Juha Vakkilainen

Relationships Between Low-Density Lipoprotein Particle Size, Plasma Lipoproteins, and Progression of Coronary Artery Disease The Diabetes Atherosclerosis Intervention Study (DAIS)

Background—The Diabetes Atherosclerosis Intervention Study showed that treatment with fenofibrate decreases progression of coronary atherosclerosis in subjects with type 2 diabetes. We determined whether on-treatment plasma lipid concentrations and LDL particle size contribute to the favorable effect of fenofibrate on the progression of coronary artery disease (CAD). Methods and Results—A total of 418 subjects with type 2 diabetes were randomly assigned to 200 mg micronized fenofibrate daily or placebo. The mean follow-up time was 39.6 months. LDL peak particle diameter (LDL size) was determined by polyacrylamide gradient gel electrophoresis from 405 subjects at baseline and at the end of the study. Progression of CAD was measured with quantitative coronary angiography. LDL size increased significantly more in the fenofibrate group than in the placebo group (0.98±1.04 versus 0.32±0.92 nm, P <0.001). In the combined group, small LDL size was significantly associated with progression of CAD measured as the increase of percentage diameter stenosis (r =−0.16, P =0.002) and decreases in minimum (r =−0.11, P =0.030) and mean (r =−0.10, P =0.045) lumen diameter. High on-treatment LDL cholesterol, apolipoprotein B, and triglyceride concentrations were also associated with the progression of CAD. In regression analyses, small LDL size added to the effect of LDL cholesterol and apolipoprotein B on the progression of CAD. Similar associations were observed in the fenofibrate group, whereas in the placebo group, lipoprotein variables were not significantly correlated with the progression of CAD. Conclusions—Changes in LDL size and plasma lipid levels account for part of the antiatherogenic effect of fenofibrate in type 2 diabetes.

Endothelial Dysfunction in Men With Small LDL Particles

BACKGROUND It is unknown whether LDL particle size is, independent of other lipids and lipoproteins, associated with endothelial dysfunction in vivo. METHODS AND RESULTS We determined in vivo endothelial function in 34 healthy men by measuring forearm blood flow responses to intrabrachial artery infusions of acetylcholine (ACh, an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator). LDL peak particle size was measured with gradient gel electrophoresis. Men with small LDL particles (LDL diameter </=25.5 nm, n=10) had a 39% lower blood flow response to ACh than men with large LDL particles (LDL diameter >25. 5 nm, n=24, blood flow 6.9+/-3.6 versus 11.4+/-5.1 mL/dL. min, P=0. 006). The groups had comparable LDL cholesterol concentrations (3. 9+/-0.6 versus 3.7+/-1.0 mmol/L, men with small versus large LDL particles), blood pressure, glucose concentrations, and body mass indexes. LDL size (r=0.45, P=0.01) but not HDL cholesterol (r=0.31, P=0.09) or triglycerides (r=-0.19, P=0.30) was significantly correlated with endothelium-dependent vasodilation. Serum triglyceride concentrations and LDL size were inversely correlated (r=-0.44, P=0.01). In multivariate regression analysis, LDL size was the only significant determinant of the ACh-induced increase in blood flow. Sodium nitroprusside-stimulated endothelium-independent vasodilation was similar in both groups. CONCLUSIONS Small LDL particles are associated with impaired in vivo endothelial function independent of HDL and LDL cholesterol and triglyceride concentrations. LDL size may therefore mediate adverse effects of hypertriglyceridemia on vascular function.

Insulin Therapy Improves Endothelial Function in Type 2 Diabetes

A total of 75 in vivo endothelial function tests (intrabrachial artery infusions of endothelium-dependent [acetylcholine] and -independent [sodium nitroprusside] vasoactive agents) were performed in 18 type 2 diabetic patients (aged 58+/-2 years, body mass index 28.5+/-0.6 kg/m(2), and fasting plasma glucose 229+/-11 mg/dL) and 27 matched normal subjects. These tests were performed before and 6 months after combination therapy with insulin and metformin and before and 6 months after metformin therapy only. Before insulin therapy, blood flow responses to acetylcholine (15 microg/min) were significantly blunted in type 2 diabetic patients (7.5+/-0.7 mL x dL(-1) x min(-1)) compared with normal subjects (11.6+/-0.9 mL x dL(-1) x min(-1), P<0.01). During insulin therapy, the acetylcholine response increased by 44% to 10.8+/-1.6 mL x dL(-1) x min(-1) (P<0.05). Insulin therapy also significantly increased the blood flow responses to both low and high doses of sodium nitroprusside. We conclude that insulin therapy improves endothelium-dependent and -independent vasodilatation. These data support the idea that insulin therapy has beneficial rather than harmful effects on vascular function.

Effects of nateglinide and glibenclamide on postprandial lipid and glucose metabolism in type 2 diabetes

Postprandial hyperlipemia and small, dense LDL particles are features of dyslipidemia in type 2 diabetes. The purpose of this study was (1) to determine whether the oral insulinotropic drugs, nateglinide and glibenclamide, can overcome the defect of insulin action to suppress the hepatic VLDL release after a meal and decrease the postprandial lipemia and (2) to evaluate the acute effect of postprandial hypertriglyceridemia on LDL particle size in subjects with type 2 diabetes.

Serum C3 but Not Plasma Acylation-Stimulating Protein Is Elevated in Finnish Patients With Familial Combined Hyperlipidemia

A trapping defect of fatty acids due to impaired function of acylation-stimulating protein (ASP) has been suggested as one mechanism underlying the metabolic abnormalities in familial combined hyperlipidemia (FCHL). The study aimed at defining the role of ASP and complement C3 in 35 Finnish FCHL families. There was no difference in plasma ASP levels between the 66 hypertriglyceridemic FCHL patients and their 84 normotriglyceridemic relatives. No response in plasma ASP could be observed after a fatty meal in 10 FCHL patients or in 10 control subjects. In familial correlation analyses, C3 exhibited a significant sibling-sibling correlation. The FCHL patients had higher serum C3 levels than their unaffected relatives (P <0.001). Furthermore, serum C3 levels correlated significantly with several lipid parameters. The correlations between ASP and lipid variables were weaker than those of C3. These analyses suggest that common genes might contribute to the regulation of serum C3, triglycerides, HDL-C, free fatty acids, and insulin. The present data do not support the hypothesis that defects of the ASP pathway are reflected in plasma lipoproteins or in impaired plasma lipid clearance postprandially.

Susceptibility of LDL to oxidation in vitro and antioxidant capacity in familial combined hyperlipidemia: comparison of patients with different lipid phenotypes

BACKGROUND. There is increasing evidence that oxidation of low-density lipoprotein (LDL) plays an important role in atherogenesis. AIM. To explore the LDL oxidizability and its determinants in familial combined hyperlipidemia (FCHL) patients with different phenotypes. METHOD. The study included 59 FCHL family members with different lipid phenotypes, 39 non-affected relatives, and 30 spouses as healthy controls. RESULTS. The lag time for LDL oxidation was significantly shorter in FCHL patients with different lipid phenotypes as compared to healthy controls. There were no significant differences in the propagation rate and conjugated diene formation and f -tocopherol content in LDL between the FCHL groups and healthy controls. Plasma concentrations of f -tocopherol in all FCHL patients and uric acid in FCHL patients with IIB and IV phenotypes were significantly higher than in healthy controls. Plasma total peroxyl radical trapping capacity measured (TRAP mea ) and TRAP calc tended to be higher in affected FCHL groups, but the difference was significant only for IIB phenotype. The peak LDL particle size in the combined group of FCHL patients was significantly smaller than in healthy controls. The lag time for LDL oxidation correlated significantly with LDL size both in the group of FCHL family members (r = 0.477, P < 0.001) and in the healthy controls (r = 0.482, P < 0.01). CONCLUSIONS. LDL from FCHL patients irrespectively of lipid phenotypes is more susceptible to oxidation in vitro than LDL from healthy controls. This increased susceptibility of LDL to oxidation in vitro seems to be attributed to the abundance of small dense LDL particles and not to the defect of antioxidant capacity in FCHL.

The Increase of Apolipoprotein A-V During Postprandial Lipemia Parallels the Response of Triglyceride-Rich Lipoproteins in Type 2 Diabetes: No relationship between apoA-V and postheparin plasma lipolytic activity

Postprandial lipemia is a distinct feature of diabetic dyslipidemia and may partly explain the atherogeneity of the lipid profile in type 2 diabetes (1). Several genetic factors contribute to the elevation of triglyceride-rich lipoproteins (TRLs). The role of apolipoprotein (apo)C-III as a regulator of TRL metabolism is well documented (2). Recently, apoA-V has been identified as a novel regulator of triglyceride metabolism. When the human APOA5 gene was expressed in transgenic mice, plasma triglyceride concentration was decreased by 70%, whereas apoA 5 gene knockout mice had fourfold elevation of plasma triglyceride levels (3). Inherited apoA-V deficiency results in severe hypertriglyceridemia in humans (4). A mutation in the APOA5 gene causes hypertriglyceridemia due to decreased lipoprotein lipase (LPL) mass and activity (5). Thus, previous studies have proposed that apoA-V decreases triglycerides by stimulating lipolysis. The present study focused on the response of apoA-V and apoC-III during postprandial lipemia and the associations between apoA-V and apoC-III and postheparin plasma LPL and hepatic lipase activities in type 2 diabetes. The present study cohort was comprised of 39 men and 8 women with type 2 diabetes who were enrolled in the previously published nateglinide study with the same inclusion and exclusion criteria (6). A total of 17 patients were treated with diet alone, 20 with sulfonylurea, and 11 with metformin. The …

Genetic influences contributing to LDL particle size in familial combined hyperlipidaemia

The nature of the genetic and environmental factors influencing low density lipoprotein (LDL) particle size in patients with familial combined hyperlipidaemia (FCHL) is under debate. We measured LDL peak particle size in 553 subjects belonging to 48 Finnish FCHL families. Individuals with high triglyceride (TG) concentrations (phenotype IV) or combined hyperlipidaemia (phenotype IIB) had significantly smaller LDL particles than those with hypercholesterolaemia (phenotype IIA) or unaffected subjects (P<0.001). In stepwise regression analyses, serum TGs (r2=43%, P<0.001) and high density lipoprotein cholesterol (HDL-C) (r2=4.5%, P<0.001) were the only significant predictors of LDL peak particle size. Familial correlations support the conclusion that LDL peak particle size is familial, and most probably influenced by genes in these families. Segregation analysis of LDL peak particle size, a quantitative trait, was performed to model this genetic influence. Our results suggest a polygenic background for LDL size with a recessive major gene that may contribute to large LDL peak particle size in women. Serum TG and HDL-C concentrations predict the majority of variations in LDL particle size.