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Background Functional properties of high density lipoproteins (HDL) are increasingly recognized to play a physiological role in atheroprotection. Type 2 diabetes mellitus (T2DM) is characterized by low HDL cholesterol, but the effect of chronic hyperglycemia on the anti-inflammatory capacity of HDL, a metric of HDL function, is unclear. Therefore, the aim of the present study was to establish the impact of T2DM on the HDL anti-inflammatory capacity, taking paraoxonase-1 (PON-1) activity and low grade inflammation into account. Methods The HDL anti-inflammatory capacity, determined as the ability to suppress tumor necrosis factor-α (TNF-α) induced vascular cell adhesion molecule-1 (VCAM-1) mRNA expression in endothelial cells in vitro (higher values indicate lower anti-inflammatory capacity), PON-1 (arylesterase) activity, hs-C-reactive protein (hs-CRP), serum amyloid A (SAA) and TNF-α were compared in 40 subjects with T2DM (no insulin or statin treatment) and 36 non-diabetic subjects. Results T2DM was associated with impaired HDL anti-inflammatory capacity (3.18 vs 1.05 fold increase in VCAM-1 mRNA expression; P  < 0.001), coinciding with decreased HDL cholesterol ( P  = 0.001), apolipoprotein A-I ( P  = 0.038) and PON-1 activity ( P  = 0.023), as well as increased hs-CRP ( P  = 0.043) and TNF-α ( P  = 0.005). In all subjects combined, age- and sex-adjusted multivariable linear regression analysis demonstrated that impaired HDL anti-inflammatory capacity was associated with hyperglycemia (β = 0.499, P  < 0.001), lower PON-1 activity (β = − 0.192, P  = 0.030) and higher hs-CRP (β = 0.220, P  = 0.016). Conclusions The HDL anti-inflammatory capacity is substantially impaired in T2DM, at least partly attributable to the degree of hyperglycemia, decreased PON-1 activity and enhanced low grade chronic inflammation. Decreased anti-inflammatory protection capacity of HDL conceivably contributes to the increased atherosclerosis risk associated with T2DM.

Atherosclerotic cardiovascular disease is the leading cause of mortality worldwide, with arterial stiffness being an important predictor of cardiovascular mortality. This study aimed to examine in the Swedish longitudinal cohort of males and females (SPAF-1958) whether aerobic capacity measured at early- (34 years) and mid-adulthood (52 years) can predict arterial stiffness assessed by pulse wave velocity later in life (63 years). Further, we determined whether this association is modified by traditional cardiovascular risk factors such as obesity, smoking, blood pressure, advanced lipoprotein profiles and high-density lipoprotein (HDL) function determined as cholesterol efflux capacity. Multiple regression analysis revealed that a higher aerobic capacity at ages 34 (B = − 0.04, P = 0.002) and 52 (B = − 0.04, P = 0.005) significantly predicted lower arterial stiffness at age 63, independent of obesity, smoking, blood pressure, HDL, and HDL-cholesterol efflux capacity. In contrast, lipoprotein profiles and HDL-mediated cholesterol efflux at age 52 were not associated with arterial stiffness at age 63 (P > 0.05). These findings suggest that maintaining aerobic capacity from early adulthood can reduce arterial stiffness and cardiovascular risk in later life, independently of traditional and contemporary cardiovascular factors. This study emphasizes the need for further research on lifestyle modifications to enhance cardiovascular health.

Background Type 2 diabetes is increasing worldwide. Traditionally, only hypertriglyceridemia is considered a risk factor. We investigated whether also normal triglycerides prospectively associate with incident type 2 diabetes in healthy subjects. Methods Incident type 2 diabetes was determined in healthy individuals with normal triglyceride levels from a prospective longitudinal cohort study (PREVEND, n = 2085, 11.4-year median follow-up). Results Type 2 diabetes incidence was 3.8%. In linear regression analysis baseline insulin, HOMA-IR, total cholesterol, HDL cholesterol, eGFR, systolic blood pressure (all p < 0.001), glucose, age and creatinine (all p < 0.01) independently associated with triglycerides within the normal range, comparable to what would be expected from associations with increased triglycerides. In Kaplan-Meier analysis sex-stratified tertiles of normal triglycerides prospectively associated with de novo type 2 diabetes (p < 0.001). Cox regression confirmed a significant prospective association independent of HOMA-IR [HR (95% CI), 1.39 (1.12, 1.74), p = 0.002] and several other recognized risk factors. Conclusions Even in healthy subjects without metabolic syndrome increasing triglyceride levels within the normal range confer a continuous increase in type 2 diabetes incidence. These data indicate that virtually everyone could potentially benefit from triglyceride lowering, further encouraging implementation of lifestyle changes in the general population.

Background: High-fat diets promote hepatic lipid accumulation. Paradoxically, these diets also induce lipogenic gene expression in rodent liver. Whether high expression of these genes actually results in an increased flux through the de novo lipogenic pathway in vivo has not been demonstrated. Methodology/Principal Findings: To interrogate this apparent paradox, we have quantified de novo lipogenesis in C57Bl/6J mice fed either chow, a high-fat or a n-3 polyunsaturated fatty acid (PUFA)-enriched high-fat diet. A novel approach based on mass isotopomer distribution analysis (MIDA) following 1-¹³C acetate infusion was applied to simultaneously determine de novo lipogenesis, fatty acid elongation as well as cholesterol synthesis. Furthermore, we measured very low density lipoprotein-triglyceride (VLDL-TG) production rates. High-fat feeding promoted hepatic lipid accumulation and induced the expression of lipogenic and cholesterogenic genes compared to chow-fed mice: induction of gene expression was found to translate into increased oleate synthesis. Interestingly, this higher lipogenic flux (+74 μg/g/h for oleic acid) in mice fed the high-fat diet was mainly due to an increased hepatic elongation of unlabeled palmitate (+66 μg/g/h) rather than to elongation of de novo synthesized palmitate. In addition, fractional cholesterol synthesis was increased, i.e. 5.8±0.4% vs. 8.1±0.6% for control and high fat-fed animals, respectively. Hepatic VLDL-TG production was not affected by high-fat feeding. Partial replacement of saturated fat by fish oil completely reversed the lipogenic effects of high-fat feeding: hepatic lipogenic and cholesterogenic gene expression levels as well as fatty acid and cholesterol synthesis rates were normalized. Conclusions/Significance: High-fat feeding induces hepatic fatty acid synthesis in mice, by chain elongation and subsequent desaturation rather than de novo synthesis, while VLDL-TG output remains unaffected. Suppression of lipogenic fluxes by fish oil prevents from high fat diet-induced hepatic steatosis in mice.

Adiponectin (APN), an adipocytokine produced by adipose tissue, exerts pleiotropic actions regulating inflammation, metabolism and vascular homeostasis. APN levels are inversely correlated with obesity, type-2 diabetes, hypertension and cardiovascular disease. Although renin angiotensin system (RAS) activation in these interrelated metabolic syndrome components increases angiotensin II (AngII) levels leading to vascular damage, it is unknown whether APN under these conditions provides atheroprotection. We investigated whether increasing plasma APN provides atheroprotection in a hypertensive and accelerated atherosclerosis model. Using adenoviral gene transfer, sustained APN expression increased plasma levels of total and high-molecular weight APN, leading to a significant elevation of plasma HDL-cholesterol (HDL-C). Elevated APN levels were strongly atheroprotective, yet had no impact on blood pressure. Notably, gene expression analyses revealed that APN significantly inhibited the expression of pro-inflammatory and atherogenic genes while it increased the expression of the anti-inflammatory cytokine, IL-10 and the cholesterol efflux transporters, ABCA1 and ABCG1 in the artery wall. These findings suggest that increasing APN levels may be an effective therapeutic strategy to inhibit vascular inflammation and accelerated atherosclerosis associated with RAS activation in the metabolic syndrome.

Background Post‐COVID condition (PCC) affects ~10% of SARS‐CoV‐2–infected individuals and manifests as persistent symptoms such as fatigue, exercise intolerance and muscle weakness. This study aimed to assess the skeletal muscle of these patients and compare them with healthy controls. Methods Biopsies were obtained from the vastus lateralis muscle of 28 nonhospitalised PCC patients without concomitant diseases (75% women, mean age 46.4 ± 10.4 years) and 28 age‐ and sex‐matched healthy controls (79% women, mean age 46.6 ± 8.7 years). The analysis included morphological and pathological alterations, fibre type composition, fibre cross‐sectional area, capillarisation, number of myonuclei, presence of developmental myosin, CD68+ cells, macroautophagy markers, mitochondrial respiration, lipidomics and RNA sequencing. Results PCC patients, compared to controls, had a higher percentage of angulated fibres (median [IQR] 0.43 [0.00–3.20] vs. 0.00 [0.00–0.00]; p < 0.001), small, rounded fibres (0.21 [0.00–1.20] vs. 0.00 [0.00–0.00]; p < 0.001) and fibres expressing fetal myosin (0.26 [0.00–1.15] vs. 0.00 [0.00–0.17]; p = 0.015). Semiquantitative analysis showed nuclear clumps (18/27, 66.6%), hypertrophic fibres (9/27, 33.3%) and fibrosis (22/27, 81.4%) in PCC patients. Fibre cross‐sectional area was significantly lower in PCC patients (4031 ± 1365 vs. 4982 ± 1463 μm2; p = 0.018), largely driven by differences in type 2 fibre size (3533 ± 1249 vs. 4275 ± 1646 μm2; p = 0.068) than type 1 fibre size (4553 ± 1422 vs. 4932 ± 1380 μm2; p = 0.325). There was a significantly lower number of myonuclei per fibre in PCC (3.4 ± 1.1 vs. 4.1 ± 1.0; p = 0.012), but no difference in the presence of CD68+ per fibre (0.28 ± 0.15 vs. 0.22 ± 1.0; p = 0.115). No group differences were observed in macroautophagy markers LC3B (0.0032 ± 0.0007 vs. 0.0030 ± 0.0006; p = 0.232) or p62 (0.0072 ± 0.0023 vs. 0.0079 ± 0.0016; p = 0.814). Capillary‐to‐fibre ratio in PCC patients was lower for both type 1 (2.2 ± 0.7 vs. 2.6 ± 0.9; p = 0.044) and type 2 fibres (1.8 ± 0.6, vs. 2.2 ± 0.8; p = 0.022). Mitochondrial respiration was 11–28% lower in PCC patients, although not statistically significant. Lipidomics showed a lower number of phospholipids, and RNA sequencing revealed downregulation of eight metabolic pathways, primarily related to oxidative phosphorylation in PCC patients compared to controls (FDR < 0.05). Conclusions Nonhospitalised patients with PCC show signs of morphological and pathological muscle changes suggestive of degeneration and regeneration. The smaller overall fibre size, lower number of phospholipids, reduced mitochondrial oxidative capacity and lower capillarisation in these patients may be a consequence of reduced physical activity levels. The presence of clusters of atrophied angular and round‐shaped fibres, signs of inflammation and fibrosis and increased expression of fetal myosin may reflect myopathic and neurogenic post‐viral effects. Trial Registration ClinicalTrials.gov Identifier: NCT05445830.

Background New onset diabetes after transplantation (NODAT) is a frequent and serious complication of renal transplantation resulting in worse graft and patient outcomes. The pathophysiology of NODAT is incompletely understood, and no prospective biomarkers have been established to predict NODAT risk in renal transplant recipients (RTR). The present work aimed to determine whether remnant lipoprotein (RLP) cholesterol could serve as such a biomarker that would also provide a novel target for therapeutic intervention. Methods This longitudinal cohort study included 480 RTR free of diabetes at baseline. 53 patients (11%) were diagnosed with NODAT during a median [interquartile range, IQR] follow-up of 5.2 [4.1–5.8] years. RLP cholesterol was calculated by subtracting HDL and LDL cholesterol from total cholesterol values (all directly measured). Results Baseline remnant cholesterol values were significantly higher in RTR who subsequently developed NODAT (0.9 [0.5–1.2] mmol/L vs. 0.6 [0.4–0.9] mmol/L, p = 0.001). Kaplan-Meier analysis showed that higher RLP cholesterol values were associated with an increased risk of incident NODAT (log rank test, p < 0.001). Cox regression demonstrated a significant longitudinal association between baseline RLP cholesterol levels and NODAT (HR, 2.27 [1.64–3.14] per 1 SD increase, p < 0.001) that remained after adjusting for plasma glucose and HbA1c (p = 0.002), HDL and LDL cholesterol (p = 0.008) and use of immunosuppressive medication (p < 0.001), among others. Adding baseline remnant cholesterol to the Framingham Diabetes Risk Score significantly improved NODAT prediction (change in C-statistic, p = 0.01). Conclusions This study demonstrates that baseline RLP cholesterol levels strongly associate with incident NODAT independent of several other recognized risk factors.

Reverse cholesterol transport (RCT) constitutes a key part of the atheroprotective properties of high-density lipoproteins (HDL). Hepatic lipase (HL) and endothelial lipase (EL) are negative regulators of plasma HDL cholesterol levels. Although overexpression of EL decreases overall macrophage-to-feces RCT, knockout of both HL and EL leaves RCT essentially unaffected. With respect to important individual steps of RCT, current data on the role of EL and HL in cholesterol efflux are not conclusive. Both enzymes increase hepatic selective cholesterol uptake; however, this does not translate into altered biliary cholesterol secretion, which is regarded the final step of RCT. Also, the impact of HL and EL on atherosclerosis is not clear cut; rather it depends on respective experimental conditions and chosen models. More mechanistic insights into the diverse biological properties of these enzymes are therefore required to firmly establish EL and HL as targets for the treatment of atherosclerotic cardiovascular disease.

Oxidative stress participates in the development and exacerbation of cardiovascular diseases (CVD). The ability to promptly quantify an imbalance in an individual reductive-oxidative (RedOx) state could improve cardiovascular risk assessment and management. Derivatives-reactive oxygen metabolites (d-ROMs) are an emerging biomarker of oxidative stress quantifiable in minutes through standard biochemical analysers or by a bedside point-of-care test. The current review evaluates available data on the prognostic value of d-ROMs for CVD events and mortality in individuals with known and unknown CVD. Outcome studies involving small and large cohorts were analysed and hazard ratio, risk ratio, odds ratio, and mean differences were used as measures of effect. High d-ROM plasma levels were found to be an independent predictor of CVD events and mortality. Risk begins increasing at d-ROM levels higher than 340 UCARR and rises considerably above 400 UCARR. Conversely, low d-ROM plasma levels are a good negative predictor for CVD events in patients with coronary artery disease and heart failure. Moreover, combining d-ROMs with other relevant biomarkers routinely used in clinical practice might support a more precise cardiovascular risk assessment. We conclude that d-ROMs represent an emerging oxidative-stress-related biomarker with the potential for better risk stratification both in primary and secondary cardiovascular prevention.

BackgroundThe apolipoprotein E-deficient (apoE−/−) mouse is a well-established model for studying atherosclerosis. However, its small size limits its use in longitudinal positron emission tomography (PET) imaging studies. Recently, the apoE−/− rat has emerged as an alternative. With this study, we investigate the feasibility of using apoE−/− rats as an in vivo model for longitudinal atherosclerotic PET/CT imaging.ResultsApoE−/− rats showed significantly higher [18F]FDG uptake than controls in the aortic arch (+ 18.5%, p < 0.001) and abdominal aorta (+ 31.0%, p < 0.001) at weeks 12, 26, and 51. ApoE−/− rats exhibited hypercholesterolemia, as evidenced by plasma cholesterol levels that were up to tenfold higher, and total hepatic cholesterol levels that were up to threefold higher than the control rats at the end of the study. Fast protein liquid chromatography cholesterol profiling indicated very high levels of pro-atherogenic apoB-containing very low-density lipoprotein and low-density lipoprotein fractions in the apoE−/− rats. Atherosclerotic lesions cover 19.9% of the surface of the aortic arch (p = 0.0013), and there was a significantly higher subendothelial accumulation of ED1-positive macrophages in the abdominal aorta of the apoE−/− rats compared to control rats (Ctrl) (p = 0.01). No differences in neutral sterols were observed but higher levels of bile acids were found in the apoE−/− rats.ConclusionThese data demonstrate early signs of hypercholesterolemia, high levels of bile acids, the development of atherosclerotic lesions, and macrophage accumulation in apoE−/− rats. Therefore, this model shows promise for atherosclerosis imaging studies.