and progesterone were performed on day 3 before starting ovarian stimulation, on the day of human chorionic gonadotrophin (HCG) administration and on day 15 after HCG administration, respectively. The relationship between lipid and apolipoprotein concentrations and serum oestradiol and progesterone concentrations was sought. All women completed the ovarian stimulation protocol successfully. Plasma concentrations of HDL-C and Apo-A1 were significantly raised on the day of HCG administration and then returned to baseline values within 2 weeks. LDL-C, TG, Apo-B and Lp(a) were significantly increased on day 15 after HCG administration. Lp(a) variation between the first sample and the third sample correlated positively with serum progesterone concentrations (r = 0.472, P < 0.04). No other significant correlations were found between lipid and apolipoprotein variations and either oestradiol or progesterone concentrations. It was concluded that an increase of plasma lipid and apolipoprotein concentrations deserves particular consideration and all women undergoing ovarian stimulation should be monitored for long-term atherogenic and thrombogenic risks.

Serum apolipoprotein(a) concentrations and apo(a) phenotypes in patients with liver cirrhosis

Objective:The liver is the major site of apolipoprotein(a) synthesis, and an inverse correlation between the size of apolipoprotein(a) isoforms and its serum levels have been described. We evaluated the Apo(a) serum levels and its isoforms in patients with liver cirrhosis at different stages of the disease (Childe Turcotte classification), and during the characteristic phase of liver synthesis decline.Methods:We studied 84 patients with liver cirrhosis and 185 control subjects with normal liver function.Results:Apo(a) serum levels were significantly lower (p < 0.01) in cirrhotic patients and, after 24 months, six patients showing a change from class A to class B had a statistically significant decrease in Apo(a) concentrations (p= 0.0313). Moreover, our data showed an inversion of the small/large isoforms ratio in patient with cirrhosis in spite of the reduction in plasma concentration.Conclusion:We showed a reduction of Apo(a) serum concentrations in a large number of patients with cirrhosis and, for the first time, during the characteristic phase of liver synthesis decline, confirming the liver as the major site of Apoliprotein(a) synthesis. Moreover we showed in the cirrhotic patients that the normal correlation between Apo(a) isoforms and Apo(a) concentrations is not conserved and the low levels are not dependent upon a high prevalence of large isoforms.

Lipid pattern, apolipoproteins A1 and B and lipoprotein (a) in type 1 diabetic patients with microalbuminuria

The plasma lipid changes commonly observed in patients with diabetic nephropathy may play a major role in determining the increased cardiovascular risk in these patients. Contrasting results have been reported on the patterns of lipids and lipoproteins in diabetic subjects with microalbuminuria. We examined 20 patients with type 1 (insulin-dependent) diabetes who had a urinary albumin excretion >30 mg/24 h (11 males and 9 females, age range 16–45 years, mean diabetes duration 11.7 years) and 20 type 1 diabetic patients without microalbuminuria matched for sex, age, diabetes duration, daily insulin requirement and degree of metabolic control. In all patients we measured plasma total cholesterol, highdensity lipoprotein (HDL)-cholesterol, triglycerides, apolipoproteins A1 and B and lipoprotein (a) [Lp(a)]. No significant differences were found for any parameter between subjects with a urinary albumin excretion <20 mg/ 24 h and microalbuminuric patients. Moreover in nondiabetic controls the levels of plasma Lp(a) and of the other parameters measured were not significantly different from those of the two diabetic groups. Our results suggest that in type 1 diabetic patients with fairly good glycaemic control microalbuminuria is not associated with significant changes in the lipoprotein pattern.