Chronic mitral regurgitation (MR) is associated with adverse clinical outcomes, and the role of renin-angiotensin system inhibitors (RASI) in patients with MR remains uncertain. This study evaluated the association between RASI use patterns and 2-year all-cause mortality and disease progression in patients with primary MR (PMR) and secondary MR (SMR). This registry-based study included 3,297 patients with moderate-to-severe chronic MR from the China Valvular Heart Disease registry, including 955 with PMR and 2,342 with SMR. RASI use was assessed at baseline and during follow-up, and patients were categorized as always users, never users, or inconsistent users. The primary endpoint was 2-year all-cause mortality. The secondary endpoint was change in MR severity. Associations between RASI use and outcomes were assessed using multivariable Cox regression, propensity-score matching, and time-varying Cox analyses. Consistent RASI use was associated with lower 2-year all-cause mortality in both PMR and SMR. In multivariable Cox regression, never users had higher mortality risk than always users in both cohorts (PMR: HR 5.40, 95

BACKGROUND:Transcatheter aortic valve replacement (TAVR) has transformed the treatment of severe aortic stenosis in patients at high or prohibitive surgical risk. Despite high procedural success, postoperative complications remain common and clinically consequential. Understanding how research on these complications has evolved is essential for guiding future investigations and improving outcomes. This study maps the global research landscape of TAVR-associated postoperative complications, with emphasis on thematic evolution, collaboration patterns, and emerging mechanistic and analytical approaches. METHODS:A bibliometric analysis of publications from 2006 to 2025 was conducted using the Web of Science Core Collection. Publication trends, contributing countries and institutions, authors, subject categories, and journals were analysed. CiteSpace and VOSviewer were used to visualise keyword co-occurrence, citation bursts, collaboration networks, and thematic clusters. RESULTS:A total of 3587 publications were identified, with rapid growth after 2014. The United States led in publication output and international collaboration, followed by Germany, Italy, and the United Kingdom. Research themes shifted from early feasibility studies towards complication-focused topics. High-frequency keywords included stroke, paravalvular leak, and bundle branch block, while recent attention has increasingly focused on frailty, sarcopenia, and multimorbidity. Biomechanical terms such as finite element and fluid-structure interaction reflected deeper mechanistic exploration. The literature spanned over 20 disciplines, indicating strong interdisciplinarity. CONCLUSIONS:The field has shifted from procedural feasibility to multidisciplinary, mechanism-oriented studies of complications affecting long-term outcomes, with frailty emerging as a key patient-centred determinant in older TAVR populations.

OBJECTIVE:To compare the distribution, aetiology, treatment patterns and 2-year outcomes of moderate to severe valvular heart disease (VHD) between men and women in China. DESIGN:Nationwide, prospective, multicentre cohort study. SETTING:46 tertiary hospitals across China, representing a mix of primary and secondary care settings. PARTICIPANTS:A total of 13 917 adult patients with moderate-to-severe VHD were enrolled between April and June 2018. Of these, 6296 (45.24%) were women. Inclusion criteria included moderate or severe native valve disease, infective endocarditis or prior valve intervention. INTERVENTIONS:Patients received either conservative therapy or valve interventions, including surgical repair/replacement or transcatheter procedures. Intervention decisions were based on clinical assessment. MAIN OUTCOME MEASURES:2-year all-cause mortality, cardiovascular mortality, heart failure hospitalisation and major adverse cardiovascular events. Multivariable Cox and logistic regression analyses were conducted to identify outcome predictors. RESULTS:The overall intervention rate was 31.72%, with no gender difference (men: 31.26% vs women: 32.27%). Among the 5427 patients with severe symptomatic VHD, 49.11% received interventional therapy. The sex-specific pattern was particularly significant in severe symptomatic multiple valvular heart disease, where women had a higher propensity for intervention (p<0.001, OR: 1.19-1.66). In severe symptomatic aortic regurgitation patients, women were less likely to receive valve replacement (p=0.03, OR: 0.39-0.95).The 2-year survival rate was 90.85% with no gender difference (men: 90.41% vs women: 91.38%, p=0.086). Valve intervention improved survival to 97.0%, with no gender disparity (men: 96.92% vs women: 97.01%, p=0.87). Multivariate Cox regression confirmed no significant gender effect (p>0.05). CONCLUSIONS:Significant gender differences exist in VHD aetiology and subtypes in China. Women had more rheumatic VHD, while men had more degenerative and functional VHD. Intervention improved survival, with no gender disparity. Age and VHD subtype influenced intervention rates and prognosis, supporting individualised, sex- and age-stratified management strategies. TRIAL REGISTRATION NUMBER:NCT03484806.

BACKGROUND:Valvular heart disease (VHD) is a major cause of cardiovascular morbidity and mortality worldwide. The impact of environmental stress on the prognosis of patients with VHD is unknown. This study aims to explore the impact of ambient air pollution exposure on the clinical outcomes of patients with VHD. METHODS:Data were derived from the China-VHD registry, a national multicentre prospective cohort study. Monthly ambient particulate matter with a diameter <2.5 μm (PM2.5) exposure was derived from the ChinaHighAirPollutants (CHAP) dataset at 1×1 km resolution. Using residential address, clinical data from patients diagnosed with VHD between April and June 2018 were linked to ambient PM2.5 exposure concentrations. Patients were followed up until they lost or experienced the primary outcome (defined as all-cause mortality or heart failure hospitalisation) for 2 years. Time-varying Cox proportional hazards regression models were applied to evaluate the association between monthly ambient PM2.5 exposure and outcomes. RESULTS:A total of 12 258 VHD patients were included. Mean age at enrolment was 61.2±13.7 years, and 54.7% were male. Mean baseline ambient PM2.5 exposure was 43.50±12.25 µg/m3. After 2 years of follow-up, 1577 patients (12.9%) experienced the primary outcome. The estimated HR for all-cause mortality or heart failure hospitalisation was 1.24 (95% CI 1.07 to 1.43) for individuals in the highest tertile of monthly ambient PM2.5 exposure compared with those in the lowest tertile. Each IQR (21.80 µg/m³) increase in monthly ambient PM2.5 exposure was associated with a 1.11-fold higher risk of the primary outcome (95% CI 1.04 to 1.18). This association was consistent across subgroups. CONCLUSIONS:Exposure to air pollution was associated with adverse outcomes in patients with VHD. These findings highlight the potential role of a key environmental factor in the progression and prognosis of VHD. TRIAL REGISTRATION NUMBER:NCT03484806.

Background Frailty is a known predictor of adverse outcomes in aortic valve replacement. However, its impact on the broader population with valvular heart disease (VHD) remains less explored. Objectives This study aimed to evaluate the prevalence of frailty across major VHD subtypes and investigate the association between frailty and adverse clinical events. Methods A total of 2,147 elderly patients with severe VHD from the China-DVD2 Study underwent the frailty assessment using the Fried, Fried+, Essential Frailty Toolset, and a simplified 4-item score. The primary outcome was a 1-year all-cause death, whereas the secondary outcome was 1-year all-cause death and heart failure hospitalization. Results The median age was 72.8 years (43.5% female). Frailty prevalence ranged from 16.8% to 39.3% and prefrailty from 50.9% to 64.5%, depending on the assessment tool. Among the evaluated scales, the simplified frailty score was the most consistent association with adverse outcomes (adjusted HR: 1.50 [95% CI: 1.25-1.81] for all-cause mortality; 1.53 [95% CI: 1.32-1.77] for the composite outcome). These associations were preserved across the exploratory subgroups and specific VHD subtypes. Adding frailty score to the European System for Cardiac Operative Risk Evaluation II improved risk stratification for all-cause mortality (C-statistic: 0.715 vs 0.668; likelihood ratio test P < 0.001) and the composite outcome (0.722 vs 0.688; likelihood ratio test P < 0.001). Conclusions Frailty is highly prevalent and independently associated with poor prognosis in severe VHD. The simplified 4-item frailty score offers a practical and incrementally valuable tool for enhancing risk stratification in routine clinical practice.

BACKGROUND:Chronic inflammation and insulin resistance (IR) are key drivers of cardiovascular disease (CVD); however, their joint impact on cardiovascular risk remains poorly understood. METHODS:We developed the metabolic-inflammatory index (eMII) based on estimated glucose disposal rate (eGDR) in a derivation cohort (ELSA) and evaluated its transportability in two external validation cohorts (CHARLS, HRS). Multivariate Cox regression was utilised to assess the joint impact of IR and inflammation on long-term CVD risk. RESULTS:A total of 14,168 middle-aged and older adults were included (mean age 61.68 ± 9.67 years). In fully adjusted Cox models, low eGDR, elevated hs-CRP and their combined status were all associated with increased CVD risk, with the highest risk observed in participants with both poor metabolic function and high inflammation. Exploratory mediation analysis indicated that eGDR accounted for 41.14%, 46.50% and 75.47% of the inflammation-CVD association in ELSA, CHARLS and HRS, respectively. In terms of the new index-eMII, higher eMII levels were consistently linked to elevated CVD risk across all cohorts; compared with the lowest quartile, the highest quartile showed hazard ratios of 1.66 (ELSA), 2.28 (CHARLS) and 1.83 (HRS) (all p < 0.001). Lastly, incorporating eMII into traditional risk models showed potential for improving cardiovascular risk prediction, with a more noticeable reclassification benefit observed within CHARLS. CONCLUSIONS:eMII is a cross-population predictor of CVD, highlighting metabolic impairment as a key factor through which inflammation drives cardiovascular risk. It provides a practical perspective for observing joint metabolic-inflammatory burdens in middle-aged and older adults.

BACKGROUND Combined mitral regurgitation (MR) and tricuspid regurgitation (TR) is related to more complicated hemodynamic burdens than isolated atrioventricular valve regurgitation. OBJECTIVES This study aimed to investigate clinical characteristics and outcomes of combined MR and TR, as well as developing dedicated prognostic instruments. METHODS A total of 6,704 patients with >= moderate MR or TR from the China Valvular Heart Disease study were included in this analysis. The study outcomes included all-cause mortality, death or hospitalization for heart failure, and worsening functional status or death within 2 years. RESULTS Compared with those with isolated valvular regurgitation, patients with combined MR and TR more often experienced atrial fibrillation or flutter and pulmonary hypertension. During a median follow-up of 733 days (Q1, Q3: 706, 749 days), 624 (9.3%) deaths occurred. Combined MR and TR was related to poorer 2-year outcomes than isolated MR, and was independently associated with worse prognosis in symptomatic patients (all-cause mortality: MR vs MR & thorn;TR, HR: 0.776 [95% CI: 0.616-0.978]; P = 0.031) and those with normal left ventricular systolic function (composite endpoint: HR: 0.629 [95% CI: 0.400-0.990]; P = 0.045). Based on carefully evaluated predictors of mortality, a prognostic nomogram and a risk score were developed and externally validated for patients with combined MR and TR, with superior predictive performance than the MitraScore and comparable discrimination compared with artificial intelligence-derived models. CONCLUSIONS Patients with combined MR and TR displayed worse clinical profiles and poorer outcomes compared with those with isolated MR. The novel prognostic tools may improve personalized risk assessment of combined MR and TR. (JACC Asia. 2025;5:436-452) (c) 2025 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

BACKGROUND:Lipoprotein(a) (Lp[a]) has been identified as a significant risk factor for aortic stenosis (AS). However, its impact on outcomes post-transcatheter aortic valve replacement (TAVR) remains unknown. OBJECTIVE:To investigate the association between Lp(a) levels and long-term outcomes as well as its impact on the bioprosthetic valve degeneration in patients post-TAVR. METHODS:Patients with severe AS who underwent TAVR were consecutively recruited. Lp(a) was measured before TAVR procedure. The subjects were divided according to levels of Lp(a). The outcomes were all-cause mortality and possible structural valve degeneration (SVD) measured by Doppler echocardiography. Cox regression models and competing risk models were used to explore the association between Lp(a) levels and outcomes. RESULTS:Of the 601 included patients (mean age: 75.5 ± 7.2, male: 58.7%), 137 patients (22.7%) experienced mortality after a median follow-up of 3.9 years. After multivariable adjustment, elevated Lp(a) (defined as ≥30 mg/dL) was identified as an independent predictor of all-cause mortality (hazard ratio [HR]: 1.81, 95% CI: 1.27-2.57, P = .001) and cardiovascular mortality (HR: 2.02, 95% CI: 1.12-3.66, P = .020). Elevated Lp(a) was also associated with increased risk of possible SVD (subdistribution HR: 3.40, 95% CI: 1.32-8.79, P = .012). Using a threshold value of 50 mg/dL for elevated Lp(a) still supported the main findings. CONCLUSION:Elevated baseline Lp(a) levels are associated with poor clinical outcomes and possible SVD in patients with severe AS undergoing TAVR. Further research is warranted to confirm these findings.

Background::Valvular heart disease (VHD) has become increasingly common with the aging in China. This study aimed to evaluate regional differences in the clinical features, management strategies, and outcomes of patients with VHD across different regions in China.Methods::Data were collected from the China-VHD Study. From April 2018 to June 2018, 12,347 patients who presented with moderate or severe native VHD with a median of 2 years of follow-up from 46 centers at certified tertiary hospitals across 31 provinces, autonomous regions, and municipalities in Chinese mainland were included in this study. According to the locations of the research centers, patients were divided into five regional groups: eastern, southern, western, northern, and central China. The clinical features of VHD patients were compared among the five geographical regions. The primary outcome was all-cause mortality or rehospitalization for heart failure. Kaplan–Meier survival analysis was used to compare the cumulative incidence rate.Results::Among the enrolled patients (mean age, 61.96 years; 6877 [55.70%] male), multiple VHD was the most frequent type (4042, 32.74%), which was mainly found in eastern China, followed by isolated mitral regurgitation (3044, 24.65%), which was mainly found in northern China. The etiology of VHD varied significantly across different regions of China. The overall rate of valve interventions was 32.67% (4008/12,268), with the highest rate in southern China at 48.46% (205/423). In terms of procedure, the proportion of transcatheter valve intervention was relatively low compared to that of surgical treatment. Patients with VHD in western China had the highest incidence of all-cause mortality or rehospitalization for heart failure. Valve intervention significantly improved the outcome of patients with VHD in all five regions (all P <0.05). Conclusions::This study revealed that patients with VHD in China are characterized by significant geographic disparities in clinical features, treatment, and clinical outcomes. Targeted efforts are needed to improve the management and prognosis of patients with VHD in China according to differences in geographical characteristics.Registration::ClinicalTrials.gov, NCT03484806.

Background:Based on the China-VHD database, this study sought to develop and validate a Valvular Heart Disease- specific Age-adjusted Comorbidity Index (VHD-ACI) for predicting mortality risk in patients with VHD. Methods & Results:The China-VHD study was a nationwide, multi-centre multi-centre cohort study enrolling 13,917 patients with moderate or severe VHD across 46 medical centres in China between April-June 2018. After excluding cases with missing key variables, 11,459 patients were retained for final analysis. The primary endpoint was 2-year all-cause mortality, with 941 deaths (10.0%) observed during follow-up. The VHD-ACI was derived after identifying 13 independent mortality predictors: cardiomyopathy, myocardial infarction, chronic obstructive pulmonary disease, pulmonary artery hypertension, low body weight, anaemia, hypoalbuminaemia, renal insufficiency, moderate/severe hepatic dysfunction, heart failure, cancer, NYHA functional class and age. The index exhibited good discrimination (AUC, 0.79) and calibration (Brier score, 0.062) in the total cohort, outperforming both EuroSCORE II and ACCI (P < 0.001 for comparison). Internal validation through 100 bootstrap iterations yielded a C statistic of 0.694 (95% CI: 0.665-0.723) for 2-year mortality prediction. VHD-ACI scores, as a continuous variable (VHD-ACI score: adjusted HR (95% CI): 1.263 (1.245-1.282), P < 0.001) or categorized using thresholds determined by the Yoden index (VHD-ACI ≥ 9 vs. < 9, adjusted HR (95% CI): 6.216 (5.378-7.184), P < 0.001), were independently associated with mortality. The prognostic performance remained consistent across all VHD subtypes (aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, tricuspid valve disease, mixed aortic/mitral valve disease and multiple VHD), and clinical subgroups stratified by therapeutic strategy, LVEF status (preserved vs. reduced), disease severity and etiology. Conclusion:The VHD-ACI is a simple 13-comorbidity algorithm for the prediction of mortality in VHD patients and providing a simple and rapid tool for risk stratification.

Background: Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality in middle-aged and older adults. Both the estimated glucose disposal rate (eGDR), and hs-CRP have been identified as important risk factors for CVD. However, their combined influence on CVD risk in this population remains inadequately explored. Aim: This study aims to investigate the association between eGDR, hs-CRP, and the risk of CVD in middle-aged and older adults. Methods: Data were from the China Health and Retirement Longitudinal Study (CHARLS), which included 17,708 participants at baseline in 2011. After excluding those with cardiovascular disease (CVD) and missing follow-up data, 6,823 participants were enrolled. eGDR was calculated using the following formula: eGDR=24.31−(0.22×Waist Circumference)−(0.33×Systolic Blood Pressure)+(0.43×Fasting Plasma Glucose)eGDR=24.31−(0.22×Waist Circumference)−(0.33×Systolic Blood Pressure)+(0.43×Fasting Plasma Glucose). eGDR was categorized according to quartiles. The primary outcome was the incidence of heart diseases and stroke. Results: Among the 6,823 participants enrolled, the mean age was 59.14 ± 8.75 years, and 3,080 (45.1%) were male. During a maximum follow-up period of 9 years, 1,950 (28.6%) developed CVD. After adjusting for confounding factors, the risk of CVD incidence was highest in the lowest quartile (Q1) of eGDR compared to the highest quartile (Q4) (HR: 1.62, 95% CI: 1.38-1.88), followed by Q2 (HR: 1.34, 95% CI: 1.16-1.54). Elevated hs-CRP levels (≥2 mg/L) were associated with a 1.15-fold increased risk of CVD (95% CI: 1.04-1.27) compared to lower hs-CRP levels (<2 mg/L). When considering both eGDR and hs-CRP levels, the combined effect revealed the highest risk in individuals with the lowest eGDR (Q1) and elevated hs-CRP (HR: 1.75, 95% CI: 1.44-2.12), followed by those with Q1 of eGDR and low hs-CRP (HR: 1.59, 95% CI: 1.34-1.89), Q2 of eGDR with high hs-CRP (HR: 1.50, 95% CI: 1.22-1.84), and Q2 of eGDR with low hs-CRP (HR: 1.31, 95% CI: 1.12-1.54) (Table 1) Conclusion: In this large real-world study, we found that individuals with high eGDR and elevated hs-CRP had the highest risk of CVD. These findings highlight the combined role of insulin sensitivity and inflammation in predicting CVD risk and provide valuable insights into cardiovascular risk, aiding in early detection and targeted prevention strategies for CVD.

OBJECTIVES:To create a mixed valvular heart disease (MVHD)-related age-adjusted comorbidity index (MVACI) model for predicting mortality risk of patients with MVHD. METHODS:A total of 4080 patients with moderate or severe MVHD in the China-VHD study were included. The primary endpoint was 2-year all-cause mortality. A MVACI model prediction model was constructed based on the mortality risk factors identified by univariate and multivariate Cox regression analysis. Restricted cubic splines were used to assess the relationship between MVACI scores and 2-year all-cause mortality. The optimal threshold, determined by the maximum Youden index from receiver operator characteristic (ROC) curve analysis, was used to stratify patients. Kaplan-Meier method was used to calculate 2-year all-cause mortality and compared using the Log-rank test. Univariate and multivariate Cox proportional hazards models were employed to calculate hazard ratios (HR) and 95% confidence intervals (CI), evaluating the association between MVACI scores and mortality. Paired ROC curves were used to compare the discriminative ability of MVACI scores with the European System for Cardiac Operative Risk Evaluation Ⅱ(EuroSCORE Ⅱ) or the age-adjusted Charlson comorbidity index (ACCI) in predicting 2-year clinical outcomes, while calibration curves assessed the calibration of these models. Internal validation was performed using the Bootstrap method. Subgroup analyses were conducted based on etiology, treatment strategies, and disease severity. RESULTS:Multivariate analysis identified the following variables independently associated with 2-year all-cause mortality in patients: pulmonary hypertension, myocardiopathy, heart failure, low body weight (body mass index <18.5 kg/m2), anaemia, hypoalbuminemia, renal insufficiency, cancer, New York Heart Association (NYHA) class and age. The score was independently associated with the risk of all-cause mortality, and exhibited good discrimination (AUC=0.777, 95%CI: 0.755-0.799) and calibration (Brier score 0.062), with significantly better predictive performance than EuroSCORE Ⅱ or ACCI (both adjusted P<0.01). The internal validation showed that the MVACI model's predicted probability of 2-year all-cause mortality was generally consistent with the actual probability. The AUCs for predicting all-cause mortality risk were all above 0.750, and those for predicting adverse events were all above 0.630. The prognostic value of the score remained consistent in patients regardless of their etiology, therapeutic option, and disease severity. CONCLUSIONS:The MVACI was constructed in this study based on age and comorbidities, and can be used for mortality risk prediction and risk stratification of MVHD patients. It is a simple algorithmic index and easy to use.

Background and Aim:Anemia may affect cardiac function and outcomes in cardiovascular diseases. However, there is scarce evidence on the impact of anemia in patients with mitral valve dysfunction. This study sought to investigate the prevalence of anemia in patients with significant mitral regurgitation (MR), as well as its association with outcomes. Methods:A total of 4339 patients with moderate or greater MR in the China Valvular Heart Disease study were included in this analysis. Anemia was determined according to the World Health Organization definition. The primary outcome of this study was two-year all-cause mortality, and the secondary outcome was the composite of death and hospitalization for heart failure. Results:Anemia was present in 33.1% (1435/4339) of the study population. During a median follow-up of 732 (704-748) days, 426 (9.8%) patients died and 686 (15.8%) experienced the composite endpoint. Both anemia and hemoglobin were independently associated with two-year outcomes (all P < 0.001). Similar results were observed in patients with conservatively managed MR, left ventricular ejection fraction ≤60%, or in subsets according to New York Heart Association functional class (I/II-IV), the diagnosis of heart failure, severity of valvular lesion, etiology of MR, and the presence of malnutrition. The combination of anemia with left atrial dilatation or impaired left ventricular systolic function identified high-risk patients with significantly poor survival, and the inclusion of anemia to EuroSCORE II model enhanced risk prediction in MR. Conclusion:Anemia was common in patients with MR, and it was a significant predictor of poor prognosis. The high prevalence and negative impact of anemia make it as an important risk factor for prognostic evaluation and clinical decision-making.

Background:Frailty and sarcopenia are two related conditions, but how they lead to cardiovascular disease (CVD) remain unclear. The study aimed to investigate the combined and progressive effect of them. Methods:The data were from China Health and Retirement Longitudinal Study (CHARLS). Frailty status was evaluated by the Rockwood frailty index and sarcopenia status was classified according to the Asia Working Group for Sarcopenia 2019. Results:A total of 7187 participants aged over 45 years (49.41% male; mean age 57.38 ± 8.41 years) were enrolled in 2011. Among them, 4265 individuals without CVD events between 2011 and 2015 were included in the analysis of dynamic changes. Over the nine-year period, both frailty and sarcopenia status were independently associated with an increased risk of CVD. A significant interaction for CVD was observed between frailty and sarcopenia status (P for interaction <0.001). Furthermore, the coexistence of frailty and sarcopenia was associated with the highest risk of incident CVD (hazard ratios (HR) = 2.18; 95% confidence interval (CI) = 1.81-2.62), indicating that individuals with both conditions had more than double the risk of developing CVD, highlighting a substantially elevated cardiovascular vulnerability. Additionally, frailty was found to statistically mediate approximately 35.38% of the association between sarcopenia and CVD. Regarding dynamic changes, individuals who remained frail or experienced worsening sarcopenia were associated with the highest incidence of CVD, with HRs of 3.29 (95% CI = 2.44-4.45) and 1.56 (95% CI = 1.28-1.90), respectively, compared to those who remained robust or non-sarcopenic. These findings indicate that persistent frailty and deteriorating muscle health substantially increase CVD risk. Conclusions:The study indicated there was a combined and progressive effect of frailty and sarcopenia on CVD. These findings highlighted the importance of identifying and improving sarcopenia and frailty.

Background: Frailty is a common condition in older adults, associated with an increased risk of cardiovascular disease (CVD). The triglyceride-glucose index (TyG), a marker of insulin resistance, has also emerged as a potential predictor of CVD risk. Frailty and insulin resistance often coexist in the elderly, however, the combined role of frailty and TyG in the incidence of CVD remain unclear. Purpose: This study investigates the combined association of frailty and TyG with the incidence of CVD in middle-aged and older adults. Methods: This study utilized data from five waves of the China Health and Retirement Longitudinal Study (CHARLS). Frailty status was assessed using the Rockwood frailty index, which classified participants into three categories: robust (FI ≤ 0.10), pre-frail (0.10 < FI < 0.25), and frail (FI ≥ 0.25). The TyG index was calculated as Ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL) / 2] and categorized based on the median value. The cox regression and mediation analysis were used to assess the association between frailty status, TyG, and the incidence of CVD. Results: A total of 5,997 participants aged 45 years and older (48.40% male; mean age 57.51 ± 8.40 years) with no cardiovascular disease were enrolled in 2011. Over a maximum follow-up period of 9 years, 1,640 (27.3%) individuals developed CVD. After adjusting for potential confounders, the combined impact of frailty status and TyG showed the highest risk in frail individuals with high TyG (HR 2.30, 95% CI: 1.86-2.86), followed by frail individuals with low TyG (HR 1.92, 95% CI: 1.52-2.43), pre-frail individuals with high TyG (HR 1.85, 95% CI: 1.58-2.15), pre-frail individuals with low TyG (HR 1.76, 95% CI: 1.50-2.06), and robust individuals with high TyG (HR 1.17, 95% CI: 1.02-1.36) (Figure 1). Additionally, frailty status was found to significantly mediate 17.21% of the association between TyG and CVD (Figure 2). Conclusions: The results highlight the combined effect and mutual mediation between frailty status and TyG on the incidence of CVD. It is important to consider both frailty status and TyG together in risk assessments for better residual risk stratification and primary prevention of cardiovascular diseases, particularly in older populations.