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Associations between CDKAL1 variants and cholesterol efflux capacity (CEC) have been reported. This study aimed to investigate the effects of Cdkal1 deficiency on high-density lipoprotein (HDL) metabolism, atherosclerosis, and related pathways. Lipid and glucose metabolic profiles, CEC, and in vivo reverse cholesterol transport (RCT) were compared in liver-specific Alb-Cre : Cdkal1 fl/fl and Cdkal1 fl/fl mice. Aortic atherosclerosis was compared in Apoe −/− Alb-Cre : Cdkal1 fl/fl and Apoe −/− mice fed high-fat diets. HDL subclasses and mediators of HDL metabolism from Alb-Cre : Cdkal1 fl/fl mice were examined. HDL-cholesterol level tended to be higher in the Alb-Cre : Cdkal1 fl/fl mice (p = 0.050). Glucose and other lipid profiles were similar in the two groups of mice, irrespective of diet. The mean CEC was 27% higher (p = 0.007) in the Alb-Cre : Cdkal1 fl/fl mice, as were the radioactivities of bile acids (mean difference 17%; p = 0.035) and cholesterol (mean difference 42%; p = 0.036) from faeces. The radioactivity tendency was largely similar in mice fed a high-fat diet. Atherosclerotic lesion area tended to be smaller in the Apoe −/− Alb-Cre : Cdkal1 fl/fl mice than in the Apoe −/− mice (p = 0.067). Cholesterol concentrations in large HDLs were higher in the Alb-Cre : Cdkal1 fl/fl mice (p = 0.024), whereas in small HDLs, they were lower (p = 0.024). Endothelial lipase (mean difference 39%; p = 0.002) and hepatic lipase expression levels (mean difference 34%; p < 0.001) were reduced in the Alb-Cre : Cdkal1 fl/fl mice, whereas SR-B1 expression was elevated (mean difference 35%; p = 0.007). The promotion of CEC and RCT in Alb-Cre : Cdkal1 fl/fl mice verified the effect of CDKAL1 seen in human genetic data. These phenotypes were related to regulation of HDL catabolism. This study suggests that CDKAL1 and associated molecules could be targets for improving RCT and vascular pathology. [Display omitted] • Liver-specific Cdkal1 deficient mice showed higher CEC and RCT with less tendency of atherosclerosis. • This study verified the effect of CDKAL1 found in our previous human genetic data. • Downregulation of EL and HL and upregulation of SR-B1 indicated altered HDL catabolism mediators. • Cholesterol concentrations were higher in the large HDL subclass in these mice. • CDKAL1 and related molecules could be therapeutic targets against vascular pathology. [ABSTRACT FROM AUTHOR]

Associations between CDKAL1 variants and cholesterol efflux capacity (CEC) have been reported. This study aimed to investigate the effects of Cdkal1 deficiency on high-density lipoprotein (HDL) metabolism, atherosclerosis, and related pathways. Lipid and glucose metabolic profiles, CEC, and in vivo reverse cholesterol transport (RCT) were compared in liver-specific Alb-Cre : Cdkal1 fl/fl and Cdkal1 fl/fl mice. Aortic atherosclerosis was compared in Apoe −/− Alb-Cre : Cdkal1 fl/fl and Apoe −/− mice fed high-fat diets. HDL subclasses and mediators of HDL metabolism from Alb-Cre : Cdkal1 fl/fl mice were examined. HDL-cholesterol level tended to be higher in the Alb-Cre : Cdkal1 fl/fl mice (p = 0.050). Glucose and other lipid profiles were similar in the two groups of mice, irrespective of diet. The mean CEC was 27% higher (p = 0.007) in the Alb-Cre : Cdkal1 fl/fl mice, as were the radioactivities of bile acids (mean difference 17%; p = 0.035) and cholesterol (mean difference 42%; p = 0.036) from faeces. The radioactivity tendency was largely similar in mice fed a high-fat diet. Atherosclerotic lesion area tended to be smaller in the Apoe −/− Alb-Cre : Cdkal1 fl/fl mice than in the Apoe −/− mice (p = 0.067). Cholesterol concentrations in large HDLs were higher in the Alb-Cre : Cdkal1 fl/fl mice (p = 0.024), whereas in small HDLs, they were lower (p = 0.024). Endothelial lipase (mean difference 39%; p = 0.002) and hepatic lipase expression levels (mean difference 34%; p < 0.001) were reduced in the Alb-Cre : Cdkal1 fl/fl mice, whereas SR-B1 expression was elevated (mean difference 35%; p = 0.007). The promotion of CEC and RCT in Alb-Cre : Cdkal1 fl/fl mice verified the effect of CDKAL1 seen in human genetic data. These phenotypes were related to regulation of HDL catabolism. This study suggests that CDKAL1 and associated molecules could be targets for improving RCT and vascular pathology. [Display omitted] • Liver-specific Cdkal1 deficient mice showed higher CEC and RCT with less tendency of atherosclerosis. • This study verified the effect of CDKAL1 found in our previous human genetic data. • Downregulation of EL and HL and upregulation of SR-B1 indicated altered HDL catabolism mediators. • Cholesterol concentrations were higher in the large HDL subclass in these mice. • CDKAL1 and related molecules could be therapeutic targets against vascular pathology. [ABSTRACT FROM AUTHOR]

High-density lipoprotein (HDL) functionality is an important determinant of coronary artery disease (CAD) development. We recently developed cholesterol-uptake capacity (CUC), a rapid cell-free assay system that directly evaluates the capacity of HDL to accept additional cholesterol. We aimed to evaluate the association between CUC and revascularization in patients who have undergone percutaneous coronary intervention (PCI). We retrospectively reviewed patients who underwent PCI with subsequent revascularization or coronary angiography (CAG) without revascularization. The patients who had frozen blood samples for which CUC were measurable at the index PCI and follow-up were enrolled. We finally enrolled 74 patients who underwent subsequent revascularization and 183 patients who underwent follow-up CAG without revascularization. The serum CUC level at the index PCI was significantly lower in the revascularization group than that in the non-revascularization group (84.3 [75.2–98.9] vs. 92.0 [81.6–103.3 A U.]; p = 0.004). Multivariate logistic regression analysis revealed that decreased serum CUC level at the index PCI was independently associated with subsequent revascularization (odds ratio, 0.98; 95% confidence interval, 0.969–1.000). After adjusting for 16 cardiovascular risk factors, the serum CUC level at the index PCI and follow-up and the absolute change in serum CUC level from the index PCI to follow-up were significantly lower in the revascularization group than those in the non-revascularization group. Serum CUC level at index PCI was independently associated with subsequent revascularization after PCI. Continuous assessment of HDL functionality by CUC might help predict subsequent revascularization after PCI. [Display omitted] • Cholesterol-uptake capacity (CUC) is a simple and rapid cell-free assay to evaluate high-density lipoprotein (HDL) functionality. • CUC directly evaluates the capacity of HDL to accept additional cholesterol. • Lower serum CUC at index percutaneous coronary intervention (PCI) was associated with subsequent revascularization. • Decreased change value in CUC during the follow-up in the revascularization group. [ABSTRACT FROM AUTHOR]

Low cardiorespiratory fitness is a strong and independent risk factor for cardiovascular disease (CVD). Serum profiling of healthy individuals with large differences in cardiorespiratory fitness may therefore reveal early biomarkers of CVD development. Thus, we aimed to identify circulating lipoprotein subfractions differentially expressed between groups of individuals with large differences in cardiorespiratory fitness, measured as maximal oxygen uptake (VO 2max). Healthy subjects (40–59 years) were selected from the third wave of the Trøndelag health study (HUNT3) based on having an age-dependent high VO 2max (47.1 ± 7.7 mL kg−1·min−1, n = 103) or low VO 2max (31.4 ± 4.9 mL kg−1·min−1, n = 108). The individuals were matched on gender, age, physical activity level and fasting status. 99 lipoprotein subfractions were quantified in serum samples using nuclear magnetic resonance (NMR) lipidomics. Standard clinical analyses showed similar levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol and high-density lipoprotein (HDL)-cholesterol between the groups, and slightly higher levels of triglycerides in participants with low VO 2max. Thirteen lipoprotein subfractions were increased in the low VO 2max group compared to the high VO 2max group (p < 0.005), including mainly large very low-density lipoprotein (VLDL) subfractions. In addition, triglyceride levels in small-sized HDL and LDL particles were increased in participants with low VO 2max. Correlation analyses between VO 2max and lipoproteins subfractions displayed a negative correlation between VO 2max and the levels of cholesterol and phospholipids in the small HDL particles. The lipoprotein profile of individuals with low VO 2max is similar to the profile of insulin resistant individuals. Low VO 2max was associated with enrichment of large VLDL particles, as well as an increased triglycerides content in the small and dense HDL and LDL particles. This unfavorable lipid profile is likely to be involved in the strong associations between VO 2max and CVD. [Display omitted] • The circulating levels of very low-density lipoprotein (VLDL) subfractions were significantly higher in participants with low cardiorespiratory fitness (VO 2max) compared to participants with high VO 2max. • Triglyceride levels in small-sized high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles were higher in participants with low VO 2max. • When comparing healthy individuals with high and low VO 2max , the lipoprotein subfraction profile of individuals with low VO 2max showed similarities to the profile of insulin resistant individuals. • The identified lipoprotein subfractions associated with VO 2max may represent early risk markers of CVD development. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular disease (ASCVD) represents the primary cause of mortality among patients with Type 2 Diabetes Mellitus (T2DM). In this population, High-Density Lipoprotein (HDL) particles exhibit abnormalities in number, composition, and function, culminating in diminished anti-atherosclerotic capabilities despite normal HDL cholesterol (HDL-C) concentrations. Hyperglycemic conditions contribute to these alterations in HDL kinetics, composition, and function, causing T2DM patients' HDL particles to exhibit decreased concentrations of diverse lipid species and proteins. Treatment of hyperglycemia has the potential to correct abnormal HDL particle attributes in T2DM; however, pharmacological interventions, including metformin and thiazolidinediones, yield inconsistent outcomes with respect to HDL-C concentrations and functionality. Despite numerous attempts with diverse drugs, pharmacologically augmenting HDL-C levels has not resulted in clinical benefits in mitigating ASCVD risk. In contrast, reducing Low Density Lipoprotein cholesterol (LDL-C) via statins and ezetimibe has demonstrated significant efficacy in curtailing CVD risk among T2DM individuals. Promising results have been observed in animal models and early-phase trials utilizing recombinant HDL and Lecitin Cholesterol Acyl Transferase (LCAT) -enhancing agents, but the evaluation of their efficacy and safety in large-scale clinical trials is ongoing. While aberrant HDL metabolism constitutes a prevalent aspect of dyslipidemia in T2DM, HDL cholesterol concentrations and composition no longer offer valuable insights for informing therapeutic decisions. Nevertheless, HDL metabolism remains a critical research area in T2DM, necessitating further investigation to elucidate the role of HDL particles in the development of diabetes-associated complications. [Display omitted] • Abnormal high density lipoproteins (HDL) metabolism constitutes a major component of dyslipidemia in type 2 diabetes (T2DM). • HDL concentration and composition are not useful to modify therapeutic decisions. • Despite this, HDL metabolism remains a major area of research in T2DM. • HDL particles play a major homeostatic, tissue repair role that may protect against diabetes-related chronic complications. [ABSTRACT FROM AUTHOR]

Sodium glucose co-transporter 2 (SGLT2)-inhibitors were developed as glucose-lowering drugs. Surprisingly, SGLT2-inhibitors also reduced risk of cardiovascular disease. The impact of SGLT2-inhibitors on lipids and lipoproteins is unclear, but an effect might contribute to the observed lower cardiovascular risk. We conducted a meta-analysis to examine this, overall and by dose, ethnicity, and drug type. PubMed, EMBASE and Web of Science were searched for randomized controlled trials examining all available SGLT2-inhibitors. Studies with available lipid measurements were included. Quantitative data synthesis was performed using random and fixed effects models. We identified 60 randomized trials, including 147,130 individuals. Overall, using random effects models, SGLT2-inhibitor treatment increased total cholesterol by 0.09 mmol/L (95% CI: 0.06, 0.13), low-density lipoprotein (LDL) cholesterol by 0.08 mmol/L (0.05, 0.10), and high-density lipoprotein (HDL) cholesterol by 0.06 mmol/L (0.05, 0.07), while it reduced triglycerides by 0.10 mmol/L (0.06, 0.14). Fixed effects estimates were similar but with smaller effect sizes for HDL cholesterol and triglycerides. For higher SGLT2-inhibitor doses, there was a nominally higher non-significant effect on lipids and lipoproteins. In Asian compared to non-Asian populations, a slightly larger increase in HDL cholesterol and a decrease in triglycerides were observed, but with similar results for total and LDL cholesterol. Treatment effects on lipids and lipoproteins were generally robust across different SGLT2-inhibitor drugs. In meta-analyses, SGLT2-inhibition increased total, LDL, and HDL cholesterol and decreased triglycerides. Effect sizes varied slightly by drug dose and ethnicity but were generally robust by drug type. [Display omitted] • SGLT2-inhibitor treatment increases total, LDL, and HDL cholesterol slightly. • SGLT2-inhibitor treatment lowers triglycerides slightly. • Higher vs. lower treatment dose had minimal influence on the results. • Results were generally robust across different types of SGLT2-inhibitors. • Overall, changes were modest and not likely to be of clinical relevance. [ABSTRACT FROM AUTHOR]

Apolipoprotein M (apoM) is a member of the lipocalin superfamily and is predominantly associated with high-density lipoprotein (HDL). It was found that apoM is the chaperon to the bioactive sphingolipid, sphingosine-1-phosphate (S1P). Several studies have since contributed to expand the knowledge on apoM, S1P, and the apoM/S1P-complex in cardiovascular diseases. For instance, the HDL-bound apoM/S1P complex serves as a bridge between HDL and endothelial cells, maintaining a healthy endothelial barrier. Evidence indicates, however, that the apoM/S1P complex may has both protective and harmful effects on the cardiovascular system, which suggests the need for more research to understand the interplay between these molecules. This review aims to shed light on the most recent findings on apoM/S1P-signaling and its impact on endothelial dysfunction, inflammation, and cardiovascular diseases. Finally, it will be discussed whether drugs that target apoM and/or S1P-signaling may be beneficial to patients with cardiovascular and inflammatory diseases. [Display omitted] • An imbalanced apoM/S1P-axis can interfere with triglyceride turnover and endothelial functions. • S1P-analogues may introduce a risk of disrupting the natural apoM/S1P axis and thereby the endothelial barrier homeostasis. • ApoM and S1P levels may predict the outcome of sepsis severity and SARS-CoV2. • ApoM and S1P may serve as a target in restoring endothelial dysfunction. [ABSTRACT FROM AUTHOR]

The atherogenic index of plasma (AIP) has been suggested as a marker of plasma atherogenicity. This study aimed to assess the association between AIP and the rapid progression of coronary atherosclerosis using serial coronary computed tomography angiography (CCTA). A total of 1488 adults (60.9 ± 9.2 years, 58.9% male) who underwent serial CCTA with a median inter-scan period of 3.4 years were included. AIP was defined as the base 10 logarithm of the ratio of the concentrations of triglyceride to high-density lipoprotein cholesterol. Rapid plaque progression (RPP) was defined as the change of percentage atheroma volume (PAV) ≥1.0%/year. All participants were divided into three groups based on AIP tertiles. Baseline total PAV (median [interquartile range (IQR)]) (%) (group I [lowest]: 1.91 [0.00, 6.21] vs. group II: 2.82 [0.27, 8.83] vs. group III [highest]: 2.70 [0.41, 7.50]), the annual change of total PAV (median [IQR]) (%/year) (group I: 0.27 [0.00, 0.81] vs. group II: 0.37 [0.04, 1.11] vs. group III: 0.45 [0.06, 1.25]), and the incidence of RPP (group I: 19.7% vs. group II: 27.3% vs. group III: 31.4%) were significantly different among AIP tertiles (all p < 0.05). In multiple logistic regression analysis, the risk of RPP was increased in group III (odds ratio: 1.52, 95% confidence interval: 1.02–2.26; p = 0.042) compared to group I after adjusting for clinical factors and baseline total PAV. Based on serial CCTA findings, AIP is an independent predictive marker for RPP beyond traditional risk factors. [Display omitted] • The association of atherogenic index of plasma (AIP) with the rapid progression of coronary atherosclerosis is uncertain. • This study identified that high AIP levels were independently associated with an increased risk of rapid plaque progression. • This finding suggests that AIP has additive values for cardiovascular risk stratification. [ABSTRACT FROM AUTHOR]

While low concentrations of high-density lipoprotein-cholesterol (HDL-C) represent a well-established cardiovascular risk factor, extremely high HDL-C is paradoxically associated with elevated cardiovascular risk, resulting in the U-shape relationship with cardiovascular disease. Free cholesterol transfer to HDL upon lipolysis of triglyceride-rich lipoproteins (TGRL) was recently reported to underlie this relationship, linking HDL-C to triglyceride metabolism and atherosclerosis. In addition to free cholesterol, other surface components of TGRL, primarily phospholipids, are transferred to HDL during lipolysis. It remains indeterminate as to whether such transfer is linked to HDL-C and cardiovascular disease. When TGRL was labelled with fluorescent phospholipid 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI), time- and dose-dependent transfer of DiI to HDL was observed upon incubations with lipoprotein lipase (LPL). The capacity of HDL to acquire DiI was decreased by −36% (p< 0.001) in low HDL-C patients with acute myocardial infarction (n = 22) and by -95% (p <0.001) in low HDL-C subjects with Tangier disease (n = 7), unchanged in low HDL-C patients with Type 2 diabetes (n = 17) and in subjects with high HDL-C (n = 20), and elevated in subjects with extremely high HDL-C (+11%, p< 0.05) relative to healthy normolipidemic controls. Across all the populations combined, HDL capacity to acquire DiI was directly correlated with HDL-C (r = 0.58, p< 0.001). No relationship of HDL capacity to acquire DiI with both overall and cardiovascular mortality obtained from epidemiological studies for the mean HDL-C levels observed in the studied populations was obtained. These data indicate that the capacity of HDL to acquire phospholipid from TGRL upon LPL-mediated lipolysis is proportional to HDL-C and does not reflect cardiovascular risk in subjects widely differing in HDL-C levels. [Display omitted] • DiI, a fluorescent phospholipid, was transferred from TGRL to HDL upon lipolysis by LPL in a time- and dose-dependent manner. • HDL capacity to acquire DiI was decreased in low HDL-C patients with acute myocardial infarction and Tangier disease. • HDL capacity to acquire DiI was elevated in subjects with extremely high HDL-C and was correlated with HDL-C. • HDL capacity to acquire DiI was unrelated to overall and CV mortality obtained from epidemiological studies. • HDL capacity to acquire phospholipid from TGRL upon lipolysis by LPL is proportional to HDL-C and is unrelated to CV risk. [ABSTRACT FROM AUTHOR]

Apolipoprotein A-II (apoAII) is the second major apolipoprotein of the high-density lipoprotein (HDL) particle, after apoAI. Unlike apoAI, the biological and physiological functions of apoAII are unclear. We aimed to gain insight into the specific roles of apoAII in lipoprotein metabolism and atherosclerosis using a novel rabbit model. Wild-type (WT) rabbits are naturally deficient in apoAII, thus their HDL contains only apoAI. Using TALEN technology, we replaced the endogenous apoAI in rabbits through knock-in (KI) of human apoAII. The newly generated apoAII KI rabbits were used to study the specific function of apoAII, independent of apoAI. ApoAII KI rabbits expressed exclusively apoAII without apoAI, as confirmed by RT-PCR and Western blotting. On a standard diet, the KI rabbits exhibited lower plasma triglycerides (TG, 52%, p < 0.01) due to accelerated clearance of TG-rich particles and higher lipoprotein lipase activity than the WT littermates. ApoAII KI rabbits also had higher plasma HDL-C (28%, p < 0.05) and their HDL was rich in apoE, apoAIV, and apoAV. When fed a cholesterol-rich diet for 16 weeks, apoAII KI rabbits were resistant to diet-induced hypertriglyceridemia and developed significantly less aortic atherosclerosis compared to WT rabbits. HDL isolated from rabbits with apoAII KI had similar cholesterol efflux capacity and anti-inflammatory effects as HDL isolated from the WT rabbits. ApoAII KI rabbits developed less atherosclerosis than WT rabbits, possibly through increased plasma HDL-C, reduced TG and atherogenic lipoproteins. These results suggest that apoAII may serve as a potential target for the treatment of atherosclerosis. Image 1 • We generated a human apoAII knock-in (KI) rabbit, in which human a poAII replaced the endogenous rabbit a poAI gene. • On a standard diet, apoAII KI rabbits exhibited lower TG-rich lipoproteins and higher lipoprotein lipase activity than WT. • ApoAII KI rabbits had higher HDL-C levels and HDL particles rich in apoE, apoAIV, and apoAV protein. • On a cholesterol-rich diet, apoAII KI rabbits developed significantly less aortic atherosclerosis. • These results underscore a better function of apoAII HDL compared with apoAI, suggesting a potential for targeted therapies. [ABSTRACT FROM AUTHOR]

The lipid profile is consistently associated with coronary artery disease (CAD) and ischemic stroke (IS). However, the lipoprotein subfractions have not been deeply explored in stroke subtypes, especially in IS outcome. We performed two-sample Mendelian randomization (MR) analysis using 92 lipid traits measured by nuclear magnetic resonance in 115,000 subjects from the UK Biobank. Data for genetic associations with IS, its subtypes, and long-term outcome (LTO) were obtained from three cohorts of European ancestry: GIGASTROKE (73,652 cases, 1,234,808 controls), GODS (n = 1791) and GISCOME (n = 6165). Results obtained using CARDIoGRAMPlusC4D were used to identify differences with CAD. Genetically determined low concentration of medium high-density lipoprotein (HDL) particles (odds ratio (OR) = 0.92, 95% CI 0.88–0.96; p = 3.6 × 10−4) and its cholesterol content (OR = 0.92, 95% CI 0.88–0.96; p = 1.9 × 10−4) showed causal associations with an increased risk of stroke. Genetic predisposition to high apolipoprotein (apo)B to apoA-I ratio was causally associated with an increased risk of IS (OR = 1.12, 95% CI 1.06–1.18, p = 1.1 × 10−4), and a highly suggestive association was found between non-esterified cholesterol in low-density lipoprotein (LDL) and increased risk of atherothrombotic stroke (LAS) (OR = 1.35, 95% CI 1.10–1.66; p = 4.0 × 10−3). Low cholesterol in small and medium LDL was suggestively associated with poor LTO. Our results support that low medium HDL concentration was causally associated with an increased stroke risk, while high levels of non-esterified cholesterol in LDL were suggestively associated with an increased risk of LAS and with a better LTO. [Display omitted] • Causal association of low HDL-C with stroke risk is due to the medium subfraction. • Free cholesterol content is implicated in the association of high LDL with stroke risk. • The association of triglyceride-rich lipoproteins with stroke remains inconclusive. • ApoB-lipoproteins play a more important role in CAD risk than in stroke risk. • The association of low LDL-C with a poor long-term outcome needs further studies. [ABSTRACT FROM AUTHOR]

Individuals with a higher abdominal adipose tissue accumulation are at higher risk of developing cardiometabolic diseases. For a given body mass index (BMI), women typically present lower abdominal adipose tissue accumulation compared to men. Whether abdominal adiposity is a causal driver of cardiometabolic risk, or a mere marker of ectopic fat deposition is debated. We investigated the sex-specific and sex-combined impact of height and BMI-adjusted gluteofemoral adipose tissue (GFATadj) adjusted abdominal subcutaneous adipose tissue (ASATadj) and adjusted visceral adipose tissue (VATadj) on cardiometabolic traits and diseases using Mendelian randomization. Leveraging genome-wide summary statistics on GFATadj, ASATadj and VATadj from 39,076 UK Biobank participants with full-body magnetic resonance imaging available, we found that GFATadj is associated with a more favourable cardiometabolic risk profile including lower low density lipoprotein (LDL) cholesterol, triglycerides, fasting glucose, fasting insulin, liver enzyme levels and blood pressure as well as higher high density lipoprotein (HDL) cholesterol levels. GFATadj also is negatively associated with ischemic stroke, coronary artery disease, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). ASATadj is not associated with cardiometabolic traits and diseases, whereas VATadj is associated with liver fat accumulation but not with NAFLD or other cardiometabolic traits or diseases. Although the absolute effect sizes of GFATadj on LDL cholesterol were more pronounced in women compared to men, most associations did not differ by sex. The inability of subcutaneous fat depots to efficiently store energy substrates could be the causal factor underlying the association of visceral lipid deposition with cardiometabolic health. [Display omitted] • For a given body mass index, body fat distribution influences metabolic risk. • Gluteofemoral adipose tissue accumulation may protect against metabolic risk. • Subcutaneous abdominal adipose tissue accumulation may not influence metabolic risk. • Visceral adipose tissue accumulation may increase liver fat. [ABSTRACT FROM AUTHOR]

During fat tolerance tests, plasma triglycerides increase while high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and intermediate-density lipoprotein (IDL) cholesterol decrease. However, it is unknown whether triglyceride content increases and cholesterol content decreases in HDL and LDL + IDL fractions following normal meals in the general population. Therefore, we tested the hypothesis that triglyceride content increases while cholesterol content decreases in HDL and LDL + IDL fractions following normal meals. In this cross-sectional study, we included 25,656 individuals aged 20–100 years, all without lipid-lowering therapy at examination and selected for metabolomic profiling from the Copenhagen General Population Study. Triglyceride and cholesterol content of 14 lipoprotein fractions weas measured using nuclear magnetic resonance (NMR) spectroscopy. Time since last meal was recorded by the examiner immediately before blood sampling. Following normal meals in age and sex-adjusted analyses and when compared with fasting levels, plasma triglycerides were higher for up to 5–6 h, and triglyceride content was higher for up to 6–7 h in HDL fractions, for up to 6–7 h in LDL + IDL fractions, and for up to 5–6 h in very-low-density lipoprotein (VLDL) fractions. Further, plasma cholesterol was lower for up to 2–3 h, and cholesterol content was lower for up to 0–1 h in HDL fractions and for up to 4–5 h in LDL + IDL fractions, while cholesterol content was higher for up to 4–5 h in VLDL fractions. Following normal meals, triglyceride content increases while cholesterol content decreases in HDL and LDL + IDL fractions. [Display omitted] • Following normal meals, triglyceride content increases in HDL and LDL + IDL fractions. • Following normal meals, cholesterol content decreases in HDL and LDL + IDL fractions. • Following normal meals, cholesterol content decreases in the smallest HDL fractions. • Following normal meals, cholesterol content increases in the largest VLDL fractions. • Results were similar in women and men, and in individuals with low and high BMI. [ABSTRACT FROM AUTHOR]

Dyslipidemia refers to unhealthy changes in blood lipid composition and is a risk factor for atherosclerotic cardiovascular diseases (ASCVD). Usually, low-density lipoprotein-cholesterol (LDL-C) is the primary goal for dyslipidemia management. However, non-high-density lipoprotein cholesterol (non-HDL-C) has gained attention as an alternative, reliable goal. It encompasses all plasma lipoproteins like LDL, triglyceride-rich lipoproteins (TRL), TRL-remnants, and lipoprotein a [Lp(a)] except high-density lipoproteins (HDL). In addition to LDL-C, several other constituents of non-HDL-C have been reported to be atherogenic, aiding the pathophysiology of atherosclerosis. They are acknowledged as contributors to residual ASCVD risk that exists in patients on statin therapy with controlled LDL-C levels. Therefore, non-HDL-C is now considered an independent risk factor or predictor for CVD. The popularity of non-HDL-C is attributed to its ease of estimation and non-dependency on fasting status. It is also better at predicting ASCVD risk in patients on statin therapy, and/or in those with obesity, diabetes, and metabolic disorders. In addition, large follow-up studies have reported that individuals with higher baseline non-HDL-C at a younger age (<45 years) were more prone to adverse CVD events at an older age, suggesting a predictive ability of non-HDL-C over the long term. Consequently, non-HDL-C is recommended as a secondary goal for dyslipidemia management by most international guidelines. Intriguingly, geographical patterns in recent epidemiological studies showed remarkably high non-HDL-C attributable mortality in high-risk countries. This review highlights the independent role of non-HDL-C in ASCVD pathogenesis and prognosis. In addition, the need for a country-specific approach to dyslipidemia management at the community/population level is discussed. Overall, non-HDL-C can become a co-primary or primary goal in dyslipidemia management. [Display omitted] • Non-HDL-C is a consistent and reliable residual risk predictor of ASCVD and all non-HDL-C contributing lipoproteins independently promote ASCVD. • Non-HDL-C is recommended as a co-primary treatment goal, particularly for high-risk patients. • The reliability of measuring non-HDL-C in a non-fasting state adds to its ease of use. • Baseline non-HDL-C levels <45 yrs. are predictive of CVD events at a later age. • There is an intriguing geographical pattern in non-HDL-C levels and related mortality. [ABSTRACT FROM AUTHOR]

LCAT esterifies cholesterol in both HDL (α-activity) and apoB-containing lipoproteins (β-activity). The main activator of LCAT β-activity is apoE, which in humans exists in 3 main different isoforms (E2, E3 and E4). Here, to gather insights into the potential role of LCAT in apoB-containing lipoprotein metabolism, we investigated the ability of apoE isoforms to promote LCAT-mediated cholesterol esterification. We evaluated the plasma cholesterol esterification rate (CER) in 311 individuals who express functional LCAT and either apoE2, apoE3, or apoE4 and in 28 individuals who also carried LCAT mutations causing selective loss of LCAT α-activity (Fish-Eye Disease (FED)-causing mutations). The association of carrier status with CER was determined using an adjusted linear regression model. The kinetic of LCAT activity towards reconstituted HDLs (rHDLs) containing each apoE isoform was determined using the Michaelis-Menten model. Plasma CER was ∼20% higher in apoE2 carriers compared to apoE3 carriers, and ∼30% higher in apoE2 carriers compared to apoE4 carriers. After adjusting for age, sex, total cholesterol, HDL-C, apoA-I, apoB, chronic kidney disease diagnosis, zygosity, and LCAT concentration, CER remained significantly different among carriers of the three apoE isoforms. The same trend was observed in carriers of FED-causing mutations. rHDLs containing apoE2 were associated with a lower affinity but higher maximal esterification rate, compared to particles containing apoE3 or apoE4. The present results suggest that the apoE2 isoform is associated with a higher LCAT-mediated cholesterol esterification. This observation may contribute to the characterization of the peculiar functional properties of apoE2. [Display omitted] • ApoE2 carriers have higher HDL-independent cholesterol esterification compared to carriers of apoE3 and apoE4. • RHDLs containing apoE2 have higher maximal esterification rate compared to rHDLs containing apoE3 or apoE4. • Cholesterol esterification in apoE2 carriers is higher in partial LCAT deficiency. [ABSTRACT FROM AUTHOR]

The accumulation of low-density lipoproteins (LDL) in the arterial wall plays a pivotal role in the initiation and pathogenesis of atherosclerosis. Conversely, the removal of cholesterol from the intima by cholesterol efflux to high density lipoproteins (HDL) and subsequent reverse cholesterol transport shall confer protection against atherosclerosis. To reach the subendothelial space, both LDL and HDL must cross the intact endothelium. Traditionally, this transit is explained by passive filtration. This dogma has been challenged by the identification of several rate-limiting factors namely scavenger receptor SR-BI, activin like kinase 1, and caveolin-1 for LDL as well as SR-BI, ATP binding cassette transporter G1, and endothelial lipase for HDL. In addition, estradiol, vascular endothelial growth factor, interleukins 6 and 17, purinergic signals, and sphingosine-1-phosphate were found to regulate transendothelial transport of either LDL or HDL. Thorough understanding of transendothelial lipoprotein transport is expected to elucidate new therapeutic targets for the treatment or prevention of atherosclerotic cardiovascular disease and the development of strategies for the local delivery of drugs or diagnostic tracers into diseased tissues including atherosclerotic lesions. Image 1 • The endothelium limits the entry and exit of lipoproteins into and from the arterial wall, respectively. • SR-BI, activin like kinase 1, and caveolin-1 as well as GPER and sphingosine-1-phosphate regulate the transcytosis of LDL. • SR-BI, ABCG1, endothelial lipase, the ecto-ATPase/P2Y-receptor axis, VEGF, IL-6/17, and S1P regulate HDL transcytosis. [ABSTRACT FROM AUTHOR]

An inverse relationship between lipid levels and atrial fibrillation (AF) has been suggested, but whether the association is upheld for all age groups remains unclear. The aim of the study was to examine associations between lipid levels and AF by age groups in a nationwide study in Poland. Multivariate Poisson regression models were used to estimate prevalence ratios (PRs) for AF by lipid levels. Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), total cholesterol (TC), non-HDL-C and LDL-C/HDL-C ratios were grouped into quartiles. Of the 13,724 participants, 5.2% (n = 708) had AF. People with AF were older with more comorbidities, but lower lipid levels (all p < 0.05). The prevalence of AF was inversely associated with LDL-C (Adjusted PR (95% Confidence Interval) highest versus lowest quartile: 0.60 (0.48, 0.75)), TC (0.61 (0.49, 0.75)) and non-HDL-C (0.63 (0.51, 0.78)). The prevalence of AF was inversely associated with HDL-C (0.58 (0.46, 0.74)), but this was not statistically significant for people aged 75 years and older. For the LDL-C/HDL-C ratio, the prevalence of AF was only inversely associated with higher levels for people aged 75 years and older (0.75 (0.61, 0.94)). There was no statistically significant difference in prevalence of AF by TG levels. The results suggest an inverse relationship between lipid levels and AF. The inverse association between higher HDL-C and AF was only significant for people aged <75 years, whereas the inverse association between higher LDL-C/HDL-C ratio and AF was only significant for people aged 75 years and older. Image 1 • Cholesterol levels inversely associate with prevalence of atrial fibrillation (AF). • Inverse association between high-density lipoprotein cholesterol (HDL-C) and AF was only apparent for people aged <75 years. • Inverse association between low-density lipoprotein cholesterol/HDL-C ratio AF was only apparent for people aged ≥75 years. [ABSTRACT FROM AUTHOR]

Infusion of high-density lipoprotein (HDL) mimetics failed to induce regression of atherosclerosis in recent randomized clinical trials. However, patients in these previous trials had normal levels of HDL-cholesterol, which potentially limited efficacy. Patients with very low levels of HDL-cholesterol and impaired cholesterol efflux capacity can be expected to derive the most potential benefit from infusion of HDL mimetics. This randomized clinical trial evaluated the efficacy of infusions of the HDL mimetic CER-001 in patients with genetically determined very low levels of HDL cholesterol. In this multicenter, randomized clinical trial, we recruited patients with familial hypoalphalipoproteinemia (due to ABCA1 and/or APOA1 loss-of-function variants). Participants were randomized to intravenous infusions of 8 mg/kg CER-001 or placebo (2:1 ratio), comprising 9 weekly infusions followed by infusions every two weeks. Patients underwent repeated 3T-MRI to assess mean vessel wall area and 18F-FDG PET/CT to quantify arterial wall inflammation. A total of 30 patients with a mean age of 52.7 ± 7.4 years and HDL-cholesterol of 0.35 ± 0.25 mmol/L were recruited. After 24 weeks, the absolute change in mean vessel wall area was not significantly different in the CER-001 group compared with placebo (n = 27; treatment difference: 0.77 mm2, p = 0.21). Furthermore, there was no significant difference in carotid arterial wall inflammation (n = 24, treatment difference: 0.10 target-to-background ratio of the most diseased segment, p = 0.33) after 24 weeks. In patients with genetically determined very low HDL-cholesterol, 24 weeks of treatment with HDL mimetic CER-001 did not reduce carotid vessel wall dimensions or arterial wall inflammation, compared with placebo. Image 1 • This randomized clinical trial evaluated HDL mimetic CER-001 in patients with familial hypoalphalipoproteinemia (FHA). • FHA is characterized by very low HDL-c levels and diminished cholesterol efflux capacity. • CER-001 did not reduce carotid artery wall dimensions or arterial wall inflammation after 24 weeks of infusions. • HDL mimetics have been unsuccessful in regressing atherosclerosis in randomized clinical trials. [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key regulators of low-density lipoprotein cholesterol plasma levels. Circulating PCSK9, which differs between genders, represents a valid pharmacological target for preventing cardiovascular (CV) events. We aimed to investigate sex-related associations between PCSK9 plasma levels and biochemical and anthropomorphic factors, and familial and personal morbidities, in a large European cohort (n = 3673) of men (47.9%) and women (52.1%). Individuals (aged 54–79 years) free of CV diseases were enrolled in seven centers of five European countries: Finland, France, Italy, the Netherlands, and Sweden. PCSK9 plasma levels were measured by ELISA. PCSK9 was higher in women than in men. Multiple linear regression analysis showed that latitude, sex, and treatments with statins and fibrates were the strongest predictors of PCSK9 in the whole group. These variables, together with triglycerides and high-density lipoprotein cholesterol, were also associated with PCSK9 in men or women. Mean corpuscular hemoglobin concentration and pack-years were PCSK9 independent predictors in women, whereas hypercholesterolemia and physical activity were independent predictors in men. The associations between PCSK9 and latitude, uric acid, diabetes, hypercholesterolemia and physical activity were significantly different in men and women (p interaction <0.05 for all). Besides confirming the association with lipids in the whole group, our study revealed previously unknown differences in PCSK9 predictors in men and women. These might be taken into account when defining individual risk for CV events and/or for refining PCSK9 lowering treatments. Image 1 • PCSK9 plasma levels are higher in women than in men. • The major determinants of PCSK9 levels are lipid-lowering therapies and latitude. • Hypercholesterolemia and physical activity are independent predictors of PCSK9 only in men. [ABSTRACT FROM AUTHOR]

Eicosapentaenoic acid (EPA) has been reported to reduce cardiovascular risk in patients with hypertriglyceridemia. Although several mechanisms underlying the effects of EPA have been demonstrated, those responsible for its beneficial role in patients with hypertriglyceridemia without evidence of coronary artery disease (CAD) have not been fully elucidated. We sought to clarify the main factors associated with EPA administration that led to improved endothelial function. Forty-seven consecutive patients with mild hypertriglyceridemia (mean age, 59 ± 13 years) without evidence of CAD were prospectively enrolled and administered purified EPA (1800 mg/day). Forty-four patients who were not administered EPA were enrolled as age- and sex-matched controls. Clinical variables and flow-mediated dilation (FMD) were examined before and after 6 months of treatment. Univariate and multivariate regression analyses were performed between FMD changes and clinical variables. EPA treatment decreased triglyceride levels (from 224.6 ± 58.8 to 151.8 ± 54.5 mg/dl, p < 0.001) and increased FMD (from 4.21% ± 1.91% to 6.21% ± 2.30%, p < 0.001). Multivariate analysis showed that the change in FMD was associated with the baseline high-density lipoprotein cholesterol (HDL-C) level (β = −0.331, p = 0.027) and the change in EPA/arachidonic acid (AA) ratio (β = 0.301, p = 0.048). EPA treatment improved triglyceride levels and FMD in patients with mild hypertriglyceridemia and without evidence of CAD. The baseline HDL-C level and the change in EPA/AA ratio predicted FMD improvement. The beneficial effects of EPA on triglyceride-rich lipoproteins and vascular endothelium may help improve endothelial function. Image 1 • Predictors of endothelial function improvement in eicosapentaenoic acid (EPA)-treated patients were studied. • Patients had mild hypertriglyceridemia and no evidence of coronary artery disease. • Triglyceride levels and flow-mediated dilation (FMD) were improved after treatment. • Change in FMD was associated with baseline HDL-C level and change in EPA/arachidonic acid (AA) ratio. • Effects of EPA on triglyceride-rich lipoproteins and endothelium would contribute. [ABSTRACT FROM AUTHOR]

Dyslipidemia with elevated triglycerides (TGL) and low high-density lipoprotein cholesterol (HDL-C) predicts residual cardiovascular risk, despite goal LDL-C levels and optimal statin therapy. Coronary plaque characterization by CCTA can provide mechanistic understanding of coronary artery disease and associated prognosis. The role of HDL-C in the pathogenesis of atherosclerosis is not well understood in statin-treated patients with elevated TGL. We sought to examine the association of HDL-C levels with baseline coronary plaque volumes, namely total plaque (TP) and total non-calcified plaque (TNCP) volumes by CCTA in participants enrolled in the EVAPORATE trial. We analyzed 80 participants who were enrolled in the trial. Linear regression analysis as a univariate and multivariate model adjusted for significant cardiovascular risk factors was performed to evaluate independent association of HDL-C and baseline coronary plaque volumes. In an exploratory analysis, stratified by sex, we compared the association of serum HDL-C levels with baseline coronary plaque volumes in males and females. Mean (SD) age of participants (n = 80) was 57.1 (8.6) years and 43% were male. Median (Inter Quartile Range/IQR) log-TNCP volume was 83.0 (0.1–7.3) mm3 and median (IQR) log-TP volume was 144.8 (0.1–7.1) mm3. After adjustment for relevant clinical covariates including age, gender, BMI, hypertension, diabetes, past smoking and baseline TGL levels, increasing levels of HDL-C remain independently associated with lower baseline log-TNCP volumes (β: 0.043 ± 0.021, p = 0.042) and baseline log-TP volumes (β: 0.046 ± 0.022, p = 0.035) on CCTA. On stratifying by sex in a multivariable regression analysis, HDL-C levels were inversely associated with baseline log-TNCP volumes (β: 0.066 ± 0.026, p = 0.018) and log-TP volumes (β: 0.077 ± 0.025, p = 0.004) in females, but not in males (log-TNCP volumes β: 0.038 ± 0.034, p = 0.282) and log-TP volumes (β: −0.033 ± 0.036, p = 0.364). In a cohort of statin treated patients with known atherosclerosis and residually elevated TGL, there was a significant inverse relationship between HDL-C levels and baseline coronary plaque, TP and TNCP volumes on CCTA. Our findings provide more detailed mechanistic evidence regarding the protective role of HDL-C in coronary atherosclerosis in a high-risk cohort. Further investigation to evaluate the interaction of HDL-C levels and coronary plaque volumes on differential CVD risk in statin-treated patients with elevated TGL levels is warranted. Image 1 • Dyslipidemia with elevated triglycerides (TGL) and low high-density lipoprotein cholesterol (HDL-C) predicts residual cardiovascular risk, despite goal LDL-C levels and optimal statin therapy. • In our study, HDL-C levels were associated with decreasing volumes of baseline coronary plaque volumes on CCTA in statin treated participants with elevated TGL, enrolled in the EVAPORATE trial. • Our findings provides mechanistic evidence for the protective role of HDL-C in coronary atherosclerosis in a vulnerable cohort of statin-treated patients with at-goal LDL-C levels and residually elevated TGL. [ABSTRACT FROM AUTHOR]

This study aimed to elucidate whether high-density lipoprotein cholesterol (HDL-C) at 3-month follow-up for patients receiving contemporary lipid-lowering therapy after acute coronary syndrome (ACS) could predict cardiac events. The HIJ-PROPER study was a multicenter, prospective, randomized trial comparing intensive lipid-lowering therapy (pitavastatin + ezetimibe) and conventional lipid-lowering therapy (pitavastatin monotherapy) after ACS. The entire cohort was divided into three groups according to tertiles of HDL-C levels at 3-month follow-up (Group 1, HDL-C ≤43 mg/dL; Group 2, HDL-C >43, <53.6 mg/dL; Group 3; HDL-C ≥53.6 mg/dL). Baseline characteristics and incidence of the primary endpoint (a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina pectoris, or ischemia-driven revascularization) were compared among the three groups. The primary endpoint event occurred in 34.8%, 30.1%, and 24.6% of patients in Groups 1, 2, and 3, respectively, and its incidence was significantly higher in Group 1 than in Group 3 (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.19–1.9; p = 0.001). Irrespective of the treatment regimen, Group 1 had significantly higher rates of the primary endpoint than Group 3 (pitavastatin + ezetimibe therapy: HR, 1.6; 95% CI, 1.12–2.22; p = 0.01 and pitavastatin monotherapy: HR, 1.4; 95% CI, 1.05–1.98; p = 0.02). These trends remained even after adjustment for baseline characteristics and lipid profiles. Multivariate analysis revealed that lower body mass index, prevalence of diabetes mellitus, higher levels of high-sensitivity C reactive protein at baseline, and lower levels of HDL-C at 3-month follow-up were independent predictors of the incidence of primary endpoint. Lower levels of HDL-C at 3-month follow-up are independently associated with higher incidence of cardiovascular events in ACS patients receiving contemporary lipid-lowering therapy. Image 1 • This study evaluated HDL-C and cardiovascular (CV) risk in acute coronary syndrome. • Lower HDL-C is associated with higher incidence of CV events. • Predictive ability is independent of intensive or conventional lipid-lowering therapy. • These trends remained after adjustment for baseline values and lipid profiles. • Lower BMI, diabetes mellitus, and higher hs-CRP at baseline independently predicted CV events. [ABSTRACT FROM AUTHOR]

The aim of this systematic review and meta-analysis is to synthesize studies assessing the associations between high-density lipoprotein functionality and risk of cardiovascular disease and mortality. We searched Medline and Embase for the identification of observational studies meeting the inclusion criteria. This meta-analysis was conducted following the PRISMA statement and was registered in PROSPERO (CRD42017065857). We pooled risk estimates with a random-effect model separately for cardiovascular disease (fatal and non-fatal) and all-cause mortality. Out of 29 manuscripts, 20 articles investigated cholesterol efflux capacity (13 prospective and 7 cross-sectional), 10 antioxidant capacity (7 prospective and 3 cross-sectional) and two anti-inflammatory capacity of high-density lipoprotein (1 prospective and 1 cross-sectional). A greater cholesterol efflux capacity was associated with lower risk of cardiovascular disease in 8 studies (RR for 1SD increase: 0.86; 95% CI: 0.76–0.98) and of mortality in 5 studies (RR for 1SD increase: 0,77; 0.60–1.00). Better antioxidant capacity was non-significantly associated with lower cardiovascular disease risk in 2 studies (RR for 1SD increase 0.70; 0.32–1.53) and significantly with mortality in 3 studies (RR for 1SD increase 0.48; 0.28–0.81). High-density lipoprotein anti-inflammatory ability was associated with a lower cardiovascular disease risk in the only prospective study. Greater high-density lipoprotein cholesterol efflux capacity and antioxidant/anti-inflammatory capacities were associated with lower risk of cardiovascular disease. However, the heterogeneity between studies and evidence of publication bias warrants caution and highlights the need for larger prospective studies with standardized assays and specific outcomes. Image 1 • First meta-analysis on the association between a wide range of HDL functions and the risk of cardiovascular disease and all-cause mortality • Higher cholesterol efflux and antioxidant/anti-inflammatory capacities promoted by HDL are associated with lower cardiovascular disease risk. • Higher cholesterol efflux capacity and antioxidant activity are associated with lower risk of all-cause mortality • Heterogeneity between studies and evidence of publication bias warrants caution and highlights the need for larger prospective studies [ABSTRACT FROM AUTHOR]

Although serum lipids are widely accepted as independent predictors of myocardial infarction (MI), there is insufficient evidence for associations of changes in lipid levels with MI. The present study aimed at investigating the associations between changes in lipids and incidence of MI in people without lipid-lowering therapy. 64,031 Chinese participants (mean age: 53.42 ± 11.95 years) without previous MI were enrolled in the study. The participants were divided into four categories based on quartiles of lipid changes. Multivariable Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for MI. During a median follow-up of 7.03 years, 599 individuals developed MI. After adjustment for covariates, increased total cholesterol (TC), increased low-density lipoprotein cholesterol (LDL-C), increased non-high-density lipoprotein cholesterol (non-HDL-C), and decreased high-density lipoprotein cholesterol (HDL-C) were associated with elevated risk of MI, with HRs (95% CIs) in the highest quartile group compared with the lowest quartile group of 1.56 (1.21–2.01), 1.96 (1.49–2.57), 1.95 (1.52–2.50), and 0.69 (0.53–0.90), respectively. However, changes in triglyceride (TG) were not associated with MI risk (p = 0.8030). Changes in levels of TC, LDL-C, non-HDL-C, and HDL-C, but not TG, were associated with risk of MI. Early detection and control of lipid levels may be beneficial and necessary for young people and those with healthy lipid levels at baseline. Image 1 • Changes in lipids would increase the predictive value of conventional risk factors. • Changes in lipids except triglyceride are related to myocardial infarction risk. • Early detection and control of lipids is also beneficial for young people. [ABSTRACT FROM AUTHOR]

Cohort studies found blood lipid traits were associated with the risk of chronic kidney disease (CKD). We aimed to investigate whether blood lipid traits were causally associated with the risk of CKD in the Chinese. 15,244 participants without kidney disease and cancer from the Dongfeng-Tongji cohort were recruited in 2008–2010 in Shiyan City, China. Blood total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and triglyceride (TG) levels were measured. 5251 participants had genotype data and were included in the Mendelian randomization analysis. Incident CKD was defined as estimated glomerular filtration rate <60 ml/min per 1.73 m2 in 2013. Logistic regression and Mendelian randomization methods were used to estimate the observed and causal associations of blood lipid traits with incident CKD. Various blood lipid traits were associated with CKD risk, and the odds ratios (95% confidence intervals) for incident CKD comparing the extreme quartiles were 1.45 (1.24–1.70) for TG, 1.26 (1.08–1.46) for nonHDL-c, 2.21 (1.91–2.57) for TC:HDL-c ratio, 2.14 (1.83–2.51) for TG:HDL-c ratio, and 0.47 (0.40–0.55) for HDL-c. The Mendelian randomization analysis indicated that 1 mmol/l increase in the genetic predicted blood TG level was associated with a 5% (95% confidence interval, 0–10%) higher risk of CKD. Although blood levels of HDL-c, TG, nonHDL-c, TC:HDL-c ratio, and TG:HDL-c ratio were observed to be associated with incident CKD, the Mendelian randomization analysis provided genetic evidence to support causal relation for blood TG level only. Image 1 • Whether blood lipid is causally related to the risk of chronic kidney disease (CKD), especially in the Chinese, is unclear. • The relation of blood lipid with the risk of CKD was prospectively investigated in 15,244 Chinese. • The top quartile of blood TG was related to a 45% higher risk of CKD compared with the bottom quartile. • Blood nonHDL-c, HDL-c, TC:HDL-c, and TG:HDL-c were related to the risk of CKD. • Mendelian randomization showed 1 mmol/l increase in blood TG was related to a 5% higher risk of CKD. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is associated with inflammation and atherogenic lipoprotein abnormalities. Previous studies suggest an association of fibroblast growth factor 21 (FGF21) with NAFLD. Therefore, we assessed the association of circulating FGF21 levels with inflammatory markers, lipoprotein profile and NAFLD in the Multi-Ethnic Study of Atherosclerosis (MESA). Among 6814 participants free of apparent cardiovascular disease at baseline (2000–2002), 3634 participants had valid data on variables of interest. After excluding participants with excessive alcohol consumption, 3446 participants were included in the analysis. NAFLD was defined using non-contrast cardiac computed tomography with a liver-to-spleen ratio (LSR) < 1 or liver attenuation <40 Hounsfield units (HU). The mean age of the participants was 63.5 years with 54% females, 36% Caucasian, 10% Chinese American, 31% African American and 23% Hispanic. 17% of the participants had NAFLD. After adjustment for demographic, socioeconomic and other confounders, a 1-SD increment in ln-transformed FGF21 level was associated with a 5.1% higher IL-6 level, a 0.31 nm larger very-low-density lipoprotein particle diameter, a 0.014 nm smaller high-density lipoprotein particle diameter, and a 5.25 nmol/L lower intermediate-density lipoprotein particle concentration (all p < 0.05). A 1-SD increment in ln-transformed FGF21 level was associated with LSR<1 and liver attenuation <40 HU (OR = 1.38 and 1.48; both p < 0.01), even after adjusting for the aforementioned inflammation and lipoprotein parameters. This study suggests an association between FGF21 and NAFLD, independent of inflammation and atherogenic lipoprotein abnormalities. Further studies are needed to assess FGF21 as a biomarker for future NAFLD risk. Image 1 • FGF21 was associated with IL-6 and an atherogenic lipoprotein profile. • The association of FGF21 with IL-6 is pronounced in individuals with non-alcoholic fatty liver disease (NAFLD). • FGF21 is independently associated with NAFLD. [ABSTRACT FROM AUTHOR]

Lipoprotein(a) [Lp(a)] is an important independent cardiovascular risk factor. However, Lp(a) levels are lower in patients with chronic liver disease than in healthy subjects. Furthermore, Lp(a) levels decrease as residual liver function declines. Although non-alcoholic fatty liver disease (NAFLD), especially advanced non-alcoholic steatohepatitis (NASH), increases the risk of cardiovascular diseases, the relationship between serum Lp(a) level and NASH is unknown. Thus, we examined the relationship between serum Lp(a) levels and biopsy-proved NAFLD and clarified the significance of Lp(a) measurements for cardiovascular disease screening in patients with NAFLD. A total of 176 patients with NAFLD were enrolled. Comprehensive blood chemistry tests and histological examinations of liver samples were conducted. The relationship between serum Lp(a) levels and NAFLD was analyzed. Serum Lp(a) levels in advanced fibrosis (stage 3–4) were lower than those in non-advanced fibrosis (stage 0–2) (p < 0.05). After adjustment for age, sex, body mass index, alanine aminotransferase (ALT), creatinine (Cre), HbA 1c level, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and the use of lipid-lowering agents, the significant inverse association between advanced fibrosis and serum Lp(a) levels remained (p < 0.01). Although the Lp(a) level was inversely associated with an NAFLD Activity Score (NAS) of 5–8, there was no significant association between Lp(a) levels and NAS adjusted for age, sex, body mass index, ALT, Cre, HbA 1c level, HDL-C, LDL-C, TG, and the use of lipid-lowering agents. Advanced NASH is associated with low serum Lp(a) levels; therefore, Lp(a) levels may not be useful in evaluating cardiovascular risk. Image 1 • Non-alcoholic fatty liver disease (NAFLD), especially advanced non-alcoholic steatohepatitis (NASH), is closely related to cardiovascular disease. • Advanced NASH is associated with low serum Lp(a) levels. • Lp(a) levels in advanced NASH may not be useful in evaluating cardiovascular risk. [ABSTRACT FROM AUTHOR]

Exercise training (ET) helps treat atherosclerosis. However, many patients stop regular ET for various reasons. The effect of detraining on atherosclerosis is not well studied. We examined the effects of ET vs. short-term detraining on atheromatous matrix-metalloproteinase (MMP) activity in preexisting plaque and circulating cytokines/lipids. Eighteen-week-old apolipoprotein-E −/− mice (n = 56) on a Western diet underwent: 1) ET for 6-weeks (ET5+1), 2) ET for 5-weeks and detraining for 1-week (ET5+0), 3) ET for the last 1-week (ET0+1), or 4) no treadmill ET at all for 6-weeks (ET0+0). Atheromatous MMP-activity was visualized using molecular imaging with an MMP-2/9-activatable near-infrared-fluorescent probe. Compared with no ET (ET0+0), regular ET (ET5+1) decreased carotid atheromatous MMP activity, but this protective effect was significantly blunted by short-term detraining (ET5+0). Short-term detraining after longer-term ET showed a reduction in MMP-activity similar to short-term ET (ET0+1). Blood levels of lipids and cytokines paralleled the molecular imaging results: exercise caused higher levels of high-density lipoprotein, adiponectin, and interleukin-10 and lower levels of vascular cell adhesion molecule, monocyte chemoattractant protein-1, interleukin-1β, and low-density lipoprotein. However, this beneficial effect was short-lived, with the ET5+0 group being similar to the ET0+0 group, and the ET0+1 group being similar to the ET5+1 group. The effect of exercise can be modeled with an exponential-decay of the protective factor of about 15%/day. Even short-term detraining reduces atheroprotective effects, and tips the balance towards atherosclerosis. This suggests that ET, to be effective, needs to be prolonged and regular, and that detraining should be avoided. Image 1 • Exercise training (ET) causes favorable effects on atheromatous MMP-2/9 activity and on blood lipids and cytokines. • Molecular optical imaging with an MMP-2/9 activatable probe demonstrated that the ET effect is short-lived and non-durable. • The ET effect can be modeled similar to a potent but short-lived drug, with an exponential decay factor of 15%/day. [ABSTRACT FROM AUTHOR]

We aimed to assess the relationship of HDL (high-density lipoprotein)-mediated cholesterol mass efflux capacity (CMEC) with risk of incident peripheral artery disease (PAD). CMEC was measured in 1458 Multi-Ethnic Study of Atherosclerosis participants between 2000 and 2002 as part of a case-control study matched for incident cardiovascular disease and progression of carotid plaque by ultrasound. Incident clinical PAD, adjudicated on the basis of a positive history for the presence of disease-related symptoms or treatment, was ascertained through 2015 in 1419 individuals without clinical PAD at baseline. Subclinical PAD, defined as an ankle-brachial index (ABI) ≤1.0, was assessed among 1255 individuals with a baseline ABI > 1.0 and at least one follow-up ABI measurement 3–10 years later. Cox proportional hazards and relative risk regression modeling per SD increment of CMEC were used to determine the association of CMEC with clinical and subclinical PAD, respectively. There were 38 clinical PAD and 213 subclinical PAD events that occurred over a mean follow-up of 6.0 and 6.5 years respectively. After adjustment for age, gender, and race, higher CMEC levels were not associated with clinical PAD (hazard ratio 1.25; 95% CI 0.89, 1.75) or subclinical PAD (risk ratio 1.02; 95% CI, 0.94, 1.11). These findings suggest that HDL-mediated cholesterol efflux is not significantly associated with incident clinical and subclinical PAD. Image 1 • Cholesterol mass efflux capacity (CMEC) quantifies the net movement of cholesterol between cells and HDL. • We determined the association of CMEC with incident PAD in a multi-ethnic cohort. • After adjustment for age, gender, race, higher CMEC levels were not associated with development of PAD. • Our findings suggest that CMEC may differentially impact atherosclerotic development across various vascular beds. [ABSTRACT FROM AUTHOR]

Several genes are known to contribute to the levels and metabolism of HDL-C, however, their protective effects in cardiovascular disease (CVD), healthy aging, and longevity are complex and poorly understood. It is also unclear if these genes predict longitudinal HDL-C change. We aimed to identify loci influencing HDL-C change. We performed a genome-wide association study (GWAS) with harmonized HDL-C and imputed genotype in three family-based studies recruited for exceptional survival (Long Life Family Study), from community-based (Framingham Heart Study) and enriched for CVD (Family Heart Study). In 7738 individuals with at least 2 visits, we employed a growth curve model to estimate the random linear trajectory parameter of age-sex-adjusted HDL-C for each person. GWAS was performed using a linear regression model on HDL-C change accounting for kinship correlations, population structure, and differences among studies. We identified a novel association for HDL-C with GRID1 (p = 5.43 × 10−10), which encodes a glutamate receptor channel subunit involved in synaptic plasticity. Seven suggestive novel loci (p < 1.0 × 10−6; MBOAT2 , LINC01876 - NR4A2 , NTNG2 , CYSLTR2 , SYNE2 , CTXND1-LINC01314 , and CYYR1) and a known lipid gene (ABCA10) showed associations with HDL-C change. Two additional sex-specific suggestive loci were identified in women (DCLK2 and KCNJ2). Several of these genetic variants are associated with lipid-related conditions influencing cardiovascular and metabolic health, have predictive regulatory function, and are involved in lipid-related pathways. Modeling longitudinal HDL-C in prospective studies, with differences in healthy aging, longevity and CVD risk, contributed to gene discovery and provided insights into mechanisms of HDL-C regulation. Image 1 • Longitudinal HDL-C level change in prospective family‐based populations using GWAS contributed to gene discovery and provided insights into mechanisms of HDL-C regulation. • The gene discovery for HDL-C level change provided biological insights into protective effects of HDL-C in healthy‐aging and longevity. • The HDL-C level change loci have been reported with biomarkers of health-aging and longevity. • The identified loci for HDL-C level change suggested to play a role in cardiovascular risk factors. • Some of HDL-C level change genes have participate in lipid‐related signaling and metabolic pathways. [ABSTRACT FROM AUTHOR]

Cholesteryl ester storage disease (CESD) due to LIPA gene mutations is characterized by hepatic steatosis, hypercholesterolemia and hypoalphalipoproteinemia, exposing affected patients to an increased cardiovascular risk. Further insights into the impact of LIPA gene mutations on lipid/lipoprotein metabolism are limited. Aim of the study was to investigate the effect of carrying one or two mutant LIPA alleles on lipoprotein composition and function. Lipoproteins were isolated from 6 adult CESD patients, 5 relatives carrying one mutant LIPA allele (carriers) and 12 sex/age matched controls. Lipid profile, lipoprotein mass composition and the fatty acid distribution of cholesteryl esters (CEs) were assessed. HDL function was evaluated as the ability to promote nitric oxide release by endothelial cells. Despite the lipid-lowering therapy, total cholesterol, LDL-cholesterol and triglycerides were increased in CESD patients compared to controls, while HDL-cholesterol was reduced. Carriers also displayed elevated total and LDL-cholesterol. Very low and intermediate density lipoproteins from CESD patients and carriers were enriched in CEs compared to the control ones, with a concomitant reduction of triglycerides. Fatty acid composition of CEs in serum and lipoproteins showed a depletion of linoleate content in CESD patients, due to the reduced LCAT activity. In CESD HDL, fatty acid distribution of CEs was shifted towards saturated ones, if compared to control HDL. The changes in HDL composition did not affect HDL ability to promote nitric oxide release by endothelial cells. LIPA gene mutations significantly affected plasma levels and lipid composition of lipoproteins, likely contributing to the increased cardiovascular risk of affected patients. Image 1 • CESD is associated with increased levels of apoB-containing lipoproteins and reduced HDL. • VLDL and IDL from CESD patients and carriers of one mutant LIPA allele are enriched in CEs and depleted in TGs. • The linoleate content of cholesteryl esters is reduced in the lipoproteins from CESD patients. • HDL ability to promote nitric oxide release by endothelial cells is preserved in CESD. [ABSTRACT FROM AUTHOR]

Heterogeneous high-density lipoprotein (HDL) particles, which can contain hundreds of proteins, affect human health and disease through dynamic molecular interactions with cell surface proteins. How HDL mediates its long-range signaling functions and interactions with various cell types is largely unknown. Due to the complexity of HDL, we hypothesize that multiple receptors engage with HDL particles resulting in condition-dependent receptor-HDL interaction clusters at the cell surface. Here we used the mass spectrometry-based and light-controlled proximity labeling strategy LUX-MS in a discovery-driven manner to decode HDL-receptor interactions. Surfaceome nanoscale organization analysis of hepatocytes and endothelial cells using LUX-MS revealed that the previously known HDL-binding protein scavenger receptor B1 (SCRB1) is embedded in a cell surface protein community, which we term HDL synapse. Modulating the endothelial HDL synapse, composed of 60 proteins, by silencing individual members, showed that the HDL synapse can be assembled in the absence of SCRB1 and that the members are interlinked. The aminopeptidase N (AMPN) (also known as CD13) was identified as an HDL synapse member that directly influences HDL uptake into the primary human aortic endothelial cells (HAECs). Our data indicate that preformed cell surface residing protein complexes modulate HDL function and suggest new theragnostic opportunities. [Display omitted] • Using LUX-MS we mapped the endothelial interactome of HDL, termed HDL synapse. • The endothelial HDL synapse is dynamically interconnected. • The endothelial HDL synapse is distinct from the HDL synapse of hepatic cell lines. • AMPN/CD13 influences endothelial HDL uptake. [ABSTRACT FROM AUTHOR]

Plant-based diets (PBDs) are associated with favourable lipid profiles and cardiometabolic outcomes. However, limited data regarding PBD indices (PDIs) and lipoprotein subclasses exist. We examined overall PDI, healthful PDI (hPDI) and unhealthful PDI (uPDI) associations with lipid and lipoprotein profiles. This cross-sectional analysis includes 1,986 middle- to older-aged adults from the Mitchelstown Cohort. The PDI, hPDI and uPDI scores were calculated from validated food frequency questionnaires. Higher PDI, hPDI and uPDI scores indicate a more PBD, healthful PBD and unhealthful PBD, respectively. Lipoprotein particle size and subclass concentrations were measured using nuclear magnetic resonance spectroscopy. Relationships between PDIs and lipid and lipoprotein profiles were examined via correlation and regression analyses adjusted for covariates. In fully adjusted regression analyses, higher PDI scores were associated with lower high-density lipoprotein (HDL) cholesterol concentrations and more triglyceride-rich lipoprotein and small very low-density lipoprotein (VLDL) particles. Higher hPDI scores were negatively associated with non-HDL cholesterol concentrations, large VLDL and small HDL particles, the Lipoprotein Insulin Resistance Index (LP-IR) score and VLDL particle size. Higher uPDI scores were associated with lower HDL cholesterol and greater triglyceride concentrations and more medium and large VLDL, total LDL, small LDL and total non-HDL particles, less large LDL and large HDL particles, a greater LP-IR score, greater VLDL particle size and smaller LDL and HDL particle size. This study provides novel evidence regarding associations between PBD quality and lipoprotein subclasses. A more unhealthful PBD was robustly associated with a more pro-atherogenic lipoprotein profile. [Display omitted] • Evidence shows that plant-based diet quality affects cardiometabolic disease risk. • This study explored relations between plant-based indices and lipoprotein profiles. • A healthful plant-based diet associated with a favourable lipoprotein profile. • An unhealthful plant-based diet associated with an atherogenic lipoprotein profile. • Results suggest that unhealthy plant foods should be minimised in plant-based diets. [ABSTRACT FROM AUTHOR]

Abstract Background and aims Although studies in mice have suggested that lesion regression is feasible, the underlying mechanisms remain largely unknown. Here we determined the impact of high-density lipoprotein (HDL) on atherosclerosis regression outcome. Methods Atherosclerotic lesion dynamics were studied upon bone marrow transplantation-mediated re-introduction of apolipoprotein E (Apoe) in Apoe knockout mice. Probucol was used to pharmacologically deplete HDL. Results Restoration of Apoe function was associated with an initial growth of atherosclerotic lesions and parallel decrease in lesional macrophage foam cell content (47 ± 4% at 4 weeks versus 72 ± 2% at baseline: p < 0.001), despite the fact that cholesterol levels were markedly reduced. Notably, significant lesion regression was detected from 4 weeks onwards, when plasma cholesterol levels had returned to the normolipidemic range. As a result, lesions were 41% smaller (p < 0.05) at 8 weeks than at 4 weeks after bone marrow transplantation. Regressed lesions contained an even lower level of macrophage foam cells (33 ± 5%: p < 0.001) and were rich in collagen. Probucol co-treatment was associated with a 3.2-fold lower (p < 0.05) plasma HDL-cholesterol level and a more pro-inflammatory (CCR2+) monocyte phenotype. Importantly, probucol-treated mice exhibited atherosclerotic lesions that were larger than those of regular chow diet-fed bone marrow transplanted mice at 8 weeks (186 ± 15*103 μm2 for probucol-treated versus 120 ± 19*103 μm2 for controls: p < 0.05). Conclusions We have shown that probucol-induced HDL deficiency impairs the ability of established lesions to regress in response to reversal of the genetic hypercholesterolemia in Apoe knockout mice. Our studies thus highlight a crucial role for HDL in the process of atherosclerosis regression. Highlights • Reversal of hypercholesterolemia reduces lesional foam cell content in Apoe KO mice. • Normalization of cholesterol levels induces lesion regression in Apoe KO mice. • Probucol treatment is associated with a more pro-inflammatory monocyte phenotype. • Probucol-induced HDL lowering impairs the ability of established lesions to regress. [ABSTRACT FROM AUTHOR]

Abstract Background and aims Increased transcytosis of low-density lipoprotein (LDL) across the endothelium and oxidation of LDL deposited within the subendothelial space are crucial early events in atherogenesis. C1q/TNF-related protein (CTRP) 5 is a novel secreted glycoprotein and its biological functions are largely undefined. Methods Expression of CTRP5 was analyzed in sera and atherosclerotic plaques of patients with coronary artery disease (CAD). The role of CTRP5 in atherogenesis was investigated in vitro and in vivo. Results We found CTRP5 serum levels were higher in patients with than without CAD (247.26 ± 61.71 vs. 167.81 ± 68.08 ng/mL, p < 0.001), and were positively correlated with the number of diseased vessels (Spearman's r = 0.611, p < 0.001). Increased expression of CTRP5 was detected in human coronary endarterectomy specimens as compared to non-atherosclerotic arteries. Immunofluorescence further showed that CTRP5 was predominantly localized in the endothelium, infiltrated macrophages and smooth muscle cells in the neointima. In vivo and in vitro experiments demonstrated that CTRP5 promoted transcytosis of LDL across endothelial monolayers, as well as the oxidative modification of LDL in endothelial cells. Mechanistically, we found that CTRP5 up-regulated 12/15-lipoxygenase (LOX), a key enzyme in mediating LDL trafficking and oxidation, through STAT6 signaling. Genetic or pharmacological inhibition of 12/15-LOX dramatically attenuated the deposition of oxidized LDL in the subendothelial space and the development of atherosclerosis. Conclusions These data indicate that CTRP5 is a novel pro-atherogenic cytokine and promotes transcytosis and oxidation of LDL in endothelial cells via up-regulation of 12/15-LOX. Highlights • CTRP5 is elevated in sera of patients with than without CAD and correlates with the severity of atherosclerosis. • CTRP5 expression is increased in atherosclerotic plaques and localized in endothelial cells, infiltrated macrophages, and smooth muscle cells in the neointima. • CTRP5 promotes transcytosis and oxidative modification of low-density lipoprotein in the subendothelial space through a STAT6-12/15-lipoxygenase-dependent pathway. • Inhibition of 12/15-lipoxygenase attenuates CTRP5-induced transcytosis and oxidation of LDL and atherogenesis. [ABSTRACT FROM AUTHOR]

Abstract The cholesteryl ester transfer protein (CETP) system moves cholesteryl esters (CE) from high density lipoproteins (HDL) to lower density lipoproteins, i.e. very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) in exchange for triglycerides (TGs). This shuttle process will ultimately form complexes facilitating a bidirectional exchange of CE and TGs, the end process being CE delivery to catabolic sites. The CETP system is generally characteristic of higher animal species; lower species, not provided with this system, have higher and enlarged HDL enriched with apo E, suitable for tissue receptor interaction. Discovery of the CETP system has led to the development of agents interfering with CETP, thus elevating HDL-C and potentially preventing cardiovascular (CV) disease. Activation of CETP leads instead to reduced HDL-C levels, but also to an enhanced removal of CE from tissues. CETP antagonists are mainly small molecules (torcetrapib, anacetrapib, evacetrapib, dalcetrapib) and have provided convincing evidence of a HDL-C raising activity, but disappointing results in trials of CV prevention. In contrast, the CETP agonist probucol leads to HDL-C lowering followed by an increment of tissue cholesterol removal (reduction of xanthomas, xanthelasmas) and positive findings in secondary prevention trials. The drug has an impressive anti-inflammatory profile (markedly reduced interleukin-1β expression). Newer agents, some of natural origin, have additional valuable pharmacodynamic properties. The pharmacological approach to the CETP system remains enigmatic, although the failure of CETP antagonists has dampened enthusiasm. Studies on the system, a crossroad for any investigation on cholesterol metabolism, have however provided crucial contributions and will still be confronting any scientist working on CV prevention. Highlights • The CETP system transfers-exchanges cholesteryl esters for triglycerides from HDL to VLDL-LDL. • Changes of the system may lead to either higher or lower HDL-cholesterol levels. • Blockade of CETP leads to higher HDL-cholesterol but disappointing cardiovascular protection. • Activation of CETP leads to lower HDL-cholesterol but may result in arterial benefit. • Choice between agonism and antagonism to CETP is presently an object of debate. [ABSTRACT FROM AUTHOR]

Abstract Background and aims High density lipoprotein cholesterol (HDL-C) is associated with risk of cardiovascular disease (CVD); however, therapeutic manipulations of HDL-C have failed to reduce CVD events. This suggests that HDL-C and the atheroprotective capacity of HDL are not directly linked. The goal of this study was to evaluate the relationships between HDL-bound proteins and measures of atherosclerosis burden and HDL function. Methods The HDL proteome was analyzed using mass spectrometry in 126 human subjects, who had undergone coronary computed tomography angiography (CCTA) to quantify calcified (CB) and non-calcified (NCB) atherosclerosis burden. Partial least squares regression analysis was used to evaluate associations between HDL-bound proteins and CB, NCB, or cholesterol efflux capacity (CEC). Results Significant overlap was found among proteins associated with NCB and CEC. Proteins that were associated with NCB displayed an inverse relationship with CEC, supporting a link between this protective function of HDL and clinical plaque burden. CB was associated with a set of proteins mostly distinct from NCB and CEC. When CVD risk factors were evaluated, BMI had a stronger influence on important HDL proteins than gender, age, or HDL-C. Most HDL proteins associated with function or atherosclerosis burden were not significantly correlated with HDL-C. Conclusions These findings indicate that the HDL proteome contains information not captured by HDL- C and, therefore, has potential for future development as a biomarker for CVD risk. Additionally, the proteome effects detected in this study may provide HDL compositional goals for evaluating new and existing HDL-modification therapies. Graphical abstract Image 1 Highlights • The human HDL proteome is associated with HDL function and atherosclerosis burden. • Traditional CVD risk factors influence the HDL proteome, especially BMI. • HDL proteins that influence cholesterol efflux also associate with soft plaque. • Calcified plaque is associated with a unique HDL proteome signature. [ABSTRACT FROM AUTHOR]

Abstract Background and aims Exchange of cholesterol between high-density lipoprotein (HDL) particles and cells is a key process for maintaining cellular cholesterol homeostasis. Recently, we have shown that amphiphilic cargo derived from HDL can be transferred directly to lipid bilayers. Here we pursued this work using a fluorescence-based method to directly follow cargo transfer from HDL particles to the cell membrane. Methods HDL was either immobilized on surfaces or added directly to cells, while transfer of fluorescent cargo was visualized via fluorescence imaging. Results In Chinese hamster ovary (CHO) cells expressing the scavenger receptor class B type 1 (SR-B1), transfer of amphiphilic cargo from HDL particles to the plasma membrane was observed immediately after contact, whereas hydrophobic cargo remained associated with the particles; about 60% of the amphiphilic cargo of surface-bound HDL was transferred to the plasma membrane. Essentially no cargo transfer was observed in cells with low endogenous SR-B1 expression. Interestingly, transfer of fluorescently-labeled cholesterol was also facilitated by using an artificial linker to bind HDL to the cell surface. Conclusions Our data hence indicate that the tethering function of SR-B1 is sufficient for efficient transfer of free cholesterol to the plasma membrane. Graphical abstract Image 1 Highlights • Transfer of amphiphilic cargo from HDL to the plasma membrane occurs immediately after contact. • Tethering function of SR-B1 is sufficient for efficient transfer of free cholesterol. • After HDL is captured, SR-B1 is dispensable for the cargo transfer process itself. [ABSTRACT FROM AUTHOR]

Abstract Although calcific aortic stenosis is a very common disease with major adverse cardiovascular events and healthcare costs, there are no effective medical interventions to delay or halt its progression. Cardiometabolic risk factors, including smoking and male sex, are linked to aortic stenosis. Emerging studies have identified important regulatory roles for immunological and inflammatory responses, including oxidized lipids, various cytokines, and biomineralization. Recent clinical and experimental studies in atherosclerosis and osteoporosis have demonstrated that oxidative stress and oxidized lipids decrease bone formation in the skeletal system while they increase bone formation in the cardiovascular system. Multidisciplinary factors contribute to vascular calcification, including inflammation and metabolic regulation of osteogenesis in the cardiovascular system via similar signaling pathways as bone formation. Calcific aortic valve disease (CAVD) is no longer considered a simple passive process of calcium deposition that occurs with advanced age. Biomineralization in CAVD is a complex, regulated process that involves valvular, circulating, bone marrow–derived cells, macrophage heterogeneity and genetic factors along with biochemical and mechanical factors. The current review will discuss the recently discovered important role of inflammation, metabolic risk factors, and molecular and cellular mechanisms that promote CAVD, as well as the link between osteogenic signals in the skeletal and cardiovascular systems. This may inform future therapeutic strategies for CAVD progression. Highlights • There are currently no medical interventions capable of delaying or halting progression of calcific aortic stenosis. • Calcific aortic valve disease (CAVD) is an active process that involves mechanical and biochemical factors. • This review will focus on the role of inflammation and metabolic risk factors. • This provides the future therapeutic strategies for the CAVD progression. [ABSTRACT FROM AUTHOR]

Abstract Background and aims Atherosclerosis is critically fueled by vascular inflammation through oxidized lipids and inflammatory cytokines such as tumor necrosis factor (TNF)-α. Genetic disruption of Tnf-α reduces atherosclerosis in experimental mouse models. However, less is known about the therapeutic potential of Tnf-α blockage by pharmacological inhibitors such as monoclonal antibodies, which are already approved for several inflammatory disorders in patients. Therefore, we investigated the effect of pharmacological TNF-α inhibition on plaque development in experimental atherosclerosis. Results 10 week old male Ldlr −/− mice were divided into 4 groups (n = 7–10) and fed a high fat, high cholesterol diet for 6 and 12 weeks. Simultaneously, the mouse-specific anti-Tnf-α monoclonal antibody CNTO5048 (CNT) or a control IgG was administered. Results CNT reduced circulating inflammatory markers without affecting body weight and glucose metabolism. Unexpectedly, CNT treatment increased plasma triglyceride levels and pro-atherogenic very-low-density lipoprotein (VLDL) cholesterol as well as plaque burden in the thoracoabdominal aorta and in the aortic root. In addition, we observed decreased smooth muscle cell content in the lesions and a trend towards reduced collagen deposition upon Tnf-α inhibition. Furthermore, inflammatory gene expression in the aortic arch was increased following Tnf-α inhibitor treatment. Conclusions Although up to 12-week pharmacological inhibition of TNF-α in Ldlr −/− mice diminishes systemic inflammation, experimental plaque burden and vascular inflammatory gene expression are increased, while markers of plaque stability decrease. These observations may be explained by the development of a pro-atherogenic plasma lipid profile. Graphical abstract Image 1 Highlights • The mouse-specific anti-TNF-α monoclonal antibody CNTO5048 (CNT) reduces circulating inflammatory markers in Ldlr-KO mice. • However, CNT increases pro-atherosclerotic cholesterol levels as well as experimental plaque burden. • In addition, CNT decreased smooth muscle cell content in the lesions and increased inflammatory aortic gene expression. [ABSTRACT FROM AUTHOR]

Abstract Background and aims Research on the biologic activities of HDL, such as cholesterol efflux capacity and HDL composition, has allowed the understanding of the effect of interventions directed to improve cardiovascular risk. Previously, statin therapy has shown conflicting results about its effects on cholesterol efflux capacity of HDL; the underlying mechanisms are unclear but studies with positive effects are associated with an increase of HDL-cholesterol levels. We investigated if 10 weeks of atorvastatin therapy changes HDL efflux capacity and the chemical composition of its subpopulations. Methods In a before-after design basis, HDL-cholesterol levels, chemical composition and cholesterol efflux capacity from HDL subpopulations isolated by isophynic ultracentrifugation were assessed in plasma samples from 60 patients with type 2 diabetes mellito (T2DM) at baseline and after 10 weeks of treatment with 20 mg atorvastatin. Cholesterol efflux was measured from human THP-1 cells using large, light HDL2b and small, dense 3c subpopulations as well as total HDL as acceptors. Changes of cholesterol efflux and chemical composition of HDL after treatment were analyzed. Correlations among variables potentially involved in cholesterol efflux were evaluated. Results A significant decrease of 4% in HDL-cholesterol levels was observed from 47 (42–54) to 45 (39–56) mg/dL, p = 0.02. Cholesterol efflux from total-HDL and HDL2b and 3c subfractions was maintained unchanged after treatment. The total mass of HDL remained unaffected, except for the HDL3a subpopulation accounted for by a significant increase in total protein content. No significant correlations for variables previously known to be associated with cholesterol efflux were found in our study. Conclusions Short therapy of 10 weeks with 20 mg of atorvastatin does not modify the cholesterol efflux capacity neither the total mass of HDL2b, HDL3c and total HDL. The discrepancy with previous reports may be due to the selective effects among different classes of statins or differences in the approaches to measure cellular cholesterol efflux. Highlights • Cholesterol Efflux capacity of HDL is altered in subjects with type 2 diabetes. • Low levels of HDL-Cholesterol and mild hypertriglyceridemia are typical in T2DM. • Statin effects on HDL biological activities are contradictory across studies. • Different classes of statins could have differentiated effects on HDL. [ABSTRACT FROM AUTHOR]

Background and aims PDZK1 (Post-synaptic density protein/Drosophila disc-large protein/Zonula occludens protein containing 1) stabilizes the HDL receptor protein, SR-B1, in the liver, and mediates SR-B1 signaling outside of the liver. Complete knockout of pdzk1 increases atherosclerosis in apoE -deficient mice, but the effect of PDZK1 in leukocytes is not known. In this study, we tested the role of leukocyte PDZK1 in atherosclerosis development by using bone marrow transplantation to generate ldlr deficient mice lacking PDZK1 in leukocytes. Methods Ldlr −/- mice were transplanted with either pdzk1 −/− or pdzk1 +/+ bone marrow and fed a high-fat diet to induce atherosclerosis. Results Bone marrow specific pdzk1 knockout slightly increased atherosclerotic plaque sizes but strikingly increased sizes of necrotic cores and cellular apoptosis in within plaques. PDZK1 deficiency prevented HDL dependent protection of macrophages from apoptosis in vitro and sensitized peritoneal macrophages to apoptosis in situ . PDZK1 deficiency in macrophages also impaired their ability to engulf apoptotic cells, and attenuated the IL-4 dependent induction of mannose receptor in vitro and mannose receptor protein levels in macrophages in atherosclerotic plaques. Conclusions PDZK1 is required for anti-atherogenic responses in macrophages including HDL dependent protection against apoptosis and macrophage mediated efferocytosis and limits the accumulation of apoptotic cells within atherosclerotic plaques protecting against necrotic core development. [ABSTRACT FROM AUTHOR]

Background and aims Lecithin:cholesterol acyltransferase (LCAT), a key enzyme in high-density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT), has been associated with atheroprotection. However, its relation to plaque characteristics has not been confirmed to date. We aimed to determine the relationship between plasma LCAT mass concentration and plaque burden in a multi-center imaging study. Methods Two hundred sixty-seven patients with angiographically proven coronary artery disease (CAD) underwent intravascular ultrasonography (IVUS) imaging. Ninety-six patients without CAD served as controls for biochemistry assessments. Results Plasma LCAT mass concentration was higher in CAD patients as compared to controls (8.94 ± 2.51 μg/mL vs. 7.89 ± 2.99 μg/mL, p  = 0.003), while cholesterol esterification rate (CER) was downregulated (253.6 ± 83.9 μM/2 h vs. 315.3 ± 115.0 μM/2 h, p <0.0001). Both parameters correlated inversely with total atheroma volume (r = −0.14, p  = 0.027 and r = −0.14, p  = 0.024, respectively), while only LCAT mass was found to be a significant predictor of atheroma volume (β-coefficient −0.18, p  = 0.0047) when tested in a stepwise linear regression model against known CAD risk factors as predictor variables. Accordingly, patients with LCAT mass in the highest quartile had significantly less atheroma burden than those in the lower quartiles (39.7 ± 10.7% vs. 45.4 ± 10.4%, p  = 0.0014 for highest vs. lowest quartile of LCAT mass). Conclusions Plasma LCAT mass concentration is upregulated in CAD patients and inversely related to plaque volume, suggesting atheroprotective effects. LCAT mass concentration outperformed LCAT activity in risk prediction models for atheroma burden, suggesting that LCAT mass is a key variable in atheroprotection. Further studies assessing LCAT as a therapeutic target in cardiovascular disease are warranted. [ABSTRACT FROM AUTHOR]

Plasma HDL levels have an inverse relationship to coronary artery disease (CAD) risk, which led to the idea that increasing HDL levels therapeutically would ameliorate atherosclerosis. Human genetic deficiency of CETP caused markedly elevated HDL and moderately reduced non-HDL cholesterol levels, suggesting that CETP inhibitors might produce cardiovascular benefit. The CETP inhibitor anacetrapib reproduced the phenotype of homozygous CETP deficiency and showed a highly significant benefit for CAD in the REVEAL trial. However, the magnitude of this effect was moderate, and the mechanism of benefit remains unclear. Insights into the mechanisms underlying macrophage cholesterol efflux and reverse cholesterol transport have come from monogenic human disorders and transgenic mouse studies. In particular, the importance of the ATP binding cassette transporters ABCA1 and ABCG1 in promoting cholesterol efflux from myeloid and other hematopoietic cells has been shown and linked to aberrant myelopoiesis and macrophage inflammation. Recent studies have shown that myeloid deficiency of ABCA1 and ABCG1 leads to macrophage and neutrophil inflammasome activation, which in turn promotes atherosclerotic plaque development and notably the formation of neutrophil extracellular traps (NETs) in plaques. In addition, clonal hematopoiesis has emerged as an important CAD risk factor, likely involving macrophage inflammation and inflammasome activation. Further elucidation of the mechanisms linking plaque accumulation of cholesterol and oxidized lipids to myeloid cell inflammation may lead to the development of new therapeutics specifically targeting atherogenic inflammation, with likely benefit for CAD. [ABSTRACT FROM AUTHOR]

Background and aims To evaluate changes in the high-density lipoprotein (HDL) proteome and HDL function in active rheumatoid arthritis (RA) patients initiating therapy with abatacept or adalimumab in the Abatacept Versus Adalimumab Comparison in Biologic-Naïve RA Subjects with Background Methotrexate (AMPLE) study. Methods Ultra high-pressure liquid chromatography (UHPLC) coupled with ion mobility mass spectrometry (LC-IM-MS) was used to analyze proteins associated with immunoaffinity-captured HDL from plasma of 30 patients with RA randomized to either abatacept (n = 15) or adalimumab (n = 15) therapy. Paraoxonase 1 (PON1) activity, HDL anti-oxidant capacity, cholesterol profiles, and homocysteine levels were also measured at baseline and following treatment. Repeated-measures analyses were performed using mixed-effect linear models to model the within-subject covariance over time. Results In models controlling for age, sex and treatment group, improvement in inflammation measured by decreases in CRP was associated with improvement in HDL function and changes in several HDL-associated proteins including significant decreases in lipopolysaccharide-binding protein, serum amyloid A-I (SAA-I) and inter-alpha-trypsin inhibitor heavy chain H4 ( p values < 0.05). Improvement in disease activity was also associated with changes in multiple HDL-associated proteins. Adalimumab was associated with higher PON1 activity, HDL-associated serotransferrin, and HDL-associated immunoglobulin J chain, and lower HDL-associated SAA-I over time compared with abatacept. Conclusions Improvement in inflammation associated with treatment of RA, using either abatacept or adalimumab in the AMPLE study, was associated with improvement in HDL function and significant alterations in the HDL proteome, including proteins involved in the immune response, proteinase inhibition, and lipid metabolism. [ABSTRACT FROM AUTHOR]

Background and aims Plasma apolipoprotein M (APOM) is bound to HDL-particles and has anti-atherogenic effects. The present study explored whether plasma APOM is reduced in patients with chronic kidney disease (CKD), and associated with cardiovascular disease (CVD). In addition, we tested the hypothesis that the excretion of APOM into the urine is increased in patients with kidney disease. Methods Plasma samples were collected from a cohort of patients with CKD stages 1 to 5D (N = 409) and controls (N = 35). Urine was collected from 47 subjects. Plasma APOM was measured with sandwich ELISA and urine APOM with competitive ELISA. Results Plasma APOM levels were reduced in patients with CKD stages 3-5D as compared to patients with CKD stages 1 + 2 and controls ( p  < 0.01). CKD patients with known CVD displayed even further reduction in plasma APOM levels than CKD patients without known CVD ( p  < 0.001). Fast-phase liquid chromatography showed that plasma APOM was primarily associated with HDL-cholesterol (HDL-C) across CKD stages. Accordingly, when plasma APOM values were corrected for HDL-C, a significant difference only persisted between patients with CKD stage 3 and stages 1 + 2 ( p  < 0.05), and the difference between CKD patients with and without known CVD disappeared. Urine APOM/creatinine ratio was not significantly increased in patients with kidney disease. Conclusions The results show that the difference in plasma APOM levels observed between patients with mild and advanced CKD may mainly be due to differences in plasma HDL-C. Whether APOM plays a role in human uremic atherogenesis warrants further experimental studies. [ABSTRACT FROM AUTHOR]