Plasma High-density Lipoprotein Concentrations Research Articles

Low Levels of Serum Paraoxonase Activities are Characteristic of Metabolic Syndrome and May Influence the Metabolic-Syndrome-Related Risk of Coronary Artery Disease

Low concentrations of plasma high-density lipoprotein (HDLs) are characteristic in metabolic syndrome (MS). The antioxidant ability of HDLs is, at least in part, attributable to pleiotropic serum paraoxonase (PON1). Different PON1 activities have been assessed in 293 subjects with (n = 88) or without MS (n = 205) and with (n = 195) or without (n = 98) angiographically proven coronary artery disease (CAD). MS subjects had low PON1 activities, with a progressively decreasing trend by increasing the number of MS abnormalities. The activity versus 7-O-diethyl phosphoryl,3-cyano,4-methyl,7-hydroxycoumarin (DEPCyMC), which is considered a surrogate marker of PON1 concentration, showed the most significant association with MS, independently of both HDL and apolipoprotein A-I levels. Subjects with MS and low DEPCyMCase activity had the highest CAD risk (OR 4.34 with 95% CI 1.44–13.10), while no significant increase of risk was found among those with MS but high DEPCyMCase activity (OR 1.45 with 95% CI 0.47–4.46). Our results suggest that low PON1 concentrations are typical in MS and may modulate the MS-related risk of CAD.

Adipose Tissue ATP Binding Cassette Transporter A1 Contributes to High-Density Lipoprotein Biogenesis In Vivo

Adipose tissue (AT) is the body's largest free cholesterol reservoir and abundantly expresses ATP binding cassette transporter A1 (ABCA1), a key cholesterol transporter for high-density lipoprotein (HDL) biogenesis. However, the extent to which AT ABCA1 expression contributes to HDL biogenesis in vivo is unknown. Adipocyte-specific ABCA1 knockout mice (ABCA1(-A/-A)) were generated by crossing ABCA1(floxed) mice with aP2Cre transgenic mice. AT from ABCA1(-A/-A) mice had <10% of wild-type ABCA1 protein expression but normal hepatic and intestinal expression. Deletion of adipocyte ABCA1 resulted in a significant decrease in plasma HDL cholesterol (approximately 15%) and apolipoprotein A-I (approximately 13%) concentrations. AT from ABCA1(-A/-A) mice had a 2-fold increase in free cholesterol content compared with wild-type mice and failed to efflux cholesterol to apolipoprotein A-I. However, cholesterol efflux from AT to plasma HDL was similar for both genotypes of mice. Incubation of wild-type AT explants with apolipoprotein A-I resulted in the formation of multiple discrete-sized nascent HDL particles ranging in diameter from 7.1 to 12 nm; similar incubations with ABCA1(-A/-A) AT explants resulted in nascent HDL <8 nm. Plasma decay and tissue uptake of wild-type (125)I-HDL tracer were similar in both genotypes of recipient mice, suggesting that adipocyte ABCA1 deficiency reduces plasma HDL concentrations solely by reducing nascent HDL particle formation. We provide in vivo evidence that AT ABCA1-dependent cholesterol efflux and nascent HDL particle formation contribute to systemic HDL biogenesis and that AT ABCA1 expression plays an important role in adipocyte cholesterol homeostasis.

Association between moderately oxidized low-density lipoprotein and high-density lipoprotein particle subclass distribution in hemodialyzed and post-renal transplant patients

Disturbances in the metabolism of lipoprotein profiles and oxidative stress in hemodialyzed (HD) and post-renal transplant (Tx) patients are proatherogenic, but elevated concentrations of plasma high-density lipoprotein (HDL) reduce the risk of cardiovascular disease. We investigated the concentrations of lipid, lipoprotein, HDL particle, oxidized low-density lipoprotein (ox-LDL) and anti-ox-LDL, and paraoxonase-1 (PON-1) activity in HD (n=33) and Tx (n=71) patients who were non-smokers without active inflammatory disease, liver disease, diabetes, or malignancy. HD patients had moderate hypertriglyceridemia, normocholesterolemia, low HDL-C, apolipoprotein A-I (apoA-I) and HDL particle concentrations as well as PON-1 activity, and increased ox-LDL and anti-ox-LDL levels. Tx patients had hypertriglyceridemia, hypercholesterolemia, moderately decreased HDL-C and HDL particle concentrations and PON-1 activity, and moderately increased ox-LDL and anti-ox-LDL levels as compared to the reference, but ox-LDL and anti-ox-LDL levels and PON-1 activity were more disturbed in HD patients. However, in both patient groups, lipid and lipoprotein ratios (total cholesterol (TC)/HDL-C, LDL-C/HDL-C, triglyceride (TG)/HDL-C, HDL-C/non-HDL-C, apoA-I/apoB, HDL-C/apoA-I, TG/HDL) were atherogenic. The Spearman's rank coefficient test showed that the concentration of ox-LDL correlated positively with HDL particle level (R=0.363, P=0.004), and negatively with TC (R=-0.306, P=0.012), LDL-C (R=-0.283, P=0.020), and non-HDL-C (R=-0.263, P=0.030) levels in Tx patients. Multiple stepwise forward regression analysis in Tx patients demonstrated that ox-LDL concentration, as an independent variable, was associated significantly positively with HDL particle level. The results indicated that ox-LDL and decreased PON-1 activity in Tx patients may give rise to more mildly-oxidized HDLs, which are less stable, easily undergo metabolic remodeling, generate a greater number of smaller pre-β-HDL particles, and thus accelerate reverse cholesterol transport, which may be beneficial for Tx patients. Further studies are necessary to confirm this.

Inhibition of rupture of established atherosclerotic plaques by treatment with apolipoprotein A-I.

Plasma concentrations of high-density lipoprotein (HDL)-cholesterol correlate inversely with the incidence of myocardial infarction in humans. We investigated the effect of treatment with human apolipoprotein A-I (apoA-I), the principal protein of HDL, on plaque disruption in an animal model. Seventy apolipoprotein E knockout mice were induced to develop atherosclerotic lesions in the brachiocephalic artery by feeding a high-fat diet for 9 weeks. Mice then received twice-weekly treatment with human apoA-I (8 mg/kg) or vehicle, for 2 weeks. The incidence of acute plaque disruption was reduced by 65% in mice receiving apoA-I (P < 0.01). Plaques in treated mice had a more stable phenotype, with an increase in smooth muscle cell (SMC): macrophage ratio (P = 0.05), principally the consequence of an increase in the number of SMC in plaques. In the fibrous cap, there were reductions in matrix metalloproteinase-13 (-69%, P < 0.0001) and S100A4, a marker of SMC de-differentiation (-60%, P < 0.0001). These results indicate that 2 weeks of treatment with small amounts of human apoA-I produces more stable plaques in a mouse model. Treatment with apoA-I has the potential to stabilize plaques and prevent plaque rupture in humans.

Inverse Correlation Between Plasma Beta-Carotene and Interleukin-6 in Patients with Advanced Coronary Artery Disease

The interrelationships between plasma beta-carotene, alpha-tocopherol, and the level of systemic inflammation and oxidative stress were investigated in patients with advanced coronary artery disease (CAD). Plasma beta-carotene, alpha-tocopherol, malondialdehyde, free radicals, interleukin-6, high sensitive C-reactive protein levels, and other risk factors of CAD were determined in a group of patients with advanced CAD [significant stenosis according to coronarographic examination (n=91) and a control group of examined patients with coronary arteries with no stenosis (n=49)]. Between-group differences in continuous variables were analyzed with the Hotelling T2-test (software NCSS2000), analyses of correlation matrix with the software STATISTICA. Advanced CAD coincided with significantly lower plasma concentrations of high-density lipoprotein (HDL)-cholesterol and beta-carotene as well as with elevated levels of all inflammatory markers, but only with mild increase of oxidative stress. Beta-carotene significantly inversely correlated with interleukin-6. This inverse correlation could suggest potential protective effect of beta-carotene on atherosclerosis due to the inhibition of inflammatory processes.

Epistasis contributes to the genetic buffering of plasma HDL cholesterol in mice

Stressful environmental factors, such as a high-fat diet, can induce responses in the expression of genes that act to maintain physiological homeostasis. We observed variation in plasma concentrations of high-density lipoprotein (HDL) cholesterol across inbred mouse strains in response to high dietary fat intake. Several strains, including C57BL/6J, have stable levels of plasma HDL independent of diet, whereas other strains, including DBA2/J, show marked changes in plasma HDL. To explore this phenomenon further, we used publicly available data from a C57BL/6J × DBA/2J intercross to identify genetic factors that associate with HDL under high-fat diet conditions. Our analysis identified an epistatic interaction that plays a role in the buffering of HDL levels in C57BL/6J mice, and we have identified Arl4d as a candidate gene that mediates this effect. Structural modeling further elucidates the interaction of genetic factors that contribute to the robustness of HDL in response to high-fat diet in the C57BL/6J strain.

Differential impact of milk fatty acid profiles on cardiovascular risk biomarkers in healthy men and women

The objective of this study was to evaluate the impact of three specific ruminant (R) milk fats resulting from modification of the cow's diet on cardiovascular risk factors in healthy volunteers. R-milk fats were characterized by increased content in total trans fatty acids (R-TFAs) and parallel decrease in saturated fatty acids (SFAs). A total of 111 healthy, normolipemic men and women have been recruited for a monocentric, randomized, double-blind and parallel intervention, 4-week controlled study. Volunteers consumed three experimental products (butter, dessert cream and cookies) made with one of the three specific milk fats (55 g fat per day). During the first week (run-in period), the subjects consumed on a daily basis dairy products containing 72% SFA/2.85% R-TFA (called 'L0'). For the next 3 weeks of the study (intervention period), the first group continued to consume L0 products. The second group received dairy products containing 63.3% SFA/4.06% R-TFA (called 'L4'), and the third group received dairy products containing 56.6% SFA/12.16% R-TFA (called 'L9'). Plasma concentrations of high-density lipoprotein (HDL)-cholesterol were not significantly altered by either diet (P=0.38). Compared to L0 diet, L4 diet contributed to reduce low-density lipoprotein (LDL)-cholesterol (-0.14+/-0.38 mmol/l, P=0.04), total cholesterol (-0.13+/-0.50 mmol/l, P=0.04), LDL-cholesterol/HDL-cholesterol (-0.14+/-0.36, P=0.03) and total cholesterol/HDL-cholesterol (-0.18+/-0.44, P=0.02). Different milk fat profiles can change cardiovascular plasma parameters in human healthy volunteers. A limited increase of the R-TFA/SFA ratio in dairy products is associated with an improvement in some cardiovascular risk factors. However, a further increase in R-TFA/SFA ratio has no additional benefit.

White button mushroom (Agaricus bisporus) lowers blood glucose and cholesterol levels in diabetic and hypercholesterolemic rats

Agaricus bisporus (white button mushroom; WBM) contains high levels of dietary fibers and antioxidants including vitamin C, D, and B(12); folates; and polyphenols that may provide beneficial effects on cardiovascular and diabetic diseases. The objective of this study was to examine the hypothesis that intake of the fruiting bodies of WBM regulates anticholesterolemic and antiglycemic responses in rats fed a hypercholesterolemic diet (0.5% cholesterol; 14% fat) and rats with type 2 diabetes induced by injection of streptozotocin (STZ) (50 mg/kg body weight), respectively. The STZ-induced diabetic male Sprague-Dawley rats fed the Agaricus bisporus powder (ABP; 200 mg/kg of body weight) for 3 weeks had significantly reduced plasma glucose and triglyceride (TG) concentrations (24.7% and 39.1%, respectively), liver enzyme activities, alanine aminotransferase and aspartate aminotransferase (11.7% and 15.7%, respectively), and liver weight gain (P < .05). In hypercholesterolemic rats, oral feeding of ABP for 4 weeks resulted in a significant decrease in plasma total cholesterol (TC) and low-density lipoprotein (LDL) (22.8% and 33.1%, respectively) (P < .05). A similar significant decrease in hepatic cholesterol and TG concentrations was observed (36.2% and 20.8%, respectively) (P < .05). Decrease in TC, LDL, and TG concentrations was accompanied by a significant increase in plasma high-density lipoprotein concentrations. It was concluded that A bisporus mushroom had both hypoglycemic and hypolipidemic activity in rats.

Review of extended-release niacin/laropiprant fixed combination in the treatment of mixed dyslipidemia and primary hypercholesterolemia.

Although statins reduce cardiovascular morbidity and mortality further risk reduction is needed. In this respect low HDL-cholesterol concentrations and/or elevated triglyceride concentrations may be potential treatment targets. Niacin (nicotinic acid) is an effective drug which increases the plasma concentration of high-density lipoprotein (HDL)-cholesterol and decreases the concentration of low-density lipoprotein (LDL)-cholesterol, triglycerides and lipoprotein(a). Clinical studies indicate that niacin can significantly reduce the risk for cardiovascular events. However, niacin is not very commonly used because of significant side effects (especially flushing). Laropiprant is a potent selective antagonist of PGD2-receptor subtype-1 and can thus reduce niacin-induced flushing. Although the addition of laropiprant will reduce the frequency of flushing, it will not completely eliminate this side effect. Laropiprant does not change the effect of niacin on lipids or other side effects of niacin (ie, gastro-intestinal problems, glucose elevation). The combination of niacin with laropiprant may therefore enable use of niacin at higher doses and therefore exploit the full potential of the drug. Endpoint studies that will be published over the next few years will show whether this treatment modality also translates into clinical effect in patients treated with statins. Until publication of these studies niacin/laropiprant should be used only in high-risk patients not achieving lipid goals on statins.

The Effects of Cholesterol Ester Transfer Protein Inhibition on Cholesterol Efflux

Cholesterol ester transfer protein (CETP) deficiency or inhibition results in dramatic elevations of high-density lipoprotein (HDL) levels, but there has been concern that HDL might be dysfunctional in its ability to promote efflux of cholesterol from macrophage foam cells or to mediate reverse cholesterol transport. Using cholesterol-loaded cultured macrophages, HDL that was isolated from subjects with homozygous CETP deficiency or who had been treated with high levels of CETP inhibitor (120 mg torcetrapib) had an increased cholesterol efflux potential when matched for unit mass of HDL in media. This correlated with the accumulation of HDL(2) species enriched in apolipoprotein E and lecithin-cholesterol acyltransferase. At lower levels of inhibition (60 mg torcetrapib), HDL had a similar ability to promote cholesterol efflux as pretreatment HDL but showed increased cholesterol efflux in parallel with the increase in plasma HDL concentration. Cholesterol efflux measurements appear to correlate with the finding that subjects who attained the highest levels of HDL on torcetrapib showed regression of coronary atheroma as determined by intravascular ultrasound. Although these in vitro measurements may not fully capture the in vivo complexities of HDL metabolism, they suggest that increased HDL attributable to CETP inhibition results in particles that have normal or enhanced ability to promote cholesterol efflux from macrophage foam cells.

High plasma high-density lipoprotein levels, very low cardiovascular risk profile, and subclinical carotid atherosclerosis in postmenopausal women

Low plasma concentrations of high-density lipoprotein (HDL) are associated with increased risk of cardiovascular disease. However, recently several studies have questioned the protective role of high plasma HDL levels. This study was designed to evaluate HDL functions in women with high plasma HDL cholesterol and very low risk profile with relation to subclinical carotid atherosclerosis (ATS). Included were 158 middle-aged women with plasma HDL >60 mg/dL and Framingham risk score <7% who had B-mode ultrasound of the carotid arteries. Subclinical ATS was determined by the presence of plaques and/or intima-media thickness (IMT) >1.0 mm. ATS was observed in 51 women, with the majority (n=41) having carotid plaques, some with advanced morphology. In a multivariable model analysis, each, HDL or age, were independently associated with increased prevalence of ATS. Odds ratios for ATS were 3.1 and 2.5 greater for age>60 years and HDL >70 mg/dL, respectively. None of HDL functions determined by its antioxidative properties, reverse-cholesterol transport, or activities of HDL-associated enzyme were different between -ATS and +ATS. C-reactive protein was similar in both groups. Subclinical carotid ATS is present in one-third of middle-aged women independently of conventional risk factors. A greater ATS prevalence was associated with very high HDL values. We could not find association between ATS and HDL dysfunction.

Influence of orally administered bovine lactoferrin on lipid metabolism in lipopolysaccharide‐injected preruminant calves

ABSTRACT The aim of this study was to investigate the influence of oral lactoferrin (LF) administration on lipid metabolism changes in calves given lipopolysaccharide (LPS). Twenty-one 4-day-old Holstein calves were divided into three groups, with each group receiving one of three oral doses of LF (0, 1, 3 g/day) for 10 consecutive days (day -10 to day -1). All calves were intravenously injected with LPS (50 ng/kg BW) on day 0, the day after LF treatment ended. Plasma triglyceride concentrations were lower (P < 0.05) in the LF-treated calves than in the control calves given 0 g/day of LF at 12 and 24 h after LPS injection. Plasma NEFA concentrations were elevated between 6 and 24 h after LPS treatment. At 12 h, the concentration of plasma NEFA was lower (P < 0.05) in the calves given LF 3 g/day than in the control calves. On day 0, plasma total cholesterol and phospholipid concentrations tended to be lower in the LF groups administered 1 and 3 g of LF/day than in the control group, but did not differ significantly among the groups. The plasma very-low-density and low-density lipoprotein concentrations were lower (P < 0.05) at 12, 24, and 72 h in the LF groups than in the control calves. The concentrations of plasma high-density lipoprotein tended to be lower in the LF groups than in the control group between day 0 and 96 h, though there were no significant group differences. The concentration of plasma interleukin-1beta was lower (P < 0.05) in the calves fed LF 3 g/day than in the control calves at 2 and 12-48 h after LPS injection. These data suggest that LF inhibits LPS-induced alterations in lipid metabolism in preruminant calves.

Mental retardation is associated with plasma omega-3 fatty acid levels and the omega-3/omega-6 ratio in children.

There is evidence that alteration in plasma fatty acid composition may play a role in certain neurological disorders. This case control study was conducted to evaluate the association between plasma fatty acid levels and mental retardation in Korean children. Plasma phospholipid fatty acids, plasma lipids, dietary fatty acids and selected nutrients were measured in 31 mentally retarded boys (mean age 9.93 +/-1.5 yrs) and matched controls. Total plasma omega-3 fatty acids (Sigmaw3), docosahexaenoic acid (DHA) and high density lipoprotein (HDL) concentrations were significantly lower and the Sigmaomega-6/Sigmaomega-3 ratio was significantly higher in cases than in controls. The odds in favor of mental retardation increased by 69 % for each unit increase in the Sigmaomega-6/ Sigmaomega-3 ratio (adjusted odds ratio = 1.69, 95% CI = 1.25-2.29). Significant variation in plasma Sigmaomega-3 and the Sigmaomega-6/ Sigmaomega-3 ratio was explained by mental retardation and plasma HDL concentrations (45% and 37 % respectively). There was a significant inverse association between plasma DHA and mental retardation. For each unit increase in plasma DHA, odds of mental retardation decreased by 74 %. There was no significant difference in either total dietary fat or fatty acids intakes between cases and controls. The energy intake of cases was significantly higher than the controls. These results suggest that proportion of plasma Sigmaomega-3 fatty acids, particularly, DHA, and the Sigmaomega-6/ Sigmaomega-3 ratio are associated with mental retardation in children in this study.

Is HDL function as important as HDL quantity in the coronary artery disease risk assessment?

Over the past several decades, it has been clearly established that higher plasma concentrations of high-density lipoprotein (HDL) are related to lower risk of coronary artery disease (CAD). According to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines, theHDL level of <40 mg/dL is considered low and is one of the CAD risk predictors. However, in the last decade, several studies have indicated the importance of the quality of HDL as another potential measure for CAD risk assessment. The loss of normal biological function of HDL particles as a result of multifactorial actions of chronic inflammation and acute phase responses has suggested a new potential pathway in the pathophysiology of atherosclerosis. The concept of "dysfunctional HDL" or "proinflammatory HDL," which exhibits chameleon-like properties of converting a positive force protecting arteries to a negative one, enhancing atherogenesis is now under active investigation. Measurements of this dysfunctional quality of HDL in cell-based or cell-free assays by analyzing anti-inflammatory functions may link these changes to in vivo assessments of vascular disease. This review provides details on functional and dysfunctional HDL and summarizes recent studies into dysfunctional HDL and its potential links to CAD.

Impaired antioxidant activity of high-density lipoprotein in chronic kidney disease

Chronic kidney disease (CKD) is associated with accelerated atherosclerosis and increased mortality from cardiovascular disease. CKD results in oxidative stress, inflammation, and high-density lipoprotein (HDL) deficiency, which work in concert to promote atherosclerosis. Normal HDL confers protection against atherosclerosis by inhibiting the oxidation of lipids and lipoproteins and by retrieving surplus cholesterol and phospholipids from lipid-laden cells in the artery wall for disposal in the liver (reverse cholesterol transport). The plasma level of oxidized low-density lipoprotein (LDL) is increased, plasma HDL-cholesterol is reduced, and HDL maturation is impaired in CKD. This study was designed to examine the antioxidant properties of HDL in patients with CKD. In all, 32 stable hemodialysis-dependent patients and 13 age-matched controls were studied. HDL was isolated and used for determination of in vitro antioxidant activity. In addition, the plasma level of key components of HDL, namely paraoxonase (PON), glutathione peroxidase (GPX), platelet activating factor acetylhydrolase (PAF-AH), lecithin cholesterol acyltransferase (LCAT), and apolipoprotein A-I (ApoA-I), were measured. The end-stage renal disease (ESRD) patients exhibited significant reductions of HDL-cholesterol, ApoA-I (-41%), GPX (-50%), and LCAT (-60%) concentrations, and a decrease in PON (-30%) and GPX (-50%) activities. These results were accompanied by a marked reduction of antioxidant activity of HDL (-127%), which was unaffected by the hemodialysis procedure. Thus, in addition to diminished plasma HDL concentration, the composition and antioxidant activity of HDL are altered in CKD; these events can contribute to a heightened risk of atherosclerosis.

Adult-type hypolactasia is not a predisposing factor for the early functional and structural changes of atherosclerosis: the Cardiovascular Risk in Young Finns Study

Individuals suffering from ATH (adult-type hypolactasia), defined by the LCT (gene encoding lactase-phlorizin hydrolase) C/C(-13910) genotype (rs4988235), use less milk and dairy products and may have higher plasma HDL (high-density lipoprotein) and lower triacylglycerol (triglyceride) concentrations than their counterparts without ATH. To investigate the effects of ATH status on the early markers of atherosclerosis, we examined its association with CIMT (carotid intima-media thickness), CAC (carotid artery compliance) and brachial artery FMD (flow-mediated dilation) in a young population-based cohort of otherwise healthy individuals. As part of the Cardiovascular Risk in Young Finns Study, we performed CIMT, CAC and FMD analyses, LCT C/T(-13910) genotyping and risk factor determination in 2109 young subjects 24-39 years of age (45% males) at the time of the examination. The consumption of both milk and dairy products was lowest and the consumption of alcohol highest in subjects with the C/C(-13910) genotype (P<0.001 for all) in comparison with subjects without ATH (TT+CT). In multivariate analysis, no significant association between ATH status and CIMT, CAC or brachial artery FMD was found after adjustment for the use of alcohol, dairy products and all other major risk factors of coronary artery disease. In otherwise similar statistical analysis, the results remained non-significant when females and males were analysed in their own groups. In conclusion, the finding does not support the involvement of ATH in the pathogenesis of early atherosclerosis.

Trimetazidine, a Metabolic Modulator, Has Cardiac and Extracardiac Benefits in Idiopathic Dilated Cardiomyopathy

The anti-ischemic agent trimetazidine improves ejection fraction in heart failure that is hypothetically linked to inhibitory effects on cardiac free fatty acid (FFA) oxidation. However, FFA oxidation remains unmeasured in humans. We investigated the effects of trimetazidine on cardiac perfusion, efficiency of work, and FFA oxidation in idiopathic dilated cardiomyopathy. Nineteen nondiabetic patients with idiopathic dilated cardiomyopathy on standard medication were randomized to single-blind trimetazidine (n=12) or placebo (n=7) for 3 months. Myocardial perfusion, FFA, and total oxidative metabolism were measured using positron emission tomography with [(15)O]H(2)O, [(11)C]acetate, and [(11)C]palmitate. Cardiac function was assessed echocardiographically; insulin sensitivity was assessed by the homeostasis model assessment index. Trimetazidine increased ejection fraction from 30.9+/-8.5% to 34.8+/-12% (P=0.027 versus placebo). Myocardial FFA uptake was unchanged, and beta-oxidation rate constant decreased only 10%. Myocardial perfusion, oxidative metabolism, and work efficiency remained unchanged. Trimetazidine decreased insulin resistance (glucose: 5.9+/-0.7 versus 5.5+/-0.6 mmol/L, P=0.047; insulin: 10+/-6.9 versus 7.6+/-3.6 mU/L, P=0.031; homeostasis model assessment index: 2.75+/-2.28 versus 1.89+/-1.06, P=0.027). The degree of beta-blockade and trimetazidine interacted positively on ejection fraction. Plasma high-density lipoprotein concentrations increased 11% (P<0.001). In idiopathic dilated cardiomyopathy with heart failure, trimetazidine increased cardiac function and had both cardiac and extracardiac metabolic effects. Cardiac FFA oxidation modestly decreased and myocardial oxidative rate was unchanged, implying increased oxidation of glucose. Trimetazidine improved whole-body insulin sensitivity and glucose control in these insulin-resistant idiopathic dilated cardiomyopathy patients, thus hypothetically countering the myocardial damage of insulin resistance. Additionally, the trimetazidine-induced increase in ejection fraction was associated with greater beta1-adrenoceptor occupancy, suggesting a synergistic mechanism.

Anti-inflammatory therapy with tumour necrosis factor alpha inhibitors improves high-density lipoprotein cholesterol antioxidative capacity in rheumatoid arthritis patients

Objective:High-density lipoprotein (HDL) antiatherogenic functions seem to be diminished during inflammatory conditions such as rheumatoid arthritis (RA). The aim of this study was to investigate the effects of tumour necrosis...

Nicotinic Acid: Pharmacological Effects and Mechanisms of Action

Pharmacological doses of nicotinic acid induce a profound change in the plasma levels of various lipids and lipoproteins. The ability of nicotinic acid to strongly increase the plasma concentration of high-density lipoprotein (HDL) cholesterol has in recent years led to an increased interest in the pharmacological potential of nicotinic acid. There is increasing evidence that nicotinic acid alone or in addition to LDL cholesterol-lowering drugs can reduce the progression of atherosclerosis and reduce the risk of cardiovascular events. The clinical use of nicotinic acid is, however, hindered by harmless but unpleasant side effects, especially by a strong cutaneous vasodilation called flushing. The recent discovery of the G protein-coupled receptor GPR109A (HM74A or PUMA-G) as a receptor for nicotinic acid has allowed for better understanding of the mechanisms underlying the metabolic and vascular effects of nicotinic acid. On the basis of recent progress in understanding the pharmacological effects of nicotinic acid, new strategies are in development to better exploit the pharmacological potential of nicotinic acid. New drugs acting via the nicotinic acid receptor or related receptors, as well as new co-medications that suppress unwanted effects of nicotinic acid, will most likely be introduced as new therapeutic options in the treatment of dyslipidemia and the prevention of cardiovascular diseases.

Antiatherogenic Functionality of High Density Lipoprotein: How Much versus How Gooden-subtitle=

Plasma concentration of high density lipoprotein (HDL) is one of the most reliable negative risk factors for CVD. There is however convincing experimental and clinical evidence that plasma concentration of HDL does not convey the full picture of atheroprotective properties of HDL. HDL functionality, i.e. the ability of HDL to perform its many atheroprotective functions, is partly independent of HDL concentration and may be as important, if not more important, in determining the atheroprotective capacity of HDL. The capacity of HDL to support cholesterol efflux, its anti-inflammatory, anti-oxidant, anti-thrombotic and other atheroprotective functions are affected dramatically in conditions like coronary artery disease, chronic and acute inflammation, diabetes as well as through various interventions. The mechanisms connecting changes in HDL functionality to HDL structure are only beginning to emerge. Modifications of HDL proteins and lipids, such as advanced glycation and oxidation, changes in HDL composition and size of HDL particles, changes in abundance of various proteins and lipids carried by HDL are among factors affecting HDL functionality. A single common denominator reflecting the multiple HDL functions is yet to be found and may not exist leaving direct measurements of each HDL function as the way to assess atheroprotective capacity of HDL.