Atherosclerosis (AS) is one of the most common causes of death from cardiovascular disease, and low folic acid (FA) levels have been reported to be strongly associated with an increased risk of AS. We aimed to obtain causal estimates of the association between FA and AS and to quantify the mediating role of known modifiable risk factors. Based on the largest genome-wide association study (GWAS) from the IEU Open GWAS Project for all human studies, we conducted a two-sample Mendelian randomization (MR) study of genetically predicted FA and AS. A two-step MR design was then used to assess the causal mediating effect of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) on the relationship between FA and AS. This MR analysis showed that genetically determined FA levels [IVW: Odds Ratio (OR) = 0.623, 95% CI 0.421-0.924, P = 0.018] were associated with a reduced risk of AS. Inverse variance weighted (IVW) MR analysis also showed that genetically predicted FA was positively correlated with HDL-C levels (OR = 1.358, 95% CI 1.029-1.792, P = 0.031) and negatively correlated with LDL-C (OR = 0.956, 95% CI 0.920-0.994, P = 0.023) and TG levels (OR = 0.929, 95% CI 0.886-0.974, P = 0.003). LDL-C, HDL-C, and TG mediate 3.00%, 6.80%, and 4.40%, respectively, of the total impact of FA on AS. The combined effect of these three factors accounts for 13.04% of the total effect. Sensitivity analysis verifies the stability and reliability of the results. These results support a potential causal protective effect of FA on AS, with considerable mediation through many modifiable risk factors. Thus, interventions on levels of LDL-C, HDL-C, and TG have the potential to substantially reduce the burden of AS caused by low FA.

OBJECTIVE: Klotho is a protein that is closely related to human aging. Soluble Klotho (S-Klotho) is a circulating protein, and its level decreases in response to systemic inflammation. The relationship between the platelet/high-density lipoprotein cholesterol ratio (PHR), an emerging inflammatory index, and S-Klotho concentrations is still unclear. In addition, the mean platelet volume has been confirmed to have a significant negative association with S-Klotho concentrations, but the relationship between the platelet count (PC) and S-Klotho concentrations has not yet been reported.
METHODS: Data from individuals who participated in the National Health and Nutrition Examination Survey (NHANES) during the five cycles from 2007 to 2016 were retrieved for analysis. Linear regression, two-piecewise linear regression, and restricted cubic spline (RCS) methods were used to analyze the associations of the PHR index and its components with S-Klotho concentrations. In addition, subgroup analysis and effect modification tests were conducted.
RESULTS: A total of 11,123 participants (5463 men (48.17%)), with an average age of 56.2 years, were included. After full adjustment, the S-Klotho levels of participants in the highest quartile group of PHR (β: -51.19, 95% CI: -75.41 to -26.97, P < 0.001) and the highest quartile group of PC (β: -72.34, 95% CI: -93.32 to -51.37, P < 0.0001) were significantly lower than those in their respective lowest quartile groups, and a significant downward trend was presented among the four groups (P for trend < 0.05, respectively). However, high-density lipoprotein cholesterol (HDL-C) concentrations were not significantly associated with S-Klotho concentrations. RCS revealed that the PHR and PC were nonlinearly associated with S-Klotho concentrations; two-piecewise linear regression revealed that the inflection points were 175.269 and 152, respectively, and that these associations slightly weakened after the inflection point. According to the subgroup analysis, liver disease status enhanced the association between the PC and S-Klotho concentrations.
CONCLUSIONS: Both the PHR and PC were significantly negatively associated with S-Klotho concentrations, and these associations were nonlinear. There was no significant association between HDL-C and S-Klotho concentrations. Liver disease status enhances the negative association between the PC and S-Klotho concentrations, and the specific mechanism deserves further exploration.

Metabolic syndrome has been associated with reduced brain white matter integrity in older individuals. However, less is known about how metabolic syndrome might impact white matter integrity in younger populations. This study examined metabolic syndrome-related global and regional white matter integrity differences in a sample of 537 post-9/11 Veterans. Metabolic syndrome was defined as ≥3 factors of: increased waist circumference, hypertriglyceridemia, low high-density lipoprotein cholesterol, hypertension, and high fasting glucose. T1 and diffusion weighted 3 T MRI scans were processed using the FreeSurfer image analysis suite and FSL Diffusion Toolbox. Atlas-based regions of interest were determined from a combination of the Johns Hopkins University atlas and a Tract-Based Spatial Statistics-based FreeSurfer WMPARC white matter skeleton atlas. Analyses revealed individuals with metabolic syndrome (n = 132) had significantly lower global fractional anisotropy than those without metabolic syndrome (n = 405), and lower high-density lipoprotein cholesterol levels was the only metabolic syndrome factor significantly related to lower global fractional anisotropy levels. Lobe-specific analyses revealed individuals with metabolic syndrome had decreased fractional anisotropy in frontal white matter regions compared with those without metabolic syndrome. These findings indicate metabolic syndrome is prevalent in this sample of younger Veterans and is related to reduced frontal white matter integrity. Early intervention for metabolic syndrome may help alleviate adverse metabolic syndrome-related brain and cognitive effects with age.

UNASSIGNED: Cardiovascular disease (CVD) and depression have a bidirectional association, with inflammation and metabolic factors being common important triggers for both conditions. However, as a novel inflammatory and metabolic marker, platelet-to-HDL-C ratio (PHR) has not been established in relation to depression and cardiovascular disease.
UNASSIGNED: Participants aged 20 years and older were included in the 2005-2018 NHANES database. PHR was calculated as the ratio of platelet count (1000 cells/μL) to HDL-C (mmol/L). The Patient Health Questionnaire (PHQ-9) was used to diagnose depression, with a cutoff value of 10. Weighted logistic regression analysis and restricted cubic spline (RCS) analysis were employed to examine the association between PHR and depression-related features. Additionally, weighted COX regression and RCS were used to analyze the association of PHR with CVD mortality in patients with depression. Receiver operating characteristic curves were used to assess whether PHR had an advantage over HDL-C in predicting depression. Finally, the mediating role of PHR in the latest cardiovascular health indicator Life\'s Essential 8 and depression was explored.
UNASSIGNED: A total of 26,970 eligible participants were included, including 2,308 individuals with depression, representing approximately 160 million U.S. adults when weighted. After full adjustment, we estimated that the odds ratio (OR) of depression associated with a per standard deviation (SD) increase in PHR was 1.06 (95% CI: 1.01-1.12, P=0.03). The restricted cubic spline (RCS) analysis indicated a linear association (Nonlinear P=0.113). When PHR was divided into four groups based on quartiles and included in the model after full adjustment for depression risk factors, participants in quartile 2, quartile 3, and quartile 4 of PHR showed a trend of increasing risk of depression compared to the lowest quartile group (P trend=0.01). In addition, weighted COX regression and RCS revealed that a per SD increase in PHR was associated with a higher risk of CVD mortality among patients with depression (HR: 1.38, 95% CI: 1.05-1.81, P=0.02, Nonlinear P=0.400). Subgroup analyses showed that current alcohol consumption enhanced the association between PHR and depression (P for interaction=0.017). Furthermore, the areas under the ROC curves (AUC) were 0.556 (95% CI, 0.544-0.568; P < 0.001) for PHR and 0.536 (95% CI, 0.524-0.549; P < 0.001) for HDL-C (PDeLong = 0.025). Finally, mediation analysis indicated that PHR was an intermediate mechanism between LE8 and depression (mediation proportion=5.02%, P=0.02).
UNASSIGNED: In U.S. adults, an increase in PHR linearly increases the risk of depression and CVD mortality among individuals with depression. Additionally, PHR has a better predictive advantage for depression compared to HDL-C. Furthermore, PHR significantly mediates the association between LE8 scores and depression.

UNASSIGNED: This study aims to explore the relationship between cardiovascular calcification (CVC) and serum levels of high-density lipoprotein cholesterol (HDL-C) and its subfractions in hemodialysis (HD) patients.
UNASSIGNED: HD patients and healthy participants were recruited based on specific inclusion and exclusion criteria. Various blood indicators were measured, and demographic information was recorded. HDL-C particle levels were quantified using lipophilic fluorescent dye staining and capillary electrophoresis (microfluidic platform). Coronary artery calcium scores and valve calcification were used to classify HD patients into calcification and non-calcification groups.
UNASSIGNED: Compared to healthy participants, HD patients showed a significant increase in HDL-C, high-density lipoprotein 2 cholesterol (HDL2-C), and high-density lipoprotein 3 cholesterol (HDL3-C) levels (p < 0.001). Further division of HD patients into calcification and non-calcification groups revealed higher serum HDL3-C concentrations (p = 0.002) and a higher HDL3-C/HDL-C ratio (p = 0.04) in the calcification group. Additionally, elevated HDL3-C levels were found to be an independent risk factor for CVC in HD patients (p = 0.040). The ROC curve analysis showed an AUC value of 0.706 for HDL3-C (p = 0.002).
UNASSIGNED: Our study indicates that elevated serum HDL3-C levels in HD patients are an independent risk factor for CVC and can serve as a potential predictor for CVC events. However, more studies need to verify its potential as a predictive indicator..

UNASSIGNED: The occurrence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. The link between serum remnant cholesterol (RC) to high-density lipoprotein cholesterol (HDL-C) ratio and NAFLD remains unclear. Therefore, we sought to clarify the relationship between the RC/HDL-C ratio and the NAFLD.
UNASSIGNED: Data for our cross-sectional study came from the 2017-2018 National Health and Nutrition Examination Survey (NHANES) with 2,269 participants. Associations between RC/HDL-C levels and the prevalence of NAFLD and hepatic fibrosis were evaluated using adjusted multivariate logistic regression analyses. A generalized additive model examined the non-linear relationship between RC/HDL-C and the probability of developing NAFLD.
UNASSIGNED: Among 2,269 participants, 893 (39.36%) were diagnosed with NAFLD. In each of the three models, RC/HDL-C and NAFLD had a strong positive statistical relationship: model 1 (OR = 9.294, 95%CI: 6.785, 12.731), model 2 (OR = 7.450, 95%CI: 5.401, 10.278), and model 3 (OR = 2.734, 95%CI: 1.895, 3.944). In addition, the subgroup analysis by gender and BMI suggested that RC/HDL-C showed a positive correlation with NAFLD. The RC/HDL-C ratio was positively correlated with the degree of liver steatosis. There was an inverted U-shaped connection between the prevalence of NAFLD and RC/HDL-C, with an inflection point of 0.619 for all participants and 0.690 for men. Receiver operating characteristic (ROC) analysis showed that the predictive value of RC/HDL-C for NAFLD (area under the curve: 0.7139; 95%CI: 0.6923, 0.7354; P < 0.001), was better than traditional lipid parameters.
UNASSIGNED: Increased RC/HDL-C levels are independently associated with an increased risk of NAFLD and the severity of liver steatosis in the American population. In addition, the RC/HDL-C ratio can be used as a simple and effective non-invasive biomarker to identify individuals with a high risk of NAFLD.

BACKGROUND: There may be severe difficulties in determining the severity of LMCA (left main coronary artery) lesions. The use of intravascular ultrasound (IVUS) facilitates decisions about lesion severity in these patients. The aim of this study was to investigate the relationship between the UHR (uric acid to HDL-C ratio) and lesion severity in patients who underwent LMCA IVUS.
METHODS: This study included 205 patients with ICS (intermediate coronary stenosis) in the LMCA who underwent IVUS. In the IVUS measurements of these patients, the plaque burden (PB) and the minimal lumen area (MLA) showing lesion severity were measured.
RESULTS: The patients were separated into two groups according to plaque burden (< 65% and ≥ 65%). The UHR was significantly greater in the high plaque burden group (479.5 vs. 428.6, P = 0.001). When the patients were separated into two groups according to the MLA (< 6mm2 and ≥ 6mm2), the UHR was determined to be significantly greater in the group with low MLA (476.8 vs. 414.9, P < 0.001). In the ROC analysis performed according to the MLA and plaque burden values, the UHR cutoff value of 450 was found to have similar sensitivity and the same specificity for both parameters.
CONCLUSIONS: The results of this study suggested that there is a relationship between UHR and MLA < 6mm2 and plaque burden ≥ 65%, which are independently evaluated as critical in IVUS, and this could predict anatomically significant lesions in patients with a moderate degree of LMCA stricture.

BACKGROUND: The prognosis of idiopathic pulmonary fibrosis (IPF) patients is highly heterogeneous. Abnormalities in lipids and their metabolism play an important role in the development of IPF.
OBJECTIVE: To investigate the value of lipid parameters, C-reactive protein (CRP), and high-density lipoprotein cholesterol/C-reactive protein (HDL-C/CRP) ratio levels in the prognosis of IPF patients.
METHODS: An observational cohort study.
METHODS: We collected baseline data of non-IPF controls and IPF patients, and IPF patients were followed up for 4 years. All-cause death or lung transplantation and IPF-related death were the outcome events. Receiver operating characteristic (ROC) curves and Cox proportional hazards models were used to analyze the predictive effect of lipid parameters, CRP and HDL-C/CRP ratio on the prognosis of IPF patients.
RESULTS: IPF patients had lower HDL-C, HDL-C/CRP ratio and higher CRP compared to non-IPF controls. IPF patients who died or underwent lung transplantation were older and had worse pulmonary function, lower HDL-C, HDL-C/CRP ratio and higher CRP compared with surviving patients. HDL-C/CRP ratio was better than HDL-C and CRP in predicting all-cause death or lung transplantation. IPF patients with low HDL-C/CRP ratio had shorter survival times. HDL-C/CRP ratio and DLCO% of predicted were independent protective factors for all-cause death or lung transplantation and IPF-related death in IPF patients, while age and GAP stage ≥ 2 (HR = 4.927)were independent risk factors for all-cause death or lung transplantation. Age > 65 years (HR = 3.533) was an independent risk factor for IPF-related death.
CONCLUSIONS: HDL-C/CRP ratio was a valid predictor of clinical outcomes in IPF patients, including all-cause death or lung transplantation and IPF-related death.

The protective effect of high-density lipoprotein (HDL) on atherosclerosis is well known, and its mechanisms of action has been extensively studied. However, the impact of HDL on heart failure and its mechanisms are still controversial or unknown. The cardioprotective role of HDL may be reflected in its antioxidant, anti-inflammatory, anti-apoptotic, and endothelial function protection. In epidemiological studies, high-density lipoprotein cholesterol (HDL-C) levels have been negatively associated with heart failure (HF). The major protein component of HDL-C is apolipoprotein (Apo) A-I, while paraoxonase-1 (PON-1) is an essential mediator for many protective functions of HDL, and HDL may act through components like (Apo) A-I or PON-1 to delay heart failure progress. HDL can slow heart failure disease progression through parts like (Apo) A-I or PON-1. The potential causality between HDL and heart failure, the role of HDL in the pathogenesis of HF, and its interaction with C-reactive protein (CRP), triglycerides (TG), and monocytes in the process of heart failure have been briefly summarized and discussed in this article. HDL plays an important role in the pathogenesis, progression and treatment of HF.

UNASSIGNED: This study aimed to explore the association between the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and the risk and severity of CHD among NAFLD patients.
UNASSIGNED: This retrospective study included 278 patients with NAFLD and chest pain. The TG/HDL-C ratio was calculated and coronary angiography performed. All individuals were divided into NAFLD + CHD and NAFLD groups. The severity of coronary artery stenosis is quantified using the Gensini score based on angiographic results. In NAFLD patients, the association between the TG/HDL-C ratio and the risk and severity of CHD was explored.
UNASSIGNED: CHD was detected in 139 of 278 patients. Compared to NAFLD group, multivariate logistic regression showed that TG/HDL-C ratio was a risk factor for CHD among NAFLD patients after adjustment for confounding factors with the odds ratio (OR 1.791, 95% CI 1.344-2.386, P<0.001). Further analysis using multivariate logistic regression based on tertiles revealed that, after adjusting for confounding factors, compared to the T1 group, the risk of CHD in the T2 group was 2.17-fold higher (OR, 2.17; 95% CI, 1.07-4.38; P = 0.031). Similarly, the risk of CHD in the T3 group increased by 2.84-fold (OR, 2.84; 95% CI, 1.36-5.94; P = 0.005). The multifactor linear regression analysis showed each 1-unit increase in TG/HDL-C ratio in the NAFLD + CHD group was associated with a 7.75-point increase in Gensini score (β=7.75, 95% CI 5.35-10.15, P<0.001).
UNASSIGNED: The TG/HDL-C ratio was positively correlated with CHD risk and reflected coronary atherosclerosis severity in NAFLD patients.