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Non-HDL-cholesterol and apolipoprotein B compared with LDL-cholesterol in atherosclerotic cardiovascular disease risk assessment.
Carr, SS, Hooper, AJ, Sullivan, DR, Burnett, JR
Pathology. 2019;(2):148-154
Abstract
Low density lipoprotein (LDL) is the predominant atherogenic lipoprotein particle in the circulation. Conventionally, a fasting lipid profile has been used for atherosclerotic cardiovascular disease (ASCVD) risk assessment. A non-fasting sample is now regarded as a suitable alternative to a fasting sample. In routine clinical practice, the Friedewald equation is used to estimate LDL-cholesterol, but it has limitations. Commercially available direct measures of LDL-cholesterol are not standardised. LDL-cholesterol is a well-established risk factor for ASCVD, being the primary therapeutic target in both primary and secondary prevention. Non-high-density lipoprotein (HDL)-cholesterol is a measure of the cholesterol content in the atherogenic lipoproteins, but it does not reflect the particle number. Non-HDL-cholesterol has the advantage over LDL-cholesterol of including remnant cholesterol and being independent of triglyceride variability, but it is compromised by the non-specificity bias of direct HDL-cholesterol methods used in the calculation. Apolipoprotein (apo) B, the major structural protein in very low-density lipoprotein, intermediate density lipoprotein, LDL and lipoprotein (a), is a measure of the number of atherogenic lipoproteins. ApoB methods are standardised, but the assay comes at an additional, albeit relatively low cost. Non-HDL-cholesterol and apoB are more accurate measures than LDL-cholesterol in hypertriglyceridaemic individuals, non-fasting samples, and in those with very-low LDL-cholesterol concentrations. Accumulating evidence suggests that non-HDL-cholesterol and apoB are superior to LDL-cholesterol in predicting ASCVD risk, and both have been designated as secondary targets in some treatment guidelines. We review the measurement, potential role, utility and current status of non-HDL-cholesterol and apoB when compared with LDL-cholesterol in ASCVD risk assessment.
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Favorable effects of hydroxychloroquine on serum low density lipid in patients with systemic lupus erythematosus: A systematic review and meta-analysis.
Babary, H, Liu, X, Ayatollahi, Y, Chen, XP, Doo, L, Uppaluru, LK, Kwak, MK, Kulaga, C, Modjinou, D, Olech, E, et al
International journal of rheumatic diseases. 2018;(1):84-92
Abstract
AIMS: Hydroxychloroquine (HCQ) has shown to have significant immunomodulatory effects in the treatment of systemic lupus erythematosus (SLE). Current studies show favorable effects of HCQ on traditional cardiac risk factors in patients with SLE. This review examined the effects of HCQ on serum low-density lipoprotein (LDL) level in patients with SLE. METHODS A systematic search of seven major literature search databases from their inception until 3 April, 2017 identified nine studies. Random-effects pooled mean difference with corresponding 95% confidence intervals (CI) were estimated. Heterogeneity was measured by I2 . Publication bias was assessed by visual inspection of funnel plots. Sensitivity analysis examined whether HCQ effect on serum total cholesterol level was similar to the main analysis. The Grading of Recommendations Assessment, Development, and Evaluation system was used to assess the overall quality of evidence. RESULTS Pooled study participants were 559 patients from eight observation studies (two before-after studies; six case-control studies) examining the effects of HCQ on serum LDL. Pooled study participants' characteristics were as follows: mean age 45.719, female 95.262%, and prednisone use 58.366%. HCQ reduced mean LDL levels by 24.397 mg/dL (95% CI 8.921-39.872; P = 0.002). The number of studies identifying statin use was too few to perform meta-regression analysis of statin use. Heterogeneity was extensive (I2 = 94.739%). Symmetrical funnel plot visualized no evidence of publication bias. CONCLUSION HCQ was associated with serum LDL level reduction by mean 24.397 mg/dL in patients with SLE. Future prospective studies are need to fully characterize the treatment effect.
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3.
Incretins and Lipid Metabolism.
Tsimihodimos, V, Elisaf, M
Current medicinal chemistry. 2018;(18):2133-2139
Abstract
BACKGROUND Recent findings indicate that incretin hormones and incretin-based therapies may affect the metabolism of lipoproteins, although the corresponding mechanisms are not clearly defined. OBJECTIVE To summarize the available data on the mechanisms linking incretins with the characteristics of serum lipoproteins and discuss the clinical implications of these relationships. METHODS PubMed was searched using the terms "incretins", "GLP-1", "GIP" and "lipids", "dyslipidemia", "triglycerides", "apolipoprotein B48". All articles published in the English language until June 2016 were assessed and the relevant information is presented here. RESULTS GLP-1, and therapies that increase its activity, exert a beneficial effect on lipoprotein metabolism that is translated in a reduction in the fasting and postprandial concentration of triglycerides and a small improvement in the concentration and function of HDLs. In addition, a shift towards larger, less atherogenic particles usually follows the administration of GLP-1 receptor agonists. The mechanisms that underlie these changes involve a direct effect of GLP- 1 on the hepatic and intestinal production of triglyceride-rich lipoproteins, the GLP-1 induced increase in the production and function of insulin, the activation of specific areas of central nervous system as well as the increase in the peripheral utilization of triglycerides for energy production. On the other hand, GLP-2 increases the absorption of dietary fat and the production of triglyceride-rich lipoproteins while the role of GIP on lipid metabolism remains indeterminate. CONCLUSION GLP-1 and incretin-based therapies favorably affect lipid metabolism. These effects may contribute to the beneficial effects of incretin-based therapies on atherosclerosis and fatty liver disease.
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4.
The enigmatic membrane fatty acid transporter CD36: New insights into fatty acid binding and their effects on uptake of oxidized LDL.
Jay, AG, Hamilton, JA
Prostaglandins, leukotrienes, and essential fatty acids. 2018;:64-70
Abstract
The scavenger receptor CD36 binds numerous small biomolecules, including fatty acids, and even large ligands such as oxidized LDL, for which it is considered a receptor. Although CD36 has often been postulated to "transport" fatty acids across the plasma membrane, fatty acids translocation (mass transport or kinetics) was not affected by expression of CD36 in HEK293 cells; however, esterification of fatty acids (cellular uptake) was increased. These recent results from our lab are consistent with the established mechanism of fatty acid entry into cells by passive diffusion (flip-flop) and also with the well-documented enhancement of uptake of fatty acids by CD36 in other cell types. A fascinating new discovery is that CD36 has multiple fatty acid binding sites on the extracellular domain of CD36. As illuminated by new methodologies that we have applied, these sites have high affinity and exhibit rapid exchange with the medium. In an initial study of functional consequences of binding, several dietary fatty acids enhanced uptake of oxidized LDL into HEK293 cells expressing CD36. This is the first established link between physical binding of fatty acids and a function of CD36, and has implications for obesity and atherosclerosis. New methods as those used in our study could also be applied to elucidate other functional roles of fatty acid binding to CD36.
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5.
Association Between Circulating Oxidized LDL and Atherosclerotic Cardiovascular Disease: A Meta-analysis of Observational Studies.
Gao, S, Zhao, D, Wang, M, Zhao, F, Han, X, Qi, Y, Liu, J
The Canadian journal of cardiology. 2017;(12):1624-1632
Abstract
BACKGROUND Although basic research has suggested that oxidized low-density lipoprotein (ox-LDL) is involved in the pathogenesis of atherosclerosis, population observational studies have yielded conflicting results about the association between circulating ox-LDL and atherosclerotic cardiovascular disease (ASCVD). Therefore, we performed a systematic review and meta-analysis of currently available observational studies to verify the association between circulating ox-LDL and ASCVD. METHODS We systematically searched PubMed and the Cochrane Library from their inception to March 27, 2017, for nested case-control studies, case-cohort studies, and prospective cohort studies on the relationship between ox-LDL and ASCVD. Studies that did not assess the hazard ratio, relative risk, or odds ratio of ox-LDL or did not adjust for other risk factors, or those without examination of ox-LDL before collection of ASCVD occurrences were excluded. The summarized effect size was combined using fixed effect models. Subgroup analyses were performed on the basis of study quality, study design, definition of ASCVD events, effect size types, types of ox-LDL assay, ox-LDL contrast level, and whether low-density lipoprotein cholesterol was adjusted in a multivariate model. RESULTS A total of 12 included studies consisted of 3 nested case-control studies, 1 case-cohort study, 5 hospital-based cohort studies, and 3 community-based cohort studies. The summary effect size of increased circulating ox-LDL was 1.79 (95% confidence interval, 1.56-2.05) for ASCVD. Similar associations were shown in all subgroups. CONCLUSIONS Our findings indicate that increased levels of circulating ox-LDL are associated with clinical ASCVD events. Further well designed community-based cohort studies or intervention studies are needed to confirm our findings.
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6.
Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
Ference, BA, Ginsberg, HN, Graham, I, Ray, KK, Packard, CJ, Bruckert, E, Hegele, RA, Krauss, RM, Raal, FJ, Schunkert, H, et al
European heart journal. 2017;(32):2459-2472
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Abstract
AIMS: To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD). METHODS AND RESULTS We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects. CONCLUSION Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.
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Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and their mechanisms of action on apolipoprotein B-containing lipoproteins in humans: a review.
Oscarsson, J, Hurt-Camejo, E
Lipids in health and disease. 2017;(1):149
Abstract
BACKGROUND Epidemiological and genetic studies suggest that elevated triglyceride (TG)-rich lipoprotein levels in the circulation increase the risk of cardiovascular disease. Prescription formulations of omega-3 fatty acids (OM3FAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduce plasma TG levels and are approved for the treatment of patients with severe hypertriglyceridemia. Many preclinical studies have investigated the TG-lowering mechanisms of action of OM3FAs, but less is known from clinical studies. METHODS We conducted a review, using systematic methodology, of studies in humans assessing the mechanisms of action of EPA and DHA on apolipoprotein B-containing lipoproteins, including TG-rich lipoproteins and low-density lipoproteins (LDLs). A systematic search of PubMed retrieved 55 articles, of which 30 were used in the review; 35 additional arrticles were also included. RESULTS In humans, dietary DHA is retroconverted to EPA, while production of DHA from EPA is not observed. Dietary DHA is preferentially esterified into TGs, while EPA is more evenly esterified into TGs, cholesterol esters and phospholipids. The preferential esterification of DHA into TGs likely explains the higher turnover of DHA than EPA in plasma. The main effects of both EPA and DHA are decreased fasting and postprandial serum TG levels, through reduction of hepatic very-low-density lipoprotein (VLDL)-TG production. The exact mechanism for reduced VLDL production is not clear but does not include retention of lipids in the liver; rather, increased hepatic fatty acid oxidation is likely. The postprandial reduction in TG levels is caused by increased lipoprotein lipase activity and reduced serum VLDL-TG concentrations, resulting in enhanced chylomicron clearance. Overall, no clear differences between the effects of EPA and DHA on TG levels, or on turnover of TG-rich lipoproteins, have been observed. Effects on LDL are complex and may be influenced by genetics, such as APOE genotype. CONCLUSIONS EPA and DHA diminish fasting circulating TG levels via reduced production of VLDL. The mechanism of reduced VLDL production does not involve hepatic retention of lipids. Lowered postprandial TG levels are also explained by increased chylomicron clearance. Little is known about the specific cellular and biochemical mechanisms underlying the TG-lowering effects of EPA and DHA in humans.
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The affection of the disturbance of the hydrodynamics of blood in case of stress on pathological increase of level of low density lipoproteins in blood. The formation of cylindrical plaques, and their participation in the development of acute ischemic disorders of heart and brain.
Rusanov, SE
Medical hypotheses. 2017;:61-70
Abstract
In this article is given the new insight about the affection of stress on the increase of level of low density lipoproteins (LDL) in the blood, which is connected with the disturbance of hydrodynamics in the bloodstream, the attention was paid to the cylindrical cholesterol plaque, and it's classification. The disturbance of hydrodynamics of blood under the stress leads to the formation of a cylindrical cholesterol plaque, which repeats the contour of the vessel, and leads to the ischemic disorders of the heart and brain. The cylindrical cholesterol plaque goes through several stages of development: friable, yielding, dense, old. In the case of destruction of friable, fresh cholesterol plaque, releases a big quantity of low-density lipoproteins. This leads to the pathological increase of level of LDL in the blood. In the case of long disturbance of hydrodynamics, occurs the formation of strong links between low-density lipoproteins. Yielding cholesterol plaque is formed. Further maturation of cylindrical cholesterol plaque, leads to it's densifying and damage. We may emphasize, that short periods of strong contraction and expansion of vessels lead to the increase of level of LDL in the blood. Self-dependent restoration of normal level of LDL in blood occurs in the case of restoration of pressure in the limits of numbers, which are specific for particular person, and which don't exceed the physiological standard. Among patients with long duration of stress, the duration of vasospasm increases. LDL, without having a possibility to crumble, begin to stick together and form the yielding cylindrical plaque. It is characterized by having of not so strong connection with the vascular wall, and maintains only at the expanse of iteration of the vascular wall, it has cylindrical shape, is elastic and yellow. The thickness and length of walls depends on the degree of cross-clamping during the time of formation of yielding cylindrical plaque. In the case of stopping of spasm, yielding cylindrical plaque can resolve slowly. Among hypotensive and individuals, which have normal pressure, the increase of level of LDL isn't noted. There aren't such investigations, where such link was noted. The increasing of level of LDL among these people (especially under the stress) can say about cases of short-term increase of pressure, which could be unnoticed. These patients require pressure monitoring and, accordingly, the adjustment of the state of stress and anger.
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High-density Lipoprotein and Low-density Lipoprotein Therapeutic Approaches in Acute Coronary Syndromes.
Androulakis, E, Zacharia, E, Papageorgiou, N, Lioudaki, E, Bertsias, D, Charakida, M, Siasos, G, Tousoulis, D
Current cardiology reviews. 2017;(3):168-182
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Abstract
BACKGROUND Low-density lipoprotein cholesterol (LDL), and especially its oxidized form, renders the atherosclerotic plaque vulnerable to rupture in acute coronary syndromes (ACS). On the other hand, high-density lipoprotein (HDL) is considered an anti-atherogenic molecule. The more recent HDL-targeted drugs may prove to be superior to those used before. Indeed, delipidated HDL and HDL mimetics are efficient in increasing HDL levels, while the apoA-I upregulation with RVX-208 appears to offer a clinical benefit which is beyond the HDL related effects. HDL treatment however has not shown a significant improvement in the outcomes of patients with ACS so far, studies have therefore focused again on LDL. In addition to statins and ezetimibe, novel drugs such as PSCK9 inhibitors and apolipoprotein B inhibitors appear to be both effective and safe for patients with hyperlipidemia. CONCLUSION Data suggest these could potentially improve the cardiovascular outcomes of patient with ACS. Yet, there is still research to be done, in order to confirm whether ACS patients would benefit from LDL- or HDL-targeted therapies or a combination of both.
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10.
[DESIALATED LOW DENSITY LIPOPROTEINS IN HUMAN BLOOD].
Ryzhkova, AI, Karagodin, VP, Sukhorukov, VN, Sazonova, MA, Orekhov, AN
Klinicheskaia meditsina. 2017;(3):216-21
Abstract
The present article is a review of literature on circulating low-density lipoproteins (LDLP) which can induce accumulation of lipids (mainly, cholesterol), in a SMA(+) cell culture of normal human aortic intima. An attempt was undertaken to resolve the paradox of the absence of both native LDLP influence on intracellular lipid accumulation and modifications of in vitro obtained LDLP in the blood-vascular system. It was showed that atherogenic LDLPs are characterized by a number of changes in carbon, protein and lipid components which can be regarded as multiple modifications of LDLP taking place in human blood plasma. Multiply modified circulating LDLP possess of capacity to interact with various cell membrane receptors differing from B and E receptor, and with proteoglycans. Marked absorption of desiliated LDLPs by the cells simultaneous with a decrease in the degradation of apolipoproteins and cholesterol esters as well as induction of peresterification of free cholesterol leads to intracellular accumulation of esterified cholesterol. Formation of large LDLP-containing complexes especially circulating low-density lipoproteins can stimulate accumulation of lipids by smooth muscle cells of intima. Desiliated LDLPs stimulated cell proliferation and connective tissue matrix synthesis despite cholesterol ester accumulation. In conclusion, the authors of this article found and characterized natural multiply modified LDLPs that can be responsible for the symptoms of atherosclerosis at the cellular level.