Cardiovascular Diabetology最新文献

Background: Dysregulation of lysophosphatidylcholines (LPCs) and phosphatidylcholines (PCs) is linked to endothelial dysfunction and impaired tissue repair. Nevertheless, the organ-specific modulation of lysolecithin remodeling in T2DM remains unexplored. Here, we investigate the LPC/PC remodeling dynamics in a T2DM model and propose a novel therapeutic approach using an orally bioavailable peptide (SP6) derived from Spirulina platensis.

Methods: LPC/PC levels were analyzed by UHPLC-HRMS. Membrane fluidity, VEGF/API5, LPCAT1, VE-cadherin, and GLUT1 were evaluated by merocyanine assay, qPCR, immunoblotting, and immunofluorescence. In vivo, T2DM was induced by a high-fat diet and streptozotocin, and SP6 was orally administered. Tissue lipidomics, GLUTs expression, and insulin secretion were assessed, with the latter also spatially characterized in pancreatic tissue by MALDI-MS imaging.

Results: High glucose induced LPC/PC imbalance, enhanced membrane fluidity, impaired VEGF/API5 expression, and hindered wound healing and VE-cadherin localization via LPCAT1 downregulation and subsequent impact on GLUT1 translocation. In vivo analysis of diabetic mice revealed a multi-organ influence of SP6 preserving LPCAT1 mRNA levels in pancreas, liver, skeletal muscle, and adipose tissue and a specific pattern of lysolecithin remodeling, with selective modulation of LPC 16:0, 18:0, and 20:4 in plasma. Finally, its effects in T2DM are mediated by preserving insulin secretion and glycemic control through increased ATP production.

Conclusion: These findings reveal tissue-specific lysolecithin reprogramming in T2DM development and identify LPCAT1-mediated lysolecithin remodeling as a mechanism involved in T2DM-related endothelial and metabolic dysfunction. SP6 modulates lipid metabolism, vascular integrity, and glucose regulation at the transcript level, suggesting its potential as a new preventive treatment for T2DM and its complications.

Background: Combining biomarkers and anthropometric indicators is a common way to improve predictive efficacy. Yet the effect of the C-reactive protein-triglycerides-glucose index (CTI) and its derivatives on stroke is unknown. This study aims to explore their association with stroke and compare their predictive value.

Methods: A total of 10,070 participants from the China Health and Retirement Longitudinal Study (CHARLS) were included. Covariate selection was performed using the Boruta algorithm and complementary methods. The predictive performance of various indicators was compared via metrics including area under the curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) to determine the optimal predictive indicator. Subsequently, Cox proportional hazards models, trajectory pattern analysis, restricted cubic spline (RCS) analysis, Kaplan-Meier curves were used to investigate its association with stroke.

Results: From 2011 to 2020, 950 participants (9.43%) experienced an incident stroke during follow-up. CTI derivatives outperformed standalone CTI in prediction, with CTI-waist-to-height ratio (CTI-WHtR) exhibiting the strongest association with stroke risk. In the fully adjusted model, each one-unit increase in CTI-WHtR linked to a 73% higher risk of stroke [odds ratio (OR) = 1.73, 95% confidence interval (CI) 1.45-2.07], and participants in the highest quartile of CTI-WHtR had more than double the risk compared with those in the lowest quartile (OR = 2.20, 95% CI 1.71-2.83). There were three distinct trajectories of CTI-WHtR over time. Compared with Cluster 1 (low value rising), Cluster 2 (stable high value) was associated with a 69% higher risk of stroke (OR = 1.69, 95% CI 1.34-2.13), and Cluster 3 (moderate value rising) with a 26% higher risk (OR = 1.26, 95% CI 1.06-1.52). A clear dose-response relationship was observed between CTI-WHtR and stroke risk, with risk increasing sharply when CTI-WHtR exceeded 2.52.

Conclusion: The consistent positive linear association between CTI-WHtR and stroke risk highlights its potential utility as a clinical and public health indicator. Monitoring and maintaining optimal CTI-WHtR levels may aid in identification of individuals at elevated stroke risk. Graphical Abstract.

Background: Type 2 diabetes mellitus (T2DM) predisposes patients to adverse cardiac remodeling even before the development of cardiomyopathic symptoms. The mechanisms for such early perturbations remain elusive. Given that myosin is the most abundant and energy‑demanding cardiac protein, we tested whether its regulation is impaired even in non‑failing human diabetic hearts.

Methods: Left ventricular strips were individually isolated from organ donors with and without T2DM. These strips were then subjected to a combination of acetyl‑proteomics, X-ray diffraction, in-silico simulations and Mant-ATP chase experiments.

Results: Strikingly, we identified nine cardiac myosin (MYH7) lysine residues with significantly altered acetylation levels in T2DM ventricles, many of which were predicted to destabilize the protein coiled‑coil regions. Consistently, X‑ray diffraction revealed increased lattice spacing and a shift towards myosin ON‑state in T2DM tissue. However, and surprisingly, Mant‑ATP chase analyses indicated no bioenergetic consequences at the myosin level.

Conclusions: Human T2DM myocardium exhibits early, site‑specific myosin acetylations that destabilize myosin structural OFF‑state. This myosin 'preload' remodeling occurs at no energetic cost and may constitute a potential early marker of latent myocardial vulnerability in T2DM.

Background: Epicardial adipose tissue (EAT) is a metabolically active visceral fat depot contributing to coronary atherosclerosis, yet the molecular mechanisms underlying EAT-related coronary artery disease (CAD) in type 2 diabetes mellitus (T2DM) remain unclear. Previously, we identified novel circulating miRNAs targeting fatty acid metabolism in T2DM-CAD. This study aimed to investigate whether EAT may explain the association between dysregulated hsa-miR-4505, hsa-miR-4743-5p, hsa-miR-4750-3p and CAD in T2DM patients and whether it can detect diabetic atherosclerosis alone or in a multi-modal combination.

Methods: Seventy-six patients with T2DM and/or CAD along with eighteen healthy controls were enrolled in the study. All participants underwent transthoracic echocardiography to assess EAT thickness on the free wall of the right ventricle at end-systole and bioelectrical impedance analysis for body composition determination. Spearman's rank correlation and multivariate linear regression accounting for relevant clinical confounders were used to explore the associations between EAT and miRNAs. To further investigate whether EAT acts as an intermediary between miRNA and CAD in T2DM, causal mediation analysis was employed. The receiver operating characteristics curves were generated to evaluate the diagnostic performance of the combined models built using multivariate logistic regression.

Results: The median EAT thickness was significantly higher in T2DM-CAD patients compared to T2DM subjects and controls (p < 0.0001). The bivariate analysis showed a positive correlation between triglyceride concentration and EAT thickness, and a negative one with hsa-miR-4750-3p expression. After multivariable adjustment, hsa-miR-4750-3p (β = - 0.445, p = 0.003) emerged as a standalone predictor of EAT thickness. Logistic regression analysis identified enlarged EAT, up-regulated hsa-miR-4505, hsa-miR-4743-5p and down-regulated hsa-miR-4750-3p to be independently associated with higher CAD risk in T2DM. Adding miRNAs to EAT improved CAD detection in T2DM (AUC = 0.988), outperforming both EAT (AUC = 0.869), clinical factors (AUC = 0.829), and their combination (AUC = 0.901). The mediation analysis revealed that EAT accounted for 48.79% of the total effect of hsa-miR-4750-3p on CAD in T2DM.

Conclusions: These findings suggest that the proposed miRNA-EAT regulatory axis may be involved in the pathogenesis of diabetic atherosclerosis, with EAT appearing to partially mediate the relationship between hsa-miR-4750-3p and CAD. The integrated approach linking EAT and miRNAs holds potential for CAD risk stratification in T2DM.

Background: Cardiovascular metabolic diseases (CMDs) are a major contributor to global mortality and disability, yet their pathogenesis remains incompletely understood, partly because existing in vitro models fail to capture disease complexity. Conventional engineered heart tissues (EHT), which typically contain only a limited set of cell types and lack neural components, cannot replicate the intricate neuro-cardiac interactions involved in CMDs.

Objective: This study aimed to develop a neuron-like-Integrated Engineered Heart Tissue for investigating neuro-cardiac interactions under both physiological and pathological conditions, offering a new tool for CMD research.

Methods: We constructed a Sympathetic-like-Integrated Engineered Heart Tissue (SIEHT) by incorporating sympathetic-like neuronal cells into EHT. The structural and functional properties of SIEHT were systematically compared with conventional EHT using morphological analysis, immunofluorescence staining, contractility measurements, qPCR, and RNA sequencing. The model was then exposed to advanced glycation end products (AGEs) to assess pathological remodeling through multiple parameters, including cell viability, oxidative stress, structural and functional integrity, and transcriptomic profiles.

Results: SIEHT exhibited greater structural and functional maturation than EHT, as indicated by improved cardiomyocyte alignment, increased contraction amplitude, and upregulated expression of connexin 43. Transcriptomic analysis revealed enriched pathways associated with multi-system development. Under AGEs-induced pathological conditions, SIEHT demonstrated a more pronounced reduction in cell viability, elevated reactive oxygen species levels, more severe contractile dysfunction, a higher frequency of abnormal spontaneous beating, and greater neural injury relative to controls. Transcriptome profiling further identified significant enrichment of the AGE-RAGE signaling pathway in diabetic complications.

Conclusions: We successfully established a novel SIEHT model that recapitulates physiological neuro-cardiac interactions and AGEs-induced adverse remodeling across multiple dimensions, providing a powerful and innovative tool for elucidating the pathophysiological mechanisms of neuro-cardiac dysregulation in CMDs.

Background: The triglyceride-glucose (TyG) index, estimated glucose disposal rate (eGDR), and metabolic score for insulin resistance (METS-IR) are well-established surrogate indices of insulin resistance (IR). Although both IR and elevated basal metabolic rate (BMR) are recognized risk factors for cardiometabolic diseases, their joint effects on the risk of cardiometabolic multimorbidity (CMM) remain unclear. This study aimed to investigate the separate and combined associations of these IR surrogates and BMR with incident CMM.

Methods: We included 7204 eligible participants from the 2011-2020 survey waves of the China Health and Retirement Longitudinal Study (CHARLS). Participants were stratified by median values of IR surrogate indices and BMR. The associations with CMM were assessed using Kaplan-Meier curves, multivariable Cox regression, and restricted cubic splines (RCS). Predictive performance was evaluated using receiver operating characteristic (ROC) curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Mediation and interaction analyses were performed to explore potential underlying relationships.

Results: Over a median follow-up of 9 years, 1103 participants (15.31%) developed CMM. Compared to those with low IR and low BMR, participants with high levels of both exhibited the highest risk of CMM, with hazard ratios of 2.13 (95% CI 1.73-2.63) for TyG, 1.93 (95% CI 1.57-2.36) for eGDR, and 1.92 (95% CI 1.61-2.29) for METS-IR. These associations remained consistent in subgroup and sensitivity analyses. Adding IR indices and BMR to the baseline model significantly improved CMM prediction: TyG (AUC 0.759, NRI 0.371, IDI 0.017; all P < 0.001), eGDR (AUC 0.753, NRI 0.330, IDI 0.012; all P < 0.01), and METS-IR (AUC 0.747, NRI 0.170, IDI 0.004; all P < 0.01). Mediation analysis demonstrated that all IR indices significantly mediated the association between BMR and CMM, and a bidirectional mediation relationship was specifically observed between BMR and the TyG index. Notably, no significant additive or multiplicative interactions were detected.

Conclusion: IR surrogate indices and BMR independently and jointly predicted the risk of CMM, with IR pathways substantially mediating the effect of BMR. The combined assessment of these parameters may improve CMM risk stratification and guide primary prevention strategies.

Background: Cardiovascular-kidney-metabolic (CKM) syndrome integrates metabolic, renal, and cardiovascular disease risk. While increasing evidence suggests that triglyceride-glucose (TyG)-related indices are associated with the future risk of cardiometabolic multimorbidity (CMM), their link to CMM in CKM syndrome has not been established.

Methods: This study analyzed participants with CKM syndrome stage 0-3 from the China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2020. We used Cox regression analysis, restricted cubic spline (RCS) curves, and Kaplan-Meier (K-M) survival curves to evaluate the relationship between TyG-related indices and CMM risk in patients with CKM stage 0-3 syndrome. Receiver operating characteristic (ROC) curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) analyses were used to assess the predictive performance of the TyG-related indices for CMM.

Results: During a median follow-up of 9 years, 652 participants (9.5%) developed CMM. The fully adjusted model revealed an elevated CMM risk across the highest quartiles of all indices, with hazard increases ranging from 72 to over 200%. A linear dose-response relationship was observed for most indices, except for triglyceride glucose-a body shape index (TyG-ABSI) and C-reactive protein-triglyceride-glucose index (CTI). The triglyceride glucose-Chinese visceral adiposity index (TyG-CVAI) achieved the highest area under the curve (AUC) for CMM prediction (0.679), and compared with the fully adjusted model (Model 4), all indices provided significant incremental predictive values.

Conclusion: Nine TyG-related indices, particularly TyG-CVAI, are strong independent predictors of future CMM in patients with CKM syndrome stage 0-3. These findings underscore the utility of TyG-related indices, particularly TyG-CVAI, in identifying high-risk individuals, thereby informing strategies for the early detection and prevention of CKM syndrome.