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HPLC with spectrophotometric or mass spectrometric detection for quantifying very-long chain fatty acids in human plasma and its association with cardiac risk factors.
Shrestha, R, Chen, Z, Gao, Z, Chen, Y, Okada, E, Ukawa, S, Nakagawa, T, Nakamura, K, Tamakoshi, A, Chiba, H, et al
Annals of clinical biochemistry. 2021;(5):400-410
Abstract
BACKGROUND We developed and compared two liquid chromatography methods, one with UV/Visible spectrophotometric detection (HPLC) and the other with mass spectrometric detection (LC-MS), for quantifying very-long chain fatty acids (VLCFA) in human plasma. Association of VLCFA with various cardiovascular risk factors were evaluated. METHOD Fasting blood samples were collected from 541 human volunteers (242 men and 299 women; mean age ±SD, 58.9 ± 12.4 years), including 429 and 112 individuals with and without hypertriglyceridemia, respectively. Esterified VLCFA were saponified and derivatized with 2-nitrophenylhydrazine. Separation of VLCFA species was achieved with C4 Mightysil column (HPLC) and Ascentis Express Phenyl-Hexyl column (LC-MS) followed by spectrophotometric and selected-reaction monitoring mode of mass spectrometric detection, respectively. RESULTS The HPLC assay of VLCFA was precise with intra-assay imprecision of 2.5% to 6.9% and inter-assay imprecision of 3.2% to 9.5%. Moreover, there was an excellent correlation (r > 0.96) between HPLC and LC-MS methods. The 95 percentile reference intervals (RI; upper limit) of VLCFA were determined to be 41.3 µmol/L in healthy volunteers. Plasma VLCFA were significantly correlated with triglycerides (Spearman's ρ = 0.306, P < 0.001) and total cholesterol (Spearman's ρ = 0.251, P < 0.001). All species of VLCFA were significantly elevated in hypertriglyceridaemic individuals compared with control. CONCLUSION We established LC-based assays of VLCFA with either spectrophotometry or mass spectrometry as a detection system. Hypertriglyceridaemia is significantly associated with elevated concentration of each species of VLCFA.
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Topical simvastatin-cholesterol for disseminated superficial actinic porokeratosis: An open-label, split-body clinical trial.
Byth, LA, Byth, J
The Australasian journal of dermatology. 2021;(3):310-313
Abstract
BACKGROUND/OBJECTIVES Disseminated superficial actinic porokeratosis (DSAP) is a porokeratosis variant that is cosmetically disfiguring and may be associated with squamous cell carcinoma. It is an autosomal dominant condition caused by germline mutations in mevalonate pathway genes involved in cholesterol synthesis. Lesions are precipitated by ultraviolet radiation-induced second-hit mutations. Modulation of this pathway by topical simvastatin-cholesterol may lead to improvement. METHODS This open-label, split-body clinical trial was carried out in 2020 at a metropolitan dermatology clinic. Eight patients contributing 13 limb pairs were recruited. Limbs within each pair were randomly allocated to 2% simvastatin/2% cholesterol cream applied twice daily or bland emollients. Lesion number, erythema, scale and patient-reported disease activity were measured at baseline and 6 weeks. Data were analysed using Bayesian ordinal logistic regression. Odds ratios compare the odds of a higher score at 6 weeks in treated limbs with the odds in controls. Values less than one indicate improvement. RESULTS Patients had a median age of 65 years (interquartile range [IQR] 58 to 69 years). The median baseline DLQI was 5 (range 2-21). Odds ratios were 0.12 (95% credible interval [CI] 0.01 to 0.72) for lesion number, 0.25 (95% CI 0.05 to 0.79) for erythema score, 0.18 (95% CI 0.03 to 0.64) for scale score and 0.33 (95% CI 0.09 to 0.89) for patient-reported disease activity. CONCLUSIONS Topical simvastatin-cholesterol cream improved lesion number, erythema and scale on treated limbs compared with controls. Patient-reported disease activity also improved. These findings warrant confirmation in blinded, vehicle-controlled trials.
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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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Risk Factor Control and Cardiovascular Event Risk in People With Type 2 Diabetes in Primary and Secondary Prevention Settings.
Wright, AK, Suarez-Ortegon, MF, Read, SH, Kontopantelis, E, Buchan, I, Emsley, R, Sattar, N, Ashcroft, DM, Wild, SH, Rutter, MK
Circulation. 2020;(20):1925-1936
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Abstract
BACKGROUND To examine the association between the degree of risk factor control and cardiovascular disease (CVD) risk in type 2 diabetes and to assess if the presence of cardio-renal disease modifies these relationships. METHODS A retrospective cohort study using data from English practices from CPRD GOLD (Clinical Practice Research Datalink) and the SCI-Diabetes dataset (Scottish Care Information-Diabetes), with linkage to hospital and mortality data. We identified 101 749 with type 2 diabetes (T2D) in CPRD matched with 378 938 controls without diabetes and 330 892 with type 2 diabetes in SCI-Diabetes between 2006 and 2015. The main exposure was number of optimized risk factors: nonsmoker, total cholesterol ≤4 mmol/L, triglycerides ≤1.7 mmol/L, glycated haemoglobin (HbA1c) ≤53 mmol/mol (≤7.0%), systolic blood pressure <140mm Hg, or <130 mm Hg if high risk. Cox models were used to assess cardiovascular risk associated with levels of risk factor control. RESULTS In CPRD, the mean baseline age in T2D was 63 years and 28% had cardio-renal disease (SCI-Diabetes: 62 years; 35% cardio-renal disease). Over 3 years follow-up (SCI-Diabetes: 6 years), CVD events occurred among 27 900 (27%) CPRD-T2D, 101 362 (31%) SCI-Diabetes-T2D, and 75 520 (19%) CPRD-controls. In CPRD, compared with controls, T2D participants with optimal risk factor control (all risk factors controlled) had a higher risk of CVD events (adjusted hazard ratio, 1.21; 95% confidence interval, 1.12-1.29). In T2D participants from CPRD and SCI-Diabetes, pooled hazard ratios for CVD associated with 5 risk factors being elevated versus optimal risk factor control were 1.09 (95% confidence interval, 1.01-1.17) in people with cardio-renal disease but 1.96 (95% confidence interval, 1.82-2.12) in people without cardio-renal disease. People without cardio-renal disease were younger and more likely to have likely to have suboptimal risk factor control but had fewer prescriptions for risk factor modifying medications than those with cardio-renal disease. CONCLUSIONS Optimally managed people with T2D have a 21% higher CVD risk when compared with controls. People with T2D without cardio-renal disease would be predicted to benefit greatly from CVD risk factor intervention.
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Macrophage Cholesterol Efflux Downregulation Is Not Associated with Abdominal Aortic Aneurysm (AAA) Progression.
Canyelles, M, Tondo, M, Lindholt, JS, Santos, D, Fernández-Alonso, I, de Gonzalo-Calvo, D, Blanco-Colio, LM, Escolà-Gil, JC, Martín-Ventura, JL, Blanco-Vaca, F
Biomolecules. 2020;(4)
Abstract
Recent studies have raised the possibility of a role for lipoproteins, including high-density lipoprotein cholesterol (HDLc), in abdominal aortic aneurysm (AAA). The study was conducted in plasmas from 39 large size AAA patients (aortic diameter > 50 mm), 81 small/medium size AAA patients (aortic diameter between 30 and 50 mm) and 38 control subjects (aortic diameter < 30 mm). We evaluated the potential of HDL-mediated macrophage cholesterol efflux (MCE) to predict AAA growth and/or the need for surgery. MCE was impaired in the large aortic diameter AAA group as compared with that in the small/medium size AAA group and the control group. However, no significant difference in HDL-mediated MCE capacity was observed in 3 different progression subgroups (classified according to growth rate < 1 mm per year, between 1 and 5 mm per year or >5 mm per year) in patients with small/medium size AAA. Moreover, no correlation was found between MCE capacity and the aneurysm growth rate. A multivariate Cox regression analysis revealed a significant association between lower MCE capacity with the need for surgery in all AAA patients. Nevertheless, the significance was lost when only small/medium size AAA patients were included. Our results suggest that MCE, a major HDL functional activity, is not involved in AAA progression.
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Volixibat in adults with non-alcoholic steatohepatitis: 24-week interim analysis from a randomized, phase II study.
Newsome, PN, Palmer, M, Freilich, B, Sheikh, MY, Sheikh, A, Sarles, H, Herring, R, Mantry, P, Kayali, Z, Hassanein, T, et al
Journal of hepatology. 2020;(2):231-240
Abstract
BACKGROUND & AIMS Volixibat is an inhibitor of the apical sodium-dependent bile acid transporter (ASBT) that has been hypothesized to improve non-alcoholic steatohepatitis (NASH) by blocking bile acid reuptake and stimulating hepatic bile acid production. We studied the safety, tolerability and efficacy of volixibat in patients with NASH. METHODS In this double-blind, phase II dose-finding study, adults with ≥5% steatosis and NASH without cirrhosis (N = 197) were randomized to receive volixibat (5, 10 or 20 mg) or placebo once daily for 48 weeks. The endpoints of a predefined interim analysis (n = 80), at week 24, were: ≥5% reduction in MRI-proton density fat fraction and ≥20% reduction in serum alanine aminotransferase levels. The primary endpoint was a ≥2-point reduction in non-alcoholic fatty liver disease activity score without worsening fibrosis at week 48. RESULTS Volixibat did not meet either interim endpoint; the study was terminated owing to lack of efficacy. In participants receiving any volixibat dose, mean serum 7-alpha-hydroxy-4-cholesten-3-one (C4; a biomarker of bile acid synthesis) increased from baseline to week 24 (+38.5 ng/ml [SD 53.18]), with concomitant decreases in serum total cholesterol (-14.5 mg/dl [SD 28.32]) and low-density lipoprotein cholesterol (-16.1 mg/dl [SD 25.31]). These changes were generally dose-dependent. On histological analysis, a greater proportion of participants receiving placebo (38.5%, n = 5/13) than volixibat (30.0%, n = 9/30) met the primary endpoint. Treatment-emergent adverse events (TEAEs) were mainly mild or moderate. No serious TEAEs were related to volixibat. Diarrhoea was the most common TEAE overall and the most common TEAE leading to discontinuation. CONCLUSIONS Increased serum C4 and decreased serum cholesterol levels provide evidence of target engagement. However, inhibition of ASBT by volixibat did not elicit a liver-related therapeutic benefit in adults with NASH. LAY SUMMARY A medicine called volixibat has previously been shown to reduce cholesterol levels in the blood. This study investigated whether volixibat could reduce the amount of fat in the liver and reduce liver injury in adults with an advanced form of non-alcoholic fatty liver disease. Volixibat did not reduce the amount of fat in the liver, nor did it have any other beneficial effect on liver injury. Participants in the study generally tolerated the side effects of volixibat and, as in previous studies, the main side effect was diarrhoea. These results show that volixibat is not an effective treatment for people with fatty liver disease. CLINICAL TRIAL IDENTIFIER NCT02787304.
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Chia (Salvia hispanica)-supplemented diet ameliorates non-alcoholic fatty liver disease and its metabolic abnormalities in humans.
Medina-Urrutia, A, Lopez-Uribe, AR, El Hafidi, M, González-Salazar, MDC, Posadas-Sánchez, R, Jorge-Galarza, E, Del Valle-Mondragón, L, Juárez-Rojas, JG
Lipids in health and disease. 2020;(1):96
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a public health problem lacking an approved pharmacological treatment. Omega-3 fatty acids have shown to reverse NAFLD. Chia is a seed rich in α-linolenic acid (ALA), antioxidants, and fiber; therefore, it could be useful to treat NAFLD. METHODS In a single arm experimental design study, the effect of 25 g/day of milled chia was assessed in 25 patients with NAFLD. After two weeks of dietary stabilization (basal condition) and eight weeks of a chia-supplemented isocaloric diet, liver:spleen attenuation index and visceral abdominal fat (VAF) were measured by computed tomography. Lipids, lipoproteins, free fatty acids (FFA), and ALA plasma concentrations were also determined. RESULTS Dietary chia supplementation induced an increase in plasma ALA concentration (75%) and dietary fiber (55%) consumption. After chia supplementation, VAF (9%), body weight (1.4%), total cholesterol (2.5%), non-high density lipoprotein cholesterol (3.2%), and circulating FFA (8%) decreased. Furthermore, NAFLD regressed in 52% of the treated patients (P < 0.05 for all). CONCLUSIONS The results of the present study show that 25 g/day of milled chia ameliorates NAFLD. Chia is an accessible vegetal source of omega-3 fatty acids, antioxidants, and fiber, which could have the potential to prevent metabolic abnormalities in NAFLD patients. Considering that there is no pharmacological treatment approved for NAFLD, the findings of the present study suggest that a chia-supplemented diet could be an innovative alternative to control this disease. RETROSPECTIVELY REGISTERED https://clinicaltrials.gov/show/NCT03942822.
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Phytosterols Supplementation Reduces Endothelin-1 Plasma Concentration in Moderately Hypercholesterolemic Individuals Independently of Their Cholesterol-Lowering Properties.
Oliveira Godoy Ilha, A, Sutti Nunes, V, Silva Afonso, M, Regina Nakandakare, E, da Silva Ferreira, G, de Paula Assis Bombo, R, Rodrigues Giorgi, R, Marcondes Machado, R, Carlos Rocha Quintão, E, Lottenberg, AM
Nutrients. 2020;(5)
Abstract
Experimental and clinical studies have demonstrated the effect of phytosterols (PS) on reducing plasma levels of cholesterol and LDL-c, but the effects of plant sterols beyond cholesterol-lowering are still questionable. Since inflammation and endothelial dysfunction are involved in the pathogenesis of atherosclerosis, this study aims to evaluate the effect of PS on biomarkers involved in atherosclerosis progression and whether these effects are independent of alterations in plasma LDL-c levels. Thirty-eight moderately hypercholesterolemic volunteers (58 ± 12 years; LDL-c ≥ 130 mg/dL) were randomly assigned to consume 400 mL/day of soy milk or soy milk + PS (1.6 g/day) for 4 weeks in a double-blind, placebo-controlled, cross-over study. Blood samples were collected and lipid profiles and biomarkers for inflammation and endothelial dysfunction determined. The results showed that PS treatment reduced endothelin-1 plasma concentration by 11% (p = 0.02) independently of variations in plasma levels of LDL-c. No alterations were observed regarding fibrinogen, IL-6, hs-CRP, SAA, TNFα, or VCAM-1 between placebo and PS-treated groups. Furthermore, PS reduced total plasma cholesterol concentration (-5,5%, p < 0.001), LDL-c (-6.4%, p < 0.05), triglycerides (-8.3%, p < 0.05), and apo B (-5.3%, p < 0.05), without changing HDL-c concentration (p > 0.05). Therefore, PS supplementation effectively lowers endothelin-1 independently of the reductions in plasma levels of LDL-c, contributing to the comprehension of the effect of plant sterols on endothelial function and prevention of cardiovascular diseases.
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In vivo evidence for transintestinal cholesterol efflux in patients with complete common bile duct obstruction.
Moreau, F, Blanchard, C, Perret, C, Flet, L, Douane, F, Frampas, E, Mirallie, E, Croyal, M, Aguesse, A, Krempf, M, et al
Journal of clinical lipidology. 2019;(1):213-217.e1
Abstract
BACKGROUND Beyond the hepatobiliary pathway, studies have demonstrated that direct transintestinal cholesterol efflux (TICE) of plasma-derived cholesterol may contribute to reverse cholesterol transport. The clinical evidence of TICE in human remains challenged because of the difficulty to discriminate the hepatobiliary and transintestinal routes in vivo. OBJECTIVE To provide the first proof of concept that TICE exists in vivo in humans by demonstrating that plasma labeled cholesterol can be excreted in the feces of patients with complete bile duct obstruction. METHODS Plasma, bile, and fecal cholesterol excretion was measured by mass spectrometry 24, 48, and 72 hours after intravenous injection of D7-cholesterol in two patients presenting cholangiocarcinomas with a total obstruction of their primary bile duct. RESULTS No trace of bile acids was detected in the feces of the two patients. Despite this, a significant amount of plasma D7-cholesterol was quantified in the feces of the two patients 48 hours and 72 hours after the intravenous injection. CONCLUSION Our data bring a direct proof that TICE is an active pathway in humans.
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Generalizability of the FOURIER trial to routine clinical care: Do trial participants represent patients in everyday practice?
Yao, X, Gersh, BJ, Lopez-Jimenez, F, Shah, ND, Noseworthy, PA
American heart journal. 2019;:54-62
Abstract
BACKGROUND In the FOURIER trial, evolocumab, a proprotein convertase subtilisin-kexin type 9 inhibitor, reduced cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD). We aimed to examine how closely patients in routine practice resemble the FOURIER trial participants and to assess the observed cardiovascular risks based on trial eligibility and underrepresentativeness. METHODS Using a large US administrative database with linked laboratory data, we identified adult patients with ASCVD between January 1, 2012, and December 31, 2016. We identified the excluded and underrepresented populations and examined the risk of cardiovascular events (a composite endpoint of myocardial infarction [MI], stroke, angina, and coronary revascularization) based on trial eligibility and underrepresentativeness. RESULTS Only 15.2% of 233,977 patients met the FOURIER eligibility. Nearly 60% of the ineligible patients met at least 2 exclusion criteria. Among trial-eligible patients, elderly patients, women, minorities, and those without prior MI were underrepresented in FOURIER. Patients who would have been excluded from FOURIER had a diverse risk profile but, on average, had a lower cardiovascular risk than those who would have qualified (hazard ratio [HR] 0.84 [0.81-0.88], P < .001). Among the underrepresented patients, women and patients without prior MI had a lower cardiovascular risk (HR 0.77 [0.71-0.82], P < .001; HR 0.67 [0.63-0.72], P < .001, respectively). Only 47.2% of patients were on moderate-/high-intensity statins. CONCLUSIONS One in 7 ASCVD patients in practice would have qualified for FOURIER. The excluded and underrepresented populations were at a particularly low or high cardiovascular risk. Statin therapy was underused, and physicians may need to evaluate adherence before adding a proprotein convertase subtilisin-kexin type 9 inhibitor.