Background: This study examines the association between traditional cardiovascular health (CVH) metrics and major adverse cardiovascular events (MACE) incidence in individuals with diverse sleep patterns. Methods and Results: We analyzed data from 208 621 participants initially free of cardiovascular disease (CVD) in the UK Biobank study. Sleep patterns were assessed using scores for chronotype, duration, insomnia, snoring, and daytime dozing. Traditional CVH scores were derived from the Life's Simple 7 metrics. Cox proportional hazards multivariate regression assessed associations between distinct combinations of CVH and sleep scores and MACE, including nonfatal myocardial infarction, nonfatal stroke, and CVD mortality. Over a mean follow‐up of 12.73 years, 9253 participants experienced incident MACE. Individuals with both a healthy sleep pattern and ideal CVH levels had the lowest MACE risk compared with those with a poor sleep pattern and poor CVH levels (hazard ratio, 0.306 [95% CI, 0.257–0.365]; P <0.001). Elevated CVH scores were associated with a reduced risk of MACE across different sleep patterns. Similar trends were observed for individual MACE components, heart failure, and all‐cause mortality. These findings remained robust in sensitivity analyses and across various subgroups. Conclusions: In individuals without known CVD, maintaining a favorable sleep pattern and achieving optimal CVH levels, as measured by traditional metrics, were associated with the lowest MACE risk. Enhanced CVH significantly reduced CVD risk, even in individuals with a poor sleep pattern. These results emphasize the importance of considering multiple dimensions of sleep health alongside CVH to mitigate CVD risk. Registration: URL: https://www.ukbiobank.ac.uk ; Unique identifier: 91090.

Left atrial appendage thrombus (LAAT) is a surrogate of thromboembolic events in patients with nonvalvular atrial fibrillation (NVAF). We aimed to investigate the risk factors for LAAT formation before catheter ablation and cardioversion beside the CHA2DS2-VASc score. In this case-control study, patients with NVAF who underwent transesophageal echocardiography (TEE) were included. Demographic data, laboratory results, and echocardiographic measurements were retrospectively collected. Logistic regression analysis was performed to determine risk factors predicting LAAT. Of the 543 included patients, LAAT was identified in 50 patients (9.2%). Multivariable logistic regression analysis for the entire cohort showed that NT-proBNP (per 500 ng/L increase, OR (95% CI): 1.09 (1.00–1.19), p = 0.038) and LDL-C (per 1 mmol/L increase, OR (95% CI): 1.70 (1.05–2.77), p = 0.032) were independently correlated with the presence of LAAT after the adjustment for CHA2DS2-VASc score and anticoagulant therapy. The subgroup analysis of patients without anticoagulant therapy also yielded similar results. Regarding patients with CHA2DS2-VASc scores ≤ 1, a higher level of LDL-C (per 1 mmol/L increase, OR (95% CI): 6.31 (2.38–16.74), p < 0.001) independently correlated with the presence of LAAT. The present study suggests that beyond CHA2DS2-VASc score, raised NT-proBNP and LDL-C are additional predictors for LAAT in NVAF patients.

Background: Stroke is the leading cause of disability and death worldwide, and its pathogenesis involves various risk factors. This study aimed to investigate the associations between acquired risk factors, age, and genetic predisposition in the incidence of stroke. Methods and Results: We analyzed 404 873 participants (age, mean±SD, 56.46±8.10 years; 45.97% men) from the UK Biobank cohort, all without a history of stroke at baseline and with complete information on risk factors. Hazard ratios and population‐attributable risk percentages for incident stroke were calculated for 21 risk factors, including 3 social determinants, 8 unhealthy behaviors, 4 metabolic factors, 5 clinical comorbidities, and 1 genetic risk score. Participants were stratified by age and genetic risk. During a 4.8 million person‐year follow‐up, 8287 participants (2.05%) experienced a stroke. Metabolic factors, particularly hypertension, were key contributors to stroke risk across all age and genetic groups (population‐attributable risk percentages, 26.53–38.63 and 28.05–37.09). Stroke risk due to overall metabolic factors increased with higher genetic risk (population‐attributable risk percentages, 28.05 in low‐risk and 37.09 in high‐risk groups). The effects of certain risk factors, such as dietary risk and hypertension, were more pronounced in participants with higher genetic risk. The contributions of social factors and clinical comorbidities to stroke risk were relatively low across genetic risk groups. Conclusions: Metabolic factors, especially hypertension, are critical targets for stroke prevention across diverse age and genetic risk profiles. Tailored prevention strategies that address modifiable risk factors, considering individual age and genetic predisposition, have the potential to significantly reduce stroke incidence.

BACKGROUND: SIRT5 (sirtuin 5) is a member of the sirtuin family known to regulate cardiac metabolism, aging, and function. However, its role in cardiac fibroblast (CFB) metabolism, activation, and fibrosis remains elusive. METHODS: Expression changes of SIRT5 in CFBs from cardiac tissue of human and mouse with heart failure were determined. The functional role of SIRT5 in cardiac fibrosis was evaluated through CFB-specific knockout and overexpression of Sirt5 in mice. The involvement of succinylation of lysine 489 (Lys489) on PCK2 (phosphoenolpyruvate carboxykinase 2) in SIRT5-mediated regulation of cardiac fibrosis was assessed by introducing the Lys489-to-arginine mutation of PCK2 in Sirt5 -deficient CFBs and in CFB-specific Sirt5 knockout mice. RESULTS: SIRT5 expression was markedly reduced in CFBs from humans and mice with heart failure and showed a negative correlation with cardiac fibrosis severity. Loss of Sirt5 in CFBs exacerbated left ventricular dysfunction, cardiac hypertrophy, and cardiac fibrosis in mice subjected to transverse aortic constriction, whereas overexpression of Sirt5 in CFBs significantly attenuated these pathological changes. Sirt5 deficiency promoted CFB activation by driving a metabolic shift from oxidative phosphorylation to glycolysis. Mechanistically, Sirt5 deficiency increased the succinylation of PCK2 at Lys489, a key enzyme linking glycolysis and the tricarboxylic acid cycle, which consequently inhibited this enzyme activity in CFBs. Importantly, this specific modification at the Lys489 mutation that prevents succinylation effectively reversed both the metabolic reprogramming and the hyperactivation of CFBs induced by Sirt5 knockout. In vivo , introducing the Pck2 K489R mutation fully rescued the exacerbated cardiac fibrosis and dysfunction observed in Sirt5 -deficient mice after transverse aortic constriction. CONCLUSIONS: By desuccinylating PCK2 at Lys489, SIRT5 prevents the metabolic reprogramming and subsequent activation of CFBs, protecting against cardiac fibrosis.

Cancer survivors have nearly twice the risk of coronary heart disease (CHD) compared with the general population. We examined whether joint risk factor control was associated with cancer-related excess CHD risk and residual life expectancy. We analyzed 14,557 cancer survivors and 58,228 matched noncancer controls from the UK Biobank. Risk factor control was defined across 9 domains: blood pressure, body mass index, low-density lipoprotein cholesterol, hemoglobin A1c, renal function, smoking, physical activity, diet, and sleep. Cox proportional hazards models estimated associations with CHD, myocardial infarction (MI), and cardiovascular disease (CVD) mortality; flexible parametric survival models assessed life expectancy. Over a median follow-up of 12.60 years, 1,298 CHD events, 348 MI events, and 211 CVD-related deaths occurred among cancer survivors. After adjustment for confounders, each additional controlled risk factor was associated with lower risks of CHD (HR: 0.85; 95% CI: 0.81-0.88), MI (HR: 0.81; 95% CI: 0.74-0.88), and CVD-related mortality (HR: 0.75; 95% CI: 0.67-0.84). Participants with ≥6 controlled risk factors had the lowest risks across cardiovascular outcomes. A higher degree of risk factor control was also associated with longer residual life expectancy at age 50 (33.83 vs 30.47 years in the ≥6 vs ≤ 3 controlled risk factor groups). The joint risk factor control is associated with a lower risk of CHD, MI, and CVD-related mortality among cancer survivors. Comprehensive assessment and optimization of modifiable risk factors may be clinically relevant for cardiovascular risk management in cardio-oncology survivorship care.