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Background: Since the complication of diabetes mellitus (DM) is a risk for adverse cardiovascular outcomes in patients with coronary artery disease (CAD), appropriate risk estimation is needed in diabetic patients following percutaneous coronary intervention (PCI). However, there is no useful biomarker to predict outcomes in this population. Although stromal cell derived factor-1α (SDF-1α), a circulating chemokine, was shown to have cardioprotective roles, the prognostic impact of SDF-1α in diabetic patients with CAD is yet to be fully elucidated. Moreover, roles of SDF-1α isoforms in outcome prediction remain unclear. Therefore, this study aimed to assess the prognostic implication of three forms of SDF-1α including total, active, and inactive forms of SDF-1α in patients with DM and after PCI. Methods: This single-center retrospective analysis involved consecutive patients with diabetes who underwent PCI for the first time between 2008 and 2018 (n = 849). Primary and secondary outcome measures were all-cause death and the composite of cardiovascular death, non-fatal myocardial infarction, and ischemic stroke (3P-MACE), respectively. For determining plasma levels of SDF-1α, we measured not only total, but also the active type of SDF-1α by ELISA. Inactive isoform of the SDF-1α was calculated by subtracting the active isoform from total SDF-1α. Results: Unadjusted Kaplan–Meier analyses revealed increased risk of both all-cause death and 3P-MACE in patients with elevated levels of inactive SDF-1α. However, plasma levels of total and active SDF-1α were not associated with cumulative incidences of outcome measures. Multivariate Cox hazard analyses repeatedly indicated the 1 higher log-transformed inactive SDF-1α was significantly associated with increased risk of all-cause death (hazard ratio (HR): 2.64, 95% confidence interval (CI): 1.28–5.34, p = 0.008) and 3P-MACE (HR: 2.51, 95% CI: 1.12–5.46, p = 0.02). Moreover, the predictive performance of inactive SDF-1α was higher than that of total SDF-1α (C-statistics of inactive and total SDF-1α for all-cause death: 0.631 vs 0.554, for 3P-MACE: 0.623 vs 0.524, respectively). Conclusion: The study results indicate that elevated levels of plasma inactive SDF-1α might be a useful indicator of poor long-term outcomes in diabetic patients following PCI. Trial registration: This study describes a retrospective analysis of a prospective registry database of patients who underwent PCI at Juntendo University Hospital, Tokyo, Japan (Juntendo Physicians' Alliance for Clinical Trials, J-PACT), which is publicly registered (University Medical Information Network Japan—Clinical Trials Registry, UMIN-CTR 000035587). [ABSTRACT FROM AUTHOR]

Background: The reduction of myocardial infarction (MI) and narrowing the gap between the populations with and without diabetes are important goals of diabetes care. We analyzed time trends for sex-specific incidence rates (IR) of first MI (both non-fatal MI and fatal MI) as well as separately for first non-fatal MI and fatal MI in the population with and without diabetes. Methods: Using data from the KORA myocardial infarction registry (Augsburg, Germany), we estimated age-adjusted IR in people with and without diabetes, corresponding relative risks (RR), and time trends from 1985 to 2016 using Poisson regression. Results: There were 19,683 people with first MI (34% fatal MI, 71% men, 30% with diabetes) between 1985 and 2016. In the entire study population, the IR of first MI decreased from 359 (95% CI: 345–374) to 236 (226–245) per 100,000 person years. In men with diabetes, IR decreased only in 2013–2016. This was due to first non-fatal MI, where IR in men with diabetes increased until 2009–2012, and slightly decreased in 2013–2016. Overall, fatal MI declined stronger than first non-fatal MI corresponding to IRs. The RR of first MI substantially increased among men from 1.40 (1.22–1.61) in 1985–1988 to 2.60 (2.26–2.99) in 1997–2000 and moderately decreased in 2013–2016: RR: 1.75 (1.47–2.09). Among women no consistent time trend for RR was observed. Time trends for RR were similar regarding first non-fatal MI and fatal MI. Conclusions: Over the study period, we found a decreased incidence of first MI and fatal MI in the entire study population. The initial increase of first non-fatal MI in men with diabetes needs further research. The gap between populations with and without diabetes remained. [ABSTRACT FROM AUTHOR]

Background: Diabetes-induced trained immunity contributes to the development of atherosclerosis and its complications. This study aimed to investigate in humans whether epigenetic signals involved in immune cell activation and inflammation are initiated in hematopoietic stem/progenitor cells (HSPCs) and transferred to differentiated progeny. Methods and results: High glucose (HG)-exposure of cord blood (CB)-derived HSPCs induced a senescent-associated secretory phenotype (SASP) characterized by cell proliferation lowering, ROS production, telomere shortening, up-regulation of p21 and p27genes, upregulation of NFkB-p65 transcription factor and increased secretion of the inflammatory cytokines TNFα and IL6. Chromatin immunoprecipitation assay (ChIP) of p65 promoter revealed that H3K4me1 histone mark accumulation and methyltransferase SetD7 recruitment, along with the reduction of repressive H3K9me3 histone modification, were involved in NFkB-p65 upregulation of HG-HSPCs, as confirmed by increased RNA polymerase II engagement at gene level. The differentiation of HG-HSPCs into myeloid cells generated highly responsive monocytes, mainly composed of intermediate subsets (CD14hiCD16+), that like the cells from which they derive, were characterized by SASP features and similar epigenetic patterns at the p65 promoter. The clinical relevance of our findings was confirmed in sternal BM-derived HSPCs of T2DM patients. In line with our in vitro model, T2DM HSPCs were characterized by SASP profile and SETD7 upregulation. Additionally, they generated, after myeloid differentiation, senescent monocytes mainly composed of proinflammatory intermediates (CD14hiCD16+) characterized by H3K4me1 accumulation at NFkB-p65 promoter. Conclusions: Hyperglycemia induces marked chromatin modifications in HSPCs, which, once transmitted to the cell progeny, contributes to persistent and pathogenic changes in immune cell function and composition. [ABSTRACT FROM AUTHOR]

Background: Randomized controlled trials and real-world studies suggest that combination therapy with sodium–glucose transport protein 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is associated with improvement in fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), systolic blood pressure (SBP), body mass index (BMI), and total cholesterol levels. However, a systematic review of available real-world evidence may facilitate clinical decision-making in the real-world scenario. This meta-analysis assessed the safety and effectiveness of combinations of SGLT2is + GLP-1RAs with a focus on their cardioprotective effects along with glucose-lowering ability in patients with type 2 diabetes mellitus (T2DM) in a real-world setting. Methods: Electronic searches were performed in the PubMed/MEDLINE, PROQuest, Scopus, CINAHL, and Google Scholar databases. Qualitative analyses and meta-analyses were performed using the Joanna Briggs Institute SUMARI software package and Review Manager v5.4, respectively. Results: The initial database search yielded 1445 articles; of these, 13 were included in this study. The analyses indicated that SGLT2is + GLP-1RAs combinations were associated with significantly lower all-cause mortality when compared with individual therapies (odds ratio [95% confidence interval [CI] 0.49 [0.41, 0.60]; p < 0.00001). Significant reductions in BMI (− 1.71 [− 2.74, − 0.67]; p = 0.001), SBP (− 6.35 [− 10.17, − 2.53]; p = 0.001), HbA1c levels (− 1.48 [− 1.75, − 1.21]; p < 0.00001), and FPG (− 2.27 [− 2.78, − 1.76]; p < 0.00001) were associated with the simultaneous administration of the combination. Changes in total cholesterol levels and differences between simultaneous and sequential combination therapies for this outcome were not significant. Conclusion: This systematic review and meta-analysis based on real-world data suggests that the combination of SGLT2is + GLP-1RAs is associated with lower all-cause mortality and favorable improvements in cardiovascular, renal, and glycemic measurements. The findings drive a call-to–action to incorporate this combination early and simultaneously in managing T2DM patients and achieve potential cardiovascular benefits and renal protection. [ABSTRACT FROM AUTHOR]

Background Recent guidelines propose N-terminal pro-B-type natriuretic peptide (NT-proBNP) for recognition of asymptomatic left ventricular (LV) dysfunction (Stage B Heart Failure, SBHF) in type 2 diabetes mellitus (T2DM). Wavelet Transform based signal-processing transforms electrocardiogram (ECG) waveforms into an energy distribution waveform (ew)ECG, providing frequency and energy features that machine learning can use as additional inputs to improve the identifcation of SBHF. Accordingly, we sought whether machine learning model based on ewECG features was superior to NT-proBNP, as well as a conventional screening tool—the Atherosclerosis Risk in Communities (ARIC) HF risk score, in SBHF screening among patients with T2DM. Methods Participants in two clinical trials of SBHF (defned as diastolic dysfunction [DD], reduced global longitudinal strain [GLS≤18%] or LV hypertrophy [LVH]) in T2DM underwent 12-lead ECG with additional ewECG feature and echocardiography. Supervised machine learning was adopted to identify the optimal combination of ewECG extracted features for SBHF screening in 178 participants in one trial and tested in 97 participants in the other trial. The accuracy of the ewECG model in SBHF screening was compared with NT-proBNP and ARIC HF. Results SBHF was identifed in 128 (72%) participants in the training dataset (median 72 years, 41% female) and 64 (66%) in the validation dataset (median 70 years, 43% female). Fifteen ewECG features showed an area under the curve (AUC) of 0.81 (95% CI 0.787–0.794) in identifying SBHF, signifcantly better than both NT-proBNP (AUC 0.56, 95% CI 0.44–0.68, p<0.001) and ARIC HF (AUC 0.67, 95%CI 0.56–0.79, p=0.002). ewECG features were also led to robust models screening for DD (AUC 0.74, 95% CI 0.73–0.74), reduced GLS (AUC 0.76, 95% CI 0.73–0.74) and LVH (AUC 0.90, 95% CI 0.88–0.89). Conclusions Machine learning based modelling using additional ewECG extracted features are superior to NTproBNP and ARIC HF in SBHF screening among patients with T2DM, providing an alternative HF screening strategy for asymptomatic patients and potentially act as a guidance tool to determine those who required echocardiogram to confrm diagnosis. [ABSTRACT FROM AUTHOR]

Early since the onset of the COVID-19 pandemic, the medical and scientific community were aware of extra respiratory actions of SARS-CoV-2 infection. Endothelitis, hypercoagulation, and hypofibrinolysis were identified in COVID-19 patients as subsequent responses of endothelial dysfunction. Activation of the endothelial barrier may increase the severity of the disease and contribute to long-COVID syndrome and post-COVID sequelae. Besides, it may cause alterations in primary, secondary, and tertiary hemostasis. Importantly, these responses have been highly decisive in the evolution of infected patients also diagnosed with diabetes mellitus (DM), who showed previous endothelial dysfunction. In this review, we provide an overview of the potential triggers of endothelial activation related to COVID-19 and COVID-19 under diabetic milieu. Several mechanisms are induced by both the viral particle itself and by the subsequent immune-defensive response (i.e., NF-κB/NLRP3 inflammasome pathway, vasoactive peptides, cytokine storm, NETosis, activation of the complement system). Alterations in coagulation mediators such as factor VIII, fibrin, tissue factor, the von Willebrand factor: ADAMST-13 ratio, and the kallikrein-kinin or plasminogen-plasmin systems have been reported. Moreover, an imbalance of thrombotic and thrombolytic (tPA, PAI-I, fibrinogen) factors favors hypercoagulation and hypofibrinolysis. In the context of DM, these mechanisms can be exacerbated leading to higher loss of hemostasis. However, a series of therapeutic strategies targeting the activated endothelium such as specific antibodies or inhibitors against thrombin, key cytokines, factor X, complement system, the kallikrein-kinin system or NETosis, might represent new opportunities to address this hypercoagulable state present in COVID-19 and DM. Antidiabetics may also ameliorate endothelial dysfunction, inflammation, and platelet aggregation. By improving the microvascular pathology in COVID-19 and post-COVID subjects, the associated comorbidities and the risk of mortality could be reduced. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is increasing at an alarming rate, primary due to the rising in aging, obesity and diabetes. Notably, individuals with type 1 diabetes (T1D) face a significantly elevated risk of HF, leading to more hospitalizations and increased case fatality rates. Several risk factors contribute to HF in T1D, including poor glycemic control, female gender, smoking, hypertension, elevated BMI, and albuminuria. However, early and intensive glycemic control can mitigate the long-term risk of HF in individuals with T1D. The pathophysiology of diabetes-associated HF is complex and multifactorial, and the underlying mechanisms in T1D remain incompletely elucidated. In terms of treatment, much of the evidence comes from type 2 diabetes (T2D) populations, so applying it to T1D requires caution. Sodium-glucose cotransporter 2 inhibitors have shown benefits in HF outcomes, even in non-diabetic populations. However, most of the information about HF and the evidence from cardiovascular safety trials related to glucose lowering medications refer to T2D. Glycemic control is key, but the link between hypoglycemia and HF hospitalization risk requires further study. Glycemic variability, common in T1D, is an independent HF risk factor. Technological advances offer the potential to improve glycemic control, including glycemic variability, and may play a role in preventing HF. In summary, HF in T1D is a complex challenge with unique dimensions. This review focuses on HF in individuals with T1D, exploring its epidemiology, risk factors, pathophysiology, diagnosis and treatment, which is crucial for developing tailored prevention and management strategies for this population. [ABSTRACT FROM AUTHOR]

Aim: Patients with diabetes mellitus have poor prognosis after myocardial ischemic injury. However, the mechanism is unclear and there are no related therapies. We aimed to identify regulators of diabetic myocardial ischemic injury. Methods and results: Mass spectrometry-based, non-targeted metabolomic approach was used to profile coronary sinus blood from diabetic and non-diabetic Bama-mini pigs at 0.5-h post coronary artery ligation. Six metabolites had a |log2 (Fold Change)|> 1.3. Among them, the most changed is arachidonic acid (AA), levels of which were 32 times lower in diabetic pigs than in non-diabetic pigs. The AA-derived products, PGI2 and 6-keto-PGF1α, were also significantly reduced. AA treatment of cultured cardiomyocytes protected against cell death by 30% at 48 h of high glucose and oxygen deprivation, which coincided with increased mitophagic activity (as indicated by increased LC3II/LC3I, decreased p62 and increased parkin & PINK1), improved mitochondrial renewal (upregulation of Drp1 and FIS1), reduced ROS generation and increased ATP production. These cardioprotective effects were abolished by PINK1(a crucial mitophagy protein) knockdown or the autophagy inhibitor 3-Methyladenine. The protective effect of AA was also inhibited by indomethacin and Cay10441, a prostacyclin receptor antagonist. Furthermore, diabetic Sprague Dawley rats were subjected to coronary ligation for 40 min and AA treatment (10 mg/day per animal gavaged) decreased myocardial infarct size, cell apoptosis index, inflammatory cytokines and improved heart function. Scanning electron microscopy showed more intact mitochondria in the border zone of infarcted myocardium in AA treated rats. Lastly, diabetic patients after myocardial infarction had lower plasma levels of AA and 6-keto-PGF1α and reduced cardiac ejection fraction, compared with non-diabetic patients after myocardial infarction. Plasma AA level was inversely correlated with fasting blood glucose. Conclusions: AA protects against diabetic ischemic myocardial damage by promoting mitochondrial autophagy and renewal, which is related to AA derived PGI2 signaling. AA may represent a new strategy to treat diabetic myocardial ischemic injury. Highlights: Diabetic myocardial ischemic injury causes plasma AA reduction. AA supplementation protects cardiomyocytes against diabetic ischemic injury in vitro and in vivo. The effect of AA is attributable to PINK-parkin mediated mitophagy, enhanced mitochondrial turnover and decreased cell apoptosis, which is PGI2 dependent. AA might be beneficial for diabetic patients at risk of ischemic injury. [ABSTRACT FROM AUTHOR]

Background: The outcomes of percutaneous coronary intervention (PCI) in diabetic patients are still suboptimal, and it is unclear if diabetic patients might derive a benefit from the use of drug-coated balloons. Aims: To evaluate the impact of diabetes mellitus on the outcomes of patients undergoing PCI with sirolimus-coated balloon (SCB) MagicTouch (Concept Medical, India). Methods: We conducted a subgroup analysis of the prospective, multicenter, investigator-initiated EASTBOURNE registry, evaluating the performance of MagicTouch SCB in patients with and without diabetes. The study primary endpoint was target lesion revascularization (TLR) at 12-month follow-up. Secondary clinical endpoints were major adverse clinical events (MACE), death, myocardial infarction (MI), and BARC 2–5 bleedings. Results: Among 2,083 enrolled patients, a total of 864 suffered from diabetes (41.5%). Patients with diabetes had a numerically higher occurrence of TLR (6.5% vs. 4.7% HR 1.38, 95%CI 0.91–2.08), all-cause death (3.8% vs. 2.6%, HR 1.81, 95%CI 0.95–3.46), and MACE (12.2% vs. 8.9%; HR 1.26 95%CI 0.92–1.74). The incidence of spontaneous MI was significantly higher among diabetic patients (3.4% vs. 1.5%, HR 2.15 95%CI 1.09–4.25); bleeding events did not significantly differ. The overall incidence of TLR was higher among in-stent restenosis (ISR) as compared to de-novo coronary lesions, irrespectively from diabetes status. Conclusions: In the EASTBOURNE DIABETES registry, diabetic patients treated with the MagicTouch SCB did not have a significant increase in TLR when compared to non-diabetic patients; moreover, diabetic status did not affect the study device performance in terms of TLR, in both de-novo lesions and ISR. [ABSTRACT FROM AUTHOR]

Background: Underweight imposes significant burden on cardiovascular outcomes in patients with diabetes mellitus. However, less is known about the impact of serial change in body weight status measured as body mass index (BMI) on the risk of sudden cardiac arrest (SCA). This study investigated the association between SCA and temporal change in BMI among patients with diabetes mellitus. Methods: Based on Korean National Health Insurance Service database, participants with diabetes mellitus who underwent health examination between 2009 and 2012 and had prior health examination data (four years ago, 2005–2008) were retrospectively analyzed. BMI was measured at baseline (2005–2008) and 4-year follow-up health examination (2009–2012). Patients were classified in four groups according to the body weight status and its temporal change: sustained non-underweight, sustained underweight, previous underweight, and newly developed underweight. Primary outcome was defined as occurrence of SCA. Results: A total of 1,355,746 patients with diabetes mellitus were included for analysis, and SCA occurred in 12,554 cases. SCA was most common in newly developed underweight (incidence rate = 4.45 per 1,000 person-years), followed by sustained underweight (incidence rate = 3.90), previous underweight (incidence rate = 3.03), and sustained non-underweight (incidence rate = 1.34). Adjustment of covariates resulted highest risk of SCA in sustained underweight (adjusted hazard ratio = 2.60, 95% confidence interval [2.25–3.00], sustained non-underweight as a reference), followed by newly developed underweight (2.42, [2.15–2.74]), and previous underweight (2.12, [1.77–2.53]). Conclusions: In diabetes mellitus, sustained underweight as well as decrease in body weight during 4-year follow-up imposes substantial risk on SCA. Recovery from underweight over time had relatively lower, but yet increased risk of SCA. Both underweight and dynamic decrease in BMI can be associated with increased risk of SCA. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) is associated with a worse prognosis in patients with heart failure. Our aim was to analyze the clinical and imaging features of patients with DM and their association with outcomes in comparison to nondiabetic patients in a cohort of patients with nonischemic dilated cardiomyopathy (DCM). Methods: This is a prospective cohort study of patients with DCM evaluated in a tertiary care center from 2018 to 2021. Transthoracic echocardiography and cardiac magnetic resonance findings were assessed. A high-risk late gadolinium enhancement (LGE) pattern was defined as epicardial, transmural, or septal plus free-wall. The primary outcome was a composite of heart failure hospitalizations and all-cause mortality. Multivariable analyses were performed to evaluate the impact of DM on outcomes. Results: We studied 192 patients, of which 51 (26.6%) had DM. The median left ventricular ejection fraction was 30%, and 106 (55.2%) had LGE. No significant differences were found in systolic function parameters between patients with and without DM. E/e values were higher (15 vs. 11.9, p = 0.025), and both LGE (68.6% vs. 50.4%; p = 0.025) and a high-risk LGE pattern (31.4% vs. 18.5%; p = 0.047) were more frequently found in patients with DM. The primary outcome occurred more frequently in diabetic patients (41.2% vs. 23.6%, p = 0.017). DM was an independent predictor of outcomes (OR 2.01; p = 0.049) and of LGE presence (OR 2.15; p = 0.048) in the multivariable analysis. Patients with both DM and LGE had the highest risk of events (HR 3.1; p = 0.003). Conclusion: DM is related to a higher presence of LGE in DCM patients and is an independent predictor of outcomes. Patients with DM and LGE had a threefold risk of events. A multimodality imaging approach allows better risk stratification of these patients and may influence therapeutic options. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) increases the risk of coronary heart disease (CHD) by 2–4 fold, and is associated with endothelial dysfunction, dyslipidaemia, insulin resistance, and chronic hyperglycaemia. The aim of this investigation was to assess, by a multimarker mass spectrometry approach, the predictive role of circulating proteins as biomarkers of cardiovascular damage progression associated with diabetes mellitus. Methods: The study considered 34 patients with both T2DM and CHD, 31 patients with T2DM and without CHD, and 30 patients without diabetes with a diagnosis of CHD. Plasma samples of subjects were analysed through a multiplexed targeted liquid chromatography mass spectrometry (LC-MS)-based assay, namely Multiple Reaction Monitoring (MRM), allowing the simultaneous detection of peptides derived from a protein of interest. Gene Ontology (GO) Analysis was employed to identify enriched GO terms in the biological process, molecular function, or cellular component categories. Non-parametric multivariate methods were used to classify samples from patients and evaluate the relevance of the analysed proteins' panel. Results: A total of 81 proteins were successfully quantified in the human plasma samples. Gene Ontology analysis assessed terms related to blood microparticles, extracellular exosomes and collagen-containing extracellular matrix. Preliminary evaluation using analysis of variance (ANOVA) of the differences in the proteomic profile among patient groups identified 13 out of the 81 proteins as significantly different. Multivariate analysis, including cluster analysis and principal component analysis, identified relevant grouping of the 13 proteins. The first main cluster comprises apolipoprotein C-III, apolipoprotein C-II, apolipoprotein A-IV, retinol-binding protein 4, lysozyme C and cystatin-C; the second one includes, albeit with sub-grouping, alpha 2 macroglobulin, afamin, kininogen 1, vitronectin, vitamin K-dependent protein S, complement factor B and mannan-binding lectin serine protease 2. Receiver operating characteristic (ROC) curves obtained with the 13 selected proteins using a nominal logistic regression indicated a significant overall distinction (p < 0.001) among the three groups of subjects, with area under the ROC curve (AUC) ranging 0.91–0.97, and sensitivity and specificity ranging from 85 to 100%. Conclusions: Targeted mass spectrometry approach indicated 13 multiple circulating proteins as possible biomarkers of cardiovascular damage progression associated with T2DM, with excellent classification results in terms of sensitivity and specificity. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia is frequently found in patients with heart failure with reduced ejection fraction (HFrEF) and is associated with reduced exercise capacity, poor quality of life and adverse outcomes. Recent evidence suggests that axial thoracic skeletal muscle size could be used as a surrogate to assess sarcopenia in HFrEF. Since diabetes mellitus (DM) is one of the most common comorbidities with HFrEF, we aimed to explore the potential association of axial thoracic skeletal muscle size with left ventricular (LV) remodeling and determine its prognostic significance in this condition. Methods: A total of 243 diabetes patients with HFrEF were included in this study. Bilateral axial thoracic skeletal muscle size was obtained using cardiac MRI. Patients were stratified by the tertiles of axial thoracic skeletal muscle index (SMI). LV structural and functional indices, as well as amino-terminal pro-B-type natriuretic peptide (NT-proBNP), were measured. The determinants of elevated NT-proBNP were assessed using linear regression analysis. The associations between thoracic SMI and clinical outcomes were assessed using a multivariable Cox proportional hazards model. Results: Patients in the lowest tertile of thoracic SMI displayed a deterioration in LV systolic strain in three components, together with an increase in LV mass and a heavier burden of myocardial fibrosis (all P < 0.05). Moreover, thoracic SMI (β = -0.25; P < 0.001), rather than body mass index (β = -0.04; P = 0.55), was independently associated with the level of NT-proBNP. The median follow-up duration was 33.6 months (IQR, 20.4–52.8 months). Patients with adverse outcomes showed a lower thoracic SMI (40.1 [34.3, 47.9] cm2/m2 vs. 45.3 [37.3, 55.0] cm2/m2; P < 0.05) but a similar BMI (P = 0.76) compared with those without adverse outcomes. A higher thoracic SMI indicated a lower risk of adverse outcomes (hazard ratio: 0.96; 95% confidence interval: 0.92–0.99; P = 0.01). Conclusions: With respect to diabetes patients with HFrEF, thoracic SMI is a novel alternative for evaluating muscle wasting in sarcopenia that can be obtained by a readily available routine cardiac MRI protocol. A reduction in thoracic skeletal muscle size predicts poor outcomes in the context of DM with HFrEF. [ABSTRACT FROM AUTHOR]

Background: It is unknown whether high hemoglobin A1c (HbA1c) is associated with increases in the risk of cardiovascular disease among individuals with elevated genetic susceptibility. We aimed to investigate the association between HbA1c and atrial fibrillation (AF), coronary artery disease (CAD), and ischemic stroke according to the polygenic risk score (PRS). Methods: The UK Biobank cohort included 502,442 participants aged 40–70 years who were recruited from 22 assessment centers across the United Kingdom from 2006 to 2010. This study included 305,605 unrelated individuals with available PRS and assessed new-onset AF, CAD, and ischemic stroke. The participants were divided into tertiles based on the validated PRS for each outcome. Within each PRS tertiles, the risks of incident events associated with HbA1c levels were investigated and compared with HbA1c < 5.7% and low PRS. Data were analyzed from November 2022 to May 2023. Results: Of 305,605 individuals, 161,605 (52.9%) were female, and the mean (SD) age was 56.6 (8.1) years. During a median follow-up of 11.9 (interquartile range 11.1–12.6) years, the incidences of AF, CAD, and ischemic stroke were 4.6, 2.9 and 1.1 per 100 person-years, respectively. Compared to individuals with HbA1c < 5.7% and low PRS, individuals with HbA1c ≥ 6.5% and high PRS had a 2.67-times higher risk for AF (hazard ratio [HR], 2.67; 95% confidence interval (CI), 2.43–2.94), 5.71-times higher risk for CAD (HR, 5.71; 95% CI, 5.14–6.33) and 2.94-times higher risk for ischemic stroke (HR, 2.94; 95% CI, 2.47–3.50). In the restricted cubic spline models, while a U-shaped trend was observed between HbA1c and the risk of AF, dose-dependent increases were observed between HbA1c and the risk of CAD and ischemic stroke regardless PRS tertile. Conclusions: Our results suggest that the nature of the dose-dependent relationship between HbA1c levels and cardiovascular disease in individuals with different PRS is outcome-specific. This adds to the evidence that PRS may play a role together with glycemic status in the development of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Data are limited on the association of metabolic dysfunction-associated fatty liver disease (MAFLD) with systemic atherosclerosis. This study aimed to examine the relationship between MAFLD and the extent of atherosclerotic plaques and stenosis, and presence of polyvascular disease (PolyVD). Methods: In this cross-sectional study, MAFLD was diagnosed based on the presence of metabolic dysfunction (MD) and fatty liver disease (FLD). MAFLD was divided into three subtypes: MAFLD with diabetes mellitus (DM), MAFLD with overweight or obesity (OW), as well as MAFLD with lean/normal weight and at least two metabolic abnormalities. Atherosclerosis was evaluated, with vascular magnetic resonance imaging for intracranial and extracranial arteries, thoracoabdominal computed tomography angiography for coronary, subclavian, aorta, renal, iliofemoral arteries, and ankle-brachial index for peripheral arteries. The extent of plaques and stenosis was defined according to the number of these eight vascular sites affected. PolyVD was defined as the presence of stenosis in at least two vascular sites. Results: This study included 3047 participants, with the mean age of 61.2 ± 6.7 years and 46.6% of male (n = 1420). After adjusting for potential confounders, MAFLD was associated with higher extent of plaques (cOR, 2.14, 95% CI 1.85–2.48) and stenosis (cOR, 1.47, 95% CI 1.26–1.71), and higher odds of presence of PolyVD (OR, 1.55, 95% CI 1.24–1.94) as compared with Non-MAFLD. In addition, DM-MAFLD and OW-MAFLD were associated with the extent of atherosclerotic plaques and stenosis, and presence of PolyVD (All P < 0.05). However, lean-MAFLD was only associated with the extent of atherosclerotic plaques (cOR, 1.63, 95% CI 1.14–2.34). As one component of MAFLD, FLD per se was associated with the extent of plaques and stenosis in participants with MAFLD. Furthermore, FLD interacted with MD to increase the odds of presence of systemic atherosclerosis (P for interaction ≤ 0.055). Conclusions: MAFLD and its subtypes of DM-MAFLD and OW-MAFLD were associated with the extent of atherosclerotic plaques and stenosis, and presence of PolyVD. This study implicated that FLD might be a potential target of intervention for reducing the deleterious effects of MAFLD on systemic atherosclerosis. [ABSTRACT FROM AUTHOR]

Background: The effects of diabetes on the cardiac and aortic structure and function remain unclear. Detecting and intervening these variations early is crucial for the prevention and management of complications. Cardiovascular magnetic resonance imaging-derived traits are established endophenotypes and serve as precise, early-detection, noninvasive clinical risk biomarkers. We conducted a Mendelian randomization (MR) study to examine the association between two types of diabetes, four glycemic traits, and preclinical endophenotypes of cardiac and aortic structure and function. Methods: Independent genetic variants significantly associated with type 1 diabetes, type 2 diabetes, fasting insulin (FIns), fasting glucose (FGlu), 2 h-glucose post-challenge (2hGlu), and glycated hemoglobin (HbA1c) were selected as instrumental variables. The 96 cardiovascular magnetic resonance imaging traits came from six independent genome-wide association studies. These traits serve as preclinical endophenotypes and offer an early indication of the structure and function of the four cardiac chambers and two aortic sections. The primary analysis was performed using MR with the inverse-variance weighted method. Confirmation was achieved through Steiger filtering and testing to determine the causal direction. Sensitivity analyses were conducted using the weighted median, MR-Egger, and MR-PRESSO methods. Additionally, multivariable MR was used to adjust for potential effects associated with body mass index. Results: Genetic susceptibility to type 1 diabetes was associated with increased ascending aortic distensibility. Conversely, type 2 diabetes showed a correlation with a reduced diameter and areas of the ascending aorta, as well as decreased distensibility of the descending aorta. Genetically predicted higher levels of FGlu and HbA1c were correlated with a decrease in diameter and areas of the ascending aorta. Furthermore, higher 2hGlu levels predominantly showed association with a reduced diameter of both the ascending and descending aorta. Higher FIns levels corresponded to increased regional myocardial-wall thicknesses at end-diastole, global myocardial-wall thickness at end-diastole, and regional peak circumferential strain of the left ventricle. Conclusions: This study provides evidence that diabetes and glycemic traits have a causal relationship with cardiac and aortic structural and functional remodeling, highlighting the importance of intensive glucose-lowering for primary prevention of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Background: High-sensitivity C-reaction protein (hsCRP), a biomarker of residual inflammatory risk, has been demonstrated with poor cardiovascular outcomes. We aimed to investigate the prognostic value of hsCRP in patients undergoing percutaneous coronary intervention (PCI) with or without diabetes mellitus (DM). Methods: In this large-scale, prospective cohort study, we enrolled 8050 consecutive patients who underwent PCI for coronary artery stenosis. All subjects were stratified as high hsCRP (> 3 mg/L) and low hsCRP (≤ 3 mg/L) and were divided into four groups (hsCRP-L/non-DM, hsCRP-H/non-DM, hsCRP-L/DM, hsCRP-H/DM). The primary endpoint of the study was major adverse cardiovascular events (MACEs), including all-cause mortality, myocardial infarction, stroke, and unplanned vessel revascularization, evaluated at a 3 year follow-up. Results: After 35.7 months (interquartile range: 33.2 to 36.0 months) of median follow-up time, 674 patients suffered from MACEs. We found elevated hsCRP was highly associated with an increased risk of MACEs in both diabetic (hazard ratio [HR] = 1.68, 95% confidence interval CI 1.29–2.19, P < 0.001) and non-diabetic patients (HR = 1.31, 95% CI: 1.05–1.62, P = 0.007) after adjustment for other confounding factors. Kaplan-Meier survival analysis showed the highest incidence of MACEs in hsCRP-H/DM (P < 0.001). In addition, the results of the restricted cubic spline analysis suggested a positive linear relationship between hsCRP and MACEs. Conclusion: Elevated hsCRP is an independent risk factors of MACEs in patients undergoing PCI irrespective of glycemic metabolism status. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) is the most common metabolic disease worldwide and a major risk factor for adverse cardiovascular events, while the additive effects of DM on left ventricular (LV) deformation in the restrictive cardiomyopathy (RCM) cohort remain unclear. Accordingly, we aimed to investigate the additive effects of DM on LV deformation in patients with RCM. Materials and methods: One hundred thirty-six RCM patients without DM [RCM(DM−)], 46 with DM [RCM (DM+)], and 66 age- and sex-matched control subjects who underwent cardiac magnetic resonance (CMR) scanning were included. LV function, late gadolinium enhancement (LGE) type, and LV global peak strains (including radial, circumferential, and longitudinal directions) were measured. The determinant of reduced LV global myocardial strain for all RCM patients was assessed using multivariable linear regression analyses. The receiver operating characteristic curve (ROC) was performed to illustrate the relationship between DM and decreased LV deformation. Results: Compared with the control group, RCM (DM−) and RCM(DM+) patients presented increased LV end-diastolic index and end-systolic volume index and decreased LV ejection fraction. LV GPS in all three directions and longitudinal PDSR progressively declined from the control group to the RCM(DM−) group to the RCM(DM+) group (all p < 0.05). DM was an independent determinant of impaired LV GPS in the radial, circumferential, and longitudinal directions and longitudinal PDSR (β = − 0.217, 0.176, 0.253, and − 0.263, all p < 0.05) in RCM patients. The multiparameter combination, including DM, showed an AUC of 0.81(95% CI 0.75–0.87) to predict decreased LV GLPS and an AUC of 0.69 (95% CI 0.62–0.76) to predict decreased LV longitudinal PDSR. Conclusions: DM may have an additive deleterious effect on LV dysfunction in patients with RCM, especially diastolic dysfunction in RCM patients, indicating the importance of early identification and initiation of treatment of DM in patients with RCM. [ABSTRACT FROM AUTHOR]

Diabetes microangiopathy, a hallmark complication of diabetes, is characterised by structural and functional abnormalities within the intricate network of microvessels beyond well-known and documented target organs, i.e., the retina, kidney, and peripheral nerves. Indeed, an intact microvascular bed is crucial for preserving each organ's specific functions and achieving physiological balance to meet their respective metabolic demands. Therefore, diabetes-related microvascular dysfunction leads to widespread multiorgan consequences in still-overlooked non-traditional target organs such as the brain, the lung, the bone tissue, the skin, the arterial wall, the heart, or the musculoskeletal system. All these organs are vulnerable to the physiopathological mechanisms that cause microvascular damage in diabetes (i.e., hyperglycaemia-induced oxidative stress, inflammation, and endothelial dysfunction) and collectively contribute to abnormalities in the microvessels' structure and function, compromising blood flow and tissue perfusion. However, the microcirculatory networks differ between organs due to variations in haemodynamic, vascular architecture, and affected cells, resulting in a spectrum of clinical presentations. The aim of this review is to focus on the multifaceted nature of microvascular impairment in diabetes through available evidence of specific consequences in often overlooked organs. A better understanding of diabetes microangiopathy in non-target organs provides a broader perspective on the systemic nature of the disease, underscoring the importance of recognising the comprehensive range of complications beyond the classic target sites. [ABSTRACT FROM AUTHOR]

Purpose: The study was designed to assess the effect of co-occurrence of diabetes mellitus (DM) and hypertension on the deterioration of left atrioventricular coupling index (LACI) and left atrial (LA) function in comparison to individuals suffering from DM only. Methods: From December 2015 to June 2022, we consecutively recruited patients with clinically diagnosed DM who underwent cardiac magnetic resonance (CMR) at our hospital. The study comprised a total of 176 patients with DM, who were divided into two groups based on their blood pressure status: 103 with hypertension (DM + HP) and 73 without hypertension (DM-HP). LA reservoir function (reservoir strain (εs), total LA ejection fraction (LAEF)), conduit function (conduit strain (εe), passive LAEF), booster-pump function (booster strain (εa) and active LAEF), LA volume index (LAVI), LV global longitudinal strain (LVGLS), and LACI were evaluated and compared between the two groups. Results: After adjusting for age, sex, body surface area (BSA), and history of current smoking, total LAEF (61.16 ± 14.04 vs. 56.05 ± 12.72, p = 0.013) and active LAEF (43.98 ± 14.33 vs. 38.72 ± 13.51, p = 0.017) were lower, while passive LAEF (33.22 ± 14.11 vs. 31.28 ± 15.01, p = 0.807) remained unchanged in the DM + HP group compared to the DM-HP group. The DM + HP group had decreased εs (41.27 ± 18.89 vs. 33.41 ± 13.94, p = 0.006), εe (23.69 ± 12.96 vs. 18.90 ± 9.90, p = 0.037), εa (17.83 ± 8.09 vs. 14.93 ± 6.63, p = 0.019), and increased LACI (17.40±10.28 vs. 22.72±15.01, p = 0.049) when compared to the DM-HP group. In patients with DM, multivariate analysis revealed significant independent associations between LV GLS and εs (β=-1.286, p < 0.001), εe (β=-0.919, p < 0.001), and εa (β=-0.324, p = 0.036). However, there was no significant association observed between LV GLS and LACI (β=-0.003, p = 0.075). Additionally, hypertension was found to independently contribute to decreased εa (β=-2.508, p = 0.027) and increased LACI in individuals with DM (β = 0.05, p = 0.011). Conclusions: In DM patients, LV GLS showed a significant association with LA phasic strain. Hypertension was found to exacerbate the decline in LA booster strain and increase LACI in DM patients, indicating potential atrioventricular coupling index alterations. [ABSTRACT FROM AUTHOR]

Background: Coronary bifurcation lesion, as a complex coronary lesion, is associated with higher risk of long-term poor prognosis than non-bifurcation lesions. The triglyceride-glucose (TyG) index has been shown to predict cardiovascular (CV) events in patients with coronary artery disease (CAD). However, the prognostic value of the TyG index in patients with bifurcation lesions who are at high risk of CV events remains undetermined. Therefore, this study aimed to investigate the association between the TyG index and CV events in patients with bifurcation lesions. Methods: A total of 4530 consecutive patients with angiography-proven CAD and bifurcation lesions were included in this study from January 2017 to December 2018. The TyG index was calculated as Ln [fasting triglyceride (mg/dL) × fasting plasma glucose (mg/dL)/2]. Patients were assigned into 3 groups according to TyG tertiles (T) (T1: <8.633; T2: 8.633–9.096 and T3: ≥9.096). The primary endpoint was CV events, including CV death, nonfatal myocardial infarction and nonfatal stroke at 3-year follow-up. Restricted cubic spline (RCS) analysis, Kaplan-Meier curves and Cox proportional hazard models were used to investigate the associations between the TyG index and study endpoints. Results: During a median follow-up of 3.1 years, 141 (3.1%) CV events occurred. RCS analysis demonstrated a linear relationship between the TyG index and events after adjusting for age and male sex (non-linear P = 0.262). After multivariable adjustments, elevated TyG index (both T2 and T3) was significantly associated with the risk of CV events (hazard ratio [HR], 1.68; 95% confidence interval [CI],1.06–2.65; HR, 2.10; 95%CI, 1.28–3.47, respectively). When study patients were further stratified according to glycemic status, higher TyG index was associated with significantly higher risk of CV events in diabetic patients after adjusting for confounding factors (T3 vs. T1; HR, 2.68; 95%CI, 1.17–6.11). In addition, subgroup analysis revealed consistent associations of the TyG index with 3-year CV events across various subgroups. Furthermore, adding the TyG index to the original model significantly improved the predictive performance. Conclusions: High TyG index was associated with CV events in patients with bifurcation lesions, suggesting the TyG index could help in risk stratification and prognosis in this population. [ABSTRACT FROM AUTHOR]

Background and objectives: Evidence on the associations between baseline stromal cell-derived factor (SDF)-1 and clinical outcomes in acute ischemic stroke patients is lacking. The present study aimed to examine the relationship between plasma SDF-1 levels and clinical outcomes based on a large multicenter study of the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). Methods: Secondary analysis was conducted among 3,255 participants from the CATIS trial with a baseline measurement of plasma SDF-1 levels. We evaluated the associations between plasma SDF-1 levels and one-year recurrent stroke, cardiovascular events, and all-cause mortality using Cox regression models. We further investigated the prognostic effect of SDF-1 on clinical outcomes in patients with different characteristics. Results: Higher plasma SDF-1 levels were not associated with recurrent stroke, cardiovascular events, and all-cause mortality at one-year after ischemic stroke (all P trend ≥ 0.05). There were significant interactions between plasma SDF-1 levels and history of diabetes mellitus on recurrent stroke (P = 0.005), cardiovascular events (P = 0.007) and all-cause mortality (P = 0.04) at one year. In patients with diabetes mellitus, plasma SDF-1 was significantly associated with an increased risk of recurrent stroke and cardiovascular events after adjustment for confounders. For example, 1-SD higher log–SDF-1 was associated with a hazard ratio (95% confidence interval) of 1.65 (1.18–2.32) for recurrent stroke and 1.47 (1.08–1.99) for the cardiovascular events, but not all-cause mortality 1.36 (0.96–1.93) at one year. However, there were no associations between plasma SDF-1 and clinical outcomes in patients without diabetes mellitus (all P > 0.05). The addition of plasma SDF-1 to the conventional risk factors model significantly improved the risk prediction of all outcomes. Similarly, findings between elevated SDF-1 levels and two-year outcomes were found only in patients with diabetes mellitus. Conclusions: Elevated plasma SDF-1 was significantly associated with an increased risk of recurrent stroke and cardiovascular events only in ischemic patients with diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background: This study aimed to reveal the prevalence of sodium-glucose co-transporter 2 (SGLT2) inhibitor treatment and its association with restenosis risk in patients with diabetes mellitus undergoing endovascular therapy for symptomatic peripheral artery disease. Methods: We used the database of a multicenter prospective study registering patients with symptomatic peripheral artery disease undergoing femoropopliteal drug-coated balloon treatment in Japan. The current analysis included 1058 patients with diabetes mellitus free from end-stage renal disease. The association of clinical characteristics with SGLT2 inhibitor use was investigated using the logistic regression model. The propensity score matching was adopted to compare the primary patency, i.e., freedom from restenosis, after endovascular therapy between patients treated with and without a SGLT2 inhibitor. Results: The proportion of SGLT2 inhibitor treatment at revascularization was 14.8% (95% confidence interval, 12.8–17.1%). Younger age, increased body mass index, and increased hemoglobin A1c levels were independently associated with SGLT2 inhibitor use (all P < 0.05). The proportion of SGLT2 inhibitor reached 38.2% (95% confidence interval, 25.4–52.3%) in patients with the three associated factors. The propensity score-matching analysis demonstrated that primary patency was not different between patients treated with a SGLT2 inhibitor and those without it (72.0% [95% confidence interval, 64.1–80.9%] versus 67.8% [62.7–73.3%] at 2 years; P = 0.45). Conclusions: SGLT2 inhibitors were not rarely used in patients with diabetes mellitus who underwent femoropopliteal endovascular therapy using a drug coated balloon for symptomatic peripheral artery disease in real-world settings. SGLT2 inhibitor treatment was not associated with an increased risk of restenosis. [ABSTRACT FROM AUTHOR]

Peripheral artery disease (PAD) is a major health problem with increased cardiovascular mortality, morbidity and disabling critical limb threatening ischemia (CLTI) and amputation. Diabetes mellitus (DM) and cigarette smoke are the main risk factors for the development of PAD. Although diabetes related PAD shows an accelerated course with worse outcome regarding complications, mortality and amputations compared with non-diabetic patients, current medical treatment does not make this distinction and includes standard antiplatelet and lipid lowering drugs for all patients with PAD. In this review we discuss the pathophysiologic mechanisms of PAD, with focus on differences in thrombo-inflammatory processes between diabetes-related and smoking-related PAD, and hypothesize on possible mechanisms for the progressive course of PAD in DM. Furthermore, we comment on current medical treatment and speculate on alternative medical drug options for patients with PAD and DM. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) is associated with thrombogenicity, clinically manifested with atherothrombotic events after percutaneous cutaneous intervention (PCI). This study aimed to investigate association between DM status and platelet reactivity, and their prognostic implication in PCI-treated patients. Methods: The Platelet function and genoType-Related long-term Prognosis-Platelet Function Test (PTRG-PFT) cohort was established to determine the linkage of platelet function test (PFT) with long-term prognosis during dual antiplatelet therapy including clopidogrel in patients treated with drug-eluting stent (DES). We assessed platelet reactivity using VerifyNow and 'high platelet reactivity (HPR)' was defined as ≥ 252 P2Y12 reaction unit (PRU). Major adverse cardiac and cerebrovascular event (MACCE) was a composite of all-cause death, myocardial infarction, stent thrombosis or stroke. Results: Between July 2003 and Aug 2018, DES-treated patients with available PFT were enrolled (n = 11,714). Diabetic patients demonstrated significant higher levels of platelet reactivity (DM vs. non-DM: 225.7 ± 77.5 vs. 213.6 ± 79.1 PRU, P < 0.001) and greater prevalence of HPR compared to non-diabetic patients (38.1% vs. 32.0%, P < 0.001). PRU level and prevalence of HPR were significantly associated with insulin requirement and HbA1c level, as well as diabetic status. DM status and HPR phenotype had a similar prognostic implication, which showed the synergistic clinical impact on MACCE. Association between PRU level and MACCE occurrence seemed higher in diabetic vs. non-diabetic patients. In non-DM patients, HPR phenotype did not significantly increase the risk of MACCE (adjusted hazard ratio [HRadj]: 1.073; 95% confidence interval [CI]: 0.869–1.325; P = 0.511), whereas HPR was an independent determinant for MACCE occurrence among diabetic patients (HRadj: 1.507; 95% CI: 1.193–1.902; P < 0.001). Conclusion: The levels of on-clopidogrel platelet reactivity are determined by diabetic status and the severity of DM. In addition, HPR phenotype significantly increases the risk of MACCE only in diabetic patients. Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT04734028. [ABSTRACT FROM AUTHOR]

Background: We examined ethnic differences in the association between age at diagnosis of diabetes and the risk of cardiovascular complications. Methods: We conducted a population-based cohort study in Ontario, Canada among individuals with diabetes and matched individuals without diabetes (2002-18). We fit Cox proportional hazards models to determine the associations of age at diagnosis and ethnicity (Chinese, South Asian, general population) with cardiovascular complications. We tested for an interaction between age at diagnosis and ethnicity. Results: There were 453,433 individuals with diabetes (49.7% women) and 453,433 matches. There was a significant interaction between age at diagnosis and ethnicity (P < 0.0001). Young-onset diabetes (age at diagnosis < 40) was associated with higher cardiovascular risk [hazard ratios: Chinese 4.25 (3.05–5.91), South Asian: 3.82 (3.19–4.57), General: 3.46 (3.26–3.66)] than usual-onset diabetes [age at diagnosis ≥ 40 years; Chinese: 2.22 (2.04–2.66), South Asian: 2.43 (2.22–2.66), General: 1.83 (1.81–1.86)] versus ethnicity-matched individuals. Among those with young-onset diabetes, Chinese ethnicity was associated with lower overall cardiovascular [0.44 (0.32–0.61)] but similar stroke risks versus the general population; while South Asian ethnicity was associated with lower overall cardiovascular [0.75 (0.64–0.89)] but similar coronary artery disease risks versus the general population. In usual-onset diabetes, Chinese ethnicity was associated with lower cardiovascular risk [0.44 (0.42–0.46)], while South Asian ethnicity was associated with lower cardiovascular [0.90 (0.86–0.95)] and higher coronary artery disease [1.08 (1.01–1.15)] risks versus the general population. Conclusions: There are important ethnic differences in the association between age at diagnosis and risk of cardiovascular complications. [ABSTRACT FROM AUTHOR]

Background: Today, diabetes mellitus (DM) has become a worldwide concern. DM is a major risk factor for the development of cardiovascular diseases (CVD). Eligible patients with CVD are treated invasively by percutaneous coronary intervention (PCI) whereby a stent is implanted inside the coronary vessel with the particular lesion to allow sufficient blood flow. Newer scientific research have shown that even though associated with a lower rate of re-stenosis, first-generation drug eluting stents (DES) were associated with a higher rate of late stent thrombosis. Recently, newer stents, namely biodegradable polymer DES (BP-DES) have been developed to overcome the safety issues of earlier generation DES. In this analysis we aimed to systematically compare the long term (≥ 12 months) adverse cardiovascular outcomes observed in DM versus non-DM patients who were implanted with BP-DES. Methods: Cochrane central, MEDLINE (Subset PubMed), EMBASE, Web of Science, http://www.ClinicalTrials.gov and Google scholar were searched for relevant publications involving BP-DES in patients with DM versus non-DM and their associated adverse cardiovascular outcomes. The mean follow-up time period ranged from 12 to 120 months. Data analysis was carried out with the latest version of the RevMan software (version 5.4). Based on the Mantel-Haenszel test, risk ratios (RR) with 95% confidence intervals (CI) were calculated and used to represent the results following analysis. Results: Seven (7) studies with a total number of 10,246 participants were included in this analysis. Stents which were implanted during PCI were BP-DES. Participants were enrolled from the year 2006 to 2013. Our current results showed that in patients who were implanted with BP-DES, the risks of major adverse cardiac events (RR: 1.30, 95% CI: 1.18–1.43; P = 0.00001), myocardial infarction (RR: 1.48, 95% CI: 1.14–1.93; P = 0.003), all-cause mortality (RR: 1.70, 95% CI: 1.29–2.23; P = 0.0002), cardiac death (RR: 1.93, 95% CI: 1.28–2.93; P = 0.002), target vessel revascularization (RR: 1.35, 95% CI: 1.03–1.77; P = 0.03), target lesion revascularization (RR: 1.28, 95% CI: 1.07–1.54; P = 0.007) and target lesion failure (RR: 1.79, 95% CI: 1.52–2.12; P = 0.00001) were significantly higher in the DM group. Definite and probable stent thrombosis (RR: 1.80, 95% CI: 1.28–2.55; P = 0.0009) were also significantly higher in the DM group. Conclusions: Diabetes mellitus was an independent risk factor associated with long term adverse cardiovascular outcomes following PCI with BP-DES. [ABSTRACT FROM AUTHOR]

Aims: As cardiovascular disease (CVD) is a leading cause of death for patients with diabetes mellitus (DM), we aimed to find important factors that predict cardiovascular (CV) risk using a machine learning (ML) approach. Methods and results: We performed a single center, observational study in a cohort of 238 DM patients (mean age ± SD 52.15 ± 17.27 years, 54% female) as a part of the Silesia Diabetes-Heart Project. Having gathered patients' medical history, demographic data, laboratory test results, results from the Michigan Neuropathy Screening Instrument (assessing diabetic peripheral neuropathy) and Ewing's battery examination (determining the presence of cardiovascular autonomic neuropathy), we managed use a ML approach to predict the occurrence of overt CVD on the basis of five most discriminative predictors with the area under the receiver operating characteristic curve of 0.86 (95% CI 0.80–0.91). Those features included the presence of past or current foot ulceration, age, the treatment with beta-blocker (BB) and angiotensin converting enzyme inhibitor (ACEi). On the basis of the aforementioned parameters, unsupervised clustering identified different CV risk groups. The highest CV risk was determined for the eldest patients treated in large extent with ACEi but not BB and having current foot ulceration, and for slightly younger individuals treated extensively with both above-mentioned drugs, with relatively small percentage of diabetic ulceration. Conclusions: Using a ML approach in a prospective cohort of patients with DM, we identified important factors that predicted CV risk. If a patient was treated with ACEi or BB, is older and has/had a foot ulcer, this strongly predicts that he/she is at high risk of having overt CVD. [ABSTRACT FROM AUTHOR]

Background: Diabetes and hyperlipidaemia are both risk factors for coronary artery disease, and both are associated with a high triglyceride-glucose index (TyG index). The TyG index has been presented as a marker of insulin resistance (IR). Its utility in predicting and detecting cardiovascular disease has been reported. However, few studies have found it to be a helpful marker of atherosclerosis in patients with symptomatic coronary artery disease (CAD). The purpose of this study was to demonstrate that the TyG index can serve as a valuable marker for predicting coronary and carotid atherosclerosis in symptomatic CAD patients, regardless of diabetes mellitus and hyperlipidaemia. Methods: This study included 1516 patients with symptomatic CAD who underwent both coronary artery angiography and carotid Doppler ultrasound in the Department of Cardiology at Tianjin Union Medical Center from January 2016 to December 2022. The TyG index was determined using the Ln formula. The population was further grouped and analysed according to the presence or absence of diabetes and hyperlipidaemia. The Gensini score and carotid intima-media thickness were calculated or measured, and the patients were divided into four groups according to TyG index quartile to examine the relationship between the TyG index and coronary or carotid artery lesions in symptomatic CAD patients. Results: In symptomatic CAD patients, the TyG index showed a significant positive correlation with both coronary lesions and carotid plaques. After adjusting for sex, age, smoking, BMI, hypertension, diabetes, and the use of antilipemic and antidiabetic agents, the risk of developing coronary lesions and carotid plaques increased across the baseline TyG index. Compared with the lowest quartile of the TyG index, the highest quartile (quartile 4) was associated with a greater incidence of coronary heart disease [OR = 2.55 (95% CI 1.61, 4.03)] and carotid atherosclerotic plaque [OR = 2.31 (95% CI 1.27, 4.20)] (P < 0.05). Furthermore, when compared to the fasting blood glucose (FBG) or triglyceride (TG) level, the TyG index had a greater area under the ROC curve for predicting coronary lesions and carotid plaques. The subgroup analysis demonstrated the TyG index to be an equally effective predictor of coronary and carotid artery disease, regardless of diabetes and hyperlipidaemia. Conclusion: The TyG index is a useful marker for predicting coronary and carotid atherosclerosis in patients with symptomatic CAD, regardless of diabetes mellitus and hyperlipidaemia. The TyG index is of higher value for the identification of both coronary and carotid atherosclerotic plaques than the FBG or TG level alone. [ABSTRACT FROM AUTHOR]

Background: High-sensitivity C-reaction protein (hsCRP), a biomarker of residual inflammatory risk, has been demonstrated with poor cardiovascular outcomes. We aimed to investigate the prognostic value of hsCRP in patients undergoing percutaneous coronary intervention (PCI) with or without diabetes mellitus (DM). Methods: In this large-scale, prospective cohort study, we enrolled 8050 consecutive patients who underwent PCI for coronary artery stenosis. All subjects were stratified as high hsCRP (> 3 mg/L) and low hsCRP (≤ 3 mg/L) and were divided into four groups (hsCRP-L/non-DM, hsCRP-H/non-DM, hsCRP-L/DM, hsCRP-H/DM). The primary endpoint of the study was major adverse cardiovascular events (MACEs), including all-cause mortality, myocardial infarction, stroke, and unplanned vessel revascularization, evaluated at a 3 year follow-up. Results: After 35.7 months (interquartile range: 33.2 to 36.0 months) of median follow-up time, 674 patients suffered from MACEs. We found elevated hsCRP was highly associated with an increased risk of MACEs in both diabetic (hazard ratio [HR] = 1.68, 95% confidence interval CI 1.29–2.19, P < 0.001) and non-diabetic patients (HR = 1.31, 95% CI: 1.05–1.62, P = 0.007) after adjustment for other confounding factors. Kaplan-Meier survival analysis showed the highest incidence of MACEs in hsCRP-H/DM (P < 0.001). In addition, the results of the restricted cubic spline analysis suggested a positive linear relationship between hsCRP and MACEs. Conclusion: Elevated hsCRP is an independent risk factors of MACEs in patients undergoing PCI irrespective of glycemic metabolism status. [ABSTRACT FROM AUTHOR]

Background: Albuminuria has been suggested as an atherosclerotic risk factor among the general population. However, whether this association will be amplified in patients with coronary artery disease (CAD) is unknown. It is also unknown whether diabetes mellitus confounds the association. We aim to analyse the prognosis of elevated urine albumin creatinine ratio (uACR) in the CAD population with or without type 2 diabetes mellitus (T2DM). Methods: This multi-center registry cohort study included 5,960 patients with CAD. Patients were divided into T2DM and non-T2DM group, and baseline uACR levels were assessed on three grades (low: uACR < 10 mg/g, middle: 10 mg/g ≤ uACR < 30 mg/g, and high: uACR ≥ 30 mg/g). The study endpoints were cardiovascular mortality and all-cause mortality. Results: During the median follow-up of 2.2 [1.2–3.1] years, 310 (5.2%) patients died, of which 236 (4.0%) patients died of cardiovascular disease. CAD patients with elevated uACR had a higher risk of cardiovascular mortality (middle: HR, 2.32; high: HR, 3.22) than those with low uACR, as well as all-cause mortality. Elevated uACR increased nearly 1.5-fold risk of cardiovascular mortality (middle: HR, 2.33; high: HR, 2.34) among patients without T2DM, and increased 1.5- fold to 3- fold risk of cardiovascular mortality in T2DM patients (middle: HR, 2.49; high: HR, 3.98). Conclusions: Even mildly increased uACR could increase the risk of cardiovascular mortality in patients with CAD, especially when combined with T2DM. [ABSTRACT FROM AUTHOR]

Background: Higher chemokine C-X-C motif ligand 5 (CXCL5) level was observed in type 2 diabetes mellitus (DM) patients; however, its role in diabetic vasculopathy was not clarified. This study aimed to explore the impacts and mechanistic insights of CXCL5 in neovasculogenesis and wound healing in DM. Methods: Endothelial progenitor cells (EPCs) and human aortic endothelial cells (HAECs) were used in vitro. Streptozotocin-induced diabetic mice and Leprdb/JNarl mice were used as type 1 and type 2 DM models. Moreover, CXCL5 knockout mice were used to generate diabetic mice. Hindlimb ischemia surgery, aortic ring assays, matrigel plug assay, and wound healing assay were conducted. Results: CXCL5 concentrations were increased in plasma and EPCs culture medium from type 2 DM patients. CXCL5 neutralizing antibody upregulated vascular endothelial growth factor (VEGF)/stromal cell-derived factor-1 (SDF-1) and promoted cell function in EPCs from type 2 DM patients and high glucose-treated EPCs from non-DM subjects as well as HAECs. CXCL5 directly up-regulated interleukin (IL)-1β/IL-6/tumor necrosis factor-α and down-regulated VEGF/SDF-1 via ERK/p65 activation through chemokine C-X-C motif receptor 2 (CXCR2). CXCL5 neutralizing antibody recovered the blood flow after hindlimb ischemia, increased circulating EPC number, and enhanced VEGF and SDF-1 expression in ischemic muscle. CXCL5 suppression promoted neovascularization and wound healing in different diabetic animal models. The above observation could also be seen in streptozotocin-induced CXCL5 knockout diabetic mice. Conclusions: CXCL5 suppression could improve neovascularization and wound healing through CXCR2 in DM. CXCL5 may be regarded as a potential therapeutic target for vascular complications of DM. [ABSTRACT FROM AUTHOR]

Background: We aimed to examine the association between smoking behavior change and risk of cardiovascular disease (CVD) incidence and mortality in patients with type 2 diabetes mellitus (T2DM). Methods: This study used nationwide data from the Korean National Health Insurance System and included 349,137 T2DM patients who smoked. Smoking behavior changes were defined with five groups: quitters, reducers I (≥ 50% reduction), reducers II (20–50% reduction), sustainers (± 20%), and increasers (≥ 20% increase) from the number of cigarettes/day at the baseline. Results: During a median follow-up of 5.1 years, 6,514 cases of myocardial infarction (MI) (1.9%), 7,837 cases of ischemic stroke (IS) (2.2%), and 14,932 deaths (4.3%) were identified. Quitters had a significantly decreased risk of MI (adjusted hazard ratio [aHR] 0.80, 95% CI 0.75–0.86) and IS (aHR 0.80, 95% CI 0.75–0.85) compared to sustainers, whereas reducers did not have a significant association with the risk of MI (aHR 1.03, 95% CI 0.94–1.13) and IS (aHR 1.00, 95% CI 0.92–1.08) in reducer I. Quitters also had a lower all-cause and CVD mortality than sustainers. Conclusions: Smoking cessation was associated with decreased CVD incidence, and all-cause and CVD mortality among T2DM patients. However, smoking reduction was not associated with decreased risks for these. [ABSTRACT FROM AUTHOR]

Background: Coronary computed tomography angiography (CCTA)-derived fractional flow reserve (CT-FFR) enables physiological assessment and risk stratification, which is of significance in diabetic patients with nonobstructive coronary artery disease (CAD). We aim to evaluate prognostic value of the global trans-lesional CT-FFR gradient (GΔCT-FFR), a novel metric, in patients with diabetes without flow-limiting stenosis. Methods: Patients with diabetes suspected of having CAD were prospectively enrolled. GΔCT-FFR was calculated as the sum of trans-lesional CT-FFR gradient in all epicardial vessels greater than 2 mm. Patients were stratified into low-gradient without flow-limiting group (CT-FFR > 0.75 and GΔCT-FFR < 0.20), high-gradient without flow-limiting group (CT-FFR > 0.75 and GΔCT-FFR ≥ 0.20), and flow-limiting group (CT-FFR ≤ 0.75). Discriminant ability for major adverse cardiovascular events (MACE) prediction was compared among 4 models [model 1: Framingham risk score; model 2: model 1 + Leiden score; model 3: model 2 + high-risk plaques (HRP); model 4: model 3 + GΔCT-FFR] to determine incremental prognostic value of GΔCT-FFR. Results: Of 1215 patients (60.1 ± 10.3 years, 53.7% male), 11.3% suffered from MACE after a median follow-up of 57.3 months. GΔCT-FFR (HR: 2.88, 95% CI 1.76–4.70, P < 0.001) remained independent risk factors of MACE in multivariable analysis. Compared with the low-gradient without flow-limiting group, the high-gradient without flow-limiting group (HR: 2.86, 95% CI 1.75–4.68, P < 0.001) was associated with higher risk of MACE. Among the 4 risk models, model 4, which included GΔCT-FFR, showed the highest C-statistics (C-statistics: 0.75, P = 0.002) as well as a significant net reclassification improvement (NRI) beyond model 3 (NRI: 0.605, P < 0.001). Conclusions: In diabetic patients with non-obstructive CAD, GΔCT-FFR was associated with clinical outcomes at 5 year follow-up, which illuminates a novel and feasible approach to improved risk stratification for a global hemodynamic assessment of coronary artery in diabetic patients. [ABSTRACT FROM AUTHOR]

Background: Higher chemokine C-X-C motif ligand 5 (CXCL5) level was observed in type 2 diabetes mellitus (DM) patients; however, its role in diabetic vasculopathy was not clarified. This study aimed to explore the impacts and mechanistic insights of CXCL5 in neovasculogenesis and wound healing in DM. Methods: Endothelial progenitor cells (EPCs) and human aortic endothelial cells (HAECs) were used in vitro. Streptozotocin-induced diabetic mice and Leprdb/JNarl mice were used as type 1 and type 2 DM models. Moreover, CXCL5 knockout mice were used to generate diabetic mice. Hindlimb ischemia surgery, aortic ring assays, matrigel plug assay, and wound healing assay were conducted. Results: CXCL5 concentrations were increased in plasma and EPCs culture medium from type 2 DM patients. CXCL5 neutralizing antibody upregulated vascular endothelial growth factor (VEGF)/stromal cell-derived factor-1 (SDF-1) and promoted cell function in EPCs from type 2 DM patients and high glucose-treated EPCs from non-DM subjects as well as HAECs. CXCL5 directly up-regulated interleukin (IL)-1β/IL-6/tumor necrosis factor-α and down-regulated VEGF/SDF-1 via ERK/p65 activation through chemokine C-X-C motif receptor 2 (CXCR2). CXCL5 neutralizing antibody recovered the blood flow after hindlimb ischemia, increased circulating EPC number, and enhanced VEGF and SDF-1 expression in ischemic muscle. CXCL5 suppression promoted neovascularization and wound healing in different diabetic animal models. The above observation could also be seen in streptozotocin-induced CXCL5 knockout diabetic mice. Conclusions: CXCL5 suppression could improve neovascularization and wound healing through CXCR2 in DM. CXCL5 may be regarded as a potential therapeutic target for vascular complications of DM. [ABSTRACT FROM AUTHOR]

Background: Coronary computed tomography angiography (CCTA)-derived fractional flow reserve (CT-FFR) enables physiological assessment and risk stratification, which is of significance in diabetic patients with nonobstructive coronary artery disease (CAD). We aim to evaluate prognostic value of the global trans-lesional CT-FFR gradient (GΔCT-FFR), a novel metric, in patients with diabetes without flow-limiting stenosis. Methods: Patients with diabetes suspected of having CAD were prospectively enrolled. GΔCT-FFR was calculated as the sum of trans-lesional CT-FFR gradient in all epicardial vessels greater than 2 mm. Patients were stratified into low-gradient without flow-limiting group (CT-FFR > 0.75 and GΔCT-FFR < 0.20), high-gradient without flow-limiting group (CT-FFR > 0.75 and GΔCT-FFR ≥ 0.20), and flow-limiting group (CT-FFR ≤ 0.75). Discriminant ability for major adverse cardiovascular events (MACE) prediction was compared among 4 models [model 1: Framingham risk score; model 2: model 1 + Leiden score; model 3: model 2 + high-risk plaques (HRP); model 4: model 3 + GΔCT-FFR] to determine incremental prognostic value of GΔCT-FFR. Results: Of 1215 patients (60.1 ± 10.3 years, 53.7% male), 11.3% suffered from MACE after a median follow-up of 57.3 months. GΔCT-FFR (HR: 2.88, 95% CI 1.76–4.70, P < 0.001) remained independent risk factors of MACE in multivariable analysis. Compared with the low-gradient without flow-limiting group, the high-gradient without flow-limiting group (HR: 2.86, 95% CI 1.75–4.68, P < 0.001) was associated with higher risk of MACE. Among the 4 risk models, model 4, which included GΔCT-FFR, showed the highest C-statistics (C-statistics: 0.75, P = 0.002) as well as a significant net reclassification improvement (NRI) beyond model 3 (NRI: 0.605, P < 0.001). Conclusions: In diabetic patients with non-obstructive CAD, GΔCT-FFR was associated with clinical outcomes at 5 year follow-up, which illuminates a novel and feasible approach to improved risk stratification for a global hemodynamic assessment of coronary artery in diabetic patients. [ABSTRACT FROM AUTHOR]

Background: Although sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated cardiovascular benefits in patients with type 2 diabetes mellitus, real-world evidence regarding their benefits to diabetic patients with acute myocardial infarction (AMI) is insufficient. This study evaluated cardiovascular outcomes by comparing SGLT2i with dipeptidyl peptidase-4 inhibitors (DPP-4i) in combination with metformin in diabetic patients with AMI. Methods: This study involved 779 diabetic participants with AMI from a Korean nationwide multicenter observational cohort, who were divided into two groups: (1) metformin plus SGLT2i group (SGLT2i group, n = 186) and (2) metformin plus DPP-4i (DPP-4i group, n = 593). The primary endpoint was one year of major adverse composite events (MACEs), a composite outcome of all-cause mortality, non-fatal myocardial infarction, any revascularization, cerebrovascular accident, and stent thrombosis. To balance the baseline differences, inverse probability of treatment weighting (IPTW) was performed. Results: After IPTW, the rate of MACEs in the SGLT2i group was not significantly lower than that in the DPP-4i group (hazard ratio [HR], 0.99; 95% confidence interval [Cl], 0.46 to 2.14, p = 0.983). In the unadjusted and adjusted analyses, all items for clinical outcomes were comparable between the two groups. In our exploratory analysis, the left ventricular ejection fraction showed a significant improvement in the SGLT2i group than in the DPP-4i group before achieving statistical balancing (6.10 ± 8.30 versus 2.95 ± 10.34, p = 0.007) and after IPTW adjustment (6.91 ± 8.91 versus 3.13 ± 10.41, p = 0.027). Conclusions: Our findings demonstrated that SGLT2i did not influence the rate of MACEs compared with DPP-4i in combination with metformin in diabetic patients with AMI but did improve left ventricular ejection fraction. Trial registration: Not applicable (retrospectively registered). [ABSTRACT FROM AUTHOR]

Background: This ANAFIE Registry sub-analysis investigated 2-year outcomes and oral anticoagulant (OAC) use stratified by glycated hemoglobin (HbA1c) levels among Japanese patients aged ≥ 75 years with non-valvular atrial fibrillation (NVAF) with and without clinical diagnosis of diabetes mellitus (DM). Methods: The ANAFIE Registry was a large-scale multicenter, observational study conducted in Japan; this sub-analysis included patients with baseline HbA1c data at baseline. The main endpoints evaluated (stroke/systemic embolic events [SEE], major bleeding, intracranial hemorrhage, cardiovascular death, all-cause death, and net clinical outcome [a composite of stroke/SEE, major bleeding, and all-cause death]) were stratified by HbA1c levels (< 6.0%; 6.0% to < 7.0%; 7.0% to < 8.0%; and ≥ 8.0%). Results: Of 17,526 patients with baseline HbA1c values, 8725 (49.8%) patients had HbA1c < 6.0%, 6700 (38.2%) had 6.0% to < 7.0%, 1548 (8.8%) had 7.0% to < 8.0%, and 553 (3.2%) had ≥ 8.0%. Compared with other subgroups, patients with HbA1c ≥ 8.0% were more likely to have lower renal function, higher CHA2DS2-VASc and HAS-BLED scores, higher prevalence of non-paroxysmal AF, and lower direct OAC (DOAC) administration, but higher warfarin administration. The HbA1c ≥ 8.0% subgroup had higher event rates for all-cause death (log-rank P = 0.003) and net clinical outcome (log-rank P = 0.007). Similar trends were observed for stroke/SEE. In multivariate analysis, risk of all-cause death (adjusted hazard ratio [aHR]: 1.46 [95% confidence interval 1.11–1.93]) and net clinical outcome (aHR 1.33 [1.05–1.68]) were significantly higher in the HbA1c ≥ 8.0% subgroup. No significant differences were observed in risks of major bleeding or other outcomes in this and other subgroups. No interaction was observed between HbA1c and OACs. Use/non-use of antidiabetic drugs was not associated with risk reduction; event risks did not differ with/without injectable antidiabetic drugs. Conclusions: Among elderly Japanese patients with NVAF, only HbA1c ≥ 8.0% was associated with increased all-cause death and net clinical outcome risks; risks of the events did not increase in other HbA1c subgroups. Relative event risks between patients treated with DOACs and warfarin were not modified by HbA1c level. Trial registration: UMIN000024006; date of registration: September 12, 2016. [ABSTRACT FROM AUTHOR]

Background: The insulin-like growth factors (IGF) play a crucial role in regulating cellular proliferation, apoptosis, and key metabolic pathways. The ratio of IGF-1 to IGF binding protein-3 (IGFBP-3) is an important factor in determining IGF-1 bioactivity. We sought to investigate the association of IGF-1 and IGFBP-3 with cardio-renal outcomes among persons with type 2 diabetes. Methods: Samples were available from 2627 individuals with type 2 diabetes and chronic kidney disease that were randomized to receive canagliflozin or placebo and were followed up for incident cardio-renal events. Primary outcome was defined as a composite of end-stage kidney disease, doubling of the serum creatinine level, or renal/cardiovascular death. IGF-1 and IGFBP-3 were measured at baseline, Year-1 and Year-3. Elevated IGF-1 level was defined according to age-specific cutoffs. Cox proportional hazard regression was used to investigate the association between IGF-1 level, IGFBP-3, and the ratio of IGF-1/IGFBP-3 with clinical outcomes. Results: Elevated IGF-1 was associated with lower glomerular filtration rate at baseline. Treatment with canagliflozin did not significantly change IGF-1 and IGFBP-3 concentrations by 3 years (p-value > 0.05). In multivariable models, elevated IGF-1 (above vs below age-specific cutoffs) was associated with the primary composite outcome (incidence rate:17.8% vs. 12.7% with a hazard ratio [HR]: 1.52; 95% confidence interval CI 1.09–2.13;P: 0.01), renal composite outcome (HR: 1.65; 95% CI 1.14–2.41; P: 0.01), and all-cause mortality (HR: 1.52; 95% CI 1.00–2.32; P; 0.05). Elevations in log IGFBP-3 did not associate with any clinical outcomes. Increase in log IGF-1/IGFBP-3 ratio was also associated with a higher risk of the primary composite outcome (HR per unit increase: 1.57; 95% CI 1.09–2.26; P; 0.01). Conclusions: These results further suggest potential importance of IGF biology in the risk for cardio-renal outcomes in type 2 diabetes. SGLT2 inhibition has no impact on the biology of IGF despite its significant influence on outcomes. Trial registration: CREDENCE; ClinicalTrials.gov Identifier: NCT02065791. [ABSTRACT FROM AUTHOR]

Background: Higher chemokine C-X-C motif ligand 5 (CXCL5) level was observed in type 2 diabetes mellitus (DM) patients; however, its role in diabetic vasculopathy was not clarified. This study aimed to explore the impacts and mechanistic insights of CXCL5 in neovasculogenesis and wound healing in DM. Methods: Endothelial progenitor cells (EPCs) and human aortic endothelial cells (HAECs) were used in vitro. Streptozotocin-induced diabetic mice and Leprdb/JNarl mice were used as type 1 and type 2 DM models. Moreover, CXCL5 knockout mice were used to generate diabetic mice. Hindlimb ischemia surgery, aortic ring assays, matrigel plug assay, and wound healing assay were conducted. Results: CXCL5 concentrations were increased in plasma and EPCs culture medium from type 2 DM patients. CXCL5 neutralizing antibody upregulated vascular endothelial growth factor (VEGF)/stromal cell-derived factor-1 (SDF-1) and promoted cell function in EPCs from type 2 DM patients and high glucose-treated EPCs from non-DM subjects as well as HAECs. CXCL5 directly up-regulated interleukin (IL)-1β/IL-6/tumor necrosis factor-α and down-regulated VEGF/SDF-1 via ERK/p65 activation through chemokine C-X-C motif receptor 2 (CXCR2). CXCL5 neutralizing antibody recovered the blood flow after hindlimb ischemia, increased circulating EPC number, and enhanced VEGF and SDF-1 expression in ischemic muscle. CXCL5 suppression promoted neovascularization and wound healing in different diabetic animal models. The above observation could also be seen in streptozotocin-induced CXCL5 knockout diabetic mice. Conclusions: CXCL5 suppression could improve neovascularization and wound healing through CXCR2 in DM. CXCL5 may be regarded as a potential therapeutic target for vascular complications of DM. [ABSTRACT FROM AUTHOR]

Objects: This study aimed to investigate the impact of lipoprotein(a) [Lp(a)] levels on the prognosis of Chinese patients with ST-segment elevation myocardial infarction (STEMI), and to explore if the impact may differ in the diabetes mellitus (DM) and nonDM groups. Methods: Between March 2017 and January 2020, 1543 patients with STEMI who underwent emergency percutaneous coronary intervention (PCI) were prospectively recruited. The primary outcome was a composite of all-cause death, MI recurrence (reMI), and stroke, known as major adverse cardiovascular events (MACE). Analyses involving the Kaplan–Meier curve, Cox regression, and restricted cubic spline (RCS) were conducted. Results: During the 1446-day follow-up period, 275 patients (17.8%) experienced MACEs, including 141 with DM (20.8%) and 134 (15.5%) without DM. As for the DM group, patients with Lp(a) ≥ 50 mg/dL showed an apparently higher MACE risk compared to those with Lp(a) < 10 mg/dL (adjusted hazard ratio [HR]: 1.85, 95% confidence interval [CI]:1.10–3.11, P = 0.021). The RCS curve indicates that the HR for MACE appeared to increase linearly with Lp(a) levels exceeding 16.9 mg/dL. However, no similar associations were obtained in the nonDM group, with an adjusted HR value of 0.57 (Lp(a) ≥ 50 mg/dL vs. < 10 mg/dL: 95% CI 0.32–1.05, P = 0.071). Besides, compared to patients without DM and Lp(a) ≥ 30 mg/dL, the MACE risk of patients in the other three groups (nonDM with Lp(a) < 30 mg/dL, DM with Lp(a) < 30 mg/dL, and DM with Lp(a) ≥ 30 mg/dL) increased to 1.67-fold (95% CI 1.11–2.50, P = 0.013), 1.53-fold (95% CI 1.02–2.31, P = 0.041), and 2.08-fold (95% CI 1.33–3.26, P = 0.001), respectively. Conclusions: In this contemporary STEMI population, high Lp(a) levels were linked to an increased MACE risk, and very high Lp(a) levels (≥ 50 mg/dL) significantly indicated poor outcomes in patients with DM, while not for those without DM. Trial registration: clinicaltrials.gov NCT: 03593928 [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes is associated with an increased risk of developing cardiovascular events. Previous studies have reported that advanced glycation end products (AGEs) were related to cardiovascular events in type 2 diabetes. However, data on associations between long-term AGEs and cardiovascular events in type 2 diabetes are lacking. This study aimed to determine whether a long-time shift in the levels of serum AGEs is associated with cardiovascular events in patients with poorly controlled type 2 diabetes. Methods: Two-time serum methyl-glyoxal-hydroimidazoline (MG-H1) levels were measured in 138 patients with type 2 diabetes whose mean glycated hemoglobin level was 10.1%. We categorized patients whose serum MG-H1 levels were < 2.8 µg/mL at both times as the continuous low MG-H1 group. The primary endpoints of this study were combined cardiovascular events, which were defined as heart disease, peripheral arterial disease, stroke, and all-cause death. Hazard ratios (HRs) for combined cardiovascular events with 95% confidence intervals (CIs) were calculated using the Cox proportional hazard models to compare the outcomes between the continuous low MG-H1 group and others. Results: The continuous low MG-H1 group was associated with a significantly lower risk than others in combined cardiovascular events after adjusting for possible confounders (HR: 0.50; 95% CI, 0.28–0.87; P = 0.02). Furthermore, the same relationship was observed in patients without a history of cardiovascular events. Conclusions: Continuous low serum MG-H1 levels are associated with a low frequency of diabetes-related complications in patients with poorly controlled type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Coagulation function monitoring is important for the occurrence and development of diabetes. A total of 16 related proteins are involved in coagulation, but how these proteins change in diabetic urine exosomes is unclear. To explore the expression changes of coagulation-related proteins in urine exosomes and their possible roles in the pathogenesis of diabetes, we performed proteomic analysis and finally applied them to the noninvasive monitoring of diabetes. Methods: Subject urine samples were collected. LC-MS/MS was used to collect the information on coagulation-related proteins in urine exosomes. ELISA, mass spectrometry and western blotting were used to further verify the differential protein expression in urine exosomes. Correlations with clinical indicators were explored, and receiver operating characteristic (ROC) curves were drawn to evaluate the value of differential proteins in diabetes monitoring. Results: Analyzing urine exosome proteomics data, eight coagulation-related proteins were found in this study. Among them, F2 was elevated in urine exosomes of diabetic patients compared with healthy controls. The results of ELISA, mass spectrometry and western blotting further verified the changes in F2. Correlation analysis showed that the expression of urine exosome F2 was correlated with clinical lipid metabolism indexes, and the concentration of F2 was strongly positively correlated with blood TG levels (P < 0.05). ROC curve analysis showed that F2 protein in urine exosomes had a good monitoring value for diabetes. Conclusion: Coagulation-related proteins were expressed in urine exosomes. Among them, F2 was increased in diabetic urine exosomes and may be a potential biomarker for monitoring diabetic changes. [ABSTRACT FROM AUTHOR]

Purpose: An accurate prediction of survival prognosis is beneficial to guide clinical decision-making. This prospective study aimed to develop a model to predict one-year mortality among older patients with coronary artery disease (CAD) combined with impaired glucose tolerance (IGT) or diabetes mellitus (DM) using machine learning techniques. Methods: A total of 451 patients with CAD combined with IGT and DM were finally enrolled, and those patients randomly split 70:30 into training cohort (n = 308) and validation cohort (n = 143). Results: The one-year mortality was 26.83%. The least absolute shrinkage and selection operator (LASSO) method and ten-fold cross-validation identified that seven characteristics were significantly associated with one-year mortality with creatine, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and chronic heart failure being risk factors and hemoglobin, high density lipoprotein cholesterol, albumin, and statins being protective factors. The gradient boosting machine model outperformed other models in terms of Brier score (0.114) and area under the curve (0.836). The gradient boosting machine model also showed favorable calibration and clinical usefulness based on calibration curve and clinical decision curve. The Shapley Additive exPlanations (SHAP) found that the top three features associated with one-year mortality were NT-proBNP, albumin, and statins. The web-based application could be available at https://starxueshu-online-application1-year-mortality-main-49cye8.streamlitapp.com/. Conclusions: This study proposes an accurate model to stratify patients with a high risk of one-year mortality. The gradient boosting machine model demonstrates promising prediction performance. Some interventions to affect NT-proBNP and albumin levels, and statins, are beneficial to improve survival outcome among patients with CAD combined with IGT or DM. [ABSTRACT FROM AUTHOR]

In this review, we summarise new insights into diagnostic approaches and treatment strategies for coronary artery disease (CAD) in patients with diabetes mellitus (DM). Despite the improvements in therapy, the clinical management of DM patients remains challenging as they develop more extensive CAD at a younger age and consistently have worse clinical outcomes than non-DM patients. Current diagnostic modalities as well as revascularisation treatments mainly focus on ischemic lesions. However, the impact of plaque morphology and composition are emerging as strong predictors of adverse cardiac events even in the absence of identified ischemia. In particular, the presence of vulnerable plaques such as thin-cap fibroatheroma (TCFA) lesions has been identified as a very strong predictor of future adverse events. This emphasises the need for an approach combining both functional and morphological methods in the assessment of lesions. In particular, optical coherence tomography (OCT) has proven to be a valuable asset by truly identifying TCFAs. New treatment strategies should consist of individualised and advanced medical regimens and may evolve towards plaque sealing through percutaneous treatment. [ABSTRACT FROM AUTHOR]

Background: Data on drug-coated balloon (DCB) treatment in the context of diabetes mellitus (DM) and multivessel coronary artery disease (CAD) are limited. We aimed to investigate the clinical impact of DCB-based revascularization on percutaneous coronary intervention (PCI) in patients with DM and multivessel CAD. Methods: A total of 254 patients with multivessel disease (104 patients with DM) successfully treated with DCB alone or combined with drug-eluting stent (DES) were retrospectively enrolled (DCB-based group) and compared with 254 propensity-matched patients treated with second-generation DES from the PTRG-DES registry (n = 13,160 patients) (DES-only group). Major adverse cardiovascular events (MACE) comprised cardiac death, myocardial infarction, stroke, stent or target lesion thrombosis, target vessel revascularization, and major bleeding at 2 years. Results: The DCB-based group was associated with a reduced risk of MACE in patients with DM (hazard ratio [HR] 0.19, 95% confidence interval [CI] 0.05–0.68, p = 0.003], but not in those without DM (HR 0.52, 95% CI 0.20–1.38, p = 0.167) at the 2-year follow-up. In patients with DM, the risk of cardiac death was lower in the DCB-based group than the DES-only group, but not in those without DM. In both patients with or without DM, the burdens of DES and small DES (less than 2.5 mm) used were lower in the DCB-based group than in the DES-only group. Conclusions: In multivessel CAD, the clinical benefit of a DCB-based revascularization strategy appears to be more evident in patients with DM than in those without DM after 2 years of follow-up. (Impact of Drug-Coated Balloon Treatment in De Novo Coronary Lesion; NCT04619277) [ABSTRACT FROM AUTHOR]

Background: Metabolic abnormalities such as dyslipidemia, glucose and high blood pressure are common in diabetic patients. Visit-to-visit variabilities in these measures have been reported as potential residual cardiovascular risk factors. However, the relationship between these variabilities and their effects on cardiovascular prognosis have not been studied. Methods: A total of 22,310 diabetic patients with ≥ 3 measurements of systolic blood pressure (SBP), blood glucose, total cholesterol (TC), and triglyceride (TG) levels during a minimum of three years at three tertiary general hospitals were selected. They were divided into high/low variability groups for each variable based on the coefficient of variation (CV) values. The primary outcome was the incidence of major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke. Results: All high CV groups had a higher incidence of MACE than those with low CV (6.0% vs. 2.5% for SBP-CV groups, 5.5% vs. 3.0% for TC-CV groups, 4.7% vs. 3.8% for TG-CV groups, 5.8% vs. 2.7% for glucose-CV groups). In multivariable Cox regression analysis,, high SBP-CV (HR 1.79 [95% CI 1.54–2.07], p < 0.01), high TC-CV (HR 1.54 [95% CI 1.34–1.77], p < 0.01), high TG-CV (HR 1.15 [95% CI 1.01–1.31], p = 0.040) and high glucose-CV (HR 1.61 [95% CI 1.40–1.86], p < 0.01) were independent predictors of MACE. Conclusion: Variability of SBP, TC, TG and glucose are important residual risk factors for cardiovascular events in diabetic patients. [ABSTRACT FROM AUTHOR]

Background: To investigate the difference of right ventricular (RV) structural and functional alteration in patients with diabetes mellitus (DM) with preserved left ventricular ejection fraction (LVEF), and the ventricular interdependence in these patients, using cardiac MR (CMR) feature tracking. Methods: From December 2016 to February 2022, 148 clinically diagnosed patients with DM who underwent cardiac MR (CMR) in our hospital were consecutively recruited. Fifty-four healthy individuals were included as normal controls. Biventricular strains, including left/right ventricular global longitudinal strain (LV-/RVGLS), left/right ventricular global circumferential strain (LV-/RVGCS), left/right ventricular global radial strain (LV-/RVGRS) were evaluated, and compared between patients with DM and healthy controls. Multiple linear regression and mediation analyses were used to evaluate DM's direct and indirect effects on RV strains. Results: No differences were found in age (56.98 ± 10.98 vs. 57.37 ± 8.41, p = 0.985), sex (53.4% vs. 48.1%, p = 0.715), and body surface area (BSA) (1.70 ± 0.21 vs. 1.69 ± 0.17, p = 0.472) between DM and normal controls. Patients with DM had decreased RVGLS (− 21.86 ± 4.14 vs. − 24.49 ± 4.47, p = 0.001), RVGCS (− 13.16 ± 3.86 vs. − 14.92 ± 3.08, p = 0.011), and no decrease was found in RVGRS (22.62 ± 8.11 vs. 23.15 ± 9.05, p = 0.743) in patients with DM compared with normal controls. The difference in RVGLS between normal controls and patients with DM was totally mediated by LVGLS (indirect effecting: 0.655, bootstrapped 95%CI 0.138–0.265). The difference in RVGCS between normal controls and DM was partly mediated by the LVGLS (indirect effecting: 0.336, bootstrapped 95%CI 0.002–0.820) and LVGCS (indirect effecting: 0.368, bootstrapped 95%CI 0.028–0.855). Conclusions: In the patients with DM and preserved LVEF, the difference in RVGLS between DM and normal controls was totally mediated by LVGLS. Although there were partly mediating effects of LVGLS and LVGCS, the decrease in RVGCS might be directly affected by the DM. [ABSTRACT FROM AUTHOR]

L-Arginine (L-Arg), is a semi-essential amino acid involved in the formation of nitric oxide. The functional relevance of L-Arg in diabetes mellitus has been evaluated both in animal models and in human subjects. In the literature there are several lines of evidence indicating that L-Arg has beneficial effects in diabetes and numerous studies advocate its administration to attenuate glucose intolerance in diabetic patients. Here we present a comprehensive overview of the main studies exploring the effects of L-Arg in diabetes, including preclinical and clinical reports on this topic. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease (CKD) is a common comorbidity in people with diabetes mellitus, and a key risk factor for further life-threatening conditions such as cardiovascular disease. The early prediction of progression of CKD therefore is an important clinical goal, but remains difficult due to the multifaceted nature of the condition. We validated a set of established protein biomarkers for the prediction of trajectories of estimated glomerular filtration rate (eGFR) in people with moderately advanced chronic kidney disease and diabetes mellitus. Our aim was to discern which biomarkers associate with baseline eGFR or are important for the prediction of the future eGFR trajectory. Methods: We used Bayesian linear mixed models with weakly informative and shrinkage priors for clinical predictors (n = 12) and protein biomarkers (n = 19) to model eGFR trajectories in a retrospective cohort study of people with diabetes mellitus (n = 838) from the nationwide German Chronic Kidney Disease study. We used baseline eGFR to update the models' predictions, thereby assessing the importance of the predictors and improving predictive accuracy computed using repeated cross-validation. Results: The model combining clinical and protein predictors had higher predictive performance than a clinical only model, with an R 2 of 0.44 (95% credible interval 0.37–0.50) before, and 0.59 (95% credible interval 0.51–0.65) after updating by baseline eGFR, respectively. Only few predictors were sufficient to obtain comparable performance to the main model, with markers such as Tumor Necrosis Factor Receptor 1 and Receptor for Advanced Glycation Endproducts being associated with baseline eGFR, while Kidney Injury Molecule 1 and urine albumin-creatinine-ratio were predictive for future eGFR decline. Conclusions: Protein biomarkers only modestly improve predictive accuracy compared to clinical predictors alone. The different protein markers serve different roles for the prediction of longitudinal eGFR trajectories potentially reflecting their role in the disease pathway. [ABSTRACT FROM AUTHOR]