Cognitive impairment and depression precede increased HDL-C levels in middle-aged and older Chinese adults: cross-lagged panel analyses.

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) is widely recognized for its protective effects against cognitive decline. However, recent studies have presented conflicting results, with some suggesting no significant cognitive benefits or even an increased risk of dementia associated with high HDL-C levels. For those who suffer from depression, the cognitive benefits of HDL-C may be diminished or reversed. The purpose of this study is to investigate the associations between HDL-C, cognitive ability, and depressive symptoms in middle-aged and older Chinese adults. METHODS: The datasets utilized were sourced from the China Health and Retirement Longitudinal Study (CHARLS) for the years 2011 and 2015, comprising 4,302 participants. Cross-lagged models were employed to explore the temporal sequence between cognitive performance and HDL-C levels, and to examine the interplay among depression, cognition, and HDL-C. Confounding factors such as sociodemographic characteristics, sleep conditions, and history of chronic diseases were controlled for. RESULTS: The analysis revealed unidirectional effects of baseline impaired cognition and greater severity of depression on increased HDL-C levels at follow-up (ß = - 0.036 and ß = 0.028, respectively, P < 0.05). However, higher baseline HDL-C levels did not significantly predict cognitive performance or depression 4 years later (ß = - 0.008 and ß = 0.023, respectively, P > 0.05). Depressive symptoms and cognition were found to have a significant bidirectional association (ß = - 0.026 and ß = - 0.053, respectively, P < 0.05). CONCLUSIONS: Cognitive impairment and depression are associated with higher HDL-C levels, whereas higher HDL-C levels do not appear to protect against cognitive decline or depressive symptoms. These findings underscore the importance of preserving cognitive and mental health, which may lower the likelihood of cardiovascular disease and dementia. Future studies should validate these findings and develop targeted interventions tailored to specific populations.

Non-linear association of the platelet/high-density lipoprotein cholesterol ratio with bone mineral density a cross-sectional study.

BACKGROUND: Numerous studies have demonstrated shared risk factors and pathophysiologic mechanisms between osteoporosis and cardiovascular disease. High-density lipoprotein cholesterol (HDL-C) and platelets have long been recognized as crucial factors for cardiovascular health. The platelet to HDL-C ratio (PHR) combines platelet count and high-density lipoprotein cholesterol (HDL-C) level, It is a novel biomarker for metabolic syndrome and cardiovascular disease. The platelet to HDL-C ratio (PHR) possibly reflects the balance between proinflammatory and anti-inflammatory states in the body. Therefore, we hypothesized that changes in PHR ratios may predict a predisposition to pro-inflammatory and increased bone resorption. However, the relationship between the platelet to HDL-C ratio (PHR) and bone mineral density (BMD) remains insufficiently understood. This study aimed to elucidate the relationship between the platelet to HDL-C ratio (PHR) index and bone mineral density (BMD). METHODS: Data from the NHANES 2005-2018 were analyzed, excluding adults with missing key variables and specific conditions. Nonlinear relationships were explored by fitting smoothed curves and generalized additive models, with threshold effects employed to calculate inflection points. Additionally, subgroup analyses and interaction tests were conducted. RESULTS: The study included 13,936 individuals with a mean age of 51.19 ± 16.65 years. Fitted smoothed curves and generalized additive models revealed a nonlinear, inverted U-shaped relationship between the two variables. Threshold effect analysis showed a significant negative association between PHR and total femur bone mineral density (BMD) beyond the inflection point of platelet to HDL-C ratio (PHR) 33.301. Subgroup analyses showed that a significant interaction between these two variables was observed only in the age and sex subgroups (P-interaction < 0.05). CONCLUSIONS: Our study identified a complex, nonlinear, inverted U-shaped relationship between platelet to HDL-C ratio (PHR) and total femur bone mineral density (BMD). These findings underscore the importance of maintaining optimal PHR levels to support bone health, especially in high-risk populations.

Polygenic risk of high LDL cholesterol and ischemic heart disease in the general population.

BACKGROUND AND AIMS: We tested the association of polygenic risk scores (PRS) for low-density lipoprotein cholesterol (LDL-C) and coronary artery disease (CAD) with LDL-C and risk of ischemic heart disease (IHD) in the Danish general population. METHODS: We included a total of 21,485 individuals from the Copenhagen General Population Study and Copenhagen City Heart Study. For everyone, LDL-PRS and CAD-PRS were calculated, each based on >400,000 variants. We also genotyped four rare variants in LDLR or APOB known to cause familial hypercholesterolemia (FH). RESULTS: Heterozygous carriers of FH-causing variants in APOB or LDLR had a mean LDL-C of 5.40 and 6.09 mmol/L, respectively, and an odds ratio for IHD of 2.27 (95 % CI 1.43-3.51) when compared to non-carriers. The LDL-PRS explained 13.8 % of the total variation in LDL-C in the cohort. Individuals in the lowest and highest 1 % of LDL-PRS had a mean LDL-C of 2.49 and 4.75 mmol/L, respectively. Compared to those in the middle 20-80 %, those in the lowest and highest 1 % of LDL-PRS had odds ratios for IHD of 0.58 (95 % CI, 0.38-0.88) and 1.83 (95 % CI, 1.33-2.53). The corresponding odds ratios for CAD-PRS were 0.61 (95 % CI, 0.41-0.92) and 2.06 (95 % CI, 1.49-2.85). CONCLUSIONS: The top 1 % of LDL-PRS and CAD-PRS conferred effects on LDL-C and risk of IHD comparable to those seen for carriers of rare FH-causing variants in APOB or LDLR. These results highlight the potential value of implementing such PRS clinically.

Bone turnover: the role of lipoproteins in a population-based study.

BACKGROUND: Dyslipidemia has been associated with reduced bone mineral density and osteoporotic fractures, but the relation between lipid and bone metabolism remains poorly understood. Analysing the effects of lipoprotein subclasses on bone turnover may provide valuable insights into this association. We therefore examined whether lipoprotein subclasses, measured by proton nuclear magnetic resonance (1H-NMR) spectroscopy, are associated with bone turnover markers (BTMs) and with the ultrasound-based bone stiffness index. METHODS: Data from 1.349 men and 1.123 women, who participated in the population-based Study of Health in Pomerania-TREND were analysed. Serum intact amino-terminal propeptide of type I procollagen (P1NP, bone formation) and carboxy-terminal telopeptide of type I collagen (CTX, bone resorption) concentrations were measured. Associations between the lipoprotein data and the BTMs or the stiffness index were investigated using linear regression models. RESULTS: The triglyceride or cholesterol content in very-low-density lipoprotein and intermediate-density lipoprotein particles was inversely associated with both BTMs, with effect estimates being slightly higher for CTX than for P1NP. The triglyceride content in low-density lipoprotein and high-density lipoprotein particles and the Apo-A2 content in high-density lipoprotein particles was further inversely associated with the BTMs. Associations with the ultrasound-based bone stiffness index were absent. CONCLUSIONS: Consistent inverse associations of triglycerides with bone turnover were observed, which argue for a protective effect on bone health, at least in the normal range. Yet, the presented associations did not translate into effects on the ultrasound-based bone stiffness. Further, there was no relevant gain of information by assessing the lipoprotein subclasses. Nevertheless, our study highlights the close relations between lipid and bone metabolism in the general population.

Increased oxidative stress biomarkers in central serous chorioretinopathy.

Current data suggest that oxidative stress may play an important role in the occurrence of acute central serous chorioretinopathy (CSC), as chorioretinal integrity may be affected by disruption of the patient's metabolic redox balance, indicating the need for biomarkers. In addition to oxidative stress, high-density lipoprotein (HDL) dysfunction due to dyslipidemia can also lead to many types of physical discomfort. However, little is known about the pathophysiology of the disease resulting from oxidative stress and HDL dysfunction in CSC. The aim of this study was to investigate whether serum oxidative stress and HDL functionality markers have an impact on CSC disease. The case series of this study included 33 consecutive patients with treatment-naïve acute CSC. Thirty-five healthy volunteers of similar age were included in this study as non-CSC controls. Serum samples of the participants were taken and routine lipid values, serum Total Antioxidant Status (TAS), Total Oxidant Status (TOS), Oxidized Low Density Lipoprotein (ox-LDL), and Paraoxonase (PON1) levels were measured quantitatively. Serum oxidative stress index (OSI) was then calculated. Serum Ox-LDL, TOS and OSI levels in the acute CSC group, consisting of patients who had never been treated before and had no other disease, were statistically significantly higher than the control group. Conversely, serum PON1 and TAS levels were lower in CSC than in the control group. The relationship between CSC and deterioration in serum redox balance and decrease in PON1 activity, an important marker of HDL functionality, was demonstrated for the first time through this study. According to the literature, serum levels of these biomarkers, which identify acute/chronic inflammation and oxidative stress, have not been measured before in CSC disease. Finally, it is conceivable that redox balance and HDL functionality may be important in the diagnosis and treatment of the acute phase of CSC.

Real-world experience of inclisiran prescription at the University of Pennsylvania Health Systems.

Inclisiran is a novel small interfering RNA targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) that was approved by the US FDA in December 2021. After two doses three months apart, it is administered biannually as a subcutaneous injection and has been shown to lower LDL-C by ∼50 % in clinical trials. Here, we present real-world data on the prescription and administration of inclisiran at the University of Pennsylvania Health Systems. Over a 2-year period, there were 243 patients who were prescribed inclisiran, of whom 153 were approved by insurance and initiated therapy. Approved patients were disproportionately Medicare enrollees and more likely to have a history of ASCVD. Mean post-treatment LDL-C for patients who received at least two doses was 74.7 ± 45.6 mg/dL. For patients new to PCSK9-targeted therapy, a reduction in LDL-C of ∼50 % was observed after initiating inclisiran, supporting clinical trial results. 60 % of patients with ASCVD achieved an LDL-C level of <70 mg/dL after adding inclisiran.

Association Between Lipoprotein(a) and Obstructive Coronary Artery Disease and High-Risk Plaque: Insights From the PROMISE Trial.

The role of lipoprotein (a) (Lp[a]) in the development of obstructive coronary artery disease (CAD) and high-risk plaque (HRP) in primary prevention patients with stable chest pain is unknown. We sought to evaluate the relation of Lp(a), independent of low-density lipoprotein cholesterol (LDL-C), with the presence of obstructive CAD and HRP to improve understanding of the residual risk imparted by Lp(a) on CAD. We performed a secondary analysis in Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) Trial participants who had coronary computed tomographic angiography (CTA) performed and Lp(a) data available. Lp(a) concentration was analyzed as a binary variable, with elevated Lp(a) defined as ≥50 mg/100 ml. "Stenosis ≥50%" was defined as ≥50% coronary artery stenosis in any epicardial vessel, and "stenosis ≥70%" was defined as ≥70% coronary artery stenosis in any epicardial vessel and/or ≥50% left main coronary artery stenosis. HRP was defined as presence of plaque on CTA imaging with evidence of positive remodeling, low computed tomography attenuation, or napkin-ring sign. Multivariate logistic regression models were constructed to evaluate the association between Lp(a) and the outcomes of obstructive CAD and HRP stratified by LDL-C ≥100 versus <100 mg/100 ml. Of the 1,815 patients who underwent CTA and had Lp(a) data available, those with elevated Lp(a) were more commonly women and Black than those with lower Lp(a). Elevated Lp(a) was associated with stenosis ≥50% (odds ratio 1.57, 95% confidence interval 1.14 to 2.15, p = 0.005) and stenosis ≥70% (odds ratio 2.05, 95% confidence interval 1.34 to 3.11, p = 0.0008) in the multivariate models, and this relation was not modified by LDL-C ≥100 versus <100 mg/100 ml (interaction p >0.4). Elevated Lp(a) was not associated with HRP when adjusted for obstructive CAD. This study of patients without known CAD found that elevated Lp(a) ≥50 mg/100 ml was independently associated with the presence of obstructive CAD regardless of controlled versus uncontrolled LDL-C but was not independently associated with HRP when stenosis ≥50% or ≥70% was accounted for. Further research is warranted to delineate the role of Lp(a) in the residual risk for atherosclerotic cardiovascular disease that patients may have despite optimal LDL-C lowering.

Lipoprotein(a) in interventional cardiology: identifying patients at highest risk of recurrent cardiovascular events through early recognition - a case based review.

INTRODUCTION: Lipoprotein(a) [Lp(a)] is linked to higher risks of atherosclerotic cardiovascular disease (ASCVD). Current guideline recommendations are quite liberal on measuring Lp(a) (Class IIa, Level C), and may lead to underuse among (interventional) cardiologists. AREAS COVERED: This case-based narrative review outlines four clinical cases of patients with elevated Lp(a) to illustrate its pathophysiological impact on coronary artery disease (CAD). The expert consensus statements from the American Heart Association (AHA) and European Atherosclerosis Society (EAS) served as the basis of this review. More recent publications, from 2023 to 2024, were accessed through the MEDLINE online library. EXPERT OPINION: We highlighted the importance of routine Lp(a) measurement in identifying patients at high risk for atherosclerosis, necessitating potent risk mitigation. Measuring Lp(a) helps clinicians identify which patients are at highest residual risk, who require potent pharmacological treatment and special attention during catheter interventions. As noninvasive and advanced intravascular imaging modalities evolve, future catheterization laboratories will integrate advanced imaging, diagnostics, and treatment, facilitating tailored patient care. Knowing Lp(a) levels is crucial in this context. While Lp(a)-lowering drugs are currently investigated in clinical trials, it is of paramount importance to know Lp(a) levels and strive toward aggressive management of other modifiable risk factors in patients with elevated Lp(a) and established symptomatic CAD being diagnosed or treated in catheterization laboratories.

Is There a Need for Sex-Tailored Lipoprotein(a) Cut-Off Values for Coronary Artery Disease Risk Stratification?

BACKGROUND: Lipoprotein(a) [Lp(a)] plasma level is a well-known risk factor for coronary artery disease (CAD). Existing data regarding the influence of sex on the Lp(a)-CAD relationship are inconsistent. OBJECTIVE: To investigate the relationship between Lp(a) and CAD in men and women and to elucidate any sex-specific differences that may exist. METHODS: Data of patients with Lp(a) measurements who were admitted to a tertiary university hospital, Koc University Hospital, were analyzed. The relationship between Lp(a) levels and CAD was explored in all patients and in subgroups created by sex. Two commonly accepted Lp(a) thresholds ≥ 30 and ≥ 50 mg/dL were analyzed. RESULTS: A total of 1858 patients (mean age 54 ± 17 years; 53.33% females) were included in the analysis. Lp(a) was an independent predictor of CAD according to the multivariate regression model for the entire cohort. In all cohort, both cut-off values (≥ 30 and ≥ 50 mg/dL) were detected as independent predictors of CAD (p < 0.001). In sex-specific analysis, an Lp(a) ≥ 30 mg/dL was an independent predictor of CAD only in women (p < 0.001), but Lp(a) ≥ 50 mg/dL was a CAD predictor both in men and women (men, p = 0.004; women, p = 0.047). CONCLUSION: The findings of this study may suggest that different thresholds of Lp(a) level can be employed for risk stratification in women compared to men.

First patient diagnosed with lipoprotein glomerulopathy and Alport syndrome.

Alport syndrome (AS) is one of the most common inherited kidney disorders, involving pathogenic variants of COL4A3, COL4A4 and COL4A5 genes that lead to disruption of the normal structure of collagen IV protein through improper chain or heterotrimer folding or degradation of heterotrimer components. Lipoprotein glomerulopathy (LPG) is an autosomal dominant disease involving APOE gene mutations disturbing lipoprotein metabolism. We report the first case with both AS and LPG in an 11-year-old girl. The patient presented with blepharedema, and decreased vision. Laboratory examinations showed hematemesis, proteinuria, hypoproteinemia, hyperlipidemia and progressive renal failure. Renal biopsy showed the changes of LPG and AS. Whole-exome sequencing (WES) identified two pathogenic variants, c.127C > T in exon 3 of APOE gene, and c.930 + 1G > A in exon 15 of COL4A4 gene. We emphasize the importance of early completion of renal biopsy and WES for early diagnosis of LPG and AS.

Association of lipid levels at different stages of pregnancy with gestational diabetes mellitus and the incidence of neonatal macrosomia: A retrospective study.

OBJECTIVE: To investigate the correlation between lipid levels during gestation and the incidence rate of gestational diabetes mellitus (GDM) and macrosomia. METHOD: Clinical records of 607 pregnant women with GDM (GDM group) who delivered in the Obstetrics Department of Fujian Maternal and Child Health Hospital from May to December 2018 and of 833 women with uncomplicated pregnancies (control group) were retrospectively analyzed. After delivery, the entire cohort was further grouped based on the weight of the neonates: women who delivered newborns with body mass <4 kg comprised the normal group (n = 1367), and pregnancies that resulted in delivery of neonates with body mass >4 kg were classified as the macrosomia group (n = 73). Fasting serum levels of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and TG/HDL-C ratio were compared between the groups at the early (10-12 weeks), middle (24-28 weeks), and late (28 weeks-delivery) stages of pregnancy, and the correlation between the lipid indices and the rates of GDM and macrosomia were analyzed. RESULTS: There was a gradual increase in TC, TG, LDL-C, and TG/HDL-C levels with increasing gestational weeks in pregnant women. TG and TG/HDL-C levels were markedly higher, while HDL-C was lower in women with GDM compared with women of the same gestational age with uncomplicated pregnancies (p < 0.05). CONCLUSION: Lipid metabolism disorders exist in pregnant women with GDM at different gestational stages and are closely related to the higher incidence of macrosomia. TG, TG/HDL-C, and HDL-C in early and late pregnancy are independent risk factors for macrosomia in all trimesters, and TG/HDL-C ratio at different gestational stages has a good predictive value for macrosomia.

A comprehensive analysis of the role of native and modified HDL in ER stress in primary macrophages.

Introduction: Recent findings demonstrate that high density lipoprotein (HDL) function rather than HDL-cholesterol levels themselves may be a better indicator of cardiovascular disease risk. One mechanism by which HDL can become dysfunctional is through oxidative modification by reactive aldehydes. Previous studies from our group demonstrated that HDL modified by reactive aldehydes alters select cardioprotective functions of HDL in macrophages. To identify mechanisms by which dysfunctional HDL contributes to atherosclerosis progression, we designed experiments to test the hypothesis that HDL modified by reactive aldehydes triggers endoplasmic reticulum (ER) stress in primary murine macrophages. Methods and results: Peritoneal macrophages were harvested from wild-type C57BL/6J mice and treated with thapsigargin, oxLDL, and/or HDL for up to 48 hours. Immunoblot analysis and semi-quantitative PCR were used to measure expression of BiP, p-eIF2α, ATF6, and XBP1 to assess activation of the unfolded protein response (UPR). Through an extensive set of comprehensive experiments, and contrary to some published studies, our findings led us to three novel discoveries in primary murine macrophages: (i) oxLDL alone was unable to induce ER stress; (ii) co-incubation with oxLDL or HDL in the presence of thapsigargin had an additive effect in which expression of ER stress markers were significantly increased and prolonged as compared to cells treated with thapsigargin alone; and (iii) HDL, in the presence or absence of reactive aldehydes, was unable blunt the ER stress induced by thapsigargin in the presence or absence of oxLDL. Conclusions: Our systematic approach to assess the role of native and modified HDL in mediating primary macrophage ER stress led to the discovery that lipoproteins on their own require the presence of thapsigargin to synergistically increase expression of ER stress markers. We further demonstrated that HDL, in the presence or absence of reactive aldehydes, was unable to blunt the ER stress induced by thapsigargin in the presence or absence of oxLDL. Together, our findings suggest the need for more detailed investigations to better understand the role of native and modified lipoproteins in mediating ER stress pathways.

Association between non-high-density lipoprotein cholesterol and type 2 diabetes: a systematic review and meta-analysis of cohort studies.

Non-high-density lipoprotein cholesterol (non-HDL), a more readily available and reliable lipid parameter, is unclear in its association with type 2 diabetes (T2D). Previous studies assessing the relationship between non-HDL and T2D risk remains inconsistent results. We performed a meta-analysis to systematically evaluate this association. The PubMed, EMBASE, Medline, Web of Science, and Cochrane Library databases were systematically searched to find articles on "non-HDL" and "T2D" from inception to December 6, 2023. A random-effects model was used to calculate the effect estimates and 95% confidence intervals. Subgroup analyses and univariate Meta-regression were performed to explore sources of heterogeneity. The main exposure and outcome were non-HDL and T2D, respectively, in the general population. A total of 8 studies included 251,672 participants who met the inclusion criteria for this study. Meta-analysis showed that higher non-HDL increased the risk of T2D compared with the lower non-HDL group (total effect size: 1.16; 95% CI 1.079-1.251, p < 0.001). Subgroup analyses and Meta-regression of the association between non-HDL and T2D were not affected by region, proportion of men, sample size, or adjustment for confounders (including BMI, hypertension, waist circumference, and family history of diabetes). Higher non-HDL may be associated with an increased risk of T2D. Large prospective cohort studies are needed to validate these findings, and further studies are required in order to elucidate the underlying pathophysiologic mechanisms underlying the association between non-HDL and T2D.

Enhanced Plaque Stabilization Effects of Alirocumab　- Insights From Artificial Intelligence-Aided Optical Coherence Tomography Analysis of the Alirocumab for Thin-Cap Fibroatheroma in Patients With Coronary Artery Disease Estimated by Optical Coherence Tomography (ALTAIR) Study.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors stabilize vulnerable plaque, reducing cardiovascular events. However, manual optical coherence tomography (OCT) analysis of drug efficacy is challenging because of signal attenuation within lipid plaques. METHODS AND RESULTS: Twenty-four patients with thin-cap fibroatheroma were prospectively enrolled and randomized to receive alirocumab (75 mg every 2 weeks) plus rosuvastatin (10 mg/day) or rosuvastatin (10 mg/day) alone. OCT images at baseline and 36 weeks were analyzed manually and with artificial intelligence (AI)-aided software. AI-aided OCT analysis showed significantly greater percentage changes in the alirocumab+rosuvastatin vs. rosuvastatin-alone group in fibrous cap thickness (FCT; median [interquartile range] 212.3% [140.5-253.5%] vs. 88.6% [63.0-119.6%]; P=0.006) and lipid volume (median [interquartile range] -30.8% [-51.8%, -16.6%] vs. -2.1% [-21.6%, 4.3%]; P=0.015). Interobserver reproducibility for changes in minimum FCT and lipid index was relatively low for manual analysis (interobserver intraclass correlation coefficient [ICC] 0.780 and 0.499, respectively), but high for AI-aided analysis (interobserver ICC 0.999 and 1.000, respectively). Agreements between manual and AI-aided OCT analyses of FCT and the lipid index were acceptable (concordance correlation coefficients 0.859 and 0.833, respectively). CONCLUSIONS: AI-aided OCT analysis objectively showed greater plaque stabilization of adding alirocumab to rosuvastatin. Our results highlight the benefits of a fully automated AI-assisted approach for assessing drug efficacy, offering greater objectivity in evaluating serial changes in plaque stability vs. conventional OCT assessment.

Serum High-Density Lipoprotein Cholesterol Levels and the Risk of Kidney Function Decline: The Japan Specific Health Checkups (J­SHC) Study.

AIMS: Both low and high serum levels of high-density lipoprotein cholesterol (HDL-C) were reported to be associated with adverse kidney outcomes. However, this association has not been well investigated in the general Japanese population. METHODS: This nationwide longitudinal study used data from the Japan Specific Health Checkups Study conducted between 2008-2014. The association between serum HDL-C levels and 40% decline in estimated glomerular filtration rate (eGFR) was analyzed using Cox regression analysis. Trajectories of eGFR were compared using mixed-effects model. RESULTS: Among 768,495 participants, 6,249 developed 40% decline in eGFR during the median follow-up period of 34.6 (interquartile range: 14.8-48.4) months. Using serum HDL-C levels of 40-59 mg/dL as a reference, the adjusted hazard ratios (95% confidence intervals) for the kidney outcome of serum HDL-C levels of ＜40, 60-79 and ≥ 80 mg/dL were 1.26 (1.14-1.39), 0.91 (0.86-0.96), and 0.86 (0.78-0.93), respectively. Restricted cubic spline analysis showed that HDL-C levels of less than approximately 60 mg/dL were associated with an increased risk of kidney outcomes. Subgroup analysis showed that baseline eGFR and proteinuria modified the effects of serum HDL-C levels on kidney outcomes. The mixed-effects model showed that the lower category of HDL-C level was associated with a higher eGFR decline rate (p for interaction ＜0.001). CONCLUSIONS: Low HDL-C levels were associated with kidney function decline; however, high HDL-C levels were not associated with adverse kidney outcomes in the general Japanese population.

Association between cardiometabolic index and gestational diabetes mellitus: a cross-sectional study.

BACKGROUND: Cardiometabolic index (CMI) is a novel marker of diabetes mellitus. However, few studies have examined its association with gestational diabetes mellitus (GDM) risk. This study aimed to explore the association between CMI and GDM risk among pregnant women in the United States. METHODS: We performed a cross-sectional study utilizing data recorded in the National Health and Nutrition Examination Survey database from 1999 to 2018. Univariate and multivariate logistic regression, restricted cubic splines (RCS), sensitivity, and subgroup analyses were performed to clarify the relationship between CMI and GDM risk. RESULTS: A total of 710 pregnant women were recruited, among whom 113 were diagnosed with GDM based on established criteria. This population showed a significant association between a higher CMI value and GDM (odds ratio: 1.75, 95% confidence interval: 1.03-2.99, P = 0.038). RCS regression analysis identified a linear relationship between CMI and GDM (P-value < 0.001, P-nonlinear = 0.702). Sensitivity analysis further confirmed the validity of this relationship. Subgroup analysis indicated a positive association between CMI and GDM among women who drink or smoke and Mexican Americans. CONCLUSION: This study demonstrates a significant positive association between CMI and GDM risk, suggesting that a higher CMI predicts GDM incidence during pregnancy. Further research is required to investigate the CMI index as an early predictor of GDM.

High-resolution spiral microfluidic channel integrated electrochemical device for isolation and detection of extracellular vesicles without lipoprotein contamination.

Recent studies have indicated significant correlation between the concentration of immune checkpoint markers borne by extracellular vesicles (EVs) and the efficacy of immunotherapy. This study introduces a high-resolution spiral microfluidic channel-integrated electrochemical device (HiMEc), which is designed to isolate and detect EVs carrying the immune checkpoint markers programmed death ligand 1 (PD-L1) and programmed death protein 1 (PD-1), devoid of plasma-abundant lipoprotein contamination. Antigen-antibody reactions were applied to immobilize the lipoproteins on bead surfaces within the plasma, establishing a size differential with EVs. A plasma sample was then introduced into the spiral microfluidic channel, which facilitated the acquisition of nanometer-sized EVs and the elimination of micrometer-sized lipoprotein-bead complexes, along with the isolation and quantification of EVs using HiMEc. PD-L1 and PD-1 expression on EVs was evaluated in 30 plasma samples (10 from healthy donors, 20 from lung cancer patients) using HiMEc and compared to the results obtained from standard tissue-based PD-L1 testing, noting that HiMEc could be utilized to select further potential candidates. The obtained results are expected to contribute positively to the clinical assessment of potential immunotherapy beneficiaries.

Association between changes in high-density lipoprotein cholesterol and risk of cardiovascular disease.

BACKGROUND: The present study was performed to determine the association between changes in the HDL-C concentration and incident CVD. METHODS: Time-dependent Cox regression models were used to evaluate the association between changes in the HDL-C concentration and the risk of incident CVD. Participants were followed up from 2015 to 2021. RESULTS: In total, 24,123 participants with a median follow-up of 4.26 years were analyzed, and the mean age of the cohort was 56.24 years, 57.8 % were female, 24.3 % were current smokers, and 12.8 % had a history of alcohol use. Low, normal, and high HDL-C was defined as <40, 40-80, and >80 mg/dL, respectively. The average time for the two HDL-C measurements was 2.8 years,compared with participants whose HDL-C was maintained at a normal level, the risk of CVD was higher in those whose HDL-C changed to a low level, remained unchanged at a low level(HR, 1.24; 95 % CI, 1.01-1.40,P < 0.001), similarly, the risk of CVD was higher in those whose HDL-C changed from very high level to normal level(HR, 0.81; 95 % CI, 0.67-0.99,P = 0.039). Also compared with participants whose HDL-C was maintained at a normal level, the risk of CVD was lower in those whose HDL-C increased from low to normal and high(HR, 0.80; 95 % CI, 0.66-0.98,P = 0.029). CONCLUSIONS: Participants whose HDL-C changed to a low level and whose low HDL-C level was maintained had a higher risk of CVD, whereas participants whose HDL-C changed from low to high had a lower risk of CVD.

Evolution, Structure, and Drug-Metabolising Activity of Mammalian Prenylcysteine Oxidases.

Prenylcysteine oxidases (PCYOXs) metabolize prenylated cysteines produced by protein degradation. They utilize oxygen as co-substrate to produce free cysteine, an aldehyde, and hydrogen peroxide through the unusual oxidation of a thioether bond. In this study, we explore the evolution, structure, and mechanism of the two mammalian PCYOXs. A gene duplication event in jawed vertebrates originated these two paralogs. Both enzymes are active on farnesyl- and geranylgeranylcysteine, but inactive on molecules with shorter prenyl groups. Kinetics experiments outline a mechanism where flavin reduction and re-oxidation occur rapidly without any detectable intermediates, with the overall reaction rate limited by product release. The experimentally determined three-dimensional structure of PCYOX1 reveals long and wide tunnels leading from the surface to the flavin. They allow the isoprene substrate to curl up within the protein and position its reactive cysteine group close to the flavin. A hydrophobic patch on the surface mediates membrane association, enabling direct substrate and product exchange with the lipid bilayer. Leveraging established knowledge on flavoenzyme inhibition, we designed sub-micromolar PCYOX inhibitors. Additionally, we discovered that PCYOXs bind and slowly degrade salisirab, an anti-RAS compound. This activity suggests potential and previously unknown roles of PCYOXs in drug metabolism.

Relationship Between Control of Cardiovascular Risk Factors and Chronic Kidney Disease Progression, Cardiovascular Disease Events, and Mortality in Chinese Adults.

BACKGROUND: Patients with chronic kidney disease (CKD) are at an elevated risk of cardiovascular disease (CVD) and premature mortality compared to the general population. OBJECTIVES: This study aimed to investigate whether the excess risk of CVD events and death among patients with CKD could be reduced or eliminated through strict control of blood pressure (systolic blood pressure: <130 mm Hg), lipids (low-density lipoprotein cholesterol: <2.6 mmol/L), and glucose (fasting blood glucose: <6.1 mmol/L). METHODS: The authors included 20,254 patients with CKD who were free of CVD or end-stage renal disease and matched them with 35,236 control individuals based on age (±2 years) and sex from the Kailuan study. RESULTS: During a median follow-up period of 12.2 to 12.8 years, 3,875 deaths, 1,888 cases of stroke, 513 cases of myocardial infarction, and 4,825 cases of CKD progression were documented. Among patients with CKD, risk factor controls showed an association with a reduction in myocardial infarction, stroke, CKD progression, and all-cause mortality risk in a dose-dependent manner. Moreover, compared to the non-CKD control individuals, having all 3 risk factors within the target ranges could theoretically eliminate the excess risk of CVD and mortality associated with CKD. Among patients with CKD who had all 3 risk factors controlled, the HRs were 0.80 (95% CI: 0.56-1.14) for myocardial infarction, 0.93 (95% CI: 0.78-1.12) for stroke, and 1.10 (95% CI: 0.98-1.24) for all-cause mortality compared to the non-CKD control individuals. CONCLUSIONS: Patients with CKD who had controlled blood pressure, lipids, and glucose showed no excess risk of death, myocardial infarction, or stroke compared to the general population.