Reduced circulating CD63+ extracellular vesicle levels associate with atherosclerosis in hypercholesterolaemic mice and humans.

AIMS: The association and co-isolation of low-density lipoproteins (LDL) and extracellular vesicles (EVs) have been shown in blood plasma. Here we explore this relationship to better understand the role of EVs in atherogenesis. METHODS AND RESULTS: Wild type (WT), PCSK9-/-, and LDLR-/- C57BL/6 mice were used in this study. Eleven week-old male mice were fed high-fat diet (HFD) for 12 weeks or kept on normal diet until old age (22-months). Cardiac function was assessed by ultrasound, cholesterol was quantified with a colorimetric kit and circulating EVs were measured using flow cytometry. Plaques were analysed post-mortem using Oil-Red-O staining of the aortic arch. EVs were measured from platelet free blood plasma samples of normal and hypercholesterolaemic clinical patients. Based on annexin V and CD63 staining, we found a significant increase in EV levels in LDLR-/- and PCSK9-/- mice after HFD, but CD81 showed no significant change in either group. There was no significant change in plaque formation after HFD. PCSK9-/- mice show a favourable cardiac function after HFD. Blood cholesterol levels progressively increased during HFD, with LDLR-/- mice showing high levels while PCSK9-/- were significantly lowered compared to WT animals. In mice at old age, similar cholesterol levels were observed as in young mice. In old age, LDLR-/- mice showed significantly increased plaques. At old age, ejection fraction was decreased in all groups of mice, as were CD63+ EVs. Similarly to mice, in patients with hypercholesterolaemia, CD63+ EVs were significantly depleted. CONCLUSIONS: This research demonstrates an inverse relationship between circulating EVs and cholesterol, making EVs a potential marker for cardiovascular disease (CVD). HFD causes reduced cardiac function, but atherosclerotic development is slowly progressing in hypercholesterolaemic models and only observed with old animals. These results also bring further evidence for the benefit of using of PCSK9 inhibitors as therapeutic agents in CVD.

Elevated Plasma Atherogenic and Triglyceride-Glucose Indices: Markers of Cardiovascular Risk in Transfusion-Dependent Thalassemia.

BACKGROUND: Transfusion-dependent thalassemia (TDT) is an autosomal recessive disorder characterized by defective hemoglobin synthesis, leading to severe complications such as iron overload and multi-organ dysfunction. This study aims to elucidate the distinctive clinical and biochemical profiles of TDT patients compared to healthy controls, with an emphasis on cardiovascular risk assessment using novel markers such as the Plasma Atherogenic Index (PAI) and Triglyceride-Glucose (TyG) index. METHODS: This cross-sectional study included 32 TDT patients and 36 healthy controls, matched for age and gender. Comprehensive demographic, laboratory, and imaging data were collected and analyzed. TDT patients were further stratified based on cardiac involvement and ferritin levels. Key assessments included hemoglobin levels, liver enzymes, lipid profiles, and cardiac imaging. The PAI and TyG index were calculated to evaluate cardiovascular risks. Statistical analyses were performed using SPSS 27.0, employing Student's t-test, Mann-Whitney U test, and Pearson chi-square test as appropriate. RESULTS: No significant differences in basic demographic parameters were observed between groups; however, TDT patients exhibited significant clinical and laboratory differences. Notably, these patients had lower hemoglobin levels, higher platelet counts, elevated liver enzymes (ALT and AST), and markedly increased ferritin levels. Lipid profiles were significantly altered, with lower levels of total cholesterol, HDL, and LDL but elevated triglycerides. Importantly, the PAI was significantly higher in TDT patients, suggesting an increased atherosclerotic risk. Subgroup analysis revealed that patients with cardiac involvement had worse metabolic profiles, higher TyG indices, and prolonged QT intervals, indicating heightened cardiovascular risk. As the iron burden increases, the TyG index and PAI may lose their sensitivity in distinguishing between varying levels of iron overload, suggesting that their effectiveness plateaus beyond a certain threshold of iron accumulation. CONCLUSION: TDT patients show significant hematological and metabolic deviations, including elevated cardiovascular risk markers like PAI and TyG index. As iron burden increases, these markers lose discriminative power, and cardiac involvement escalates rapidly once a critical iron threshold is surpassed, as supported by studies showing a non-linear relationship between iron load and cardiac complications. Comprehensive cardiovascular risk assessment and tailored management are essential for these patients. Future studies should focus on tracking cardiovascular risk progression and the effects of targeted interventions.

Exposure of cumulative atherogenic index of plasma and the development of prediabetes in middle-aged and elderly individuals: evidence from the CHARLS cohort study.

BACKGROUND: The impact of dynamic changes in the degree of atherosclerosis on the development of prediabetes remains unclear. This study aims to investigate the association between cumulative atherogenic index of plasma (CumAIP) exposure during follow-up and the development of prediabetes in middle-aged and elderly individuals. METHODS: A total of 2,939 prediabetic participants from the first wave of the China Health and Retirement Longitudinal Study (CHARLS) were included. The outcomes for these patients, including progression to diabetes and regression to normal fasting glucose (NFG), were determined using data from the third wave. CumAIP was calculated as the ratio of the average AIP values measured during the first and third waves to the total exposure duration. The association between CumAIP and the development of prediabetes was analyzed using multivariable Cox regression and restricted cubic spline (RCS) regression. RESULTS: During a median follow-up period of 3 years, 15.21% of prediabetic patients progressed to diabetes, and 22.12% regressed to NFG. Among the groups categorized by CumAIP quartiles, the proportion of prediabetes progressing to diabetes gradually increased (Q1: 10.61%, Q2: 13.62%, Q3: 15.65%, Q4: 20.95%), while the proportion regressing to NFG gradually decreased (Q1: 23.54%, Q2: 23.71%, Q3: 22.18%, Q4: 19.05%). Multivariable-adjusted Cox regression showed a significant positive linear correlation between high CumAIP exposure and prediabetes progression, and a significant negative linear correlation with prediabetes regression. Furthermore, in a stratified analysis, it was found that compared to married individuals, those who were unmarried (including separated, divorced, widowed, or never married) had a relatively higher risk of CumAIP-related diabetes. CONCLUSION: CumAIP is closely associated with the development of prediabetes. High CumAIP exposure not only increases the risk of prediabetes progression but also hinders its regression within a certain range. These findings suggest that monitoring and maintaining appropriate AIP levels may help prevent the deterioration of blood glucose levels.

The association of ideal cardiovascular health and its change with subclinical atherosclerosis according to glucose status: A prospective cohort study.

BACKGROUND: An updated definition was developed to better evaluate cardiovascular health (CVH). We aimed to investigate whether optimal or improvement of six CVH metrics defined by new Life's Essential 8 (LE8) may counteract the risk of subclinical atherosclerosis among patients with hyperglycemia. METHODS: We conducted a prospective analysis of 5225 participants without prior cardiovascular diseases, of whom 4768 had complete data on CVH change. Subjects with CVH scores of 0-49, 50-79, and 80-100 points were categorized as having low, moderate, or high CVH, respectively. Subclinical atherosclerosis was evaluated by brachial-ankle pulse wave velocity, pulse pressure and albuminuria, both separately and in combination. RESULTS: Of the 5225 participants, 1937 (37.1%) had normal glucose regulation, while 3288 (62.9%) had hyperglycemia. The multivariable-adjusted odds ratio (OR) for composite subclinical atherosclerosis was 2.34 (95% confidence interval [CI], 1.88-2.91), 1.43 (95% CI, 1.21-1.70), and 0.74 (95% CI, 0.46-1.18), for participants with hyperglycemia who had low, moderate, or high overall CVH scores, respectively, compared with participants with normal glucose regulation. In addition, compared with those with stable CVH and normal glucose regulation, participants who exhibited greater improvements in overall CVH from 2010 to 2014 had a reduced risk of composite subclinical atherosclerosis with an OR of 0.72 (95% CI, 0.53-0.98) for those with normal glucose regulation, and 1.13 (95% CI, 0.87-1.48) for those with hyperglycemia. CONCLUSIONS: The novel defined CVH using six metrics was inversely associated with subsequent risk of subclinical atherosclerosis. Both the status of CVH and its changes modified the relationship between hyperglycemia and subclinical atherosclerosis.

Physical activity modifies the association between atherogenic index of plasma and prediabetes and diabetes: A cross-sectional analysis.

BACKGROUND: Although research has explored the association between atherogenic index of plasma (AIP) and prediabetes and diabetes, there is still not sufficient available evidence the role of physical activity (PA) in this relationship. Our purpose is to examine the complex connections between AIP, PA, and prediabetes and diabetes in a young and middle-aged population. METHODS: This study included 2220 individuals from the general population, aged 20-60 years. AIP was calculated from the logarithm of the triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio. PA was assessed depending to the American Heart Association (AHA) criteria and categorized into medium-high and low PA levels. We used binary logistic regression to explore associations and subsequently performed sensitivity and subgroup analyses. RESULTS: The 2220 participants had a mean age of 38 years, with a mean AIP of -0.1185, and a prediabetes and diabetes prevalence of 7.2%. After adjusting for auxiliary variables, AIP was positively correlated with prediabetes and diabetes (odds ratio [OR]: 3.447, 95% confidence interval [CI]: 1.829-6.497). In the low PA population, the prevalence of prediabetes and diabetes raised significantly with higher AIP (OR: 3.678, 95% CI: 1.819-7.434). This association was not meaningful in the medium to high PA population (OR: 1.925, 95% CI: 0.411-9.007). Joint and sensitivity analyze results also showed agreement. Restricted cubic spline identified a linear relationship between AIP and the prevalence of prediabetes and diabetes. Notably, the prevalence significantly increases when AIP values exceed -0.16 (p for linearity <0.05). The findings revealed heterogeneity across subgroups stratified by sex and age. CONCLUSIONS: PA may modify the link as regards AIP with prediabetes and diabetes in young and middle-aged populations. Adherence to PA prevents the adverse effects of abnormal glucose metabolism caused by dyslipidemia, particularly in women.

Assessment of Paraoxonase 1 and Arylesterase Activities and Lipid Profile in Bodybuilders: A Comparative Study of Physical Activity and Anthropometry on Atherosclerosis.

Background and Objectives: Atherosclerosis, driven by dyslipidaemia and oxidative stress, is a leading cause of cardiovascular morbidity and mortality. This study evaluates the effects of vigorous-intensity bodybuilding exercise (VIBBE) on atherosclerosis biomarkers-including paraoxonase-1 (PON1) and arylesterase (ARE) activities-and lipid profiles in male bodybuilders who do not use anabolic-androgenic steroids. Comparisons were made with individuals engaged in moderate-intensity aerobic exercise (MIAE), as well as overweight/obese sedentary (OOS) and normal-weight sedentary (NWS) individuals. Materials and Methods: A cross-sectional study was conducted involving 122 healthy male participants aged 18-45 years, divided into four groups: VIBBE (n = 31), OOS (n = 30), MIAE (n = 32), and NWS (n = 29). Anthropometric assessments were performed, and fasting blood samples were collected for biochemical analyses, including lipid profiles and PON1 and ARE activities. Statistical analyses compared the groups and evaluated correlations between adiposity measures and atherosclerosis biomarkers. Results: The VIBBE group exhibited significantly lower levels of low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and logarithm of the TG to high-density lipoprotein cholesterol (HDL-C) ratio [log(TG/HDL-C)] compared to the OOS group (p < 0.05 for all), indicating improved lipid profiles. However, these improvements were not significant when compared to the NWS group (p > 0.05), suggesting that VIBBE may not provide additional lipid profile benefits beyond those associated with normal weight status. PON1 and ARE activities were significantly lower in the VIBBE group compared to the MIAE group (p < 0.05 for both), suggesting that VIBBE may not effectively enhance antioxidant defences. Correlation analyses revealed significant inverse relationships between PON1 and ARE activities and adiposity measures, including body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), body fat percentage (BFP), fat mass index (FMI), and obesity degree (OD) (p < 0.05 for all). Positive correlations were observed between oxLDL and log(TG/HDL-C) and adiposity measures (p < 0.05 for all). Conclusions: Vigorous-intensity bodybuilding exercise improves certain lipid parameters compared to sedentary obese individuals but does not significantly enhance antioxidant enzyme activities or further improve lipid profiles beyond those observed in normal-weight sedentary men. Conversely, moderate-intensity aerobic exercise significantly enhances PON1 and ARE activities and improves lipid profiles, offering superior cardiovascular benefits. These findings underscore the importance of incorporating moderate-intensity aerobic exercise into physical activity guidelines to optimize cardiovascular health by balancing improvements in lipid metabolism with enhanced antioxidant defences.

Elevated circulating LncRNA NORAD fosters endothelial cell growth and averts ferroptosis by modulating the miR-106a/CCND1 axis in CAD patients.

Atherosclerosis is a leading cause of cardiovascular diseases, characterized by endothelial dysfunction and lipid accumulation. Long non-coding RNAs (lncRNAs) are emerging as key regulators of endothelial cell behavior. This study aimed to investigate the role of lncRNA NORAD in endothelial cell proliferation and as a potential therapeutic target for atherosclerosis. A total of 75 CAD patients and 76 controls were recruited, and plasma NORAD levels were measured using qRT-PCR. HUVECs were transfected with si-NORAD to evaluate its effects on cell cycle, proliferation, migration, and apoptosis. Plasma NORAD levels were significantly elevated in CAD patients. The NORAD-miRNA-mRNA ceRNA regulatory network was constructed based on GEO database, and G1/S-specific cyclin-D1 (CCND1) was identified as one of the hub factors. NORAD deficiency suppressed cell migration and induced G1 cell cycle arrest in HUVECs by downregulating CCND1 in vitro. NORAD upregulated CCND1 in HUVECs via sponging miR-106a that inhibited cell migration. The dual-luciferase assay confirmed the direct targeting of miR-106a by NORAD, and overexpression of miR-106a inhibited HUVEC proliferation and migration. Si-NORAD transfection resulted in induced early apoptosis, increased intracellular ROS levels, decreased GSH levels, and reduced mitochondrial membrane potential. Additionally, si-NORAD decreased the expression of GPX4, FTH1, KEAP1, NCOA4, and Nrf2, while increasing Xct levels, confirming the involvement of ferroptosis. Our findings reveal that NORAD plays a critical role in endothelial cell proliferation, migration, and apoptosis, and its silencing induces ferroptosis. The regulatory network involving NORAD, miR-106a, and their target genes provides a potential therapeutic avenue for atherosclerosis.

Blood eosinophil count is associated with early atherosclerotic artery changes in asthma.

OBJECTIVE: Asthma is linked to atherosclerosis, yet the underlying mediators remain elusive. Eosinophils may contribute to both asthmatic and atherosclerotic inflammation. Hence, this study aimed to explore the potential associations of eosinophils with artery changes among patients with asthma. METHODS: We assessed strain values of the common carotid arteries (CCAs) via vascular speckle tracking and compared asthma patients with low (< 300/µl) and high (≥ 300/µl) blood eosinophil counts (BEC). RESULTS: We enrolled 100 patients, 42 with a BEC of < 300 and 58 with a BEC of ≥ 300 n/µl. Patients with high BEC exhibited more severe disease, characterized, e.g., by a higher frequency of acute exacerbations (1.3 ± 2.1 vs. 2.6 ± 2.4 n/year, p = 0.005). Both groups presented similar profiles in terms of conventional cardiovascular risk. The high BEC group demonstrated elevated arterial stiffness, reflected by reduced radial strain (mean radial strain of the right CCA: 2.7 ± 1.4% for BEC ≥ 300 n/µl vs. 3.5 ± 1.7% for BEC < 300 n/µl, p = 0.008; left CCA: 2.6 ± 1.4% vs. 4.1 ± 2.2%, p < 0.001). A weak yet statistically significant negative correlation was observed between BEC and radial strain for the right CCA (R2 = 0.131, b=-0.001, p = 0.001) and left CCA (R2 = 0.086, b=-0.001, p = 0.015). However, the prevalence of cerebrovascular disease was similar in both groups (31,0% vs. 50,0%, p = 0.057). CONCLUSION: We identified a correlation between BEC and vascular stiffness, which supports the hypothesis that eosinophils may promote atherosclerosis. CLINICAL TRIAL NUMBER: Due to the exploratory and predominantly retrospective nature of the study, trial registration was not conducted. The only prospective procedure conducted was the angiological sonography to evaluate the current state. No ensuing health-related interventions were performed specifically for this study.

Relationship between angiogenic growth factors and atherosclerosis in renal transplantation recipients: a cross-sectional study.

BACKGROUND: Accelerated development of atherosclerosis has been observed in renal transplant recipients (RTRs). Angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) are vascular enzymes that play important roles in vascular development and angiogenesis. OBJECTIVE: This study aimed to investigate the relationship between Ang-2 and VEGF and atherosclerosis in RTRs. DESIGN AND SETTING: This study was conducted at Ankara City Hospital, Turkey. METHODS: This cross-sectional study included 36 (37.5%) female and 60 (62.5%) male RTRs. All findings were compared with those of 70 healthy controls. Ultrasonographic measurements of the carotid artery intima-media thickness (CA-IMT) and renal resistive index (RRI) were used as indicators of atherosclerosis. RESULTS: Log10 Ang-2, log10 VEGF, CA-IMT, and RRI levels were significantly higher in patients than in healthy controls. No significant differences were detected in CA-IMT and RRI between those with log10 Ang-2 ≥ 3.53 pg/mL and those with < 3.53 pg/mL. No significant differences were detected in CA-IMT and RRI between those with log10 VEGF ≥ 1.98 pg/mL and those with < 1.98 pg/mL. No correlation was detected between log10 Ang-2 and log10 VEGF, CA-IMT, or RRI. CONCLUSIONS: Increased serum angiogenic growth factor levels and increased atherosclerosis development were detected in RTRs compared to healthy individuals. No relationship was observed between angiogenic growth factors and atherosclerosis. This may be due to the decreased synthesis and effect of angiogenic growth factor receptors synthesized from atherosclerotic plaques due to atherosclerosis, which improves after renal transplantation.

Association of diabetic retinopathy with plasma atherosclerotic index, visceral obesity index, and lipid accumulation products: NHANES 2005-2008.

BACKGROUND: Abdominal obesity, a significant risk factor for the progression of diabetic retinopathy (DR), may lead to improved visual outcomes through early assessment. This study aims to evaluate any potential associations between DR and novel lipid metabolism markers, including the Atherogenic Index of Plasma (AIP), Visceral Adiposity Index (VAI), and Lipid Accumulation Product (LAP). METHODS: This study aimed to elucidate the association between various lipid markers and DR by screening the National Health and Nutrition Examination Survey (NHANES) database in the United States from 2005 to 2008. To examine the correlation, multifactor logistic regression analysis, subgroup analysis, threshold effect analysis, interaction test, and smooth curve fitting were used. RESULTS: Among the 2591 participants included, the incidence of DR was 13.6% and the mean age was 59.55 ± 12.26 years. After adjusting for important confounding covariates, logistic regression studies suggested a possible positive association between LAP, VAI, AIP, and DR occurrence (odds ratio [OR] = 1.004; 95% confidence interval [CI]: 1.002, 1.006; P < 0.0001; [OR] = 1.090; 95% [CI]: 1.037, 1.146; P = 0.0007; [OR] = 1.802; 95% [CI]: 1.240, 2.618; P = 0.0020). The nonlinear association between LAP and DR was further illustrated using an S-shaped curve by smoothing curve fitting, with the inflection point of the curve located at 63.4. Subgroup analyses and interaction tests were performed with full variable adjustment (P > 0.05 for all interactions). CONCLUSION: Studies have shown that elevated levels of LAP, VAI, and AIP increase the likelihood of DR, suggesting that they have the potential to be predictive markers of DR, emphasizing their potential utility in risk assessment and prevention strategies, and advocating for early intervention to mitigate the likelihood of DR.

Plasma atherogenicity index is a powerful indicator for identifying metabolic syndrome in adults with type 2 diabetes mellitus: A cross-sectional study.

Metabolic syndrome (MetS) is an important risk factor for atherosclerotic cardiovascular disease (ASCVD). Elevated triglyceride (TG) levels and decreased high-density lipoprotein levels (HDL-C) are predisposing factors for the development of ASCVD. Evidence on the association between atherosclerotic index of plasma [AIP = log (TG/HDL-C)] and MetS is limited. Our study aimed to investigate the association between AIP and MetS. This is a cross-sectional study that determines the presence of MetS by assessing anthropometric and biochemical parameters. Multivariate log-binomial regression models were used to analyze the relationship between AIP and MetS risk. To further test the stability of the results, we performed sensitivity analyses in young, non-obese, and normal lipid population. Smoothing plots explored the potential nonlinear relationship between the AIP index for MetS and the estimated potential risk threshold. Predictive power of AIP for MetS using respondent operating characteristic (ROC) curves. The prevalence of MetS was 67.35%. Multivariate logistic regression analysis showed an independent and positive association between AIP and MetS (Per 1 SD increase, PR = 1.31, 95% CI: 1.15-1.47). Sensitivity analysis demonstrated the stability of the results. Smoothing plot showed a nonlinear relationship between AIP and MetS, with an inflection point of 0.66. ROC curve analysis, AIP was an accurate indicator for assessing MetS in type 2 diabetics (AUC = 0.840, 95% CI: 0.819-0.862). AIP is a stable and independently powerful predictor of MetS in T2DM patients. AIP can be used as a simple assessment tool for the early detection of MetS and disease management for the prevention of cardiovascular disease.

Development, characterization, and replication of proteomic aging clocks: Analysis of 2 population-based cohorts.

BACKGROUND: Biological age may be estimated by proteomic aging clocks (PACs). Previous published PACs were constructed either in smaller studies or mainly in white individuals, and they used proteomic measures from only one-time point. In this study, we created de novo PACs and compared their performance to published PACs at 2 different time points in the Atherosclerosis Risk in Communities (ARIC) study of white and black participants (around 75% white and 25% black). MEDTHODS AND FINDINGS: A total of 4,712 plasma proteins were measured using SomaScan in blood samples collected in 1990 to 1992 from 11,761 midlife participants (aged 46 to 70 years) and in 2011 to 2013 from 5,183 late-life participants (aged 66 to 90 years). The de novo ARIC PACs were constructed by training them against chronological age using elastic net regression in two-thirds of healthy participants in midlife and late life and validated in the remaining one-third of healthy participants at the corresponding time point. We also computed 3 published PACs. We estimated age acceleration for each PAC as residuals after regressing each PAC on chronological age. We also calculated the change in age acceleration from midlife to late life. We examined the associations of age acceleration and change in age acceleration with mortality through 2019 from all-cause, cardiovascular disease (CVD), cancer, and lower respiratory disease (LRD) using Cox proportional hazards regression in participants (irrespective of health) after excluding the training set. The model was adjusted for chronological age, smoking, body mass index (BMI), and other confounders. We externally validated the midlife PAC using the Multi-Ethnic Study of Atherosclerosis (MESA) Exam 1 data. The ARIC PACs had a slightly stronger correlation with chronological age than published PACs in healthy participants at each time point. Associations with mortality were similar for the ARIC PACs and published PACs. For late-life and midlife age acceleration for the ARIC PACs, respectively, hazard ratios (HRs) per 1 standard deviation were 1.65 and 1.38 (both p < 0.001) for all-cause mortality, 1.37 and 1.20 (both p < 0.001) for CVD mortality, 1.21 (p = 0.028) and 1.04 (p = 0.280) for cancer mortality, and 1.68 and 1.36 (both p < 0.001) for LRD mortality. For the change in age acceleration, HRs for all-cause, CVD, and LRD mortality were comparable to the HRs for late-life age acceleration. The association between the change in age acceleration and cancer mortality was not significant. The external validation of the midlife PAC in MESA showed significant associations with mortality, as observed for midlife participants in ARIC. The main limitation is that our PACs were constructed in midlife and late-life participants. It is unknown whether these PACs could be applied to young individuals. CONCLUSIONS: In this longitudinal study, we found that the ARIC PACs and published PACs were similarly associated with an increased risk of mortality. These findings suggested that PACs show promise as biomarkers of biological age. PACs may be serve as tools to predict mortality and evaluate the effect of anti-aging lifestyle and therapeutic interventions.

Vascular Cytokines and Atherosclerosis: Differential Serum Levels of TRAIL, IL-18, and OPG in Obstructive Coronary Artery Disease.

The risk-factor-based prediction of atherosclerotic coronary artery disease (CAD) remains suboptimal, particularly in the absence of any of the standard modifiable cardiovascular risk factors (SMuRFs), making the discovery of biomarkers that correlate with atherosclerosis burden critically important. We hypothesized that cytokines and receptors associated with inflammation in CAD-tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interleukin-18 (IL-18), and osteoprotegerin (OPG)-would be independently associated with CAD. To determine this, we measured the serum biomarker levels of 993 participants from the BioHEART study who had CT coronary angiograms that were scored for severity of stenosis and plaque composition. We found that the quartiles of TRAIL, OPG, and IL-18 were significantly associated with disease scores, and that the IL-18/TRAIL and OPG/TRAIL ratios demonstrated significant differences between no CAD vs. STEMI whereas only the OPG/TRAIL ratio showed differences between no CAD and obstructive CAD (stenosis > 50%). However, these associations did not persist after adjustment for age, sex, SMuRFs, and a family history of CAD. In conclusion, TRAIL, IL-18, and OPG and the derived ratios of IL-18/TRAIL and OPG/TRAIL demonstrate significant associations with raw disease scores and risk factors, but these markers are not discriminatory biomarkers for the prediction of CAD when incorporated into multi-variable risk models.

Nonlinear association between atherogenic index of plasma and chronic kidney disease: a nationwide cross-sectional study.

BACKGROUND: The interplay between metabolic disorders and chronic kidney disease (CKD) has been well-documented. However, the connection between CKD and atherogenic index of plasma (AIP) remains understudied. This research delves into the correlation between these two factors, aiming to shed new light on their potential association. METHODS: The relationship between AIP and CKD was evaluated using a weighted multivariate logistic regression model, and the curvilinear relationship between AIP and CKD was explored through smooth curve fitting. We engaged a recursive partitioning algorithm in conjunction with a two-stage linear regression model to precisely determine the inflection point. By conducting stratified analyses, the heterogeneity within subpopulations was explored. RESULTS: In the regression model that accounted for all covariates, ORs (95% CI) for the association between CKD and AIP were 1.12 (0.91, 1.36), indicating no significant association between AIP and CKD. However, sensitivity analyses suggested that the relationship between them may be non-linear. Smooth curve analysis confirmed the non-linear relationship between AIP and CKD, identifying an inflection point at -0.55. Below this threshold, AIP exhibited a significant inverse correlation with CKD. Conversely, above this threshold, a pronounced positive correlation was detected. Stratified analyses elucidated that a non-linear association between AIP and CKD was observed among female participants and those aged 50 and above. CONCLUSION: We found a curvilinear relationship between chronic kidney disease and atherogenic index of plasma.

Insulin resistance assessed by estimated glucose disposal rate and risk of atherosclerotic cardiovascular diseases incidence: the multi-ethnic study of atherosclerosis.

BACKGROUND: To investigate the relationship between estimated glucose disposal rate (eGDR), a surrogate indicator of insulin resistance, and atherosclerotic cardiovascular diseases (ASCVD) incidence risk. METHODS: This prospective cohort study utilized data from the 6026 participants from the Multi-Ethnic Study of Atherosclerosis. The eGDR (mg/kg/min) was computed as 21.158 - (0.09 × waist circumference [cm]) - (3.407 × hypertension [yes/no]) - (0.551 × HbA1c [%]). The population was categorized into four subgroups according to the quartiles (Q) of eGDR. Cox proportional hazard models were applied to assess the associations between eGDR and ASCVD incidence, and restricted cubic spine (RCS) was employed to examine the dose-response relationship. RESULTS: The mean age of participants was 63.6 ± 10.1 years, comprising 3163 (52.5%) women. Over a median follow-up duration of 14.1 years, 565 (9.4%) developed ASCVD, including 256 (4.2%) myocardial infarctions, 234 (3.9%) strokes, and 358 (5.9%) fatal coronary heart disease. Compared to the lowest quartile, the adjusted hazard ratios (95% confidence intervals) for incident ASCVD for Q2-Q4 were 0.87 (0.68-1.10), 0.63 (0.47-0.84), and 0.43 (0.30-0.64), respectively. Per 1 standard deviation increase in eGDR was associated with a 30% (HR: 0.70, 95% CI 0.60-0.80) risk reduction of ASCVD, with the subgroup analyses indicating that age and hypertension modified the association (P for interaction < 0.05). RCS analysis indicated a significant and linear relationship between eGDR and ASCVD incidence risk. CONCLUSION: eGDR level was negatively associated with incident ASCVD risk in a linear fashion among the general population. Our findings may contribute to preventive measures by improving ASCVD risk assessment.

Assessment of Lipoprotein (a) Levels in Patients with Atherosclerotic Cardiovascular Disease: Single Center Experience from Türkiye.

OBJECTIVE: This study aims to evaluate the role of elevated lipoprotein (a) [Lp(a)] levels as a potential contributor to residual risk in individuals with atherosclerotic cardiovascular disease (ASCVD). Considering that approximately 90% of Lp(a) levels are genetically determined and can vary regionally, we assessed Lp(a) levels in a cohort of ASCVD patients from the Turkish population, where data is currently limited. METHODS: We conducted a retrospective analysis of data and Lp(a) measurements collected from individuals diagnosed with ASCVD at a single center. RESULTS: The analysis included Lp(a) levels of 1193 consecutive individuals. The mean Lp(a) level was 28.2 mg/dL, with a median of 16 mg/dL and an interquartile range (IQR) from the 25th to the 75th percentile, 7 mg/dL to 39 mg/dL. The highest recorded Lp(a) level was 326 mg/dL. Among the cases, 18.7% exhibited Lp(a) levels ≥ 50 mg/dL, 10.8% had levels ≥ 70 mg/dL, and 5.8% had levels ≥ 90 mg/dL. The mean levels of low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) were 132 ± 47 mg/dL and 212 ± 54 mg/dL, respectively. Lp(a) levels were significantly higher in females compared to males. Furthermore, the proportion of females with Lp(a) levels ≥ 90 mg/dL was higher than in males (11.4% vs. 1.4%; P < 0.01). Additionally, a modest but significant correlation was observed between Lp(a) levels and TC (r = 0.075, P = 0.01) as well as LDL-C (r = 0.106, P < 0.01). CONCLUSION: This study revealed that Lp(a) concentrations were higher in women and statin users among ASCVD patients and identified a weak but significant correlation between Lp(a) levels and both TC and LDL-C.

Lipoprotein(a) and risk-weighted apolipoprotein B: a novel metric for atherogenic risk.

BACKGROUND: Retention of apolipoprotein B (apoB)-containing lipoproteins within the arterial wall plays a major causal role in atherosclerotic cardiovascular disease (ASCVD). There is a single apoB molecule in all apoB-containing lipoproteins. Therefore, quantitation of apoB directly estimates the number of atherogenic particles in plasma. ApoB is the preferred measurement to refine the estimate of ASCVD risk. Low-density lipoprotein (LDL) particles are by far the most abundant apoB-containing particles. In patients with elevated lipoprotein(a) (Lp(a)), apoB may considerably underestimate risk because Mendelian randomization studies have shown that the atherogenicity of Lp(a) is approximately 7-fold greater than that of LDL on a per apoB particle basis. In subjects with increased Lp(a), the association between LDL-cholesterol and incident CHD (coronary heart disease) is increased, but the association between apoB and incident CHD is diminished or even lost. Thus, there is a need to understand the mechanisms of Lp(a), LDL-cholesterol and apoB-related CHD risk and to provide clinicians with a simple practical tool to address these complex and variable relationships. How can we understand a patient's overall lipid-driven atherogenic risk? What proportion of this risk does apoB capture? What proportion of this risk do Lp(a) particles carry? To answer these questions, we created a novel metric of atherogenic risk: risk-weighted apolipoprotein B. METHODS: In nmol/L: Risk-weighted apoB = apoB - Lp(a) + Lp(a) x 7 = apoB + Lp(a) x 6. Proportion of risk captured by apoB = apoB divided by risk-weighted apoB. Proportion of risk carried by Lp(a) = Lp(a) × 7 divided by risk-weighted apoB. RESULTS: Risk-weighted apoB agrees with risk estimation from large epidemiological studies and from several Mendelian randomization studies. CONCLUSIONS: ApoB considerably underestimates risk in individuals with high Lp(a) levels. The association between apoB and incident CHD is diminished or even lost. These phenomena can be overcome and explained by risk-weighted apoB.

DNA Methylation Age Mediates Effect of Metabolic Profile on Cardiovascular and General Aging.

BACKGROUND: Alterations in lipid metabolism and DNA methylation are 2 hallmarks of aging. Connecting metabolomic, epigenomic, and aging outcomes help unravel the complex mechanisms underlying aging. We aimed to assess whether DNA methylation clocks mediate the association of circulating metabolites with incident atherosclerotic cardiovascular disease (ASCVD) and frailty. METHODS: The China Kadoorie Biobank is a prospective cohort study with a baseline survey from 2004 to 2008 and a follow-up period until December 31, 2018. We used the Infinium Methylation EPIC BeadChip to measure the methylation levels of 988 participants' baseline blood leukocyte DNA. Metabolite profiles, including lipoprotein particles, lipid constituents, and various circulating metabolites, were measured using quantitative nuclear magnetic resonance. The pace of DNA methylation age acceleration (AA) was calculated using 5 widely used epigenetic clocks (the first generation: Horvath, Hannum, and Li; the second generation: Grim and Pheno). Incident ASCVD was ascertained through linkage with local death and disease registries and national health insurance databases, supplemented by active follow-up. The frailty index was constructed using medical conditions, symptoms, signs, and physical measurements collected at baseline. RESULTS: A total of 508 incident cases of ASCVD were documented during a median follow-up of 9.5 years. The first generation of epigenetic clocks was associated with the risk of ASCVD (P<0.05). For each SD increment in LiAA, HorvathAA, and HannumAA, the corresponding hazard ratios for ASCVD risk were 1.16 (1.05-1.28), 1.10 (1.00-1.22), and 1.17 (1.04-1.31), respectively. Only LiAA mediated the association of various metabolites (lipids, fatty acids, histidine, and inflammatory biomarkers) with ASCVD, with the mediating proportion reaching up to 15% for the diameter of low-density lipoprotein (P=1.2×10-2). Regarding general aging, a 1-SD increase in GrimAA was associated with an average increase of 0.10 in the frailty index (P=2.0×10-3), and a 33% and 63% increased risk of prefrailty and frailty at baseline (P=1.5×10-2 and 5.8×10-2), respectively; this association was not observed with other clocks. GrimAA mediated the effect of various lipids, fatty acids, glucose, lactate, and inflammatory biomarkers on the frailty index, with the mediating proportion reaching up to 22% for triglycerides in very small-sized very low-density lipoprotein (P=6.0×10-3). CONCLUSIONS: These findings suggest that epigenomic mechanisms may play a role in the associations between circulating metabolites and the aging process. Different mechanisms underlie the first and second generations of DNA methylation age in cardiovascular and general aging.

ADLM Guidance Document on the Measurement and Reporting of Lipids and Lipoproteins.

BACKGROUND: The accurate measurement of blood lipids and lipoproteins is crucial for the clinical management of atherosclerotic disease risk. Despite progress in standardization, there are still significant variations in pre-analytical requirements, methods, nomenclature, and reporting work flows. CONTENT: The guidance document aims to improve standardization of clinical lipid testing work flows. It provides recommendations for the components of the lipid panel, fasting requirements, reporting of results, and specific recommendations for non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) [Lp(a)], apolipoprotein B (apo B), point-of-care lipid testing, and LDL subfraction testing. SUMMARY: Lipid panels should always report non-HDL-C and LDL-C calculations if possible. Fasting is not routinely required except in specific cases. Modern equations should be utilized for LDL-C calculation. These equations allow for LDL-C reporting at elevated concentrations of triglycerides and obviate the need for direct measured LDL-C in most cases.

Association of atherogenic index of plasma and triglyceride glucose-body mass index and sarcopenia in adults from 20 to 59: a cross-sectional study.

Background: The relationship between atherogenic index of plasma (AIP) and triglyceride glucose-body mass index (TyG-BMI) and sarcopenia has not been studied in the United States (US) population. Methods: This research included 4,835 people from the National Health and Nutrition Examination Survey (NHANES) conducted between 2011 and 2018. The relationship between sarcopenia and TyG-BMI, as well as the AIP index, was examined through the utilization of restricted cubic spline (RCS) analysis, subgroup analysis, and multivariate logistic regression analysis. Diagnostic value of AIP and TyG-BMI for sarcopenia was compared by receiver operating characteristic (ROC) curves. Results: In this research, 428 people with sarcopenia were identified among the 4,835 subjects that were included in the experiment. AIP and sarcopenia were positively associated with an odds ratio (OR) of 1.58 and a 95% confidence interval (CI) of (1.07, 2.34) on fully adjusted multivariate logistic regression analysis. Similarly, TyG-BMI and sarcopenia were positively associated with an OR of 8.83 and a 95% CI of (5.46, 14.26). AIP and sarcopenia had a non-linear positive connection (P-value<0.001, P-Nonlinear=0.010), while TyG-BMI and sarcopenia had a linear positive correlation (P-value<0.001, P-Nonlinear=0.064), according to RCS analysis. Subgroup analyses showed a significant interaction between TyG-BMI and sarcopenia due to gender (P = 0.023). ROC curves showed that TyG-BMI (AUC:0.738, 95% CI: 0.714 - 0.761) was more useful than AIP (AUC:0.648, 95% CI: 0.622 - 0.673) in diagnosing sarcopenia. Conclusion: In US adults aged 20-59 years, our study revealed a correlation between elevated AIP and TyG-BMI levels and heightened sarcopenia risk. Moreover, TyG-BMI has better diagnostic validity than AIP.