Treatment of small dense LDL

The increased frequency of small, dense LDL is associated with the risk of coronary heart disease (CHD). Possible mechanisms include the increased susceptibility of small, dense LDL to oxidation and its high affinity for LDL-receptor-independent cell surface binding sites. Although more than 30% of adult men in the USA have been reported to have small,dense LDL, only 5.4% of young Japanese men are affected. However, more than 76% of Japanese diabetics with coronary heart disease have small, dense LDL. Furthermore, almost half of all obese women (BMI > 35 kg/m(2)) have small, dense LDL. Our previous observation revealed that type 2 diabetics had smaller LDL even if they were apparently normolipidemic. In the normotriglycelidemic group there was also a close relationship between LDL size and plasma triglyceride. Diabetics with microalbuminuria had smaller LDL than those with normoalbuminuria, indicating the early nephrotoxicity of small, dense LDL. We also found that young men with high-normal blood pressure have smaller LDL than those with optimal blood pressure. Furthermore, LDL size was decreased not only in preeclamptic women but also in normal pregnant women. Finally, weight reduction by obese women through strict diet control, the treatment of diabetics by acarbose or troglitazone, and the treatment of hyperlipidemia by new statins as well as fibrates were all successful in increasing LDL size associated with decreased plasma triglyceride.     

Postprandial hyperlipidemia, small and dense LDL, HDL sub-fractions]

The association of postprandial hyperlipidemia, small and dense LDL particles and low HDL cholesterol levels is a major cardiovascular risk factor, highly prevalent in insulin resistant and diabetic patients. Several recent epidemiological studies have demonstrated that an abnormal increase in the postprandial triglyceride levels is an independent cardiovascular risk factor, independent from fasting triglyceride levels. A decreased clearance of postprandial triglycerides is related to an abnormal intravascular lipoprotein metabolism, most of the time secondary to an insulin resistant state and genetic factors. This abnormal lipoprotein metabolism also induces a redistribution of LDL particles towards small and dense particles and a decrease in the HDL cholesterol levels. Small, dense LDL are associated with a 3 fold increase in the risk of ischemic heart disease, but does not remain a significant risk factor after adjustment for triglyceride levels. Decreased HDL cholesterol and apolipoprotein A-I levels are strong cardiovascular risk factors, which does not seem to be better assessed with the assay of various HDL sub-fractions (HDL(2) et HDL(3), LpA-I et LpA-I: A-II.).     

Enhanced oxidative susceptibility and reduced antioxidant content of metabolic precursors of small, dense low-density lipoproteins

PURPOSE: Elevated plasma concentrations of low-density lipoproteins (LDL) increase risk for coronary heart disease. However, lipoprotein profiles rich in small, dense LDL particles confer greater risk than those that mainly consist of large, buoyant LDL. This may be due, in part, to the greater oxidative susceptibility of small, dense LDL. In the current studies, we tested whether differences in the oxidative behavior of buoyant and dense LDL arise from differences in their immediate metabolic precursors, intermediate-density lipoproteins. SUBJECTS AND METHODS: We compared the properties of intermediate-density lipoproteins and buoyant and dense LDL subfractions in 9 subjects with the large, buoyant LDL phenotype versus 6 with the small, dense LDL phenotype. Oxidative susceptibility was evaluated based on conjugated diene formation and parinaric acid oxidation induced by copper. Antioxidants (ubiquinol-10 and alpha-tocopherol) were measured by high-performance liquid chromatography. RESULTS: Oxidative susceptibility was increased and antioxidant concentrations were decreased with increasing lipoprotein density (intermediate intermediate-density lipoproteins to buoyant LDL to dense LDL). Intermediate-density lipoproteins from subjects with the small, dense LDL phenotype had a greater oxidative susceptibility (by the parinaric acid test) and lower antioxidant concentrations than corresponding particles from subjects with the large, buoyant LDL phenotype. CONCLUSIONS: Differences in oxidative susceptibility between large, buoyant and small, dense LDL particles are apparent in their lipoprotein precursors. These results suggest that lipoprotein oxidative susceptibility may be metabolically programmed and that intermediate-density lipoproteins may contribute to the increased risk associated with the small, dense LDL phenotype.     

The small, dense LDL phenotype as a correlate of postprandial lipemia in men

The atherogenic dyslipidemia of the insulin resistance syndrome is characterized by hypertriglyceridemia (hyperTG), elevated apolipoprotein (apo) B levels, reduced high-density lipoprotein (HDL) cholesterol concentrations and by an increased proportion of small, dense low-density lipoprotein (LDL) particles. Although the hyperTG-low HDL cholesterol dyslipidemia has been associated with an impaired clearance of dietary fat, the contribution of the small, dense LDL phenotype as an independent predictor of postprandial triglyceride (TG) clearance remains uncertain. We have therefore compared the postprandial TG response among three subgroups of men characterized by small, intermediate or large LDL particles in a total sample of 69 men (mean age +/- SD; 45.1 +/- 10.5 years). To identify men with small versus large LDL particles, the first (LDL peak particle diameter < 251.9 A) and the third (> 257.6 A) tertiles of the distribution of LDL particle diameters were used as cutoff points. Men with small, dense LDL particles had the expected fasting dyslipidemic profile (high TG-low HDL cholesterol levels) compared to men with large, buoyant LDL particles. The oral lipid tolerance test revealed that men with small, dense LDL particles had significantly higher total-, large-, and medium-TG-rich lipoprotein (TRL) responses to a fatty meal than men with large LDL particles (P < 0.03). In addition, within a subgroup of normolipidemic men (TG < 2.3 mmol/l and HDL cholesterol > 0.9 mmol/l), those with small, dense LDL particles had higher levels of total-, medium- and small-TRL responses compared to men with large, buoyant LDL particles (P < 0.05). Moreover, normotriglyceridemic men with small, dense LDL had higher levels of small-TRLs measured 8 h after the ingestion of the fat meal (P < 0.05) compared to normolipidemic men with large, buoyant LDL particles. Results of the present study suggest that the dense LDL phenotype may be an additional fasting marker of an exaggerated postprandial TG response and of an impaired clearance of TRLs.     

The role of small, dense low density lipoprotein (LDL): a new look

Plasma low density lipoprotein (LDL) plays a central role in atherogenesis, and elevated levels of LDL are associated with an increased risk of coronary heart disease (CHD). Studies have now revealed that LDL is structurally heterogeneous, based on its size and density. Patients with combined hyperlipidemia exhibit a lipid profile - the so-called atherogenic lipoprotein phenotype - that is associated with elevated triglyceride levels, low levels of high density lipoprotein and a preponderance of atherogenic, small, dense LDL particles. Such individuals are at an increased risk of CHD events, regardless of their total LDL circulating mass. Evidence suggests that when plasma triglycerides exceed a critical threshold of approximately 133 mg/dl (1.5 mmol/l), this favours the formation of small, dense LDL from larger, less dense species. Lipid-lowering agents that are capable of lowering triglyceride levels below this threshold value will cause a shift to a less dense and, therefore, less atherogenic LDL profile. This effect has been demonstrated for the HMG-CoA reductase inhibitor atorvastatin which, in addition to its ability to markedly decrease the total LDL circulating mass, can also shift the LDL profile towards less dense, larger species. This suggests that atorvastatin may also affect the atherogenic lipoprotein phenotype found in patients with combined hyperlipidemia.     

Cholesteryl ester storage disease. Report of a case

Cholesteryl ester storage disease (CESD) is a rare disorder of familial incidence characterized by the accumulation of cholesteryl ester and triglycerides in the liver, intestine and bone marrow. Until now only 21 cases have been reported in the literature. We present a 9 months old girl presenting with increased abdominal girth. She had normal liver function tests and increased cholesterol and triglycerides serum levels. The liver biopsy showed many cholesterol cristals seen as needle shaped cristals under polarized light. This is the youngest patient being diagnosed clinically in the literature.     

Autophagy is a key feature in the pathogenesis of systemic sclerosis

Autophagosomes are formed during autophagy, which is activated by hypoxia and starvation. Autophagy is important for mast cell degranulation. We hypothesized that autophagy is a key feature in the pathogenesis of systemic sclerosis (SSc). We examined SSc clinical features and mast cell density across the presence and severity of autophagy. Skin punch biopsy was performed on 33 SSc patients and 6 healthy controls (HC). Autophagy was evaluated by immunofluorescence on paraffin sections using LC3-FITC staining on these patients. The intensity of staining and mast cell density was examined across clinical features in 19 of the SSc patients. Presence of autophagosome formation was assessed by EM in 17 of the SSc patients and 4 HC. In our SSc study population, 29 of subjects were female and 23 were limited cutaneous. Twenty-nine of 33 SSc patients had autophagy by LC3-FITC staining. Intensity of staining decreased with longer duration of SSc (p = 0.09) and RP (p = 0.10). Bloating and distention differed across level of intensity staining (Wilcoxon signed-rank test, p = 0.05), with the greatest levels among those with moderate intensity. On EM, autophagosome formation was present in 16 of 17 SSc patients and no HC. All SSc patients had perivascular mast cells. Autophagy was present in 29 of 33 SSc patients, and none of our HC suggesting importance in pathogenesis. Autophagy staining was greater among those with shorter duration of SSc. Bloating and distention were higher in patients with moderate autophagy staining. Perivascular mast cells were present in all SSc patients. The role of autophagy in vasculopathy and mast cell activation in SSc warrants further studies.     

Hypothyroidism results in small dense LDL independent of IRS traits and hypertriglyceridemia

There is evidence of an association between hypothyroidism and coronary heart disease. We decided to look at the relationship between hypothyroidism and LDL subclasses' pattern including small, dense LDL to define a biochemical basis for better management of the CHD risk of these patients. We utilized a case-control design to evaluate differences in lipid parameters between cases and controls. Univariate analysis revealed that many factors were associated with LDL particle size. Binary logistic regression however revealed that only thyroid status and serum triglyceride (TG) levels were independently associated with LDL particle size. Results from this study support an independent association between LDL particle size phenotype and both plasma TG concentrations and thyroid status. After adjusting for TG levels, other insulin resistance syndrome (IRS) traits were not associated with LDL size phenotype, suggesting that the IRS related sdLDL is linked most strongly to alterations in TG levels.     

Usefulness of serum total cholesterol/triglyceride ratio for predicting the presence of small, dense LDL

OBJECTIVE: We examined the usefulness of the serum total cholesterol (TC)/triglyceride (TG) and LDL-cholesterol (LDL-C)/TG ratios for predicting the presence of small, dense LDL, by comparing them with the established indicators of small, dense LDL, such as the LDL-migration index (LDL-MI) and LDL-C/Apolipoprotein B (ApoB) ratio. MATERIALS AND METHODS: Fasting serum lipid was analyzed in 99 Japanese hyperlipidemic and normolipidemic subjects (34 males and 65 females, 59.4 +/- 11.9 years old). RESULTS: A good negative correlation was observed between LDL-MI and log (TC/TG) (R(2) = 0.473, p < 0.0001). There was a strong positive correlation between LDL-C/ApoB and log (TC/TG) (R(2) = 0.665, p < 0.0001). Similar results were obtained using LDL-C instead of TC. Using LDL-MI > 0.4 as an indicator of small, dense LDL, the upper limit of TG was estimated to be 140-142 mg/dl. CONCLUSION: TC/TG and LDL-C/TG may offer a convenient and simple clinical tool for predicting the presence of small, dense LDL. Particularly, TC/TG could be an easy-to-use indicator of small, dense LDL for general practitioners.     

Ex vivo measures of LDL oxidative susceptibility predict carotid artery disease

AIM: The purpose of the study was to assess whether ex vivo measures of low-density lipoprotein (LDL) oxidation improved prediction of carotid artery disease (CAAD) case-control status compared to standard lipid and smoking measures. METHODS: One hundred and forty cases with a high degree of carotid artery stenosis aged 40-83 years and an equal number of controls without stenosis or other vascular disease were matched by censored age within 2 years. Matched logistic regression evaluated the significance of copper-induced oxidative measures with and without covariates. The relationship of LDL oxidation measures with statin use and current smoking was also evaluated. RESULTS: Logistic regression demonstrated a significant effect of the three correlated measures of oxidative susceptibility (lag time, oxidation rate and maximal rate of oxidation) separately on disease prediction (all p<0.05). These oxidative measures remained significant predictors of case-control status when other cardiovascular disease predictors (age; LDL-C, HDL-C and ApoAI levels; current smoking, ever smoking and pack-years smoked) were jointly considered. This relationship was not attributable to the effects of statin use on LDL oxidation. CONCLUSIONS: Ex vivo measures of oxidation improved the prediction of carotid artery disease status, suggesting that this is an important determinant of atherosclerotic risk in this older population.     

A preponderance of small dense LDL is associated with specific insulin,proinsulin and the components of the insulin resistance syndrome in non-diabetic subjects

Summary Recently, the presence of small dense low density lipoprotein (LDL) has been postulated to be a stronger risk factor for coronary heart disease than large LDL. While small dense LDL has been associated with individual components of the insulin resistance syndrome such as hypertension, high triglyceride level, low high density (HDL) cholesterol, and diabetess mellitus, there has been little work exploring whether LDL size is decreased in subjects with multiple metabolic disorders. We examined the association of LDL size and pattern to specific insulin (which does not cross-react with proinsulin), proinsulin, increased triglyceride, decreased HDL, hypertension and impaired glucose tolerance in 488 non-diabetic subjects from the San Antonio Heart Study. LDL size was significantly related to specific insulin, proinsulin and the fasting proinsulin/insulin ratio. Small dense LDL was significantly associated with high triglyceride level, decreased HDL cholesterol, hypertension and impaired glucose tolerance. LDL size (å) decreased in a stepwise fashion with increasing number of the metabolic disorders described above (zero 262.6±9.4; one 257.0±9.3; two 256.4±9.4; three 249.0±9.1; and four 244.9±9.0). These results were similar in men and women and in non-Hispanic whites and Mexican Americans. The association between LDL size and the number of metabolic disorders remained statistically significant even after adjustment for obesity, body fat distribution, gender, ethnicity, proinsulin and insulin concentrations. Furthermore, decreases in LDL size are also significantly associated with both a selective beta-cell defect (as estimated by the fasting proinsulin/insulin ratio) and insulin resistance (as estimated by the fasting insulin concentrations) although the association was some-what stronger for the latter. We conclude that small dense LDL may form part of the insulin resistance syndrome in non-diabetic subjects.Abbreviations BMI Body mass index - LDL low density lipoprotein - HDL high density lipoprotein - IGT impaired glucose tolerance - NIDDM non-insulin-dependent diabetes mellitus - WHR waist-hip ratio     

Regulation of small dense LDL concentration in Korean and Scottish men and women

Small dense LDL is now emerging as an important risk factor for coronary artery disease. The amount of the LDL III has been reported to differ between ethnic groups. To investigate differences in the distribution of LDL subfractions between Korean and Scottish populations, we measured the plasma concentration and percent distribution of three major LDL subfractions in age-and sex-matched, middle aged, healthy 124 Korean and Scottish subjects (32 Korean men vs. 32 Scottish men; 30 Korean women vs. 30 Scottish women). Body mass index and waist circumference did not differ between the two ethnic groups. Total cholesterol and LDL cholesterol concentrations were higher in Scottish men compared with Korean men (P<0.01), while plasma triglyceride concentration was higher in Korean men and women (P<0.01 in men, P<0.05 in women). HDL cholesterol concentrations in both Korean men and women were lower than that of their Scottish counterparts (P<0.05 in men; P<0.001 in women). Korean men had lower concentrations of total LDL (242+/-65 vs. 325+/-122 mg/dl, P<0.01), LDL I (24+/-18 vs. 60+/-36 mg/dl, P<0.001) and LDL II (110+/-56 vs. 196+/-78 mg/dl, P<0.001). In contrast, LDL III concentration was markedly higher in Korean men (108+/-75 vs. 70+/-65 mg/dl, P<0.05). Likewise, the percent of LDL I (10.0+/-7.3 vs. 19.1+/-10.1%, P<0.001) and LDL II (47.2+/-20.7 vs. 60.1+/-10.9%, P<0.01) were lower in Korean men, while that of LDL III was higher (42.8+/-24.9 vs. 20.8+/-15.0%, P<0.001). In the female population, there were no differences in total LDL and LDL I concentrations between Korean and Scottish. LDL II concentration was lower in Korean women (106+/-53 vs. 151+/-57 mg/dl, P<0.01). Korean women showed a higher percent of LDL III (24.8+/-24.7 vs. 14.2+/-5.9%, P<0.05) and a lower LDL II (47.8+/-19.1 vs. 61.0+/-10.0%, P<0.01). Multiple linear regression revealed that plasma triglyceride concentration was the most important determinant of the LDL III subfraction concentration in Korean men and women and in Scottish men. In Korean men, the LDL III concentration rose linearly through the whole range of plasma triglyceride concentration, whereas in Scottish men, there was a threshold at 108 mg/dl triglyceride above which there was a positive association. Korean women showed the same pattern as Scottish men. We suggest that LDL concentrations and LDL subfraction distributions are regulated differently in these two ethnic groups. The different relationships between triglyceride and LDL III subfraction in Koreans versus Scots suggest that other factors, such as hepatic lipase or cholesteryl ester transfer protein may additionally play a role determining the LDL subfraction profile.     

Flow-mediated vasoactivity and circulating adhesion molecules in hypertriglyceridemia: association with small, dense LDL cholesterol particles

BACKGROUND: Endothelial dysfunction is considered one of the earliest events in the process of atherosclerosis, and an impaired vasodilatory response has been reported in patients with dyslipidemias. However, the independent association between hypertriglyceridemia and endothelial dysfunction is controversial, and the relation between endothelium-dependent vasodilation and circulating cell adhesion molecules as markers of endothelial dysfunction has not been fully determined. METHODS: Brachial artery flow mediated vasodilation (FMV) and the soluble forms of vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) were determined after overnight fasting in 16 men with hypertriglyceridemia (age 33 +/- 6 years) and in 16 age-matched healthy men with normal triglycerides and cholesterol. Subjects who smoked and those with known cardiovascular disease, diabetes, hypertension, recent or active infections, or any other disease that could affect leukocyte activation were excluded from the study. RESULTS: Compared with normal subjects, subjects with hypertriglyceridemia showed a higher level of sVCAM-1 and sICAM-1 (both P <.001), a reduced FMV (P <.01), and a smaller LDL particle size (P <.05). FMV had a significant inverse correlation with sVCAM-1 (r = -0.61, P <.001) and sICAM-1 (r = -0.38, P <.03). LDL particle size had a strong, direct association with FMV (r = 0.75, P <.001) and an inverse association with adhesion molecules. By multiple regression analysis, triglycerides (P <.001) and small LDL particle size (P <.002) predicted a reduced FMV. CONCLUSIONS: Serum level of cell adhesion molecules is increased and FMV is impaired in young healthy men with hypertriglyceridemia compared with age-matched men with normal lipid levels. Small, dense LDL particles may play a role in determining endothelial dysfunction in these subjects.     

The small, dense LDL phenotype and the risk of coronary heart disease: epidemiology, patho-physiology and therapeutic aspects.

More than decade ago, several cross-sectional studies have reported differences in LDL particle size, density and composition between coronary heart disease (CHD) patients and healthy controls. Three recent prospective, nested case-control studies have since confirmed that the presence of small, dense LDL particles was associated with more than a three-fold increase in the risk of CHD. The small, dense LDL phenotype rarely occurs as an isolated disorder. It is most frequently accompanied by hypertriglyceridemia, reduced HDL cholesterol levels, abdominal obesity, insulin resistance and by a series of other metabolic alterations predictive of an impaired endothelial function and increased susceptibility to thrombosis. Whether or not the small, dense LDL phenotype should be considered an independent CHD risk factor remains to be clearly established. The cluster of metabolic abnormalities associated with small, dense LDL particles has been referred to as the insulin resistance-dyslipidemic phenotype of abdominal obesity. Results from the Québec Cardiovascular Study have indicated that individuals displaying three of the numerous features of insulin resistance (elevated plasma insulin and apolipoprotein B concentrations and small, dense LDL particles) showed a remarkable increase in CHD risk. Our data suggest that the increased risk of CHD associated with having small, dense LDL particles may be modulated to a significant extent by the presence/absence of insulin resistance, abdominal obesity and increased LDL particle concentration. We suggest that the complex interactions among the metabolic alterations of the insulin resistance syndrome should be considered when evaluating the risk of CHD associated with the small, dense LDL phenotype. From a therapeutic standpoint, the treatment of this condition should not only aim at reducing plasma triglyceride levels, but also at improving all features of the insulin resistance syndrome, for which body weight loss and mobilization of abdominal fat appear as key elements. Finally, interventions leading to reduction in fasting triglyceride levels will increase LDL particle size and contribute to reduce CHD risk, particularly if plasma apolipoprotein B concentration (as a surrogate of the number of atherogenic particles) is also reduced.     

Alpha-tocopherol supplementation decreases the oxidative susceptibility of LDL in renal failure patients on dialysis therapy

Atherosclerotic cardiovascular disease is the leading cause of death in patients with end stage renal disease (ESRD) who have undergone dialysis treatment. The oxidation of low density lipoprotein (LDL) appears to be a crucial step in the pathogenesis of atherosclerosis. The increased oxidative stress and attendant increased oxidizability of lipoproteins, such as LDL could contribute to the accelerated atherosclerosis in dialysis patients. Since alpha-tocopherol (AT) is the major antioxidant in LDL, the aim of the present study was to test the effectiveness of RRR-AT supplementation (800 I.U. per day) for 12 weeks on the susceptibility of LDL to oxidation. The study subjects comprised patients with chronic renal failure on hemodialysis (HD), peritoneal dialysis (PD), and age and sex matched controls (C). Plasma fatty acids, lipoproteins and AT levels were measured in these subjects before and after supplementation. Also, LDL AT and oxidizability was studied. LDL was isolated by ultracentrifugation at baseline and after 12 weeks of supplementation, and subjected to a 5-h time course of copper catalyzed oxidation. Oxidation was measured by the formation of conjugated dienes (CD) and lipid peroxides (LP). Supplementation with AT did not alter the plasma lipid or lipoprotein profile of these subjects. Plasma lipid-standardized AT and LDL AT concentrations were not different among the groups at baseline. AT supplementation significantly increased plasma lipid-standardized AT (C=150%, HD=149%, PD=217%, P<0.001) and LDL AT concentrations (C=94%, HD=94%, PD=135%, P<0.003). AT enrichment of LDL resulted in a significant prolongation in conjugated diene lag phase in all groups (C=34%, HD=21%, PD=54%, P<0.02). Lipid peroxide lag phase was also increased significantly in C (27%,) and PD (40%) groups after AT supplementation (P<0.01). There was a significant positive correlation between plasma lipid standardized AT and lag phase (r=0. 54, P=0.0003). Overall, AT decreased the susceptibility of LDL to oxidation in patients with chronic renal failure but the benefit appears to be greater in patients on PD. Therefore, AT supplementation may also provide a measure of protection against CAD in patients with chronic renal failure on dialysis therapy.     

Predominance of small dense LDL differentiates metabolically unhealthy from metabolically healthy overweight adults in Korea

Objective

The purposes of this study were (1) to determine the association between lipoprotein subfraction profiles and metabolically healthy overweight (MHO) phenotype, as defined by visceral adiposity; and (2) to identify the strongest predictor of metabolic health among the lipoprotein measurements.

Materials/Methods

This cross-sectional study was comprised of 462 overweight patients, who were classified as MHO or non-MHO based on their visceral adipose tissue (VAT) area to subcutaneous adipose tissue area (SAT) ratio (VAT/SAT ratio). Serum lipoprotein subfraction analyses and other metabolic parameters were measured.

Results

Among the overweight participants, two hundred fifty-five individuals (53.7%) had the MHO phenotype. After adjusting for age, sex, medication, lifestyle factors, and confounding metabolic characteristics, the non-MHO group showed significantly higher lipid levels and a greater prevalence of unfavorable lipid profiles. LDL subclass pattern type B was the most significant predictor of the non-MHO phenotype (odds ratio 2.70; 95% CI 1.55–4.69), while serum LDL cholesterol level was not a significant predictor of the non-MHO phenotype.

Conclusions

Lipoprotein subfraction particle measurements were significantly associated with the non-MHO phenotype and a higher VAT/SAT ratio, with small dense LDL predominance being the most significant predictor of MHO phenotype. These findings will help identify MHO and non-MHO phenotypes and perhaps lead to a development of cost-effective individualized treatments.