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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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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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Statin-centric versus low-density lipoprotein-centric approach for atherosclerotic cardiovascular disease prevention: a Singapore perspective.
Yan, P, Tan, EK, Choo, JC, Liew, CF, Lau, T, Waters, DD
Singapore medical journal. 2016;(7):360-7
Abstract
The link between cholesterol levels and atherosclerotic cardiovascular disease (ASCVD) is well-established. In Singapore, there is an increasing prevalence of risk factors for ASCVD. Like many Asian countries, Singapore's population is rapidly ageing and increasingly sedentary, which predisposes individuals to chronic health problems. Current international and local guidelines recommend statin therapy for the primary and secondary prevention of ASCVD. However, despite the effectiveness of statin therapy, some studies have highlighted that Asian patients with cardiovascular disease are not achieving target lipid goals. Furthermore, it is widely believed that the responses of Asians (both patients and physicians) to statin therapy are different from those of their Western counterparts. Experts convened in 2014 to determine the impact of current guidelines on clinical practice in Singapore. This review summarises the key findings and recommendations of these guidelines, and presents key principles to aid clinicians to manage the cardiovascular risk of their patients more effectively.
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Familial Hypercholesterolemia: Advances in Recognition and Therapy.
Cartier, JL, Goldberg, AC
Progress in cardiovascular diseases. 2016;(2):125-134
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Abstract
Familial hypercholesterolemia (FH) is an autosomal co-dominant genetic disorder characterized by elevated low-density lipoprotein cholesterol levels and increased risk for premature cardiovascular disease. It is under-diagnosed, yet early detection and treatment are critical to limit premature atherosclerotic disease. High-intensity statins are the mainstay of treatment, which should be started as early as possible in homozygous FH and as soon as the diagnosis of heterozygous FH is made in adults. Combination therapy is often necessary in FH patients and can include the addition of ezetimibe and bile acid sequestrants. Lipoprotein apheresis is used when pharmacotherapy is inadequate, especially for those with homozygous FH and some patients with severe heterozygous FH. Mipomersen and lomitapide are also indicated for patients with homozygous FH. The recently approved PCSK9 inhibitors, alirocumab and evolocumab, are a promising treatment and outcome studies are ongoing. This article reviews the pathophysiology, diagnosis, and management of FH.
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Clinical Decision Support Systems and Prevention: A Community Guide Cardiovascular Disease Systematic Review.
Njie, GJ, Proia, KK, Thota, AB, Finnie, RKC, Hopkins, DP, Banks, SM, Callahan, DB, Pronk, NP, Rask, KJ, Lackland, DT, et al
American journal of preventive medicine. 2015;(5):784-795
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CONTEXT Clinical decision support systems (CDSSs) can help clinicians assess cardiovascular disease (CVD) risk and manage CVD risk factors by providing tailored assessments and treatment recommendations based on individual patient data. The goal of this systematic review was to examine the effectiveness of CDSSs in improving screening for CVD risk factors, practices for CVD-related preventive care services such as clinical tests and prescribed treatments, and management of CVD risk factors. EVIDENCE ACQUISITION An existing systematic review (search period, January 1975-January 2011) of CDSSs for any condition was initially identified. Studies of CDSSs that focused on CVD prevention in that review were combined with studies identified through an updated search (January 2011-October 2012). Data analysis was conducted in 2013. EVIDENCE SYNTHESIS A total of 45 studies qualified for inclusion in the review. Improvements were seen for recommended screening and other preventive care services completed by clinicians, recommended clinical tests completed by clinicians, and recommended treatments prescribed by clinicians (median increases of 3.8, 4.0, and 2.0 percentage points, respectively). Results were inconsistent for changes in CVD risk factors such as systolic and diastolic blood pressure, total and low-density lipoprotein cholesterol, and hemoglobin A1C levels. CONCLUSIONS CDSSs are effective in improving clinician practices related to screening and other preventive care services, clinical tests, and treatments. However, more evidence is needed from implementation of CDSSs within the broad context of comprehensive service delivery aimed at reducing CVD risk and CVD-related morbidity and mortality.
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Foam cells in atherosclerosis.
Yu, XH, Fu, YC, Zhang, DW, Yin, K, Tang, CK
Clinica chimica acta; international journal of clinical chemistry. 2013;:245-52
Abstract
Atherosclerosis is a chronic disease characterized by the deposition of excessive cholesterol in the arterial intima. Macrophage foam cells play a critical role in the occurrence and development of atherosclerosis. The generation of these cells is associated with imbalance of cholesterol influx, esterification and efflux. CD36 and scavenger receptor class A (SR-A) are mainly responsible for uptake of lipoprotein-derived cholesterol by macrophages. Acyl coenzyme A:cholesterol acyltransferase-1 (ACAT1) and neutral cholesteryl ester hydrolase (nCEH) regulate cholesterol esterification. ATP-binding cassette transporters A1(ABCA1), ABCG1 and scavenger receptor BI (SR-BI) play crucial roles in macrophage cholesterol export. When inflow and esterification of cholesterol increase and/or its outflow decrease, the macrophages are ultimately transformed into lipid-laden foam cells, the prototypical cells in the atherosclerotic plaque. The aim of this review is to describe what is known about the mechanisms of cholesterol uptake, esterification and release in macrophages. An increased understanding of the process of macrophage foam cell formation will help to develop novel therapeutic interventions for atherosclerosis.
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Low-density lipoprotein modified by myeloperoxidase in inflammatory pathways and clinical studies.
Delporte, C, Van Antwerpen, P, Vanhamme, L, Roumeguère, T, Zouaoui Boudjeltia, K
Mediators of inflammation. 2013;:971579
Abstract
Oxidation of low-density lipoprotein (LDL) has a key role in atherogenesis. Among the different models of oxidation that have been studied, the one using myeloperoxidase (MPO) is thought to be more physiopathologically relevant. Apolipoprotein B-100 is the unique protein of LDL and is the major target of MPO. Furthermore, MPO rapidly adsorbs at the surface of LDL, promoting oxidation of amino acid residues and formation of oxidized lipoproteins that are commonly named Mox-LDL. The latter is not recognized by the LDL receptor and is accumulated by macrophages. In the context of atherogenesis, Mox-LDL accumulates in macrophages leading to foam cell formation. Furthermore, Mox-LDL seems to have specific effects and triggers inflammation. Indeed, those oxidized lipoproteins activate endothelial cells and monocytes/macrophages and induce proinflammatory molecules such as TNF α and IL-8. Mox-LDL may also inhibit fibrinolysis mediated via endothelial cells and consecutively increase the risk of thrombus formation. Finally, Mox-LDL has been involved in the physiopathology of several diseases linked to atherosclerosis such as kidney failure and consequent hemodialysis therapy, erectile dysfunction, and sleep restriction. All these issues show that the investigations of MPO-dependent LDL oxidation are of importance to better understand the inflammatory context of atherosclerosis.
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Pathogenic role of modified LDL antibodies and immune complexes in atherosclerosis.
Lopes-Virella, MF, Virella, G
Journal of atherosclerosis and thrombosis. 2013;(10):743-54
Abstract
There is strong evidence supporting a key role of the adaptive immune response in atherosclerosis, given that both activated Th cells producing predominantly interferon-γ and oxidized LDL (oxLDL) and the corresponding antibodies have been isolated from atheromatous plaques. Studies carried out using immune complexes (IC) prepared with human LDL and rabbit antibodies have demonstrated proatherogenic and pro-inflammatory properties, mostly dependent on the engagement of Fcγ receptors Ⅰ and Ⅱ in macrophages and macrophage-like cell lines. Following the development of a methodology for isolating modified LDL (mLDL) antibodies from serum and isolated IC, it was confirmed that antibodies reacting with oxLDL and advanced glycation end product-modified LDL are predominantly IgG of subtypes 1 and 3 and that mLDL IC prepared with human reagents possesses pro-inflammatory and proatherogenic properties. In previous studies, LDL separated from isolated IC has been analyzed for its modifications, and the reactivity of antibodies isolated from the same IC with different LDL modifications has been tested. Recently, we obtained strong evidence suggesting that the effects of mLDL IC on phagocytic cells are modulated by the composition of the mLDL. Clinical studies have shown that the level of mLDL in circulating IC is a strong predictor of cardiovascular disease (CVD) and, in diabetic patients, other significant complications, such as nephropathy and retinopathy. In conclusion, there is convincing ex vivo and clinical data supporting the hypothesis that, in humans, the humoral immune response to mLDL is pathogenic rather than protective.
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Systematic review: Evaluating the effect of lipid-lowering therapy on lipoprotein and lipid values.
Rosenson, RS, Underberg, JA
Cardiovascular drugs and therapy. 2013;(5):465-79
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PURPOSE This systematic review was performed to summarize published experience using low density lipoprotein particle number (LDL-P) to monitor the efficacy of lipid-lowering pharmacotherapies. METHODS Studies were identified from a literature search of MEDLINE (January 1, 2000 - June 30, 2012); and abstract searches of select conferences. All accepted studies reported mean (or median) nuclear magnetic resonance (NMR)-based LDL-P values for at least 10 subjects receiving lipid lowering pharmacotherapy. RESULTS Searches revealed 36 studies (with 61 treatment arms) in which LDL-P measurements were reported pre- and post-treatment. Most studies also reported changes in low-density lipoprotein cholesterol (LDL-C), but fewer studies reported changes in apolipoprotein B (apoB)(n = 20) and non-HDL-C (n = 28). Treatments included statins (22 arms/15 studies), fibrates (7 arms/7 studies), niacin (7 arms/6 studies), bile acid sequestrants (5 arms/2 studies), an anti-apoB oligonucleotide (2 arms/2 studies), combination therapies (8 arms/6 studies), anti-diabetics (5 arms/4 studies), and, other treatments (5 arms/2 studies). Lipid-lowering pharmacotherapy resulted in reductions in mean LDL-P in all but two studies. In several statin studies, the percent reductions in LDL-P were smaller than reductions in LDL-C, comparable changes were reported when LDL-P and apoB, were reported. CONCLUSIONS Study-level data from this systemic review establish that different lipid lowering agents can lead to discordance between LDL-P and LDL-C, therefore, basing LDL-lowering therapy only on the achievement of cholesterol goals may result in a treatment gap. Therefore, the use of LDL-P for monitoring lipid-lowering therapy, particularly for statins, can provide a more accurate assessment of residual cardiovascular risk.