Cardiovasc Diabetol [JOURNAL]
Sun
200 papers
The shared genetic architecture underlying the autoimmune and cardiovascular disease: a multivariate genome-wide analysis.
Zhang J, Fang X, Ye Q … +2 more , Yin X, Ye D
Cardiovasc Diabetol · 2026 Feb · PMID 41673668 · Full text
BACKGROUND: Epidemiological studies have established that autoimmune diseases (AD) increase cardiovascular disease (CVD) risk. We aimed to elucidate their shared genetic architecture and clinical implications. METHODS: W...
BACKGROUND: Epidemiological studies have established that autoimmune diseases (AD) increase cardiovascular disease (CVD) risk. We aimed to elucidate their shared genetic architecture and clinical implications. METHODS: We conducted a cross-trait multivariate genome-wide association study (GWAS) for three autoimmune diseases (type 1 diabetes, systemic lupus erythematosus, and rheumatoid arthritis) and four cardiovascular diseases (coronary artery disease, heart failure, stroke, and peripheral artery disease). We performed both genome-wide and locus-based analysis including fine-mapping, functional annotation, enrichment analyses, transcriptome-wide association studies (TWAS), and proteome-wide and drug-repurposing Mendelian randomization (MR). We constructed a polygenic risk score (PRS) and explored its pleiotropic effects beyond AD and CVD in the UK Biobank population. RESULTS: In the multivariate GWAS, we identified 259 genome-wide significant association signals that were enriched primarily in arterial tissues and lipid metabolism pathways. Through convergent evidence from TWAS and MR analyses, we prioritized 15 therapeutic targets including TGFB1 and IL6R, and identified histone deacetylase inhibitors as candidate drugs. The polygenic risk score showed discriminative ability in cardiovascular risk stratification among autoimmune patients, with individuals in the highest PRS decile exhibiting significantly elevated CVD risk compared to those in the 2nd-9th deciles (hazard ratios: 1.60 [95% CI: 1.19-2.15] for type 1 diabetes, 2.28 [95% CI: 1.14-4.56] for systemic lupus erythematosus, and 2.33 [95% CI: 1.94-2.80] for rheumatoid arthritis). Additionally, the PRS revealed pleiotropic associations with risk of various health conditions, including polyneuropathy, chronic renal failure, and depressive episodes. CONCLUSION: Our study unveils the shared genetic architecture between autoimmune and cardiovascular diseases, providing insights for therapeutic development and risk stratification.
Causal demonstration of adiposity-induced adipose-specific signaling derangements in the pathogenesis of the clinical features of the cardiovascular-kidney metabolic syndrome.
Packer M
Cardiovasc Diabetol · 2026 Feb · PMID 41668130 · Full text
The American Heart Association has recognized that excess dysfunctional fat and its secretion of adipokines are upstream causal mechanisms that drive the clinical and pathophysiological features of the cardiovascular-kid...
The American Heart Association has recognized that excess dysfunctional fat and its secretion of adipokines are upstream causal mechanisms that drive the clinical and pathophysiological features of the cardiovascular-kidney-metabolic (CKM) syndrome. The identity of these signaling molecules can be discerned by experimental adipose tissue-specific silencing studies showing that biological events induced by adiposity and occurring selectively in adipose tissue can promote each element of the CKM syndrome. Suppression of the renin-angiotensin system specifically and selectively only in adipose tissue alleviates hypertension and atherosclerosis, whereas overexpression of the mineralocorticoid receptor specifically and only in adipocytes promotes vascular injury. Silencing of autotaxin, platelet-derived growth factor D, resistin and microRNA-410-5P selectively and specifically only in adipose tissue ameliorates the development of cardiac hypertrophy and fibrosis, thus preventing experimental HFpEF. The suppression of cytoprotective adipokines (e.g., adiponectin) simultaneous with the activation of proinflammatory adipokines (e.g., leptin) promotes renal tubular sodium reabsorption and plasma volume expansion. Experimental aldosterone-induced kidney injury is accompanied by augmented expression of lipocalin-2 in visceral adipose tissue, and selective and specific deletion of lipocalin-2 only in adipose tissue—but not in the kidney—counteracts renal inflammation and fibrosis. Silencing of fatty acid binding protein 4 and 12/15-lipoxygenase selectively and specifically in adipose tissue prevents the development of insulin resistance. These observations support the conceptual framework that the accumulation of dysfunctional fat can promote each of the pathophysiological features of the CKM syndrome by altering the expression and/or secretion of signaling molecules in an adipose tissue-specific and -selective manner.
Distinct immunometabolic signatures of type 1 versus type 2 diabetes in a murine model of myocardial infarction.
O'Quinn KR, Wright CB, Khan M … +11 more , Spitz RW, Rouhi N, Morato JG, Vidal PA, Omoto ACM, da Silva AA, do Carmo JM, Wang Z, Li X, Hall JE, Mouton AJ
Cardiovasc Diabetol · 2026 Feb · PMID 41656217 · Full text
BACKGROUND: Diabetes mellitus (DM), which consists of type I and type 2 diabetes (T1D and T2D), is a known risk factor for myocardial infarction (MI) and negatively impacts post-MI outcomes. However, the mechanisms by wh...
BACKGROUND: Diabetes mellitus (DM), which consists of type I and type 2 diabetes (T1D and T2D), is a known risk factor for myocardial infarction (MI) and negatively impacts post-MI outcomes. However, the mechanisms by which DM exacerbates cardiac remodeling in T1D versus T2D have not been well defined. Here, we assessed acute and chronic post-MI outcomes in T1D and T2D mice, focusing on immune and metabolic pathways. METHODS: T1D was induced in adult male mice by a single high dose of streptozotocin (STZ), and T2D induced by high fat/fructose feeding and multiple low STZ doses. Two weeks following STZ administration, MI was induced by permanent coronary artery ligation, and mice were studied at days (D) 0, 3, 7, and 28 post-MI. Cardiac function was assessed by echocardiography. RESULTS: Compared to non-diabetic mice, T1D and T2D mice had worse cardiac dysfunction after MI, including increased wall thinning and decreased ejection fraction, despite similar infarct sizes. T1D mice also displayed acute pulmonary congestion. By RNA-sequencing analysis, T1D and T2D mice displayed upregulation of genes associated with canonical chemokine/monocyte-mediated inflammatory pathways, and downregulation of genes associated with extracellular matrix remodeling. T1D and T2D delayed activation of M2-like (CD206+) macrophages in the heart, and impaired normal collagen and elastin deposition after MI. T2D also increased expression of genes associated with T cell activation, and increased CD8 + T cells in the infarct. T1D and T2D hearts showed signs of impaired glucose and ketone oxidation, and T1D hearts had increased markers of fatty acid oxidation. Extracted D3 cardiac macrophages from T1D and T2D mice exhibited higher basal oxygen consumption, and increased M1 markers and chemokine expression. Plasma from T1D and T2D mice increased chemokine expression (Ccl2, Ccl7, Cxcl1) in cultured bone marrow macrophages, and T2D plasma impaired mitochondrial function. CONCLUSIONS: DM promotes adverse cardiac remodeling, which is associated with activation of overlapping and unique inflammatory pathways, impaired ECM remodeling, remote metabolic remodeling, and alterations in macrophage metabolism. Our results provide novel insights into potential therapeutic pathways for DM patients suffering from MI.
Cumulative exposure to the estimated glucose disposal rate and incident stroke in individuals with cardiovascular-kidney-metabolic syndrome stages 0-4: 6-year longitudinal evidence from CHARLS.
Wang Y, Wei N, Li M … +3 more , Liu JW, Lin HB, Zhang HF
Cardiovasc Diabetol · 2026 Feb · PMID 41654871 · Full text
BACKGROUND: The estimated glucose disposal rate (eGDR), an established measure of peripheral insulin sensitivity, contributes to stratifying the risk of cardio-cerebrovascular events. Nevertheless, the association betwee...
BACKGROUND: The estimated glucose disposal rate (eGDR), an established measure of peripheral insulin sensitivity, contributes to stratifying the risk of cardio-cerebrovascular events. Nevertheless, the association between long-term eGDR exposure and stroke incidence throughout all stages (0-4) of cardiovascular-kidney-metabolic (CKM) syndrome remains unknown. METHODS: A cohort of 5248 individuals was drawn from the China Health and Retirement Longitudinal Study (CHARLS). For each participant, eGDR values for the years 2012 and 2015 were calculated using the equation: 21.158 - [0.090 × WC (cm)] - [3.407 × HTN (presence = 1)] - [0.551 × HbA1c (%)]. Cumulative eGDR was calculated as (eGDR + eGDR)/2* time (2015-2012). K-means clustering was used to analyse eGDR values from both 2012 and 2015 to identify distinct change patterns. To assess associations with stroke risk, we utilised multivariable logistic regression and restricted cubic spline models. RESULTS: During the 2015-2018 follow-up period, a total of 336 incident stroke cases were documented. Four distinct eGDR change patterns were identified. In fully adjusted models, compared with the participants in the persistent low pattern (Class 2), those in the moderate-high stable (OR 0.43, 95% CI: 0.31-0.58), stable high (OR 0.29, 0.19-0.43), and rapid decrease (OR 0.66, 0.47-0.91) patterns exhibited significantly lower stroke risk. Furthermore, each 1-unit increase in cumulative eGDR was associated with a 5% reduction in stroke odds (OR 0.95, 0.93-0.96). Restricted cubic spline analysis confirmed a linear inverse relationship between cumulative eGDR and stroke risk (P < 0.001; P for nonlinearity = 0.259). CONCLUSION: Cumulative eGDR is inversely associated with stroke risk across all CKM syndrome stages (0-4). This observation suggests that prolonged eGDR surveillance may be associated with improved risk stratification in this population.
Predictive value of an integrated insulin resistance and lipometabolic score for cardiometabolic multimorbidity in older adults: a UK cohort study.
Li C, Luo X, Chen Y … +2 more , Lin J, Gu S
Cardiovasc Diabetol · 2026 Feb · PMID 41639900 · Full text
BACKGROUND: Markers of insulin resistance, such as the triglyceride-glucose (TyG) index and estimated glucose disposal rate (eGDR), have been extensively linked to cardiometabolic multimorbidity (CMM). However, the roles...
BACKGROUND: Markers of insulin resistance, such as the triglyceride-glucose (TyG) index and estimated glucose disposal rate (eGDR), have been extensively linked to cardiometabolic multimorbidity (CMM). However, the roles of lipid metabolism indicators, including the atherogenic index of plasma (AIP) and remnant cholesterol (RC), remain less clearly defined. This study aimed to evaluate both the individual and combined effects of insulin resistance and dyslipidemia on the risk of CMM. METHODS: Data were derived from the English Longitudinal Study of Ageing. A composite metabolic index integrating the TyG, eGDR, AIP, and RC was developed using principal component analysis. The associations of individual and composite indices with incident CMM were examined using multivariable Cox proportional hazards models, while their predictive performance was assessed via receiver operating characteristic (ROC) and net reclassification improvement (NRI) analysis. RESULTS: Over a 6.8-year follow-up period, 552 cases of CMM occurred among 4232 participants. After multivariable adjustment, each standard deviation (SD) increase in TyG, AIP, and RC was linked to a higher risk of CMM by 30.8% (HR = 1.308; 95% CI: 1.202-1.422), 22.2% (HR = 1.222; 95% CI: 1.117-1.338), and 7.6% (HR = 1.076; 95% CI: 1.025-1.129), respectively. In contrast, eGDR and the composite metabolic index were linked to 35.0% (HR = 0.650; 95% CI: 0.565-0.747) and 37.4% (HR = 0.626; 95% CI: 0.554-0.707) lower risks of CMM. The eGDR and CompositeIndex showed high Population attributable fraction (PAF) of 56.3% (95% CI: 47.3-63.4) and 38.3% (95% CI: 29.8-47.8), respectively. Dose-response analyses showed near-linear relationships for all indices. ROC and NRI analysis further indicated that the CompositeIndex offered highest discrimination with a modest improvement for CMM (AUC = 0.754, 95% CI: 0.737-0.778; NRI = 0.066 (0.027-0.106). The associations were more pronounced among participants younger than 65 years and consistent across sex. CONCLUSIONS: The integrated index combining insulin resistance and lipid dysregulation was associated with incident CMM and provided modest improvements in risk discrimination and reclassification beyond traditional risk factors.
Association of various insulin resistance surrogate indices with aging acceleration and future risk of cardiovascular disease in individuals with cardiovascular-kidney-metabolic syndrome stages 0-3: insights from CHARLS 2011-2020 data.
Han SS, Liu Q, Zeng ZM … +5 more , Li Y, Li PW, Cheng FX, Zhong P, Li JB
Cardiovasc Diabetol · 2026 Feb · PMID 41639853 · Full text
BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome imposes a substantial global health burden, with most adults clustered in early stages 0-3. Insulin resistance (IR), as a core manifestation of metabolic dysfunc...
BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome imposes a substantial global health burden, with most adults clustered in early stages 0-3. Insulin resistance (IR), as a core manifestation of metabolic dysfunction, is thought to play a pivotal role in CKM progression and cardiovascular disease (CVD) development, but the relative impact of diverse IR surrogates and the mediating role of biological ageing acceleration remain unclear. METHOD: This prospective analysis included 6318 participants with CKM syndrome stages 0-3 from the China Health and Retirement Longitudinal Study (CHARLS). We evaluated twelve insulin resistance surrogates in relation to incident CVD using multivariable-adjusted logistic regression, restricted cubic splines (RCS), and quantile-based models. Mediation analyses assessed whether biological aging acceleration mediated the association between IR indices and new-onset CVD. RESULTS: 1231 (19.5%) of 6318 participants with CKM stages 0-3 developed new-onset CVD. All IR surrogates demonstrated significant associations with CVD risk, with elevated TyG-derived indices, METS-IR, CTI, and TG/HDL-C showing positive associations whereas eGDR exhibited an inverse relationship (all P-trend < 0.05). RCS analyses revealed nonlinear relationships for METS-IR, CTI, and eGDR. Significant modification effects were observed by biological ageing acceleration, gender, and CKM stage. Mediation analyses indicated that biological aging acceleration accounted for 14.9-16.4% of the TyG-ABSI-CVD association and 1.3-4.2% of other IR-CVD relationships. CONCLUSIONS: Multiple IR surrogate indices independently predict cardiovascular disease in CKM stages 0-3, with biological aging acceleration mediating this association. Integrating these measures into risk stratification could enable early identification and targeted intervention for high-risk individuals.
Association of the triglyceride glucose-Chinese visceral adiposity index with incident cardiometabolic multimorbidity in middle-aged and older adults: a nationwide prospective cohort study.
Zheng W, Man Z, Ren Y … +6 more , Li Y, Zhu X, Wang L, Zhang X, Hu G, Cao Y
Cardiovasc Diabetol · 2026 Feb · PMID 41639722 · Full text
OBJECTIVE: Cardiometabolic multimorbidity (CMM) is a growing global health challenge. Whether the baseline or cumulative triglyceride glucose and Chinese visceral adiposity index product (TyG-CVAI) can predict incident C...
OBJECTIVE: Cardiometabolic multimorbidity (CMM) is a growing global health challenge. Whether the baseline or cumulative triglyceride glucose and Chinese visceral adiposity index product (TyG-CVAI) can predict incident CMM remains unclear. METHODS: We constructed two prospective cohorts from the China Health and Retirement Longitudinal Study (CHARLS): Cohort 1 (n = 8895 patients) to assess the association of the baseline TyG-CVAI with CMM and Cohort 2 (n = 5839 patients) to assess the association of the cumulative TyG-CVAI with CMM. The cumulative TyG-CVAI was calculated as the average TyG-CVAI between baseline and the 2015 wave multiplied by the exposure time. Incident CMM was confirmed via a self-reported physician diagnosis, medication use, and clinical data. Cox regression models were used to estimate hazard ratios (HRs). Nonlinearity was assessed using restricted cubic splines, and predictive performance was evaluated by performing a receiver operating characteristic (ROC) curve analysis. RESULTS: During follow-up, 875 and 492 incident CMM cases were documented in Cohort 1 and Cohort 2, respectively. Both the baseline and cumulative TyG-CVAI showed graded, positive associations with the CMM risk. Compared with the lowest quartile, the highest quartile was associated with significantly increased risks (baseline: HR = 1.93, 95% CI = 1.46-2.54; cumulative: HR = 1.76, 95% CI = 1.22-2.53). Significant nonlinear relationships with threshold effects were observed for both indices (P for nonlinearity < 0.001). Furthermore, compared with their individual components (TyG or CVAI), both the baseline and cumulative TyG-CVAI demonstrated superior predictive ability for CMM, as indicated by a larger area under the ROC curve. CONCLUSIONS: Both the baseline and cumulative TyG-CVAI are independent and nonlinear predictors of incident CMM, outperforming TyG or CVAI alone. This easily obtainable metric may enhance risk stratification and help identify high-risk individuals for early preventive intervention.
Echocardiography and inflammatory biomarkers for predicting mortality and major adverse cardiovascular events in type 1 diabetes.
Bahrami HSZ, Jørgensen PG, Hove JD … +5 more , Dixen U, Rasmussen LJH, Eugen-Olsen J, Rossing P, Jensen MT
Cardiovasc Diabetol · 2026 Feb · PMID 41634769 · Full text
BACKGROUND/AIMS: Current clinical risk tools in type 1 diabetes do not include left ventricular dysfunction or inflammation, potentially limiting early risk detection. We aimed to evaluate the associations and predictive...
BACKGROUND/AIMS: Current clinical risk tools in type 1 diabetes do not include left ventricular dysfunction or inflammation, potentially limiting early risk detection. We aimed to evaluate the associations and predictive value of combining echocardiography with inflammatory biomarkers for mortality and major adverse cardiovascular events (MACE). METHODS: In a prospective cohort of individuals with type 1 diabetes without known cardiovascular disease, we evaluated whether subclinical left ventricular dysfunction, defined by an elevated ratio of early mitral inflow velocity to early diastolic mitral annular velocity (E/e') or impaired global longitudinal strain (GLS), combined with elevated levels of an inflammatory biomarker (interleukin-6 [IL-6], soluble urokinase-plasminogen-activator-receptor [suPAR], or high-sensitivity C-reactive-protein [hsCRP]), was associated with all-cause mortality and MACE. Cox models were adjusted for all 10 variables included in the Steno T1 Risk Engine variables: age, sex, systolic blood pressure, duration of diabetes, HbA1c, low-density lipoprotein, estimated glomerular filtration rate, albuminuria status, smoking, and physical activity. C-statistics and net reclassification improvement were assessed. RESULTS: Among 876 participants (51% male, median age 50 years), 114 deaths occurred over 14.5 years of follow-up. Elevated E/e' combined with IL-6 or suPAR, but not hsCRP, was independently associated with mortality. Compared with individuals with E/e' <8 and non-elevated IL-6, the hazard ratio (HR) for E/e' 8-13 with elevated IL-6 was 2.5 (95% CI 1.4 to 4.6, P < 0.01), and for E/e' ≥13 with elevated IL-6 was 3.4 (1.5-7.6; P < 0.01). Corresponding HRs for suPAR were 2.4 (1.2 to 4.7, P < 0.01) and 3.9 (1.8 to 8.5, P < 0.01). Adding E/e' and an inflammatory biomarker increased the C-statistic from 0.839 (Steno T1 Risk Engine alone) to 0.887 (E/e' and IL6) and 0.868 (E/e' and suPAR). Findings were similar for GLS and with MACE as the outcome. CONCLUSIONS: Echocardiography combined with inflammatory biomarkers synergistically identifies individuals with type 1 diabetes, without known cardiovascular disease, who are at high risk of mortality and MACE.
Targeting TFAM K76 acetylation attenuates mitochondrial dysfunction and kidney injury in diabetic kidney disease.
Fu T, Sun S, Wang Z … +8 more , Zhao F, Zhen J, Ji X, Xue F, Mu Q, Wang Y, Liu Y, Wan Q
Cardiovasc Diabetol · 2026 Feb · PMID 41634735 · Full text
BACKGROUND: Mitochondrial dysfunction is a hallmark of diabetic kidney disease (DKD), yet its regulatory mechanisms remain poorly defined. Mitochondrial transcription factor A (TFAM), a central regulator of mitochondrial...
BACKGROUND: Mitochondrial dysfunction is a hallmark of diabetic kidney disease (DKD), yet its regulatory mechanisms remain poorly defined. Mitochondrial transcription factor A (TFAM), a central regulator of mitochondrial homeostasis, undergoes lysine 76 (K76) acetylation, but the functional significance of this modification in DKD has not been established. METHODS: We collected kidney tissues from DKD patients and DKD mice, and assessed TFAM acetylation in HK-2 cells and primary renal tubular cells under high-glucose conditions. In addition, to investigate the potential mechanism of TFAM acetylation in mitochondrial damage within the kidney, we explored relevant pathways using proteomics and utilized streptozotocin (STZ)-induced DKD mouse models with tubular-specific expression of TFAM wild-type and mutant forms to examine kidney injury. Moreover, we identified TFAM K76 acetylation-specific inhibitors through high-throughput virtual screening and thoroughly validated them in HK-2 cells, primary cells, and DKD mice, confirming the critical role of TFAM acetylation in DKD-related kidney injury. RESULTS: Here, we identify TFAM K76 acetylation as a critical mediator of mitochondrial injury in DKD. TFAM K76 acetylation was markedly elevated in kidney tissues from DKD patients and diabetic mouse models, correlating with mitochondrial damage, inflammation, and fibrosis under hyperglycemic conditions. In vivo, overexpression of acetylation-mimetic TFAM K76Q in renal tubular epithelial cells aggravated renal injury and ultrastructural damage, whereas its deacetylation attenuated these effects. Mechanistically, TFAM K76 acetylation impaired oxidative phosphorylation and excessively activated autophagy, further exacerbating mitochondrial damage. We identified sirtuin 3 (SIRT3) as an upstream deacetylase that regulates this modification. Importantly, through high-throughput virtual screening, we discovered a novel small-molecule inhibitor (C14) that selectively reduces TFAM K76 acetylation and effectively alleviates hyperglycemia-induced mitochondrial dysfunction, inflammation, and fibrosis in both in vitro and in vivo models. CONCLUSIONS: Collectively, our findings define TFAM K76 acetylation as a pathogenic driver of DKD and propose C14 as a promising therapeutic candidate targeting mitochondrial metabolism.
Association of atherogenic index of plasma and cardiometabolic index with all-cause mortality and cardiovascular disease in NAFLD patients: NHANES 1999-2018.
Yu C, Qiu C, Zhang Q … +3 more , Wang W, Liu S, Jin Z
Cardiovasc Diabetol · 2026 Feb · PMID 41634708 · Full text
BACKGROUND: The atherogenic index of plasma (AIP) serves as a crucial indicator for assessing atherosclerotic risk. It reflects the degree of dyslipidaemia and cardiovascular disease (CVD) risk. The cardiometabolic index...
BACKGROUND: The atherogenic index of plasma (AIP) serves as a crucial indicator for assessing atherosclerotic risk. It reflects the degree of dyslipidaemia and cardiovascular disease (CVD) risk. The cardiometabolic index (CMI) provides a comprehensive evaluation of obesity-related metabolic risk, acting as a key biomarker for predicting multiple cardiometabolic diseases. The relationship between AIP and CMI in patients with non-alcoholic fatty liver disease (NAFLD) and mortality or CVD risk remains unclear. METHODS: This study included 5792 adult (≥ 18 years) NAFLD patients from the US National Health and Nutrition Examination Survey (NHANES, 1999-2018). Weighted logistic regression and Cox proportional hazards models were employed to investigate the association between AIP, CMI and all-cause mortality, CVD mortality and CVD risk. Restricted cubic spline (RCS) curves assessed non-linear associations. Subgroup analyses and mediation analyses examined the effect modifiers and mediators. The incremental predictive value of AIP and CMI was evaluated. Sensitivity analyses were conducted to validate the robustness. RESULTS: During follow-up, 721 all-cause deaths (including 241 CVD deaths) and 726 total CVD events were recorded. After adjusting for confounding factors, patients in the highest quartiles of AIP and CMI had a significantly higher risk of specific CVD events. The strongest association was observed for CHF (AIP: OR = 3.157, 95% CI 1.684, 5.922, p < 0.001; CMI: OR = 3.604, 95% CI 1.843, 7.047, p < 0.001), followed by heart attack and CHD. CMI consistently demonstrated a stronger effect than AIP. RCS analysis indicates a non-linear relationship between CMI and CHD, angina pectoris. Subgroup analysis revealed that both AIP and CMI demonstrated high predictive value for all-cause mortality in the 40-60 age cohort. Mediation analysis revealed that Mets, NLR, hypertension and HOMA-IR partially mediated the aforementioned associations. The inclusion of AIP and CMI partially improved the predictive capability of the basic model. Sensitivity analyses validated the robustness of these findings. CONCLUSIONS: In patients with NAFLD, CMI is a stronger predictor of non-fatal CVD than AIP. While both indices show limited value for predicting mortality, CMI holds promise as a practical supplementary tool for clinical risk assessment.
Clinical subgroup-stratified plasma proteomic signatures improve risk prediction for myocardial infarction: SCORE2-Pro.
Tong M, Zhang M, Xu M … +6 more , Cao Z, Ning G, Wang W, Wang J, Yang Q, Zheng J
Cardiovasc Diabetol · 2026 Feb · PMID 41629928 · Full text
BACKGROUND: Myocardial infarction (MI) remains a leading cause of global mortality, with risk varying substantially across demographic and clinical subgroups. Although SCORE2 is widely implemented for cardiovascular risk...
BACKGROUND: Myocardial infarction (MI) remains a leading cause of global mortality, with risk varying substantially across demographic and clinical subgroups. Although SCORE2 is widely implemented for cardiovascular risk stratification, the extent to which clinical subgroup specific plasma proteomics can further refine personalized MI risk prediction remains uncertain. METHODS: SCORE2-Pro, a clinical subgroup-stratified plasma proteome prediction model was built stratified by sex, age, smoking status, non-high-density lipoprotein (non-HDL) cholesterol, and systolic blood pressure. In 51,010 UK Biobank participants (aged 40-69 years; 54.9% female) without MI at baseline, 70% were used for model development, and the remaining 30% for an internal hold-out validation. We used light gradient boosting machine classifiers and Cox proportional hazards models to identify top-predictive protein combinations and stratification strategies for MI. RESULTS: The SCORE2-Pro model revealed distinct and highly effective protein panels for each subgroup. Compared with the clinical model, SCORE2-Pro remarkably enhanced predictive performance across demographic and clinical subgroups. A 9-protein model in females improved AUC by + 0.061 (P = 1.51 × 10), with a net reclassification index (NRI) of + 0.125 (P = 2.69 × 10). Similarly, a 7-protein model for middle-aged subpopulation demonstrated an AUC improvement of + 0.036 (P = 0.033) with an NRI of + 0.127 (P = 8.09 × 10). Notably, in high-risk populations, SCORE2-Pro model significantly improved reclassification performance compared with the clinical model (NRI: + 0.121, P = 0.020). CONCLUSIONS: By adopting a clinical subgroup stratification approach using factors derived from SCORE2, we identified subgroup-specific proteomic signatures for MI that considerably improve predictive accuracy and reclassification beyond traditional clinical models.
Sex‑specific cardiovascular risk in estrogen‑treated androgen‑deprived males: metabolic characterization of glucose, adipose, and lipid pathways.
Thorson AS, Schaefers KP, Litts B … +19 more , Rein J, Adapa S, Chinnarasu S, Shapiro K, Zhao Y, Yu S, Recupido B, Streng KJ, Ahn IS, Lan R, Pierre-Louis O, Forson D, Bennett M, Luviano H, Saleem M, Zhu L, Yang X, Kirabo A, M Stafford J
Cardiovasc Diabetol · 2026 Feb · PMID 41622197 · Full text
BACKGROUND: Estrogen therapy and androgen‑deprivation were once combined to treat prostate cancer (PrCa). Clinical studies later showed that prolonged estrogen exposure in androgen‑deprived men raises cardiovascular dise...
BACKGROUND: Estrogen therapy and androgen‑deprivation were once combined to treat prostate cancer (PrCa). Clinical studies later showed that prolonged estrogen exposure in androgen‑deprived men raises cardiovascular disease (CVD) risk, yet the metabolic pathways responsible remain unclear. METHODS: We generated an androgen‑deprived, 17β‑estradiol (E2)-treated mouse model by gonadectomizing male C57BL/6 J mice and implanting sub‑cutaneous delayed‑release E2 or vehicle pellets. Mice received a Western‑style diet and were housed at thermoneutrality to accelerate CVD‑risk phenotypes. Metabolic profiling included hyperinsulinemic‑euglycemic clamps, oral lipid and pyruvate tolerance tests, flow cytometry of immune cells, and single‑nucleus RNA sequencing of liver tissue. RESULTS: In hypogonadal males, E2 treatment induced several metabolic disturbances. During clamps, E2‑treated mice showed markedly elevated gluconeogenesis, corroborated by higher glucose peaks and AUC during pyruvate tolerance testing and by up‑regulation of hepatic Pck1 mRNA. Triglyceride (TG) clearance, which improves with E2 in females, was impaired in E2‑treated males: oral lipid‑tolerance testing revealed prolonged TG excursions, reduced maximal lipase activity, lower non‑lipase clearance at 6 h post-OLTT, and decreased free‑fatty‑acid peak levels. Hepatic lipase, VLDL clearance receptors Ldlr and Lrp1, and microsomal triglyceride transfer protein (MTP) transcripts were down‑regulated. SnRNA‑seq showed suppression of lipid‑clearance genes with E2 treatment in males. Subcutaneous adipocytes were hypertrophic, and flow cytometry identified increased TNFα‑positive macrophages, an inflammatory milieu that could promote insulin resistance. Cardiac morphology was modestly altered; E2‑treated males exhibited a larger left‑ventricular end‑diastolic diameter, while ejection fraction and arterial pressure remained unchanged. CONCLUSION: Estradiol administration in androgen‑deprived male mice produces a constellation of metabolic derangements-including enhanced hepatic gluconeogenesis, impaired TG clearance, and inflammatory adipocyte hypertrophy-that likely underlie the increased CVD risk observed clinically. The identified molecular nodes (PEPCK, hepatic lipase, LRP1, LDLR, MTP, and adipose‑macrophage TNFα) provide potential targets for mitigating estrogen‑induced CVD risk while preserving its therapeutic benefit for PrCa.
Advanced imaging strategies in cardiac organoids: bridging the gap between structural complexity and functional analysis.
Zhao K, Tang B, Gu R … +7 more , Liu C, Zhang H, Gao Y, Wang P, Gu Y, Shi M, Li Z
Cardiovasc Diabetol · 2026 Jan · PMID 41618376 · Full text
Cardiac organoids have emerged as pivotal models for cardiovascular disease research and drug development due to their ability to recapitulate the in vivo cardiac microenvironment, structure, and function. Imaging techno...
Cardiac organoids have emerged as pivotal models for cardiovascular disease research and drug development due to their ability to recapitulate the in vivo cardiac microenvironment, structure, and function. Imaging technologies are core tools for deciphering their three-dimensional (3D) complexity. This review outlines the key framework of cardiac organoid imaging research, focusing on pre-imaging sample processing, mainstream imaging technologies, image analysis workflows and applications in disease mechanisms and drug screening. We also provide guidelines for technique selection based on research objectives. Currently, long-term 4D imaging of cardiac organoids is still in its infancy. Future efforts should optimize imaging strategies and advance high-resolution dynamic techniques to deepen understanding of the temporal dynamics of cardiac pathology, providing technical support for cardiovascular research.
A 5-hydroxymethylcytosine-based noninvasive model for acute myocardial infarction in type 2 diabetes: implications in cardiovascular outcomes from a 5-year median follow-up study.
Yang K, Qin S, Xu S … +10 more , Cui X, Zhang Z, Cao J, Xiao M, Yang Y, He C, Zhou X, Weng X, Zhang W, Liu SM
Cardiovasc Diabetol · 2026 Jan · PMID 41618335 · Full text
BACKGROUND: Patients with type 2 diabetes (T2D) are at an increased risk of developing acute myocardial infarction (AMI), yet the role of 5-hydroxymethylcytosines (5hmC) changes in T2D-associated cardiovascular events re...
BACKGROUND: Patients with type 2 diabetes (T2D) are at an increased risk of developing acute myocardial infarction (AMI), yet the role of 5-hydroxymethylcytosines (5hmC) changes in T2D-associated cardiovascular events remains poorly understood. Despite therapeutic advances, patients with T2D who suffer an AMI continue to exhibit markedly elevated cardiovascular risk and poor prognosis, underscoring the need for improved detection and risk assessment. METHODS: We evaluated genome-wide 5hmC modifications in circulating cell-free DNA (cfDNA) for their value as noninvasive biomarkers for AMI in T2D. Genome-wide mapping of 5hmC in plasma cfDNA were obtained using the 5hmC-Seal technique from 225 participants, including 57 T2D patients with AMI (T2D + AMI), and 168 T2D patients without AMI (T2D + non-AMI). A weighted 5hmC-based model was developed to compute an epigenetic score for each individual, which was first derived from baseline cross-sectional data to discriminate between the patients from the two groups. Subsequently, the utility of the epigenetic score for predicting composite cardiovascular outcomes (CCO) was assessed prospectively within the same cohort using 5-year longitudinal follow-up data. RESULTS: 255 differential 5hmC-gene bodies (P < 0.05) associated with T2D + AMI, involving pathways related to cardiac functions, such as heart process and heart contraction. A seven-feature weighted model based on 5hmC signatures was developed for distinguishing T2D + AMI from T2D + non-AMI, which achieved an area under the curve (AUC) of 99.2% (95% CI 98.1-100.0%) in training set and 95.6% (95% CI 89.8-100.0%) in testing set. Furthermore, we established and tested a 5hmC-derived weighted epigenetic score for predicting cardiovascular events in diabetic population (eSCORE-CARD) over a median follow-up of 5.3 years. Multivariate Cox regression analysis showed that the eSCORE-CARD values were significantly associated with an increased risk of CCO (HR = 4.25; 95% CI 1.41-12.80; P < 0.05). When combined with other established risk tools (SCORE2-Diabetes and SCORE2-OP), eSCORE-CARD demonstrated improved performance achieving an AUC of 76.4% (95% CI 65.9-86.8%), which holds promise for detection and prognosis of cardiovascular events in T2D. CONCLUSIONS: Our work indicated specific 5hmC signatures implicated in AMI with T2D background, and provided the foundation for a comprehensive cardiovascular risk management tool for diabetic population.
Sex-specific cardioprotective role of miR-30a-5p through estrogen-dependent mechanisms in a mouse model of heart failure.
Zhang L, Quan M, Zhang XC … +6 more , Zhang SY, Chen JF, Yu LQ, Fu G, Li G, Wang R
Cardiovasc Diabetol · 2026 Jan · PMID 41612389 · Full text
BACKGROUND: In recent years, except for the well-known heart failure with reduced ejection fraction (HFrEF), the incidence of heart failure with preserved ejection fraction (HFpEF) and heart failure with mildly reduced e...
BACKGROUND: In recent years, except for the well-known heart failure with reduced ejection fraction (HFrEF), the incidence of heart failure with preserved ejection fraction (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF) among the classification of heart failure (HF) has been increasing. However, due to their complex mechanisms, current research remains insufficient to address clinical needs. METHODS AND RESULTS: Utilizing wild-type (WT), miR-30a-5p knockout (KO), and overexpression (OE) murine models combined with estrogen modulation and ovariectomy (OVX), this study delineates sex-specific regulatory networks in HF pathogenesis. Female KO mice lost the inherent resistance of WT females to HFpEF induction via 24-week HFD/L-NAME, whereas males exhibited comparable HFpEF susceptibility regardless of genotype, developing hallmark phenotypes including diastolic dysfunction (E/E'), myocardial hypertrophy (heart weight/tibia length), cardiac fibrosis, and hepatic steatosis. Particularly, due to the reduced ejection fraction in KO mice, combined with HFD/L-NAME, the HF phenotype was ultimately manifested as impaired diastolic function and slightly reduced ejection fraction (with the characteristics of HFpEF and HFmrEF). Mechanistically, KO-HF females displayed significant estrogen axis disruption (plasma estradiol and the expression of ERα, ERβ, ESRRA, and PELP1 expression). OVX in WT females validated the importance of estrogen for HFpEF resistance. Transcriptomic profiling identified convergent targets across cardiac (ITGAD, ITGAM, FGA, and FGB) and hepatic tissues (APOA1 and APOB), revealing miR-30a-5p's orchestration of extracellular matrix remodeling (via ITGAD/ITGAM mechanotransduction),fibrinogen-mediated microvascular homeostasis, and APOB-driven metabolic dysregulation. Notably, OE intervention failed to mitigate OVX-induced cardiac/hepatic pathology, implicating estrogen-dependent miR-30a-5p functionality. CONCLUSIONS: These findings establish miR-30a-5p as a crucial sex-specific regulator of HF (mainly HFpEF), operating through estrogen signaling to balance cardiac compliance and metabolic adaptation.
Measures of comorbid cardiometabolic burden and cardiovascular disease risk in people with MRI-confirmed steatotic liver disease: a prospective cohort study.
Feng Q, Manousou P, Izzi-Engbeaya CN … +1 more , Woodward M
Cardiovasc Diabetol · 2026 Jan · PMID 41612381 · Full text
BACKGROUND: Steatotic liver disease (SLD) is commonly associated with higher burden of cardiometabolic risk factors (CMRFs). This study aimed to examine the associations between CMRF count, patterns and risk of cardiovas...
BACKGROUND: Steatotic liver disease (SLD) is commonly associated with higher burden of cardiometabolic risk factors (CMRFs). This study aimed to examine the associations between CMRF count, patterns and risk of cardiovascular disease. METHODS: We included 10,121 UK Biobank participants (39% women) with MRI-confirmed liver steatosis. Latent class analysis was used to derive CMRF patterns based on 5 CMRFs (obesity, diabetes, hypertension, high triglycerides and low HDL). Cox models were used to estimate associations between CMRF count and patterns with incidence and mortality of cardiovascular disease (CVD), and all-cause mortality. RESULTS: Approximately 95% of SLD participants had ≥ 2 CMRFs. During a median follow-up of 4.9 years, 268 CVD events and 212 deaths were recorded. Higher CMRF count was independently associated with elevated risk of CVD (HR per each additional CMRF: 1.23 (1.08, 1.40)), CVD mortality (1.47 (1.07, 2.02)), and all-cause mortality (1.25 (1.08, 1.44)). Three distinct CMRF patterns were identified, reflecting varying levels of CMRF burden and demographic characteristics. While certain patterns with high CMRF burden were associated with increased CVD risk, the associations were substantially attenuated after adjusting for CMRF count. CONCLUSIONS: CMRF burden is a key determinant of cardiovascular risk in people with SLD, but data-driven CMRF patterns do not improve risk prediction beyond simple counts. CMRF count remains a practical measure of cardiometabolic burden.
Risk score for lower-limb amputation and its ability to predict major kidney and cardiovascular events in people with type 1 diabetes.
Camoin M, Potier L, Larroumet A … +7 more , Rigalleau V, Hadjadj S, Scheen A, Velho G, Marre M, Saulnier PJ, Mohammedi K
Cardiovasc Diabetol · 2026 Jan · PMID 41612373 · Full text
BACKGROUND: To develop a 10-year risk score to predict lower-limb amputation (LLA) in individuals with type 1 diabetes, and to assess whether this score also predicts kidney failure, and cardiovascular disease (CVD). MET...
BACKGROUND: To develop a 10-year risk score to predict lower-limb amputation (LLA) in individuals with type 1 diabetes, and to assess whether this score also predicts kidney failure, and cardiovascular disease (CVD). METHODS: The LLA risk score was derived from GENEDIAB and GENESIS, two prospective French and Belgian cohorts of 828 individuals with type 1 diabetes. External validation was assessed in SURGENE, an independent cohort of 247 individuals with type 1 diabetes. LLA was defined as a non-traumatic amputation above the metatarsophalangeal joint, kidney failure as the need for renal replacement therapy, transplantation, or an estimated glomerular filtration rate (eGFR) < 15 ml/min/1.73 m, CVD as the occurrence of myocardial infarction, heart failure, or stroke, and major adverse cardiac event (MACE) as a composite of myocardial infarction, stroke, heart failure, or all-cause death. RESULTS: During 12 years of follow-up, LLA, kidney failure, CVD and MACE occurred in 71 (9%), 84 (11%), 138 (17%) and 265 (32.0%) of participants, respectively. Sex, diabetes duration, prior LLA, eGFR, and albuminuria were identified as independent determinants of incident LLA and were used to construct the risk score. Compared to participants in the lowest score, those in the highest score had a significantly increased risks of LLA (multivariable-adjusted HR 6.02 [95% CI, 1.92-18.89]), kidney failure (8.97 [3.95-20.37]), CVD (2.50 [1.34-4.64]) and MACE (1.91 [1.24-2.96]). The score demonstrated good discriminative performance for LLA (C-index 0.82 [0.77-0.87]), kidney failure (0.86 [0.82-0.91]), CVD (0.73 [0.68-0.78]), and MACE (0.71 [0.68-0.75]). Similar predictive performance was observed in the validation cohort. CONCLUSION: This newly developed 10-year LLA risk score achieved excellent ability to identify individuals with type 1 diabetes at high risk for LLA, kidney failure, CVD, and MACE.
Comparative effects of second-line oral antidiabetic medications on atrial fibrillation risk in patients with type 2 diabetes: a nationwide retrospective cohort study.
Heo GY, Heo SJ, Ko B … +9 more , Ko YE, Koh HB, Park CH, Park JT, Han SH, Yoo TH, Kang SW, Han M, Kim HW
Cardiovasc Diabetol · 2026 Jan · PMID 41612323 · Full text
BACKGROUNDS: Despite numerous studies investigating the effects of antidiabetic medications on cardiovascular outcomes, the optimal second-line oral antidiabetic medication for atrial fibrillation (AF) prevention remains...
BACKGROUNDS: Despite numerous studies investigating the effects of antidiabetic medications on cardiovascular outcomes, the optimal second-line oral antidiabetic medication for atrial fibrillation (AF) prevention remains unclear. This study aims to compare the effects of second-line oral antidiabetic medications including sodium-glucose cotransporter 2 (SGLT2) inhibitors, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, or sulfonylureas, on the risk of incident AF in patients with type 2 diabetes. METHODS: This retrospective study analyzed data from the National Health Insurance Service data on adults with type 2 diabetes who simultaneously initiated metformin and second-line oral antidiabetic medication (SGLT2 inhibitors, thiazolidinediones, DPP-4 inhibitors, or sulfonylureas) between September 2014 and December 2017. Exact matching by sex and age categories was conducted in a 1:1:5:5 ratio corresponding to SGLT2 inhibitor, thiazolidinedione, DPP-4 inhibitor, and sulfonylurea users, with inverse probability of treatment weighting used to balance the baseline characteristics. The primary outcome was incident AF, which was analyzed using a Fine-Gray model treating all-cause mortality as a competing risk. RESULTS: During a mean follow-up of 6.2 years, 774 cases of AF occurred among the 36,744 participants (mean age 55.3 years; 33.6% female). Compared with SGLT2 inhibitors, the risk of AF was significantly higher in patients using thiazolidinediones (subdistribution hazard ratio [SHR], 1.22; 95% confidence interval [CI], 1.09-1.36), DPP-4 inhibitor (SHR, 1.14; 95% CI, 1.02-1.28), and sulfonylureas (SHR, 1.20; 95% CI, 1.07-1.34). However, pairwise comparisons among thiazolidinediones, DPP-4 inhibitors, and sulfonylureas revealed no significant differences in AF risk. Subgroup analyses revealed significant effect modifications according to age, hypertension status, and renal function. CONCLUSIONS: This study showed that SGLT2 inhibitor use was associated with a significantly lower risk of AF than use of thiazolidinediones, DPP-4 inhibitors, and sulfonylureas.
Associations of body mass index on worsening of heart failure and mortality in patients with heart failure and reduced left ventricular ejection fraction: a 10-year follow-up study (a NorthStar substudy).
Malmborg M, El-Chouli M, Andersen CF … +11 more , Elmegaard M, Garred C, Zahir D, Butt JH, Christensen DM, Nouhravesh N, Fosbøl E, Videbæk L, Køber L, Gustafsson F, Schou M
Cardiovasc Diabetol · 2026 Jan · PMID 41606731 · Full text
BACKGROUND: Obesity is prevalent in patients with heart failure with reduced ejection fraction (HFrEF). With the advent of glucagon-like peptide 1 analogues, understanding the relationship between body mass index (BMI) a...
BACKGROUND: Obesity is prevalent in patients with heart failure with reduced ejection fraction (HFrEF). With the advent of glucagon-like peptide 1 analogues, understanding the relationship between body mass index (BMI) and clinical outcomes in HFrEF is crucial. OBJECTIVE: This study investigated whether a BMI > 27 kg/m is associated with higher rates of all-cause mortality, cardiovascular mortality, and heart failure (HF) hospitalization in patients with HFrEF. METHODS: A total of 1017 clinically stable and medically optimized HFrEF patients from the NorthStar study (enrolled 2005-2009) were analyzed. Patients were followed until 2023 using Danish nationwide registries. The primary outcome was all-cause mortality, while secondary outcomes included cardiovascular mortality, HF hospitalization, and a composite of all-cause mortality or HF hospitalization. Cox proportional-hazards models adjusted for prognostic factors were used to assess associations. Interaction analyses for the primary outcome were conducted for BMI categories (< 24, 24-27, > 27 kg/m) and prognostic variables. RESULTS: Compared to patients with a BMI of 24-27 kg/m, those with a BMI > 27 had a higher prevalence of diabetes (27.8% vs. 17.7%), similar HF etiology (ischemic: 57.5% vs. 58.7%), and lower NT-proBNP levels (median 776 vs. 1163 pg/mL). Over a median follow-up of 8.8 years, the primary outcome occurred in 235 patients (71.9%) with BMI 24-27, and 338 patients (71.8%) with BMI > 27 (ref. BMI 24-27: Hazard ratios (HR) 1.11 [0.94 - 1.32]). 124 patients (37.9%) and 186 patients (39.5%) died from cardiovascular causes, respectively (HR 1.21 [0.96 - 1.53]). A first worsening HF event occurred in 214 patients (65.4%) and 317 patients (67.3%) (HR 1.12 [0.93 - 1.33]). A combined outcome of all-cause death and first worsening HF events occurred in 277 patients (84.7%) and 398 patients (84.5%) (HR 1.09 [0.93 - 1.27]). The subgroup analyses revealed a significantly higher mortality rate for BMI > 27 vs 24-27 in patients with ischemic cardiomyopathy (HR 1.31 [1.05-1.64]), but not in patients with non-ischemic cardiomyopathy (HR 0.86 [0.66-1.12]). CONCLUSION: In HFrEF patients, a BMI > 27 was not associated with increased mortality, contradicting the "obesity-survival paradox." In fact, patients with ischemic cardiomyopathy and a BMI > 27 may be associated with a higher mortality rate.
Activator protein-1 (AP-1) inhibition prevents endothelial to mesenchymal transition in diabetes-associated atherosclerosis: a translational study.
Khan AW, Aziz M, Sourris KC … +9 more , Cortes JP, Block TJ, Dai A, Maxwell S, Okabe J, Pyper E, Paneni F, Cooper ME, Jandeleit-Dahm KA
Cardiovasc Diabetol · 2026 Jan · PMID 41606610 · Full text
BACKGROUND: Endothelial to mesenchymal transition (EndMT), the transformation of endothelial cells into a mesenchymal-like state, is regulated by various factors, including transcription factors such as activator protein...
BACKGROUND: Endothelial to mesenchymal transition (EndMT), the transformation of endothelial cells into a mesenchymal-like state, is regulated by various factors, including transcription factors such as activator protein 1 (AP-1). While recent studies have confirmed the role of EndMT in atherosclerosis, the involvement of AP-1 in EndMT, particularly in the context of human diabetes, remains unclear. OBJECTIVES: This study aimed to elucidate the role of the AP-1 transcription factor complex in EndMT associated with atherosclerosis in diabetes, utilising both an in vivo preclinical model and an ex vivo model using patient-derived serum for translational relevance. Additionally, it sought to profile gene expression changes following AP-1 inhibition in an EndMT model under high glucose conditions. METHODS: Serum from patients with and without type 2 diabetes mellitus (T2DM) was used to assess EndMT in primary human aortic endothelial cells (HAECs) in the presence and absence of the AP-1 inhibitor T-5224. EndMT was evaluated through immunofluorescent staining of these cells and of aortic sections from a murine model of diabetes-associated atherosclerosis in a preclinical early intervention study. Furthermore, HAECs were used to explore the effects of AP-1 inhibition on the transcriptional signature of EndMT. RESULTS: Patient-derived serum induced EndMT in HAECs, which T-5224 effectively prevented, as confirmed by immunofluorescent staining. Immunofluorescent analysis of the aortic sinus also revealed that T-5224 treatment inhibited EndMT, leading to reduced atherosclerosis in Apoe mice. In parallel, in the HAECs-based in vitro EndMT model, T-5224 mitigated TNF-α and high glucose-induced EndMT. RNA sequencing identified 242 differentially expressed genes (DEGs) associated with EndMT under high glucose conditions, with T-5224 treatment restoring the expression of 77 DEGs. CONCLUSION: This study identifies AP-1 inhibition with T-5224 as a potential therapeutic approach for EndMT resulting in reduced atherosclerosis in diabetes. The use of human serum underscores the translational relevance of these findings.
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