Cardiovascular Diabetology最新文献

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.

Background: Cardio-renal-metabolic (CRM) comorbidity, including cardiovascular disease, chronic kidney disease, and type 2 diabetes mellitus, is prevalent in the population and closely associated with biological aging. However, longitudinal evidence and potential proteomics mediator remain limited.

Methods: We studied 330,177 UK Biobank participants free of CRM diseases at baseline. Biological aging was measured by KDM-BA, PhenoAge, their accelerations, and frailty status, and its effects on CRM progression, including no CRM disease to first, double, and triple CRM diseases, were evaluated using multistate proportional hazards model. In the subpopulation with proteomics data (n = 35,118), 2911 plasma proteins were profiled, and mediation analyses were performed to identify potential mediators.

Results: All five biological aging indicators significantly predicted CRM progression. For example, each standard deviation increase in PhenoAge was associated with hazard ratios of 1.42 [95% confidence interval (CI) 1.40-1.44], 1.26 (95% CI 1.22-1.31), and 1.24 (95% CI 1.12-1.37) for the transitions to first, double, and triple CRM disease, respectively. Mediation analyses identified nine circulating key proteins that statistically mediated the associations between biological aging and CKM progression, with GDF15, ADM, and HAVCR1 showing the largest mediated proportion (13.10-43.23%). The neutralizing antibody ponsegroumab for GDF15 is currently undergoing clinical evaluation.

Conclusion: Biological aging was strongly associated with the progression of CRM comorbidity, and these associations were partly accounted for by specific circulating proteins. These findings highlight the potential of aging-centered strategies and proteomic biomarkers for improving the risk prediction of CRM health and identifying therapeutic targets.

Background: Type 2 diabetes mellitus (T2DM) is a growing global health challenge. Conventional diagnostic tools have limited sensitivity and specificity for early-stage disease. In this context, long non-coding RNAs (lncRNAs) have emerged as promising biomarkers for T2DM risk. However, studies exploring their predictive value remain limited. This study aimed to evaluate the potential of circulating lncRNAs in T2DM development and to assess their interaction with dietary interventions.

Methods: The study included 462 non-diabetic participants from the CORDIOPREV study, followed for 5 years under Mediterranean or low-fat diet interventions. Expression levels of 22 circulating lncRNAs were quantified by qPCR. A series of statistical and machine learning methods were applied.

Results: Random forest analysis identified four lncRNAs (XIST, LINC01116, CASC2, LINC01370) as predictive of T2DM incidence. The combination of these lncRNAs with clinical variables significantly improved prediction performance (AUC = 0.730) compared to models with Hb1Ac (p = 0.015) or clinical variables alone (p < 0.001). Regarding the constructed lncRNA score from the previous model, a lower lncRNA score was associated with a reduced risk of developing T2DM (HR 0.37 (0.24-0.59), p < 0.001), and showed an inverse correlation with the disposition index among individuals following a Mediterranean diet (r = - 0.18, p = 0.009).

Conclusion: Circulating lncRNAs, particularly integrated into an epigenetic score, represent promising predictive biomarkers for T2DM development. The interaction with dietary intervention-especially the Mediterranean diet-supports their potential use in guiding personalized dietary strategies for T2DM prevention in high-risk populations.

Aims: This study aimed to assess the impacts of overweight and type 2 diabetes (T2D) on early hemodynamic and left ventricular (LV) changes using comprehensive cardiovascular magnetic resonance imaging (CMR) in three age- and sex-similar groups: lean individuals (LI group), BMI-similar overweight controls without T2D (CWO group) and overweight individuals with uncomplicated T2D (T2D group).

Methods: Middle-aged participants included 13 in the LI group, 37 in the CWO group, and 28 in the T2D group. Baseline assessments included cardiac and vascular function measured by CMR, thoracic echocardiography, insulin sensitivity, clinical measures, and cardiorespiratory fitness. 4D flow CMR was used to evaluate diastolic function via valve tracking and intraventricular flow analysis. Group differences were analyzed using ANOVA or Kruskal-Wallis tests, with Holm-Bonferroni correction applied for pairwise comparisons. Linear correlation and multivariate regression analyses were performed to evaluate the associations between CMR-derived diastolic variables and echocardiographic and clinical measures.

Results: Cardiorespiratory fitness was significantly lower in both the CWO and T2D groups compared with the LI group (all P < 0.001), with no difference between CWO and T2D. 4D flow CMR identified significant differences in the E/A velocity ratio between LI and CWO groups (P = 0.029), and in E/A velocity, flow, and vorticity ratios between CWO and T2D groups (P = 0.025, 0.031, and 0.034, respectively). The E/A vorticity ratio correlated moderately with conventional echocardiographic diastolic indices, such as MV E/A velocity ratio (Spearman's rho = 0.35, 95% CI: 0.07-0.60, P = 0.010; adjusted for age and sex). In multivariate regression, age (β =  - 0.014, P = 0.001), hypertension (β =  - 0.130, P = 0.015), heart rate (β =  - 0.009, P = 0.001), and circumferential peak early diastolic strain rate (β = 0.431, P = 0.002) emerged as independent determinants of the E/A vorticity ratio.

Conclusion: The present study suggests that the 4D flow CMR-derived E/A vorticity ratio may serve as a potential LV diastolic biomarker, given its capability in differentiating T2D-specific changes and stronger associations with clinical measures as well as CMR and echocardiographic parameters.

Trial registration:

Clinicaltrials: gov Identifier: NCT03419195 and NCT04791371.

Frailty and cardiometabolic disorders are highly prevalent in the aging population and frequently coexist, amplifying each other's adverse effects. Frailty, defined by decreased physiological reserves and heightened vulnerability to stressors, often occurs alongside cardiometabolic conditions such as diabetes, hypertension, and cardiovascular disease. The intersection of these conditions poses substantial clinical challenges, impacting morbidity, mortality, and quality of life. Understanding the shared pathophysiological mechanisms underlying frailty and cardiometabolic disorders is critical for guiding effective prevention and management strategies. This systematic review, registered in PROSPERO (CRD420251164236), documents current knowledge on the definitions, epidemiology, and pathophysiology of frailty in the context of cardiometabolic disorders and highlights the main clinical implications of their coexistence. Additionally, we discuss evidence-based strategies for assessment, prevention, and management, emphasizing the importance of an integrated approach to improve outcomes in older adults. These insights aim to inform about targeted interventions that can mitigate risk, enhance resilience, and optimize patient care.

Background: Stress hyperglycemia, reflected by the stress hyperglycemia ratio (SHR), is increasingly recognized as a marker of adverse cardiovascular outcomes in both diabetic and non-diabetic patients. Stress-induced hyperglycemia arises from acute metabolic and inflammatory stress responses and may signify impaired glycemic resilience. Heart failure with preserved ejection fraction (HFpEF) commonly coexists with metabolic abnormalities such as hyperglycemia, prediabetes, and diabetes, while physical frailty-frequent in older adults-is mechanistically linked to both dysglycemia and HFpEF. In this study, we aimed to investigate the association between SHR and physical performance in frail older adults with HFpEF.

Methods: We conducted a prospective observational study enrolling consecutive frail adults aged > 65 years with a confirmed diagnosis of HFpEF and Montreal cognitive assessment (MoCA) score < 26. Frailty was defined by ≥ 3 of 5 Fried criteria (low physical activity, unintentional weight loss, exhaustion, weakness, and slowness). SHR was calculated as the ratio of admission plasma glucose (mmol/L) to estimated chronic glucose derived from HbA1c (%). Participants were stratified into two groups: SHR ≤ 1 and SHR > 1. Physical function was assessed by gait speed (m/s).

Results: Of 295 screened individuals, 204 met inclusion criteria and completed the study. Patients with SHR > 1 demonstrated significantly reduced physical performance compared with those with SHR ≤ 1 (mean gait speed 0.65 ± 0.20 m/s vs. 0.72 ± 0.20 m/s, p = 0.0004).

Conclusions: A higher SHR was independently associated with poorer physical function in frail older adults with HFpEF. These findings suggest that stress-related dysglycemia may contribute to functional decline in this population, highlighting the potential utility of SHR as a metabolic marker of frailty severity and cardiovascular vulnerability.

Background: Disrupted cardiomyocyte energy metabolism is a hallmark of heart failure with preserved ejection fraction (HFpEF). Succinate, a key intermediate of the tricarboxylic acid cycle, is markedly decreased in HFpEF myocardium. In addition to its metabolic role, succinate functions as a signaling molecule that activates GPR91 to regulate metabolic and immune pathways. However, the precise contributions and mechanisms of cardiomyocyte succinate-GPR91 signaling in HFpEF pathogenesis remain incompletely understood.

Methods: HFpEF models were established in wild-type (WT), global GPR91 knockout (Gpr91^-/-), and cardiomyocyte-specific GPR91 knockout (Gpr91^ΔCM) mice, with or without succinate supplementation. Cardiac structure, function, and metabolic phenotypes were assessed using echocardiography, histology, and molecular assays. Transcriptome sequencing of myocardial tissues was performed to identify pathways regulated by succinate-GPR91 signaling. Mechanistic studies in human AC16 cardiomyocytes were conducted to validate pathway regulation and clarify downstream molecular mechanisms. Additionally, rescue experiments were performed to confirm the functional relevance of succinate-GPR91 signaling in cardiomyocyte metabolism and HFpEF progression.

Results: Cardiac succinate levels and GPR91 expression were markedly decreased in HFpEF mice. Succinate supplementation restored systemic metabolism, improved diastolic function, and attenuated myocardial hypertrophy and fibrosis in WT HFpEF mice, whereas these protective effects were abolished in both Gpr91^-/- and Gpr91^ΔCM mice. Transcriptomic analysis demonstrated that succinate activated AMPK signaling and enriched pathways related to glucose-lipid metabolism and NAD⁺ biosynthesis in Gpr91^fl/fl but not in Gpr91^ΔCM hearts. Mechanistically, succinate enhanced AMPK phosphorylation and NAD⁺ production via Gq-mediated signaling, thereby promoting cardiomyocyte metabolic reprogramming.

Conclusion: These findings identify the succinate-GPR91 axis as a critical regulator of cardiometabolic homeostasis and a potential therapeutic target in HFpEF.