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1.
Laparoscopic sleeve gastrectomy alters 1H-NMR-measured lipoprotein and glycoprotein profile in patients with severe obesity and nonalcoholic fatty liver disease.
Cabré, N, Gil, M, Amigó, N, Luciano-Mateo, F, Baiges-Gaya, G, Fernández-Arroyo, S, Rodríguez-Tomàs, E, Hernández-Aguilera, A, Castañé, H, París, M, et al
Scientific reports. 2021;(1):1343
Abstract
Patients with morbid obesity frequently present non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) associated with pro-atherogenic alterations. Laparoscopic sleeve gastrectomy (LSG) is an effective treatment for weight reduction, and for the remission of hepatic alterations. Using 1H-nuclear magnetic resonance (1H-NMR), we investigated the effects of LSG on lipoprotein and glycoprotein profile in patients with morbid obesity and liver disease. We included 154 patients with morbid obesity (49 non-NASH, 54 uncertain NASH, 51 definite NASH). A blood sample was obtained before surgery and, in patients with definite NASH, one year after surgery. Patients with NASH had increased concentrations of medium and small VLDL particles, VLDL and IDL cholesterol concentrations, IDL, LDL, and HDL triglyceride concentrations, and elevated glycoprotein levels. These changes were more marked in patients with type 2 diabetes mellitus. LSG produced significant decreases in the concentration of VLDL particles, VLDL cholesterol and triglycerides, an increase in the concentration LDL particles and LDL cholesterol concentrations, and a decrease in protein glycation. We conclude that patients with obesity and NASH had significant alterations in circulating levels of lipoproteins and glycoproteins that were associated with the severity of the disease. Most of these changes were reversed post-LSG.
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2.
Improvement of endothelial dysfunction is mediated through reduction of remnant lipoprotein after statin therapy in patients with coronary artery disease.
Nakamura, T, Uematsu, M, Yoshizaki, T, Kobayashi, T, Watanabe, Y, Kugiyama, K
Journal of cardiology. 2020;(3):270-274
Abstract
BACKGROUND Remnant lipoproteinemia with high levels of low-density lipoprotein cholesterol (LDL-C) is a high risk for endothelial dysfunction. Statins are the first-line lipid-lowering drugs for this combined hyperlipidemia. However, it remains undetermined whether reduction of remnant lipoprotein mediates the relationship between improvement in endothelial dysfunction and reduction of LDL-C level after statin treatment. METHODS A total of 122 coronary artery disease (CAD) patients with impaired flow-mediated dilation (FMD; <5.5%), high levels of LDL-C (≥100 mg/dL), and remnant-like lipoprotein particle cholesterol (RLP-C) (≥5 mg/dL) were examined in this study. The lipid profiles and FMD were measured before and after 6-9 months of statin treatment. The association between changes in LDL-C levels and its relationship with changes in FMD was investigated. Furthermore, mediation analysis was performed to assess the changes in RLP-C level as a mediator of the relationship between the reduction in LDL-C level and improvement of FMD. RESULTS Treatment with statins improved FMD in 69 (56.5%) patients. Patients with improved FMD showed lower percent changes of LDL-C, triglyceride (TG), RLP-C, RLP-C/TG, and C-reactive protein (CRP) levels, and higher percent change of HDL-C level, compared to patients who did not show improved FMD. The percent changes in FMD levels had a significant inverse correlation with the percent changes in LDL-C, (r = -0.18, p = 0.03), RLP-C (r = -0.39, p < 0.001), RLP-C/TG (r = -0.34, p < 0.001), and CRP (r = -0.27, p < 0.01). Mediation analysis showed that the relationship between reduction in LDL-C and improvement of FMD was mediated by reduction of RLP-C (34.5%), RLP-C/TG (24.4%), and CRP (24.9%) levels. CONCLUSION Improvement of remnant lipoproteinemia may be an important mediator for the relationship between improvement of endothelial dysfunction and LDL-lowering after statin treatment in patients with CAD.
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3.
CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients.
Pockros, PJ, Fuchs, M, Freilich, B, Schiff, E, Kohli, A, Lawitz, EJ, Hellstern, PA, Owens-Grillo, J, Van Biene, C, Shringarpure, R, et al
Liver international : official journal of the International Association for the Study of the Liver. 2019;(11):2082-2093
Abstract
BACKGROUND & AIMS Nonalcoholic steatohepatitis (NASH) is a chronic and severe form of nonalcoholic fatty liver disease that can progress to cirrhosis and hepatocellular carcinoma and is a risk factor for cardiovascular disease. Although NASH has no approved treatments, obeticholic acid (OCA), a synthetic bile acid and farnesoid X receptor (FXR) agonist, was shown to improve histological features of NASH and fibrosis. Considering that FXR activation influences plasma lipoprotein concentrations, the Combination OCA aNd sTatins for monitoRing Of Lipids (CONTROL) study evaluated how statins can regulate lipoprotein metabolism with OCA treatment in patients with NASH. METHODS This randomized, double-blind, placebo-controlled, phase 2 study began with a 5-week screening/statin washout; 84 patients with NASH were randomly assigned (1:1:1:1) to receive placebo or 5 mg, 10 mg or 25 mg OCA once daily during the 16-week double-blind phase. Concurrent once daily atorvastatin (10 mg/days) was initiated at Week 4 with subsequent titration. Enrolled patients had biopsy-confirmed diagnosis of NASH with no evidence of hepatic decompensation. Plasma was collected to analyse lipoprotein parameters. RESULTS At Week 4, all OCA groups had an increase from baseline in mean low-density lipoprotein cholesterol (LDLc) and mean LDL particle concentration (LDLpc), mostly owing to large, less atherogenic LDLc particles. Atorvastatin 10 mg decreased LDLc and LDLpc levels below baseline in all OCA groups by Week 8; higher doses did not provide additional clinical benefits. CONCLUSIONS The CONTROL study showed that OCA-induced increases in LDLc in patients with NASH were mitigated with atorvastatin. The combination of OCA and atorvastatin was generally safe and well tolerated (NCT02633956).
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4.
Remnant Lipoproteins Are Residual Risk Factor for Future Cardiovascular Events in Patients With Stable Coronary Artery Disease and On-Statin Low-Density Lipoprotein Cholesterol Levels <70 mg/dL.
Fujihara, Y, Nakamura, T, Horikoshi, T, Obata, JE, Fujioka, D, Watanabe, Y, Watanabe, K, Kugiyama, K
Circulation journal : official journal of the Japanese Circulation Society. 2019;(6):1302-1308
Abstract
BACKGROUND This study examined the predictive value of remnant lipoprotein levels for cardiovascular events (CVEs) in patients with stable coronary artery disease (CAD) and low-density lipoprotein cholesterol (LDL-C) levels <70 mg/dL on statin treatment.Methods and Results:Serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol: RLP-C) were measured by an immunoseparation method in 247 consecutive patients with CAD who had on-statin LDL-C levels <70 mg/dL. All the patients were followed prospectively for a period of ≤60 months or until the occurrence of the primary composite endpoint of cardiac death, nonfatal myocardial infarction, unstable angina requiring coronary revascularization, worsening heart failure, peripheral artery disease, aortic event, and ischemic stroke. During a mean follow-up period of 38 months, 33 CVEs occurred. Kaplan-Meier analysis demonstrated that higher RLP-C levels (≥3.9 mg/dL, determined by ROC curve) resulted in a significantly higher probability for the primary endpoint than did lower RLP-C levels (<3.9 mg/dL) (P<0.01 by log-rank test). Stepwise multivariate Cox proportional hazard analysis showed that RLP-C was a significant predictor of the primary endpoint after adjustment for known risk factors and lipid variables including triglycerides, and total apolipoprotein B (hazard ratio 1.62, 95% confidence interval 1.26-2.07, P<0.01). CONCLUSIONS RLP-C levels are a residual risk factor for future CVEs in patients with CAD and on-statin LDL-C <70 mg/dL.
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5.
Lipoprotein turnover and possible remnant accumulation in preeclampsia: insights from the Freiburg Preeclampsia H.E.L.P.-apheresis study.
Contini, C, Jansen, M, König, B, Markfeld-Erol, F, Kunze, M, Zschiedrich, S, Massing, U, Merfort, I, Prömpeler, H, Pecks, U, et al
Lipids in health and disease. 2018;(1):49
Abstract
BACKGROUND Preeclampsia is a life-threatening disease in pregnancy, and its complex pathomechanisms are poorly understood. In preeclampsia, lipid metabolism is substantially altered. In late onset preeclampsia, remnant removal disease like lipoprotein profiles have been observed. Lipid apheresis is currently being explored as a possible therapeutic approach to prolong preeclamptic pregnancies. Here, apheresis-induced changes in serum lipid parameters are analyzed in detail and their implications for preeclamptic lipid metabolism are discussed. METHODS In the Freiburg H.E.L.P.-Apheresis Study, 6 early onset preeclamptic patients underwent repeated apheresis treatments. Serum lipids pre- and post-apheresis and during lipid rebound were analyzed in depth via ultracentrifugation to yield lipoprotein subclasses. RESULTS The net elimination of Apolipoprotein B and plasma lipids was lower than theoretically expected. Lipids returned to previous pre-apheresis levels before the next apheresis even though apheresis was repeated within 2.9 ± 1.2 days. Apparent fractional catabolic rates and synthetic rates were substantially elevated, with fractional catabolic rates for Apolipoprotein B / LDL-cholesterol being 0.7 ± 0.3 / 0.4 ± 0.2 [day- 1] and synthetic rates being 26 ± 8 / 17 ± 8 [mg*kg- 1*day- 1]. The distribution of LDL-subclasses after apheresis shifted to larger buoyant LDL, while intermediate-density lipoprotein-levels remained unaffected, supporting the notion of an underlying remnant removal disorder in preeclampsia. CONCLUSION Lipid metabolism seems to be highly accelerated in preeclampsia, likely outbalancing remnant removal mechanisms. Since cholesterol-rich lipoprotein remnants are able to accumulate in the vessel wall, remnant lipoproteins may contribute to the severe endothelial dysfunction observed in preeclampsia. TRIAL REGISTRATION ClinicalTrails.gov, NCT01967355 .
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6.
PCSK9 inhibition alters the lipidome of plasma and lipoprotein fractions.
Hilvo, M, Simolin, H, Metso, J, Ruuth, M, Öörni, K, Jauhiainen, M, Laaksonen, R, Baruch, A
Atherosclerosis. 2018;:159-165
Abstract
BACKGROUND AND AIMS While inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is known to result in dramatic lowering of LDL-cholesterol (LDL-C), it is poorly understood how it affects other lipid species and their metabolism. The aim of this study was to characterize the alterations in the lipidome of plasma and lipoprotein particles after administration of PCSK9 inhibiting antibody to patients with established coronary heart disease. METHODS Plasma samples were obtained from patients undergoing a randomized placebo-controlled phase II trial (EQUATOR) for the safe and effective use of RG7652, a fully human monoclonal antibody inhibiting PCSK9 function. Lipoprotein fractions were isolated by sequential density ultracentrifugation, and both plasma and major lipoprotein classes (VLDL-IDL, LDL, HDL) were subjected to mass spectrometric lipidomic profiling. RESULTS PCSK9 inhibition significantly decreased plasma levels of several lipid classes, including sphingolipids (dihydroceramides, glucosylceramides, sphingomyelins, ceramides), cholesteryl esters and free cholesterol. Previously established ceramide ratios predicting cardiovascular mortality, or inflammation related eicosanoid lipids, were not altered. RG7652 treatment also affected the overall and relative distribution of lipids in lipoprotein classes. An overall decrease of total lipid species was observed in LDL and VLDL + IDL particles, while HDL-associated phospholipids increased. Following the treatment, LDL displayed reduced lipid cargo, whereas relative lipid proportions of the VLDL + IDL particles were mostly unchanged, and there were relatively more lipids carried in the HDL particles. CONCLUSIONS Administration of PCSK9 antibody significantly alters the lipid composition of plasma and lipoprotein particles. These changes further shed light on the link between anti-PCSK9 therapies and cardiovascular risk.
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7.
The use of probiotic L. fermentum ME-3 containing Reg'Activ Cholesterol supplement for 4 weeks has a positive influence on blood lipoprotein profiles and inflammatory cytokines: an open-label preliminary study.
Kullisaar, T, Zilmer, K, Salum, T, Rehema, A, Zilmer, M
Nutrition journal. 2016;(1):93
Abstract
BACKGROUND Cardiovascular diseases continue to be a challenge and burden to heath. The incidence of type 2 diabetes is increasing. Modifying the (common) risk factors of them is the key of longterm success. The aim of the study was to establish if the special composition of innovative food supplement Reg'Activ Cholesterol (RAC) has a positive influence to the human body cardiovascular-inflammatory and diabetic parameters. METHODS Forty-five clinically asymptomatic participants consumed an RAC containing an antioxidative and antiatherogenic probiotic Lactobacillus fermentum ME-3 (LFME-3) for 4 weeks. The parameters measured were total cholesterol, HDL cholesterol, LDL cholesterol, triglyceride, oxLDL, hsCRP, IL-6 and glycosylated haemoglobin (HbA1c%). RESULTS The cardiovascular and diabetes risk profile of the participants improved significantly after 4 weeks of the intervention. The reduction of total cholesterol (from 6.5 ± 1.0 to 5.7 ± 0.9 mmol/l, p = 9.90806E-11) was on the account of LDL cholesterol as the HDL cholesterol level rose from 1.60 ± 0.31to 1.67 ± 0.34mml/l, p = 0.01. HbA1c% was reduced from 5.85 ± 0.28 to 5.66 ± 0.25 p = 4.64E-05 and oxLDL decreased from 84 ± 20 to 71 ± 15 U/l, p = 4.66292E-08. CONCLUSIONS The consumption of RAC in clinically asymptomatic volunteers with borderline-high values of risk factors for cardiovascular disease (BMI, HbA1c%, LDL cholesterol) for 4 weeks had a positive effect on blood lipoprotein, oxidative stress and inflammatory profile. There are no human trials published before with RAC. TRIAL REGISTRATION The trial described here isa n open label pilot study within the framework of a larger special clinical trial ( ISRCTN55339917 ) [Accessed 20 Feb 2016].
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8.
Relationship between the G75A polymorphism in the apolipoprotein A1 (ApoA1) gene and the lipid regulatory effects of pravastatin in patients with hyperlipidemia.
Liu, TN, Wu, CT, He, F, Yuan, W, Li, SX, Li, HW, Yu, HY, Wu, M
Genetics and molecular research : GMR. 2016;(2)
Abstract
In this study, we investigated the relationship between the G75A polymorphism in the apolipoprotein A1 (ApoA1) gene and the lipid regulatory effect of pravastatin in patients with hyperlipidemia. A total of 179 patients were divided into two groups: the pravastatin (N = 97) and policosanol (N = 82) treatment groups. The total cholesterol (TC), triglyceride, low-density lipoprotein (LDL-c), high-density lipoprotein, ApoA, and ApoB concentrations in the serum were measured using an automatic biochemical analyzer before and after treatment for 12 weeks. The genotypes of the ApoA1 G75A SNP were detected by polymerase chain reaction-restriction fragment length polymorphism, and were subsequently statistically analyzed. Pravastatin treatment induced a significant decrease in the TC, LDL-c, and ApoB levels in patients expressing the ApoA1 AA+GA genotype (P < 0.05), and not in those expressing the GG genotype (P > 0.05). However, policosanol treatment induced a non-significant decrease in the serum TC levels (P > 0.05) and a significant decrease in the ApoB levels (P < 0.05), and did not induce a decrease in the LDL-c (P > 0.05) levels in patients with the AA+GA genotype. Policosanol also induced a significant decrease in the TC and LDL-c levels in patients with the GG genotype (P < 0.05). The various genotypes of the ApoA1 G75A SNP influence the efficacy of lipid regulation by pravastatin and policosanol in patients with hyperlipidemia.
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9.
Effect of alirocumab on specific lipoprotein non-high-density lipoprotein cholesterol and subfractions as measured by the vertical auto profile method: analysis of 3 randomized trials versus placebo.
Toth, PP, Hamon, SC, Jones, SR, Martin, SS, Joshi, PH, Kulkarni, KR, Banerjee, P, Hanotin, C, Roth, EM, McKenney, JM
Lipids in health and disease. 2016;:28
Abstract
BACKGROUND The effect of alirocumab on potentially atherogenic lipoprotein subfractions was assessed in a post hoc analysis using the vertical auto profile (VAP) method. METHODS Patients from three Phase II studies with low-density lipoprotein cholesterol (LDL-C) ≥ 2.59 mmol/L (100 mg/dL) at baseline on stable statin therapy were randomised to receive subcutaneous alirocumab 50-150 mg every 2 weeks (Q2W) or 150-300 mg every 4 weeks (according to study) or placebo for 8-12 weeks. Samples from patients treated with alirocumab 150 mg Q2W (n = 74; dose common to all three trials) or placebo (n = 71) were analysed by VAP. Percent change in lipoprotein subfractions with alirocumab vs. placebo was analysed at Weeks 6, 8 or 12 using analysis of covariance. RESULTS Alirocumab significantly reduced LDL-C and the cholesterol content of subfractions LDL1, LDL2 and LDL3+4. Significant reductions were also observed in triglycerides, apolipoproteins CII and CIII and the cholesterol content of very low-density, intermediate-density, and remnant lipoproteins. CONCLUSION Alirocumab achieved reductions across a spectrum of atherogenic lipoproteins in patients receiving background statin therapy. TRIAL REGISTRATION Clinicaltrials.gov identifiers: NCT01288443, NCT01288469, NCT01266876.
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10.
Effect of Metformin Treatment on Lipoprotein Subfractions in Non-Diabetic Patients with Acute Myocardial Infarction: A Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III) Trial.
Eppinga, RN, Hartman, MH, van Veldhuisen, DJ, Lexis, CP, Connelly, MA, Lipsic, E, van der Horst, IC, van der Harst, P, Dullaart, RP
PloS one. 2016;(1):e0145719
Abstract
OBJECTIVE Metformin affects low density lipoprotein (LDL) and high density (HDL) subfractions in the context of impaired glucose tolerance, but its effects in the setting of acute myocardial infarction (MI) are unknown. We determined whether metformin administration affects lipoprotein subfractions 4 months after ST-segment elevation MI (STEMI). Second, we assessed associations of lipoprotein subfractions with left ventricular ejection fraction (LVEF) and infarct size 4 months after STEMI. METHODS 371 participants without known diabetes participating in the GIPS-III trial, a placebo controlled, double-blind randomized trial studying the effect of metformin (500 mg bid) during 4 months after primary percutaneous coronary intervention for STEMI were included of whom 317 completed follow-up (clinicaltrial.gov Identifier: NCT01217307). Lipoprotein subfractions were measured using nuclear magnetic resonance spectroscopy at presentation, 24 hours and 4 months after STEMI. (Apo)lipoprotein measures were obtained during acute STEMI and 4 months post-STEMI. LVEF and infarct size were measured by cardiac magnetic resonance imaging. RESULTS Metformin treatment slightly decreased LDL cholesterol levels (adjusted P = 0.01), whereas apoB remained unchanged. Large LDL particles and LDL size were also decreased after metformin treatment (adjusted P<0.001). After adjustment for covariates, increased small HDL particles at 24 hours after STEMI predicted higher LVEF (P = 0.005). In addition, increased medium-sized VLDL particles at the same time point predicted a smaller infarct size (P<0.001). CONCLUSION LDL cholesterol and large LDL particles were decreased during 4 months treatment with metformin started early after MI. Higher small HDL and medium VLDL particle concentrations are associated with favorable LVEF and infarct size.