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The Effects of Statin Dose, Lipophilicity, and Combination of Statins plus Ezetimibe on Circulating Oxidized Low-Density Lipoprotein Levels: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Jamialahmadi, T, Baratzadeh, F, Reiner, Ž, Simental-Mendía, LE, Xu, S, Susekov, AV, Santos, RD, Sahebkar, A
Mediators of inflammation. 2021;:9661752
Abstract
BACKGROUND Elevated plasma low-density lipoprotein cholesterol (LDL-C) is the main risk factor for atherosclerotic cardiovascular disease (ASCVD). Statins are the drugs of choice for decreasing LDL-C and are used for the prevention and management of ASCVD. Guidelines recommend that subjects with high and very high ASCVD risk should be treated with high-intensity statins or a combination of high-intensity statins and ezetimibe. The lipophilicity or hydrophilicity (solubility) of statins is considered to be important for at least some of their LDL-C lowering independent pleiotropic effects. Oxidative modification of LDL (ox-LDL) is considered to be the most important atherogenic modification of LDL and is supposed to play a crucial role in atherogenesis and ASCVD outcomes. OBJECTIVE The aim of this systematic review and meta-analysis was to find out what are the effects of statin intensity, lipophilicity, and combination of statins plus ezetimibe on ox-LDL. METHODS PubMed, Scopus, Embase, and Web of Science were searched from inception to February 5, 2021, for randomized controlled trials (RCTs). Two independent and blinded authors evaluated eligibility by screening the titles and abstracts of the studies. Risk of bias in the studies included in this meta-analysis was evaluated according to the Cochrane instructions. Meta-analysis was performed using Comprehensive Meta-Analysis (CMA) V2 software. Evaluation of funnel plot, Begg's rank correlation, and Egger's weighted regression tests were used to assess the presence of publication bias. RESULTS Among the 1427 published studies identified by a systematic databases search, 20 RCTs were finally included in the systematic review and meta-analysis. A total of 1874 patients are included in this meta-analysis. This meta-analysis suggests that high-intensity statin treatment is associated with a significant decrease in circulating concentrations of ox-LDL when compared with low-to-moderate treatment (SMD: -0.675, 95% CI: -0.994, -0.357, p < 0.001; I 2: 55.93%). There was no difference concerning ox-LDL concentration between treatments with hydrophilic and lipophilic statins (SMD: -0.129, 95% CI: -0.330, -0.071, p = 0.206; I 2: 45.3%), but there was a significant reduction in circulating concentrations of ox-LDL associated with statin plus ezetimibe combination therapy when compared with statin monotherapy (SMD: -0.220, 95% CI: -0.369, -0.071, p = 0.004; I 2: 0%). CONCLUSION High-dose statin or combination of statins with ezetmibe reduces plasma ox-LDL in comparison low-to-moderate intensity statin therapy alone. Statin lipophilicity is not associated with reduction in ox-LDL plasma concentrations.
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Overfeeding Saturated Fat Increases LDL (Low-Density Lipoprotein) Aggregation Susceptibility While Overfeeding Unsaturated Fat Decreases Proteoglycan-Binding of Lipoproteins.
Ruuth, M, Lahelma, M, Luukkonen, PK, Lorey, MB, Qadri, S, Sädevirta, S, Hyötyläinen, T, Kovanen, PT, Hodson, L, Yki-Järvinen, H, et al
Arteriosclerosis, thrombosis, and vascular biology. 2021;(11):2823-2836
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Abstract
OBJECTIVE We recently showed that measurement of the susceptibility of LDL (low-density lipoprotein) to aggregation is an independent predictor of cardiovascular events. We now wished to compare effects of overfeeding different dietary macronutrients on LDL aggregation, proteoglycan-binding of plasma lipoproteins, and on the concentration of oxidized LDL in plasma, 3 in vitro parameters consistent with increased atherogenicity. APPROACH AND RESULTS The participants (36 subjects; age, 48+/-10 years; body mass index, 30.9+/-6.2 kg/m2) were randomized to consume an extra 1000 kcal/day of either unsaturated fat, saturated fat, or simple sugars (CARB) for 3 weeks. We measured plasma proatherogenic properties (susceptibility of LDL to aggregation, proteoglycan-binding, oxidized LDL) and concentrations and composition of plasma lipoproteins using nuclear magnetic resonance spectroscopy, and in LDL using liquid chromatography mass spectrometry, before and after the overfeeding diets. LDL aggregation increased in the saturated fat but not the other groups. This change was associated with increased sphingolipid and saturated triacylglycerols in LDL and in plasma and reduction of clusterin on LDL particles. Proteoglycan binding of plasma lipoproteins decreased in the unsaturated fat group relative to the baseline diet. Lipoprotein properties remained unchanged in the CARB group. CONCLUSIONS The type of fat during 3 weeks of overfeeding is an important determinant of the characteristics and functional properties of plasma lipoproteins in humans.
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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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Comparative effects of high-dose atorvastatin versus rosuvastatin on lipid parameters, oxidized low-density lipoprotein, and proprotein convertase subtilisin kexin 9 in acute coronary syndrome.
Altunkeser, BB, Tuncez, A, Ozturk, B, Tezcan, H, Ates, MS, Yilmaz, C, Yalcin, MU, Aygul, N, Demir, K
Coronary artery disease. 2019;(4):285-290
Abstract
AIM: Current guidelines recommend administration of high-dose statins in acute coronary syndrome (ACS). It has been reported that statins upregulate proprotein convertase subtilisin kexin 9 (PCSK9) mRNA expression and increase circulating PCSK9 levels. We aimed to compare the effects of high-dose atorvastatin and rosuvastatin on serum oxidized low-density lipoprotein (oxidized-LDL) and PCSK9 levels in statin-naive patients with ACS. PATIENTS AND METHODS One hundred and six patients with ACS were enrolled in this study. The patients were assigned randomly to receive atorvastatin (80 mg/day) or rosuvastatin (40 mg/day) by using a ratio of 1 : 1 in randomization. The levels of total cholesterol (TC), triglyceride, high-density lipoprotein cholesterol, LDL-cholesterol, oxidized-LDL, and PCSK9 were compared between groups after a 4-week treatment. RESULTS Our study population included 53 patients in the atorvastatin group (age: 58.13±11.30 years, 11.32% female) and 53 patients in the rosuvastatin group (age: 59.08±12.44 years, 15.09% female). In both groups, lipid parameters, oxidized-LDL, and PCSK9 values changed significantly according to the baseline following treatment. High-dose atorvastatin and rosuvastatin induced similar decreases in LDL-cholesterol, oxidized-LDL, and triglyceride levels and similarly increased in high-density lipoprotein cholesterol and PCSK9 levels (P>0.05). CONCLUSION We showed that atorvastatin and rosuvastatin treatment regimens have comparable effects on lipid parameters and PCSK9 levels in ACS patients.
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Novel role of the nutraceutical bioactive compound berberine in lectin-like OxLDL receptor 1-mediated endothelial dysfunction in comparison to lovastatin.
Caliceti, C, Rizzo, P, Ferrari, R, Fortini, F, Aquila, G, Leoncini, E, Zambonin, L, Rizzo, B, Calabria, D, Simoni, P, et al
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2017;(6):552-563
Abstract
BACKGROUND AND AIMS Oxidized LDL (oxLDL) or pro-inflammatory stimuli lead to increased oxidative stress linked to endothelial dysfunction and atherosclerosis. The oxLDL receptor-1 (LOX1) is elevated within atheromas and cholesterol-lowering statins inhibit LOX1 expression. Berberine (BBR), an alkaloid extracted from plants of gender Berberis, has lipid-lowering and anti-inflammatory activity. However, its role in regulating LOX1-mediated signaling is still unknown. The aim of this study was to investigate the effect of BBR on oxLDL- and TNFα-induced endothelial dysfunction in human umbilical vein endothelial cells (HUVECs) and to compare it with that of lovastatin (LOVA). METHODS AND RESULTS Cytotoxicity was determined by lactate dehydrogenase assay. Antioxidant capacity was measured with chemiluminescent and fluorescent method and intracellular ROS levels through a fluorescent dye. Gene and protein expression levels were assayed by qRT-PCR and western blot, respectively. HUVECs exposure to oxLDL (30 μg/ml) or TNFα (10 ng/ml) for 24 h led to a significant increase in LOX1 expression, effect abrogated by BBR (5 μM) and LOVA (5 μM). BBR but not LOVA treatment abolished the TNFα-induced cytotoxicity and restored the activation of Akt signaling. In spite of a low direct antioxidant capacity, both compounds reduced intracellular ROS levels generated by treatment of TNFα but only BBR inhibited NOX2 expression, MAPK/Erk1/2 signaling and subsequent NF-κB target genes VCAM and ICAM expression, induced by TNFα. CONCLUSIONS These findings demonstrated for the first time that BBR could prevent the oxLDL and TNFα - induced LOX1 expression and oxidative stress, key events that lead to NOX, MAPK/Erk1/2 and NF-κB activation linked to endothelial dysfunction. CHEMICAL COMPOUNDS STUDIED IN THIS ARTICLE Berberine (PubChem CID: 2353); Lovastatin (PubChem CID: 53232).
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Analysis of Lipoprotein Subfractions in 920 Patients With and Without Type 2 Diabetes.
Zhao, X, Zhang, HW, Zhang, Y, Li, S, Xu, RX, Sun, J, Zhu, CG, Wu, NQ, Gao, Y, Guo, YL, et al
Heart, lung & circulation. 2017;(3):211-218
Abstract
BACKGROUND It has been demonstrated that diabetic dyslipidaemia is the chief bridge between diabetes and incremental risk of cardiovascular disease in patients with diabetes. However, the characteristics of lipoprotein subfractions distribution in patients with type 2 diabetes (T2D) have not been fully investigated. The aim of present study was to evaluate the distributions of lipoprotein subfractions in T2D patients. METHODS A total of 920 patients, who have not received lipid-lowering drug treatment previously, were consecutively enrolled in this study. Based on the evidence of diabetes, patients were divided into T2D group (n=204) and non-T2D group (n=716). Both low- and high-density lipoprotein cholesterol (LDL- and HDL-C) subfractions were analysed using the Quantimetrix Lipoprint System. The distributions of lipoprotein subfractions were evaluated in patients with and without T2D. RESULTS Compared with non-T2D individuals, the T2D group manifested significantly lower large HDL-C concentration/HDL subfraction percentage, smaller mean LDL particle size but higher small HDL-C and LDL-C concentrations as well as small HDL and LDL subfraction percentages. Moreover, the data indicated that the small HDL-C/ LDL-C concentrations, the small and large HDL subfraction percentages along with the mean LDL particle size were independently related to the existence of T2D (95% CI=1.009-1.067, p=0.009; 95% CI=0.938-0.983, p=0.001; 95% CI=1.023-1.135, p=0.005; 95% CI= 1.005-1.048, p=0.014; 95% CI=0.940-0.999, p=0.040; respectively) assessed by logistic regression analysis. CONCLUSIONS The present study indicated that the changes of lipid profile in patients with T2D are characterised by abnormal distributions of lipoprotein subfractions apart from clinically atherogenic dyslipidaemia.
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Can non-cholesterol sterols and lipoprotein subclasses distribution predict different patterns of cholesterol metabolism and statin therapy response?
Gojkovic, T, Vladimirov, S, Spasojevic-Kalimanovska, V, Zeljkovic, A, Vekic, J, Kalimanovska-Ostric, D, Djuricic, I, Sobajic, S, Jelic-Ivanovic, Z
Clinical chemistry and laboratory medicine. 2017;(3):447-457
Abstract
BACKGROUND Cholesterol homeostasis disorders may cause dyslipidemia, atherosclerosis progression and coronary artery disease (CAD) development. Evaluation of non-cholesterol sterols (NCSs) as synthesis and absorption markers, and lipoprotein particles quality may indicate the dyslipidemia early development. This study investigates associations of different cholesterol homeostasis patterns with low-density (LDL) and high-density lipoproteins (HDL) subclasses distribution in statin-treated and statin-untreated CAD patients, and potential use of aforementioned markers for CAD treatment optimization. METHODS The study included 78 CAD patients (47 statin-untreated and 31 statin-treated) and 31 controls (CG). NCSs concentrations were quantified using gas chromatography- flame ionization detection (GC-FID). Lipoprotein subclasses were separated by gradient gel electrophoresis. RESULTS In patients, cholesterol-synthesis markers were significantly higher comparing to CG. Cholesterol-synthesis markers were inversely associated with LDL size in all groups. For cholesterol homeostasis estimation, each group was divided to good and/or poor synthetizers and/or absorbers according to desmosterol and β-sitosterol median values. In CG, participants with reduced cholesterol absorption, the relative proportion of small, dense LDL was higher in those with increased cholesterol synthesis compared to those with reduced synthesis (p<0.01). LDL I fraction was significantly higher in poor synthetizers/poor absorbers subgroup compared to poor synthetizers/good absorbers (p<0.01), and good synthetizers/poor absorbers (p<0.01). Statin-treated patients with increased cholesterol absorption had increased proportion of LDL IVB (p<0.05). CONCLUSIONS The results suggest the existence of different lipoprotein abnormalities according to various patterns of cholesterol homeostasis. Desmosterol/β-sitosterol ratio could be used for estimating individual propensity toward dyslipidemia development and direct the future treatment.
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Comparative effects of high-dose atorvastatin versus moderate-dose rosuvastatin on lipid parameters, oxidized-LDL and inflammatory markers in ST elevation myocardial infarction.
Aydin, MU, Aygul, N, Altunkeser, BB, Unlu, A, Taner, A
Atherosclerosis. 2015;(2):439-43
Abstract
BACKGROUND The important role of oxidized low density lipoprotein (oxidized-LDL) in preclinic atherosclerosis and pathophysiology of acute coronary syndromes studies have reported. Oxidation of LDL activates many inflammatory and atherogenic pathways and plays a pivotal role in atherosclerosis. Our aim in this study is to compare the effects of 80 mg daily dose of atorvastatin and 20 mg daily dose of rosuvastatin on lipid profiles and the levels of oxidized-LDL and inflammatory markers in ST elevation myocardial infarction (STEMI). METHODS One hundred and twenty patients with STEMI were enrolled in this study. The patients were randomly assigned to receive atorvastatin (80 mg/day) or rosuvastatin (20 mg/day) by using a ratio of 1:1 after revascularization. The levels of total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), LDL-C, apolipoprotein B and apolipoprotein A were compared between groups after 4-week therapy. The values of oxidized-LDL, tumor necrosis factor receptor 1 and 2, Interleukin-6 and hs-CRP were also compared between groups. The Student's t test was used to detect absolute and percent changes between groups, and p < 0.05 was considered as statistically significant for all tests. RESULTS After treatment in both treatment groups LDL-C, oxidized-LDL, hs-CRP, tumor necrosis factor receptor 1 and 2, Interleukin-6 values significantly decreased according to baseline. The only difference was in HDL-C levels. HDL-C slightly decreased in atorvastatin group while it increased in the rosuvastatin group compared baseline (-1.4 ± 8.9 mg/dl vs 2.0 ± 9.4 mg/dl, p = 0.04). CONCLUSION We reported that both statin treatment regiments have comparable effects on LDL-C, oxidized-LDL and inflammatory markers. Moreover, it was observed that rosuvastatin was more effective in terms of ability to increase HDL-C level. Based on these findings, 20 mg daily dose of rosuvastatin may be an alternative to 80 mg daily dose of atorvastatin in patients with acute coronary syndrome.
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Exercise training protects the LDL I subfraction from oxidation susceptibility in an aged human population.
Medlow, P, McEneny, J, Murphy, MH, Trinick, T, Duly, E, Davison, GW
Atherosclerosis. 2015;(2):516-22
Abstract
BACKGROUND Exercise training is considered an effective strategy to improve metabolic disease. Despite this, less is known regarding exercise training in the prevention and susceptibility of LDL subfraction oxidation, particularly in an aged population. METHODS Eleven aged (55 ± 4 yrs) and twelve young (21 ± 2 yrs) participants were randomly separated into an experimental or control group as follows: young exercise (n = 6); young control (n = 6); aged exercise (n = 6) and aged control (n = 5). The participants assigned to the exercise groups performed 12 weeks of moderate intensity (55-65% VO2max) exercise training. Venous blood was extracted at baseline, and 48 h following 12 weeks of exercise and assayed for a range of metabolites associated with lipid composition and lipoprotein susceptibility to oxidation. RESULTS Although there was no difference in the oxidation potential (time ½ max) of LDL I, II or III between groups at baseline (p > 0.05), there was an increase in time ½ max for LDL I following exercise within the aged exercise group (p < 0.05). Moreover, α-tocopherol concentration was selectively lower in the aged exercise group, compared to the young exercise at baseline. The lipid composition of LDL I, LDL II, LDL III, VLDL, HDL2, HDL3 and serum lipid hydroperoxides remained unchanged as a function of exercise training and ageing (p > 0.05). CONCLUSION The primary finding of this study demonstrates that adaptations in LDL resistance to oxidation occur following 12 weeks of exercise training in the aged, and this may be of clinical significance, as oxidation of LDL has been implicated in atherosclerosis.
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TIDILAP: Treatment of iron deficiency in lipoprotein apheresis patients --A prospective observational multi-center cohort study comparing efficacy, safety and tolerability of ferric gluconate with ferric carboxymaltose.
Schatz, U, Illigens, BM, Siepmann, T, Arneth, B, Siegert, G, Siegels, D, Heigl, F, Hettich, R, Ramlow, W, Prophet, H, et al
Atherosclerosis. Supplements. 2015;:199-208
Abstract
OBJECTIVES Iron deficiency (ID) and iron deficiency anemia (IDA) are common findings in patients undergoing lipoprotein apheresis (LA). Different intravenous (iv) formulations are used to treat ID in LA patients, however guidelines and data on ID/IDA management in LA patients are lacking. We therefore performed a prospective observational multi-center cohort study of ID/IDA in LA patients, comparing two approved i.v. iron formulations, ferric gluconate (FG) and ferric carboxymaltose (FCM). METHODS Inclusion criteria were a) serum ferritin <100 μg/L or b) serum ferritin <300 μg/L and transferrin saturation <20%. Patients received either FG (62.5 mg weekly) or FCM (500 mg once in ID or up to 1000 mg if IDA was present) i.v. until iron deficiency was resolved. Efficacy and safety were determined by repeated laboratory and clinical assessment. Iron parameters pre and post apheresis were measured to better understand the pathogenesis of ID/IDA in LA patients. RESULTS 80% of LA patients treated at the three participating centers presented with ID/IDA; 129 patients were included in the study. Serum ferritin and transferrin levels were reduced following apheresis (by 18% (p < 0.0001) and by 13% (p < 0.0001) respectively). Both FG and FCM were effective and well tolerated in the treatment of ID/IDA in LA patients. FCM led to a quicker repletion of iron stores (p < 0.05), while improvement of ID/IDA symptoms was not different. Number and severity of adverse events did not differ between FG and FCM, no severe adverse events occurred. CONCLUSIONS Our results suggest that FG and FCM are equally safe, well-tolerated and effective in treating ID/IDA in LA patients. These data form the basis for follow-up randomized controlled trials to establish clinical guidelines.