Cardiovascular Diabetology最新文献

Background: Dysglycemia and insulin resistance increase type 2 diabetes (T2D) and cardiovascular disease (CVD) risk, yet associations with specific glucose-insulin homeostatic biomarkers have been inconsistent. Vitamin D and marine omega-3 fatty acids (n-3 FA) may improve insulin resistance. We sought to examine the association between baseline levels of insulin, C-peptide, HbA1c, and a novel insulin resistance score (IRS) with incident cardiometabolic diseases, and whether randomized vitamin D or n-3 FA modify these associations.

Methods: VITamin D and OmegA-3 TriaL (NCT01169259) was a randomized clinical trial testing vitamin D and n-3 FA for the prevention of CVD and cancer over a median of 5.3 years. Incident cases of T2D and CVD (including cardiovascular death, myocardial infarction, stroke, and coronary revascularization) were matched 1:1 on age, sex, and fasting status to controls. Conditional logistic regressions adjusted for demographic, clinical, and adiposity-related factors were used to assess the adjusted odds ratio (aOR) per-standard deviation (SD) and 95%CI of baseline insulin, C-peptide, HbA1c, and IRS (Insulin×0.0295 + C-peptide×0.00372) with risk of T2D, CVD, and coronary heart disease (CHD).

Results: We identified 218 T2D case-control pairs and 715 CVD case-control pairs including 423 with incident CHD. Each of the four biomarkers at baseline was separately associated with incident T2D, aOR (95%CI) per SD increment: insulin 1.46 (1.03, 2.06), C-peptide 2.04 (1.35, 3.09), IRS 1.72 (1.28, 2.31) and HbA1c 7.00 (3.76, 13.02), though only HbA1c remained statistically significant with mutual adjustments. For cardiovascular diseases, we only observed significant associations of HbA1c with CVD (1.19 [1.02, 1.39]), and IRS with CHD (1.25 [1.04, 1.50]), which persisted after mutual adjustment. Randomization to vitamin D and/or n-3 FA did not modify the association of these biomarkers with the endpoints.

Conclusions: Each of insulin, C-peptide, IRS, and HbA1c were associated with incident T2D with the strongest association noted for HbA1c. While HbA1c was significantly associated with CVD risk, a novel IRS appears to be associated with CHD risk. Neither vitamin D nor n-3 FA modified the associations between these biomarkers and cardiometabolic outcomes.

Background: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 2 diabetes mellitus, and its mechanisms are complex and poorly understood. Despite growing evidence suggesting that ferroptosis plays a significant role in cardiovascular disease, it has been less extensively studied in DCM. Fibroblast growth factor 21 (FGF21), whose mechanism of action is closely related to ferroptosis, is widely utilized in studies focused on the prevention and treatment of glucolipid metabolism-related diseases and cardiovascular diseases.

Objective: To confirm the significant role of ferroptosis in DCM and to investigate whether FGF21 improves DCM by inhibiting ferroptosis and elucidating its specific molecular mechanisms.

Methods: The animal DCM models were established through high-fat feeding combined with streptozotocin injection in C57BL/6J mice or by db/db mice, and the diabetic cardiomyocyte injury model was created using high glucose and high fat (HG/HF) culture of primary cardiomyocytes. Intervention modeling of FGF21 were performed by injecting adeno-associated virus 9-FGF21 in mice and transfecting FGF21 siRNA or overexpression plasmid in primary cardiomyocytes.

Results: The findings indicated that ferroptosis was exacerbated and played a significant role in DCM. The overexpression of FGF21 inhibited ferroptosis and improved cardiac injury and function, whereas the knockdown of FGF21 aggravated ferroptosis and cardiac injury and function in DCM. Furthermore, we discovered that FGF21 inhibited ferroptosis in DCM by directly acting on ferritin and prolonging its half-life. Specifically, FGF21 binded to the heavy and light chains of ferritin, thereby reducing its excessive degradation in the proteasome and lysosomal-autophagy pathways in DCM. Additionally, activating transcription factor 4 (ATF4) served as the upstream regulator of FGF21 in DCM.

Conclusions: The ATF4-FGF21-ferritin axis mediates the protective effects in DCM through the ferroptosis pathway and represents a potential therapeutic target for DCM.

Background and aims: The association between metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM) is unclear. This study aimed to investigate the impact of spectrum of SLD on the risk of heart failure and cardiovascular (CV) mortality in patients with T2DM.

Methods: In a nationwide cohort study, 2,745,689 adults with T2DM were followed from 2009 to 2012 until 2018. Participants were categorized into no steatotic liver disease (no SLD) and SLD groups. The SLD group was stratified based on metabolic risk factors, alcohol consumption and viral hepatitis. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for heart failure (HF) and CV mortality risk.

Results: The prevalence of MASLD, metabolic alcohol-associated liver disease (MetALD), alcohol-associated liver disease with metabolic dysfunction (ALD with MD) and MASLD with viral hepatitis (VH) was 49.6%, 7.2%, 2.3%, and 2.0%. Individuals with MASLD (adjusted HR [aHR], 1.11), MetALD (aHR, 1.14), ALD with MD (aHR, 1.32) and MASLD with VH (aHR, 1.12) had a higher risk of developing HF compared with the no SLD group. The risk of CV mortality was also increased in those with SLD groups compared to those with no SLD. The risk of new-onset HF and CV mortality showed a J-shaped association with alcohol consumption regardless of SLD status.

Conclusion: SLD is independent risk factor of new-onset HF and CV mortality in persons with T2DM, and alcohol consumption has a J-shaped association with risk of HF and CV mortality, regardless of SLD status.

Background: Type 2 diabetes has traditionally been a risk factor for worse prognosis after myocardial infarction (MI), but major advances have been made in its treatment, and the use of secondary preventive measures has intensified. We evaluated the short- and long-term mortality rates of patients with type 2 diabetes after MI and explored the associations between the characteristics of patients with type 2 diabetes and MI mortality.

Methods: Mortality rates among consecutive MI patients with type 2 diabetes using oral antidiabetic medication (n = 13,152; 40% female; mean age 73.6 years) and MI patients without diabetes (n = 77,669) treated in Finland from 2004 to 2018 were retrospectively studied using a combination of national registries (median follow-up 5.7 years). Differences between groups were balanced with multivariable adjustments and propensity score matching.

Results: Mortality was higher in patients with type 2 diabetes than in the propensity score-matched controls without diabetes at 30 days (12.6% versus 12.0%: p = 0.013), at 1 year (22.4% versus 21.4%; p = 0.001), and at 15 years (83.2% vs. 73.4%; HR 1.20; 95% CI 1.17-1.24; p < 0.0001) after MI. In subgroup analyses, type 2 diabetes was associated with a poorer prognosis across the spectrum of MI patients. The excess mortality risk was attenuated by increasing age but was similar in both sexes. Male sex, age, cardiovascular and noncardiovascular co-morbidities, lack of revascularization, a longer duration of diabetes, and baseline insulin therapy were associated with increased mortality in patients with type 2 diabetes. The one-year prognosis of patients with type 2 diabetes improved during the study period, but the mortality gap compared to patients without diabetes was not altered.

Conclusions: Type 2 diabetes had a negative impact on both short- and long-term outcome after MI, but effect sizes were relatively small. Patients with longer duration of diabetes or need for insulin therapy are still at particular risk.

Background: Sedentary behavior, such as excessive sitting, increases risk of cardiovascular disease and premature mortality in the general population, but this has not been assessed in type 1 diabetes. Occupational sitting is increasingly ubiquitous and often constitutes the largest portion of daily sitting time. Our aim was to identify clinical factors associated with excessive occupational sitting in type 1 diabetes and, in a prospective setting, to explore its association with cardiovascular events and all-cause mortality, independent of leisure-time physical activity.

Methods: An observational follow-up study of 1,704 individuals (mean age 38.9 ± 10.1 years) from the Finnish Diabetic Nephropathy Study. Excessive occupational sitting, defined as ≥ 6 h of daily workplace sitting, was assessed using a validated self-report questionnaire. Data on cardiovascular events and mortality were retrieved from national registries. Multivariable logistic regression identified independently associated factors, while Kaplan-Meier curves and Cox proportional hazard models were used for prospective analyses.

Results: Factors independently and positively associated with excessive occupational sitting included a high occupational category [OR 6.53, 95% CI (4.09‒10.40)] and older age [1.02 (1.00‒1.03)], whereas negatively associated factors included current smoking [0.68 (0.50‒0.92)], moderate albuminuria [0.55 (0.38‒0.80)], and high leisure-time physical activity [0.52 (0.36‒0.74)]. During a median follow-up of 12.5 (6.5-16.4) years, 163 individuals (9.6%) suffered cardiovascular events, and during a median follow-up of 13.7 (9.4-16.6) years, 108 (6.3%) deaths occurred. Excessive occupational sitting increased cardiovascular event risk (hazard ratio [HR] 1.55 [95% CI 1.10‒2.18]) after adjustment for confounders and other covariates. Furthermore, in a stratified multivariable analysis among current smokers, excessive occupational sitting increased the risk of all-cause mortality (2.06 [1.02‒4.20]).

Conclusions: Excessive occupational sitting is associated with a higher risk of cardiovascular events and all-cause mortality in individuals with type 1 diabetes. This association persists regardless of leisure-time physical activity, after adjusting for independently associated variables identified in our cross-sectional analyses. These findings underscore the need to update physical activity guidelines to better address sedentary behavior and improve outcomes for individuals with type 1 diabetes. Targeting occupational sitting should be considered a key focus for interventions aimed at reducing overall sedentary time.

Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is well-recognized for its therapeutic benefits in type 2 diabetes (T2D) and cardiovascular diseases. In this comprehensive in vitro study, we investigated DAPA's effects on cardiomyocytes, aortic endothelial cells (AECs), and stem cell-derived beta cells (SC-β), focusing on its impact on hypertrophy, inflammation, and cellular stress. Our results demonstrate that DAPA effectively attenuates isoproterenol (ISO)-induced hypertrophy in cardiomyocytes, reducing cell size and improving cellular structure. Mechanistically, DAPA mitigates reactive oxygen species (ROS) production and inflammation by activating the AKT pathway, which influences downstream markers of fibrosis, hypertrophy, and inflammation. Additionally, DAPA's modulation of SGLT2, the Na+/H + exchanger 1 (NHE1), and glucose transporter (GLUT 1) type 1 highlights its critical role in maintaining cellular ion balance and glucose metabolism, providing insights into its cardioprotective mechanisms. In aortic endothelial cells (AECs), DAPA exhibited notable anti-inflammatory properties by restoring AKT and phosphoinositide 3-kinase (PI3K) expression, enhancing mitogen-activated protein kinase (MAPK) activation, and downregulating inflammatory cytokines at both the gene and protein levels. Furthermore, DAPA alleviated tumor necrosis factor (TNFα)-induced inflammation and stress responses while enhancing endothelial nitric oxide synthase (eNOS) expression, suggesting its potential to preserve vascular function and improve endothelial health. Investigating SC-β cells, we found that DAPA enhances insulin functionality without altering cell identity, indicating potential benefits for diabetes management. DAPA also upregulated MAFA, PI3K, and NRF2 expression, positively influencing β-cell function and stress response. Additionally, it attenuated NLRP3 activation in inflammation and reduced NHE1 and glucose-regulated protein GRP78 expression, offering novel insights into its anti-inflammatory and stress-modulating effects. Overall, our findings elucidate the multifaceted therapeutic potential of DAPA across various cellular models, emphasizing its role in mitigating hypertrophy, inflammation, and cellular stress through the activation of the AKT pathway and other signaling cascades. These mechanisms may not only contribute to enhanced cardiac and endothelial function but also underscore DAPA's potential to address metabolic dysregulation in T2D.

Epicardial adipose tissue (EAT) is a unique fat depot located between the myocardium and the visceral layer of pericardium. It can be further subdivided into pericoronary (PCAT), periatrial (PAAT) and periventricular adipose tissue (PVentAT), each of them exhibiting specific characteristics and association with the underlying tissue. Since no physical barrier separates EAT from the myocardium, this fat tissue can easily interact with the underlying cardiac structure. EAT can be visualized using various imaging modalities. Computed tomography provides not only information on EAT volume, but also on its density. Indeed, EAT density reflected by the recently developed fat attenuation index (FAI) is emerging as a useful index of PCAT inflammation, PAAT inflammation and fibrosis, while the relevance of density of PVentAT is much less known. The emerging data indicates that FAI can be an important diagnostic and prognostic tool in both coronary artery disease and atrial fibrillation. Future studies will demonstrate if it also could be used as a marker of efficacy of therapies and whether FAI PVentAT could indicate ventricular pathologies, such as heart failure. The aim of the review is to present computed tomography derived FAI as an important tool both to study and better understand the epicardial fat and as a potential predictive marker in cardiovascular disorders.

Background: Systemic stress, inflammation, and hydroelectrolytic and acid‒base abnormalities observed during diabetic ketoacidosis (DKA) can cause changes in the heart and even induce cardiovascular damage. We aimed to evaluate the structure and function of the heart during and after a DKA episode via echocardiography and biomarker assessment.

Methods: We performed a transthoracic echocardiogram (TTE) in subjects with an episode of DKA in the first 4-6 h of treatment. We evaluated left ventricular wall thickness, diameters and volumes, as well as systolic and diastolic function using tissue Doppler imaging, pulsed wave Doppler and left ventricular ejection fraction (LVEF). Left ventricular function was also assessed with global longitudinal strain (GLS). We obtained cardiac troponin levels in the first 24 h after admission. A second TTE was performed following the same protocol 6-12 h after the resolution of the DKA episode.

Results: We included a total of 20 subjects. The mean age was 33 ± 13.6 years; 70% were female, and 70% had type 1 DM. 75% of the patients experienced severe episodes, and the rest experienced moderate episodes. Left ventricular isovolumetric contraction and ejection time were significantly shorter during DKA and prolonged after the resolution of the episodes (47.6 ± 9.9 vs. 62.2 ± 14.1, p = < 0.001) and (218.6 ± 37.9 vs. 265.06 ± 34.7). The isovolumetric relaxation time was also shorter during DKA, (41.72 ± 8.29 vs. 59.32 ± 17.98, p = < 0.001). Volumes and diameters of the left ventricle increased significantly after DKA resolution. We found no difference between LVEF or GLS during and after DKA resolution. 20% of the participants had troponin elevations, half of whom had moderate episodes and half of whom had severe episodes. 35% had LV dysfunction, 28.5% both in GLS and LVEF. 28.5% occurred after DKA resolution, with alterations in GLS.

Conclusions: Diabetic ketoacidosis induces changes in the structure and function of the heart, which are mostly transient, reflect the presence of a hyperdynamic state and resolve after the resolution of the episode. Some subjects present with evidence of myocardial injury with elevated cardiac troponin and left ventricular dysfunction.

Background: Hyperglycemia upon admission is associated with poor prognosis of many cardiovascular diseases. However, the relationship of stress hyperglycemia ratio (SHR), admission blood glucose (ABG), and hemoglobin A1c (HbA1c) with pulmonary hypertension has not been reported. This study aimed to explore the association of hyperglycemia indices with disease severity and long-term adverse outcomes in patients with idiopathic pulmonary arterial hypertension (IPAH).

Methods: This multi-center cohort study included 625 consecutive patients diagnosed with or treated for IPAH between January 2015 and June 2023. SHR was calculated using the followings: ABG (mmol/L)/(1.59 × HbA1c [%] - 2.59). The primary endpoint was defined as clinical worsening events. Multivariable Cox regression and restricted cubic spline analyses were employed to evaluate the association of SHR, ABG, and HbA1c with endpoint events. The mediating effect of pulmonary hemodynamics was evaluated to investigate the potential mechanism between hyperglycemia and clinical outcomes.

Results: During a mean follow-up period of 3.8 years, 219 (35.0%) patients experienced all-cause death or clinical worsening events. Hyperglycemia indices correlated with well-validated variables that reflected the severity of IPAH, such as the World Health Organization functional class, 6-min walk distance, and N-terminal pro-brain natriuretic peptide levels. Multivariable Cox regression analyses indicated that SHR (hazard ratio [HR] 1.328, 95% confidence intervals [CI]: 1.185, 1.489 per 0.1-unit increment, P < 0.001) and ABG (HR 1.317, 95% CI: 1.134, 1.529 per 1.0-unit increment, P < 0.001) were independent predictors of primary endpoint events. Mediation analysis indicated that pulmonary vascular resistance mediated 5.65% and 14.62% of the associations between SHR and ABG and clinical worsening events, respectively. The addition of SHR significantly improved reclassification, discrimination ability, and model fit beyond the clinical risk prediction model.

Conclusions: SHR is positively associated with clinical worsening in patients with IPAH. The association appeared to be partially mediated through the pathway of pulmonary vascular remodeling, indicating that SHR may serve as a valuable indicator for providing additional risk information.

Background: Diabetes mellitus (DM) is associated with premature atherosclerotic disease, coronary artery disease (CAD) and chronic heart failure (HF), leading to increased morbidity and mortality. Sodium-Glucose Co-transporter 2 Inhibitors (SGLT2i) exhibit cardioprotective benefits beyond glucose lowering, reducing the risk of major cardiovascular events (MACE) and HF hospitalizations in patients with DM and CAD. Endothelial progenitor cells (EPCs) are bone marrow-derived cells involved in vascular repair, mobilized in response to vascular injury. The number and function of circulating EPCs (cEPCs) are negatively affected by cardiovascular risk factors, including DM. This study aimed to examine the response of cEPCs to SGLT2i treatment in DM patients with stable CAD.

Methods: A prospective single-center study included patients with DM and stable CAD who were started on an SGLT2i (empagliflozin). Peripheral blood samples were collected at baseline, 1 month, and 3 months to evaluate cEPC levels and function by flow cytometry, immunohistochemistry and MTT assays.

Results: Eighteen patients were included in the study (median age 73, (IQR 69, 77) years, 67% male). After 1 month of treatment with empagliflozin, there was no significant change in cEPCs level or function. However, following 3 months of treatment, a significant increase was observed both in cell levels (CD34(+)/VEGFR-2(+): from 0.49% (IQR 0.32, 0.64) to 1.58% (IQR 0.93, 1.82), p = 0.0006; CD133(+)/VEGFR-2(+): from 0.38% (IQR 0.27, 0.6) to 0.82% (IQR 0.7, 1.95), p = 0.0001) and in cell function (from 0.25 CFUs (IQR 0, 0.5) at baseline, to 2 CFUs (IQR 1, 2) at 3 months, p = 0.0012).

Conclusions: Empagliflozin treatment in patients with DM and stable CAD increases cEPC levels and function, implying a cardioprotective mechanism. These findings highlight the potential of SGLT2i in treating cardiovascular diseases, warranting further research to explore these effects and their long-term implications.