AIMS:To evaluate the association of frailty with mortality and incident extrahepatic diseases in individuals with metabolic dysfunction-associated steatotic liver disease and the interaction between frailty and cardiovascular health. METHODS:This prospective cohort study included 107,867 participants with metabolic dysfunction-associated steatotic liver disease from the UK Biobank. Metabolic dysfunction-associated steatotic liver disease is defined as hepatic steatosis plus cardiometabolic abnormality. Frailty was assessed as physical frailty based on five components (weight loss, exhaustion, physical activity, gait speed, and grip strength) and the Rockwood frailty index, while cardiovascular health was evaluated using the Life's Essential 8 score. RESULTS:Frailty was associated with increased risks of all-cause mortality (physical frailty: HR 2.01, 95% CI 1.87-2.16; frailty index: HR 1.63, 95% CI 1.54-1.74) and incident extrahepatic diseases with the exception of cancer (physical frailty: HRs ranged from 1.62 to 3.35; frailty index: HRs ranged from 1.34 to 8.07). Among the five components of physical frailty, slow gait speed exhibited the strongest associations with most adverse outcomes. There were significant multiplicative and additive interactions between frailty and cardiovascular health on respiratory disease mortality, heart failure, and peripheral arterial disease. Compared with participants with no frailty and good cardiovascular health, those with both frailty and poor cardiovascular health had the highest risks of all adverse outcomes. CONCLUSION:Frailty was associated with increased risks of mortality and extrahepatic complications in metabolic dysfunction-associated steatotic liver disease, particularly in those with suboptimal cardiovascular health. Early detection and interventions for frailty are needed alongside cardiovascular health promotion to enhance the prognosis of metabolic dysfunction-associated steatotic liver disease.

BACKGROUND:Identifying high-risk individuals for cardiovascular and all-cause mortality among individuals with cardiovascular-kidney-metabolic (CKM) syndrome stage 0-3 can guide the implementation of targeted interventions. This study aimed to evaluate the predictive value of plasma proteins for future cardiovascular and all-cause mortality. METHODS:This study included 39,007 participants from the UK Biobank (UKB) with CKM stage 0-3 and available proteomic data. Associations between plasma proteins and future risks of cardiovascular and all-cause mortality were assessed using Cox proportional hazards models. Key proteins were identified through an ensemble machine learning approach integrating support vector machine (SVM), random forest (RF), and extreme gradient boosting (XGBoost) algorithms. Subsequently, Cox models were applied to evaluate the incremental predictive value of these key proteins and their ability to enhance risk stratification for mortality outcomes. Furthermore, temporal trajectories of protein levels were examined in the years preceding death. RESULTS:During a median follow-up of 15.2 years, 505 participants died from cardiovascular causes and 3368 from any cause. 56 and 269 out of 2911 plasma proteins were significantly associated with cardiovascular and all-cause mortality, respectively (Bonferroni-adjusted P < 0.05). Incorporating seven and eight key proteins into conventional model significantly improved long-term predictive performance (C-statistics: 0.812 versus 0.782 for cardiovascular mortality; 0.772 versus 0.739 for all-cause mortality; both P < 0.001), and also provided incremental predictive value for 5- and 10-year mortality risks. Notably, participants died during follow-up exhibited markedly elevated certain protein levels over a decade before deaths, with progressively increasing trajectories over time. Stratification based on optimal predicted risk thresholds further revealed distinct cumulative mortality risks across groups. CONCLUSIONS:In individuals with CKM stage 0-3, plasma proteins combined with traditional risk factors may predict future cardiovascular and all-cause mortality.

Background Mosaic loss of chromosome Y (mLOY) has been linked to several cardiovascular diseases, but its association with peripheral artery disease (PAD) remains unclear. We examined the relationship between mLOY and symptomatic PAD. Methods This longitudinal study included 217 047 men without prevalent PAD. mLOY was identified using the Mosaic Chromosomal Alterations pipeline. Incident symptomatic PAD was ascertained using International Classification of Diseases, Tenth Revision (ICD‐10), and Office of Population Censuses and Surveys Classification of Interventions and Procedures, version 4 codes. Cox regression was used to evaluate the association between mLOY and PAD. We also performed exploratory mediation analyses of immune‐inflammatory biomarkers, examined the joint association of mLOY and smoking, and assessed the contribution of mLOY to sex‐related PAD disparities. Results During a median follow‐up of 13.6 years, 4910 men developed symptomatic PAD. mLOY was associated with a higher risk of symptomatic PAD (hazard ratio [HR], 1.25 [95% CI, 1.17–1.33]; P<0.001), with the strongest association observed for expanded mLOY (mosaic cell fraction ≥10%) (HR, 1.35 [95% CI, 1.24–1.47]; P<0.001). Exploratory analyses suggested that several immune‐inflammatory biomarkers were statistically related to the mLOY‐PAD association. Additive‐scale interactions were observed between mLOY and former or current smoking. Compared with nonsmokers without mLOY, current smokers carrying mLOY had the highest PAD risk (HR, 4.69). Compared with matched women, men with mLOY had an ≈1.74‐fold higher PAD risk. Conclusions mLOY was associated with symptomatic PAD, independently of other risk factors. These findings provide biologically informative evidence linking mLOY to symptomatic PAD and highlight smoking cessation as an important public‐health priority in men.

Background: Circadian rest–activity rhythm (CRAR) is a modifiable determinant of metabolic and cardiovascular health, yet its role in cardiovascular events and mortality among individuals with cardiovascular–kidney–metabolic (CKM) syndrome remains unclear. Methods: Accelerometer-derived CRAR parameters were analyzed in two nationally representative cohorts. Primary outcomes included cardiovascular incidence among participants with CKM stages 0–3 and all-cause and cardiovascular mortality among those with stages 1–4. Multinomial logistic and Cox proportional hazards models assessed associations of CRAR with CKM progression and subsequent outcomes. Mediation analyses examined inflammatory biomarkers, and improvements in prediction were evaluated using changes in C-statistics. Results: Among 74,777 participants, higher relative amplitude (RA) tertiles were associated with slower CKM progression and lower risks of cardiovascular incidence (T2: HR 0.87, 95% CI 0.82–0.93; T3: HR 0.79, 95% CI 0.73–0.85), all-cause mortality (T2: HR 0.70, 95% CI 0.64–0.77; T3: HR 0.60, 95% CI 0.54–0.67), and cardiovascular mortality (T2: HR 0.70, 95% CI 0.57–0.86; T3: HR 0.45, 95% CI 0.34–0.61). Higher intradaily variability (IV) was associated with increased all-cause mortality (T2: HR 1.12, 95% CI 1.02–1.22; T3: HR 1.19, 95% CI 1.08–1.30). Inflammatory biomarkers modestly mediated these associations (1%–5%). Optimal thresholds were RA = 0.87 for cardiovascular incidence, RA = 0.81 and IV = 0.68 for mortality. Adding CRAR to basic models improved prediction of all-cause and cardiovascular mortality (ΔC-statistic = 0.019 and 0.017). Results were validated in an independent cohort of 6046 participants. Conclusion: Adverse CRAR is associated with CKM progression and elevated risks of cardiovascular events and mortality, highlighting its utility in identifying high-risk individuals and guiding targeted interventions through risk stratification and incremental prediction.

Microplastics (MPs) are emerging environmental contaminants with potential hepatotoxicity, yet direct epidemiological evidence linking internal MP exposure to liver injury is scarce, particularly in individuals with type 2 diabetes (T2D). In this cross-sectional study nested within the METAL2 cohort, we aimed to characterize blood microplastic profiles in patients with T2D and to determine whether specific MP polymers are associated with hepatic steatosis and fibrosis risk, with experimental validation of the identified polymer. In patients with T2D, multiple MP polymers were detectable in blood, with polyvinyl chloride (PVC), polyamide 66 (PA66), and polystyrene (PS) being the most prevalent. Although PVC constituted the largest proportion of total MP burden, PS showed the most consistent nominal positive liver-related signal in the human analyses, including higher levels in participants with elevated fibrosis risk and higher FIB-4 and ALT in the highest exposure quartile. Experimental validation in diabetic mice demonstrated that PS microplastics markedly exacerbated hepatic steatosis, inflammation, and collagen deposition, leading to overt liver fibrosis. Mechanistically, PS-MPs exposure disrupted hepatic lipid homeostasis and concurrently activated the NLRP3 inflammasome and the TGF-β1/Smad signaling pathway, promoting inflammatory amplification and hepatic stellate cell activation. This integrated human and experimental study provides preliminary evidence that circulating PS-associated signals are linked to liver-related indices in T2D, while experimental findings support the biological plausibility that PS exposure may aggravate hepatic injury under diabetic conditions.

CONTEXT:Circadian rhythms may influence metabolic dysfunction-associated steatotic liver disease (MASLD), but the effect of personal light exposure and rest-activity rhythms on MASLD risk remain unclear. OBJECTIVE:To examine the associations between 24-hour light exposure, rest-activity rhythm (24-h-RAR), and the risk of incident MASLD, as well as how these factors influence genetic risk and life expectancy in individuals with MASLD. METHODS:This study used accelerometry data from both the National Health and Nutrition Examination Survey (NHANES) and UK Biobank cohorts. 24 h-RAR was assessed using nonparametric metrics, including activity level during the most active 10 hours (M10), activity level during the least active 5 hours (L5), relative amplitude (RA), M10 onset, and L5 onset. Light exposure was categorized into daytime and nighttime periods, with exposure durations recorded separately at different threshold levels. The primary outcome was MASLD, with secondary outcomes including fibrosis and cirrhosis. RESULTS:In the UK Biobank prospective analysis, each 0.1-unit and 1-unit increase in RA and M10 were associated with a 30% and 2% reduction of MASLD risk, respectively. In contrast, each 1-unit increase in L5 and delayed L5 onset were linked to an 8% and 21% increase of MASLD risk. Moreover, each additional hour of daylight exposure above 6000 lux was associated with a 9% lower risk of MASLD, while each additional 30 minutes of nocturnal light exposure above 30 lux corresponded to a 22% higher risk of MASLD. Additionally, a favorable 24 h-RAR profile and adequate light exposure were associated with a lower risk of fibrosis and cirrhosis, as well as improved life expectancy among participants with MASLD. Similar associations were observed in the NHANES analysis. CONCLUSION:Greater daytime light exposure, reduced nocturnal light exposure, and regulated RARs may protect against MASLD and prevent its progression to liver fibrosis and advanced liver disease.

Glucagon-like peptide-1 receptor (GLP1R) agonists and dual glucose-dependent insulinotropic polypeptide receptor/glucagon-like peptide-1 receptor (GIPR/GLP1R) agonists are established treatments for diabetes and obesity, but their potential effects on biological aging remain uncertain. In this drug target Mendelian randomization study, we assessed the associations of genetically proxied modulation of GLP1R, GIPR, and dual GIPR/GLP1R pathways with four aging phenotypes, including frailty index, phenotypic age (PhenoAge) acceleration, telomere length, and longevity. Glycated hemoglobin (HbA1c) lowering via GIPR, modeling the glucose-lowering effect of variants in GIPR loci, was consistently associated with a lower frailty index (primary dataset: β = − 0.10 [95

Abstract Objective To assess the association between obstructive sleep apnea (OSA) risk levels and major cardiovascular disease (CVD) subtypes in individuals with metabolic dysfunction‐associated fatty liver disease (MAFLD). Methods This cohort study included 128,022 MAFLD participants from the UK Biobank without CVD at baseline. OSA risk was assessed using the Berlin Questionnaire. Cardiovascular outcomes, including coronary heart disease (CHD), atrial fibrillation (AF), heart failure (HF), and stroke, were identified via hospital and death records. Cox proportional hazards models estimated the associations between OSA risk levels and CVD events. Results Over a median follow‐up of 13.6 years, 25,618 CVD events occurred. Compared with participants at low OSA risk, those at high OSA risk were associated with higher CHD (hazard ratios [HR], 1.10; 95% CI: 1.06–1.14) and AF (HR, 1.05; 95% CI: 1.01–1.10) after full adjustment, but not with HF (HR, 1.05; 95% CI: 0.98–1.11) or stroke (HR, 0.94; 95% CI: 0.87–1.02). Associations were strongest in overweight individuals without diabetes. No significant interaction was observed between OSA risk and genetic CVD susceptibility. Conclusion High OSA risk independently increases CHD and AF risk in MAFLD, particularly among overweight individuals without diabetes, suggesting targeted intervention may be beneficial.

OBJECTIVE:To evaluate the association between gestational diabetes mellitus (GDM) and accelerated biological aging in middle-aged and elderly women. RESEARCH DESIGN AND METHODS:We included parous women with a baseline survey on history of GDM and biological aging biomarkers from the UK Biobank. Information regarding prior GDM was collected via a touchscreen questionnaire and linkage to hospital admission records. Biological aging was evaluated using validated phenotypic age (PhenoAge) based on chronological age and nine biomarkers measured at baseline (2006-2010). Biological aging acceleration was determined as the residual by regressing PhenoAge estimates on chronological age. All-cause mortality and incident cardiometabolic disease during follow-up were also assessed. RESULTS:Among the 178,363 women (mean age, 57.0 [SD 7.9] years), 1,141 had a history of GDM. In a multivariable-adjusted model, a history of GDM was associated with an increase in PhenoAge acceleration by 2.34 (95% CI 2.02, 2.66) years. The association persisted regardless of the occurrence of type 2 diabetes and related comorbidities after GDM. Consistent results were observed across subgroups, while the GDM-related PhenoAge acceleration was more prominent among women with less physical activity and obesity (both Pinteraction < 0.01). The mediation analysis demonstrated that PhenoAge acceleration explained 57.0% (95% CI 21.0, 86.9), 12.4% (7.3, 20.4), and 21.9% (14.0, 32.5) of the positive associations between GDM and all-cause mortality, type 2 diabetes, and cardiovascular disease, respectively. CONCLUSIONS:Women with a history of GDM were biologically older than their non-GDM counterparts. The biological aging acceleration partially accounted for the associations between GDM and adverse health outcomes.

Mitochondrial redox imbalance and defective oxidative phosphorylation are central features of lipotoxic cardiac injury, but whether diet-related chemical exposures perturb cardiomyocyte mitochondrial gene-expression machinery remains unclear. Here, we investigated whether sucralose promotes cardiac redox-metabolic remodeling and lipid accumulation involving MRPL12-associated mitoribosomal impairment. Male C57BL/6J mice were exposed to sucralose in drinking water for 28 weeks; hiPSC-derived cardiomyocytes were used for mechanistic assays, and hiPSC-derived cardiomyocytes and H9c2 cardiomyoblast-like cells were used for lipid-accumulation assays under palmitic acid/oleic acid-induced lipid-loading conditions. Chronic sucralose exposure was associated with cardiac dysfunction, myocardial lipid accumulation, mitochondrial structural injury, ATP depletion, oxidative stress-associated signals, reduced glutathione redox buffering capacity, and reduced oxidative phosphorylation (OXPHOS) protein abundance. Quantitative cardiac proteomics identified mitochondrial ribosome- and oxidative phosphorylation-related changes, with MRPL12 emerging as a candidate mechanistic node. In cardiomyocytes, sucralose reduced MRPL12 abundance, altered the distribution of 39S/55S-enriched mitoribosomal fractions, suppressed residual nascent protein synthesis under cytosolic translation-suppressed conditions, reduced mitochondrially encoded OXPHOS proteins, impaired mitochondrial respiration, and aggravated lipid accumulation. Restoration of MRPL12 in cardiomyocytes or mouse hearts partially attenuated sucralose-associated redox-bioenergetic impairment, lipid deposition, and cardiac remodeling. Conversely, siRNA-mediated MRPL12 knockdown phenocopied key sucralose-associated abnormalities, including reduced abundance of mtDNA-encoded OXPHOS subunits, impaired respiration, increased mitochondrial superoxide-associated signal, and lipid accumulation. These findings support MRPL12-associated mitoribosomal impairment as a contributing mechanism linking sucralose exposure to mitochondrial redox-bioenergetic dysfunction and metabolic remodeling in the heart.

Atrial fibrillation (AF) should be recognized as a complication of diabetes, with a prevalence of up to 25% and increasing incidence rates in individuals with diabetes. Atrial fibrillation can develop in individuals with diabetes independent of hypertension, atherosclerotic cardiovascular disease, or heart failure. The pathogenesis linking diabetes to AF is multifactorial, involving atrial structural, electrical, electromechanical, and autonomic remodelling, as well as diabetes-related metabolic comorbidities. Given that the prevalence of diabetes (mainly Type 2 diabetes) is expected to increase further, the coexistent burden of AF on individuals, society, and healthcare systems will continue to increase. Thus, an integrated CARE-based management approach should be adopted to optimize care for diabetic patients across all stages of those at risk for AF and those with subclinical or clinical AF. This includes Comorbidity and risk factor management, Avoidance of stroke and thromboembolism, Reduction of symptoms by rate and rhythm control, and Evaluation and dynamic reassessment. This review outlines the intricate and close relationship between diabetes and AF, addressing the epidemiology, pathogenesis, and management strategies based on the CARE-based approach in diabetic patients. Such consideration may facilitate timely prevention, early detection, and effective intervention, ultimately improving the health outcomes of patients with AF and diabetes.

BACKGROUND AND AIMS:The Lancet Diabetes and Endocrinology Commission recently proposed the new definition of preclinical and clinical obesity. Our study aimed to investigate the associations of the novel obesity classifications with incident cardiovascular disease (CVD). METHODS:In 459,102 UK Biobank participants enrolled between 2006 and 2010, we applied the new definitions of clinical and preclinical obesity, based on the presence of excess adiposity with or without organ dysfunction, to assess their associations with incident CVD and its subtypes. Participants were further stratified into a seven-category classification integrating the Lancet framework with traditional body mass index (BMI) categories. Multivariable Cox regression estimated hazard ratios (HR) and 95% confidence intervals (CI) for each obesity classification in relation to CVD risk. RESULTS:Over a median follow-up of 11.0 years, a total of 51,640 cases of CVD incidence were recorded. Compared to those with no obesity, individuals with preclinical obesity exhibited modestly elevated risks of CVD (HR 1.11, 95% CI 1.08-1.15), while clinical obesity was associated with substantially higher risks of total CVD (HR 1.77, 95% CI 1.72-1.82) and all subtypes, including coronary heart disease (CHD), stroke, and heart failure. Furthermore, newly diagnosed preclinical and clinical obesity with BMI below the conventional obesity threshold also had elevated incident CVD risk, with strongest association for CHD. CONCLUSIONS:The new framework advances CVD risk stratification beyond BMI alone, emphasizing the importance of incorporating excess body fat and functional health assessments into obesity diagnosis. Stronger associations with clinical obesity highlight its utility as a cumulative disease burden classifier, identifying individuals at higher cardiovascular risk.

BACKGROUND:Steatotic liver disease (SLD) may increase the risk of cardiovascular disease. However, few studies investigated such associations under dynamic changes in steatotic status. Thus, we aim to investigate the association between longitudinal changes in fatty liver index (FLI), a surrogate measure for assessing hepatic steatosis, and risk of incident atrial fibrillation (AF). MATERIALS AND METHODS:This study included 15,995 individuals from the UK Biobank whose hepatic steatosis status was assessed twice via the FLI in 2006-2010 and 2012-2013. We divided individuals into four groups: non-SLD (both FLI < 60), incident SLD (the first FLI < 60 and the second FLI ≥ 60), regressed SLD (the first FLI ≥ 60 and the second FLI < 60), and persistent SLD (both FLI ≥ 60). Multivariable Cox regressions, subgroup analyses by AF polygenic risk scores and mediation analysis to identify potential inflammatory mediators were performed. RESULTS:Over a median follow-up of 4.4 years, 931 (5.8%) AF cases were documented. Compared to persistent SLD, SLD regressed was associated with a 31% lower risk of incident AF (HR: 0.69, 95%CI: 0.52-0.92). In the interaction analyses, the above association was strengthened in those with high genetic risk of AF (P for interaction = 0.013): compared with persistent SLD, for those with high genetic risk, regressed SLD and non-SLD significantly decreased AF risk (0.48, 0.31-0.74; 0.73, 0.54-0.97, respectively), but this was not the case for those with middle genetic risk (1.03, 0.62-1.69; 1.27, 0.89-1.82, respectively) and low genetic risk (0.78, 0.43-1.40; 0.88, 0.56-1.38, respectively). Additionally, in the mediation analyses, changes in the C-reactive protein-albumin-lymphocyte (CALLY) index served as potential mediators (ACME = 0.04, P = 0.04, proportion mediated = 8.5%). CONCLUSION:In the middle-to-elderly aged population, FLI decrease may reduce AF risk, especially in individuals with high genetic risk. Moreover, this association was partially mediated by a change in the CALLY index.

The EAT-Lancet diet (ELD) and plant-based diets (PBDs) are recommended for their potential health and environmental benefits, but comparative analyses of these dietary patterns in relation to mortality risk remain limited. This study aimed to evaluate the associations of ELD and PBDs with mortality and life expectancy in two nationwide cohorts. Participants from the UK Biobank and the US National Health and Nutrition Examination Survey (NHANES) (2003–2018) were included. Dietary intake was assessed using 24-h dietary recalls. The ELD index (ELD-I), overall PBD index (PDI), healthful PBD index (hPDI), and unhealthful PBD index (uPDI) were calculated and categorized into tertiles. Primary outcomes were all-cause mortality, cause-specific mortality, and life expectancy. After full adjustment, the hazard ratio (HR) for all-cause mortality when comparing the highest versus lowest tertiles was 0.87 (95

Background The impact of clonal haematopoiesis of indeterminate potential (CHIP), a novel cardiovascular risk factor, remains unclear in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), where cardiovascular disease (CVD) is the main cause of mortality. Methods We analyzed data from 140,086 UK Biobank participants with MASLD. CHIP was identified via whole-exome sequencing. Incident CVD, including coronary heart disease (CHD), stroke, and heart failure (HF), were the primary outcomes. Cox proportional hazards models assessed the association between CHIP and CVD risk. Results During a median 13.5-year follow-up, 15.7% of participants developed CVD. CHIP was associated with a higher risk of CVD (HR: 1.16, 95% CI: 1.09–1.23), driven by increased risks of stroke (HR: 1.22, 95% CI: 1.07–1.38) and HF (HR: 1.34, 95% CI: 1.21–1.49). Mutations in ASXL1, SRSF2, JAK2 , and SF3B1 conferred a particularly high risk. Additionally, a higher clonal haematopoiesis risk score (CHRS) was strongly associated with incident CVD, CHD, stroke, and HF. Conclusions CHIP is an independent risk factor for incident CVD in patients with MASLD. Early identification of CHIP may help stratify cardiovascular risk and guide preventive strategies in this population.

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic loss of the Y chromosome (mLOY) are age-related somatic genomic mutations linked to mortality, yet their independent and combined associations with mortality remain incompletely characterized. We analyzed 205,543 UK Biobank men with CHIP and mLOY status derived from genomic data and followed them for all-cause and cause-specific mortality. During a median follow-up of 15.3 years, 28,164 deaths occurred. In multivariable Cox models, CHIP was associated with higher all-cause mortality (HR 1.34, 95% CI 1.28–1.41), whereas mLOY showed a weaker association (HR 1.04, 95% CI 1.01–1.06). Men with both CHIP and mLOY had the highest absolute mortality risk (HR 1.39, 95% CI 1.27–1.52), but formal tests did not support statistically significant additive or multiplicative interaction. Similar patterns were observed across major cause-specific outcomes including cardiovascular disease mortality, cancer mortality, and respiratory mortality. Exploratory gene-specific analyses suggested heterogeneity by CHIP driver gene, with SRSF2 carriers with co-occurring mLOY showing the largest mortality estimate, although this small-subgroup finding requires replication. These findings support independent associations of CHIP and mLOY with mortality in men, while providing no clear evidence for synergistic interaction.

Exploring the association of clonal haematopoiesis of indeterminate potential (CHIP) with psychiatric disorders (PDs) may help to elucidate the biological mechanisms underlying PDs. The study aimed to identify the specific PD subtypes associated with CHIP and gene-specific CHIP for each PD subtype. A total of 360,451 participants from UK Biobank without PDs at baseline, aged 40–69 years and recruited between 2005 and 2014, were included. CHIP status was determined from whole exome sequencing for mutations in 74 driver genes. Any CHIP (variant allele fraction (VAF) ≥ 2