Tong Liu

Objective: To explore the role of sirtuin 1 (SIRT1)/PTEN-induced kinase 1 (PINK1) signaling in diabetic ventricular remodeling and investigate the effects of empagliflozin on this process. Method: Diabetes mellitus was induced in male Sprague-Dawley rats using a high-fat diet combined with low-dose streptozotocin. Successfully induced diabetic rats were enrolled in batches and randomly assigned to the diabetes mellitus, low-dose empagliflozin (10 mg/kg daily), or high-dose empagliflozin (30 mg/kg daily) group. The first batch included 6 rats per group, and additional rats were enrolled in the second batch to reach a final sample size of 8 rats per group. Age-matched non-diabetic rats served as controls ( n = 8). After 8 weeks of treatment, cardiac structure and function were evaluated by echocardiography and invasive hemodynamic measurements, and myocardial hypertrophy and fibrosis were assessed histologically. Mitochondrial respiratory function and membrane potential were evaluated by respiratory control ratio and JC-1 fluorescence, respectively. SIRT1, nuclear respiratory factor 1 (NRF-1), and PINK1 protein expression levels were assessed by Western blotting. In H9c2 cells exposed to high glucose, the involvement of SIRT1 signaling was further investigated using the SIRT1 inhibitor EX527 and SIRT1-specific small interfering RNA. Result: Compared with control rats, diabetic rats exhibited greater left atrial diameter, interventricular septal thickness, left ventricular posterior wall thickness, cardiomyocyte cross-sectional area, and myocardial fibrosis, together with impaired diastolic and hemodynamic function (all P < 0.05). Empagliflozin treatment attenuated these structural and functional abnormalities, although the significant effects varied according to dose. The mitochondrial respiratory control ratio and JC-1 red/green fluorescence ratio were significantly lower in diabetic rats than in controls (both P < 0.001) and were significantly higher following empagliflozin treatment (all P < 0.05). SIRT1, NRF-1, and PINK1 protein expression levels were significantly lower in diabetic myocardium and high-glucose-exposed H9c2 cells than in corresponding controls (all P < 0.05). In H9c2 cells, SIRT1 inhibition with EX527 was associated with lower SIRT1, NRF-1, and PINK1 protein expression following EMPA treatment (all P < 0.05). Conclusion: Empagliflozin attenuated left ventricular remodeling and improved mitochondrial function in diabetic rats, with SIRT1/PINK1 signaling potentially contributing to these beneficial effects.

Background: A positive difference between biological age (BA) and chronological age indicates accelerated aging. The application of existing BA models is limited by high technical demands, a lack of alignment across diverse populations, and difficulty in updating them to accommodate expanding cohorts. Objective: To address the issues in existing tools, this project aims to develop and validate an automated toolkit for adaptive BA estimation. Methods: The proposed toolkit, named BACalc, facilitates the processing of raw clinical datasets stored in CSV format. Within the graphical user interface, users can select (1) the chronological age column, (2) binary variables (eg, sex, smoking, and alcohol use), and (3) continuous variables (eg, creatinine levels) for BA estimation, using the principal component analysis (PCA) method with the Dubina correction or the Klemera-Doubal method (KDM). All numerical operations are implemented using the NumPy and Pandas libraries, and linear modeling components are provided by scikit-learn and SciPy. The program generates three main output files: (1) the row-wise predictions, (2) the regression statistics, and (3) the explicit linear equations and PCA loadings. Example outputs were generated using the National Health and Nutrition Examination Survey (NHANES, 1999‐2010), UK Biobank (2006‐2010), and Dalian Heart Failure (2015‐2023). The results were compared with the reference BioAge R package. Results: Using the KDM model, the BACalc-derived and BioAge-derived estimates exhibit a near-perfect correlation ( r =0.9937, mean absolute error 2.02 y). The PCA-Dubina model also shows a strong correlation with BioAge ( r =0.8871), within a ±20-year window of accelerated aging residuals. In the UK Biobank, a 1-year increase in PCA-Dubina–derived age acceleration was associated with a 1.77% higher hazard of all-cause mortality (hazard ratio [HR] 1.018, 95% CI 1.017‐1.018; P <.001). Similarly, KDM-derived age acceleration was associated with a 1.59% higher hazard of mortality per year of accelerated aging (HR 1.016, 95% CI 1.016‐1.016; P <.001). In the Dalian cohort, a 1-year increase in age acceleration derived from the PCA-Dubina model (BAc) independently predicted mortality with a 2.84% increased hazard per year (HR 1.028, 95% CI 1.022‐1.035; P <.001). Similarly, KDM-derived age acceleration (BA_EC) was associated with a 1.26% increased hazard of mortality per year of accelerated aging (HR 1.013, 95% CI 1.007‐1.018; P <.001). Conclusions: BACalc provides a reliable platform for BA estimation, consistent with previously validated computational frameworks and convenient for real-time updating. BA acceleration predicted mortality in 2 independent cohorts.

Background: Obesity is linked to higher arrhythmia risk, yet BMI overlooks its complexity. Recently, the Lancet Commission has introduced a new obesity framework. We aimed to compare arrhythmia risks across distinct obesity categories. Methods: Participants from the UK Biobank were stratified by obesity phenotypes. Co-primary outcomes included incident supraventricular, brady-, or ventricular arrhythmias, with secondary outcomes defined as their components. Obesity phenotypes were defined using five anthropometric measures, alongside ICD-10 codes, laboratory measurements, and self-reported data to ascertain organ dysfunction. Results: Of 487,806 included individuals, 36.6%, 18.7%, and 44.7% were identified with non-obesity, preclinical obesity, and clinical obesity, respectively. Compared to non-obesity without organ dysfunction, clinical obesity was associated with significantly increased risk for all primary and secondary outcomes (all FDR-corrected P < 0.05), as well as arrhythmia recurrence risk. Preclinical obesity was associated with significantly elevated risk of SVA and bradyarrhythmia, but not for VA or arrhythmia recurrence. Clinical obesity exhibited significant ECG alterations, including prolonged P wave duration, PR interval, QTc interval, QRS duration, accompanied by shortened PP interval, elevated ventricular rate, as well as altered P-wave, R-wave, and T-wave axis. For structural remodeling, clinical obesity was associated with enlarged left atrial volume and concentric left ventricular (LV) remodeling. A similar but less pronounced pattern of electrical and structural remodeling was observed for preclinical obesity. Compared to BMI, the Lancet classification's incremental prognostic value was small, mixed, and outcome-dependent. Conclusions: These findings reveal a gradient of arrhythmic and remodeling risk across obesity stages, underscoring the need for early monitoring in preclinical obesity and targeted intervention in clinical obesity to prevent cardiovascular complications.

While anthropometric indices predict cardiovascular mortality, the novel body roundness index (BRI)‘s association with all-cause mortality in myocardial infarction (MI) survivors remains unknown. This cohort study analyzed 2099 National Health and Nutrition Examination participants (1999–2018) with prior MI. Mortality was ascertained via National Death Index linkage (median follow-up ~ 9 years). Using Cox regression with covariate adjustment and penalized splines, we identified an L-shaped BRI-mortality relationship with an inflection point at 3.99. Below this threshold, each 1-unit BRI increase significantly reduced mortality risk (hazard ratio = 0.62, 95% CI: 0.50–0.75, P < .0001). Above 3.99, BRI showed no association (hazard ratio = 1.02, 95% CI: 0.98–1.06, P = .4242). This threshold pattern persisted in subgroups. Our findings first demonstrate that lower BRI was associated with higher mortality in MI survivors, suggesting maintaining BRI above critical thresholds may confer survival benefits.

Background and Aims: Evidence supporting first-line cryoballoon ablation (CBA) in treatment-naive persistent atrial fibrillation (PersAF) is limited. Consequently, we compared CBA with guideline-directed antiarrhythmic drug (AAD) therapy in this advanced form of disease. Methods: This multicenter, prospective, randomized, open-label trial assigned 320 symptomatic, treatment-naive patients with PersAF (1:1) to CBA or AAD therapy. The primary endpoint was the first documented atrial tachyarrhythmia recurrence lasting at least 30 seconds during days 91-365. Secondary endpoints included recurrence during days 1-90 and 1-365, time-to-first recurrence, quality of life, and safety. Results: In the intention-to-treat population, recurrence during days 91-365 occurred in 30/160 (18.8%) patients assigned to CBA and 71/160 (44.4%) assigned to AAD therapy (absolute difference, -25.6 percentage points; 95% confidence interval, -35.4 to -15.8; P<0.001). Supportive time-to-event analysis favored CBA (hazard ratio for AAD vs. CBA, 2.29; 95% confidence interval, 1.48-3.56; log-rank P<0.001). In CBA vs AAD comparisons, overall recurrence during days 1-365 was 23.8% vs. 55.6%, and early recurrence was 11.2% vs. 28.1% (both P<0.001; respectively). Improvement in AFEQT score was greater with CBA (17.3 vs. 6.6 points; P<0.001); whereas SF-12 component scores did not differ significantly. Adverse events recorded on event forms were infrequent in both cohorts. Conclusion: In selected treatment-naive patients with PersAF, first-line CBA reduced atrial tachyarrhythmia recurrence and improved disease-specific quality of life compared with AAD therapy.

BACKGROUND: Perfluorooctane sulfonate (PFOS) is a widely distributed persistent organic pollutant in the environment and has been associated with an increased risk of atherosclerosis. However, the underlying pathogenic mechanisms remain largely unclear. This study aimed to investigate the effects of PFOS on atherosclerosis and its associated gut–vascular axis. METHODS: Pseudo–germ-free mouse models and fecal microbiota transplantation (FMT) were used to determine the role of the gut microbiota in PFOS-induced atherosclerosis. Metagenomic sequencing was performed to characterize alterations in gut microbial composition following PFOS exposure, and targeted metabolomics was used to assess bile acid profiles in the ileum and plasma. Transcriptomic analysis of Bacteroides caecimuris ( B.caecimuris ) was conducted to explore the reasons for the increased abundance of B.caecimuris after PFOS exposure. In addition, intestinal transcriptomics and ChIP-qPCR were performed to validate transcriptional regulation within the FXR–TLR3 signaling axis. RESULTS: Among 127 participants with paired serum and fecal samples, including 82 patients undergoing coronary angiography with Gensini scores (GS score), fecal PFOS levels were significantly associated with lipid profiles and GS score, whereas serum PFOS showed no such association.Mechanistically, PFOS exposure promotes intestinal enrichment of B.caecimuris by upregulating its tolC gene, thereby enhancing efflux capacity.This microbial shift was accompanied by reduced levels of tauro-ursodeoxycholic acid (TUDCA) and aberrant activation of intestinal FXR signaling.Further analyses demonstrated that FXR activation upregulated TLR3 expression and promoted inflammatory responses and atherosclerosis progression via the TLR3–NF-κB signaling axis. Both intestinal epithelial-specific FXR deficiency ( Fxr ^ΔIE ) and TUDCA supplementation significantly suppressed pathway activation and alleviated disease phenotypes.Functional experiments identified TLR3 as a key downstream effector of FXR. Overexpression of TLR3 abolished the protective effects observed in Fxr ^ΔIE mice. Moreover, pharmacological inhibition of TLR3 using CU CPT-4a significantly improved established atherosclerotic lesions in vivo. CONCLUSIONS: This study identifies a gut microbiota–driven FXR–TLR3 signaling axis that mediates PFOS-induced atherosclerosis. These findings provide new mechanistic insights into environmentally induced cardiovascular disease and suggest potential targets for risk assessment and therapeutic intervention.

Aims: PCSK9 inhibitors reduce major cardiovascular events in randomized trials of atherosclerotic cardiovascular disease (ASCVD), but real‐world neuropsychiatric safety remains uncertain. Methods: In a propensity score–matched retrospective cohort study using the TriNetX U.S. Federated Research Network, adults with established ASCVD initiating alirocumab or evolocumab between 2017 and 2024 were matched 1:1 to statin‐monotherapy initiators. The 12‐month primary analysis assessed major adverse cardiovascular events (MACE: myocardial infarction, heart failure [HF], ischaemic stroke, all‐cause death), neurodegenerative disease (dementia, Parkinson's disease) and psychiatric disorders (psychosis, bipolar disorder, depression, anxiety), with Bonferroni correction and negative control. Secondary analyses examined individual agents, ASCVD subtypes, statin use, an intensified lipid‐lowering comparator and extended follow‐up. Results: Among 60 885 matched pairs (mean age 70 years; 61% male), PCSK9 inhibitor therapy was associated with lower 12‐month risks of MACE (HR 0.84, 95% CI 0.80–0.88), myocardial infarction (HR 0.82, 0.79–0.86), HF (HR 0.87, 0.83–0.92) and all‐cause mortality (HR 0.40, 0.37–0.43); ischaemic stroke did not differ. After Bonferroni correction, no neurodegenerative association remained significant. PCSK9 inhibitor use was associated with higher risks of any psychiatric diagnosis (HR 1.33, 1.25–1.42), depression (HR 1.44, 1.28–1.61) and anxiety (HR 1.39, 1.28–1.50), persisting in secondary analyses; negative control outcomes did not differ. Conclusions: PCSK9 inhibitor use was associated with favourable cardiovascular outcomes and no clear neurodegenerative harm, but higher rates of depression and anxiety. Given the observational design and potential residual confounding, statin‐intolerance‐related treatment selection and surveillance bias, these findings should be interpreted as hypothesis‐generating and warrant further prospective evaluation.