BACKGROUND:Cardiomyocytes exhibit marked susceptibility to ferroptosis after myocardial infarction (MI), rendering ferroptosis inhibition a promising therapeutic strategy to mitigate ischemic myocardial injury. Although mitochondrial dysfunction is recognized as a core driver of ferroptosis, the potential role of mitochondrial DNA transcription in regulating cardiomyocyte ferroptosis remains unexplored. METHODS:To clarify the temporal role of the various modes of cell death in MI progression, we performed time-course echocardiography in MI models treated with various cell death inhibitors. To characterize the crucial process and molecular regulator in cardiomyocyte ferroptosis, we integrated RNA sequencing and single-nucleus RNA sequencing data from murine post-MI hearts and performed functional rescue experiments using mitochondrial protective agents. To determine the role of ABHD11 (αβ-hydrolase domain-containing protein 11) in cardiomyocyte ferroptosis and cardiac repair after MI, we used loss- and gain-of-function approaches. To elucidate the underlying mechanisms, we conducted transcriptomics, nontargeted lipidomics, site-specific mutagenesis, molecular docking, coimmunoprecipitation, native gel electrophoresis, proximity ligation assay, methylation-specific polymerase chain reaction, and chromatin immunoprecipitation assay. RESULTS:We found that cardiac ferroptosis peaked at day 7 after MI and was enriched in peri-infarct cardiomyocytes. Mitochondrial dysfunction was a key driver of cardiomyocyte ferroptosis after MI, and the lipid enzyme ABHD11 was identified as a potential regulator of both processes. ABHD11 expression was consistently reduced in mouse and human MI hearts, and its transcription was repressed by DNMT1 (DNA methyltransferase 1)-mediated promoter hypermethylation. Functionally, cardiac-specific overexpression of ABHD11 markedly alleviated cardiomyocyte ferroptosis and improved cardiac function after MI. Conversely, loss of ABHD11 in adult mice exacerbated pathological cardiac remodeling and heart failure. Mechanistically, independent of its canonical enzymatic activities, ABHD11 acted as a mitochondrial DNA transcription coactivator by enhancing the TEFM (mitochondrial transcription elongation factor)-POLRMT (mitochondrial RNA polymerase) interaction. This promoted mitochondrial DNA transcription, restored mitochondrial function, and reduced reactive oxygen species/PUFA-PLs (polyunsaturated fatty acid-containing glycerophospholipids)-driven lipid peroxidation and 4-hydroxynonenal generation. The reduction in 4-hydroxynonenal stabilized YY1 (Yin Yang 1), which subsequently regulated key ferroptosis-driving genes governing iron deposition, reactive oxygen species production, and polyunsaturated fatty acid lipids accumulation, further inhibiting lipid peroxidation and ferroptosis, and ultimately promoting cardiac recovery after MI. CONCLUSIONS:This study revealed that ABHD11-mediated mitochondrial DNA transcription attenuated cardiomyocyte ferroptosis after MI by orchestrating a mitochondrial-nuclear crosstalk, offering a novel therapeutic strategy for ischemic myocardial injury.

BACKGROUND:We aimed to examine relationships between cumulative life-course burdens and trajectories of cardiovascular risk factors and midlife cognitive function in a longitudinal cohort of the Bogalusa Heart Study. METHODS:The study cohort consisted of 912 participants who had cognitive function measured in middle age, and body mass index, blood pressure (BP), atherogenic index of plasma, and LDLC (low-density lipoprotein cholesterol) examined 4 to 15 times from childhood to adulthood. Total and incremental area under the curve (AUC) were calculated as a measure of long-term burden and trend of risk factors, respectively. RESULTS:Trajectories of systolic BP were separated markedly around 25 to 45 years of age, with the group below the median of cognition score having higher levels of systolic BP than the group above the median. Adjusting for covariates, midlife cognitive function was associated with total and incremental AUCs of systolic BP. Standardized regression coefficients were -0.086 (95% CI, -0.161 to -0.010; P=0.027) for total AUC and -0.084 (95% CI, -0.144 to -0.017; P=0.007) for incremental AUC. These inverse associations were consistent across race and sex groups. Single measures of systolic BP in childhood and adulthood were not associated with midlife cognitive function. Single and long-term measures of body mass index, LDLC, and atherogenic index of plasma were not associated with midlife cognitive function, with the exception of the incremental AUC of body mass index. CONCLUSIONS:Data suggest that the impact of exposure to high BP on the brain accumulates across the lifespan. A life-course approach is superior in risk assessment for cognitive decline and dementia.

Although the relationships between birthweight, gestational age (GA), and cognitive function (CF) before midlife have been demonstrated, the relationships after midlife and potential racial disparities remain inconclusive. This study examined the association between birthweight, GA, and midlife CF stratified by race. 1,032 subjects from the Bogalusa Heart Study (67

The cardiometabolic index (CMI) is a marker for evaluating visceral adipose distribution and lipid metabolism. This index is useful for detecting metabolic diseases as well as some cardiovascular diseases. The link between the CMI and heart disease among elderly and middle-aged individuals has yet to be fully explored. This study aimed to investigate the relationship between the CMI and heart disease incidence in individuals aged 45 and over. A total of 987 participants aged 45 years and above were enrolled. Only patients without heart disease at baseline were included in the 15-year observation. The CMI was calculated by multiplying the ratio of triglycerides to high-density lipoprotein cholesterol by the waist‒to-height ratio. Participants were then grouped into CMI tertiles. The Kruskal‒Wallis H test and Cox regression analysis were performed. Longitudinal/panel data mixed-effects linear regression models were applied to analyze the relationships between the CMI and nonspecific inflammatory markers. In the highest tertile, there was a 1.60-fold increased risk of coronary heart disease (CHD) after adjusting for age and sex. There was also a positive association between time-varying CMI and hs-CRP. These findings suggest that a higher CMI is related to inflammatory processes and elevated CHD risk, thus highlighting its potential role as a marker for CHD in elderly and middle-aged Chinese individuals.

BACKGROUND:Inosine has been investigated as a dietary supplement for athlete performance, inflammation, and neurological disease. A recent study in a hypercholesterolemic rat model has shown its potential for treating atherosclerosis. OBJECTIVE:This study aimed to investigate the associations between plasma inosine and lipid parameters, and to discover potential mediating pathways. METHODS:We profiled inosine and 886 known metabolites in plasma samples from 1,121 participants of a biracial cohort. Linear regression models assessed inosine's association with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), log transformed triglycerides (log-TG), and TC to HDL-C ratio (TC/HDL-C), adjusting for relevant covariates. Significant findings were replicated in 78 adults from the Protein and Blood Pressure (ProBP) study, a cross-over randomized control trial by testing longitudinal associations between inosine changes and lipid changes after dietary supplementation of soy protein, milk protein, and carbohydrates. For a replicated association, we employed two complementary approaches to identify potential mediators for enrichment analysis. RESULTS:In the discovery cohort, inosine was positively associated with HDL-C (β = 1.77, 95 % confidence interval [CI]: 0.003 to 3.54) and negatively associated with TC/HDL-C (β = -0.24, 95 % CI: -0.41 to -0.08) and log-TG (β = -0.08, 95 % CI: -0.15 to -0.02). These results were replicated in ProBP after soy protein intervention with inosine changes leading to increase of HDL-C (β = 1.82, 95 % CI: 0.36 to 3.27) and decrease of TC/HDL-C (β = -0.14, 95 % CI:-0.28 to -0.002) and TG (β = -12.79, 95 % CI: -21.00 to -4.58). Sex-stratified analyses revealed a more pronounced association in women than men, particularly for HDL-C. Six metabolites and 29 enriched pathways of high confidence were identified. CONCLUSION:In humans, inosine is associated with better profiles of HDL-C, TC/HDL-C, and log-TG, with more pronounced effects in women for HDL-C. The ProBP trial was registered at ClinicalTrials.gov as NCT00107744.

The relationship between epigenetic age acceleration (EAA) and midlife cognitive function remains unclear, with limited causal evidence. We investigated this association in 1252 Black and White middle-aged adults from the Bogalusa Heart Study (BHS) and conducted a two-sample Mendelian randomization (MR) analysis using GWAS summary statistics for EAA (N = 34,710) and cognition (N ≤ 106,162). In BHS, higher Hannum age acceleration, PhenoAge acceleration, and GrimAge acceleration (GrimAA) were each associated with slower processing speed (p < 0.05). Additionally, GrimAA was linked to lower global cognition scores (p < 0.001), independent of covariates. MR analysis suggested a potential link, showing that genetically predicted GrimAA was nominally associated with slower processing speed (p = 0.05). These findings suggest that epigenetic aging, particularly GrimAA, is independently associated with lower cognitive function in midlife and may play an important role in cognitive impairment, especially in processing speed.

AIMS:The obesity paradox has been controversial and is mostly observed when body mass index (BMI) is used. We aimed to examine the presence of the obesity paradox using body fatness (body fat percentage, BF%) and central obesity (waist-to-hip ratio adjusted for BMI, WHRadjBMI). We also used Mendelian randomisation to explore causality for the associations of BMI, BF% and WHRadjBMI with cardiovascular disease (CVD) mortality. MATERIALS AND METHODS:A total of 85 926 participants with CVD from the UK Biobank were included. Prospective associations of BMI, BF% and WHRadjBMI with CVD mortality in these patients were examined. Polygenic risk scores (PRSs) for BMI, BF% and WHRadjBMI were used as instrumental variables in Mendelian randomisation analyses. RESULTS:A total of 5432 patients died of CVD causes during a median follow-up period of 13.6 years. BMI in the overweight and class-I obesity ranges was associated with reduced mortality, with class-II or more severe obesity associated with increased mortality; however, there was a linear trend toward increased mortality with increasing BF% and WHRadjBMI. There was no clear indication that increased obesity-PRSs were associated with reduced risk of CVD mortality among patients with known CVD. Sensitivity analyses by sex, age group and disease type, and by using a single variant from the FTO gene rs1558902 as an instrumental variable showed similar results. CONCLUSION:Increased obesity does not show a protective effect in patients with CVD. Previously reported obesity paradox in observational studies may be a result of confounding or other biases.

BACKGROUND AND AIMS:Deviations from the population mean in sleep duration have been associated with increased risk for developing dyslipidemia and atherosclerotic cardiovascular disease, but the mechanism of effect is poorly characterized. We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets. METHODS:We collected data from 55 cohorts with a combined sample size of 732,564 participants (87 % European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20 % of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for one-degree of freedom tests of interaction and two-degree of freedom joint tests of the SNP-main and -interaction effect on lipid levels. RESULTS:The one-degree of freedom variant-sleep interaction test identified 10 novel loci (Pint<5.0e-9), and we additionally identify 7 loci within the two-degree of freedom analyses (Pjoint<5.0e-9 in combination with Pint<6.6e-6). Multiple loci, including those mapped to APSH (target for aspartic and succinic acid) and SLC8A1 showed biological plausibility and druggability potential based on literature. CONCLUSIONS:Collectively, the 17 (9 with short and 8 with long sleep) loci provided evidence into the biomolecular mechanisms underlying sleep-associated lipid changes, including potential involvement of the vitamin D receptor pathway. Collectively, these findings may contribute developing novel interventions for treating dyslipidemia in people with sleep disturbances.

Pulmonary hypertension (PH) secondary to bronchopulmonary dysplasia (BPD) is associated with increased mortality. This study aims to elucidate the risk factors for BPD-PH development and the long-term prognostic factors in pediatric BPD. We analyzed 1082 BPD patients under the age of three. Univariate and multivariate regression were performed to determine the final model. Risk stratification was performed based on the predicted risk score, and Kaplan–Meier survival curves were used to compare survival rates. The in-hospital mortality rate of severe BPD was three times than non-severe BPD, and pediatric BPD-PH had twice the mortality compared to BPD without PH. The incidence of BPD was 1.7 times higher in males, but there were no sex-specific differences in BPD severity. However, female children with BPD had a higher likelihood of developing BPD-PH and lower survival rates. Females, severity of BPD, congenital diaphragmatic hernia, ventricular septal defect, patent ductus arteriosus, uric acid, aspartate aminotransferase/alanine transaminase (ALT), and albumin were independent factors of PH in BPD. Severity of BPD, PH, severe pneumonia, budesonide use, use of adrenaline or noradrenaline, ALT, and day of respiratory support were independent factors for overall survival in pediatric BPD. Two web servers were constructed based on these predictive factors for risk prediction of BPD-PH ( https://sex-ph.shinyapps.io/Nomapp1/ ) and overall survival prediction in BPD patients ( https://zds88.shinyapps.io/DynNomapp/ ). This study confirmed sex differences in BPD-PH and emphasized the role of sex in the development and prognosis of the disease. Two web servers predicted personalized PH risk and survival outcomes in BPD.

Background:Hyperhomocysteinemia (elevated homocysteine, Hcy) is common in chronic kidney disease (CKD) patients, but its effect on glomerular filtration rate (GFR), a key renal function indicator, is unclear. Objective:This meta-analysis aimed to clarify the association between hyperhomocysteinemia (HHcy, defined as Hcy > 15 µmol/L) and reduced glomerular filtration rate (GFR) in chronic kidney disease (CKD) patients, hypothesizing that HHcy is associated with a more significant GFR reduction. To test this hypothesis, a comprehensive search was conducted in PubMed, Embase, Cochrane databases, and reference lists. The primary outcome of interest was the relationship between HHcy and GFR decline in CKD. Methods For this meta-analysis, we established clear inclusion and exclusion criteria to identify eligible studies. Studies were included if they involved patients with chronic kidney disease (CKD), employed randomized controlled, cross-sectional, or cohort study designs, included participants aged 14 years or older, and reported or permitted the calculation of glomerular filtration rate (GFR) and homocysteine (Hcy) levels. We excluded studies that were not in English, focused on acute kidney injury, end-stage kidney disease, or dialysis patients, lacked clear group definitions, were based on animal models, or used non-standard CKD definitions. A comprehensive search strategy was employed to identify relevant studies. We combined MeSH terms (e.g., "homocysteine [MeSH]" and "renal insufficiency, chronic [MeSH]") with free-text keywords in major databases, including PubMed, Embase, and Web of Science. Additionally, we utilized the "related items" function and applied Boolean operators to refine search results. Data were synthesized through meta-analysis, and the mean ± SD of GFR in CKD patients according to Hcy levels were calculated for comparison. All databases were searched from their inception dates to June 2024. Results:CKD patients with hyperhomocysteinemia had a lower GFR (SMD = 2.26, 95% CI [1.37-3.15]). However, significant inter-study heterogeneity (P < 0.01, I 2 = 99.5%) was found. Five articles (Z 2016, Ye, Z 2017, Zhang, Y 2020, Shen, Z 2022, Wu, and J 2022) contributed to it (P = 0.015 < 0.05). Subgrouping them eliminated heterogeneity (P = 0.52, I 2 = 0.00%). Sensitivity analysis showed individual article exclusion had little effect on the result. But Egger tests showed publication bias (P < 0.05), while scissors graph analysis supported result stability (P < 0.01). Conclusions:In CKD, elevated Hcy is related to kidney function decline.

ABSTRACT Aims To examine the association between non‐traditional lipid parameters and adverse pregnancy outcomes (APOs) in women with gestational diabetes mellitus (GDM) and the mediating role of maternal serum metabolites during pregnancy. Materials and Methods This prospective observational study enrolled 399 women with GDM. Multivariate logistic regression was used to examine the association between non‐traditional lipid parameters and APOs risk. Additionally, we assessed the mediating role of single and composite maternal serum metabolites during pregnancy using causal mediation analysis and high‐dimensional mediation analysis, respectively. Results APOs were observed in 12.0% ( N = 48) of participants. Seven non‐traditional lipid parameters, except for the RC/HDL‐C ratio, were associated with APOs risk, with the highest estimate for the atherogenic index of plasma (AIP) (OR = 3.873, 95% CI: 1.079–13.934, p = 0.037) after adjusting for confounders. Maternal metabolic markers mediated these associations, with mediation effect proportions of 21.9%–39.4%. Seven key metabolic markers were identified as potential mediators primarily involved in the biosynthesis of the unsaturated fatty acids pathway. Gene set variation analysis revealed significant differences in the positive regulation of this pathway between the APO and normal pregnancy outcome groups ( p = 0.015). Conclusions Non‐traditional lipid parameters were positively associated with APOs risk in women with GDM. Maternal serum metabolites, predominantly involved in the biosynthesis of unsaturated fatty acids, contribute to these associations.

Current evidence suggests that the deposition of lipid plaques is frequently observed in the walls of intracranial aneurysms (IAs). Therefore, the objective of this research was to determine the causal link between plasma lipids and IAs. Genetic instrumental variables for 179 plasma lipids were acquired from a genome-wide association study of 7174 unrelated Finnish individuals. Outcome data for individuals with IAs were retrieved from a genome-wide association study involving 23 cohorts, comprising 79,429 individuals of European ancestry. An inverse-variance weighted method was employed as the key analysis method. To ensure the reliability of the findings, Mendelian randomization (MR)-Egger regression, weighted-median, and weighted-mode methods were employed. Sensitivity analyses included Cochran Q test, MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO), Radial MR test, MR-Egger intercept test, and leave-one-out analysis. Following rigorous screening, MR tests, and Bonferroni correction, the genetically predicted level of phosphatidylethanolamine (18:2_0:0) (LPE[18:2]) (OR:1.28, P = 1.42 × 10-4), phosphatidylcholine (PC) (16:0_20:4) (OR:0.86, P = 1.38 × 10-4), PC (18:0_20:3) (OR:1.29, P = 2.33 × 10-4), and PC (O-16:0_20:4) (OR:0.83, P = 2.22 × 10-4) showed significant causal relationships with aSAH. Two plasma lipids, LPE (18:2) (OR:1.22, P = 3.14 × 10-5) and PC (16:1_18:2) (OR:1.19, P = 1.53 × 10-4) exhibited a positive correlation with the risk of IAs. No significant causal link was found between 179 plasma lipids and uIA. Genetically determined LPE (18:2), PC (18:0_20:3), and PC (16:1_18:2) can increase the risk of IAs rupture; while PC (16:0_20:4) and PC (O-16:0_20:4) can reduce the risk of IAs rupture. PCs with arachidonic acid chains and the metabolism of arachidonic acid may be crucially involved in the occurrence and development of IAs.

AIMS:This study aimed to investigate the relationship between visceral adipose tissue (VAT), measured using a body shape index (ABSI), and outcomes in patients with heart failure with preserved ejection fraction (HFpEF). METHODS:ABSI data and cardiovascular outcomes were obtained from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial. ABSI was calculated using waist circumference, body mass index, and height. ABSI values were categorized into tertiles for analysis (≤0.078, 0.078-0.084, and >0.084). RESULTS:In total, 3319 patients with HFpEF were enrolled during a mean follow-up period of 3.9 years. ABSI was positively associated with a high risk of cardiovascular events in patients with HFpEF after multivariate adjustment. In the highest tertile, higher risks of all-cause mortality [hazard ratio (HR): 1.464, 95% confidence interval (CI): 1.150-1.864], cardiovascular death (HR: 1.685, 95% CI: 1.241-2.289), myocardial infarction (MI) (HR: 1.778, 95% CI: 1.088-2.904), and major adverse cardiovascular events (MACEs) (HR: 1.430, 95% CI: 1.123-1.822) were noted. Patients with previous or current high ABSI had poorer long-term prognoses, with increased risks of all-cause mortality (HR: 1.635, 95% CI: 1.116-2.396), cardiovascular death (HR: 1.724, 95% CI: 1.071-2.775), MI (HR: 2.021, 95% CI: 0.878-4.653), and MACEs (HR: 1.653, 95% CI: 1.117-2.447). CONCLUSION:ABSI was independently associated with long-term prognosis in patients with HFpEF, and a history of high ABSI was associated with a poorer prognosis later in life, underscoring the importance of reducing VAT in HFpEF.

BACKGROUND:Co-occurrence of depression and diabetes is a prototypical example of mental-physical comorbidity. This study aims to investigate the association between first-degree family history of diabetes (FHD) and the presence of depressive symptoms. METHODS:The present work was one part of the baseline survey from the REACTION study. First-degree FHD was defined as having one or more first-degree relatives with diabetes. The Patient Health Questionnaire-9 was administered to detect the presence of depressive symptoms with its score ≥ 5. Logistic regression analyses were performed to determine the association between first-degree FHD and the presence of depressive symptoms. RESULTS:A total of 4804 participants were enrolled in the present study. Individuals with first-degree FHD were more likely to suffer from depressive symptoms compared with those without first-degree FHD (7.2% versus 4.9%, p = 0.004). The odds ratio (OR) of depressive symptoms was increased by 49.8% with the presence of first-degree FHD after adjustment of gender, age, socioeconomic factors, lifestyle risk factors, and cardiometabolic risk factors (p = 0.007). There were no significant interactions of gender, age, each socioeconomic factor, lifestyle risk factor, and cardiometabolic risk factors on the association between first-degree FHD and the presence of depressive symptoms, respectively (all p > 0.05). CONCLUSIONS:First-degree FHD was associated with depressive symptoms independent of socioeconomic factors, lifestyle risk factors, and cardiometabolic risk factors. Genetic background might mainly contribute to the familial aggregation of depressive symptoms in individuals with first-degree FHD, who should be paid early attention to their mental health.

BACKGROUND:Nocturnal blood pressure (BP) is correlated with an increased risk of cardiovascular events and is an important predictor of cardiovascular death in hypertensive patients. OBJECTIVE:Nocturnal BP control is of great importance for cardiovascular risk reduction. This systematic review and meta-analysis aimed to explore the efficacy of angiotensin receptor blockers (ARBs) for nocturnal BP reduction in patients with mild to moderate hypertension. METHODS:PICOS design structure was used to formulate the data extraction. All statistical calculations and analyses were performed with R. RESULTS:Seventy-seven studies with 13,314 participants were included. The overall analysis indicated that nocturnal BP drop varied considerably among different ARBs. Allisartan (13.04 [95% CI (-18.41, -7.68)] mmHg), olmesartan (11.67 [95% CI (-14.12, -9.21)] mmHg), telmisartan (11.11 [95% CI (-12.12, -10.11)] mmHg) were associated with greater reduction in nocturnal systolic BP. In the aspect of the nocturnal-diurnal BP drop ratio, only allisartan was greater than 1. While, the variation tendency of last 4-6 h ambulatory BP was basically consistent with nocturnal BP. Additionally, allisartan showed improvement effect in the proportion of patients with dipping BP pattern. CONCLUSIONS:This study demonstrates that for patients with mild to moderate hypertension, allisartan, olmesartan and telmisartan have more advantages in nocturnal BP reduction among the ARBs, while allisartan can reduce nighttime BP more than daytime BP and improve the dipping pattern.

We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify novel genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets. We collected data from 55 cohorts with a combined sample size of 732,564 participants (87% European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20% of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for the one-degree of freedom tests of interaction and two-degree of freedom joint tests of the main and interaction effect. In the cross-population meta-analyses, the one-degree of freedom variant-sleep interaction test identified 10 loci (Pint<5.0e-9) not previously observed for lipids. Of interest, the ASPH locus (TG, LTST) is a target for aspartic and succinic acid metabolism previously shown to improve sleep and cardiovascular risk. The two-degree of freedom analyses identified an additional 7 loci that showed evidence for variant-sleep interaction (Pjoint<5.0e-9 in combination with Pint<6.6e-6). Of these, the SLC8A1 locus (TG, STST) has been considered a potential treatment target for reduction of ischemic damage after acute myocardial infarction. Collectively, the 17 (9 with STST; 8 with LTST) loci identified in this large-scale initiative provides evidence into the biomolecular mechanisms underpinning sleep-duration-associated changes in lipid levels. The identified druggable targets may contribute to the development of novel therapies for dyslipidemia in people with sleep disturbances.

Introduction: Inosine, a naturally occurring purine nucleotide, has been used as a dietary supplement to enhance overall health. An emerging study in a rat model has indicated that inosine holds promise as a potential treatment for atherosclerosis by reducing cholesterol-driven inflammation and improving vascular function, providing a foundational concept for further investigation in humans. Hypothesis: We hypothesize that inosine can improve lipid profiles among humans. Methods: We profiled inosine and 886 known metabolites using plasma samples from 1,261 participants of the Bogalusa Heart Study (BHS) 2013-2016 survey. Linear regression models were used to evaluate the relationship between inosine and four lipid phenotypes, including total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, while controlling for age, sex, race, education, smoking, drinking, BMI, lipid medication, and total physical activity. Statistically significant findings in the BHS were validated in the Protein and Blood Pressure (ProBP) study, where 80 adults with available stored samples underwent 8-week dietary supplementation of carbohydrate, milk protein, and soy protein in a random order with 2-week washouts. Inosine and lipids were measured at baseline and post-intervention. We tested associations of longitudinal changes of inosine with changes in lipids profile. We also performed formal mediation analyses in the BHS to identify metabolites and metabolic pathways that might mediate inosine’s association with lipids. Results: In the BHS, inosine was significantly associated with HDL cholesterol (β=1.85, 95% CI: 0.72- 2.98) but not with LDL cholesterol, triglycerides, or TC. In the ProBP trial, inosine change was positively associated with HDL cholesterol change during the soy protein intervention (β=2.13, 95% CI: 0.59-3.66). Our mediation analysis identified 74 metabolites that nominally mediated (p<0.05) the inosine-HDL association. After Bonferroni correction for 228 independent metabolite clusters, three metabolites, including PC(18:2(9Z,12Z)/20:4(5Z,8Z,11Z,14Z)), arachidonic acid, and LysoPC(18:2/0:0) were significant mediators (p<0.05/228). The 74 nominally significant metabolites were enriched in the sphingolipid metabolic pathway (False Discovery Rate= 0.00312). Conclusion: Inosine appears to enhance HDL cholesterol, possibly through the sphingolipid metabolic pathway.