Cardiovascular Diabetology最新文献

Up to 40-60% of patients undergoing coronary angiography because of angina and/or evidence of inducible ischaemia on non-invasive stress testing are diagnosed with ischaemia and non-obstructive coronary artery disease (INOCA). The pathogenesis of this condition is primarily attributed to two mechanisms: coronary microvascular dysfunction (CMD) and coronary vasospasm. Notably, ischaemic heart disease is the leading cause of death in patients with type 2 diabetes mellitus (T2DM). Insulin resistance (IR), affecting 10-25% of the general adult population, plays a major role in the pathophysiology of T2DM, but can precede diabetes by years. IR is recognised as a major cardiovascular risk factor, involved in endothelial dysfunction and inflammation, two key processes leading to CMD and vasomotor dysfunction. Hyperinsulinaemia, dysglycaemia, and oxidative stress contribute to this complex relationship, yet the connection between IR, CMD and coronary vasospasm remains incompletely defined. Moreover, IR may represent a target for tailored therapies aimed at improving microvascular function and alleviating symptom burden. Although a few studies have investigated this relationship, the molecular mechanisms by which multiple pathways lead to different INOCA endotypes remain incompletely defined. The aim of this review is to summarise current evidence linking IR, CMD and coronary vasospasm, with emphasis on pathophysiological mechanisms and diagnostic approaches, and to highlight future research directions in this clinical setting.

Background: Large-scale proteomics provides an opportunity to understand chronic kidney disease (CKD) and cardiovascular disease, yet research in this field is limited. This study utilized proteomics to inform biology and risk stratification for these diseases.

Methods: This cohort study included 44,779 participants free of prevalent CKD, and 3,749-4,272 participants with prevalent CKD from the UK Biobank. The Olink Explore 3072 platform quantified 2,923 plasma proteins. Cox proportional hazards models were used to assess associations of proteins with kidney diseases including CKD and end stage kidney disease, and cardiovascular diseases including coronary heart disease (CHD), stroke, and heart failure (HF). Mendelian randomization examined genetic associations, pathway analyses identified biological pathways, and predictive models were developed for incident diseases.

Results: Median follow-up periods were 12.2-12.6 years. We identified 598 (20.5%) proteins shared across ≥ 2 diseases, with 595 (20.4%) showing consistent directions of associations, and 471 (16.1%) unique to a single disease. CKD and HF specifically shared the largest number of 279 (9.6%) proteins. POLR2F, TNFRSF10B, and IGFBP2 were positively associated with all five diseases, with Mendelian randomization supporting genetic associations of POLR2F with CHD and IGFBP2 with hypertensive renal disease. Pathway analyses highlighted cell adhesion, signal transduction, and cytokine-cytokine receptor interaction for disease-associated proteins. Incorporating predictive proteins into clinical models improved risk prediction for CKD, CHD, stroke, and HF, yielding Harrell's C indices of 0.750-0.818 (corresponding increases of 0.027-0.090).

Conclusions: This study deepens insights into disease biology and provides a foundation for early detection and integrated risk stratification in CKD and cardiovascular disease.

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.