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Background: The link between cardiometabolic disease and mental illness has been well established but remains incompletely explained. One hypothesis suggests that circadian rhythm dysregulation links cardiometabolic disease and mental illnesses. BMAL1 is a circadian rhythm regulatory gene. Human genetic studies have implicated BMAL1 in depression, schizophrenia, bipolar disorder as well as body mass index, blood pressure and lipid levels., Objective: We investigated the BMAL1 locus genetic variants for associations with both cardiometabolic and mental illness., Methods: Genetic and phenotypic data from UK Biobank (~500 000 participants) of White British, African-Caribbean, South Asian, white European and Multiple ancestries were used. Regression analyses using Plink 1.09 was used to identify significant associations, with Bonferroni multiple testing correction. Multiple ancestry meta-analyses using METAL software was used to investigate trans-ancestry consistency in genetic effects., Findings: We identified associations for body mass index, anhedonia, diastolic and systolic blood pressure, waist-hip ratio, major depressive disorder, neuroticism and risk-taking. Meta-analyses indicated that there are ancestry-wide and ancestry-specific effects on cardiometabolic, mental illness and related traits., Conclusions: Our results suggest that the associations for mental illness (and related traits) and those for cardiometabolic traits are distinct rather than shared and that these associations were consistent across ancestry groups., Clinical Implications: Further investigation into the tissue-specific roles of BMAL1 is required to fully understand the clinical impact of these findings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Clonal hematopoiesis of indeterminate potential (CHIP) was initially linked to a twofold increase in atherothrombotic events. However, recent investigations have revealed a more nuanced picture, suggesting that CHIP may confer only a modest rise in myocardial infarction (MI) risk. This observed lower risk might be influenced by yet unidentified factors that modulate the pathological effects of CHIP. Mosaic loss of the Y chromosome (mLOY), a common marker of clonal hematopoiesis in men, has emerged as a potential candidate for modulating cardiovascular risk associated with CHIP. In this study, we aimed to ascertain the risk linked to each somatic mutation or mLOY and explore whether mLOY could exert an influence on the cardiovascular risk associated with CHIP., Methods: We conducted an examination for the presence of CHIP and mLOY using targeted high-throughput sequencing and digital PCR in a cohort of 446 individuals. Among them, 149 patients from the CHAth study had experienced a first MI at the time of inclusion (MI(+) subjects), while 297 individuals from the Three-City cohort had no history of cardiovascular events (CVE) at the time of inclusion (MI(-) subjects). All subjects underwent thorough cardiovascular phenotyping, including a direct assessment of atherosclerotic burden. Our investigation aimed to determine whether mLOY could modulate inflammation, atherosclerosis burden, and atherothrombotic risk associated with CHIP., Results: CHIP and mLOY were detected with a substantial prevalence (45.1% and 37.7%, respectively), and their occurrence was similar between MI(+) and MI(-) subjects. Notably, nearly 40% of CHIP(+) male subjects also exhibited mLOY. Interestingly, neither CHIP nor mLOY independently resulted in significant increases in plasma hs-CRP levels, atherosclerotic burden, or MI incidence. Moreover, mLOY did not amplify or diminish inflammation, atherosclerosis, or MI incidence among CHIP(+) male subjects. Conversely, in MI(-) male subjects, CHIP heightened the risk of MI over a 5 y period, particularly in those lacking mLOY., Conclusions: Our study highlights the high prevalence of CHIP and mLOY in elderly individuals. Importantly, our results demonstrate that neither CHIP nor mLOY in isolation substantially contributes to inflammation, atherosclerosis, or MI incidence. Furthermore, we find that mLOY does not exert a significant influence on the modulation of inflammation, atherosclerosis burden, or atherothrombotic risk associated with CHIP. However, CHIP may accelerate the occurrence of MI, especially when unaccompanied by mLOY. These findings underscore the complexity of the interplay between CHIP, mLOY, and cardiovascular risk, suggesting that large-scale studies with thousands more patients may be necessary to elucidate subtle correlations., Funding: This study was supported by the Fondation Cœur & Recherche (the Société Française de Cardiologie), the Fédération Française de Cardiologie, ERA-CVD (« CHEMICAL » consortium, JTC 2019) and the Fondation Université de Bordeaux. The laboratory of Hematology of the University Hospital of Bordeaux benefitted of a convention with the Nouvelle Aquitaine Region (2018-1R30113-8473520) for the acquisition of the Nextseq 550Dx sequencer used in this study., Clinical Trial Number: NCT04581057., Competing Interests: SF, SM, MD, YP, AG, JB, AB, AS, GM, CT, SD, DT, CJ, OM, TC No competing interests declared, (© 2024, Fawaz, Marti, Dufossee et al.)

Purpose: Studies consistently show abnormally high levels of lactate acid in cardiovascular disease patients, suggested that targeting lactate production may serve as potential strategies for the treatment in the future. However, observational results may be subject to residual confounding and bias., Methods: This study used the dataset from GWAS database to examine confounding in epidemiologic associations between lactate and cardiovascular diseases. A genome-wide genetic association study using Mendelian randomization (MR) was performed from December 02, 2023 to January 15, 2024 to reduce confounding and enhance causal inference. Primary analysis was conducted using inverse-variance-weighted MR. All studies included patients predominantly of European ancestry., Results: The association between lactate and cardiovascular diseases, including 60801 cases from coronary heart disease, 7018 cases from myocardial infarction, 14334 cases from coronary atherosclerosis, 60620 cases from atrial fibrillation, 54358 cases from hypertension, 71 cases from hypertrophic cardiomyopathy, 47309 cases from heart failure, 7055 cases from stroke, 7193 cases from cardioembolic ischemic stroke, 4373 cases from ischemic stroke caused by large vascular atherosclerosis, 2118 cases from pulmonary embolism, 1230 cases from peripheral artery disease, and 4620 cases from venous thromboembolism. Genetically predicted coronary atherosclerosis was associated with a higher risk of lactate level (OR = 1.950; 95% CI (0.087, 1.249); P = 0.024); this association was also evident for peripheral artery disease (OR = 1.003; 95% CI (0.000, 0.005); P = 0.021). No genetically predicted associations were noted for the other cardiovascular diseases., Conclusion: The findings of this study provide genetic evidence supporting a higher risk of lactate level only in coronary atherosclerosis and peripheral artery disease. However, no genetic association between lactate level and the other cardiovascular diseases., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Chang et al.)

Cardiovascular diseases and dermatological conditions are prevalent health issues worldwide. Previous studies have suggested that risk factors for cardiovascular diseases may be associated with the development of dermatological conditions. However, the causal association between these factors remain unclear. This study utilized data from genome-wide association studies and applied Mendelian randomization (MR) to explore the potential causal association between cardiovascular risk factors and common dermatological conditions. Genetic variants significantly associated with low-density lipoprotein cholesterol (LDL-C), serum uric acid, blood glucose, and hypertension were selected as instrumental variables. We employed inverse variance weighted, MR Egger, and weighted mode methods for analysis. Sensitivity analyses, including Cochran Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis, were conducted to ensure the robustness of the results. The MR analysis indicated a positive association between LDL-C levels and the risk of psoriasis (odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.03-1.47, P = .02). Additionally, hypertension and serum uric acid levels were positively associated with the risk of dermatitis eczema (hypertension: OR = 2.77, 95% CI: 1.23-6.24, P = .01; serum uric acid: OR = 1.09, 95% CI: 1.01-1.06, P = .01). This study provides evidence of a potential causal association between LDL-C levels and psoriasis, as well as between hypertension and serum uric acid levels and dermatitis eczema. These findings highlight the potential importance of cardiovascular health management in the prevention and treatment of common dermatological conditions. Further research is needed to validate these results and explore the underlying biological mechanisms., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Telomere length (TL) serves as a pivotal gauge of cellular aging, with shorter TL linked to various age-related ailments. Recently, a DNA methylation-based TL estimator, known as DNAmTL, has emerged as a novel TL measurement tool. Our current investigation scrutinized the correlation between DNAmTL and the risks of cardiovascular disease (CVD) and enduring mortality among middle-aged and elderly individuals., Methods: We enrolled a nationwide, population-based cohort of subjects from the National Health and Nutrition Examination Survey spanning 1999 to 2002, possessing data on both DNAmTL and quantitative polymerase chain reaction-based TL (qPCRTL). Logistic regression models and Cox proportional hazards models were employed to evaluate the associations of DNAmTL with CVD risk and mortality, respectively., Results: The cohort comprised 2532 participants, with a weighted CVD prevalence of 19.06%. Notably, each one-kilobase increase in DNAmTL was linked to a 53% diminished CVD risk [odds ratio (OR): 0.47, 95% confidence interval (CI): 0.23-0.95, P = 0.035]. Over a median follow-up period of 206 months, 1361 deaths were recorded (53.75%), with 590 (23.30%) ascribable to CVD. Individuals with the lengthiest DNAmTL exhibited a 36% lower risk of all-cause mortality (hazard ratio (HR): 0.64, 95% CI: 0.49-0.85, P = 0.002) and a 35% decrease in CVD mortality (HR: 0.65, 95% CI: 0.43-0.98, P = 0.044) compared to those with shortest DNAmTL. Notably, a stronger association with age was observed for DNAmTL compared to qPCRTL (r = -0.58 vs. r = - 0.25). Analysis of receiver operating characteristic (ROC) curves suggested superior predictive performance of DNAmTL over qPCRTL for CVD (area under curve (AUC): 0.63 vs. 0.55, P < 0.001), all-cause (AUC: 0.74 vs. 0.62, P < 0.001), and CVD mortality (AUC: 0.75 vs. 0.64, P < 0.001)., Conclusion: Longer DNAmTL was positively correlated with reduced CVD risk and long-term mortality in middle-aged and elderly cohorts. Notably, DNAmTL outperformed qPCRTL as an aging biomarker in the stratification of CVD risks and mortality., Competing Interests: Declarations. Ethics approval and consent to participate: The study protocol of NHANES was approved by the National Center for Health Statistics of the Center for Disease Control and Prevention Institutional Review Board. Informed consent was obtained from all participants included in the study. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Growth differentiation factor 15 (GDF15) is a crucial biomarker in various physiological and pathological processes. While elevated GDF15 levels are linked to increased mortality risk, the role of DNA methylation (DNAm)-predicted GDF15 in predicting mortality has not been extensively studied. The purpose of the study is to investigate the association between DNAm-predicted GDF15 levels and all-cause and cardiovascular disease (CVD) mortality in a nationally representative cohort., Methods: Data from NHANES 1999-2002 were analyzed. DNAm-predicted GDF15 levels were estimated using a regression model. Weighted multivariate Cox regressions were employed to assess the relationship between DNAm-predicted GDF15 and mortality outcomes. Restricted cubic splines were used to explore dose-response relationships, and subgroup analyses were conducted to enhance result reliability., Results: Higher DNAm-predicted GDF15 levels were significantly associated with increased all-cause mortality risk (HR = 1.08, 95% CI: 1.02-1.15). Participants in the highest DNAm-predicted GDF15 tertile showed significantly higher all-cause mortality risk (HR = 1.56, 95% CI: 1.16-2.10) and a 2.52-fold increased risk of cardiovascular mortality (HR = 2.52, 95% CI: 1.22-5.19). Kaplan-Meier curves revealed decreasing survival probability with higher DNAm-predicted GDF15 tertiles. Restricted cubic spline analysis demonstrated a non-linear dose-response relationship between DNAm-predicted GDF15 levels and cardiovascular mortality. The positive correlation between DNAm-predicted GDF15 and mortality remained robust in most of subgroups., Conclusions: DNAm-predicted GDF15 independently predicts all-cause and cardiovascular mortality. This association persists across multiple models and stratified subgroups, supporting GDF15's value as a biomarker for mortality risk stratification. Future research should elucidate underlying biological mechanisms and evaluate GDF15's clinical utility in guiding mortality risk reduction interventions., Competing Interests: Declarations. Ethics approval and standards of reporting: The NHANES project was reviewed and approved by the Research Ethics Review Board of the NCHS. The research followed the Declaration of Helsinki and the manuscript followed the STROBE Statement for reporting observational studies. Consent to participate: All NHANES participants gave written informed consent. Consent for publication: All NHANES participants provided written informed consent. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Cardiovascular disease remains the foremost cause of morbidity and mortality globally, affecting millions of individuals. Recent discoveries illuminate the substantial role of genetics in cardiovascular disease pathogenesis, encompassing both monogenic and polygenic mechanisms and identifying tangible targets for gene therapies. Innovative strategies have emerged to rectify pathogenic variants that cause monogenic disorders such as hypertrophic, dilated, and arrhythmogenic cardiomyopathies and hypercholesterolemia. These include delivery of exogenous genes to supplement insufficient protein levels caused by pathogenic variants or genome editing to correct, delete, or modify mutant sequences to restore protein function. However, effective delivery of gene therapy to specified cells presents formidable challenges. Viral vectors, notably adeno-associated viruses and nonviral vectors such as lipid and engineered nanoparticles, offer distinct advantages and limitations. Additional risks and obstacles remain, including treatment durability, tissue-specific targeting, vector-associated adverse events, and off-target effects. Addressing these challenges is an ongoing imperative; several clinical gene therapy trials are underway, and many more first-in-human studies are anticipated. This science advisory reviews core concepts of gene therapy, key obstacles, patient risks, and ongoing research endeavors to enable clinicians to understand the complex landscape of this emerging therapy and its remarkable therapeutic potential to benefit cardiovascular disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) exhibits considerable variability in clinical outcomes. Identifying specific phenotypic profiles within MASLD is essential for developing targeted therapeutic strategies. Here we investigated the heterogeneity of MASLD using partitioning around medoids clustering based on six simple clinical variables in a cohort of 1,389 individuals living with obesity. The identified clusters were applied across three independent MASLD cohorts with liver biopsy (totaling 1,099 participants), and in the UK Biobank to assess the incidence of chronic liver disease, cardiovascular disease and type 2 diabetes. Results unveiled two distinct types of MASLD associated with steatohepatitis on histology and liver imaging. The first cluster, liver-specific, was genetically linked and showed rapid progression of chronic liver disease but limited risk of cardiovascular disease. The second cluster, cardiometabolic, was primarily associated with dysglycemia and high levels of triglycerides, leading to a similar incidence of chronic liver disease but a higher risk of cardiovascular disease and type 2 diabetes. Analyses of samples from 831 individuals with available liver transcriptomics and 1,322 with available plasma metabolomics highlighted that these two types of MASLD exhibited distinct liver transcriptomic profiles and plasma metabolomic signatures, respectively. In conclusion, these data provide preliminary evidence of the existence of two distinct types of clinically relevant MASLD with similar liver phenotypes at baseline, but each with specific underlying biological profiles and different clinical trajectories, suggesting the need for tailored therapeutic strategies., Competing Interests: Competing interests: The authors declare no conflicts of interest related to this manuscript., (© 2024. The Author(s).)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by an excess of lipids, mainly triglycerides, in the liver and components of the metabolic syndrome, which can lead to cirrhosis and liver cancer. While there is solid epidemiological evidence that MASLD clusters with cardiometabolic disease, several leading genetic risk factors for MASLD do not increase the risk of cardiovascular disease, suggesting no causal relationship between MASLD and cardiometabolic derangement. In this work, we leveraged measurements of visceral adiposity identifying 27 previously unknown genetic loci associated with MASLD (n = 36,394), six replicated in four independent cohorts (n = 3,903). Next, we generated two partitioned polygenic risk scores based on the presence of lipoprotein retention in the liver. The two polygenic risk scores suggest the presence of at least two distinct types of MASLD, one confined to the liver resulting in a more aggressive liver disease and one that is systemic and results in a higher risk of cardiometabolic disease. These findings shed light on the heterogeneity of MASLD and have the potential to improve the prediction of clinical trajectories and inform precision medicine approaches., Competing Interests: Competing interests: S.R. has been consulting for AstraZeneca, GSK, Celgene Corporation, Ribo-cure AB and Pfizer in the last 5 years and received a research grant from AstraZeneca. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the paper or in the decision to publish the results. L.V. has received speaking fees from MSD, Gilead, AlfaSigma and AbbVie, served as a consultant for Gilead, Pfizer, AstraZeneca, Novo Nordisk, Intercept, Diatech Pharmacogenetics, Ionis Pharmaceuticals, Boehringer Ingelheim and Resalis Therapeutics, and received unrestricted research grants from Gilead. R.L.G. is a part-time contractor for Metabolon. O.J. is a part-time consultant to Ribo-cure AB. The other authors declare no competing interests., (© 2024. The Author(s).)

Cardiovascular disorders (CVDs) are a major global health concern, but their underlying molecular mechanisms are not fully understood. Recent research highlights the role of long noncoding RNAs (lncRNAs), particularly ANRIL, in cardiovascular development and disease. ANRIL, located in the human genome's 9p21 region, significantly regulates cardiovascular pathogenesis. It controls nearby tumor suppressor genes CDKN2A/B through epigenetic pathways, influencing cell growth and senescence. ANRIL interacts with epigenetic modifiers, leading to altered histone modifications and gene expression changes. It also acts as a transcriptional regulator, impacting key genes in CVD development. ANRIL's involvement in cardiovascular epigenetic regulation suggests potential therapeutic strategies. Manipulating ANRIL and its associated epigenetic modifiers could offer new approaches to managing CVDs and preventing their progression. Dysregulation of ANRIL has been linked to various cardiovascular conditions, including coronary artery disease, atherosclerosis, ischemic stroke, and myocardial infarction. This abstract provides insights from recent research, emphasizing ANRIL's significance in the epigenetic landscape of cardiovascular disorders. By shedding light on ANRIL's role in cellular processes and disease development, the abstract highlights its potential as a therapeutic target for addressing CVDs., (© 2024 Wiley Periodicals LLC.)

Background and Aims: This study aims to evaluate the impact of ultra-processed food (UPF) on type 2 diabetes (T2D), cardiovascular disease (CVD), hypertension, and cardiometabolic multimorbidity (CMM), and to explore the role of genetic susceptibility in these associations., Methods and Results: 90 631 participants from the UK Biobank were included (collected between 2006 and 2010). The outcomes assessed included T2D, CVD, hypertension and CMM. The Cox proportional hazards model was used to evaluate their associations and the potential modification by genetic risk, which was estimated using the polygenic risk score (PRS). Participants with high UPF consumption had a higher risk of T2D, CVD, and CMM, with the adjusted hazard ratio (HR) of 1.36 (95 % confidence interval [CI]: 1.15, 1.61), 1.13 (95%CI: 1.03, 1.23), and 1.14 (95%CI: 1.05, 1.24), respectively. Those with high UPF consumption and high PRS for T2D, CVD, and hypertension had the highest risk of T2D (HR: 4.01; 95%CI: 2.83, 5.69), CVD (HR: 2.18; 95%CI: 1.86, 2.56), and hypertension (HR: 1.79; 95%CI: 1.61, 1.99), respectively. In participants with one cardiometabolic disease (CMD), those with high UPF consumption and high PRS T2D or PRS CVD had the highest risk of developing CMM. A significant additive interaction was observed between PRS T2D and UPF consumption on the risk of T2D., Conclusion: Our study underscored the importance of identifying individuals with high UPF consumption for targeted dietary interventions to mitigate the risk of CMDs and CMM, particularly among those with a high genetic risk of CMDs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Previous observational studies have explored the association between serum lipids, apolipoproteins, and adverse ventricular/aortic structure and function. However, whether a causal link exists is uncertain. This study employed a two-sample Mendelian randomization (MR), colocalization, reverse, and multivariable MR (MVMR) approach to examine the causal associations among five serum lipids, two apolipoproteins, and 32 cardiac magnetic resonance (CMR) traits. Utilizing single-nucleotide polymorphisms (SNPs) linked to serum lipids and apolipoproteins as instrumental variables. CMR traits from seven independent genome-wide association studies served as preclinical endophenotypes, offering insights into aortic and cardiac structure/function. The primary analysis utilized a random-effects inverse variance method (IVW), followed by sensitivity and validation analyses. In the primary IVW MR analyses, genetically predicted low-density lipoprotein cholesterol (LDL-C) levels were positively correlated with increased descending aorta strain (DAo strain) (β = 0.098; P = 2.69E-07) and ascending aorta strain (AAo strain) (β = 0.079; P = 5.19E-05). Genetically predicted high-density lipoprotein cholesterol (HDL-C) levels were positively correlated with left ventricular radial peak diastolic strain rate (LV-PDSRll) (β = 0.176; P = 2.89E-05) and the left ventricular longitudinal peak diastolic strain rate (LV-PDSRrr) (β = 0.059; P = 2.44E-06), and negatively correlated with left ventricular regional wall thickness (LVRWT). While apolipoprotein B (ApoB) levels were positively correlated with AAo strain (β = 0.076; P = 1.16E-05), DAo strain (β = 0.065; P = 2.77E-05). A shared causal variant was identified to demonstrate the associations of ApoB with AAo strain and DAo strain using colocalization analysis. Sensitivity analyses confirmed the robustness of these associations. Targeting lipid and apolipoprotein levels through interventions may provide novel strategies for the primary prevention of CVDs., Competing Interests: Declarations Competing Interest All authors declare that they have no competing interests. Ethical Approval Ethical approval and participant consent have been obtained in the original study. The use of summary-level data in our analysis is not considered to require approval., (© 2024. The Author(s).)

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme primarily involved in the detoxification of alcohol-derived aldehyde and endogenous toxic aldehydes. It exhibits widespread expression across various organs and exerts a broad and significant impact on diverse acute cardiovascular diseases, including acute coronary syndrome, acute aortic dissection, hypoxic pulmonary hypertension, and heart failure. The ALDH2 rs671 variant represents the most prevalent genetic variant in East Asian populations, with carriage rates ranging from 30 to 50% among the Chinese population. Given its widespread presence in the body, the wide range of diseases it affects, and its high rate of variation, it can serve as a crucial tool for the precise prevention and treatment of acute cardiovascular diseases, while offering individualized medication guidance. This review aims to provide a comprehensive overview of the latest advancements in factors affecting ALDH2 activity, encompassing post-transcriptional modifications, modulators of ALDH2, and relevant clinical drugs., Competing Interests: Declarations Competing Interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: Various anthropometric measures capture distinct as well as overlapping characteristics of an individual's body composition. To characterize independent body composition measures, we aimed to reduce easily-obtainable individual measures reflecting adiposity, anthropometrics and energy expenditure into fewer independent constructs, and to assess their potential sex- and age-specific relation with cardiometabolic diseases., Methods: Analyses were performed within European ancestry participants from UK Biobank (N = 418,963, mean age 58.0 years, 56% women). Principal components (PC) analyses were used for the dimension reduction of 11 measures of adiposity, anthropometrics and energy expenditure. PCs were studied in relation to incident type 2 diabetes mellitus (T2D) and coronary artery disease (CAD). Multivariable-adjusted Cox regression analyses, adjusted for confounding factors, were performed in all and stratified by age. Genome-wide association studies were performed in half of the cohort (N = 156,295) to identify genetic variants as instrumental variables. Genetic risk score analyses were performed in the other half of the cohort stratified by age of disease onset (N = 156,295)., Results: We identified two PCs, of which PC1 reflected lower overall adiposity (negatively correlated with all adiposity aspects) and PC2 reflected more central adiposity (mainly correlated with higher waist-hip ratio, but with lower total body fat) and increased height, collectively capturing 87.8% of the total variance. Similar to that observed in the multivariable-adjusted regression analyses, we found associations between the PC1 genetic risk score and lower risks of CAD and T2D [CAD cases <50 years, odds ratio: 0.91 (95% confidence interval 0.87, 0.94) per SD; T2D cases <50 years, odds ratio: 0.76 (0.72, 0.81)], which attenuated with higher age (p-values 8.13E-4 and 2.41E-6, respectively). No associations were found for PC2., Conclusions: The consistently observed weaker associations of the composite traits with cardiometabolic disease suggests the need for age-specific cardiometabolic disease prevention strategies., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Recent studies of noncoding genomes have shown important implications for regulating gene expression and genetic programs during development and their association with health, including cardiovascular disease. There are nearly 2,500 microRNAs (miRNAs), 12,000 long-chain non-coding RNAs (lncRNA), and nearly 4,000 circular RNAs (circles). Even though they do not code for proteins, they make up nearly 99% of the human genome. Non-coding RNA families (ncRNAs) have recently been discovered and established as novel and necessary controllers of cardiovascular risk factors and cellular processes and, therefore, have the potential to improve the diagnosis and prediction of cardiovascular disease. The increase in the prevalence of cardiovascular disease can be explained by the shortcomings of existing therapies, which focus only on the non-coding RNAs that protein codes for. On the other hand, recent studies point to the possibility of using ncRNAs in the early detection and intervention of CVD. These findings suggest that developing diagnostic tools and therapies based on miRNAs, lncRNAs, and circRNAs will potentially enhance the clinical management of patients with cardiovascular disease. Cardiovascular diseases include CH, HF, RHD, ACS, MI, AS, MF, ARR, and PAH, of which CH is the most common cardiovascular disease, followed by HF and RHD. This paper aims to elucidate the biological and clinical significance of miRNAs, increase, and circles, as well as their expression profiles and the possibility of regulating non-coding transcripts in cardiovascular diseases to improve the application of ncRNAs in diagnosis and treatment., Competing Interests: Declaration of competing interest There is no conflict of interest among authors., (Copyright © 2024. Published by Elsevier Inc.)

Human genetic and transgenic mouse studies have highlighted a potential liver-adipose tissue endocrine axis, involving activin C (Act-C) and/or Act-E and ALK7, influencing fat distribution and systemic metabolism. We investigated the bidirectional effects between circulating INHBC, which homodimerizes into Act-C, and adiposity traits, insulin resistance, inflammation, and cardiometabolic disease risk. Additionally, we examined whether Act-C is an ALK7 ligand in human adipocytes. We used Mendelian randomization and in vitro studies in immortalized human abdominal and gluteal adipocytes. Circulating INHBC was causally linked to reduced lower-body fat, dyslipidemia, and increased risks of coronary artery disease (CAD) and nonalcoholic fatty liver disease (NAFLD). Conversely, upper-body fat distribution, obesity, hypertriglyceridemia, subclinical inflammation, and type 2 diabetes positively impacted plasma INHBC levels. Mechanistically, an atherogenic lipid profile may partly explain the INHBC-CAD link, while inflammation and hypertriglyceridemia may partly explain how adiposity traits affect circulating INHBC. Phenome-wide Mendelian randomization showed weak causal relationships between higher plasma INHBC and impaired kidney function and higher gout risk. In human adipocytes, recombinant Act-C activated SMAD2/3 signaling via ALK7 and suppressed lipolysis. In summary, INHBC influences systemic metabolism by activating ALK7 in adipose tissue and may serve as a drug target for atherogenic dyslipidemia, CAD, and NAFLD., (© 2024 by the American Diabetes Association.)

Background and Aims: Evidence is increasingly suggesting that shift work is a risk factor for cardiometabolic disease. However, the causal relationship between shift work and cardiometabolic disease is not yet fully understood. In this study, we employed two-sample Mendelian randomization (MR) to investigate the causal relationship between shift work and the risk of cardiometabolic outcomes., Methods and Results: Genome-wide association study (GWAS) statistics for shift work were obtained from the UK Biobank. Mendelian randomization analyses were conducted to explore the causal effects of shift work on cardiometabolic outcomes, using single-nucleotide polymorphisms (SNPs) as instrumental variables. The results suggested a causal effect between shift work and body mass index, body fat percentage, triglycerides, high-density lipoprotein, type 2 diabetes, hypertension, and cardiorespiratory fitness. After correcting for multiple tests, only body mass index and high-density lipoprotein showed significant associations. No causal effects were found between shift work and overweight, obesity, total cholesterol, low-density lipoprotein, fasting glucose, 2-h glucose, fasting insulin, coronary artery disease, myocardial infarction, heart failure, atrial fibrillation, or ischemic stroke., Conclusion: This MR study provides genetic evidence for a suggestive causal link between shift work and certain cardiometabolic outcomes. Our research may have the significance of providing insight into public hygiene to improve the understanding of shift work and cardiometabolic disease risk. Further experimental studies are needed to confirm our findings., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose of Review: Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent, genetic risk factor for cardiovascular disease. Though crucial for adequate risk assessment, detection of individuals at increased risk because of elevated Lp(a) is severely lacking in practice. In this light, several consensus statements have recommended familial cascade screening strategies to increase detection of elevated Lp(a). This review aims to synthesize findings from recent research into the effectiveness of cascade screening for elevated Lp(a)., Recent Findings: Cascade screening is an effective method for identifying individuals with elevated Lp(a) and is superior to opportunistic screening. Cascade screening identifies approximately one new case of elevated Lp(a) ≥ 125 nmol/L for every two first-degree relatives screened. The number needed to screen (NNS) ranged from 1.3 to 2.9, depending on Lp(a) threshold values and selected population., Summary: Cascade screening appears to be a promising strategy for identifying individuals with elevated Lp(a). However, several challenges persist regarding the implementation of this strategy in clinical practice. Deciding on threshold values for initiating cascade screening, considering the implications of ethnicity-related variability of Lp(a) levels, and further research into the clinical relevance of cascade screening are crucial steps. Understanding these factors will be essential for optimizing cascade screening protocols and enhancing its effectiveness in clinical practice., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The psychological and cardiovascular health impacts on family members of patients who have been diagnosed with cancer have not been well characterized. The purpose of this study is to determine whether a family member's cancer diagnosis influences the risk of psychological illness and cardiovascular disease in first-degree relatives and spouses of patients affected by cancer., Methods: This retrospective cohort analysis evaluated the risk of psychological illness and cardiovascular disease in first-degree relatives and spouses of patients diagnosed with a genitourinary cancer between 1990 and 2015 compared to relatives of those not diagnosed with a genitourinary cancer. The Utah Population Database was used and familial linkage was determined. Follow-up included 1-, 3-, and 5-year intervals. Patients residing outside of Utah and first-degree relatives and spouses with psychological or cardiovascular disease diagnosed before a family member's cancer diagnosis were excluded., Results: A total of 49,284 patients with a genitourinary cancer were identified with 77,938 first-degree relatives and spouses. A matched control group included 246,775 patients with 81,022 first-degree relatives and spouses. Via Cox proportional hazards models, a 10% increased risk of developing a psychological illness (hazard ratio [HR], 1.10; 95% CI, 1.00-1.20) and a 28% increased risk of developing cardiovascular disease (HR, 1.28; 95% CI, 1.17-1.41) at 1 year after a family member's cancer diagnosis were found., Conclusions: This study provides population-level evidence to support the hypothesis that cancer diagnoses will lead to adverse health outcomes for family members of patients with cancer. Increased clinical attention and support are needed to reduce the harm to families caused by cancer., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Objective: This review aims to assess the effectiveness of receiving cardiovascular disease (CVD) genetic risk information on individual health behaviors, psychological responses, and risk factor modification., Introduction: Advancements in genomics have identified strong genetic predispositions for CVD, leading to the development of CVD genetic risk information. Integrating genetic risk information into clinical practice shows promise in predicting CVD risk and facilitating multifactorial management., Inclusion Criteria: This review will focus on randomized controlled trials assessing individual responses to CVD genetic risk information. Participants will be adults aged 18 or older, either with or without CVD. The review will compare the effectiveness of receiving genetic risk information with receiving traditional risk information or no risk information, assessing outcomes such as health behaviors, psychological responses, and risk factor modification., Methods: Cochrane CENTRAL, MEDLINE, Embase, and Emcare will be searched for relevant studies. Current or unpublished trials will be searched for in ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform. Articles will be screened and assessed for inclusion by 2 independent reviewers. Methodological quality will be assessed using the standardized instrument from JBI. Data will be extracted and synthesized according to the objectives of the review. If data are sufficient, a meta-analysis will be conducted; otherwise, the findings will be presented in narrative format, including tables and figures. The certainty of evidence will be assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach., Review Registration: PROSPERO CRD42023390876., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 JBI.)

Study Objectives: Observational studies suggest associations between insomnia and cardiovascular diseases (CVDs), but the causal mechanism remains unclear. We investigated the potential causal associations between insomnia and CVDs by a combined systematic meta-review and meta-analysis of observational and Mendelian randomization studies., Methods: We searched PubMed, Web of Science, and Embase for English-language articles from inception to July 11, 2023. Two reviewers independently screened the articles to minimize potential bias. We summarized the current evidence on the associations of insomnia with coronary artery disease, atrial fibrillation, heart failure, myocardial infarction, hypertension, and stroke risk by combining meta-analyses of observational and Mendelian randomization studies., Results: Four meta-analyses of observational studies and 9 Mendelian randomization studies were included in the final data analysis. A systematic meta-review of observational studies provided strong evidence that insomnia is an independent risk factor for many CVDs, including atrial fibrillation, myocardial infarction, and hypertension. A meta-analysis of Mendelian randomization studies revealed that insomnia may be potentially causally related to coronary artery disease (odds ratio [OR] = 1.14, 95% confidence interval [CI] = 1.10-1.19, I 2 = 97%), atrial fibrillation (OR = 1.02, 95% CI = 1.01-1.04, I 2 = 94%), heart failure (OR = 1.04, 95% CI = 1.03-1.06, I 2 =97%), hypertension (OR = 1.16, 95% CI = 1.13-1.18, I 2 = 28%), large artery stroke (OR = 1.14, 95% CI = 1.05-1.24, I 2 = 0%), any ischemic stroke (OR = 1.09, 95% CI = 1.03-1.14, I 2 = 60%), and primary intracranial hemorrhage (OR = 1.16, 95% CI = 1.05-1.27, I 2 = 0%). No evidence suggested that insomnia is causally associated with cardioembolic or small vessel stroke., Conclusions: Our results provide strong evidence supporting a possible causal association between insomnia and CVD risk. Strategies to treat insomnia may be promising targets for preventing CVDs., Citation: Zhang X, Sun Y, Ye S, et al. Associations between insomnia and cardiovascular diseases: a meta-review and meta-analysis of observational and Mendelian randomization studies. J Clin Sleep Med. 2024;20(12):1975-1984., (© 2024 American Academy of Sleep Medicine.)

Stochastic epigenetic mutations (SEMs) have been proposed as novel aging biomarkers to capture heterogeneity in age-related DNA methylation changes. SEMs are defined as outlier methylation patterns at cytosine-guanine dinucleotide sites, categorized as hypermethylated (hyperSEM) or hypomethylated (hypoSEM) relative to a reference. Because SEMs are defined by their outlier status, it is critical to differentiate extreme values due to technical noise or data artifacts from those due to real biology. Using technical replicate data, we found SEM detection is not reliable: across 3 datasets, 24 to 39% of hypoSEM and 46 to 67% of hyperSEM are not shared between replicates. We identified factors influencing SEM reliability-including blood cell type composition, probe beta-value statistics, genomic location, and presence of SNPs. We used these factors in a training dataset to build a machine learning-based filter that removes unreliable SEMs, and found this filter enhances reliability in two independent validation datasets. We assessed associations between SEM loads and aging phenotypes in the Framingham Heart Study and discovered that associations with aging outcomes were in large part driven by hypoSEMs at baseline methylated probes and hyperSEMs at baseline unmethylated probes, which are the same subsets that demonstrate highest technical reliability. These aging associations were preserved after filtering out unreliable SEMs and were enhanced after adjusting for blood cell composition. Finally, we utilized these insights to formulate best practices for SEM detection and introduce a novel R package, SEMdetectR, which uses parallel programming for efficient SEM detection with comprehensive options for detection, filtering, and analysis., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Background: Hematopoietic transcription factor RUNX1 is expressed from proximal P2 and distal P1 promoters to yield isoforms RUNX1 B and C, respectively. The roles of these isoforms in RUNX1 autoregulation and downstream gene regulation in megakaryocytes and platelets are unknown., Objectives: To understand the regulation of RUNX1 and its target genes by RUNX1 isoforms., Methods: We performed studies on RUNX1 isoforms in megakaryocytic human erythroleukemia (HEL) cells and HeLa cells (lack endogenous RUNX1), in platelets from 85 healthy volunteers administered aspirin or ticagrelor, and on the association of RUNX1 target genes with acute events in 587 patients with cardiovascular disease (CVD)., Results: In chromatin immunoprecipitation and luciferase promoter assays, RUNX1 isoforms B and C bound and regulated P1 and P2 promoters. In HeLa cells, RUNX1B decreased and RUNX1C increased P1 and P2 activities, respectively. In HEL cells, RUNX1B overexpression decreased RUNX1C and RUNX1A expression; RUNX1C increased RUNX1B and RUNX1A. RUNX1B and RUNX1C regulated target genes (MYL9, F13A1, PCTP, PDE5A, and others) differentially in HEL cells. In platelets, RUNX1B transcripts (by RNA sequencing) correlated negatively with RUNX1C and RUNX1A; RUNX1C correlated positively with RUNX1A. RUNX1B correlated positively with F13A1, PCTP, PDE5A, RAB1B, and others, and negatively with MYL9. In our previous studies, RUNX1C transcripts in whole blood were protective against acute events in CVD patients. We found that higher expression of RUNX1 targets F13A1 and RAB31 associated with acute events., Conclusion: RUNX1 isoforms B and C autoregulate RUNX1 and regulate downstream genes in a differential manner, and this is associated with acute events in CVD., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

RNA methylation is a widespread regulatory mechanism that controls gene expression in physiological processes. In recent years, the mechanisms and functions of RNA methylation under diseased conditions have been increasingly unveiled by RNA sequencing technologies with large scale and high resolution. In this review, the fundamental concept of RNA methylation is introduced, and the common types of transcript methylation and their machineries are described. Then, the regulatory roles of RNA methylation, particularly N6-methyladenosine and 5-methylcytosine, in the vascular lesions of ocular and cardiopulmonary diseases are discussed and compared. The ocular diseases include corneal neovascularization, retinopathy of prematurity, diabetic retinopathy, and pathologic myopia; whereas the cardiopulmonary ailments involve atherosclerosis and pulmonary hypertension. This review hopes to shed light on the common regulatory mechanisms underlying the vascular lesions in these ocular and cardiopulmonary diseases, which may be conducive to developing therapeutic strategies in clinical practice.

Background & Aims: The mechanisms underlying the association of steatotic liver disease with cardiovascular and cancer outcomes are poorly understood. We aimed to use MRI-derived measures of liver fat and genetics to investigate causal mechanisms that link higher liver fat to various health outcomes., Methods: We conducted a genome-wide association study on 37,358 UK Biobank participants to identify genetic variants associated with liver fat measured from MRI scans. We used a Mendelian randomisation approach to investigate the causal effect of liver fat on health outcomes independent of BMI, alcohol consumption and lipids using data from published genome-wide association studies and FinnGen., Results: We identified 13 genetic variants associated with liver fat that had differing effects on the risks of health outcomes. Genetic variants associated with impaired hepatic triglyceride export showed liver fat-increasing alleles to be correlated with a reduced risk of coronary artery disease and myocardial infarction but an elevated risk of type 2 diabetes, while variants associated with enhanced de novo lipogenesis showed liver fat-increasing alleles to be linked to a higher risk of myocardial infarction and coronary artery disease. Genetically higher liver fat content increased the risk of non-alcohol-related cirrhosis, hepatocellular carcinoma, and intrahepatic bile duct and gallbladder cancers, exhibiting a dose-dependent relationship, irrespective of the mechanism., Conclusion: This study provides fresh insight into the heterogeneous effect of liver fat on health outcomes. It challenges the notion that liver fat per se is an independent risk factor for cardiovascular disease, underscoring the dependency of this association on the specific mechanisms that drive fat accumulation in the liver. However, excess liver fat, regardless of the underlying mechanism, appears to be causally linked to cirrhosis and cancers in a dose-dependent manner., Impact and Implication: This research advances our understanding of the heterogeneity in mechanisms influencing liver fat accumulation, providing new insights into how liver fat accumulation may impact various health outcomes. The findings challenge the notion that liver fat is an independent risk factor for cardiovascular disease and highlight the mechanistic effect of some genetic variants on fat accumulation and the development of cardiovascular diseases. This study is of particular importance for healthcare professionals including physicians and researchers, as well as patients, as it allows for more targeted and personalised treatment by understanding the relationship between liver fat and various health outcomes. The findings emphasise the need for a personalised management approach and a reshaping of risk assessment criteria. It also provides room for prioritising a clinical intervention aimed at reducing liver fat content (likely via intentional weight loss) that could help protect against liver-related fibrosis and cancer., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The combined effect of cardiovascular risk factors on breast cancer in women is unknown. The relationship between genetic risk combined with cardiovascular health (CVH) levels and breast cancer has not been confirmed. This study aims to explore the relationship between CVH level based on life's essential 8 (LE8) score and breast cancer risk in women with different menopausal statuses and to estimate further the effect of CVH level combined with genetic susceptibility on breast cancer risk. A total of 118,911 women from UK Biobank were included in the study, including 22,676 premenopausal women and 96,235 postmenopausal women. The association between the CVH level and the risk of breast cancer in women with different menopausal statuses was assessed using the Cox proportional hazards regression models, with the healthiest CVH group as the reference. In addition, risk ratios (HRs) and 95% confidence intervals (95% CIs) for the joint effect of the CVH level and polygenic risk score (PRS) were calculated using the PRS from the UK Biobank. During a mean follow-up period of 13.8 years, we observed 733 cases and 3,645 cases of breast cancer in premenopausal and postmenopausal women, respectively. In premenopausal women, the risk of breast cancer was significantly increased in the intermediate CVH group (HR, 1.28; 95%CI 1.08-1.52) and the low CVH group (HR, 1.44; 95%CI 1.13-1.85). In postmenopausal women, the risk of incidence was also significantly increased in the intermediate CVH group (HR, 1.20; 95%CI 1.07-1.32) and the low CVH group (HR, 1.34; 95%CI 1.17-1.54). In the joint effect analysis, the risk of breast cancer for women in the low CVH group and the high genetic risk group was highest in both premenopausal (HR, 8.26; 95%CI 4.44-15.35) and postmenopausal (HR, 8.10; 95%CI 5.50-11.93) women. Women with lower LE8 scores and higher genetic susceptibility have the higher risk of breast cancer. This suggests that women with lower levels of CVH and higher genetic susceptibility have an increased risk of breast cancer under different menopausal statuses., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: The study was approved by the North West Multi-center Research Ethics Committee, the National Information Governance Board for Health and Social Care in England and Wales, and the Community Health Index Advisory Group in Scotland ( http://www.ukbiobank.ac.uk/ethics/ ). Informed consent: All participants provided written informed consent before participation in the study. Consent for publication: Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Vitamin D plays important roles in various physiological processes such as cardiovascular health, calcium balance regulation, bone health, immune system support, neurological function regulation, muscle function maintenance, and anti-inflammatory effects. Therefore, maintaining its adequate levels is essential for overall health. Genetic polymorphisms in vitamin D metabolic pathways have become a key factor affecting the susceptibility and progression of cardiovascular disease (CVD). This article reviews the relationship between gene polymorphisms in vitamin D metabolic pathways and vitamin D levels or CVD. It is emphasized that the polymorphisms of key genes such as GC, VDR, CYP2R1, CYP24A1 and CYP27B1 are related to the pathogenesis of CVD. These polymorphisms can regulate serum levels of vitamin D, thereby affecting the susceptibility, comorbidities and clinical manifestations of CVD. Despite the progress made, there are still inconsistencies and gaps in the literature. Thus, it is necessary to conduct large-scale, multicenter studies to verify these findings and deepen our understanding of the intricate interactions between gene polymorphisms in vitamin D metabolic pathways and CVD.

Psychological stress contributes to cardiovascular disease (CVD) and sudden cardiac death, yet its molecular basis remains obscure. RNA binding protein RBM24 plays a critical role in cardiac development, rhythm regulation, and cellular stress. Here, we show that psychological stress activates RBM24 S181 phosphorylation through eIF4E2-GSK3β signaling, which causally links psychological stress to CVD by promoting APOE translation (apolipoprotein E). Using an Rbm24 S181A KI mouse model, we show that impaired S181 phosphorylation leads to cardiac contractile dysfunction, atrial fibrillation, dyslipidemia, reduced muscle strength, behavioral abnormalities, and sudden death under acute and chronic psychological stressors. The impaired S181 phosphorylation of RBM24 inhibits cardiac translation, including APOE translation. Notably, cardiomyocyte-specific expression of APOE rescues cardiac electrophysiological abnormalities and contractile dysfunction, through preventing ROS stress and mitochondrial dysfunction. Moreover, RBM24-S181 phosphorylation acts as a serum marker for chronic stress in human. These results provide a functional link between RBM24 phosphorylation, eIF4E-regulated APOE translation, and psychological-stress-induced CVD., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

An increasing number of studies have shown that lead is an important cardiovascular risk factor, but the impact of cardiovascular related gene polymorphisms on lead induced cardiovascular diseases is still unclear. To assess the interaction of lead exposure and related key cardiovascular regulating gene polymorphisms on blood pressure traits, three single-nucleotide polymorphisms including NOTCH1 rs3124591, Cerebral cavernous malformations 3 (CCM3) rs3804610 and Vascular endothelial growth factor receptor type 2 (VEGFR2) rs2305948 were selected and genotyped using improved multiplex ligase detection reaction method in 568 lead exposure workers in South China. General characteristics, blood lead and biochemical parameters including glucose, lipid profile and creatinine were also collected according to standard protocols. Regression analysis was used to evaluate the association of blood pressure with lead exposure, polymorphisms and their interaction. This study displayed that CCM3 rs3804610 had a positive interaction with lead and VEGFR2 rs2305948 had a negative interaction with lead. Specifcally, compared with the wild-type population, the blood lead of the genotype population carrying the risk allele increased by 1 µg/dL, systolic blood pressure increased by 0.53 mmHg (p < 0.01) and diastolic blood pressure increased by 0.34 mmHg (p < 0.05) for CCM3 rs3804610, and systolic blood pressure decreased by 0.28 mmHg (p < 0.05) and diastolic blood pressure decreased by 0.22 mmHg (p < 0.05) for VEGFR2 rs2305948. Thus our findings showed that the interaction between CCM3 rs3804610 and VEGFR2 rs2305948 and lead exposure were associated with blood pressure and may provide guidance for future research on hypertension prevention and personalized clinical treatment in lead exposed populations., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Informed consent: Informed consent was acquired through all subjects included in this investigation. Ethical approval: This study was approved by the Medical Ethics Committee of the School of Public Health at Sun Yat-sen University and this study was conducted in accordance with the guidelines of Medical Ethics Committees., (© 2024. The Author(s).)

Introduction: Early mid-life is marked by accumulating risks for cardiometabolic illness linked to health-risk behaviors like nicotine use. Identifying polygenic indices (PGI) has enriched scientific understanding of the cumulative genetic contributions to behavioral and cardiometabolic health, though few studies have assessed these associations alongside socioeconomic (SES) and lifestyle factors., Aims and Methods: Drawing on data from 2337 individuals from the United States participating in the National Longitudinal Study of Adolescent to Adult Health, the current study assesses the fraction of variance in five related outcomes-use of conventional and electronic cigarettes, body mass index (BMI), waist circumference, and glycosylated hemoglobin (A1c)-explained by PGI, SES, and lifestyle., Results: Regression models on African ancestry (AA) and European ancestry (EA) subsamples reveal that the fraction of variance explained by PGI ranges across outcomes. While adjusting for sex and age, PGI explained 3.5%, 2.2%, and 0% in the AA subsample of variability in BMI, waist circumference, and A1c, respectively (in the EA subsample these figures were 7.7%, 9.4%, and 1.3%). The proportion of variance explained by PGI in nicotine-use outcomes is also variable. Results further indicate that PGI and SES are generally complementary, accounting for more variance in the outcomes when modeled together versus separately., Conclusions: PGI are gaining attention in population health surveillance, but polygenic variability might not align clearly with health differences in populations or surpass SES as a fundamental cause of health disparities. We discuss future steps in integrating PGI and SES to refine population health prediction rules., Implications: Study findings point to the complementary relationship of PGI and socioeconomic indicators in explaining population variance in nicotine outcomes and cardiometabolic wellness. Population health surveillance and prediction rules would benefit from the combination of information from both polygenic and socioeconomic risks. Additionally, the risk for electronic cigarette use among users of conventional cigarettes may have a genetic component tied to the cumulative genetic propensity for heavy smoking. Further research on PGI for vaping is needed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Cardiovascular diseases (CVDs) continue to be the leading cause of mortality worldwide, necessitating the development of novel therapies. Despite therapeutic advancements, the underlying mechanisms remain elusive. Reactive oxygen species (ROS) show detrimental effects at high concentrations but act as essential signalling molecules at physiological levels, playing a critical role in the pathophysiology of CVD. However, the link between pathologically elevated ROS and CVDs pathogenesis remains poorly understood. Recent research has highlighted the remodelling of the epigenetic landscape as a crucial factor in CVD pathologies. Epigenetic changes encompass alterations in DNA methylation, post-translational histone modifications, adenosine triphosphate (ATP)-dependent chromatin modifications, and noncoding RNA transcripts. Unravelling the intricate link between ROS and epigenetic changes in CVD is challenging due to the complexity of epigenetic signals in gene regulation. This review aims to provide insights into the role of ROS in modulating the epigenetic landscape within the cardiovascular system. Understanding these interactions may offer novel therapeutic strategies for managing CVD by targeting ROS-induced epigenetic changes. It has been widely accepted that epigenetic modifications are established during development and remain fixed once the lineage-specific gene expression pattern is achieved. However, emerging evidence has unveiled its remarkable dynamism. Consequently, it is now increasingly recognized that epigenetic modifications may serve as a crucial link between ROS and the underlying mechanisms implicated in CVD., (© 2024 The Author(s). Published by IMR Press.)

Background: Cardiometabolic risk factors among youth are rising. Epigenetic age acceleration, a biomarker for aging and disease-risk, has been associated with adiposity in children, but its association with other cardiometabolic risk markers remains understudied. We employed data from the Health Outcomes and Measures of the Environment (HOME) study, a prospective pregnancy and birth cohort in the greater Cincinnati metropolitan area, to examine whether accelerated epigenetic age at birth as well as accelerated epigenetic age and faster pace of biological aging at age 12 years were associated with higher cardiometabolic risk in adolescents., Results: After adjusting for potential confounders, including estimated cell type proportions, epigenetic gestational age acceleration at birth, derived from the Bohlin, Knight, and Haftorn clocks using cord blood DNA methylation data, was not associated with cardiometabolic risk z-scores or individual cardiometabolic risk score components (visceral fat, leptin to adiponectin ratio, HOMA-IR, triglycerides to HDL-C ratio, HbA1c, or systolic blood pressure) at age 12 years. We also did not observe any associations of epigenetic age acceleration, calculated with Horvath's skin and blood, Hannum's, and Wu's epigenetic clocks using peripheral blood at age 12 years, with these same cardiometabolic risk markers. In contrast, faster pace of biological aging was associated with higher cardiometabolic risk [βs (95% CIs)] cardiometabolic risk score 0.25 (0.07, 0.42); visceral fat 0.21 (0.05, 0.38); and hemoglobin A1c 0.23 (0.05, 0.41) per standard deviation increase in pace of biological aging. Faster pace of biological aging was also positively associated with systolic blood pressure, triglycerides to HDL-C ratio, HOMA-IR, and leptin to adiponectin ratio, although these associations were not statistically significant., Conclusions: Our findings provide evidence that faster pace of biological aging was associated with higher cardiometabolic risk score, visceral fat, and HbA1c at age 12 years. Further research is needed to determine whether these associations persist from adolescence through adulthood., Competing Interests: Declarations Ethics approval and consent to participate The institutional review boards of Cincinnati Children’s Hospital Medical Center, the participating delivery hospitals, and the CDC approved this study. During a face-to-face visit, research assistants explained study protocols to each prospective participant and completed a checklist to ensure women were fully informed. At the 12-year visit, adolescents provided written informed assent after study protocols were explained and their questions answered. Consent for publication Not applicable. Competing interests Dr. Joseph Braun has served as an expert witness for plaintiffs involved in litigation related to PFAS-contaminated drinking water. The other authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Whether genetic susceptibility to cardiovascular diseases (CVDs) enhances the vulnerability to adverse cardiovascular outcomes by air pollution is unknown. We assessed the combined effect of air pollution and genetic predispositions on CVD risk., Methods and Results: From the UK Biobank cohort, we selected genetically unrelated White British participants without CVD. Levels of ambient particulate matter with a diameter of <2.5 μm (PM 2.5 ) and <10 μm were estimated using land use regression models. An individual's genetic predisposition to CVDs was determined by polygenic risk scores for coronary artery disease, myocardial infarction, stroke, ischemic stroke, heart failure, and atrial fibrillation. We stratified mortality and CVD risk by PM 2.5 exposure across high and low genetic risk groups. A total of 249 082 participants (aged 56.9±8.0 years, 46.8% men) were followed for a median of 10.8 years. The combined effect of PM 2.5 exposure and the genetic predisposition of CVD demonstrated the highest risk of cardiovascular death in the high genetic risk group with the greatest PM 2.5 exposure (adjusted hazard ratios ranging from 1.73 to 2.12 across the polygenic risk score of each CVD). The combination of higher exposure to ambient PM 2.5 and high genetic risk was associated with higher incidence of all CVDs, although no significant interactions were observed between genetic risk and PM 2.5 exposure on cardiovascular death or CVD events., Conclusions: A combination of greater PM 2.5 exposure and higher genetic predisposition to particular CVDs was modestly associated with elevated risks of cardiovascular death and CVDs. Not only alleviating PM 2.5 exposure in the general population but also implementing individualized preventive approach for those at high genetic risk might be beneficial.

Type 2 diabetes (T2D) is often comorbid with cardiovascular diseases (CVDs). The direction of causation between T2D and CVD is difficult to determine; however, there may be a common underlying pathway attributable to shared genetic factors. We aimed to determine whether there is a shared genetic susceptibility to T2D and CVD. This study utilizes large-scale datasets from the UK Biobank (UKB) and DIAGRAM consortium to investigate the genetic association between T2D and CVD through phenotypic association analyses, linkage disequilibrium score (LDSC) analysis, and polygenic risk score (PRS) analysis. LDSC analysis demonstrates significant genetic associations between T2D and various CVD subtypes, including angina, heart failure (HF), myocardial infarction (MI), peripheral vascular disease (PVD), and stroke. Although the genetic association between T2D and atrial fibrillation (AF) was not significant, individuals in the high-T2D PRS group had a significantly increased risk of CVD. These findings suggest a common genetic basis and suggest that genetic susceptibility to T2D may be a potential predictor of CVD risk.

Once considered unconventional cellular structures, membraneless organelles (MLOs), cellular substructures involved in biological processes or pathways under physiological conditions, have emerged as central players in cellular dynamics and function. MLOs can be formed through liquid-liquid phase separation (LLPS), resulting in the creation of condensates. From neurodegenerative disorders, cardiovascular diseases, aging, and metabolism to cancer, the influence of MLOs on human health and disease extends widely. This review discusses the underlying mechanisms of LLPS, the biophysical properties that drive MLO formation, and their implications for cellular function. We highlight recent advances in understanding how the physicochemical environment, molecular interactions, and post-translational modifications regulate LLPS and MLO dynamics. This review offers an overview of the discovery and current understanding of MLOs and biomolecular condensate in physiological conditions and diseases. This article aims to deliver the latest insights on MLOs and LLPS by analyzing current research, highlighting their critical role in cellular organization. The discussion also covers the role of membrane-associated condensates in cell signaling, including those involving T-cell receptors, stress granules linked to lysosomes, and biomolecular condensates within the Golgi apparatus. Additionally, the potential of targeting LLPS in clinical settings is explored, highlighting promising avenues for future research and therapeutic interventions., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Psoriatic disease (PsD) is closely associated with cardiovascular (CV) disease. The Life's Essential 8 (LE8) score is a new metric to assess CV health (CVH), where a higher score indicates better CVH. However, the longitudinal association between LE8 score and the risk of PsD remains uncertain., Objectives: To investigate, in a cohort study, the association between LE8 score, genetic susceptibility and the risk of PsD., Methods: This cohort study included 261 642 participants in the UK Biobank without PsD at baseline. LE8 comprises eight indicators: diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose and blood pressure. Cox proportional hazard models were used to examine the association between participants' LE8 scores, genetic risk of PsD and the risk of PsD. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated., Results: During an average follow-up of 12.3 years, 1501 participants developed PsD. Compared with participants with low LE8 scores, the HRs of developing PsD for those with moderate and high LE8 scores were 0.51 (95% CI 0.43-0.59) and 0.34 (95% CI 0.27-0.42) after adjustments, respectively. Dose-response analysis revealed a linear negative association between continuous LE8 score and the risk of developing PsD (P < 0.001), with no evidence of nonlinear association detected. Genetic susceptibility to PsD did not modify this association (P-interaction = 0.63). Subgroup analyses revealed that women had a more pronounced beneficial association between LE8 scores and PsD risk (P-interaction = 0.02)., Conclusions: Our study suggests that a higher LE8 score, regardless of genetic risk, is associated with a lower risk of PsD, particularly in women. Consequently, maintaining good CVH status is recommended to prevent PsD and assess associated risks., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

MFGE8 is a major exosome (EV) protein known to mediate inflammation and atherosclerosis in type 2 diabetes mellitus (T2DM) in animal studies. The pathophysiological role of this protein in obesity, T2DM, and cardiovascular disease is less investigated in humans. Earlier we reported a rare Asian Indian population-specific missense variant (rs371227978; Arg148His) in the MFGE8 gene associated with increased circulating Mfge8 and T2DM. We have further investigated the role of Mfge8 with T2DM risk in additional Asian Indians (n = 4897) and Europeans and other multiethnic cohorts from UK Biobank (UKBB) (n = 455,808) and the US (n = 1150). We also evaluated the exposure of Mfge8-enriched human EVs in zebrafish (ZF) for their impact on cardiometabolic organ system. Most individual carriers of Arg148His variant not only had high circulating Mfge8 but also revealed a positive significant correlation with glucose (r = 0.42; p = 4.9 × 10 -04 ), while the non-carriers showed a negative correlation of Mfge8 with glucose (r = -0.38; p = 0.001) in Asian Indians. The same variant was monomorphic in non-South Asian ethnicities. Even without the variant, serum Mfge8 correlated significantly with blood glucose in other non-South Asian ethnicities (r = 0.47; p = 2.2 × 10 -13 ). Since Mfge8 is an EV marker, we tested the exposure of Mfge8-enriched human EVs to ZF larvae as an exploratory study. The ZF larvae showed rapid effects on insulin-sensitive organs, developing fatty liver disease, heart hypertrophy and exhibiting redundant growth with poor muscular architecture with and without the high-fat diet (HFD). In contrast, the control group fishes developed fatty liver disease and heart hypertrophy only after the HFD feeding. Backed with strong support from animal studies on the role of Mfge8 in obesity, insulin resistance, and atherosclerosis, the current research suggests that circulating Mfge8 may become a potential marker for predicting the risk of T2DM and cardiovascular disease in humans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Several cardiovascular traits and diseases co-occur with Alzheimer's disease. We mapped their shared genetic architecture using multi-trait genome-wide association studies. Subsequent fine-mapping and colocalisation highlighted 16 genetic loci associated with both Alzheimer's and cardiovascular diseases. We prioritised rs11786896, which colocalised with Alzheimer's disease, atrial fibrillation and expression of PLEC in the heart left ventricle, and rs7529220, which colocalised with Alzheimer's disease, atrial fibrillation and expression of C1Q family genes. Single-cell RNA-sequencing data, co-expression network and protein-protein interaction analyses provided evidence for different mechanisms of PLEC, which is upregulated in left ventricular endothelium and cardiomyocytes with heart failure and in brain astrocytes with Alzheimer's disease. Similar common mechanisms are implicated for C1Q in heart macrophages with heart failure and in brain microglia with Alzheimer's disease. These findings highlight inflammatory and pleomorphic risk determinants for the co-occurrence of Alzheimer's and cardiovascular diseases and suggest PLEC, C1Q and their interacting proteins as potential therapeutic targets., Competing Interests: Competing interests The authors declare no comparing interests., (© 2024. The Author(s).)

Emerging evidence suggests that ADHD is associated with increased risk for metabolic and cardiovascular (cardiometabolic) diseases. However, an understanding of the mechanisms underlying these associations is still limited. In this study we estimated the associations of polygenic scores (PGS) for ADHD with several cardiometabolic diseases and biomarkers. Furthermore, we investigated to what extent the PGS effect was influenced by direct and indirect genetic effects (i.e., shared familial effects). We derived ADHD-PGS in 50,768 individuals aged 18-90 years from the Dutch Lifelines Cohort study. Using generalised estimating equations, we estimated the association of PGS with cardiometabolic diseases, derived from self-report and several biomarkers measured during a physical examination. We additionally ran within-sibling PGS analyses, using fixed effects models, to disentangle direct effects of individuals' own ADHD genetic risk from confounding due to indirect genetic effects of relatives, as well as population stratification. We found that higher ADHD-PGS were statistically significantly associated with several cardiometabolic diseases (R-squared [R 2 ] range = 0.03-0.50%) and biomarkers (related to inflammation, blood pressure, lipid metabolism, amongst others) (R 2 range = 0.01-0.16%) (P < 0.05). Adjustment for shared familial factors attenuated the associations between ADHD-PGS and cardiometabolic outcomes (on average 56% effect size reduction), and significant associations only remained for metabolic disease. Overall our findings suggest that increased genetic liability for ADHD confers a small but significant risk increase for cardiometabolic health outcomes in adulthood. These associations were observable in the general population, even in individuals without ADHD diagnosis, and were partly explained by familial factors shared among siblings., Competing Interests: Competing interests EDR has served as a speaker for Shire Sweden AB, a Takeda Pharmaceutical Company outside of this work. HL reports receiving grants from Shire Pharmaceuticals; personal fees from and serving as a speaker for Medice, Shire/Takeda Pharmaceuticals and Evolan Pharma AB; all outside the submitted work. HL is editor-in-chief of JCPP Advances., (© 2024. The Author(s).)

Sclerostin inhibitors protect against osteoporotic fractures, but their cardiovascular safety remains unclear. We conducted a cis-Mendelian randomisation analysis to estimate the causal effect of sclerostin levels on cardiovascular risk factors. We meta-analysed three GWAS of sclerostin levels including 49,568 Europeans and selected 2 SNPs to be used as instruments. We included heel bone mineral density and hip fracture risk as positive control outcomes. Public GWAS and UK Biobank patient-level data were used for the study outcomes, which include cardiovascular events, risk factors, and biomarkers. Lower sclerostin levels were associated with higher bone mineral density and 85% reduction in hip fracture risk. However, genetically predicted lower sclerostin levels led to 25-85% excess coronary artery disease risk, 40% to 60% increased risk of type 2 diabetes, and worse cardiovascular biomarkers values, including higher triglycerides, and decreased HDL cholesterol levels. Results also suggest a potential (but borderline) association with increased risk of myocardial infarction. Our study provides genetic evidence of a causal relationship between reduced levels of sclerostin and improved bone health and fracture protection, but increased risk of cardiovascular events and risk factors., Competing Interests: Competing interests DPA’s department has received grant/s from Amgen, Chiesi-Taylor, Lilly, Janssen, Novartis, and UCB Biopharma. His research group has received consultancy fees from Astra Zeneca and UCB Biopharma. Amgen, Astellas, Janssen, Synapse Management Partners and UCB Biopharma have funded or supported training programmes organised by DPA’s department. The views expressed in this study are the personal views of MGM and do not represent the views of her current employer, the European Medicines Agency. All other authors declare no conflicts of interest. Ethics approval & consent to participate All participants provided informed consent to participate in each one of the GWAS we have used. UK Biobank received ethical approval from the North West Multi-centre Research Ethics Committee (REC reference: 16/NW/0274). All participants provided informed consent to participate., (© 2024. The Author(s).)

Cardiometabolic and psychiatric disorders often co-exist and share common early life risk factors, such as low birth weight. However, the biological pathways linking early adversity to adult cardiometabolic/psychiatric comorbidity remain unknown. Dopamine (DA) neurotransmission in the striatum is sensitive to early adversity and influences the development of both cardiometabolic and psychiatric diseases. Here we show that a co-expression based polygenic score (ePGS) reflecting individual variations in the expression of the striatal dopamine transporter gene (SLC6A3) network significantly interacts with birth weight to predict psychiatric and cardiometabolic comorbidities in both adults (UK Biobank, N = 225,972) and adolescents (ALSPAC, N = 1188). Decreased birth weight is associated with an increased risk for psychiatric and cardiometabolic comorbidities, but the effect is dependent on a striatal SLC6A3 ePGS, that reflects individual variation in gene expression of genes coexpressed with the SLC6A3 gene in the striatum. Neuroanatomical analyses revealed that SNPs from the striatum SLC6A3 ePGS were significantly associated with prefrontal cortex gray matter density, suggesting a neuroanatomical basis for the link between early adversity and psychiatric and cardiometabolic comorbidity. Our study reveals that psychiatric and cardiometabolic diseases share common developmental pathways and underlying neurobiological mechanisms that includes dopamine signaling in the striatum., (© 2024. The Author(s).)

Background/Objectives : Mitochondria are the main organelles for ATP synthesis able to produce energy for several different cellular activities. Cardiac cells require high amounts of energy and, thus, they contain a high number of mitochondria. Consequently, mitochondrial dysfunction in these cells is a crucial factor for the development of cardiovascular diseases. Mitochondria constitute central regulators of cellular metabolism and energy production, producing approximately 90% of the cells' energy needs in the form of ATP via oxidative phosphorylation. The mitochondria have their own circular, double-stranded DNA encoding 37 genes. Any mitochondrial DNA sequence anomaly may result in defective oxidative phosphorylation and lead to cardiac dysfunction. Methods : In this study, we investigated the potential association between mitochondrial DNA mutation and cardiovascular disease. Cardiac tissue and serum samples were collected from seven patients undergoing coronary artery bypass grafting. Total DNA was extracted from cardiac muscle tissue specimens and serum and each sample was subjected to polymerase chain reaction (PCR) to amplify the NADH dehydrogenase 1 ( ND1 ) gene, which is part of the mitochondrial complex I enzyme complex and was screened for mutations. Results : We identified one patient with a homoplasmic A to G substitution mutation in cardiac tissue DNA and two patients with heteroplasmic A3397G mutation in serum DNA. Specifically, amplicon sequence analysis revealed a homoplasmic A3397G substitution in the ND1 gene in a tissue sample of the patient with ID number 1 and a heteroplasmic mutation in A3397G in serum samples of patients with ID numbers 3 and 6, respectively. The A to G substitution changes the amino acid from methionine (ATA) to valine (GTA) at position 31 of the ND1 gene. Conclusions : The detection of this novel mutation in patients with coronary artery disease may contribute to our understanding of the association between mitochondrial dysfunction and the disease, implying that mitochondria may be key players in the pathogenesis of cardiovascular diseases.

Determining whether someone has cardiometabolic disease (CMD), especially in the early stages, can be complicated. Risk stratification ordinarily depends on an extended process relying on medical history that typically considers blood pressure, cholesterol, smoking and diabetes status. Physicians have long relied on these key patient characteristics to assess CMD risk. However, these widely used clinical assessments are often identified later in life and by definition, in those individuals with progressed disease. This is partly because the onset of CMD naturally occurs in adulthood, however, the underlying processes can occur much earlier in life, even in the absence of obvious symptoms. For one thing, the pathways towards pathology may exist for years before symptom onset. Thus, among other things, there are opportunities to provide doctors with better insights into future disease prediction especially in younger adults with diabetes. The rapid rise in CMD together with the increased rates of obesity and diabetes in this population only emphasises the importance of predictive molecular biomarkers. One notable aspect is that traditional risk scores, such as those based on cholesterol measurements, are frequently found to be within normal ranges in younger populations. At the same time, given the significant overlap in risk factors for cardiovascular disease (CVD) and diabetes, the unmet clinical need is for early biomarkers of CMD that may help improve risk assessment in younger adults. This editorial highlights advances in the use of polygenic risk scores and emerging utility of genetic biomarkers to define intermediate CMD phenotypes discussing new classification criteria involving DNA methylation of genes to improve risk assessment. CMD is the number one cause of mortality and accounts for 31% of all global deaths. CMD is also multifactorial, comprising cardiovascular disease (CVD) and diabetes that have significant overlap in risk factors and disease biology. Diabetes is arguably the strongest risk factor for CVD development. Accounting for almost 90% of diabetes cases worldwide, type 2 diabetes (T2D) affects about 527 million people. The global economic burden is estimated at 1.3 trillion USD annually and is close to 1.8% of global GDP [1]. Despite the progress in preventive and therapeutic measures of CVD, the increasing CMD rates only underscore the important need of molecular biomarkers for early detection [2]. Determining whether someone has CMD usually involves an extended diagnostic process that has become essential for risk stratification and disease prevention [3]. While the onset of CMD typically occurs in adulthood, disease development commences much earlier, and this has scientists questioning whether molecular biomarkers could improve current prognostic risk scores. Predicting which people with T2D are most likely to develop CVD remains a significant challenge despite the recent advances in genetic mapping., (© 2024. The Author(s).)

Serum lipids have been associated with an increased risk of various cardiovascular diseases (CVDs) in several observational studies, but the causal inference between the remnant cholesterol (RC) levels and several CVDs risk has not been established. The purpose of this study was to investigate whether there is a causal relationship between RC levels and risk of developing CVDs by a bidirectional two-sample Mendelian randomization (TSMR) analysis. One TSMR analysis was performed using the publicly released large-scale genome-wide association study (GWAS) data. Inverse variance weighted (IVW) method was chosen as the main analysis method, and MR-Egger, weighted median, simple mode, and weighted mode were used as supplementary methods. We conducted a series of sensitivity analyses to assess the robustness of the main results, including the Cochran's Q test, MR-Egger intercept test, leave-one-out sensitivity analysis, and funnel plot. The main IVW method revealed that genetically predicted serum level of RC is significantly associated with an increased risk of developing ischemic heart disease (OR = 1.409, 95%CI = 1.284-1.546, P value = 4.753E-13), unstable angina pectoris (OR = 1.621, 95%CI = 1.398-1.880, P value = 1.672E-10), myocardial infarction (OR = 1.526, 95%CI = 1.337-1.741, P value = 3.771E-10), cardiac arrest (OR = 1.595, 95%CI = 1.322-1.924, P value = 1.076E-06), heart failure (OR = 1.086, 95%CI = 1.009-1.169, P value = 0.028), hypertension (OR = 1.089, 95%CI = 1.043-1.136, P value = 9.458E-05), major coronary heart disease (CHD) events (OR = 1.515, 95%CI = 1.376-1.669, P value = 3.217E-17), coronary atherosclerosis (OR = 1.388, 95%CI = 1.231-1.564, P value = 7.739E-08), cardiac arrhythmias (OR = 1.067, 95%CI = 1.008-1.130, P value = 0.025), and atrial fibrillation and flutter (OR = 1.122, 95%CI = 1.039-1.211, P value = 0.003). Additionally, the causal associations between the RC levels and these CVDs remained significant after correcting for the false discovery rate (all P value < 0.05). However, this study did not find any significant association of RC with cardiomyopathy and pericarditis (both P value > 0.05). Heterogeneity existed in the IVs of RC and ischemic heart disease, unstable angina pectoris, myocardial infarction, heart failure, hypertension, major CHD events, cardiomyopathy, coronary atherosclerosis, cardiac arrhythmias and atrial fibrillation and flutter using the Cochran's Q test (all P value < 0.05). Moreover, there was no horizontal pleiotropy in this study (all P value > 0.05). The leave-one-out sensitivity analyses showed that the causal effects between RC level and CVDs (except for heart failure, cardiomyopathy, pericarditis and cardiac arrhythmias) are not driven by a single SNP. The funnel plots showed that there is no obvious potential bias in our study. In the replication analysis, the genetically predicted RC levels were positively associated with a 43.12% higher risk of coronary artery disease. This present study supported the causal link between RC and heightened the risk of CVDs, indicating that RC-lowering treatment might be effective in preventing CVDs., (© 2024. The Author(s).)

Osteoarthritis is one of the most common musculoskeletal diseases and increases the risk of severe cardiovascular disease, like heart attack and stroke. In some individuals, osteoarthritis and cardiovascular disease will co-occur. This co-occurrence might be due to shared risk factors, for example high age, lifestyle factors and/or a shared genetic liability for the two diseases. Here, we show that the correlation between osteoarthritis and cardiovascular disease can be explained by shared genetic factors, independent of high age and body weight, and also likely independent of lifestyle factors, like smoking and physical activity level. Findings suggest that genetic factors that are shared for osteoarthritis and cardiovascular disease may contribute to both diseases. Thus, the prevailing idea that osteoarthritis is predominantly a risk factor for cardiovascular disease is challenged. Our findings imply that the current diagnostic boundaries between these diseases may need to be re-evaluated., (© 2024. The Author(s).)

The exposome encompasses the full range of environmental exposures throughout a person's lifetime and plays an important role in cardiovascular health. Interactions with the social, natural, and built components of the exposome significantly impact cardiovascular disease prevalence and mortality. Robust data analytics, including machine learning and geospatial analysis, have advanced our understanding of how these factors converge to influence cardiovascular disease risk. The integration of multiomics platforms and advanced computational approaches enhances our ability to characterize the exposome, leading to targeted public health interventions and innovative risk reduction strategies aimed at improving cardiovascular health globally. These multiomics platforms that integrate factors such as genomics, epigenomics, clinical data, social factors, environmental factors, and wearable technology will characterize the exposome in greater detail concerning cardiovascular health. In this review, we aimed to elucidate the components of the exposome and discuss recent literature regarding their relationship to cardiovascular health., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Precision medicine, which among other aspects includes an individual's genomic data in diagnosis and management, has become the standard-of-care for Mendelian cardiovascular disease (CVD). However, early identification and management of asymptomatic patients with potentially lethal and manageable Mendelian CVD through screening, which is the promise of precision health, remains an unsolved challenge. The reduced costs of genomic sequencing have enabled the creation of biobanks containing in-depth genetic and health information, which have facilitated the understanding of genetic variation, penetrance, and expressivity, moving us closer to the genotype-first screening of asymptomatic individuals for Mendelian CVD. This approach could transform health care by diagnostic refinement and facilitating prevention or therapeutic interventions. Yet, potential benefits must be weighed against the potential risks, which include evolving variant pathogenicity assertion or identification of variants with low disease penetrance; costly, stressful, and inappropriate diagnostic evaluations; negative psychological impact; disqualification for employment or of competitive sports; and denial of insurance. Furthermore, the natural history of Mendelian CVD is often unpredictable, making identification of those who will benefit from preventive measures a priority. Currently, there is insufficient evidence that population-based genetic screening for Mendelian CVD can reduce adverse outcomes at a reasonable cost to an extent that outweighs the harms of true-positive and false-positive results. Besides technical, clinical, and financial burdens, ethical and legal aspects pose unprecedented challenges. This review highlights key developments in the field of genotype-first approaches to Mendelian CVD and summarizes challenges with potential solutions that can pave the way for implementing this approach for clinical care.

Cardiovascular diseases (CVDs) are complex, multifactorial conditions that require personalized assessment and treatment. Advancements in multi-omics technologies, namely RNA sequencing and whole-genome sequencing, have provided translational researchers with a comprehensive view of the human genome. The efficient synthesis and analysis of this data through integrated approach that characterizes genetic variants alongside expression patterns linked to emerging phenotypes, can reveal novel biomarkers and enable the segmentation of patient populations based on personalized risk factors. In this study, we present a cutting-edge methodology rooted in the integration of traditional bioinformatics, classical statistics, and multimodal machine learning techniques. Our approach has the potential to uncover the intricate mechanisms underlying CVD, enabling patient-specific risk and response profiling. We sourced transcriptomic expression data and single nucleotide polymorphisms (SNPs) from both CVD patients and healthy controls. By integrating these multi-omics datasets with clinical demographic information, we generated patient-specific profiles. Utilizing a robust feature selection approach, we identified a signature of 27 transcriptomic features and SNPs that are effective predictors of CVD. Differential expression analysis, combined with minimum redundancy maximum relevance feature selection, highlighted biomarkers that explain the disease phenotype. This approach prioritizes both biological relevance and efficiency in machine learning. We employed Combination Annotation Dependent Depletion scores and allele frequencies to identify variants with pathogenic characteristics in CVD patients. Classification models trained on this signature demonstrated high-accuracy predictions for CVD. The best performing of these models was an XGBoost classifier optimized via Bayesian hyperparameter tuning, which was able to correctly classify all patients in our test dataset. Using SHapley Additive exPlanations, we created risk assessments for patients, offering further contextualization of these predictions in a clinical setting. Across the cohort, RPL36AP37 and HBA1 were scored as the most important biomarkers for predicting CVDs. A comprehensive literature review revealed that a substantial portion of the diagnostic biomarkers identified have previously been associated with CVD. The framework we propose in this study is unbiased and generalizable to other diseases and disorders., (© 2024. The Author(s).)

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes joint pain and disability. The connection between RA and cardiovascular (CV) disease is still being studied. This research aims to explore the relationship between CV-related microRNAs, inflammation, and glycosylated proteins to understand RA's inflammatory pathophysiology concerning CV disease. The study included 219 RA patients, 82 with metabolic disorders, and 64 controls. Clinical evaluations and blood samples were collected. Quantification of microRNAs (Let7a, 24, 96, 103, 125a, 125b, 132, 146, 191, 223, 425, 451) and measurement of glycoproteins (GlycA, GlycB, GlycF) using proton nuclear magnetic resonance (1 H-NMR) were performed. Multivariate linear models were applied. RA patients showed higher glycoprotein levels than those with metabolic disorders and controls. Significant associations between miRNAs 24, 451, Let7a and glycoprotein levels were found in RA patients, particularly in women. Glycoprotein levels were positively correlated with inflammatory markers, highlighting their role in indicating RA severity. This study highlights elevated glycoprotein levels in RA patients, indicating a severe inflammatory pattern. Moreover, glycoproteins were highly associated with CV-disease-related miRNAs, indicating that glycoproteins are involved in both inflammation and CV disease. Finally, the inflammatory profile of glycoproteins was validated as they were highly associated with inflammatory markers of RA., (© 2024. The Author(s).)

Although observational studies have linked primary aldosteronism (PA) with cardiovascular diseases (CVDs), the causality remains uncertain. In this study, we aimed to investigate whether PA is causally associated with CVD risk and cardiac magnetic resonance (CMR) parameters using the Mendelian randomization (MR) method. Independent and genome-wide significant single nucleotide polymorphisms for PA were extracted from genome-wide association study (GWAS) summary statistics. Genetic associations with the CVDs and CMR parameters were obtained from recent large-scale GWASs or genetic consortia. Inverse-variance weighted (IVW) method was utilized for the preliminary estimates, and multiple sensitivity analyses (including weighted median, Cochran's Q test, MR-Egger, MR-PRESSO, and leave-one-out analysis) were conducted to verify the robustness of the results. The MR analyses using the IVW method showed that genetically predicated PA was significantly associated with atrial fibrillation (OR = 1.046, 95% CI: 1.029-1.062, padj < 0.001), myocardial infarction (OR = 1.029, 95% CI: 1.005-1.053, padj = 0.027), heart failure (OR = 1.023, 95% CI: 1.004-1.042, padj = 0.027), any stroke (OR = 1.062, 95% CI: 1.031-1.095, padj < 0.001), any ischemic stroke (OR = 1.058, 95% CI: 1.022-1.095, padj = 0.004), and small vessel stroke (OR = 1.116, 95% CI: 1.041-1.196, padj = 0.004). Notably, PA also had a causal effect on adverse cardiac remodeling, including larger ventricular and atrial volumes, higher ventricular stroke volume, and reduced left atrial emptying fraction. Our findings support a causal role of PA in higher cardiovascular disease risk and adverse cardiac remodeling. Given the diagnostic delay and disease burden in PA, more attention should be paid to the screening and treatment of PA to reduce the incidence of cardiovascular outcomes., (© 2024 The Author(s). The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)