Da Zhu

Chronic kidney disease (CKD) markedly accelerates calcific aortic valve disease (CAVD), yet the underlying mechanisms and therapeutic targets remain poorly defined. Here, we integrate population-scale analyses, single-cell transcriptomics, genetic inference and functional experiments to identify a central role for Sirtuin 1 (SIRT1) in CKD-associated aortic valve calcification. Analysis of UK Biobank data linked CKD to accelerated ageing and increased aortic stenosis risk. Single-cell RNA sequencing of human aortic valves identified SIRT1 downregulation and NLRP3 pathway activation specifically in myofibroblast valve interstitial cells (VICs), coupled with enhanced senescence and osteogenic programmes. Consistently, genetic analyses, including eQTL-based Mendelian randomization, supported an inverse association between SIRT1 expression and CAVD risk. SIRT1 deficiency was associated with enhanced glycolysis, increased NF-κB activation and NLRP3 inflammasome signalling, accompanied by augmented osteogenic differentiation and calcification of VICs. Pharmacological or genetic inhibition of NLRP3 attenuated valve calcification in vivo, establishing the SIRT1-NF-κB-NLRP3 axis as a critical pathway linking CKD to CAVD. Finally, screening of anti-diabetic compounds identified semaglutide as a potent modulator that restores the SIRT1/NLRP3 balance and alleviates calcification in vitro and in vivo. These findings define a metabolic-inflammatory coupling mechanism underlying CKD-induced CAVD and highlight SIRT1 as a therapeutic target. Modulation of the SIRT1-NLRP3 axis, particularly by semaglutide, may represent a promising strategy for preventing valve calcification.

Transcatheter mitral valve implantation (TMVI) device featuring an apical fixation design is now the most mature TMVI system and widely applied in routine

Background: Cardiometabolic disorders, including hypertension, dyslipidemia, and diabetes, are increasingly prevalent globally, yet evidence in economically underdeveloped high-altitude areas remains limited. This study sought to assess the prevalence and control of these diseases in the southwestern plateau areas of China and to evaluate their associations with altitude and sociodemographic factors. Methods: We conducted two cross-sectional surveys among adults aged ≥35 years in the southwestern plateau areas of China. Disease definitions were based on measured biomarkers, self-reported diagnoses, and medication use. Logistic regression and restricted cubic spline models were applied to examine associations between sociodemographic factors, altitude, and prevalence and control rates of cardiometabolic disorders. Results: 7,668 adults with an average age of 54.88 ± 12.64 years were investigated. The prevalence, awareness, treatment, and control rates were 46.20%, 58.65%, 43.80%, and 15.75% for hypertension; 37.06%, 15.90%, 5.77%, and 2.11% for dyslipidemia; 11.79%, 27.54%, 21.68%, and 6.86% for diabetes. Higher disease prevalence was associated with male, older age, higher income, overweight/obesity, and alcohol use. Reduced control and treatment rates were observed at altitudes ≥2,242 m, among younger adults, smokers, and drinkers. Altitude significantly modified the association between sociodemographic factors and cardiometabolic disorders. Furthermore, there was a non-linear relationship between these rates and both age and altitude of residence. Conclusions: This study reveals a high burden of cardiometabolic disorders with suboptimal management in the southwestern plateau areas of China. Altitude and sociodemographic factors significantly interact with disease prevalence and control. Targeted public health efforts should prioritize high-risk populations and regions to improve prevention and management.

(1) Aim: The incidence of high-altitude pulmonary hypertension (HAPH) has risen in recent years and is expected to continue increasing; however, its diagnosis remains challenging. In this study, we employed proteomics and metabolomics to identify the proteins and metabolic biomarkers that contribute to the development of HAPH. (2) Methods: We applied integrated proteomics and metabolomics to match blood samples from 40 HAPH patients and 40 healthy controls in Yunnan’s high-altitude regions to characterize molecular profiles, identify biomarkers, and develop a predictive model. (3) Results: Proteomic analysis identified four proteins (A2IPH7, K1C14, PSME2, SERPINE2) commonly dysregulated in HAPH patients from two high-altitude regions. SERPINE2 was notably downregulated and showed a negative correlation with clinical severity, which was further validated in HAPH rat lung tissues and supported by UK Biobank data for idiopathic PAH. Concurrent metabolomics uncovered 11 shared metabolites, largely acyl fatty acids, enriched in pathways such as unsaturated fatty acid synthesis. Integration of these multi-omics data enabled the development of a robust predictive model. (4) Conclusion: Our study identified key protein and metabolic biomarkers involved in HAPH development, which were validated in animal models. Based on these findings, a predictive model was developed, highlighting SERPINE2 and 11 metabolites as promising targets for the prediction and prevention of HAPH.

Background: Calcific aortic stenosis (CAS) is frequently accompanied by systemic comorbidities, but their causal relationships and shared genetic architecture remain poorly defined. We aimed to map the multisystem comorbidity network of CAS and clarify underlying genetic mechanisms. Methods: In 467 484 participants from the UK Biobank, observational and polygenic phenome-wide association studies evaluated associations between CAS and 1571 phenotypes, integrating disease-trajectory analyses to visualise temporal patterns. Associations replicated across observational and polygenic analyses were tested using two-sample Mendelian randomisation (MR) based on 22 CAS-related variants from FinnGen. Polygenic risk score (PRS) analyses excluding specific genes assessed their contributions, particularly LPA and plasma lipoprotein(a) (Lp(a)) levels. Results: CAS was associated with higher risks of 42 cardiovascular and non-cardiovascular conditions, most prominently metabolic, endocrine, haematological and respiratory disorders. Temporal analyses showed that circulatory and metabolic diseases typically precede other comorbidities in CAS trajectories. MR findings were consistent with causal effects of CAS on multiple cardiovascular diseases, iron-deficiency anaemia, mental disorders and pleural effusion. When LPA variants were removed from the CAS PRS or plasma Lp(a) concentration was adjusted for, most associations lost significance, indicating a shared LPA/Lp(a)-mediated genetic pathway. Conclusions: CAS is embedded within a broad multisystem comorbidity network, driven largely by genetic variation at LPA and elevated Lp(a). These findings highlight pleiotropic mechanisms linking valvular calcification with systemic disease and support LPA-targeted therapies as a promising avenue for reducing the multisystem burden of CAS.

The triglyceride-glucose (TyG) index is a straightforward and widely used surrogate marker for identifying insulin resistance (IR). The association between

Background: The combined health effects of the triglyceride–glucose (TyG) index and altitude of residence on the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) remain unknown. We examined the combined effect of the TyG index and altitude of residence on ASCVD using data from two cross-sectional studies. Methods: We included 6,861 participants with no history of ASCVD from two cross-sectional studies and assessed their 10-year risk of ASCVD using the China-PAR model. We stratified the TyG index and altitude of residence and used multivariate-adjusted logistic models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for a high 10-year risk of ASCVD. Both additive and multiplicative effects were considered. Results: A total of 6,861 participants free of ASCVD at baseline were included in the analysis. Among them, 559 study participants were classified as being at high risk for ASCVD. Compared with participants with the lowest TyG index levels, those with the highest TyG index levels were more likely to be at high risk for ASCVD [(OR): 2.17, 95% C1: 1.67, 2.82]. Non-linear relationships were observed in the restricted cubic spline analyses. Altitude of residence was also associated with an increased risk of ASCVD [(OR): per standard deviation: 1.46, 95% Cl: 1.29, 1.65]. However, there was limited evidence of interaction between the TyG index and altitude of residence. Similar findings were observed in a series of sensitivity analyses. Conclusion: Both the TyG index and altitude of residence were positively associated with a high risk of ASCVD separately; however, there was no significant interaction between the associations.

The purpose of the study was to determine the prevalence and clustering changes of cardiovascular disease (CVD) risk factors, the atherosclerotic cardiovascular diseases (ASCVD) risk change in ethnic minority areas of the Southwest China Plateau from the perspective of sex disparity. This study conducted two cross-sectional studies in Yunnan Province, China, in 2018 and 2024, respectively, enrolling 1,197 and 1,047 participants aged 35–75 years with no history of CVD. The China-PAR model was used to assess participants’ 10-year risk of ASCVD. Changes in the prevalence and clustering of 9 CVD risk factors were described. Multivariate-adjusted Poisson regression by robust was used to calculate the association between the number of CVD risk factors and high risk of ASCVD. Compared with 2018, the age-standardized prevalence of modifiable metabolic CVD risk factors such as hypertension (22.4% to 41.7%), central obesity (24.2% to 39.1%), and overweight and obesity (11.2% to 15.1%) has risen rapidly; the increase among males was much higher than among females, while the age-standardized prevalence of modifiable behavioral CVD risk factors has declined. There was no significant change in the clustering number of CVD risk factors, but there was a significant change in the combination of CVD risk factors, particularly a significant increase associated with hypertension. The proportion of individuals classified as being at high risk for ASCVD also increased significantly (6.7% vs 10.6%). For each CVD risk factor, the high risk of ASCVD increased by 5%, with a higher risk among males and 55–75 years. From 2018 to 2024, modifiable metabolic CVD risk factors increased substantially in high-altitude ethnic minority regions of Southwest China. Comprehensive lifestyle interventions should be implemented in the future to promote the prevention and control of ASCVD risk and gradually reduce sex disparity.