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Background: Pathogenic variants in PLIN1 -encoding PLIN1 (perilipin-1) are responsible for an autosomal dominant form of familial partial lipodystrophy (FPL) associated with severe insulin resistance, hepatic steatosis, and important hypertriglyceridemia. This study aims to decipher the mechanisms of hypertriglyceridemia associated with PLIN1 -related FPL., Methods: We performed an in vivo lipoprotein kinetic study in 6 affected patients compared with 13 healthy controls and 8 patients with type 2 diabetes. Glucose and lipid parameters, including plasma LPL (lipoprotein lipase) mass, were measured. LPL mRNA and protein expression were evaluated in abdominal subcutaneous adipose tissue from patients with 5 PLIN1 -mutated FPL and 3 controls., Results: Patients with PLIN1 -mutated FPL presented with decreased fat mass, insulin resistance, and diabetes (glycated hemoglobin A1c, 6.68±0.70% versus 7.48±1.63% in patients with type 2 diabetes; mean±SD; P =0.27). Their plasma triglycerides were higher (5.96±3.08 mmol/L) than in controls (0.76±0.27 mmol/L; P <0.0001) and patients with type 2 diabetes (2.94±1.46 mmol/L, P =0.006). Compared with controls, patients with PLIN1 -related FPL had a significant reduction of the indirect fractional catabolic rate of VLDL (very-low-density lipoprotein)-apoB100 toward IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein; 1.79±1.38 versus 5.34±2.45 pool/d; P =0.003) and the indirect fractional catabolic rate of IDL-apoB100 toward LDL (2.14±1.44 versus 7.51±4.07 pool/d; P =0.005). VLDL-apoB100 production was not different between patients with PLIN1 -related FPL and controls. Compared with patients with type 2 diabetes, patients with PLIN1 -related FPL also showed a significant reduction of the catabolism of both VLDL-apoB100 ( P =0.031) and IDL-apoB100 ( P =0.031). Plasma LPL mass was significantly lower in patients with PLIN1 -related FPL than in controls (21.03±10.08 versus 55.76±13.10 ng/mL; P <0.0001), although the LPL protein expression in adipose tissue was similar. VLDL-apoB100 and IDL-apoB100 indirect fractional catabolic rates were negatively correlated with plasma triglycerides and positively correlated with LPL mass., Conclusions: We show that hypertriglyceridemia associated with PLIN1 -related FPL results from a marked decrease in the catabolism of triglyceride-rich lipoproteins (VLDL and IDL). This could be due to a pronounced reduction in LPL availability, related to the decreased adipose tissue mass., Competing Interests: None.

The current first-line treatment for atherosclerotic cardiovascular disease (ASCVD) involves the reduction of a patient's low-density lipoprotein cholesterol (LDL-C) levels through the use of lipid-lowering drugs. However, even when other risk factors such as hypertension and diabetes are effectively managed, there remains a residual cardiovascular risk in these patients despite achieving target LDL-C levels with statins and new lipid-lowering medications. This risk was previously believed to be associated with lipid components other than LDL, such as triglycerides. However, recent studies have unveiled the crucial role of remnant cholesterol (RC) in atherosclerosis, not just triglycerides. The metabolized product of triglyceride-rich lipoproteins is referred to as triglyceride-rich remnant lipoprotein particles, and its cholesterol component is known as RC. Numerous pieces of evidence from epidemiological investigations and genetic studies demonstrate that RC plays a significant role in predicting the incidence of ASCVD. As a novel marker for atherosclerosis prediction, when LDL-C is appropriately controlled, RC should be prioritized for attention and intervention among individuals at high risk of ASCVD. Therefore, reducing RC levels through the use of various lipid-lowering drugs may yield long-term benefits. Nevertheless, routine testing of RC in clinical practice remains controversial, necessitating further research on the treatment of elevated RC levels to evaluate the advantages of reducing RC in patients at high risk of ASCVD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: LCAT (lecithin cholesterol acyl transferase) catalyzes the conversion of unesterified, or free cholesterol, to cholesteryl ester, which moves from the surface of HDL (high-density lipoprotein) into the neutral lipid core. As this iterative process continues, nascent lipid-poor HDL is converted to a series of larger, spherical cholesteryl ester-enriched HDL particles that can be cleared by the liver in a process that has been termed reverse cholesterol transport., Methods: We conducted a randomized, placebocontrolled, crossover study in 5 volunteers with atherosclerotic cardiovascular disease, to examine the effects of an acute increase of recombinant human (rh) LCAT via intravenous administration (300-mg loading dose followed by 150 mg at 48 hours) on the in vivo metabolism of HDL APO (apolipoprotein)A1 and APOA2, and the APOB100-lipoproteins, very low density, intermediate density, and low-density lipoproteins., Results: As expected, recombinant human LCAT treatment significantly increased HDL-cholesterol (34.9 mg/dL; P ≤0.001), and this was mostly due to the increase in cholesteryl ester content (33.0 mg/dL; P =0.014). This change did not affect the fractional clearance or production rates of HDL-APOA1 and HDL-APOA2. There were also no significant changes in the metabolism of APOB100-lipoproteins., Conclusions: Our results suggest that an acute increase in LCAT activity drives greater flux of cholesteryl ester through the reverse cholesterol transport pathway without significantly altering the clearance and production of the main HDL proteins and without affecting the metabolism of APOB100-lipoproteins. Long-term elevations of LCAT might, therefore, have beneficial effects on total body cholesterol balance and atherogenesis., Competing Interests: Disclosures R. George was an employee of AstraZeneca during the time this study was conducted. H. Ginsberg has consulted for AstraZeneca intermittently, including on 2 occasions during the time period that this study was conducted. However, those consultations were not related to recombinant human lecithin cholesterol acyl transferase.

Objective: The aim of this study is to evaluate the association between burn injury and admission plasma levels of Syndecan-1 (SDC-1) and Tissue Factor Pathway Inhibitor (TFPI), and their ability to predict 30-day mortality., Background: SDC-1 and TFPI are expressed by vascular endothelium and shed into the plasma as biomarkers of endothelial damage. Admission plasma biomarker levels have been associated with morbidity and mortality in trauma patients, but this has not been well characterized in burn patients.Methods: This cohort study enrolled burn patients admitted to a regional burn center between 2013 and 2017. Blood samples were collected within 4 h of admission and plasma SDC-1 and TFPI were quantified by ELISA. Demographics and injury characteristics were collected prospectively. The primary outcome was 30-day in-hospital mortality., Results: Of 158 patients, 74 met inclusion criteria. Most patients were male with median age of 41.5 years and burn TBSA of 20.5%. The overall mortality rate was 20.3%. Admission SDC-1 and TFPI were significantly higher among deceased patients. Plasma SDC-1 >34 ng/mL was associated with a 32-times higher likelihood of mortality [OR: 32.65 (95% CI, 2.67-399.78); P = 0.006] and a strong predictor of mortality (area under the ROC [AUROC] 0.92). TFPI was associated with a nine-times higher likelihood of mortality [OR: 9.59 (95% CI, 1.02-89.75); P = 0.002] and a fair predictor of mortality (AUROC 0.68)., Conclusions: SDC-1 and TFPI are associated with a higher risk of 30-day mortality. We propose the measurement of SDC-1 on admission to identify burn patients at high risk of mortality. However, further investigation with a larger sample size is warranted., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

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Abstract: This work aims to explore risk factors for ischemic stroke in young adults and analyze the Traditional Vascular Risk Factors Model based on age, hypertension, diabetes, smoking history, and drinking history. Further, the Lipid Metabolism Model was analyzed based on lipoprotein a [LP (a)], high-density lipoprotein (HDL), low-density lipoprotein (LDL), apolipoprotein AI (apo AI), apolipoprotein B (apo B), and the Early Renal Injury Model based on urinary microalbuminuria/creatinine ratio (UACR). Besides, we estimated glomerular filtration rate (eGFR), cystatin C (Cys-C), homocysteine (Hcy), β2 microglobulin (β2m), and validated their predictive efficacy and clinical value for the development of ischemic stroke in young adults.We selected and retrospectively analyzed the clinical data of 565 young inpatients admitted to Zhejiang Provincial Hospital of Chinese Medicine between 2010 and 2020, 187 of whom were young stroke patients. A single-factor analysis was used to analyze the risk factors for stroke in young people and developed a traditional vascular risk factors model, a lipid metabolism model, and an early kidney injury model based on backpropagation (BP) neural networks technology to predict early stroke occurrence. Moreover, the prediction performance by the area under the receiver operating characteristics (ROC) curve (AUC) was assessed to further understand the risk factors for stroke in young people and apply their predictive role in the clinical setting.Single-factor analysis showed that ischemic stroke in young adults was associated with hypertension, diabetes, smoking history, drinking history, LP(a), HDL, LDL, apo AI, apo B, eGFR, Cys-C, and β2m (P < .05). The BP neural networks technique was used to plot the ROC curves for the Traditional Vascular Risk Factors Model, the Lipid Metabolism Model, and the Early Kidney Injury Model in enrolled patients, and calculated AUC values of 0.7915, 0.8387, and 0.9803, respectively.The early kidney injury model precisely predicted the risk of ischemic stroke in young adults and exhibited a certain clinical value as a reference for morbidity assessment. Whereas the prediction performance of the Traditional Vascular Risk Factors Model and the Lipid Metabolism Model were inferior to that of the early kidney injury model., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The aim of this study was to comprehensively assess the association of multiple lipid measures with incident peripheral artery disease (PAD). Approach and Results: We used Cox proportional hazards models to characterize the associations of each of the fasting lipid measures (total cholesterol, LDL-C [low-density lipoprotein cholesterol], HDL-C [high-density lipoprotein cholesterol], triglycerides, RLP-C [remnant lipoprotein cholesterol], LDL-TG [LDL-triglycerides], sdLDL-C [small dense LDL-C], and Apo-E-HDL [Apo-E-containing HDL-C]) with incident PAD identified by pertinent International Classification of Diseases, Ninth Revision, Clinical Modification ( ICD-9-CM ) hospital discharge codes (eg, 440.2) among 8330 Black and White ARIC (Atherosclerosis Risk in Communities) participants (mean age 62.8 [SD 5.6] years) free of PAD at baseline (1996-1998) through 2015. Since lipid traits are biologically correlated to each other, we also conducted principal component analysis to identify underlying components for PAD risk. There were 246 incident PAD cases with a median follow-up of 17 years. After accounting for potential confounders, the following lipid measures were significantly associated with PAD (hazard ratio per 1-SD increment [decrement for HDL-C and Apo-E-HDL]): triglycerides, 1.21 (95% CI, 1.08-1.36); RLP-C, 1.18 (1.08-1.29); LDL-TG, 1.18 (1.05-1.33); HDL-C, 1.39 (1.16-1.67); and Apo-E-HDL, 1.27 (1.07-1.51). The principal component analysis identified 3 components (1: mainly loaded by triglycerides, RLP-C, LDL-TG, and sdLDL-C; 2: by HDL-C and Apo-E-HDL; and 3: by LDL-C and RLP-C). Components 1 and 2 showed independent associations with incident PAD., Conclusions: Triglyceride-related and HDL-related lipids were independently associated with incident PAD, which has implications on preventive strategies for PAD. However, none of the novel lipid measures outperformed conventional ones. Graphic Abstract: A graphic abstract is available for this article.

Objective: Increased risk of atherosclerotic cardiovascular disease in subjects with type 2 diabetes is linked to elevated levels of triglyceride-rich lipoproteins and their remnants. The metabolic effects of PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors on this dyslipidemia were investigated using stable-isotope-labeled tracers. Approach and Results: Triglyceride transport and the metabolism of apos (apolipoproteins) B48, B100, C-III, and E after a fat-rich meal were investigated before and on evolocumab treatment in 13 subjects with type 2 diabetes. Kinetic parameters were determined for the following: apoB48 in chylomicrons; triglyceride in VLDL 1 (very low-density lipoprotein) and VLDL 2 ; and apoB100 in VLDL 1 , VLDL 2 , IDL (intermediate-density lipoprotein), and LDL (low-density lipoprotein). Evolocumab did not alter the kinetics of apoB48 in chylomicrons or apoB100 or triglyceride in VLDL 1 . In contrast, the fractional catabolic rates of VLDL 2 -apoB100 and VLDL 2 -triglyceride were both increased by about 45%, which led to a 28% fall in the VLDL 2 plasma level. LDL-apoB100 was markedly reduced by evolocumab, which was linked to metabolic heterogeneity in this fraction. Evolocumab increased clearance of the more rapidly metabolized LDL by 61% and decreased production of the more slowly cleared LDL by 75%. ApoC-III kinetics were not altered by evolocumab, but the apoE fractional catabolic rates increased by 45% and the apoE plasma level fell by 33%. The apoE fractional catabolic rates was associated with the decrease in VLDL 2 - and IDL-apoB100 concentrations., Conclusions: Evolocumab had only minor effects on lipoproteins that are involved in triglyceride transport (chylomicrons and VLDL 1 ) but, in contrast, had a profound impact on lipoproteins that carry cholesterol (VLDL 2 , IDL, LDL). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02948777.

Rationale: Single-nucleotide polymorphisms near the ILRUN (inflammation and lipid regulator with ubiquitin-associated-like and NBR1 [next to BRCA1 gene 1 protein]-like domains) gene are genome-wide significantly associated with plasma lipid traits and coronary artery disease (CAD), but the biological basis of this association is unknown., Objective: To investigate the role of ILRUN in plasma lipid and lipoprotein metabolism., Methods and Results: ILRUN encodes a protein that contains a ubiquitin-associated-like domain, suggesting that it may interact with ubiquitinylated proteins. We generated mice globally deficient for Ilrun and found they had significantly lower plasma cholesterol levels resulting from reduced liver lipoprotein production. Liver transcriptome analysis uncovered altered transcription of genes downstream of lipid-related transcription factors, particularly PPARα (peroxisome proliferator-activated receptor alpha), and livers from Ilrun -deficient mice had increased PPARα protein. Human ILRUN was shown to bind to ubiquitinylated proteins including PPARα, and the ubiquitin-associated-like domain of ILRUN was found to be required for its interaction with PPARα., Conclusions: These findings establish ILRUN as a novel regulator of lipid metabolism that promotes hepatic lipoprotein production. Our results also provide functional evidence that ILRUN may be the casual gene underlying the observed genetic associations with plasma lipids at 6p21 in human.

Objective: Patients with schizophrenia have increased long-term mortality attributable to cardiovascular disease and commonly demonstrate features of mixed dyslipidemia with low HDL-C (high-density lipoprotein cholesterol). The removal of cholesterol from cells by HDL via specific ATP-binding cholesterol transporters is a major functional property of HDL, and its measurement as cholesterol efflux capacity (CEC) can predict cardiovascular risk. Whether HDL function is impaired in patients with schizophrenia is unknown. Approach and Results: We measured basal and ABCA1 (ATP-binding cassette transporter A1)- and ABCG1 (ATP-binding cassette transporter G1)-dependent CEC, comparing patients with schizophrenia with age- and sex-matched healthy controls, and related our findings to nuclear magnetic resonance analysis of lipoprotein subclasses. Total plasma cholesterol and LDL-C (low-density lipoprotein cholesterol) were comparable between healthy controls (n=51) and patients (n=120), but patients with schizophrenia had increased total plasma triglyceride, low HDL-C and apo (apolipoprotein) A-I concentrations. Nuclear magnetic resonance analysis indicated a marked (15-fold) increase in large triglyceride-rich lipoprotein particle concentration, increased small dense LDL particles, and fewer large HDL particles. Despite lower HDL-C concentration, basal CEC was 13.7±1.6% higher, ABCA1-specific efflux was 35.9±1.6% higher, and ABCG1 efflux not different, in patients versus controls. In patients with schizophrenia, ABCA1-specific efflux correlated with the abundance of small 7.8 nm HDL particles but not with serum plasminogen or triglyceride levels., Conclusions: Patients with schizophrenia have increased concentrations of atherogenic apoB-containing lipoproteins, decreased concentrations of large HDL particles, but enhanced ABCA1-mediated CEC. In this population, preventative strategies should focus on reducing atherogenic lipoproteins rather than increasing CEC.

Background: The target of this study is to summarize the association between the serum lipoprotein levels and neurological function in patients with acute ischemic stroke., Methods: A comprehensive search of Cochrane Library, PUBMED, EMBASE, Web of Science, and Chinese Biomedical Literature Database, China National Knowledge Infrastructure from inception to the February 29, 2020 without language and publication date restrictions. All searched studies will be selected by 2 authors independently against the eligibility criteria. Included studies will be critically appraised, and essential data will be extracted by 2 independent authors. If necessary, meta-analysis will be utilized to synthesize the outcome data from included articles. If it is not possible, a narrative synthesis will be undertaken., Results: This study will summarize the up-to-date evidence to investigate the association between serum lipoprotein levels and neurological function in patients with acute ischemic stroke., Conclusion: Its results may present beneficial evidence and guidance for the clinical practice and further studies., Study Registration Number: INPLASY202040043.

Background: The objective of this study is to examine the association between serum lipoprotein levels (SLL) and cognitive impairment (CI) in patients with acute cerebral infarction (ACI)., Methods: All published studies will be searched from the following electronic databases: PubMed, EMBASE, Cochrane Library, PsycINFO, Web of Science, WANGFANG, and China National Knowledge Infrastructure from inauguration of each electronic database up to March 1, 2020. In addition, we will also search other sources, such as dissertations, Google scholar, conference proceedings, and reference lists of relevant reviews. We will not apply any language restrictions to the electronic databases. Two researchers will independently carry out literature selection, data collection, and methodological quality. A third researcher will help to solve any divergences by discussion. The RevMan 5.3 software will be employed to pool the collected data and to analyze the outcome data., Results: This study will scrutinize the association between SLL and CI in patients with ACI., Conclusions: The results of this study will present helpful evidence of the association between SLL and CI in patients with ACI.Registration number: INPLASY202040018.

Purpose of Review: Angiopoietin-like protein-3 (ANGPTL3) is emerging as a key player in lipoprotein transport with an expanding role on fatty acid and glucose metabolism. Its deficiency is associated with a favorable metabolic profile. The present review will highlight the recent understanding of metabolic and cardiovascular consequences of ANGPTL3 inactivation by considering both genetic and pharmacological investigations., Recent Findings: Experimental studies have further illustrated the complex interplay between ANGPTL3 and ANGPTL4-8 in orchestrating lipid transport in different nutritional status. Individuals with familial combined hypolipidemia due to homozygous loss-of-function mutations in ANGPTL3 gene showed improved metabolism of triglyceride-rich lipoproteins during fasting and postprandial state and increased fatty acid oxidation and insulin sensitivity. Moreover, mendelian randomizations studies demonstrated that partial ANGPTL3 deficiency associates with reduced risk of atherosclerotic cardiovascular events and, eventually, diabetes mellitus. Finally, inactivation of ANGPTL3, using either a specific mAb or antisense oligonucleotide, was reported to reduce plasma levels of atherogenic lipoprotein in humans and improve hepatic fat infiltration in animal models., Summary: Human and animal studies have further dissected the complex role of ANGPTL3 in the regulation of energy substrate metabolism. Moreover, genetic and pharmacological investigations have convincingly indicated that the inactivation of ANGPTL3 may be a very promising strategy to treat atherogenic metabolic disorders.

The aim of this study was to investigate the relationship between blood lipid level and the parameters of embryo morphology of in vitro fertilization (IVF).A total of 488 patients undergoing conventional IVF were divided into pregnant (n = 286) and nonpregnant (n = 202) groups. Levels of triglycerides (TG), total cholesterol (TC), high-density lipoproteins (HDL), low-density lipoprotein (LDL), lipoprotein (a), lipoprotein (b), and embryo outcomes were studied. Spearman correlation was performed to analyze the correlation between blood lipid levels and embryo quality in pregnant group.The normal fertilization rate and number of good quality embryos were higher than nonpregnant group (P < .05). TG, TC, and LDL levels were negatively correlated with number of normal fertilized oocytes, while TG, TC, and Lp(b) were negatively correlated with number of good quality embryos. TG level was negatively correlated with number of oocytes and cleavage embryos while HDL and Lp(a) were positively correlated with number of oocytes, normal fertilized oocytes and cleavage embryos (P < .05).TG, TC, LDL, and Lp(b) levels had negative correlation with embryo quality, while HDL and Lp(a) had positive correlation with the embryo quality. Our present findings showed blood lipid levels may provide certain reference for the prediction of IVF pregnancy outcome.

Rationale: In black women, triglycerides are paradoxically normal in the presence of insulin resistance. This relationship may be explained by race-related differences in central adiposity and SCD (stearoyl-CoA desaturase)-1 enzyme activity index., Objective: In a cross-sectional study, to compare fasting and postprandial triglyceride-rich lipoprotein particle (TRLP) concentrations and size in black compared with white pre- and postmenopausal women and determine the relationship between TRLP subfractions and whole-body insulin sensitivity, hepatic and visceral fat, and SCD-1 levels., Methods and Results: In 122 federally employed women without diabetes mellitus, 73 black (58 African American and 15 African immigrant) and 49 white; age, 44±10 (mean±SD) years; body mass index, 30.0±5.6 kg/m 2 , we measured lipoprotein subfractions using nuclear magnetic resonance. Hepatic fat was measured by proton magnetic resonance spectroscopy, insulin sensitivity index calculated by minimal modeling from a frequently sampled intravenous glucose test, and red blood cell fatty acid profiles were measured by gas chromatography and were used to estimate SCD-1 indices. Hepatic fat, insulin sensitivity index, and SCD-1 were similar in black women and lower than in whites, regardless of menopausal status. Fasting and postprandial large, medium, and small TRLPs, but not very small TRLPs, were lower in black women. Fasting large, medium, and very small TRLPs negatively correlated with insulin sensitivity index and positively correlated with visceral and hepatic fat and SCD-1 activity in both groups. In multivariate models, visceral fat and SCD-1 were associated with total fasting TRLP concentrations (adjR2, 0.39; P =0.001). Black women had smaller postprandial changes in large ( P =0.005) and medium TRLPs ( P =0.007)., Conclusions: Lower visceral fat and SCD-1 activity may contribute to the paradoxical association of lower fasting and postprandial TRLP subfractions despite insulin resistance in black compared with white pre- and postmenopausal women. Similar concentrations of very small TRLPs are related to insulin resistance and could be important mediators of cardiometabolic disease risk in women., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01809288.

We investigated associations between inflammatory marker levels and hepatitis C virus (HCV)-related compensated liver cirrhosis risk in patients with chronic hepatitis C (CHC) infection in China. We used a case-control design and data from the records of 110 Chinese patients with CHC and cirrhosis for the study; 458 CHC patients who did not have a diagnosis of cirrhosis were matched to the case group by age and sex characteristics. We also investigated fatty liver disease risk factors. The group of patients with CHC infection and cirrhosis had lower platelet-to-lymphocyte ratio (PLR) values (60.63 [44.09, 89.31]) compared with the control group patients (80.24 [57.85, 111.08]). The results indicated that the group of patients with cirrhosis had higher 4-factor fibrosis index and aspartate aminotransferase (AST)-to-platelet ratio index (APRI) values compared with the group of patients with CHC-only (1.66 [0.98, 2.60] vs 0.71 [0.45, 1.17], respectively; P < .001 and 2.12 [0.97, 4.25] vs 0.99 [0.51, 2.01], respectively; P < .001). Compared with the control group, the AST/alanine aminotransferase ratio (AAR) values in the group of patients with cirrhosis were significantly higher (P < .001). Logistic regression analysis that included model adjustment for demographic characteristics and other factors that could affect cirrhosis risk revealed that greater 1/PLR values were associated with an increased odds of having cirrhosis (adjusted odds ratio [AOR], 95% confidence interval [CI] 0.991 [0.985-0.996]); APRI and AAR values were also independent predictors of the presence of compensated cirrhosis. We found that compared with the patients with CHC-only, the triglyceride, cholesterol, and low-density lipoprotein cholesterol levels in the patients with both CHC and fatty liver disease were significantly higher. The multivariate analysis of the risk of fatty liver development in patients with CHC infection found that cholesterol level was a statistically significant risk factor (AOR [95% CI] 1.380 [1.089-1.750], P = .008). Increased 1/PLR, APRI, and AAR values were associated with increased risks for development of cirrhosis in this population of Chinese patients with CHC infection. Higher cholesterol levels increased the risk of development of fatty liver disease in patients with CHC.

Introduction: Arising evidence suggests that resistance training has the potential to induce beneficial modulation of biomarker profile. To date, however, only immediate responses to resistance training have been investigated using high-throughput metabolomics whereas the effects of chronic resistance training on biomarker profile have not been studied in detail., Methods: A total of 86 recreationally active healthy men without previous systematic resistance training background were allocated into (i) a resistance training (RT) group (n = 68; age, 33 ± 7 yr; body mass index, 28 ± 3 kg·m) and (ii) a non-RT group (n = 18; age, 31 ± 4 yr; body mass index, 27 ± 3 kg·m). Blood samples were collected at baseline (PRE), after 4 wk (POST-4wk), and after 16 wk of resistance training intervention (POST-16wk), as well as baseline and after the non-RT period (20-24 wk). Nuclear magnetic resonance-metabolome platform was used to determine metabolomic responses to chronic resistance training., Results: Overall, the resistance training intervention resulted in favorable alterations (P < 0.05) in body composition with increased levels of lean mass (~2.8%), decreased levels of android (~9.6%), and total fat mass (~7.5%). These changes in body composition were accompanied by antiatherogenic alterations in serum metabolome profile (false discovery rate < 0.05) as reductions in non-high-density lipoprotein cholesterol (e.g., free cholesterol, remnant cholesterol, intermediate-density lipoprotein cholesterols, low-density lipoprotein cholesterols) and related apolipoprotein B, and increments in conjugated linoleic fatty acids levels were observed. Individuals with the poorest baseline status (i.e., body composition, metabolome profile) benefitted the most from the resistance training intervention., Conclusions: In conclusion, resistance training improves cardiometabolic risk factors and serum metabolome even in previously healthy young men. Thus, suggesting attenuated risk for future cardiovascular disease.

Purpose of Review: Acute phase serum amyloid A (SAA) is persistently elevated in chronic inflammatory conditions, and elevated levels predict cardiovascular risk in humans. More recently, murine studies have demonstrated that over-expression of SAA increases and deficiency/suppression of SAA attenuates atherosclerosis. Thus, beyond being a biomarker, SAA appears to play a causal role in atherogenesis. The purpose of this review is to summarize the data supporting SAA as a key player in atherosclerosis development., Recent Findings: A number of pro-inflammatory and pro-atherogenic activities have been ascribed to SAA. However, the literature is conflicted, as recombinant SAA, and/or lipid-free SAA, used in many of the earlier studies, do not reflect the activity of native human or murine SAA, which exists largely lipid-associated. Recent literatures demonstrate that SAA activates the NLRP3 inflammasome, alters vascular function, affects HDL function, and increases thrombosis. Importantly, SAA activity appears to be regulated by its lipid association, and HDL may serve to sequester and limit SAA activity., Summary: SAA has many pro-inflammatory and pro-atherogenic activities, is clearly demonstrated to affect atherosclerosis development, and may be a candidate target for clinical trials in cardiovascular diseases.

Objective- Loss-of-function (LOF) variants in the ANGPTL3 (angiopoietin-like protein 3) have been associated with low levels of plasma lipoproteins and decreased coronary artery disease risk. We aimed to determine detailed metabolic effects of genetically induced ANGPTL3 deficiency in fasting and postprandial state. Approach and Results- We studied individuals carrying S17X LOF mutation in ANGPTL3 (6 homozygous and 32 heterozygous carriers) and 38 noncarriers. Nuclear magnetic resonance metabolomics was used to quantify 225 circulating metabolic measures. We compared metabolic differences between LOF carriers and noncarriers in fasting state and after a high-fat meal. In fasting, ANGPTL3 deficiency was characterized by similar extent of reductions in LDL (low-density lipoprotein) cholesterol (0.74 SD units lower concentration per LOF allele [95% CI, 0.42-1.06]) as observed for many TRL (triglyceride-rich lipoprotein) measures, including VLDL (very-low-density lipoprotein) cholesterol (0.75 [95% CI, 0.45-1.05]). Within most lipoprotein subclasses, absolute levels of cholesterol were decreased more than triglycerides, resulting in the relative proportion of cholesterol being reduced within TRLs and their remnants. Further, β-hydroxybutyrate was elevated (0.55 [95% CI, 0.21-0.89]). Homozygous ANGPTL3 LOF carriers showed essentially no postprandial increase in TRLs and fatty acids, without evidence for adverse compensatory metabolic effects. Conclusions- In addition to overall triglyceride- and LDL cholesterol-lowering effects, ANGPTL3 deficiency results in reduction of cholesterol proportion within TRLs and their remnants. Further, ANGPTL3 LOF carriers had elevated ketone body production, suggesting enhanced hepatic fatty acid β-oxidation. The detailed metabolic profile in human knockouts of ANGPTL3 reinforces inactivation of ANGPTL3 as a promising therapeutic target for decreasing cardiovascular risk.

Objective: To determine the association of insulin sensitivity and metabolic status with declining cognition in HIV-infected individuals., Methods: We conducted targeted clinical and metabolic measures in longitudinal plasma samples obtained from HIV-infected patients enrolled in the Central Nervous System HIV Anti-Retroviral Therapy Effects Research Study (CHARTER). Findings were validated with plasma samples from the Multicenter AIDS Cohort Study (MACS). Patients were grouped according to longitudinally and serially assessed cognitive performance as having stably normal or declining cognition., Results: Patients with declining cognition exhibited baseline hyperinsulinemia and elevated plasma c-peptide levels with normal c-peptide/insulin ratios, suggesting that insulin production was increased, but insulin clearance was normal. The association of hyperinsulinemia with worsening cognition was further supported by low high-density lipoprotein (HDL), high low-density lipoprotein/HDL ratio, and elevated cholesterol/HDL ratio compared to patients with stably normal cognition., Conclusions: These findings suggest that hyperinsulinemia and impaired insulin sensitivity are associated with cognitive decline in antiretroviral therapy-treated HIV-infected patients., (© 2019 American Academy of Neurology.)

Before 2009 essentially all societies, guidelines, and statements required fasting before measuring a lipid profile for cardiovascular risk prediction. This was mainly due to the increase seen in triglycerides during a fat tolerance test. However, individuals eat much less fat during a normal day and nonfasting triglycerides have been shown to be superior to fasting in predicting cardiovascular risk. Lipids and lipoproteins only change minimally in response to normal food intake: in four large prospective studies, maximal mean changes were +0.3 mmol/L (26 mg/dL) for triglycerides, -0.2 mmol/L (8 mg/dL) for total cholesterol, -0.2 mmol/L (8 mg/dL) for LDL cholesterol, and -0.1 mmol/L (4 mg/dL) for HDL cholesterol. Further, in 108,602 individuals from the Copenhagen General Population Study in random nonfasting samples, the highest versus the lowest quartile of triglycerides, total cholesterol, LDL cholesterol, remnant cholesterol, non-HDL cholesterol, lipoprotein(a), and apolipoprotein B were all associated with higher risk of both ischaemic heart disease and myocardial infarction. Finally, lipid-lowering trials using nonfasting blood samples for assessment of lipid levels found that reducing levels of nonfasting lipids reduced the risk of cardiovascular disease. To date there is no sound scientific evidence as to why fasting should be superior to nonfasting when evaluating a lipid profile for cardiovascular risk prediction. Indeed, nonfasting samples rather than fasting samples have many obvious advantages. First, it would simplify blood sampling in the laboratory. Second, it would benefit the patient, avoiding the inconvenience of fasting and therefore needing to have blood drawn early in the day. Third, for individuals with diabetes, the risk of hypoglycaemia due to fasting would be minimised. Many countries are currently changing their guidelines towards a consensus on measuring a lipid profile for cardiovascular risk prediction in the nonfasting state, simplifying blood sampling for patients, laboratories, and clinicians worldwide., (Copyright © 2018 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Objective- Higher triglyceride (TG) is a risk factor for incident type 2 diabetes mellitus (T2DM), but paradoxically, genetic susceptibility for higher TG has been associated with lower T2DM risk. There is also evidence that the genetic association may be modified by baseline TG. Whether such associations can be replicated and the interaction is selective for certain TG-rich lipoprotein particles remains to be explored. Approach and Results- Cox regression involving TG, TG-rich lipoprotein particles, and genetic determinants of TG was performed among 15 813 participants with baseline fasting status in the WGHS (Women's Genome Health Study), including 1453 T2DM incident cases during a mean 18.6 (SD=5.3) years of follow-up. A weighted, 40-single-nucleotide polymorphism TG genetic risk score was inversely associated with incident T2DM (hazard ratio [95% CI], 0.66 [0.58-0.75]/10-TG risk alleles; P<0.0001) with adjustment for baseline body mass index, HDL (high-density lipoprotein) cholesterol, and TG. TG-associated risk was higher among individuals in the low compared with the high 40-single-nucleotide polymorphism TG genetic risk score tertile (hazard ratio [95% CI], 1.98 [1.83-2.14] versus 1.68 [1.58-1.80] per mmol/L; P interaction =0.0007). In TG-adjusted analysis, large and medium but not small TG-rich lipoprotein particles were associated with higher T2DM incidence for successively lower 40-single-nucleotide polymorphism TG genetic risk score tertiles, P interaction =0.013, 0.012, and 0.620 across tertiles, respectively. Conclusions- Our results confirm the previous observations of the paradoxical associations of TG with T2DM while focusing attention on the larger TG-rich lipoprotein particle subfractions, suggesting their importance in clinical profiling of T2DM risk.

Rationale: Psoriasis is a systemic inflammatory skin disease associated with cardiovascular disease and lipid dysfunction. However, traditional lipid parameters have limited prognostic value, whereas assessing oxidation-modified lipids in this inflammatory driven condition may capture additional risk. Recently, a study showed that psoriasis was associated with increased lipid-rich coronary plaques; therefore, investigating potential relationships with oxidation-modified lipids may speed understanding of increased cardiovascular disease in psoriasis., Objective: To understand whether oxidation-modified lipids associate with traditional lipid phenotypes, cardiometabolic disease biomarkers, and total coronary plaque, with focus on noncalcified burden (NCB) by coronary computed tomographic angiography in psoriasis., Methods and Results: Psoriasis subjects and controls (n=252) had profiling for oxidation-modified LDL (low-density lipoprotein), HDL (high-density lipoprotein), Lp(a) (lipoprotein[a]), cholesterol efflux capacity, lipoprotein particle size and number by NMR spectroscopy, and PON-1 (paraoxonase-1) activity. Blinded coronary computed tomographic angiography coronary artery disease characterization included total burden, NCB, and dense-calcified burden. Compared with healthy volunteers, psoriasis subjects were older (mean age, 50.1), had increased body mass index, and homeostatic model assessment of insulin resistance. Psoriasis subjects had increase in oxidized Lp(a), Lp(a), and oxidized HDL (oxHDL; P <0.05 for all) with significant association of oxidized LDL (β=0.10; P=0.020) and oxHDL (β=-0.11; P=0.007) with NCB. Moreover, psoriasis subjects expressed significantly higher PON-1 (kU/µL) activity compared with healthy volunteers (8.55±3.21 versus 6.24±3.82; P=0.01). Finally, psoriasis treatment was associated with a reduction in oxHDL (U/mL; 203.79±88.40 versus 116.36±85.03; P<0.001) and with a concomitant decrease in NCB at 1 year (1.04±0.44 versus 0.95±0.32; P=0.03)., Conclusions: Traditional lipids did not capture risk of lipid-rich plaque as assessed by NCB, whereas assaying oxidation-modification of lipids revealed significant association with oxidized LDL and oxHDL. The PON-1 activity was increased in psoriasis suggesting possible compensatory antioxidative effect. Psoriasis treatment was associated with a reduction in oxHDL. These findings support performance of larger studies to understand oxidation-modified lipids in inflammatory states.

This study aimed to explore the feasible effect of ezetimibe for postprandial hyperlipidemia (PPHP).Sixty participants were included in this study. Of these, 30 subjects in the intervention group received ezetimibe, while the remaining 30 participants in the control group did not undergo ezetimibe. All patients in intervention group were treated for a total of 2 weeks. Primary endpoints consisted of serum levels of total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG). Secondary endpoints included apoB-48, remnant lipoprotein cholesterol (RLP-C), blood glucose, insulin, hemoglobin A1c (HbA1c), and monocyte chemotactic protein (MCP). All outcomes were measured before and after 2-week treatment.After 2-week treatment, participants in the intervention group did not show better outcomes in primary endpoints of Total-C, LDL-C, HDL-C, and TG; and secondary endpoints of apoB-48, RLP-C, blood glucose, insulin, HbA1c, and MCP, compared with subjects in the control group.The results of this study showed that ezetimibe may be not efficacious for participants with PPHP after 2-week treatment.

Low-density lipoprotein (LDL) cholesterol (LDL-C) always underestimates the true cholesterol burden in diabetic patients. We aimed to explore the impact of the inclusion of apolipoprotein B (apoB) or non-high-density lipoprotein (HDL) cholesterol (non-HDL-C), which are alternative markers of LDL-related risk, results in a better classification of glycated hemoglobin (HbA1c)-defined diabetic patients into different dyslipidemic phenotypes.We used data from the nationwide China Health and Nutrition Survey 2009 in which standardized HbA1c was measured.The prevalence of abnormal LDL using non-HDL-cholesterol (74.1%) was similar to the prevalence rate using LDL-C (75.2%), whereas the prevalence was relatively lower when using apoB (69.6%). In normotriglyceridemic HbA1c-defined diabetic patients, apoB and non-HDL-C were not superior to LDL-C in detecting abnormal LDL. However, in hypertriglyceridemic patients, apoB and non-HDL-C were superior to LDL-C for the detection of abnormal lipid levels, but apoB was not superior to non-HDL-C in detecting abnormal LDL in hypertriglyceridemic participants.Both apoB and non-HDL-C identify high-risk dyslipidemic phenotypes that are not detected by LDL-C in hypertriglyceridemic HbA1c-defined diabetic patients, with the superiority of non-HDL- C over apoB.

Background: Mendelian randomization data suggest that the genetic determinants of lifetime higher triglyceride-rich lipoprotein-cholesterol (TRL-C) are causally related to cardiovascular disease and therefore a potential therapeutic target. The relevance of TRL-C among patients receiving statins is unknown. We assessed the relationship between TRL-C and cardiovascular risk, and whether this risk was modifiable among patients receiving statins in the TNT trial (Treating to New Targets)., Methods: Patients with coronary heart disease and low-density lipoprotein cholesterol (LDL-C) 130 to 250 mg/dL entered an 8-week run-in phase with atorvastatin 10 mg/d (ATV10). After this period, participants with LDL-C <130 mg/dL entered the randomized phase with ATV10 (n=5006) versus atorvastatin 80 mg/d (ATV80, n=4995). The primary end point was coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke (major adverse cardiovascular events [MACE]). TRL-C was calculated as total cholesterol minus high-density lipoprotein cholesterol minus LDL-C. The effect of atorvastatin on TRL-C was assessed during the run-in phase (ATV10) and randomized phase (ATV80 versus ATV10). The risk of MACE was assessed across quintiles (Q) of baseline TRL-C (and, for comparison, by baseline triglycerides and non-high-density lipoprotein cholesterol) during the randomized period. Last, the association between TRL-C changes with atorvastatin and cardiovascular risk was assessed by multivariate Cox regression., Results: ATV10 reduced TRL-C 10.7% from an initial TRL-C of 33.9±16.6 mg/dL. ATV80 led to an additional 15.4% reduction. Cardiovascular risk factors positively correlated with TRL-C. Among patients receiving ATV10, higher TRL-C was associated with higher 5-year MACE rates (Q1=9.7%, Q5=13.8%; hazard ratio Q5-versus-Q1, 1.48; 95% confidence interval, 1.15-1.92; P-trend<0.0001). ATV80 (versus ATV10) did not significantly alter the risk of MACE in Q1-Q2, but significantly reduced risk in Q3-Q5 (relative risk reduction, 29%-41%; all P<0.0250), with evidence of effect modification ( P-homogeneity=0.0053); results were consistent for triglycerides ( P-homogeneity=0.0101) and directionally similar for non-high-density lipoprotein cholesterol ( P-homogeneity=0.1387). Last, in adjusted analyses, a 1 SD percentage reduction in TRL-C with atorvastatin resulted in a significant lower risk of MACE (hazard ratio, 0.93; 95% confidence interval, 0.86-1.00; P=0.0482) independent of the reduction in LDL-C and of similar magnitude to that per 1 SD lowering in LDL-C (hazard ratio, 0.89; 95% confidence interval, 0.83-0.95; P=0.0008)., Conclusions: The present post hoc analysis from TNT shows that increased TRL-C levels are associated with an increased cardiovascular risk and provides evidence for the cardiovascular benefit of lipid lowering with statins among patients who have coronary heart disease with high TRL-C., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00327691.

Objective- Although postprandial hypertriglyceridemia can be a risk factor for coronary artery disease, the extent of its significance remains unknown. This study aimed to investigate the correlation between the postprandial lipid profiles rigorously estimated with the meal tolerance test and the presence of lipid-rich plaque, such as thin-cap fibroatheroma (TCFA), in the nonculprit lesion. Approach and Results- A total of 30 patients with stable coronary artery disease who underwent a multivessel examination using optical coherence tomography during catheter intervention for the culprit lesion were enrolled. Patients were divided into 2 groups: patients with TCFA (fibrous cap thickness ≤65 µm) in the nonculprit lesion and those without TCFA. Serum remnant-like particle-cholesterol and ApoB-48 (apolipoprotein B-48) levels were measured during the meal tolerance test. The value of remnant-like particle-cholesterol was significantly greater in the TCFA group than in the non-TCFA group ( P=0.045). Although the baseline ApoB-48 level was similar, the increase in the ApoB-48 level was significantly higher in the TCFA group than in the non-TCFA group ( P=0.028). In addition, the baseline apolipoprotein C-III levels was significantly greater in the TCFA group ( P=0.003). These indexes were independent predictors of the presence of TCFA (ΔApoB-48: odds ratio, 1.608; 95% confidence interval, 1.040-2.486; P=0.032; apolipoprotein C-III: odds ratio, 2.581; 95% confidence interval, 1.177-5.661; P=0.018). Conclusions- Postprandial hyperchylomicronemia correlates with the presence of TCFA in the nonculprit lesion and may be a residual risk factor for coronary artery disease.

Objective: The aim of this study was to determine whether mobile phone text messages could modify objectively measured sedentary behavior and cardiometabolic health in office workers., Methods: Nine males and 12 females [mean (SD): 27.5 (5.7) years, 23.8 (2.8) kg/m] were assigned to a control (CON) or intervention (PROMPT) group. PROMPT received an activity-promoting text message during office hours. Participants wore an actiGraph and activPAL accelerometer for 7 days during and after the intervention. Blood pressure, lipid, and metabolic profiles were measured before and after the intervention., Results: PROMPT sat less [mean (95% confidence interval, 95% CI): 4.9 (4.4 to 5.4) hours/day] than CON [6.0 (5.5 to 6.4) hours/day; P = 0.04] during the message-receiving period. There was no difference between groups after the intervention and for the other activity variables. There were no changes in cardiometabolic health markers following the intervention., Conclusion: Sitting time was lower during the message-receiving period, but the difference between groups was no longer apparent after the intervention.

Objective: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) and statins are known to lower plasma LDL (low-density lipoprotein)-cholesterol concentrations. However, the comparative effects of these treatments on the postprandial metabolism of TRLs (triglyceride-rich lipoproteins) remain to be investigated., Approach and Results: We performed a 2-by-2 factorial trial of the effects of 8 weeks of subcutaneous evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on postprandial TRL metabolism in 80 healthy, normolipidemic men after ingestion of an oral fat load. We evaluated plasma total and incremental area under the curves for triglycerides, apo (apolipoprotein)B-48, and VLDL (very-LDL)-apoB-100. We also examined the kinetics of apoB-48 using intravenous D3-leucine administration, mass spectrometry, and multicompartmental modeling. Atorvastatin and evolocumab independently lowered postprandial VLDL-apoB-100 total area under the curves ( P <0.001). Atorvastatin, but not evolocumab, reduced fasting plasma apoB-48, apoC-III, and angiopoietin-like 3 concentrations ( P <0.01), as well as postprandial triglyceride and apoB-48 total area under the curves ( P <0.001) and the incremental area under the curves for plasma triglycerides, apoB-48, and VLDL-apoB-100 ( P <0.01). Atorvastatin also independently increased TRL apoB-48 fractional catabolic rate ( P <0.001) and reduced the number of apoB-48-containing particles secreted in response to the fat load ( P <0.01). In contrast, evolocumab did not significantly alter the kinetics of apoB-48., Conclusions: In healthy, normolipidemic men, atorvastatin decreased fasting and postprandial apoB-48 concentration by accelerating the catabolism of apoB-48 particles and reducing apoB-48 particle secretion in response to a fat load. Inhibition of PCSK9 with evolocumab had no significant effect on apoB-48 metabolism., (© 2018 American Heart Association, Inc.)

Pancreatic lipidosis (nonalcoholic fatty pancreas disease, NAFPD) causes insulin resistance and dysfunction of pancreatic β-cells, with the risk of type 2 diabetes mellitus (T2DM). However, the prevalence and pathogenic factors associated with NAFPD are not clear. The aim of the study was to explore the prevalence of NAFPD in a Chinese adult population, and investigate factors associated with NAFPD aggravation.This was a cross-sectional study; 4419 subjects were enrolled for NAFPD screening and were divided into NAFPD (n = 488) and without NAFPD (n = 3930) groups. The sex, age, related concomitant diseases, general physical parameters, and serum glucose and lipid metabolism were compared between the 2 groups.The overall NAFPD prevalence was 11.05%, but increased with age. In those <55 years NAFPD prevalence was lower in females than males (P < .05), but prevalence was similar >55 years. Nonalcoholic fatty liver disease (NAFLD), T2DM, homeostasis model assessment-insulin resistance index, total cholesterol, triglyceride, lipoprotein, adiponectin, and glucagon-like peptide 1 (GLP-1) were the independent risk factors for NAFPD (P < .05). Analaysis of mild NAFPD (MN) and severe NAFPD (SN) subgroups, according to the extent of fat deposition, suggested that NAFLD, triglyceride, lipoprotein, and adiponectin were independent risk factors for NAFPD aggravation (P < .05).The NAFPD prevalence was about 11% in Chinese adults. Its development and progression was related to NAFLD, T2DM, insulin resistance, dyslipidemia, and GLP-1 levels. Severe NAFPD was associated with NAFLD and dyslipidemia.

Objective: Combined oral contraceptives induce a reversible hypercoagulable state with an enhanced risk of venous thromboembolism, but the underlying mechanism(s) remain unclear. Subjects on combined oral contraceptives also demonstrate a characteristic resistance to APC (activated protein C) in the thrombin generation assay. Here, we report the potential role of plasma factor IXa (FIXa) as a mechanism for hormone-induced systemic hypercoagulability., Approach and Results: A novel assay was used to determine FIXa activity in plasma samples from volunteer blood donors. Plasma from 36 premenopausal females on hormonal contraception and 35 not on hormonal contraception, 35 postmenopausal females, and 10 males were analyzed for FIXa activity, total PS (protein S), total tissue factor pathway inhibitor (TFPI), and TFPI-α antigen. Premenopausal females on hormonal contraception demonstrated significantly increased FIXa activity and decreased TFPI-α compared with the other groups. Remarkably, FIXa values were not normally distributed in the hormonal contraception group, but skewed toward the high end. Plasma FIXa activity inversely correlated with both TFPI-α and total PS antigen. Ex vivo determination of TF-dependent FIX activation in FV-deficient plasma demonstrated that inhibitory anti-TFPI antibodies enhanced FIXa generation by 2- to 3-fold, whereas addition of 75 nmol/L PS reduced FIXa generation by ≈2-fold. Further, increasing FIXa concentration enhanced APC resistance during TF-triggered plasma thrombin generation., Conclusions: Elevation of plasma FIXa activity in association with reductions in TFPI-α and PS is a potential mechanism for systemic hypercoagulability and resistance to APC in premenopausal females on hormonal contraception., (© 2017 American Heart Association, Inc.)

This study aimed to observe the change in nonhigh-density lipoprotein cholesterol (non-HDL-C) levels and analyzed its related factors in adults with prediabetes (impaired fasting glucose and/or impaired glucose tolerance).This case-controlled study included 56 adults with normal glucose tolerance (NGT) and 74 adults with prediabetes. The cases and controls were age and gender-matched. Anthropometric measurements including height, weight, waist circumference, and blood pressure were performed. All patients underwent an oral glucose tolerance test (OGTT) after 8 hours of fasting, and the levels of glucose, insulin, lipids, and uric acid were measured.The levels of non-HDL-C (3.63 ± 0.92 vs 3.27 ± 1.00 mmol/L) were significantly higher in prediabetic subjects than in NGT subjects (P < .05). Non-HDL-C positively correlated with HOMA-IR (r = 0.253, P = .004), triglyceride (r = 0.204, P = .020), and uric acid (r = 0.487, P = .000). After multivariate analysis, uric acid continued to be significantly associated with non-HDL-C (β = 0.006, P = .000).Non-HDL-C is elevated in adults with prediabetes. A relationship between non-HDL-C and uric acid was observed.

Objective: Apolipoprotein A-I (apoA-I) mimetic peptides have antiatherogenic properties of high-density lipoprotein in vitro and have been shown to inhibit atherosclerosis in vivo. It is unclear, however, if each in vitro antiatherogenic property of these peptides translates to a corresponding activity in vivo, and if so, which of these contributes most to reduce atherosclerosis., Approach and Results: The effect of 7 apoA-I mimetic peptides, which were developed to selectively reproduce a specific component of the antiatherogenic properties of apoA-I, on the development of atherosclerosis was investigated in apolipoprotein E-deficient mice fed a high-fat diet for 4 or 12 weeks. The peptides include those that selectively upregulate cholesterol efflux, or are anti-inflammatory, or have antioxidation properties. All the peptides studied effectively inhibited the in vivo development of atherosclerosis in this model to the same extent. However, none of the peptides had the same selective effect in vivo as they had exhibited in vitro. None of the tested peptides affected plasma lipoprotein profile; capacity of plasma to support cholesterol efflux was increased modestly and similarly for all peptides., Conclusions: There is a discordance between the selective in vitro and in vivo functional properties of apoA-I mimetic peptides, and the in vivo antiatherosclerotic effect of apoA-I-mimetic peptides is independent of their in vitro functional profile. Comparing the properties of apoA-I mimetic peptides in plasma rather than in the lipid-free state is better for predicting their in vivo effects on atherosclerosis., (© 2017 American Heart Association, Inc.)

Purpose of Review: The prevalence of cardiovascular disease differs among ethnic groups and along geographic boundaries. At present, most of the projected increase in mortality from cardiovascular disease occurs in sub-Saharan African, Chinese and Southeast Asian populations. Ethnic disparities in the prevalence of cardiovascular disease coincide with quantitative and qualitative differences in risk factors for cardiovascular disease. High plasma cholesterol is one of the most important preventable causes of ischemic heart disease., Recent Findings: The current review summarizes recent evidence on ethnic differences in ischemic heart disease and its correlates with genetic and acquired differences in plasma lipid and lipoprotein levels. The nature of ethnic differences in plasma lipid levels, apolipoprotein L1 en lipoprotein(a) [Lp(a)] is outlined, and the effects of lipid-lowering therapy and future efforts and challenges regarding implementation are discussed., Summary: Ethnic differences in HDL-cholesterol (HDL-C), triglyceride levels and Lp(a) may impact ethnic differences in cardiovascular disease and result in higher residual risk during lipid-lowering therapy. Further efforts should be made to stimulate the use of statins in both high-income and low-income countries and study their effects in individuals with different ethnic backgrounds.

Objective: Mendelian randomization studies revealed a causal role for remnant cholesterol in cardiovascular disease. Remnant particles accumulate in the arterial wall, potentially propagating local and systemic inflammation. We evaluated the impact of remnant cholesterol on arterial wall inflammation, circulating monocytes, and bone marrow in patients with familial dysbetalipoproteinemia (FD)., Approach and Results: Arterial wall inflammation and bone marrow activity were measured using 18 F-FDG PET/CT. Monocyte phenotype was assessed with flow cytometry. The correlation between remnant levels and hematopoietic activity was validated in the CGPS (Copenhagen General Population Study). We found a 1.2-fold increase of 18 F-FDG uptake in the arterial wall in patients with FD (n=17, age 60±8 years, remnant cholesterol: 3.26 [2.07-5.71]) compared with controls (n=17, age 61±8 years, remnant cholesterol 0.29 [0.27-0.40]; P <0.001). Monocytes from patients with FD showed increased lipid accumulation (lipid-positive monocytes: Patients with FD 92% [86-95], controls 76% [66-81], P =0.001, with an increase in lipid droplets per monocyte), and a higher expression of surface integrins (CD11b, CD11c, and CD18). Patients with FD also exhibited monocytosis and leukocytosis, accompanied by a 1.2-fold increase of 18 F-FDG uptake in bone marrow. In addition, we found a strong correlation between remnant levels and leukocyte counts in the CGPS (n=103 953, P for trend 5×10-276). In vitro experiments substantiated that remnant cholesterol accumulates in human hematopoietic stem and progenitor cells coinciding with myeloid skewing., Conclusions: Patients with FD have increased arterial wall and cellular inflammation. These findings imply an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to the increased cardiovascular disease risk in patients with FD., (© 2017 American Heart Association, Inc.)

Objective: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in those with HIV. An emerging CVD risk factor is triglyceride-rich remnant lipoprotein cholesterol (RLP-C: the sum of intermediate-density lipoprotein and very low-density lipoprotein cholesterol). The effects of statin therapy on lipoprotein subfractions, including RLP-C, in HIV dyslipidemia are unknown., Methods: This is a post hoc analysis of the randomized INTREPID trial (NCT 01301066) comparing pitavastatin 4 mg daily vs. pravastatin 40 mg daily in study participants with HIV. We measured apolipoproteins AI and B and lipoprotein cholesterol subfractions separated by density gradient ultracentrifugation at baseline and 12 weeks. We compared changes in atherogenic subfractions over 12 weeks in INTREPID participants using analysis of covariance., Results: Lipoprotein subfraction data were available for 213 study participants (pitavastatin n = 104, pravastatin n = 109). Baseline characteristics were similar between treatment groups. Reductions in RLP-C were significantly greater in the pitavastatin group compared with pravastatin group (-11.6 mg/dl vs. -8.5 mg/dl; P = 0.01). Similarly, ratios of risk [apolipoproteins B/apolipoproteins AI, total cholesterol/high-density lipoprotein cholesterol (HDL-C)] showed greater reductions with pitavastatin (P < 0.05). There were no differences in changes in HDL-C, HDL-C subfractions or lipoprotein(a) cholesterol levels., Conclusion: In patients with HIV, pitavastatin 4 mg/dl lowered both RLP-C and established apolipoprotein and lipid risk ratios more so than pravastatin 40 mg/dl. The impact of RLP-C reduction on CVD in HIV dyslipidemic patients merits further study.

Purpose of Review: Human genetic studies have been successfully used to identify genes and pathways relevant to human biology. Using genetic instruments composed of loci associated with human lipid traits, recent studies have begun to clarify the causal role of major lipid fractions in risk of cardiometabolic disease., Recent Findings: The causal relationship between LDL cholesterol and coronary disease has been firmly established. Of the remaining two major fractions, recent studies have found that HDL cholesterol is not likely to be a causal particle in atherogenesis, and have instead shifted the causal focus to triglyceride-rich lipoproteins. Subsequent results are refining this view to suggest that triglycerides themselves might not be causal, but instead may be a surrogate for the causal cholesterol content within this fraction. Other studies have used a similar approach to address the association between lipid fractions and risk of type 2 diabetes. Beyond genetic variation in the target of statin medications, reduced LDL cholesterol associated with multiple genes encoding current or prospective drug targets associated with increased diabetic risk. In addition, genetically lower HDL cholesterol and genetically lower triglycerides both appear to increase risk of type 2 diabetes., Summary: Results of these and future human genetic studies are positioned to provide substantive insights into the causal relationship between lipids and human disease, and should highlight mechanisms with important implications for our understanding of human biology and future lipid-altering therapeutic development.

Objective: Sphingosine-1-phosphate (S1P) is a vasoprotective lipid mediator. About two thirds of plasma S1P rides on high-density lipoprotein (HDL), and several pleiotropic properties of HDL have been ascribed to S1P. In human subjects, CETP (cholesteryl ester transfer protein) greatly influences HDL quantities. In this study, we attempted to elucidate the roles of CETP in the metabolism of S1P., Approach and Results: We overexpressed CETP in mice that lacked CETP and found that CETP overexpression decreased the HDL level but failed to modulate the levels of S1P and apolipoprotein M (apoM), a carrier of S1P, in the total plasma. We observed, however, that the distribution of S1P and apoM shifted from HDL to apoB-containing lipoproteins. When we administered C 17 S1P bound to apoM-containing lipoprotein, C 17 S1P and apoM were rapidly transferred to apoB-containing lipoproteins in CETP-overexpressing mice. When HDL containing C 17 S1P was mixed with low-density lipoprotein ex vivo, C 17 S1P shifted to the low-density lipoprotein fraction independent of the presence of CETP. Concordant with these results, apoM was distributed mainly to the same fraction as apo AI in a CETP-deficient subject, although apoM was also detected in apo AI-poor fractions in a corresponding hypercholesterolemia subject. About the bioactivities of S1P carried on each lipoprotein, S1P riding on apoB-containing lipoproteins induced the phosphorylation of Akt (AKT8 virus oncogene cellular homolog) and eNOS (endothelial nitric oxide synthase) in human umbilical vein endothelial cells, and CETP overexpression increased insulin secretion and sensitivity, which was inhibited by an S1P receptor 1 or 3 antagonist., Conclusions: CETP modulates the distribution of S1P among lipoproteins, which affects the bioactivities of S1P., (© 2017 American Heart Association, Inc.)

Introduction: Rotator cuff pathology has been proposed to occur through intrinsic and extrinsic mechanisms. Hyperlipidemia has been proposed as a mechanism of intrinsic rotator cuff pathology. This prospective observational study evaluates serum and synovial lipid profiles in patients with and without rotator cuff tears to further define the relationship of cholesterol and rotator cuff pathology., Methods: Patients were prospectively enrolled with intact rotator cuff (37 patients) and rotator cuff tear requiring a repair (40 patients) groups. Exclusion criteria were medication for hypercholesterolemia, smoking, previous ipsilateral shoulder surgery, inflammatory arthritis, or history of shoulder infection. Serum and synovial fluid samples were collected at the time of surgery and analyzed for total cholesterol, HDL, non-HDL, and triglycerides., Results: There were no significant differences seen in any lipid values between patients with rotator cuff and those without a tear. The calculated ratio of synovial lipids to serum lipids was also not significantly different between the patient groups with and without cuff tears., Discussion: This study successfully evaluates the correlation between serum and synovial lipid levels in the glenohumeral joint. The ratio of lipid values between the serum and the synovial fluid was similar, thus defining a ratio of lipid levels between the blood and the shoulder joint regardless of the presence of a rotator cuff tear. All lipid values measured were similar in both the serum and synovial fluid between patients with and without cuff tears.

Objective: Carriers of the PCSK9 (proprotein convertase subtilisin/kexin 9) R46L genetic variant (rs11591147) are characterized by low levels of low-density lipoprotein cholesterol and a decreased risk of cardiovascular disease. We studied the impact of the R46L variant on lipoprotein size and composition., Approach and Results: Lipoprotein size and composition were measured by nuclear magnetic resonance spectroscopy in 2373 participants of the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk study. After adjusting for age, sex, and cardiovascular disease status, carriers of the R46L variant (n=77) were characterized by lower concentrations of very low-density lipoprotein particles (85.8±26.2 versus 99.0±33.3 nmol/L; P<0.001), low-density lipoprotein particles (1479.7±396.8 versus 1662.9±458.3 nmol/L; P<0.001), and lipoprotein(a) (11.1 [7.2-28.6] versus 12.4 [6.7-29.1] mg/dL; P<0.001) compared with noncarriers. Total high-density lipoprotein particle and very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein particle sizes were comparable in carriers and noncarriers. Carriers were characterized by lower secretory phospholipase A2 (4.2±0.9 versus 4.6±1.3 nmol/mL/min; P=0.004) and lipoprotein-associated phospholipase A2 activity (47.5±14.1 versus 52.4±16.2 nmol/mL/min; P=0.02) compared with noncarriers., Conclusions: Results of this study suggest that carriers of the PCSK9 R46L genetic variant have lower very low-density lipoprotein and low-density lipoprotein particle concentrations, lower lipoprotein(a) levels, and lower secretory phospholipase A2 and lipoprotein-associated phospholipase A2 activity compared with noncarriers., (© 2016 American Heart Association, Inc.)

Murine models of atherosclerosis are useful for investigating the environmental and genetic influences on lesion formation and composition. Apoe(-/-) and Ldlr(-/-) mice are the 2 most extensively used models. The models differ in important ways with respect to the precise mechanism by which their absence enhances atherosclerosis, including differences in plasma lipoproteins. The majority of the gene function studies have utilized only 1 model, with the results being generalized to atherogenic mechanisms. In only a relatively few cases have studies been conducted in both atherogenic murine models. This review will discuss important differences between the 2 atherogenic models and will point out studies that have been performed in the 2 models where results are comparable and those where different results were obtained., (© 2016 American Heart Association, Inc.)

Objective: Increased production of intestinal triglyceride-rich lipoproteins (TRLs) contributes to dyslipidemia and increased risk of atherosclerotic cardiovascular disease in insulin resistance and type 2 diabetes. We have previously demonstrated that enteral glucose enhances lipid-stimulated intestinal lipoprotein particle secretion. Here, we assessed whether glucose delivered systemically by intravenous infusion also enhances intestinal lipoprotein particle secretion in humans., Approach and Results: On 2 occasions, 4 to 6 weeks apart and in random order, 10 healthy men received a constant 15-hour intravenous infusion of either 20% glucose to induce hyperglycemia or normal saline as control. Production of TRL-apolipoprotein B48 (apoB48, primary outcomes) and apoB100 (secondary outcomes) was assessed during hourly liquid-mixed macronutrient formula ingestion with stable isotope enrichment and multicompartmental modeling, under pancreatic clamp conditions to limit perturbations in pancreatic hormones (insulin and glucagon) and growth hormone. Compared with saline infusion, glucose infusion induced both hyperglycemia and hyperinsulinemia, increased plasma triglyceride levels, and increased TRL-apoB48 concentration and production rate (P<0.05), without affecting TRL-apoB48 fractional catabolic rate. No significant effect of hyperglycemia on TRL-apoB100 concentration and kinetic parameters was observed., Conclusions: Short-term intravenous infusion of glucose stimulates intestinal lipoprotein production. Hyperglycemia may contribute to intestinal lipoprotein overproduction in type 2 diabetes., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02607839., (© 2016 American Heart Association, Inc.)

Objectives: The treatment effectiveness of double filtration plasma apheresis (DFPP) on severe hypertriglyceridemia-associated acute pancreatitis (STAP) has been questioned because the currently defined serum triglyceride level--1000 mg/dL--is too low for STAP. Given this, we aimed to investigate DFPP effectiveness when we elevated STAP definition to 5000 mg/dL serum triglyceride., Methods: We performed nested case-control studies for STAP patients and divided them into groups "with" or "without" DFPP. We further recruited outpatient asymptomatic hypertriglyceridemia patients with STAP history, then divided them into groups "with" or "without" prophylactic DFPP once every 3 to 6 months for 2 years. We observed hospitalization duration and STAP recurrence between patients with and patients without DFPP., Results: Twelve STAP patients receiving DFPP had a median hospitalization of 5 days, whereas 24 patients without DFPP had 10 days (P = 0.009). Six outpatient referrals with STAP history receiving prophylactic DFPP showed no STAP recurrences whereas 6 without DFPP showed 3 recurrences (P = 0.046). For the 25 patients whose serum triglyceride exceeded 5000 mg/dL, 11 receiving DFPP had median hospitalization of 5 days while 14 without DFPP had 11 days (P = 0.012)., Conclusions: When applied to serum triglyceride in excess of 5000 mg/dL, DFPP removes oxidized and inflammatory lipoproteins, shortens hospitalization duration, and minimizes STAP recurrence.

Scientific interest in triglyceride-rich lipoproteins has fluctuated over the past many years, ranging from beliefs that these lipoproteins cause atherosclerotic cardiovascular disease (ASCVD) to being innocent bystanders. Correspondingly, clinical recommendations have fluctuated from a need to reduce levels to no advice on treatment. New insight in epidemiology now suggests that these lipoproteins, marked by high triglycerides, are strong and independent predictors of ASCVD and all-cause mortality, and that their cholesterol content or remnant cholesterol likewise are strong predictors of ASCVD. Of all adults, 27% have triglycerides >2 mmol/L (176 mg/dL), and 21% have remnant cholesterol >1 mmol/L (39 mg/dL). For individuals in the general population with nonfasting triglycerides of 6.6 mmol/L (580 mg/dL) compared with individuals with levels of 0.8 mmol/L (70 mg/dL), the risks were 5.1-fold for myocardial infarction, 3.2-fold for ischemic heart disease, 3.2-fold for ischemic stroke, and 2.2-fold for all-cause mortality. Also, genetic studies using the Mendelian randomization design, an approach that minimizes problems with confounding and reverse causation, now demonstrate that triglyceride-rich lipoproteins are causally associated with ASCVD and all-cause mortality. Finally, genetic evidence also demonstrates that high concentrations of triglyceride-rich lipoproteins are causally associated with low-grade inflammation. This suggests that an important part of inflammation in atherosclerosis and ASCVD is because of triglyceride-rich lipoprotein degradation and uptake into macrophage foam cells in the arterial intima. Taken together, new insights now strongly suggest that elevated triglyceride-rich lipoproteins represent causal risk factors for low-grade inflammation, ASCVD, and all-cause mortality., (© 2016 American Heart Association, Inc.)