Cardiovascular Diabetology最新文献

Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with increased atherosclerotic cardiovascular disease (ASCVD) risk. However, evidence on proteomic mechanisms linking MASLD to ASCVD is limited. This study aims to identify proteomic signatures of MASLD and ASCVD subtypes (ischemic heart disease [IHD], peripheral artery disease [PAD], and stroke), evaluate mediating effects of proteins, and develop a proteomic-based ASCVD risk prediction model in MASLD patients. Among 40,913 UK Biobank participants (median follow-up 13.42 years [interquartile range, 12.52-14.22]), 14,425 (35.26%) had MASLD at baseline, and 6,014 (14.70%) developed ASCVD during follow-up (4,420 IHD, 866 PAD, and 1,767 stroke events; subtypes not mutually exclusive). We constructed a binary variable representing proteomics-inferred MASLD (cProMASLD) from MASLD-associated proteins. Two-step Mendelian randomization was applied to assess the mediating effects of proteins associated with MASLD and ASCVD subtypes. Furthermore, we integrated the all shared proteins associated with both MASLD and ASCVD subtypes into the conventional SCORE2 model to develop a prediction model specifically for ASCVD subtypes in the MASLD population, named Pro-SCORE2. Both MASLD and cProMASLD were significantly associated with an increased risk of ASCVD subtypes, with stronger associations observed for cProMASLD (IHD: HR 1.50 [95% CI 1.41-1.60] vs. 1.58 [1.48-1.68]; PAD: 1.25 [1.09-1.44] vs. 1.43 [1.24-1.64]; stroke: 1.19 [1.08-1.31] vs. 1.21[1.10-1.34]). After adjusting for MASLD, cProMASLD remained positively associated with ASCVD risk. This suggests that cProMASLD may capture MASLD-related physiological heterogeneity beyond clinical MASLD classification. We found 15, 3, and 3 proteins mediating the associations of MASLD with IHD, PAD, and stroke, respectively, including FABP4 (MASLD-IHD, mediation proportion: 15.12%), IL7R (MASLD-PAD, 7.45%), and EDA2R (MASLD-stroke, 9.24%). The Pro-SCORE2 significantly improved ASCVD risk prediction in the MASLD population, with a c-index increase of 7.5-9.6% and a 10-year AUC increase of 5.8-9.2% compared to SCORE2. These findings may offer new insights for risk stratification and potential therapeutic targets for ASCVD in MASLD patients.

Background: Insulin resistance and muscle loss are interrelated processes linked to cardiovascular disease (CVD), but they are rarely assessed together. We investigated the association between a novel integrated biomarker-triglyceride-glucose muscle-loss index (TyG-MLI)-and incident CVD in a large prospective cohort.

Methods: A total of 277,418 UK Biobank participants free of CVD at baseline were included. TyG-MLI was calculated as ln[(triglycerides × fasting glucose)/2] × (cystatin C/creatinine). Incident CVD was identified through hospital admissions and death registries. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Over a median follow-up of 15.1 years, 40,398 participants developed CVD. Crude CVD incidence increased steadily across TyG-MLI quartiles, and the cumulative incidence curves demonstrated clear separation on Kaplan-Meier analysis (log-rank p < 0.001). Higher TyG-MLI was independently associated with greater CVD risk when modeled either continuously (per 1-SD: HR 1.17; 95% CI 1.16-1.18) or categorically (Q4 vs. Q1: HR 1.48; 95% CI 1.44-1.53). Restricted cubic spline analyses demonstrated a non-linear association across the TyG-MLI distribution. Sensitivity analyses yielded consistent results. In body mass index-stratified analyses, TyG-MLI showed stronger associations with CVD than TyG index, particularly among normal-weight and underweight individuals.

Conclusions: TyG-MLI, a composite marker reflecting insulin resistance and muscle loss, was independently associated with incident CVD in this large population-based cohort. These findings suggest that TyG-MLI captures cardiometabolic risk beyond traditional measures and may be particularly informative in individuals without obesity.

Intracellular calcium (Ca²⁺) homeostasis is a central determinant of cardiometabolic physiology, integrating excitation-contraction coupling, metabolic signaling, and stress adaptation across multiple organs. The sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA), regulated by the micropeptides phospholamban (PLN) and dwarf open reading frame (DWORF), governs ER/SR Ca²⁺ reuptake and thereby shapes Ca²⁺-dependent signaling dynamics. Dysregulation of the SERCA-PLN-DWORF axis is increasingly recognized as a shared pathogenic mechanism in type 2 diabetes-related complications, including diabetic cardiomyopathy and heart failure with preserved ejection fraction (HFpEF), where reduced SERCA2a activity prolongs diastolic Ca²⁺ clearance and promotes calcineurin-NFAT activation and mitochondrial Ca²⁺ overload. In the liver, loss of SERCA2b activity promotes chronic ER stress, Ca²⁺-phosphoinositide complex formation, insulin resistance, and fibrotic activation, thereby linking Ca²⁺ dysregulation to progressive metabolic liver injury in metabolic dysfunction-associated fatty liver disease (MAFLD) and steatohepatitis (MASH). These observations position Ca²⁺ dysregulation as a unifying mechanism across the cardiometabolic disease continuum, spanning myocardial dysfunction, systemic insulin resistance, and progressive fatty liver disease. Therapeutic strategies targeting the SERCA-PLN-DWORF axis, including SERCA activators, PLN-directed antisense oligonucleotides, DWORF gene therapy, and CRISPR-based modulation, have demonstrated efficacy in preclinical models by improving Ca²⁺ handling and alleviating metabolic or contractile stress. Further studies are required to determine the translational feasibility, long-term safety, and optimal patient subsets for SERCA-targeted interventions in cardiometabolic disease.

Objective: The triglyceride-glucose (TyG) index, a measure of insulin resistance, has been confirmed to be associated with adverse clinical outcomes. A new composite indicator, the TyG-A body type index (TyG-ABSI), was developed by integrating the TyG index and the A body type index. This study aimed to thoroughly investigate the association between the TyG-ABSI and the risk of atherosclerotic cardiovascular disease (ASCVD) among individuals with normoglycemia, dysglycemia, and diabetes.

Methods: Participants from the UK Biobank were included and categorized into 3 groups: normoglycemia, dysglycemia (prediabetes), and diabetes. The primary study outcome was the incidence of all-cause ASCVD. Cox regression and restricted cubic spline (RCS) analyses were performed to evaluate the linear and nonlinear associations between the TyG-ABSI and ASCVD. Furthermore, time-dependent receiver operating characteristic (ROC) curves were constructed to evaluate the discriminative performance of the TyG-ABSI and other indices. Additional analyses, including Kaplan-Meier survival curves, subgroup analyses, and sensitivity analyses, were conducted to assess robustness. A mediation analysis was performed to identify potential biomarkers.

Results: During an average follow-up of 14.8 years, a total of 29,680 ASCVD events were documented. The results indicated that elevated TyG-ABSI values were positively associated with the risk of ASCVD in the population with normoglycemia (nonlinear, P for nonlinear < 0.001) and diabetes (linear, P for nonlinear = 0.96) (HR = 1.07, 95% CI: 1.05-1.09; HR = 1.10, 95% CI: 1.06-1.14, respectively). No significant associations were detected in the dysglycemia group. Compared with the TyG index and other TyG-derived metrics, the TyG-ABSI demonstrated superior predictive performance (e.g., 10-year AUC = 0.634 in the normoglycemia group). Subgroup analyses and sensitivity analyses confirmed the robustness of our findings. Moreover, the results of the mediation analysis demonstrated that white blood cell (WBC) count (mediation proportions: 3.74-9.73%) and C-reactive protein (CRP) level (mediation proportions: 9.96-26.89%) significantly mediated the association between the TyG-ABSI and ASCVD.

Conclusions: In the normoglycemia subgroup, the association between the TyG-ABSI and ASCVD was nonlinear. Moreover, the TyG-ABSI was linearly associated with an increased risk of ASCVD in the diabetes subgroup but not in the dysglycemia subgroup. The predictive value of the TyG-ABSI across different glycemic statuses provides new evidence for medical practice. Furthermore, the TyG-ABSI may serve as a useful tool for identifying high-risk individuals within the seemingly low-risk normoglycemic population and for further risk identification among diabetic patients.

Background: Omega-3 fatty acids (FAs) are long-chain fatty acids that have shown cardioprotective effects through lipid lowering, anti-inflammatory, and membrane-stabilizing properties. In this study we investigated the molecular mechanism underlying the cardioprotective effects of icosapent ethyl (IPE), an ethyl ester of omega-3 fatty (EPA), focusing on its role on mechano-transduction, a process linking cardiac contractility to intracellular signaling, that becomes dysregulated in hyperglycaemia or disturbed blood flow, both major contributors to cardiovascular diseases.

Methods: We conducted in vivo meta-analyses to assess the beneficial effects of omega-3 fatty acids on cardiac contractility and inflammation in patients with cardiovascular and cardiometabolic diseases. We investigated the effects of IPE on mechano-transduction, assessing the activation of the YAP/TAZ signalling pathway, in cardiomyocyte cells AC16 exposed to normal (NG) or high glucose (HG) conditions. We defined the role of IPE against hyperglycaemia-induced inflammation, oxidative stress, metabolism, and apoptosis by evaluating key biomarkers by Western Blot and Real-time PCR. We evaluated IPE's impact on YAP/TAZ activation and on gene expression and protein levels of primary markers related to oxidative stress, inflammation, and metabolism in a dynamic flow model of AC16 cardiomyocytes, to mimic in vivo shear stress.

Results: In vivo meta-analyses showed a significant increase of left ventricular ejection fraction (LVEF%) (mean: 0.5, 95% CI: 0.1-0.9) and a significant reduction of inflammatory markers (mean:  - 1.24, 95% CI: 2.05-0.44) in patients treated with omega-3. IPE treatment reduced the activation of YAP/TAZ pathway induced by HG exposure in AC16 cells. IPE partially reversed HG-induced changes in markers of inflammation, oxidative stress, metabolism and apoptosis (p < 0.05). Similarly, in a dynamic model of shear stress, IPE treatment mitigated the turbulent flow-mediated changes in YAP/TAZ pathway, inflammation, oxidative stress and metabolism.

Conclusions: Our results demonstrate a cardioprotective role of IPE through modulation of hyperglycaemia-induced mechano-transduction dysregulation, inflammation, and oxidative stress. Additionally, our results on a shear stress model showing that IPE restores upstream regulators of YAP/TAZ and reduces disturbed flow-induced activation of pro-inflammatory pathways, suggest that IPE may exert a therapeutic effect on cardiovascular disorders associated with disturbed blood flow and hemodynamic stress.

Background: Soluble receptor for advanced glycation end-products (sRAGE) modulates RAGE-mediated inflammation and oxidative stress. We investigated if sRAGE stratifies cardiovascular and kidney disease risk in individuals with type 1 diabetes and baseline treatment-resistant hypertension (TRH).

Methods: This study included 1262 adults with type 1 diabetes from the FinnDiane study who were on antihypertensive therapy and whose sRAGE concentration was measured at baseline. Participants were divided into groups: controlled blood pressure (BP) (n = 295), uncontrolled BP (n = 730) or TRH (n = 237). Prospective analyses were performed in those with baseline TRH. Of them, 62 developed coronary artery disease (CAD) and 38 stroke (median follow-up 12 years), while 99 progressed to end-stage kidney disease (ESKD) (median follow-up 9.2 years).

Results: Every 100 units increase in baseline sRAGE was associated with 4% higher odds for TRH, compared to those with uncontrolled BP (P = 0.003), and 6% higher odds than those with controlled BP (P = 0.0006). Associations attenuated after adjusting for kidney markers. In the competing risk analysis, higher sRAGE was associated with greater risk of CAD (SHR 1.05, P = 0.01) in those with TRH. After adjusting for eGFR, the association attenuated (SHR 1.04, P = 0.052), but the same trend remained. sRAGE was not associated with stroke. Furthermore, sRAGE was associated with higher risk of ESKD (SHR 1.06, P < 0.0001), but no longer after adjusting for eGFR (P = 0.4).

Conclusions: Elevated sRAGE is associated with increased odds of TRH in individuals with type 1 diabetes. sRAGE further stratifies high risk of incident CAD and ESKD, even after accounting for clinical variables. Along with eGFR, sRAGE may help to identify individuals at the highest risk of adverse cardiovascular and kidney outcomes.

Background and objectives: Elevated C-reactive protein (CRP) is a well-established marker of low-grade systemic inflammation often accompanying cardiometabolic diseases like type 2 diabetes. We sought to determine if plasma CRP concentrations can be used as a predictive marker of risk for ischemic stroke and all-cause death in the general population, and to investigate whether elevated plasma CRP has a causal effect on ischemic stroke and all-cause death.

Methods: Observational and one-sample Mendelian randomization analyses were performed in 113,491 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study. Two-sample Mendelian randomization analyses were performed in up to 575,531 individuals with publicly available data from the CHARGE CIWG, UKBB, FinnGen, and MEGASTROKE.

Results: Observationally in the Copenhagen studies, higher CRP concentrations associated with stepwise higher risk of ischemic stroke and all-cause death with the highest hazard ratios of 1.51(95% confidence interval: 1.34, 1.71) and 1.69(1.60, 1.79), respectively. The cumulative incidence of ischemic stroke at age 72 was 57% higher and the cumulative incidence of all-cause death at age 80 was 62% higher in individuals with a plasma CRP ≥ 2 mg/L compared to individuals with a plasma CRP < 2 mg/L. One- and two-sample Mendelian randomization analyses did not support a causal effect of CRP on risk of ischemic stroke, nor of CRP on risk of all-cause death, with odds ratios in studies combined of 1.01(0.98, 1.05) and 1.01(0.98, 1.05), respectively.

Conclusion: In this observational and one- and two-sample Mendelian randomization study, we found that elevated CRP concentrations above the population median of 1.4 mg/L predicted risk of ischemic stroke and all-cause death. There was no causal genetic effect of C-reactive protein on risk of stroke or all-cause death.

Background: Plasma Volume Status (PVS), an index that quantifies the deviation of an individual's plasma volume from the expected volume, plays an important role in cardiovascular homeostasis. Although PVS expansion is well recognized in conditions like heart failure and chronic kidney disease, its relationship with type 2 diabetes (T2D) and antidiabetic treatment remains uncertain.

Methods: We conducted an observational study comparing PVS in adults with T2D and healthy controls matched for sex, age, and BMI. In a separate analysis of a larger T2D cohort, we investigated the association between PVS and different antidiabetic therapies. PVS was calculated using established formulas incorporating hematocrit, body weight, and sex.

Results: PVS was significantly expanded in individuals with T2D compared with healthy controls, with a mean difference of + 3.73% (95% CI 0.24 to 7.22, p = 0.041). Among individuals with T2D (n = 638 ), treatment with SGLT2 inhibitors was associated with a significantly lower PVS compared with the diet/metformin reference group (mean difference - 3.40%, 95% CI - 6.14 to - 0.66%, p = 0.015). The greatest reduction was observed under combined SGLT2i + GLP-1RA therapy (-6.50%, 95% CI - 12.25 to -0.75%, p = 0.004), while individuals on GLP-1RA showed non-significant lower PVS values (-2.10%, 95% CI - 5.48 to 1.28%). In contrast, those treated with DPP-4 inhibitors exhibited a significantly higher PVS (+ 4.15%, 95% CI + 0.05 to + 8.85, p = 0.008). No significant difference in PVS was found between insulin-treated individuals and those on diet/metformin.

Conclusions: T2D is associated with a modest but significant increase in PVS. Among antidiabetic agents, SGLT2 inhibitors -alone or in combination with GLP-1 RA- were associated with a contraction in PVS, suggesting favourable hemodynamic effects. Conversely, DPP4 inhibitors were linked to more expanded plasma volume. These findings highlight the differential hemodynamic impact of glucose-lowering therapies and support further prospective research to evaluate their role in cardiovascular protection in T2D.

Background: Heart failure and peripheral artery disease (PAD) are the two most common cardiovascular diseases (CVD) in individuals with type 2 diabetes mellitus (T2DM). The T₅₀ calciprotein crystallization test measures the transformation of calciprotein particles type 1 (CPP1) into CPP2 in vitro and has been introduced as a low-cost biomarker for arterial calcification and CVD risk. We aimed to investigate the association between T₅₀ and (1) heart failure with preserved ejection fraction (HFpEF), (2) ankle-brachial index (ABI) as measure of PAD, (3) pulse wave velocity (PWV) as measure of central arterial stiffness and (4) arterial calcification in individuals with T2DM.

Methods: Cross-sectional data was used of 771 individuals with T2DM (64% men, 67 [63-71] years). T₅₀ was measured using nephelometry on non-fasting serum samples. Presence of HFpEF was assessed with echocardiography based on current guidelines. ABI was categorized as ≤ 0.9 (PAD), 0.9-1.4 (normal) and ≥ 1.4 (high). Central arterial stiffness was measured using carotid-femoral PWV. Lower-extremity and coronary calcification were measured using computed tomography and quantified using Agatston scores categorized into zero (reference category) and tertiles > 0. Multivariable-adjusted Poisson, multinomial and linear regression analyses were used to study the associations with aforementioned surrogate CVD risk markers.

Results: Mean T₅₀ was 355 ± 55 min. HFpEF and PAD were present in 36.6% and 5.8% of the cohort, respectively. Mean cfPWV was 12.9 ± 2.5 m/s. Median calcification scores in the coronary arteries and lower-extremities were 315 [40-1246] and 791 [64-3820] Agatston units, respectively. Every 60-min decrease in T₅₀, indicating higher calcification risk, was associated with increased coronary arterial calcification (e.g. highest tertile OR = 1.63 [1.15-2.30], p = 0.006), but not with lower-extremity arterial calcification (e.g. highest tertile OR = 1.28 [0.96-1.69], p = 0.088). Moreover, T₅₀ ≤ 330 min versus T₅₀ ≥ 390 min was associated with PAD (OR = 3.04 [1.03-8.94], p = 0.044). Finally, every 60-min decrease in T₅₀ was not associated with neither HFpEF (RR = 1.02 [0.90-1.17], p = 0.736) nor cfPWV (β =  - 0.08 [ - 0.26-0.10], p = 0.398).

Conclusion: Low T₅₀ was associated with increased risks of coronary arterial calcification and PAD (measured by ABI ≤ 0.9) in individuals with T2DM, but not with HFpEF, central arterial stiffness and lower-extremity arterial calcification. Further research is warranted to evaluate the additive value of T₅₀ in CVD risk stratification in clinical care.

Background: The study aimed to investigate the effects of metabolic syndrome (MetS) and its components on myocardial microcirculation perfusion in global and assigned to three different coronary artery territories in obstructive coronary artery disease (OCAD) patients by cardiac magnetic resonance (CMR) first-pass perfusion imaging.

Materials and methods: In total, 127 patients with OCAD and 46 sex- and age-matched controls were enrolled in the study. All OCAD patients were divided into two groups: OCAD with MetS [OCAD (MetS+), n = 86] and OCAD without MetS [OCAD (MetS-), n = 41]. CMR first‑pass perfusion parameters were measured among three groups, including global and those assigned to the left anterior descending artery (LAD), the left circumflex artery (LCX), and right coronary artery (RCA) territories: Upslope, max signal intensity (MaxSI), time to maximum signal intensity (TTM) and perfusion index (PI). Multivariable linear regression analyses were constructed to investigate the independent factors of myocardial microcirculation perfusion in OCAD patients. Lasso regression analysis was used to evaluate the relationship between perfusion parameters and the components of MetS.

Results: Compared with the OCAD (MetS-) group, Upslope decreased in global, LAD, LCX and RCA perfusion territories in OCAD (MetS+) group (all p < 0.05). The MaxSI reduced in global, LAD and LCX perfusion territories in the OCAD (MetS+) group (all p < 0.05). From the controls to the OCAD (MetS-) group to the OCAD (MetS+) group, the TTM sequentially prolonged in global and RCA perfusion territories (all p < 0.05). In OCAD patients without LCX obstruction, the Upslope and MaxSI assigned to LCX territories decreased in the MetS group compared with the non-MetS group. A similar pattern was observed in OCAD patients without RCA obstruction (all P < 0.05). After adjustment for covariates, MetS was an independent factor of Upslope (global) (β = -0.309, p < 0.001), MaxSI (global) (β = -0.200, p = 0.023) and TTM (global) (β = 0.206, p = 0.014). Besides, MetS was independently associated with Upslope (LAD) (β = -0.346, p < 0.001), Upslope (LCX) (β = -0.214, p = 0.012), and Upslope (RCA) (β = -0.219, p = 0.010). High-density lipoprotein cholesterol (HDL) and obesity, were independently associated with Upslope (global) and MaxSI (global).

Conclusions: MetS aggravated global and non-stenotic coronary territories myocardial microcirculation function impairment in OCAD patients, and MetS, low HDL and obesity were independently associated with impaired myocardial perfusion.