Vasilis Tsimihodimos

Dyslipidemia in chronic kidney disease: an approach to pathogenesis and treatment.

BACKGROUND/AIMS Cardiovascular disease (CVD) is a major cause of mortality in patients with mild to moderate chronic kidney disease (CKD) and end-stage renal disease (ESRD). Dyslipidemia has been established as a well-known traditional risk factor for CVD in the general population and it is well known that patients with CKD exhibit significant alterations in lipoprotein metabolism. In this review the pathogenesis and treatment of renal dyslipidemia are discussed. METHODS Studies on lipid abnormalities in CKD stages 1-4, in nephrotic syndrome, and in hemodialysis and peritoneal dialysis patients are analyzed, as well as the lipid profile of kidney graft recipients. Also, the results of the effects of epoietin treatment and hypolipidemic drugs in CKD patients are reported. RESULTS Disturbances in lipoprotein metabolism are evident even at the early stages of CKD and usually follow a downhill course that parallels the decline of renal function. However, several intrinsic or exogenous factors can influence the phenotypic expression of these alterations. According to the literature, current evidence suggests that unlike dialysis patients, mild to moderate CKD patients could be benefit from the use of statins. CONCLUSION The use of statins is indicated in patients with mild to moderate CKD, while in subjects with ESRD lipid-lowering therapy should be individualized.

Effect of ezetimibe monotherapy on the concentration of lipoprotein subfractions in patients with primary dyslipidaemia

ABSTRACT Background: Recent studies suggest that the distribution of lipoprotein subfractions is an independent predictor of vascular events. Therefore, we evaluated the effect of ezetimibe (a selective cholesterol transport inhibitor) on the concentrations of lipoprotein subfractions in patients with primary dyslipidaemia. Materials and methods: Patients (n = 50) with primary dyslipidaemias were recruited. The concentrations of the individual lipoprotein subfractions were measured using the Lipoprint system at baseline and after 16 weeks of treatment. Results: Ezetimibe reduced total, low-density lipoprotein cholesterol (LDL‑C) and non-high-density lipoprotein cholesterol (HDL‑C) values as well as apolipoprotein B concentrations. Subfractionation of apolipoprotein B-containing lipoproteins showed that the reduction in LDL‑C values was due to a fall in the concentrations of all LDL subfractions. However, a more pronounced trend towards a decrease in the concentrations of dense LDL subfractions was observed. Patients with triglyceride values >1.7 mmol/L had significantly greater reductions in the concentrations of small, dense LDL particles compared with those with normal triglyceride levels (49 vs. 19%, respectively; p < 0.05). Ezetimibe decreased the concentrations of HDL‑C mainly due to a fall in the concentration of dense HDL subfractions. Conclusion: Ezetimibe can favourably affect the distribution of LDL subfractions, especially in patients with elevated triglyceride values. Further studies are needed to clarify the significance of the ezetimibe-induced reduction in the concentrations of dense HDL particles.

Fenofibrate: Metabolic and Pleiotropic Effects

Disturbances of lipoprotein metabolism represent one of the most important risk factors for vascular events. However, dyslipidaemic patients often have a number of additional abnormalities (such as endothelial dysfunction, hypertension, low-grade inflammation, haemostatic abnormalities and hyperuricaemia) that may accelerate the atherosclerotic process. Thus, the ideal lipid-modifying drug, along with exerting beneficial effects on lipoprotein metabolism, should also improve these coexisting disturbances. Fibric acid derivatives (fibrates) are a class of lipid-modifying drugs mainly used in patients with elevated triglyceride levels. These drugs mainly exert their actions via the activation of specific nuclear receptors called peroxisome proliferator-activated receptors alpha (PPARalpha). In this review, we summarize the current evidence suggesting that fenofibrate, one of the most widely used fibric acid derivatives, along with its well established actions on lipids also exerts several other antiatherogenic actions. Based on recently published studies, fenofibrate is a useful option for patients with primary combined dyslipidaemias or secondary dyslipidaemias, such as those associated with diabetes mellitus, metabolic syndrome or HIV infection. Additionally, in cases of refractory dyslipidaemia, the combination of fenofibrate with statins is a therapeutic option.

Effect of Fenofibrate on Serum Inflammatory Markers in Patients With High Triglyceride Values

Background: Atherosclerosis is the leading cause of death in developed countries. Although the mechanisms that underlie this process are not well defined, it has been proposed that atherosclerosis is mainly an inflammatory disease. In this context, a number of inflammatory markers have been studied for their ability to predict future cardiovascular events in asymptomatic individuals or patients with established atherosclerotic disease. Methods and Results: The aim of our study was to evaluate the effect of micronized fenofibrate on serum inflammatory markers, such as C-reactive protein, fibrinogen, and plasma platelet-activating factor acetylhydrolase (PAF-AH) in patients with high triglyceride values. An analysis of baseline values revealed that hypertriglyceridemic patients (n = 58) exhibit an atherogenic phenotype, characterized not only by elevated lipid values but also by high concentrations of serum inflammatory markers. Along with the improvement in serum lipid profile (reduction in triglycerides and total cholesterol, low-density lipoprotein, and nonhigh-density lipoprotein-cholesterol, with a concomitant increase in high-density lipoprotein-cholesterol levels), fenofibrate administration significantly reduced the values of serum inflammatory markers by 34%, 9.5%, and 24.8% for C-reactive protein, fibrinogen, and plasma PAF-AH, respectively. However, with the exception of PAF-AH, these reductions in inflammatory markers were not correlated with the changes in lipid values. Conclusions: In addition to its well-known hypolipidemic effects, fenofibrate may also possess significant anti-inflammatory properties that can contribute its antiatherogenic effect.

Dyslipidemia associated with chronic kidney disease.

Cardiovascular disease is a major cause of morbidity and mortality in patients with impaired renal function. Dyslipidemia has been established as a well-known traditional risk factor for cardiovascular disease (CVD) in the general population and it is well known that patients with chronic kidney disease (CKD) exhibit significant alterations in lipoprotein metabolism. In this review, the pathogenesis and treatment of CKD-induced dyslipidemia are discussed. Studies on lipid abnormalities in predialysis, hemodialysis and peritoneal dialysis patients are analyzed. In addition, the results of the studies that tested the effects of the hypolipidemic drugs on cardiovascular morbidity and mortality in patients with CKD are reported.

The hypertriglyceridemic waist phenotype is a predictor of elevated levels of small, dense LDL cholesterol.

The hypertriglyceridemic waist (HTGW) phenotype (hypertriglyceridemia and increased waist circumference) has been proposed as an inexpensive tool to monitor individuals with the atherogenic metabolic triad, hyperinsulinemia, hyperapobetalipoproteinemia, and increased levels of small, dense LDL (sdLDL) particles. We assessed the association of the HTGW phenotype with the metabolic syndrome (MetSyn) and the atherogenic metabolic triad in inhabitants (n=260) of northwestern Greece attending the Outpatient Lipid Clinic of the University Hospital of loannina. The LDL subfractions were assessed using the Lipoprint LDL System. HTGW (+) individuals had a more adverse lipid and lipoprotein profile compared with HTGW (−) individuals. Moreover, HTGW (+) subjects had elevated levels of sdLDL-C, as well as decreased mean and peak LDL particle size compared with HTGW (−) subjects. To our knowledge, this is the first report documenting the sdLDL-C abnormality in HTGW (+) subjects. Among men (n=105), 52.3% of the MetSyn (+) individuals and 66.7% of the HTGW (+) individuals had the metabolic triad. Among women (n=155), the corresponding percentages were 42.3% and 50.0%. Only 22.2% and 10.6% of the Metsyn (−) subjects (men and women, respectively) and 19.6% and 15.2% of the HTGW (−) subjects (men and women, respectively) had the atherogenic metabolic triad. In conclusion, the HTGW (+) phenotype is associated with a hostile lipid profile that includes higher levels of sdLDL-C and decreased LDL particle size. The HTGW phenotype, compared with the MetSyn criteria, can provide an easy and inexpensive tool to monitor patients characterized by an adverse lipid and lipoprotein profile.

Pleiotropic effects of ezetimibe: Do they really exist?

Ezetimibe represents a new lipid lowering agent which inhibits cholesterol absorption. It effectively reduces low-density lipoprotein cholesterol when administered either alone or in combination with statins. However, its effect on cardiovascular mortality remains under question since it failed to demonstrate any significant changes in the primary endpoints of the recently published ENHANCE and SEAS studies. A possible explanation for this unsuccessful outcome is that ezetimibe lacks pleiotropic effects. This article aims to review the potential pleiotropic effects of the drug mainly on inflammation markers, lipoprotein subfractions and endothelial function.

Plasma lipoproteins and triacylglycerol are predictors of small, dense LDL particles.

Recently published data suggest that the assessment of LDL subfraction profiles may contribute to the determination of the cardiovascular risk. In this study, we tested the ability of various metabolic parameters to estimate the presence or the preponderance of small, dense LDL particles (sdLDL). One hundred and fifty individuals attending the Outpatient Clinics of the University Hospital of Ioannina for suspected metabolic abnormalities were included in the study. Individuals were excluded if they were found to be diabetic or if they had a history of cardiovascular disease. Patients with thyroid dysfunction, liver or kidney diseases as well as those receiving drugs that may interfere with lipids or glucose metabolism were also excluded from the study. The ability of the various parameters to identify individuals with pattern B LDL phenotype or, alternatively, with measurable quantities of sdLDL particles was tested with the calculation of the areas under the ROC curves. The ratio of triglycerides to HDL-C was the best predictor of the presence of the pattern B LDL phenotype. Nevertheless, when the variable of interest was the presence of measurable quantities of sdLDL subfractions, the ratio of apoB to apoAI had the best predictive ability. In conclusion the ratios of apoB to apoAI and of triglycerides to HDL-C can reliably predict the presence of measurable quantities of sdLDL particles and of the pattern B LDL phenotype, respectively. However, since the quantitative determination of sdLDL concentrations may contribute to the determination of the cardiovascular risk, whereas the role of the LDL particle size remains controversial, apoB to apoAI ratio could provide more valuable information compared to markers that simply predict the presence of the pattern B LDL phenotype.

Effects of antihypertensive and hypolipidemic drugs on plasma and high-density lipoprotein-associated platelet activating factor-acetylhydrolase activity.

Background: Human plasma platelet activating factor acetylhydrolase (PAF-AH) is a phospholipase A2 primarily associated with low-density lipoprotein (LDL). PAF-AH activity has also been found on high-density lipoprotein (HDL). Most of the clinical studies that have investigated the plasma levels of PAF-AH activity in cardiovascular disease have involved patients who were under treatment with various drugs, such as antihypertensive or hypolipidemic agents. However, the influence of these drugs on the enzyme activity has not been adequately studied. Material and Methods: We evaluated the effects of representative antihypertensive and hypolipidemic drugs on the total plasma, as well as on the HDL-associated PAF-AH activity, in 121 patients with essential hypertension and in 90 patients with dyslipidemias of type IIA or type IIB. Serum lipids and enzymatic activities were determined at baseline and after 3 months of treatment. Results: The administration of lacidipine (4 mg, n = 21), valsartan (80 mg, n = 26), indapamide (2.5 mg, n = 20), benazepril (20 mg, n = 20), or atenolol (50 mg, n = 34) did not affect either the total plasma- or the HDL-associated PAF-AH activity. In contrast, treatment with fluvastatin (40 mg, n = 50) or ciprofibrate (100 mg, n = 40) reduced by 25% plasma PAF-AH activity (P < .001) associated with a decrease in serum levels of total cholesterol and LDL-cholesterol (P < .001). Furthermore, ciprofibrate induced an increase by 26% in HDL-associated PAF-AH activity (P = .004) along with an increase in serum HDL-cholesterol levels (P = .02). Conclusions: Among all types of drugs studied, only those that significantly affect lipid metabolism, such as statins and fibrates, significantly influence PAF-AH activity in human plasma.

LDL cholesterol estimation in patients with the metabolic syndrome

BackgroundThe Friedewald formula (LDL-F) for the estimation of low-density lipoprotein (LDL) cholesterol concentrations is the most often used formula in clinical trials and clinical practice. However, much concern has been raised as to whether this formula is applicable in all patient populations such as the presence of chylomicronaemia and/or hypertriglyceridaemia. The aim of the present study was to evaluate various LDL cholesterol calculation formulas as well as LDL cholesterol levels provided by the Lipoprint LDL System (LDL-L) in patients with the metabolic syndrome (MetSyn).ResultsLDL-F showed significant differences from other formulas in the total cohort, as well as in MetSyn individuals. This was not the case in nonMetSyn subjects, where LDL-F did not differ with other formulas, with the exception of one formula (LDL by Planella, LDL-P). The bias between LDL-F and other LDL estimation formulas were significantly higher in MetSyn subjects compared to nonMetSyn individuals, except for LDL-L which produced similar bias with LDL-F in both study groups.ConclusionLDL-F seems to exhibit some limitations as far as the calculation of LDL-C levels in patients with the MetSyn is concerned. LDL-L might be more accurate in MetSyn subjects, but so far its use is limited for the estimation of small, dense LDL (sdLDL) cholesterol levels and mean LDL particle size for research purposes only.