Dense LDL Research Articles

Correlation of Atherogenic Indices and IMA with Glycaemic Control in Diabetic Patients with and without Dyslipidemia

Atherosclerosis is one of the most common major complications associated with type 2 diabetes mellitus. Recent research suggests that the major culprits are modified proteins like LDL and albumin. Hence, this study focuses on the analysis of small dense LDL (sd LDL), oxidised LDL (ox LDL) and ischemia modified albumin (IMA) in type 2 diabetes mellitus patients with and without dyslipidemia and compare with healthy subjects. Further, correlate atherogenic indices (ox LDL/HDL and sdLDL/HDL) with glycated haemoglobin in these groups. 90 subjects aged between 30-60 years of both the genders were divided into 3 groups namely diabetic dyslipidemia (Group1), diabetic non dyslipidemia (Group2) and normal (group3). Serum lipid profile, ox LDL and IMA were estimated by spectrophotometric methods, sd LDL by calculation and glycated Hb by HPLC. Ox LDL showed an apparent increase in diabetics (group 1and 2) compared to normal. Though sd LDL levels in diabetic patients remained normal, the values doubled in dyslipidemic diabetics. sd LDL/HDL ratio was significantly high in both group1and 2 compared to normal. Furthermore, there was a significant positive correlation of this ratio with glycated Hb in both groups of diabetes. Serum IMA also increased significantly in diabetes with dyslipidemia compared to non dyslipidemic diabetics. The study highlights the fact that in diabetics, oxidatively modified proteins like LDL and albumin may increase with hyperglycemia even before dyslipidemia sets in. Hence, ox LDL and sd LDL may be included in the battery of extended lipid profile to monitor cardiovascular complications in diabetes.

Fibrates in the secondary prevention of cardiovascular disease (infarction and stroke). Results of a systematic review and meta-analysis of the Cochrane collaboration

Fibrates are a group of drugs that are known mainly for reducing triglycerides, increasing high density lipoproteins (HDL), and reducing the fraction of small, dense LDL particles. The results of a Cochrane Collaboration study have recently been published on their efficacy and safety in the secondary prevention of severe cardiovascular accidents, including coronary and cerebrovascular disease.The study included randomised clinical trials in which the fibrate was compared with placebo or with no treatment. Clinical trials comparing two different fibrates were excluded.The clinical trials evaluated included a total of 16,112 patients (13 trials). The meta-analysis (including all the trials with fibrates) showed evidence of a protective effect of the fibrates compared with placebo as regards a compound objective of non-fatal stroke, non-fatal myocardial infarction, and death of cardiovascular origin (hazard ration of 0.88, with a 95% confidence interval of 0.83–0.94; in 16,064 individuals included in 12 studies). Thus, the results showed, with a moderate level of evidence, that fibrates could be effective in secondary prevention considering a compound objective of non-fatal stroke, non-fatal myocardial infarction, and death of cardiovascular origin.

Hypertriglyceridemia: A new paradigm

Low-density lipoprotein cholesterol (LDL-C) has been proven time and again to be independently associated with the risk of cardiovascular diseases (CVD). However, triglycerides (TG) are now also emerging as an important as well as independent risk factor for CVD. International lipid guidelines recommend statins as first-line drugs. However, there always remains a residual risk with statins, especially in the high-risk diabetes subset of patients. The most important reason cited for increased residual CV risk with statins is the non-high density lipoprotein cholesterol component, of which high TGs are an integral part. Several large epidemiological, Mendelian randomisation, population-based and genetic studies are emerging which are pointing towards the fact that high TG leads to CV morbidity and mortality. Pathophysiological basis of hypertriglyceridemia associated with increased CV risk has been attributed to increase circulating chylomicron and TG-rich lipoprotein remnants, increased small dense LDL, heightened risk of endothelial dysfunction and plaque formation. Recent international guidelines recommend TG lowering therapy at TG >200 mg/dl when not controlled by optimal statin therapy. TG levels more than 500 mg/dl, however, require non-statin lipid-lowering agents as primary agents to reduce the risk of acute pancreatitis. Fibrates, niacin and omega 3 fatty acids are recommended as TG-lowering drugs. However, they are not without their share of adverse events. Saroglitazar is a novel dual peroxisome proliferator-activated enzyme agent which has been found to be free of many such adverse events and also adequate in providing dual control over hypertriglyceridemia along with significant glycaemic control.

Los fibratos en la prevención secundaria de la enfermedad cardiovascular (infarto e ictus). Resultados de una revisión sistemática y metaanálisis de la colaboración Cochrane

Fibrates are a group of drugs that are known mainly for reducing triglycerides, increasing high density lipoproteins (HDL), and reducing the fraction of small, dense LDL particles. The results of a Cochrane Collaboration study have recently been published on their efficacy and safety in the secondary prevention of severe cardiovascular accidents, including coronary and cerebrovascular disease.The study included randomised clinical trials in which the fibrate was compared with placebo or with no treatment. Clinical trials comparing two different fibrates were excluded.The clinical trials evaluated included a total of 16,112 patients (13 trials). The meta-analysis (including all the trials with fibrates) showed evidence of a protective effect of the fibrates compared with placebo as regards a compound objective of non-fatal stroke, non-fatal myocardial infarction, and death of cardiovascular origin (hazard ration of 0.88, with a 95% confidence interval of 0.83 to 0.94; in 16,064 individuals included in 12 studies). Thus, the results showed, with a moderate level of evidence, that fibrates could be effective in secondary prevention considering a compound objective of non-fatal stroke, non-fatal myocardial infarction, and death of cardiovascular origin.

The role of plasma lipoprotein lipase, hepatic lipase and GPIHBP1 in the metabolism of remnant lipoproteins and small dense LDL in patients with coronary artery disease

BackgroundThe relationship between plasma lipoprotein lipase (LPL), hepatic triglyceride lipase (HTGL), glycosylphosphatidylinositol anchored HDL binding protein1 (GPIHBP1) concentration and the metabolism of remnant lipoproteins (RLP) and small dense LDL (sdLDL) in patients with coronary artery disease (CAD) is not fully elucidated. MethodsOne hundred patients who underwent coronary angiography were enrolled. The plasma LPL, HTGL and GPIHBP1 concentrations were determined by ELISA. The time dependent changes in those lipases, lipids and lipoproteins were studied at a time-point just before, and 15min, 4h and 24h after heparin administration. ResultsThe LPL concentration exhibited a significant positive correlation with HDL-C, and inversely correlated with TG and RLP-C. The HTGL concentration was positively correlated with RLP-C and sdLDL-C. The HTGL ratio of the pre-heparin/post-heparin plasma concentration and sdLDL-C/LDL-C ratio were significantly greater in CAD patients than in non-CAD patients. GPIHBP1 was positively correlated with LPL and inversely correlated with RLP-C and sdLDL-C. ConclusionThe HTGL concentration was positively correlated with RLP-C and sdLDL-C, while LPL and GPIHBP1 were inversely correlated with RLP-C and sdLDL-C. These results suggest that elevated HTGL is associated with increased CAD risk, while elevated LPL is associated with a reduction of CAD risk.

Classical and emergent cardiovascular disease risk factors in type 2 diabetics from the Vallecas area (DICARIVA study).

Type 2 diabetes mellitus (T2DM) is a major independent risk factor for cardiovascular disease (CVD) and a highly prevalent disease with a wide variety of associated metabolic disorders. To describe features and prevalence of altered CVD risk factors in a T2DM population: DIabetes CArdiovascular RIsk of VAllecas (DICARIVA) study. 735 adult Spanish patients of the Vallecas area with T2DM from the Infanta Leonor Hospital (Madrid, Spain) were included in the study. Age, disease time-evolution, anthropometric measurements, glycemia, glucated haemoglobin A1c (HbA1c), lipid/lipoprotein profile, total cholesterol/high density lipoprotein cholesterol (HDL-cholesterol), low density lipoprotein cholesterol (LDL-cholesterol)/HDL-cholesterol and triglycerides/HDL-cholesterol ratios, triglycerides-glucose index (TyG), fibrinogen, high sensitivity-c reactive protein (hs-CRP) and microalbuminuria were assessed. Mean, standard deviations, and percentile distributions were obtained in males, females and the whole T2DM population for classical and emergent CVD risk markers. Obesity was found in 45% of patients, while 60% had high cardiovascular risk according to waist circumference and conicity index. Total and LDL-cholesterol were at desirable and optimum levels, respectively, in 60% of patients. One third showed the conjoint presence of low HDL-cholesterol, high triglycerides and small and dense LDL. Increased levels of hs-CRP, hyperfibrinogenia and microalbuminuria were detected in 40%, 50% and 30% of patients, respectively. Age, body mass index, total cholesterol, hs-CRP and fibrinogen were higher while weight, conicity index, total cholesterol/HDL-cholesterol, LDL-cholesterol/HDL-cholesterol and triglycerides/HDL-cholesterol ratios, and microalbuminuria lower in women. According to TyG values 62% of patients suffered metabolic syndrome. Altered anthropometric and metabolic CVD risk factors were highly prevalent in the DICARIVA study. The CVD marker cut-off points obtained in some emergent markers seems relevant and would be employed for future early T2DM diagnoses strategy in order to reduce its high morbidity and mortality impact.

Abstract 21185: Predictors of High Risk of Acute Coronary Syndrome in Diabetes: An Endothelial Damage Biomarker Approach

Background: Patients with diabetes mellitus (DM) are at increased risk of acute coronary syndrome (ACS); however, the factors predicting those at highest risk are not well-understood. We identified demographic and standard risk factors that best predict those at high risk based on a multiple biomarker algorithm. Methods: We studied adults with DM from a clinical registry who had measures of the PULS score (GD Biosciences, Irvine, CA), a biomarker algorithm identifying endothelial damage and predicting 5-year ACS risk consisting of HGF, sFAS, Fas Ligand, Eotaxin, CTACK, MCP3, Il-16, HbA1c, HDL-C, as well as age, sex, DM, and family history of CHD. We identified the proportion of patients with DM at low (<3.5%), intermediate (3.5-<7.5%), and high (≥7.5%) risk of ACS based on PULS. Stepwise logistic regression providing odds ratios and 95% confidence intervals (CIs) examined the relationship of age, gender, and individual risk factors not part of the PULS algorithm with the likelihood of a high risk PULS score. Results: There were 668 adults with DM (females: 39.5%, ages 30 to 100, mean age 66.5 years). Of these, 6.0% had a low, 12.9% intermediate, and 81.1% high risk PULS score. In the stepwise logistic regression, independent predictors of a high risk PULS score included age, sex, hypertension, body mass index (BMI), and current smoking (table). Other risk factors and biomarkers, including apolipoprotein A-1 (ApoA1), apolipoprotein B (ApoB), ratio ApoB to ApoA1, total or LDL-cholesterol, triglycerides, very low density lipoprotein cholesterol, lipoprotein (a), systolic or diastolic blood pressure, hs-CRP, and small dense LDL were not associated with a high PULS risk score. Conclusion: We demonstrated that age, male gender, hypertension, BMI, and current smoking are key factors potentially identifying persons with DM at high risk of ACS based on an algorithm identifying endothelial damage. Further validation through prospective studies with actual ACS events are needed.

Association of small, dense LDL cholesterol with acute myocardial infarction in young population

Association of small, dense LDL cholesterol with acute myocardial infarction in young population

Serum low‐density lipoprotein as a dietary responsive biomarker of cardiovascular disease risk: Consensus and confusion

AbstractThe replacement of saturated fatty acids (SFA) has been the mainstay of our dietary guidelines to help prevent cardiovascular disease (CVD) for over 30 years. However, the underlying evidence to support this guideline is now held in contentious disrepute on the grounds of an apparent lack of evidence, largely from meta‐analyses, for a direct relationship between saturated fat and CVD mortality. This can be explained by the fact that the relationship between dietary SFA and CVD is not direct, but indirect and mediated through the low‐density lipoprotein cholesterol (LDL‐C) raising effects of certain SFA, in certain foods. There is over 100 years of evidence to link raised serum cholesterol with CVD and to support the current consensus that serum LDL is causally related to CVD morbidity and mortality. Nevertheless, the role of LDL as a biomarker of CVD risk, as measured by its cholesterol content (LDL‐C), is often confused with its contribution to cardio‐metabolic risk by its conversion into small and dense LDL particles with increased potential to cause CVD. The clinical utility of serum LDL is outstanding as a biomarker for CVD, albeit through an increase in its cholesterol mass (LDL‐C), its small particle size or over‐abundance of these particles. What is of overriding importance is to identify and modify these characteristics in LDL at the earliest stage of their development and to reduce the associated CVD risk through appropriate and sustained changes in diet and lifestyle.

Small dense LDL cholesterol affects arterial stiffness in Japanese: The Nagahama study

Small dense LDL cholesterol affects arterial stiffness in Japanese: The Nagahama study

A new enzyme-linked immunosorbent assay system for human serum hepatic triglyceride lipase

There is no established method for measuring human hepatic triglyceride (TG) lipase (HTGL) concentration in serum. In this study, we developed new monoclonal Abs (MoAbs) (9A1 mouse MoAb and 141A1 rat MoAb) that react with HTGL both in serum and in postheparin plasma (PHP) and established a novel ELISA system for measuring serum HTGL and PHP-HTGL concentrations. To confirm the specificity of MoAbs, we performed immunoprecipitation-immunoblotting analysis. Both 9A1 mouse MoAb and 141A1 rat MoAb were able to immunoprecipitate not only recombinant HTGL and PHP-HTGL but also serum HTGL, demonstrating that HTGL exists in serum obtained without heparin injection. This method yielded intra- and interassay coefficients of variation of <6% and showed no cross-reactivity with LPL or endothelial lipase. In clinical analysis on 42 male subjects with coronary artery disease, there were strong positive correlations of serum HTGL concentration to PHP-HTGL concentration (r = 0.727, P < 0.01). Serum HTGL concentrations showed positive correlations to serum TGs (r = 0.314, P < 0.05) and alanine aminotransferase (r = 0.406, P < 0.01), and tendencies toward positive correlations to LDL cholesterol, small dense LDL, and γGTP. These results suggest that this new ELISA method for measuring serum HTGL is applicable in daily clinical practice.

Is lipoprotein subfraction analysis in patients in chronic hemodialysis reasonable? - a pilot study

Aim: In patients (pts) with end-stage renal disease, paradoxically inverse relationship of total cholesterol with total mortality exists. The research is now focused on the lipoprotein classes and subclasses and on the possible role of small dense LDL and small HDL particles on the atherogenesis. The aim of our study was to examine differences in individual lipoprotein classes and subclasses between chronic high volume hemodiafiltration (HD HDF) patients and healthy volunteers (CON).

Obesity is associated with increased carotid intima media thickness and presence of small dense LDL in healthy adolescents from Guanajuato, Mexico

Obesity is associated with increased carotid intima media thickness and presence of small dense LDL in healthy adolescents from Guanajuato, Mexico

Small dense LDL cholesterol as strong predictors for secondary cardiovascular events compared with LDL cholesterol in elderly patients

Small dense LDL cholesterol as strong predictors for secondary cardiovascular events compared with LDL cholesterol in elderly patients

The sdLDL Reduces MRC1 Expression Level and Secretion of Histamin e in Differentiated M2-macrophages from Patients with Coronary Artery Stenosis.

The macrophage polarization is proposed to be involved in initial events and remodeling of atherosclerosis plaques. Mannose receptor, C type 1 (MRC1) is a trans-membrane glycoprotein participating in phagocytosis and, is highly expressed in the M2 macrophages. The aim of this study was to investigate the effects of sdLDL (small dense LDL) on the MRC1 gene expression level and secretion of histamine in the differentiated M2 macrophages from monocytes of patients with coronary artery stenosis and healthy subjects. The monocytes were isolated from healthy subjects (< 5% stenosis) and patients (> 70% stenosis, SVD (Single Vessel Disease), 2VD (Two-Vessel Disease) and 3VD (Three-Vessel Disease)) by RosetteSep kit and, were differentiated into M2 macrophages by macrophage colonystimulating factor (M-CSF). The sdLDL particles were obtained by PEG-combined precipitation method. The MRC1 gene expression and histamine levels were measured by RT-qPCR and ELISA techniques, respectively. The MRC1 gene expression level was significantly increased in M2 macrophages of healthy subjects (P=0.05) while it reduced in SVD (P=0.05), 2VD (P=0.01) and 3VD (P=0.9) patients after treatment with sdLDL. The histamine value secreted from M2 macrophages (7-day) was higher (>3-fold, P=0.02) in patients as compared to healthy controls. The results showed that the sdLDL particles reduce the MRC1 gene expression levels in the differentiated M2 macrophages from patients with coronary artery disease. Furthermore, they had high inflammatory capacity for the secretion of histamine.

Association of divalent cations and insulin resistance with thyroid hormones in patients with type 2 diabetes mellitus

AimThe study was primarily aimed at investigating the association of Magnesium and Zinc levels in the serum of adult Non- obese and Obese type 2 diabetic patients, with particular reference to thyroid comorbidity. Methods108 patients with T2DM of both genders (24 Non obese and 84 Obese) were enrolled from a tertiary health care unit in Puducherry. The cardio-metabolic risk factors were assessed through body mass index, Waist hip ratio, blood pressure, fasting blood glucose, lipid profile and glycated haemoglobin. Zinc and Magnesium were quantitated. Insulin resistance was by Homeostasis model assessment. Serum free T4, T3 and TSH were also measured. ResultsIn non-obese type 2 diabetic group, Glycated haemoglobin had a strong positive correlation with free T4(r=0.784; p=0.003).TSH also depicted a positive association with HOMA-IR (r=0.924; p<0.001); whereas,T3 and Insulin had negative correlation with Magnesium (r=−0.599* and r=−0.620*; p 0.04 and 0.031). The levels of Zinc and Magnesium in the serum of obese diabetic patients had a positive correlation among them (r=0.565#; p<0.001). TAG/HDL ratio a measure of small dense LDL is positively correlated with LDL in both groups (r=0.881 and 0.912) with p value<0.001 for both. ConclusionCorrelation among Glycemic control, Insulin resistance, Thyroid hormones, divalent cations and dyslipidemia depict differential characteristics in obese and non–obese type2 diabetes with Thyroid comorbidity.

Small, dense LDL: an update.

In this review, we summarize the latest findings on small, dense LDL (sdLDL) atherogenic particles, including their associations with other biomarkers. Increased sdLDL levels have been reported not only in different metabolic disorders such as diabetes, obesity and metabolic syndrome, but also in patients with rheumatoid and psoriatic arthritis as well as hypothyroidism. A wide range of lipid-lowering, as well as other drug classes, including novel antidiabetic agents and nutraceuticals, exert favourable effects on these atherogenic particles. The 'gold standard' methodology for the assessment of sdLDL has not been established yet. However, the association between sdLDL and several biomarkers could facilitate their assessment. Estimation of sdLDL in daily clinical practice may help with the identification of patients at high cardiovascular risk and further contribute in directing specific interventions to prevent and/or decrease such risk.

Metabolism and proteomics of large and small dense LDL in combined hyperlipidemia: effects of rosuvastatin

Small dense LDL (sdLDL) has been reported to be more atherogenic than large buoyant LDL (lbLDL). We examined the metabolism and protein composition of sdLDL and lbLDL in six subjects with combined hyperlipidemia on placebo and rosuvastatin 40 mg/day. ApoB-100 kinetics in triglyceride-rich lipoproteins (TRLs), lbLDL (density [d] = 1.019-1.044 g/ml), and sdLDL (d = 1.044-1.063 g/ml) were determined in the fed state by using stable isotope tracers, mass spectrometry, and compartmental modeling. Compared with placebo, rosuvastatin decreased LDL cholesterol and apoB-100 levels in TRL, lbLDL, and sdLDL by significantly increasing the fractional catabolic rate of apoB-100 (TRL, +45%; lbLDL, +131%; and sdLDL, +97%), without a change in production. On placebo, 25% of TRL apoB-100 was catabolized directly, 37% was converted to lbLDL, and 38% went directly to sdLDL; rosuvastatin did not alter these distributions. During both phases, sdLDL apoB-100 was catabolized more slowly than lbLDL apoB-100 (P < 0.01). Proteomic analysis indicated that rosuvastatin decreased apoC-III and apoM content within the density range of lbLDL (P < 0.05). In our view, sdLDL is more atherogenic than lbLDL because of its longer plasma residence time, potentially resulting in more particle oxidation, modification, and reduction in size, with increased arterial wall uptake. Rosuvastatin enhances the catabolism of apoB-100 in both lbLDL and sdLDL.

Effect of tofacitinib on lipid levels and lipid-related parameters in patients with moderate to severe psoriasis

Psoriasis is a systemic inflammatory disease associated with increased cardiovascular (CV) risk and altered lipid metabolism. Tofacitinib is an oral Janus kinase inhibitor. The aim of the study was to investigate the effects of tofacitinib on traditional and nontraditional lipid parameters and CV risk markers in patients with psoriasis from a phase III study, OPT Pivotal1. Patients with psoriasis were randomized to tofacitinib 5 or 10mg twice daily (BID) or placebo BID. Serum samples were collected at baseline, week 4, and week 16. Analyses included serum cholesterol levels, triglycerides, lipoproteins, lipid particles, lipid-related parameters/CV risk markers, and high-density lipoprotein (HDL) function analyses. At week 16, small concurrent increases in mean low-density lipoprotein cholesterol (LDL-C) and HDL cholesterol (HDL-C) levels were observed with tofacitinib; total cholesterol/HDL-C ratio did not change. There was no significant change in the number of small dense LDL particles, which are considered to be more atherogenic than large particles, and oxidized LDL did not increase. Paraoxonase 1 activity, linked to HDL antioxidant capacity, increased, and HDL-associated serum amyloid A, which reduces the anti-atherogenic potential of HDL, decreased. HDL capacity to promote cholesterol efflux from macrophages did not change. Lecithin-cholesterol acyltransferase activity, which is associated with reverse cholesterol transport, increased. Markers of systemic inflammation, serum amyloid A and C-reactive protein, decreased with tofacitinib. While small increases in lipid levels are observed with tofacitinib treatment in patients with psoriasis, effects on selected lipid-related parameters and other circulating CV risk biomarkers are not suggestive of an increased CV risk [NCT01276639].

Interleukin 6 may be related to indoleamine 2,3-dioxygense function in M2 macrophages treated with small dense LDL particles

Macrophages are known as important immune cells involved in the improvement of atherosclerosis plaques. The M2 macrophages are beneficial because scavenging the non-functional components in vessel sub-endothelial space. In this study, we investigated the effects of small dense LDL (sdLDL) on the changes of indoleamine 2,3-dioxygense (IDO) and interleukin (IL6) in the differentiated M2 macrophages. The patients were selected from who underwent coronary artery angiography. The monocytes were isolated from the whole blood samples of healthy (<5% stenosis) and patient (>70% stenosis; SVD, 2VD and 3VD) subjects and, were differentiated into M2 macrophages. The IDO gene expression, activity and IL6 values were measured by RT-qPCR, colorimetry and ELISA techniques, respectively. In contrast with healthy group, the IDO gene expression and activity were significantly reduced in SVD and 2VD groups (P<0.05). Furthermore, they were conversely associated to secretion of IL6. In conclusion, the data suggested that inflammatory responses in M2 macrophages differentiated from monocytes of patients after treatment of sdLDL may be related to the reduced IDO function.