Both the atherogenic index of plasma (AIP) and obesity have been implicated in cardiovascular disease (CVD) risk. This study aimed to investigate the associations of AIP and AIP-obesity indices (AIP-WC, AIP-BMI, AIP-WHtR, AIP-WWI, and AIP-BRI) with CVD and mortality. This study enrolled 21,944 individuals from the National Health and Nutrition Examination Survey (NHANES) fielded during the years 1999–2018. Cox and logistic regression modeling, along with restricted cubic splines (RCS), served to assess the associations of AIP and AIP-obesity indices with all-cause mortality, CVD mortality, and CVD prevalence. The incremental predictive value of AIP and AIP-obesity indices was further assessed. Throughout an average follow-up period of 116 months, 3,326 all-cause deaths were documented, among which 1,042 were CVD deaths. AIP, AIP-WC, AIP-BMI, AIP-WHtR, AIP-WWI, and AIP-BRI were significantly associated with all-cause mortality, CVD mortality, and CVD prevalence. In the fully adjusted model, relative to the lowest-tertile participants, the highest-tertile participants of these indices had an elevated risk of 17.7–20.3% for all-cause mortality, an elevated risk of 30.3–33.8% for CVD mortality, and a 103.7–122.2% increase in the odds of CVD. RCS analyses indicated non-linear associations of AIP, AIP-WC, AIP-BMI, AIP-WHtR, AIP-WWI, and AIP-BRI with all-cause mortality and CVD prevalence, whereas linear associations were observed with CVD mortality. Incremental predictive value analyses showed that compared with AIP alone, AIP-WC, AIP-BMI, AIP-WHtR, AIP-WWI, and AIP-BRI provided superior risk reclassification and discrimination across all outcomes. AIP and AIP-obesity indices were significantly associated with CVD and mortality risk. AIP combined with obesity-related indices, particularly BRI, provides additional value for the stratification of CVD and mortality risk.

The body roundness index (BRI) is a more comprehensive anthropometric measure than the body mass index (BMI) because it reflects the distribution of visceral fat more accurately. This study evaluated the separate and joint associations of cumulative BRI (cumBRI) exposure and its variability with the risk of fragility fractures in the Chinese population. This study included 47,240 individuals from the Kailuan Study who underwent three consecutive health examinations between 2006 and 2010 (2006–2007, 2008–2009, and 2010–2011) and were followed up until December 31, 2022. Cumulative BRI exposure was calculated using the time-weighted average (TWA), and variability in BRI was assessed using indices of variability. Cox models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). Subgroup analysis and interaction testing performed. The C-index, discriminatory improvement (IDI), and net reclassification index (NRI) were used to assess fracture risk prediction. During a median follow-up of 12.03 years, 725 participants developed fragility fractures. After adjusting for confounders, the HR for fragility fracture was 1.52 (95% CI 1.15–1.99) in the highest TWA BRI quartile, 1.38 (95% CI 1.08–1.75) in those with a cumulative burden of > 0, and 1.55 (95% CI 1.20-2.00) for those with ≥ 4 years of exposure duration. Greater BRI variability was associated with an increased risk of fragility fractures (HR 1.29, 95% CI 1.05–1.60]). The risk of fragility fractures was higher in individuals with a high TWA BRI and high BRI variability than in those with a low TWA BRI and low BRI variability. Combined measures of cumulative BRI and variability were better able to predict the risk of fracture than traditional metrics. Cumulative exposure to a high cumBRI and greater BRI variability in the BRI were independently associated with a higher incidence of fragility fractures, and their coexistence could may further increase the risk further. In terms of predicting the fracture risk, the combined effects of cumulative cumBRI exposure and variability predicting fracture risk are slightly superior to the predictive ability of obesity-related indices.

Angiopoietin-like protein 3 (Angptl3), a factor secreted by the liver, inhibits lipoprotein lipase and other lipases by forming a complex with Angptl4 and 8. However, whether inhibition of Angptl3 can alleviate hepatic lipid accumulation and atherosclerosis remains unclear. Therefore, this study explored the effect of small interfering RNA (siRNA)-based inactivation of Angptl3 on metabolic dysfunction-associated fatty liver disease (MAFLD) and atherosclerosis in male LDLR-deficient hamsters. Recombinant adeno-associated virus serotype 9 (AAV9) encoding Angptl3-siRNA or empty AAV (AAV9-null) were injected into male 4-month-old LDLR−/− hamsters via the jugular vein. Subsequently, all hamsters were administered with a 16-week high-fat diet (HFD) feeding to induce atherosclerosis. RT-PCR and pathological analysis were used to investigate the mechanism of hepatic lipid accumulation and detect atherosclerotic plaque formation in the heart and aorta. On HFD, Angptl3-siRNA-treated hamsters displayed significantly decreased plasma triglyceride (TG), total cholesterol, high-density lipoprotein-cholesterol, and glucose levels, compared with the AAV9-null hamsters. FPLC analysis further revealed a marked reduction of TG and cholesterol contents in VLDL/LDL fractions. Plasma apolipoprotein analysis showed relatively lower ApoB/ApoE levels and higher ApoA1 levels. Moreover, Angptl3-siRNA markedly accelerated the clearance of triglyceride-rich lipoproteins in LDLR−/− hamsters. Consistently, results from hepatic lipid extraction, Oil Red O and Sirius Red staining demonstrated that Angptl3-siRNA reduced hepatic lipid accumulation and ameliorated HFD-induced MAFLD. RT-PCR revealed a dramatic decrease in the expression of Acc1, Fasn, Srebp1c, Cd36, Fatp1, Tgfβ, Cd68, Tnfa, and Col1a1 as well as a marked increase in Abcg5, Abcg8, Ppara, and Cpt1 expression, which participated in fatty acid synthesis and oxidation, cholesterol synthesis and efflux, inflammation and fibrosis. Pathological analysis indicated that Angptl3-siRNA attenuated the formation of atherosclerotic plaques in the aortic root and aorta when compared with the control group. These findings demonstrated that siRNA-based inactivation of Angptl3 alleviated MAFLD and atherosclerosis induced by HFD in LDLR−/− hamsters, which further confirmed that inhibition of Angptl3 may provide a novel therapeutic approach for atherosclerosis by reducing hyperlipidemia and hepatic lipid accumulation.

IgA nephropathy (IgAN) demonstrates substantial progression to end-stage kidney disease, yet metabolic risk factors remain underexplored. The atherogenic index of plasma (AIP), calculated as log(triglycerides/HDL-cholesterol), integrates pro-atherogenic and anti-atherogenic lipid components, but its association with renal function in IgAN is unclear. This cross-sectional study analyzed 1186 Chinese patients with biopsy-proven primary IgAN. AIP was standardized as Z-scores for analysis. Primary outcome was estimated glomerular filtration rate (eGFR). Secondary outcomes included eGFR < 60 mL/min/1.73 m² and proteinuria. Multivariable linear and logistic regression models assessed associations with progressive adjustments. Subgroup analyses evaluated effect modification. Median age was 34 years with 48% males. Each standard deviation increase in AIP was associated with 2.08 mL/min/1.73 m² lower eGFR (95% CI: -3.48, -0.68; p = 0.004) and 33% higher odds of eGFR < 60 mL/min/1.73 m² (OR: 1.33; 95% CI: 1.07, 1.67; p = 0.012) in fully adjusted models. Patients in the highest versus lowest AIP tertile had 4.73 mL/min/1.73 m² lower eGFR (p = 0.005) and 76% higher odds of eGFR < 60 mL/min/1.73 m² (p = 0.034). AIP was associated with higher proteinuria in patients with eGFR ≥ 60 mL/min/1.73 m² (β: 141.63 mg/24 h per SD; 95% CI: 33.75, 249.51; p = 0.01). Significant effect modification occurred by BMI (p-interaction = 0.032) and hyperuricemia (p-interaction = 0.030), with stronger associations in patients with BMI < 23 kg/m² and without hyperuricemia. Higher AIP independently associates with lower eGFR and higher proteinuria at diagnosis in IgAN patients, particularly in specific metabolic subgroups. Longitudinal studies are needed to determine whether AIP has prognostic value for renal outcomes.

Evidence has linked insulin resistance (IR) with atherosclerotic disorders, but their relationship by different cardiovascular risk profiles remains indistinct. We sought to explore the associations of triglyceride-glucose (TyG) index and C-reactive protein-triglyceride glucose index (CTI), two reliable surrogates for IR, with incident carotid plaques in a rural Chinese population, while taking into account cardiovascular risk profiles. A total of 929 participants who were aged ≥ 40 years and free of carotid plaques at baseline in 2017 were recruited from participants of the Rose Asymptomatic Intracranial Artery Stenosis (RICAS) cohort. The presence of incident carotid plaques was assessed using B-mode ultrasound at the follow-up in 2021. TyG index and CTI were calculated from triglycerides, fasting plasma glucose, and hypersensitive C-reactive protein. Logistic regression models were used to explore the association of IR surrogates with incident carotid plaques. Over a median follow-up period of 3.92 years, 190 (20.45%) participants were detected with incident carotid plaques. A higher TyG index and a higher CTI were significantly associated with an increased risk of incident carotid plaques in the total sample, and among participants with low-density lipoprotein cholesterol (LDL-C) < 2.6 mmol/L or those with low-to-intermediate atherosclerotic cardiovascular disease (ASCVD) risk. Furthermore, among participants with LDL-C < 2.6 mmol/L, TyG index and CTI were significantly associated with incident carotid plaques only in males (p for interactions < 0.05). Elevated TyG index and CTI, indicators of insulin resistance, are associated with incident carotid plaques even among individuals with low cardiovascular risk profiles. These findings have potential implications for primary prevention of atherosclerotic disorders among populations with low cardiovascular risks. URL: https://www.chictr.org.cn; Unique identifier: ChiCTR1800017197; Registration Date: July 17, 2018.

Cardiometabolic multimorbidity (CMM) poses a significant global health challenge. The atherogenic index of plasma (AIP) is a promising biomarker for cardiometabolic risk, but there is limited information on its cumulative effect on CMM and the underlying mechanisms. This study investigated the association of cumulative AIP exposure with CMM risk, and explored the mediating roles of the triglyceride glucose (TyG) index and body mass index (BMI). This study was based on data from 5,454 participants from the China Health and Retirement Longitudinal Study (CHARLS, 2011 baseline). The participants were stratified into tertiles of cumulative AIP (cuAIP) and classified into three distinct AIP trajectory groups using k-means clustering. Associations between cuAIP levels, AIP trajectories, and CMM incidence were assessed using logistic. The relationship between cuAIP and CMM was further examined using receiver operating characteristic (ROC) curve analysis and restricted cubic splines (RCS). Structural equation modeling was used to evaluate the mediating roles of the TyG index and BMI. Finally, subgroup and sensitivity analyses were conducted to validate the results. A total of 385 CMM cases were observed during the 7-year follow-up. Cluster analysis revealed the highest CMM incidence (12.1%) in the persistently high AIP trajectory group. Logistic regression models indicated that the highest cuAIP group (OR 2.81, 95% CI: 1.95-4.14) and high AIP trajectory group (OR 2.34, 95% CI: 1.68-3.28) had the highest CMM risk, with consistent results in sensitivity analyses and most subgroups. The AUC of cuAIP for predicting CMM was 0.648, and RCS curves demonstrated increasing CMM incidence with rising cuAIP levels. Mediation analysis indicated that the TyG index and BMI mediated 74% and 26% of the total effect, respectively. This study establishes AIP as an independent predictor of CMM, whereby its effect is primarily mediated by the TyG index and BMI. These findings support the implementation of integrated clinical strategies to effectively prevent CMM and its associated diseases.