<div><h4>Non-coding RNA-mediated endothelial-to-mesenchymal transition in human diabetic cardiomyopathy, potential regulation by DNA methylation.</h4><i>Wang E, Chen S, Wang H, Chen T, Chakrabarti S</i><br /><b>Aims</b><br />Diabetic cardiomyopathy (DCM) is a major complication of diabetes and a risk factor for cardiovascular disease. Endothelial dysfunction is central to DCM, and endothelial-to-mesenchymal transition (EndMT) is a key form of endothelial dysfunction in diabetes. EndMT in DCM has been well-studied in model systems and has been found to be epigenetically regulated by non-coding RNAs (ncRNAs). However, EndMT in DCM and its associated epigenetic changes need further characterization in human patients. It is also not known if ncRNAs are affected by changes in DNA methylation in DCM. This study aims to confirm in human hearts, the findings from animal and cell studies, and potentially provide novel insight into interactions between DNA methylation and ncRNAs in EndMT in DCM.<br /><b>Methods and results</b><br />Heart tissues were collected from autopsy patients, fixed in formalin, and embedded in paraffin. Thin sections from paraffin-embedded tissues were used for histology and immunofluorescence analyses, where we confirmed that diabetic patients showed increased cardiac fibrosis that EndMT had occurred. Tissue curls from the paraffin-embedded tissues were used for RT-qPCR and methylation analyses. RT-qPCR quantitatively showed that EndMT occurs in the hearts of diabetics, and that EndMT in human hearts corresponded to changes in key ncRNAs. Methylation analysis showed that some of the EndMT-related ncRNAs were regulated by DNA promoter methylation, while others may be regulated through different epigenetic mechanisms.<br /><b>Conclusions</b><br />We show that EndMT is a relevant pathological process in human hearts during DCM, and that its occurrence coincides with changes in relevant ncRNAs. We further find that interplay between DNA methylation and certain ncRNAs involved in the regulation of EndMT may contribute to the observed changes in ncRNA expression. These findings reinforce the role of EndMT in patients afflicted with DCM and underscore the complexities and importance of the interactions between different facets of epigenetic regulation.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 03 Nov 2023; 22:303</small></div>

<div><h4>Recent UK type 2 diabetes treatment guidance represents a near whole population indication for SGLT2-inhibitor therapy.</h4><i>Young KG, Hopkins R, Shields BM, Thomas NJ, ... Dennis JM, MASTERMIND consortium</i><br /><AbstractText>Recent type 2 diabetes guidance from the UK\'s National Institute for Health and Care Excellence (NICE) proposes offering SGLT2-inhibitor therapy to people with established atherosclerotic cardiovascular disease (ASCVD) or heart failure, and considering SGLT2-inhibitor therapy for those at high-risk of cardiovascular disease defined as a 10-year cardiovascular risk of > 10% using the QRISK2 algorithm. We used a contemporary population-representative UK cohort of people with type 2 diabetes to assess the implications of this guidance. 93.1% of people currently on anti-hyperglycaemic treatment are now recommended or considered for SGLT2-inhibitor therapy under the new guidance, with the majority (59.6%) eligible on the basis of QRISK2 rather than established ASCVD or heart failure (33.6%). Applying these results to the approximately 2.20 million people in England currently on anti-hyperglycaemic medication suggests 1.75 million people will now be considered for additional SGLT2-inhibitor therapy, taking the total cost of SGLT2-inhibitor therapy in England to over £1 billion per year. Given that older people, those of non-white ethnic groups, and those at lower cardiovascular disease risk were underrepresented in the clinical trials which were used to inform this guidance, careful evaluation of the impact and safety of increased SGLT2-inhibitor prescribing across different populations is urgently required. Evidence of benefit should be weighed against the major cost implications for the UK National Health Service.</AbstractText><br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 02 Nov 2023; 22:302</small></div>

<div><h4>High BMI and the risk for incident type 1 Diabetes Mellitus: a systematic review and meta-analysis of aggregated cohort studies.</h4><i>Nitecki M, Gerstein HC, Balmakov Y, Tsur E, ... Cukierman-Yaffe T, Twig G</i><br /><b>Background</b><br />There is uncertainty regarding the role of obesity in type 1 diabetes development. The aim of this systematic review and meta-analysis was to collect and synthesize evidence regarding BMI and the risk of developing type 1 diabetes.<br /><b>Methods</b><br />A systematic review and meta-analysis were conducted to assess the association between BMI and incident type 1 diabetes. Databases were searched up to June 2022. Cohort studies were included reporting the association between overweight and/or obesity, as measured by BMI after age 2 years, with incident type 1 diabetes. Independent reviewers extracted data and assessed study quality. Risk estimates were pooled using a random-effects model.<br /><b>Results</b><br />Ten cohort studies met the inclusion criteria. The seven studies that classified BMI into categories were of high quality and involved 1,690,660 individuals and 1979 incident type 1 diabetes cases. The pooled risk ratio (RR) for type 1 diabetes was 1.35 (95% CI 0.93-1.97) among people with overweight (3 studies); 2.17 (95% CI 1.75-2.69) among people with obesity (5 studies); and 1·87 (95% CI 1.52-2.29) among people with overweight/obesity (two studies merged the categories). These point estimates persisted in sensitivity analyses that addressed the duration of follow-up, variability in baseline risk for incident type 1 diabetes, and potential misclassifications related to exposure or outcome definitions. People with overweight/obesity had a 2.55 (95% CI 1.11-5.86) greater risk for incident type 1 diabetes with positive islet autoantibodies.<br /><b>Conclusion</b><br />This systematic review and meta-analysis of high-quality observational cohort studies indicated an association between high BMI and the risk of type 1 diabetes, in a graded manner.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 02 Nov 2023; 22:300</small></div>

<div><h4>Relationship between the circulating N-terminal pro B-type natriuretic peptide and the risk of carotid artery plaque in different glucose metabolic states in patients with coronary heart disease: a CSCD-TCM study in China.</h4><i>Yang T, Zheng H, Pan G, Guo R, ... Yang R, Yu C</i><br /><b>Objective</b><br />Circulating N-terminal pro B-type natriuretic peptide (NT-proBNP) is a marker for heart failure in patients with coronary heart disease (CHD) and associated with glycemic abnormalities. Studies on the association and diagnostic value of NT-proBNP in carotid plaques (CAP) in patients with CHD are limited.<br /><b>Methods</b><br />The relationships between NT-proBNP and the risk of CAP in different glucose metabolic states, sexes, and age categories were also examined using 5,093 patients diagnosed with CHD. The NT-proBNP tertiles were used to divide patients into three groups in which the NT-proBNP levels, blood glucose levels, the occurrence of CAP, and the number and nature of CAP were measured using normoglycemic (NG), prediabetes (Pre-DM), and diabetes mellitus (DM) glucose metabolic statuses. Logistic regression analyses were used to compare the relationship between NT-proBNP and the risk of CAP occurrence and the number and nature of CAP. The diagnostic value of NT-proBNP for CAP risk was measured using receiver operating characteristic (ROC) curves.<br /><b>Results</b><br />We found a 37% relative increase in the correlation between changes in NT-proBNP per standard deviation (SD) and the incidence of CAP. After adjusting for potential confounders, NT-proBNP at the T3 level was found to be associated with an increased CAP odds ratio (OR) when T1 was used as the reference. This relationship was also present in males, patients aged > 60 years, or both pre-DM and DM states. NT-proBNP was more likely to present as hypoechoic plaques at T1 and as mixed plaques at T3. We also measured the diagnostic accuracy of CAP for NT-proBNP in patients with CHD, with an AUC value of 0.627(95% CI 0.592-0.631), sensitivity of 50.7%, and specificity of 68.0%.<br /><b>Conclusion</b><br />An increase in NT-proBNP was significantly associated with the risk of CAP in patients with CHD, especially in males and patients aged > 60 years, and exhibited specific characteristics under different glucose metabolism states. Trial registration The study was approved by the Ethics Committee of Tianjin University of Traditional Chinese Medicine (Approval number TJUTCM-EC20210007) and certified by the Chinese Clinical Trials Registry on April 4, 2022 (Registration number ChiCTR2200058296) and March 25, 2022 by ClinicalTrials.gov (registration number NCT05309343).<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 02 Nov 2023; 22:299</small></div>

<div><h4>Cardioprotective function of sclerostin by reducing calcium deposition, proliferation, and apoptosis in human vascular smooth muscle cells.</h4><i>González-Salvatierra S, García-Fontana C, Lacal J, Andújar-Vera F, ... Muñoz-Torres M, García-Fontana B</i><br /><b>Background</b><br />Sclerostin is an inhibitor of the Wnt/b-catenin pathway, which regulates bone formation, and can be expressed in vascular smooth muscle cells (VSMCs). Type 2 diabetes (T2D) is associated with an increased risk of cardiovascular disease (CVD) and increased serum and tissue expression of sclerostin. However, whether the role of sclerostin is detrimental or protective in the development of CVD is unknown. Therefore, our aims are to determine the level of sclerostin in T2D patients with/without CVD and in controls, both at serum and vascular tissue, and to analyze the role of sclerostin in VSMCs under calcified environments.<br /><b>Methods</b><br />Cross-sectional study including 121 controls and 139 T2D patients with/without CVD (48/91). Sclerostin levels in serum were determined by ELISA, and sclerostin expression was analyzed by RT-qPCR and immunohistochemistry in calcified and non-calcified artery of lower limb from T2D patients (n = 7) and controls (n = 3). In vitro experiments were performed in VSMCs (mock and sclerostin overexpression) under calcifying conditions analyzing the sclerostin function by determination of calcium and phosphate concentrations, and quantification of calcium deposits by Alizarin Red. Proliferation and apoptosis were analyzed by MTT assay and flow cytometry, respectively. The regulation of the expression of genes involved in bone metabolism was determined by RT-qPCR.<br /><b>Results</b><br />A significant increase in serum sclerostin levels in T2D patients with CVD compared to T2D patients without CVD and controls (p < 0.001) was observed. Moreover, higher circulating sclerostin levels were independently associated with CVD in T2D patients. Increased sclerostin expression was observed in calcified arteries of T2D patients compared to non-calcified arteries of controls (p = 0.003). In vitro experiments using VSMCs under calcified conditions, revealed that sclerostin overexpression reduced intracellular calcium (p = 0.001), calcium deposits (p < 0.001), cell proliferation (p < 0.001) and promoted cell survival (p = 0.015). Furthermore, sclerostin overexpression exhibited up-regulation of ALPL (p = 0.009), RUNX2 (p = 0.001) and COX2 (p = 0.003) and down-regulation of inflammatory genes, such as, IL1β (p = 0.005), IL6 (p = 0.001) and IL8 (p = 0.003).<br /><b>Conclusions</b><br />Sclerostin could play a protective role in the development of atherosclerosis in T2D patients by reducing calcium deposits, decreasing proliferation and inflammation, and promoting cell survival in VSMCs under calcifying conditions. Therefore, considering the bone-vascular axis, treatment with anti-sclerostin for bone disease should be used with caution.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 02 Nov 2023; 22:301</small></div>

<div><h4>Sex-related differences for uric acid in the prediction of cardiovascular events in essential hypertension. A population prospective study.</h4><i>Perticone M, Maio R, Shehaj E, Gigliotti S, ... Andreozzi F, Perticone F</i><br /><b>Background</b><br />Uric acid (UA) is an independent prognostic factor for cardiovascular events, but there are no data demonstrating a different risk profile between women and men. Thus, we tested whether UA is associated with a possible sex-related difference in fatal and non-fatal cardiovascular events.<br /><b>Methods</b><br />In this prospective population-based study we enrolled 1,650 never-treated Caucasian hypertensive outpatients referred to Catanzaro University Hospital (Italy). Inclusion criteria were newly diagnosed hypertensive patients, aged 20 years or more. Exclusion criteria were secondary form of hypertension, previous cardiovascular events, rheumatic and non-rheumatic valvular heart disease, prosthetic valves, cardiomyopathies, type-2 diabetes, chronic kidney disease, malignant diseases, gout arthritis and secondary forms of hyperuricemia, liver diseases, peripheral vascular diseases, and heart failure. Anthropometric, clinical, and biochemical parameters were measured. UA prognostic role was investigated by Cox regression analyses. Receiver-operating characteristic curve analyses and area under the curve were used to determine the predictive validity and the optimal cut-off point of UA. We investigated following endpoints: coronary events (fatal and nonfatal myocardial infarction, unstable angina, coronary revascularization procedures, coronary death); fatal and nonfatal stroke; all-cause mortality and major adverse cardiovascular events (MACE).<br /><b>Results</b><br />We enrolled 830 males and 820 females aged 52.2 ± 11.3 years. During 9.5 ± 3.1 years follow-up, there were 424 new clinical events (2.71%): 250 coronary (1.59%), 118 (0.75%) cerebrovascular, and 56 (0.40%) deaths. Comparison between groups demonstrated a higher and significant difference in incidence rate in females for MACE (3.08 vs 2.33%, P = 0.001), coronary (1.82 vs 1.36%, P = 0.014) and cerebrovascular events (0.93 vs 0.57%, P = 0.006). UA at multiple Cox regression analysis resulted a strong and significant predictor of coronary events (HR = 1.493;95% CI 1.375-1.621), cerebrovascular events (HR = 1.256;95% CI 1.109-1.423), MACE (HR = 1.415;95% CI 1.328- 53 1.508), and all-cause mortality (HR = 1.469;95% CI 1.237-1.745) in the whole population and in both groups with a HR higher in females. The best estimated cut-off values of uric acid for males and females predicted these endpoints equally well, but it was always lower in females than males.<br /><b>Conclusions</b><br />We demonstrate, that UA operates with a sex-related impact and best cut-off value in predicting cardiovascular outcomes and all-cause mortality, reflecting a possible sex difference in disease pathophysiology.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 01 Nov 2023; 22:298</small></div>

<div><h4>FSTL3 partially mediates the association of increased nonalcoholic fatty liver disease fibrosis risk with acute myocardial infarction in patients with type 2 diabetes mellitus.</h4><i>Duan W, Shi R, Yang F, Zhou Z, ... Huang Z, Zang S</i><br /><b>Background</b><br />The study aimed to investigate an association of increased liver fibrosis with acute myocardial infarction (AMI), and to investigate the mediating effect of serum follistatin-like protein 3 (FSTL3) on the association in patients with type 2 diabetes mellitus (T2DM).<br /><b>Method</b><br />A total of 1424 participants were included in this study, and were firstly divided into two groups: 429 T2DM patients and 995 T2DM patients with NAFLD to assess the association of NAFLD and AMI. Then 995 T2DM co-existent NAFLD patients were categorized by NAFLD fibrosis risk to explore the association between NAFLD fibrosis risk and AMI. Immunohistochemistry staining and semi-quantitative analysis of liver FSTL3 were performed in 60 patients with NAFLD. There were 323 individuals (191 without AMI and 132 with AMI) in T2DM co-existent NAFLD patients who had serum samples, and serum FSTL3 was tested and mediation effect of FSTL3 in association of NAFLD fibrosis and AMI was performed.<br /><b>Results</b><br />First, increased NAFLD fibrosis risk was an independent risk factor for AMI in patients with T2DM and co-existent NAFLD. In addition, analysis of Gene Expression Omnibus (GEO) database and immunohistochemical staining confirmed the increased expression of FSTL3 in the liver of NAFLD patients with fibrosis. Serum FSTL3 significantly increased in patients with high NAFLD fibrosis risk and AMI, and closely associated with NAFLD fibrosis and AMI severity in T2DM patients with co-existent NAFLD. Most importantly, analysis of the level of mediation revealed that increased serum FSTL3 partially mediated the association of increased NAFLD fibrosis risk with AMI in T2DM patients with co-existent NAFLD.<br /><b>Conclusions</b><br />NAFLD fibrosis was closely associated with AMI in T2DM patients. FSTL3 expression was enriched in the liver of NAFLD patients with significant and advanced fibrosis, and serum FSTL3 partially mediated the association of increased liver fibrosis risk with AMI in T2DM patients.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 30 Oct 2023; 22:297</small></div>

<div><h4>Assessment of left atrioventricular coupling and left atrial function impairment in diabetes with and without hypertension using CMR feature tracking.</h4><i>Shi R, Jiang YN, Qian WL, Guo YK, ... Yang ZG, Li Y</i><br /><b>Purpose</b><br />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.<br /><b>Methods</b><br />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 (ε<sub>s</sub>), total LA ejection fraction (LAEF)), conduit function (conduit strain (ε<sub>e</sub>), passive LAEF), booster-pump function (booster strain (ε<sub>a</sub>) and active LAEF), LA volume index (LAVI), LV global longitudinal strain (LVGLS), and LACI were evaluated and compared between the two groups.<br /><b>Results</b><br />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 ε<sub>s</sub> (41.27 ± 18.89 vs. 33.41 ± 13.94, p = 0.006), ε<sub>e</sub> (23.69 ± 12.96 vs. 18.90 ± 9.90, p = 0.037), ε<sub>a</sub> (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).<br /><b>Conclusions</b><br />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.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 30 Oct 2023; 22:295</small></div>

<div><h4>Association between high sensitivity cardiac troponin and mortality risk in the non-diabetic population: findings from the National Health and Nutrition Examination Survey.</h4><i>Liu L, Cheng YT, Xu A, Cheung BMY</i><br /><b>Objective</b><br />We investigated the association of high-sensitivity cardiac troponin (Hs-cTn) with all-cause and cardiovascular mortality in non-diabetic individuals.<br /><b>Methods</b><br />This study included 10,393 participants without known diabetes and cardiovascular disease from the US National Health and Nutrition Examination Survey (NHANES). Serum Hs-cTnI and Hs-cTnT concentrations were measured. Prediabetes was defined as fasting blood glucose between 100 and 125 mg/dL or HbA1c between 5.7 and 6.4%. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality risk. Time-dependent receiver operating characteristics (tROC) curves were utilized to measure the predictive performance of the biomarkers. Net Reclassification Improvement (NRI) were calculated to estimate the improvement in risk classification for adding Hs-cTnT or Hs-cTnI to the standard models based on Framingham risk factors.<br /><b>Results</b><br />The mean age of the participants was 48.1 ± 19.1 years, with 53.3% being female and 25.8% being prediabetic. After multivariable adjustment, compared to those with Hs-cTnI concentration less than the limit of detection, the HRs (95% CIs) of the participants with Hs-cTnI concentration higher than the 99th upper reference limit were 1.74 (1.35, 2.24) for all-cause mortality and 2.10 (1.36, 3.24) for cardiovascular mortality. The corresponding HRs (95% CIs) for Hs-cTnT were 2.07 (1.53, 2.81) and 2.92 (1.47, 5.80) for all-cause and cardiovascular mortality. There was a significant interaction between prediabetes and Hs-cTnI on the mortality risk; a positive relationship was only observed in prediabetic individuals. No interaction was observed between prediabetes and Hs-cTnT on mortality risk. The Areas Under tROC indicated both Hs-cTnT and Hs-cTnI show better predictive performance in cardiovascular mortality than in all-cause mortality. NRI (95% CI) for adding Hs-cTnT to the standard model were 0.25 (0.21, 0.27) and 0.33 (0.26, 0.39) for all-cause and cardiovascular mortality. The corresponding NRI (95% CI) for Hs-cTnI were 0.04 (0, 0.06) and 0.07 (0.01, 0.13).<br /><b>Conclusions</b><br />Elevated blood levels of Hs-cTnI and Hs-cTnT are associated with increased mortality. Measurement of Hs-cTnT in non-diabetic subjects, particularly those with prediabetes, may help identify individuals at an increased risk of cardiovascular disease and provide early and more intensive risk factor modification.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 30 Oct 2023; 22:296</small></div>

<div><h4>Predictive value of the stress hyperglycemia ratio in dialysis patients with acute coronary syndrome: insights from a multi-center observational study.</h4><i>Xie E, Ye Z, Wu Y, Zhao X, ... Gao Y, Zheng J</i><br /><b>Background</b><br />Various studies have indicated that stress hyperglycemia ratio (SHR) can reflect true acute hyperglycemic status and is associated with poor outcomes in patients with acute coronary syndrome (ACS). However, data on dialysis patients with ACS are limited. The Global Registry of Acute Coronary Events (GRACE) risk score is a well-validated risk prediction tool for ACS patients, yet it underestimates the risk of major events in patients receiving dialysis. This study aimed to evaluate the association between SHR and adverse cardiovascular events in dialysis patients with ACS and explore the potential incremental prognostic value of incorporating SHR into the GRACE risk score.<br /><b>Methods</b><br />This study enrolled 714 dialysis patients with ACS from January 2015 to June 2021 at 30 tertiary medical centers in China. Patients were stratified into three groups based on the tertiles of SHR. The primary outcome was major adverse cardiovascular events (MACE), and the secondary outcomes were all-cause mortality and cardiovascular mortality.<br /><b>Results</b><br />After a median follow-up of 20.9 months, 345 (48.3%) MACE and 280 (39.2%) all-cause mortality occurred, comprising 205 cases of cardiovascular death. When the highest SHR tertile was compared to the second SHR tertile, a significantly increased risk of MACE (adjusted hazard ratio, 1.92; 95% CI, 1.48-2.49), all-cause mortality (adjusted hazard ratio, 2.19; 95% CI, 1.64-2.93), and cardiovascular mortality (adjusted hazard ratio, 2.70; 95% CI, 1.90-3.83) was identified in the multivariable Cox regression model. A similar association was observed in both diabetic and nondiabetic patients. Further restricted cubic spline analysis identified a J-shaped association between the SHR and primary and secondary outcomes, with hazard ratios for MACE and mortality significantly increasing when SHR was > 1.08. Furthermore, adding SHR to the GRACE score led to a significant improvement in its predictive accuracy for MACE and mortality, as measured by the C-statistic, net reclassification improvement, and integrated discrimination improvement, especially for those with diabetes.<br /><b>Conclusions</b><br />In dialysis patients with ACS, SHR was independently associated with increased risks of MACE and mortality. Furthermore, SHR may aid in improving the predictive efficiency of the GRACE score, especially for those with diabetes. These results indicated that SHR might be a valuable tool for risk stratification and management of dialysis patients with ACS.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 27 Oct 2023; 22:288</small></div>

<div><h4>High triglyceride-glucose index predicts cardiovascular events in patients with coronary bifurcation lesions: a large-scale cohort study.</h4><i>He J, Yuan S, Song C, Song Y, ... Gao G, Dou K</i><br /><b>Background</b><br />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.<br /><b>Methods</b><br />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.<br /><b>Results</b><br />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.<br /><b>Conclusions</b><br />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.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 27 Oct 2023; 22:289</small></div>

<div><h4>Triglyceride-glucose index is associated with poor prognosis in acute coronary syndrome patients with prior coronary artery bypass grafting undergoing percutaneous coronary intervention.</h4><i>Dong S, Zhao Z, Huang X, Ma M, ... Shi D, Zhou Y</i><br /><b>Background</b><br />The triglyceride-glucose (TyG) index, which is a reliable substitute indicator for insulin resistance, has been considered an independent risk factor for long-term outcomes in patients with cardiovascular disease. However, it remains unknown whether the TyG index is associated with poor prognosis in acute coronary syndrome (ACS) patients with prior coronary artery bypass grafting (CABG) undergoing percutaneous coronary intervention (PCI).<br /><b>Methods</b><br />A total of 1158 ACS patients with prior CABG undergoing PCI were retrospectively studied. The TyG index was calculated by ln[fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2]. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), a composite of all-cause death, nonfatal myocardial infarction, nonfatal stroke, and unplanned repeat revascularization.<br /><b>Results</b><br />During a median of 42-month follow-up, 350 patients (30.2%) experienced at least one endpoint event. Based on the optimal cut-off value of the TyG index, patients were divided into the high TyG index group and the low TyG index group. Patients in the high TyG index group had higher risks of MACCE (35.3% vs. 25.3%, p < 0.001), major adverse cardiovascular events (MACE) (31.1% vs. 23.4%, p = 0.003), nonfatal stroke (4.2% vs. 1.9%, p = 0.022) and unplanned repeat revascularization (19.4% vs. 11.3%, p < 0.001) than those in the low TyG index group. Cox regression analysis demonstrated that there was an independent association between the TyG index and MACCE regardless of whether the TyG index was a continuous or categorical variable (HR 1.42, 95% CI 1.09-1.86, p = 0.009; HR 1.53, 95% CI 1.16-2.01, p = 0.003, respectively). Restricted cubic spline curve exhibited that the relationship between the TyG index and MACCE was linear (p for non-linear = 0.595, p for overall = 0.005). By incorporating the TyG index groups into baseline risk model, the accuracy of predicting MACCE was improved [AUC: baseline risk model, 0.618 vs. baseline risk model + TyG index groups, 0.636, p for comparison = 0.042].<br /><b>Conclusions</b><br />The TyG index is independently associated with MACCE, suggesting that the TyG index may serve as a valid indicator for predicting poor prognosis in ACS patients with prior CABG undergoing PCI.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 27 Oct 2023; 22:286</small></div>

<div><h4>The triglyceride-glucose index predicts 1-year major adverse cardiovascular events in end-stage renal disease patients with coronary artery disease.</h4><i>Xie E, Ye Z, Wu Y, Zhao X, ... Gao Y, Zheng J</i><br /><b>Background</b><br />The triglyceride-glucose (TyG) index has been suggested as a dependable indicator for predicting major adverse cardiovascular events (MACE) in individuals with cardiovascular conditions. Nevertheless, there is insufficient data on the predictive significance of the TyG index in end-stage renal disease (ESRD) patients with coronary artery disease (CAD).<br /><b>Methods</b><br />This study, conducted at multiple centers in China, included 959 patients diagnosed with dialysis and CAD from January 2015 to June 2021. Based on the TyG index, the participants were categorized into three distinct groups. The study\'s primary endpoint was the combination of MACE occurring within one year of follow-up, including death from any cause, non-fatal myocardial infarction, and non-fatal stroke. We assessed the association between the TyG index and MACE using Cox proportional hazard models and restricted cubic spline analysis. The TyG index value was evaluated for prediction incrementally using C-statistics, continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI).<br /><b>Results</b><br />The three groups showed notable variations in the risk of MACE (16.3% in tertile 1, 23.5% in tertile 2, and 27.2% in tertile 3; log-rank P = 0.003). Following complete adjustment, patients with the highest TyG index exhibited a notably elevated risk of MACE in comparison to those in the lowest tertile (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.14-2.35, P = 0.007). Likewise, each unit increase in the TyG index correlated with a 1.37-fold higher risk of MACE (HR 1.37, 95% CI 1.13-1.66, P = 0.001). Restricted cubic spline analysis revealed a connection between the TyG index and MACE (P for nonlinearity > 0.05). Furthermore, incorporating the TyG index to the Global Registry of Acute Coronary Events risk score or baseline risk model with fully adjusted factors considerably enhanced the forecast of MACE, as demonstrated by the C-statistic, continuous NRI, and IDI.<br /><b>Conclusions</b><br />The TyG index might serve as a valuable and dependable indicator of MACE risk in individuals with dialysis and CAD, indicating its potential significance in enhancing risk categorization in clinical settings.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 27 Oct 2023; 22:292</small></div>

<div><h4>Dual roles of myocardial mitochondrial AKT on diabetic cardiomyopathy and whole body metabolism.</h4><i>Chen YH, Ta AP, Chen Y, Lee HC, ... Li J, Wang PH</i><br /><b>Background</b><br />The PI3K/AKT pathway transduces the majority of the metabolic actions of insulin. In addition to cytosolic targets, insulin-stimulated phospho-AKT also translocates to mitochondria in the myocardium. Mouse models of diabetes exhibit impaired mitochondrial AKT signaling but the implications of this on cardiac structure and function is unknown. We hypothesized that loss of mitochondrial AKT signaling is a critical step in cardiomyopathy and reduces cardiac oxidative phosphorylation.<br /><b>Methods</b><br />To focus our investigation on the pathophysiological consequences of this mitochondrial signaling pathway, we generated transgenic mouse models of cardiac-specific, mitochondria-targeting, dominant negative AKT1 (CAMDAKT) and constitutively active AKT1 expression (CAMCAKT). Myocardial structure and function were examined using echocardiography, histology, and biochemical assays. We further investigated the underlying effects of mitochondrial AKT1 on mitochondrial structure and function, its interaction with ATP synthase, and explored in vivo metabolism beyond the heart.<br /><b>Results</b><br />Upon induction of dominant negative mitochondrial AKT1, CAMDAKT mice developed cardiac fibrosis accompanied by left ventricular hypertrophy and dysfunction. Cardiac mitochondrial oxidative phosphorylation efficiency and ATP content were reduced, mitochondrial cristae structure was lost, and ATP synthase structure was compromised. Conversely, CAMCAKT mice were protected against development of diabetic cardiomyopathy when challenged with a high calorie diet. Activation of mitochondrial AKT1 protected cardiac function and increased fatty acid uptake in myocardium. In addition, total energy expenditure was increased in CAMCAKT mice, accompanied by reduced adiposity and reduced development of fatty liver.<br /><b>Conclusion</b><br />CAMDAKT mice modeled the effects of impaired mitochondrial signaling which occurs in the diabetic myocardium. Disruption of this pathway is a key step in the development of cardiomyopathy. Activation of mitochondrial AKT1 in CAMCAKT had a protective role against diabetic cardiomyopathy as well as improved metabolism beyond the heart.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 27 Oct 2023; 22:294</small></div>

<div><h4>Impact of SGLT2 inhibitors on patient outcomes: a network meta-analysis.</h4><i>Chen JY, Pan HC, Shiao CC, Chuang MH, ... Chu WK, Wu VC</i><br /><b>Background</b><br />A comprehensive network meta-analysis comparing the effects of individual sodium-glucose cotransporter 2 (SGLT2) inhibitors on patients with and without comorbidities including diabetes mellitus (DM), heart failure (HF), and chronic kidney disease (CKD) has not been previously conducted.<br /><b>Methods</b><br />We searched PubMed, Embase, Cochrane, and ClinicalTrials.gov for randomized controlled trials up to March 28, 2023. Network meta-analysis using a random-effects model was conducted to calculate risk ratios (RRs). Risk of Bias tool 2.0 was used to assess bias, and CINeMA to assess the certainty of evidence. In the subgroup analysis, the SGLT2 inhibitors were classified into highly (dapagliflozin, empagliflozin, and ertugliflozin) and less selective SGLT2 inhibitors (canagliflozin and sotagliflozin).<br /><b>Results</b><br />A total of fourteen trials with 75,334 patients were analyzed. Among these, 40,956 had taken SGLT2 inhibitors and 34,378 had not. One of the main results with particular findings was empagliflozin users had a significantly lower risk of all-cause death compared to dapagliflozin users in DM population (RR: 0.81, 95% CI 0.69-0.96). In HF population, sotagliflozin users had a borderline significantly lower risk of CV death or hospitalization for HF (HHF) than dapagliflozin users (RR: 0.90, 95% CI 0.80-1.01). In non-HF population, those who used canagliflozin had a significantly lower risk of CV death or HHF compared with those who used dapagliflozin (RR: 0.75, 95% CI 0.58-0.98). At last, for HF patients, those who used less selective SGLT2 inhibitors had a significantly lower risk of MACEs compared to those who used highly selective SGLT2 inhibitors (RR: 0.75, 95% CI 0.62-0.90).<br /><b>Conclusions</b><br />Our network meta-analysis revealed that empagliflozin users with diabetes experienced a lower risk of dying from any cause than those using dapagliflozin. Additionally, canagliflozin users demonstrated a reduced risk of cardiovascular death or HHF compared to dapagliflozin users in those without HF. In HF patients, less selective SGLT2 inhibitors showed superior CV composite outcomes, even surpassing the performance of highly selective SGLT2 inhibitors.<br /><b>Trial registration</b><br />PROSPERO [CRD42022361906].<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 27 Oct 2023; 22:290</small></div>

<div><h4>Klotho inhibits renal ox-LDL deposition via IGF-1R/RAC1/OLR1 signaling to ameliorate podocyte injury in diabetic kidney disease.</h4><i>Jiang W, Gan C, Zhou X, Yang Q, ... Yang H, Li Q</i><br /><b>Objective</b><br />Diabetic kidney disease (DKD) is characterized by the abnormal deposition of oxidized low-density lipoprotein (ox-LDL), which contributes to podocyte damage. Klotho, an aging suppressor that plays a critical role in protecting podocytes in DKD, is mainly expressed in kidney tubular epithelium and secreted in the blood. However, it has not been established whether Klotho can alleviate podocyte injury by inhibiting renal ox-LDL deposition, and the potential molecular mechanisms require further investigation.<br /><b>Methods</b><br />We conducted a comprehensive analysis of serum and kidney biopsy samples obtained from patients diagnosed with DKD. Additionally, to explore the underlying mechanism of Klotho in the deposition of ox-LDL in the kidneys, we employed a mouse model of DKD with the Klotho genotype induced by streptozotocin (STZ). Furthermore, we conducted meticulous in vitro experiments on podocytes to gain further insights into the specific role of Klotho in the deposition of ox-LDL within the kidney.<br /><b>Results</b><br />Our groundbreaking study unveiled the remarkable ability of the soluble form of Klotho to effectively inhibit high glucose-induced ox-LDL deposition in podocytes affected by DKD. Subsequent investigations elucidated that Klotho achieved this inhibition by reducing the expression of the insulin/insulin-like growth factor 1 receptor (IGF-1R), consequently leading to a decrease in the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1) and an enhancement of mitochondrial function. Ultimately, this series of events culminated in a significant reduction in the expression of the oxidized low-density lipoprotein receptor (OLR1), thereby resulting in a notable decrease in renal ox-LDL deposition in DKD.<br /><b>Conclusion</b><br />Our findings suggested that Klotho had the potential to mitigate podocyte injury and reduced high glucose-induced ox-LDL deposition in glomerulus by modulating the IGF-1R/RAC1/OLR1 signaling. These results provided valuable insights that could inform the development of novel strategies for diagnosing and treating DKD.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 27 Oct 2023; 22:293</small></div>

<div><h4>C-reactive protein during pregnancy and in the early postpartum predicts adverse metabolic health outcomes at 1 year postpartum in women with gestational diabetes.</h4><i>Quansah DY, Horsch A, Gilbert L, Donath MY, Puder JJ, MySweetheart research group</i><br /><b>Background</b><br />Women with gestational diabetes mellitus (GDM) have higher insulin resistance and/or reduced secretion, an increased risk of future diabetes and cardiovascular disease, which may be due to a pathological activation of the innate immune system. C-reactive protein (CRP) is induced by inflammatory cytokines and reflects innate immune activity. We investigated the prospective associations between CRP during the perinatal period with adverse metabolic outcomes at 1 year postpartum in women with previous GDM.<br /><b>Methods</b><br />We analyzed data from the MySweetheart trial that included 211 women with GDM at 28-32 weeks gestational age (GA). CRP was measured during  pregnancy at 28-32 weeks GA, at 6-8 weeks and at 1 year postpartum. Metabolic outcomes at 1 year postpartum included weight, total and central body fat, measures of insulin resistance and secretion and presence of the metabolic syndrome (MetS). A 75 g oral glucose tolerance test was performed to measure glucose and insulin values every 30 min over 2 h to calculate indices of insulin resistance (MATSUDA, HOMA-IR) and of absolute (AUC<sub>ins/glu</sub>, HOMA-B) and insulin resistance-adjusted insulin secretion (ISSI-2).<br /><b>Results</b><br />CRP during pregnancy and at 6-8 weeks postpartum predicted increased weight, body fat and visceral adipose tissue (VAT), insulin resistance (higher HOMA-IR, lower MATSUDA), absolute insulin secretion (HOMA-B, AUC<sub>ins/glu</sub>), a reduced adjusted insulin secretion (ISSI-2) and a higher prevalence of the MetS at 1 year postpartum (all p ≤ 0.036). These relationships particularly those concerning CRP during pregnancy, were independent of weight ( for VAT, insulin resistance and secretion indices, MetS; all p ≤ 0.032) and of body fat ( for VAT, MATSUDA, MetS; all p ≤ 0.038).  <br /><b>Conclusion:</b><br/>CRP during pregnancy and in the early postpartum predicted an adverse cardio-metabolic profile in women with prior GDM at 1 year postpartum independent of weight. The prospective association of CRP with increased insulin resistance and reduced adjusted insulin secretion hint to the role of inflammation in the development of impaired metabolism after GDM and could be used as an early marker for risk stratification.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 27 Oct 2023; 22:291</small></div>

<div><h4>Glycemic control, HbA1c variability, and major cardiovascular adverse outcomes in type 2 diabetes patients with elevated cardiovascular risk: insights from the ACCORD study.</h4><i>Pei J, Wang X, Pei Z, Hu X</i><br /><b>Background</b><br />Although recent guidelines advocate for HbA1c target individualization, a comprehensive criterion for patient categorization remains absent. This study aimed to categorize HbA1c variability levels and explore the relationship between glycemic control, cardiovascular outcomes, and mortality across different degrees of variability.<br /><b>Methods</b><br />Action to Control Cardiovascular Risk in Diabetes study data were used. HbA1c variability was measured using the HbA1c variability score (HVS) and standard deviation (SD). K-means and K-medians clustering were used to combine the HVS and SD.<br /><b>Results</b><br />K-means clustering was the most stable algorithm with the lowest clustering similarities. In the low variability group, intensive glucose-lowering treatment significantly reduced the risk of adverse cardiovascular outcomes (HR: 0·78 [95% CI: 0·63, 0·97]) without increasing mortality risk (HR: 1·07 [0.81, 1·42]); the risk of adverse cardiovascular events (HR: 1·33 [1·14, 1·56]) and all-cause mortality (HR: 1·23 [1·01,1·51]) increased with increasing mean HbA1c. In the high variability group, treatment increased the risk of cardiovascular events (HR: 2.00 [1·54, 2·60]) and mortality (HR: 2·20 [1·66, 2·92]); a higher mean HbA1c (7·86%, [7·66%, 8·06%]) had the lowest mortality risk, when the mean HbA1c was < 7·86%, a higher mean HbA1c was associated with a lower mortality risk (HR: 0·63 [0·42, 0·95]). In the medium variability group, a mean HbA1c around 7·5% was associated with the lowest risk.<br /><b>Conclusions</b><br />HbA1c variability can guide glycemic control targets for patients with type 2 diabetes. For patients with low variability, the lower the HbA1c, the lower the risk. For those with medium variability, controlling HbA1c at 7·5% provides the maximum benefit. For patients with high variability, a mean HbA1c of around 7·8% presents the lowest risk of all-cause mortality, a lower HbA1c did not provide cardiovascular benefits but instead increased the mortality risk. Further studies, especially those with patients that reflect the general population with type 2 diabetes undergoing the latest therapeutic approaches, are essential to validate the conclusions of this study.<br /><br />© 2023. The Author(s).<br /><br /><small>Cardiovasc Diabetol: 27 Oct 2023; 22:287</small></div>

<div><h4>Familial co-aggregation and shared genetics of cardiometabolic disorders and traits: data from the multi-generational Lifelines Cohort Study.</h4><i>Triatin RD, Chen Z, Ani A, Wang R, ... Thio CHL, Snieder H</i><br /><b>Background</b><br />It is unclear to what extent genetics explain the familial clustering and the co-occurrence of distinct cardiometabolic disorders in the general population. We therefore aimed to quantify the familial (co-)aggregation of various cardiometabolic disorders and to estimate the heritability of cardiometabolic traits and their genetic correlations using the large, multi-generational Lifelines Cohort Study.<br /><b>Methods</b><br />We used baseline data of 162,416 participants from Lifelines. Cardiometabolic disorders including type 2 diabetes (T2D), cardiovascular diseases, hypertension, obesity, hypercholesterolemia, and metabolic syndrome (MetS), were defined in adult participants. Fifteen additional cardiometabolic traits indexing obesity, blood pressure, inflammation, glucose regulation, and lipid levels were measured in all included participants. Recurrence risk ratios (λ<sub>R</sub>) for first-degree relatives (FDR) indexed familial (co-)aggregation of cardiometabolic disorders using modified conditional Cox proportional hazards models and were compared to those of spouses. Heritability (h<sup>2</sup>), shared environment, and genetic correlation (r<sub>g</sub>) were estimated using restricted maximum likelihood variance decomposition methods, adjusted for age, age<sup>2</sup>, and sex.<br /><b>Results</b><br />Individuals with a first-degree relative with a cardiometabolic disorder had a higher risk of the same disorder, ranging from λ<sub>FDR</sub> of 1.23 (95% CI 1.20-1.25) for hypertension to λ<sub>FDR</sub> of 2.48 (95% CI 2.15-2.86) for T2D. Most of these were higher than in spouses (λ<sub>Spouses</sub> < λ<sub>FDR</sub>), except for obesity which was slightly higher in spouses. We found moderate heritability for cardiometabolic traits (from h<sup>2</sup><sub>CRP</sub>: 0.26 to h<sup>2</sup><sub>HDL</sub>: 0.50). Cardiometabolic disorders showed positive familial co-aggregation, particularly between T2D, MetS, and obesity (from λ<sub>FDR obesity-MetS</sub>: 1.28 (95% CI 1.24-1.32) to λ<sub>FDR MetS-T2D</sub>: 1.61 (95% CI 1.52-1.70)), consistent with the genetic correlations between continuous intermediate traits (ranging from r<sub>g HDL-Triglycerides</sub>: - 0.53 to r<sub>g LDL-Apolipoprotein B</sub>: 0.94).<br /><b>Conclusions</b><br />There is positive familial (co-)aggregation of cardiometabolic disorder, moderate heritability of intermediate traits, and moderate genetic correlations between traits. These results indicate that shared genetics and common genetic architecture contribute to cardiometabolic disease.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 21 Oct 2023; 22:282</small></div>

<div><h4>Triglyceride-glucose index is associated with recurrent revascularization in patients with type 2 diabetes mellitus after percutaneous coronary intervention.</h4><i>Chen Q, Xiong S, Zhang Z, Yu X, ... Zheng J, Cai L</i><br /><b>Background</b><br />The Triglyceride-glucose (TyG) index, as a surrogate marker of insulin resistance, is independently associated with the severity of coronary artery lesions and the prognosis of coronary heart disease. The investigation aimed to explore the relationship between the TyG index and recurrent revascularization in individuals with type 2 diabetes mellitus (T2DM) resulting from the progression of lesions or in-stent restenosis (ISR) after percutaneous coronary intervention (PCI).<br /><b>Method</b><br />A total of 633 patients who met the inclusion and exclusion criteria were enrolled and divided into three groups based on the tertiles of the TyG index. The primary endpoint was recurrent revascularization resulting from the progression of lesions or ISR. All-cause death was considered as the competing risk event. Competing risk analysis and Cox regression analysis for predicting recurrent revascularization after PCI were conducted stepwise. Variables were standardized to make the hazard ratio (HR), subdistribution hazard ratio (SHR) and corresponding 95% CI more consistent prior to being used for fitting the multivariate risk model. The predictive ability of the TyG index was evaluated using several measures, including the ROC curve, likelihood ratio test, Akaike\'s information criteria, category-free continuous net reclassification improvement (cNRI > 0), and integrated discrimination improvement (IDI). Internal validation was conducted through bootstrapping with 1000 resamples.<br /><b>Results</b><br />During a median follow-up period of 18.33 months, a total of 64 (10.11%) patients experienced recurrent revascularization, including 55 cases of lesion progression and 9 cases of in-stent restenosis. After controlling for competitive risk events, the TyG index was independently associated with a higher risk of recurrent revascularization [SHR:1.4345, (95% CI 1.1458-1.7959), P = 0.002]. The likelihood ratio test and Akaike\'s information criteria showed that the TyG index significantly improves the prognostic ability. Additionally, adding the TyG index improved the ability of the established risk model in predicting recurrent revascularization, indicated by a C-index of 0.759 (95% CI 0.724-0.792, P < 0.01), with a cNRI > 0 of 0.170 (95% CI 0.023-0.287, P < 0.05), and an IDI of 0.024 (95% CI 0.009-0.039, P = 0.002). These results remained consistent when the models containing TyG index were confirmed using an internal bootstrap validation method.<br /><b>Conclusion</b><br />The findings highlight the potential of the TyG index as a predictor of recurrent revascularization. Lesion progression emerged as the primary contributor to recurrent revascularization instead of in-stent restenosis. The incorporation of the TyG index into risk prediction models is likely to be beneficial for accurate risk stratification in order to improve prognosis.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 21 Oct 2023; 22:284</small></div>

<div><h4>Impact of stress hyperglycemia ratio on mortality in patients with critical acute myocardial infarction: insight from american MIMIC-IV and the chinese CIN-II study.</h4><i>Liu J, Zhou Y, Huang H, Liu R, ... Tan N, Gao F</i><br /><b>Background</b><br />Among patients with acute coronary syndrome and percutaneous coronary intervention, stress hyperglycemia ratio (SHR) is primarily associated with short-term unfavorable outcomes. However, the relationship between SHR and long-term worsen prognosis in acute myocardial infarction (AMI) patients admitted in intensive care unit (ICU) are not fully investigated, especially in those with different ethnicity. This study aimed to clarify the association of SHR with all-cause mortality in critical AMI patients from American and Chinese cohorts.<br /><b>Methods</b><br />Overall 4,337 AMI patients with their first ICU admission from the American Medical Information Mart for Intensive Care (MIMIC)-IV database (n = 2,166) and Chinese multicenter registry cohort Cardiorenal ImprovemeNt II (CIN-II, n = 2,171) were included in this study. The patients were divided into 4 groups based on quantiles of SHR in both two cohorts.<br /><b>Results</b><br />The total mortality was 23.8% (maximum follow-up time: 12.1 years) in American MIMIC-IV and 29.1% (maximum follow-up time: 14.1 years) in Chinese CIN-II. In MIMIC-IV cohort, patients with SHR of quartile 4 had higher risk of 1-year (adjusted hazard radio [aHR] = 1.87; 95% CI: 1.40-2.50) and long-term (aHR = 1.63; 95% CI: 1.27-2.09) all-cause mortality than quartile 2 (as reference). Similar results were observed in CIN-II cohort (1-year mortality: aHR = 1.44; 95%CI: 1.03-2.02; long-term mortality: aHR = 1.32; 95%CI: 1.05-1.66). In both two group, restricted cubic splines indicated a J-shaped correlation between SHR and all-cause mortality. In subgroup analysis, SHR was significantly associated with higher 1-year and long-term all-cause mortality among patients without diabetes in both MIMIC-IV and CIN-II cohort.<br /><b>Conclusion</b><br />Among critical AMI patients, elevated SHR is significantly associated with and 1-year and long-term all-cause mortality, especially in those without diabetes, and the results are consistently in both American and Chinese cohorts.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 21 Oct 2023; 22:281</small></div>

<div><h4>Non-invasive detection of early microvascular changes in juveniles with type 1 diabetes.</h4><i>Bogusz-Górna K, Polańska A, Dańczak-Pazdrowska A, Żaba R, ... Fichna P, Kędzia A</i><br /><b>Aims/hypothesis</b><br />The study aimed to assess the usefulness of capillaroscopy and photoplethysmography in the search for early vascular anomalies in children with type 1 diabetes.<br /><b>Methods</b><br />One hundred sixty children and adolescents aged 6-18, 125 patients with type 1 diabetes, and 35 healthy volunteers were enrolled in the study. We performed a detailed clinical evaluation, anthropometric measurements, nailfold capillaroscopy, and photoplethysmography.<br /><b>Results</b><br />Patients with diabetes had more often abnormal morphology in capillaroscopy (68.60%, p = 0.019), enlarged capillaries (32.6%, p = 0.006), and more often more over five meandering capillaries (20.90%, p = 0.026) compared to healthy controls. Meandering capillaries correlated with higher parameters of nutritional status. In a photoplethysmography, patients with diagnosed neuropathy had a higher percentage of flow disturbance curves (p < 0.001) with a reduced frequency of normal curves (p = 0.050).<br /><b>Conclusions</b><br />Capillaroscopic and photoplethysmographic examinations are non-invasive, painless, fast, and inexpensive. They are devoid of side effects, and there are no limitations in the frequency of their use and repetition. The usefulness of capillaroscopy and photoplethysmography in the study of microcirculation in diabetic patients indicates the vast application possibilities of these methods in clinical practice.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 21 Oct 2023; 22:285</small></div>

<div><h4>Triglyceride-glucose index is associated with severe obstructive coronary artery disease and atherosclerotic target lesion failure among young adults.</h4><i>Shali S, Luo L, Yao K, Sun X, ... Ge J, the GRAND investigators</i><br /><b>Background</b><br />Early diagnosis and treatment effectiveness of early-onset coronary artery disease (EOCAD) are crucial, and non-invasive predictive biomarkers are needed for young adults. We aimed to evaluate the usefulness of the triglyceride-glucose (TyG) index, a novel marker of insulin resistance, in identifying young CAD patients and predicting their risk of developing target lesion failure (TLF).<br /><b>Methods</b><br />We recruited EOCAD patients (luminal narrowing ≥ 70%) and controls free from CAD (luminal narrowing < 30%), both aged 45 years or younger, from 38 hospitals in China between 2017 and 2020. EOCAD patients who underwent successful percutaneous coronary intervention were followed for incident TLF. TyG index was defined as Ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2]. We used logistic regression and Cox proportional hazards modeling to evaluate the association of TyG index with prevalent EOCAD and incident TLF, respectively. The discriminatory ability of TyG index was assessed by the area under the receiver-operating characteristic curve (AUC).<br /><b>Results</b><br />Among the included 1513 EOCAD patients (39.6 ± 4.4 years, 95.4% male) and 1513 age-matched controls (39.0 ± 4.4 years, 46.4% male), TyG index was positively associated with the prevalence of EOCAD (adjusted odds ratio: 1.40, 95% confidence interval [CI] 1.23-1.60, per standard deviation [SD] increase in TyG index). The addition of TyG index to an empirical risk model provided an improvement in diagnostic ability for EOCAD, with a net reclassification improvement of 0.10 (95% CI 0.03-0.17, p = 0.005). During a medium of 33 month (IQR: 31-34 months) follow-up, 43 (3.3%) patients experienced TLF. Multivariate Cox regression model revealed that TyG index was an independent risk factor for TLF (adjusted hazard ratio [HR]: 2.410, 95% CI 1.07-5.42 comparing the top to bottom TyG index tertile groups; HR: 1.30, 95% CI 1.01-1.73, per SD increase in TyG index). Compared with a model of conventional risk factors alone, the addition of the TyG index modestly improved the AUC (0.722-0.734, p = 0.04) to predict TLF.<br /><b>Conclusions</b><br />TyG index is positively associated with prevalent EOCAD and incident TLF. TyG index appeared to be a valuable component of future efforts to improve CAD risk stratification and TLF outcome prediction among young adults.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 21 Oct 2023; 22:283</small></div>

<div><h4>The triglyceride-glucose index is a predictor for cardiovascular and all-cause mortality in CVD patients with diabetes or pre-diabetes: evidence from NHANES 2001-2018.</h4><i>Zhang Q, Xiao S, Jiao X, Shen Y</i><br /><b>Background</b><br />The association between the triglyceride-glucose (TyG) index and mortality in cardiovascular disease (CVD) patients with diabetes or pre-diabetes remains unclear. This study aimed to investigate the relationship between baseline TyG index and all-cause and cardiovascular (CV) mortality in CVD patients with diabetes or pre-diabetes among American adults. .<br /><b>Methods</b><br />This study enrolled 1072 CVD patients with diabetes or pre-diabetes from the National Health and Nutrition Examination Survey (2001-2018). Mortality outcomes were determined by linking to National Death Index (NDI) records up to December 31, 2019. Multivariate Cox proportional hazards models were constructed to analyze explore the associations between baseline TyG index and mortality. Non-linear correlations were explored using restricted cubic splines, and a two-piecewise Cox proportional hazards model for both sides of the inflection point was constructed.<br /><b>Results</b><br />During 7541 person-years of follow-up, a total of 461 all-cause deaths and 154 CVD-related deaths were recorded. The restricted cubic splines revealed a U-shaped association between the baseline TyG index with all-cause and CVD mortality in CVD patients with diabetes or pre-diabetes. Specifically, baseline TyG index lower than the threshold values (TyG index < 9.05 in all-cause mortality and < 8.84 in CVD mortality) was negatively associated with mortality (HR 0.47, 95% CI = 0.27-0.81 for all-cause mortality and HR 0.25, 95% CI = 0.07-0.89 for CVD mortality). In contrast, baseline TyG index higher than the threshold values (TyG index > 9.05 in all-cause mortality and > 8.84 in CVD mortality) was positively associated with mortality (HR 1.42, 95% CI = 1.02-1.99 for all-cause mortality and HR 1.77, 95% CI = 1.08-2.91 for CVD mortality).<br /><b>Conclusions</b><br />A U-shaped association was observed between the baseline TyG index with CVD and all-cause mortality in CVD patients with diabetes or pre-diabetes in a American population. The thresholds of 8.84 and 9.05 for CVD and all-cause mortality, respectively.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 17 Oct 2023; 22:279</small></div>

<div><h4>Influence of diabetes mellitus on the pathological profile of aortic stenosis: a sex-based approach.</h4><i>Martín-Núñez E, Goñi-Olóriz M, Matilla L, Garaikoetxea M, ... Jover E, López-Andrés N</i><br /><b>Background</b><br />Diabetes mellitus (DM) accelerates the progression of aortic stenosis (AS), but how their underlying molecular mechanisms interact is not clear. Moreover, whether DM contributes to clinically relevant sex-differences in AS is unknown. In this work we aim to characterize the sex-specific profile of major pathological mechanisms fundamental to aortic valve (AV) degeneration in AS patients with or without concomitant DM.<br /><b>Methods</b><br />283 patients with severe AS undergoing surgical valve replacement (27.6% DM, 59.4% men) were recruited. Expression of pathological markers related to AS were thoroughly assessed in AVs and valve interstitial cells (VICs) according to sex and presence of DM. Complementary in vitro experiments in VICs in the presence of high-glucose levels (25 mM) for 24, 48 and 72 h were performed.<br /><b>Results</b><br />Oxidative stress and metabolic dysfunction markers were increased in AVs from diabetic AS patients compared to non-diabetic patients in both sexes. However, disbalanced oxidative stress and enhanced inflammation were more predominant in AVs from male AS diabetic patients. Osteogenic markers were exclusively increased in the AVs of diabetic women. Basal characterization of VICs confirmed that oxidative stress, inflammation, calcification, and metabolic alteration profiles were increased in diabetic VICs with sex-specific differences. VICs cultured in hyperglycemic-like conditions triggered inflammatory responses in men, whereas in women rapid and higher production of pro-osteogenic molecules.<br /><b>Conclusions</b><br />DM produces sex-specific pathological phenotypes in AV of AS patients. Importantly, women with diabetes are more prone to develop AV calcification. DM should be considered as a risk factor in AS especially in women.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 17 Oct 2023; 22:280</small></div>

<div><h4>SGLT2 inhibition, circulating metabolites, and atrial fibrillation: a Mendelian randomization study.</h4><i>Li J, Yu Y, Sun Y, Yu B, ... Lu Y, Wang N</i><br /><b>Background</b><br />Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown promise in reducing the risk of atrial fibrillation (AF). However, the results are controversial and the underlying metabolic mechanism remains unclear. Emerging evidence implied that SGLT2 inhibitors have extra beneficial metabolic effects on circulating metabolites beyond glucose control, which might play a role in reducing the risk of AF. Hence, our study aimed to investigate the effect of circulating metabolites mediating SGLT2 inhibition in AF by Mendelian randomization (MR).<br /><b>Methods</b><br />A two-sample and two-step MR study was conducted to evaluate the association of SGLT2 inhibition with AF and the mediation effects of circulating metabolites linking SGLT2 inhibition with AF. Genetic instruments for SGLT2 inhibition were identified as genetic variants, which were both associated with the expression of SLC5A2 gene and glycated hemoglobin level (HbA1c). Positive control analysis on type 2 diabetes mellitus (T2DM) was conducted to validate the selection of genetic instruments.<br /><b>Results</b><br />Genetically predicted SGLT2 inhibition (per 1 SD decrement in HbA1c) was associated with reduced risk of T2DM (odds ratio [OR] = 0.63 [95% CI 0.45, 0.88], P = 0.006) and AF (0.51 [0.27, 0.97], P = 0.039). Among 168 circulating metabolites, two metabolites were both associated with SGLT2 inhibition and AF. The effect of SGLT2 inhibition on AF through the total concentration of lipoprotein particles (0.88 [0.81, 0.96], P = 0.004) and the concentration of HDL particles (0.89 [0.82, 0.97], P = 0.005), with a mediated proportion of 8.03% (95% CI [1.20%, 14.34%], P = 0.010) and 7.59% ([1.09%, 13.34%], P = 0.011) of the total effect, respectively.<br /><b>Conclusions</b><br />This study supported the association of SGLT2 inhibition with a reduced risk of AF. The total concentration of lipoprotein particles and particularly the concentration of HDL particles might mediate this association. Further mechanistic and clinical studies research are needed to understand the mediation effects of circulating metabolites especially blood lipids in the association between SGLT2 inhibition and AF.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 17 Oct 2023; 22:278</small></div>

<div><h4>Data from network meta-analyses can inform clinical practice guidelines and decision-making in diabetes management: perspectives of the taskforce of the guideline workshop.</h4><i>Ceriello A, Rodbard HW, Battelino T, Brosius F, ... Schnell O, Taskforce of the Guideline Workshop</i><br /><AbstractText>In recent years, several novel agents have become available to treat individuals with type 2 diabetes (T2D), such as sodium-glucose cotransporter-2 inhibitors (SGLT-2i), tirzepatide, which is a dual glucose-dependent insulinotropic polypeptide receptor agonist (GIP RA)/glucagon-like peptide-1 receptor agonist (GLP-1 RA), and finerenone, a non-steroidal mineralocorticoid receptor antagonist (MRA) that confers significant renal and cardiovascular benefits in individuals with (CKD). New medications have the potential to improve the lives of individuals with diabetes. However, clinicians are challenged to understand the benefits and potential risks associated with these new and emerging treatment options. In this article, we discuss how use of network meta-analyses (NMA) can fill this need.</AbstractText><br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 13 Oct 2023; 22:277</small></div>

<div><h4>Prognostic significance of the stress hyperglycemia ratio in critically ill patients.</h4><i>Li L, Zhao M, Zhang Z, Zhou L, ... Hu Z, Yao Y</i><br /><b>Background</b><br />The stress hyperglycemia ratio (SHR) has demonstrated a noteworthy association with unfavorable cardiovascular clinical outcomes and heightened in-hospital mortality. Nonetheless, this relationship in critically ill patients remains uncertain. This study aims to elucidate the correlation between SHR and patient prognosis within the critical care setting.<br /><b>Methods</b><br />A total of 8978 patients admitted in intensive care unit (ICU) were included in this study. We categorized SHR into uniform groups and assessed its relationship with mortality using logistic or Cox regression analysis. Additionally, we employed the restricted cubic spline (RCS) analysis method to further evaluate the correlation between SHR as a continuous variable and mortality. The outcomes of interest in this study were in-hospital and 1-year all-cause mortality.<br /><b>Results</b><br />In this investigation, a total of 825 (9.2%) patients experienced in-hospital mortality, while 3,130 (34.9%) individuals died within the 1-year follow-up period. After adjusting for confounding variables, we identified a U-shaped correlation between SHR and both in-hospital and 1-year mortality. Specifically, within the SHR range of 0.75-0.99, the incidence of adverse events was minimized. For each 0.25 increase in the SHR level within this range, the risk of in-hospital mortality rose by 1.34-fold (odds ratio [OR]: 1.34, 95% CI: 1.25-1.44), while a 0.25 decrease in SHR within 0.75-0.99 range increased risk by 1.38-fold (OR: 1.38, 95% CI: 1.10-1.75).<br /><b>Conclusion</b><br />There was a U-shaped association between SHR and short- and long-term mortality in critical ill patients, and the inflection point of SHR for poor prognosis was identified at an SHR value of 0.96.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 13 Oct 2023; 22:275</small></div>

<div><h4>Direct regulation of the cardiac ryanodine receptor (RyR2) by O-GlcNAcylation.</h4><i>Okolo CA, Khaing EP, Mereacre V, Wallace RS, ... Erickson JR, Jones PP</i><br /><b>Background</b><br />O-GlcNAcylation is the enzymatic addition of a sugar, O-linked β-N-Acetylglucosamine, to the serine and threonine residues of proteins, and is abundant in diabetic conditions. We have previously shown that O-GlcNAcylation can trigger arrhythmias by indirectly increasing pathological Ca<sup>2+</sup> leak through the cardiac ryanodine receptor (RyR2) via Ca<sup>2+</sup>/calmodulin-dependent kinase II (CaMKII). However, RyR2 is well known to be directly regulated by other forms of serine and threonine modification, therefore, this study aimed to determine whether RyR2 is directly modified by O-GlcNAcylation and if this also alters the function of RyR2 and Ca<sup>2+</sup> leak.<br /><b>Methods</b><br />O-GlcNAcylation of RyR2 in diabetic human and animal hearts was determined using western blotting. O-GlcNAcylation of RyR2 was pharmacologically controlled and the propensity for Ca<sup>2+</sup> leak was determined using single cell imaging. The site of O-GlcNAcylation within RyR2 was determined using site-directed mutagenesis of RyR2.<br /><b>Results</b><br />We found that RyR2 is modified by O-GlcNAcylation in human, animal and HEK293 cell models. Under hyperglycaemic conditions O-GlcNAcylation was associated with an increase in Ca<sup>2+</sup> leak through RyR2 which persisted after CaMKII inhibition. Conversion of serine-2808 to alanine prevented an O-GlcNAcylation induced increase in Ca<sup>2+</sup> leak.<br /><b>Conclusions</b><br />These data suggest that the function of RyR2 can be directly regulated by O-GlcNAcylation and requires the presence of serine-2808.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 13 Oct 2023; 22:276</small></div>

<div><h4>Prognostic significance of plasma SDF-1 in acute ischemic stroke patients with diabetes mellitus: the CATIS trial.</h4><i>You S, Chen H, Miao M, Du J, ... Cao Y, Zhong C</i><br /><b>Background:</b><br/>and objectives</b><br />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).<br /><b>Methods</b><br />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.<br /><b>Results</b><br />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.<br /><b>Conclusions</b><br />Elevated plasma SDF-1 was significantly associated with an increased risk of recurrent stroke and cardiovascular events only in ischemic patients with diabetes mellitus.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 10 Oct 2023; 22:274</small></div>

<div><h4>Sodium-glucose co-transporter 2 inhibitor use in patients with diabetes mellitus undergoing endovascular therapy for symptomatic peripheral artery disease.</h4><i>Takahara M, Soga Y, Fujihara M, Iida O, Kawasaki D</i><br /><b>Background</b><br />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.<br /><b>Methods</b><br />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.<br /><b>Results</b><br />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).<br /><b>Conclusions</b><br />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.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 05 Oct 2023; 22:273</small></div>

<div><h4>Association between a mediterranean lifestyle and Type 2 diabetes incidence: a prospective UK biobank study.</h4><i>Maroto-Rodriguez J, Ortolá R, Carballo-Casla A, Iriarte-Campo V, ... Rodríguez-Artalejo F, Sotos-Prieto M</i><br /><b>Background</b><br />There is mounting evidence that the Mediterranean diet prevents type 2 diabetes, but little is known about the role of Mediterranean lifestyles other than diet and among non-Mediterranean populations. This work aimed to examine the association between a comprehensive Mediterranean-type lifestyle and type 2 diabetes incidence in a British adult population.<br /><b>Methods</b><br />We used data from 112,493 individuals free of cardiovascular disease and type 2 diabetes mellitus, aged 40-69 years, from the UK Biobank cohort, who were followed from 2009 to 2010 to 2021. The Mediterranean lifestyle was assessed through the 25-item MEDLIFE index, which comprises three blocks: (a) \"Mediterranean food consumption\", (b) \"Mediterranean dietary habits\", (c) \"Physical activity, rest, social habits, and conviviality\". Diabetes incidence was obtained from clinical records. Cox proportional-hazards regression models were used to analyze associations and adjusted for the main potential confounders.<br /><b>Results</b><br />After a median follow-up of 9.4 years, 2,724 cases of type 2 diabetes were ascertained. Compared to the first quartile of MEDLIFE adherence, the hazard ratios (95% confidence interval) for increasing quartiles of adherence were 0.90 (0.82-0.99), 0.80 (0.72-0.89) and 0.70 (0.62-0.79) (p-trend < 0.001). All three blocks of MEDLIFE were independently associated with lower risk of diabetes.<br /><b>Conclusions</b><br />Higher adherence to the MEDLIFE index was associated with lower risk of type 2 diabetes in the UK Biobank. A Mediterranean-type lifestyle, culturally adapted to non-Mediterranean populations, could help prevent diabetes.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 04 Oct 2023; 22:271</small></div>

<div><h4>Association between estimated glomerular filtration rate slope and cardiovascular disease among individuals with and without diabetes: a prospective cohort study.</h4><i>Ramezankhani A, Azizi F, Hadaegh F</i><br /><b>Background</b><br />Previous studies have reported an association between a significant decline in estimated glomerular filtration rate (eGFR) over time and an increased risk of cardiovascular disease (CVD). This study aimed to investigate the association between the eGFR slope and CVD among individuals with and without diabetes.<br /><b>Methods</b><br />This prospective cohort study was conducted within the Tehran Lipid and Glucose Study (TLGS) framework. We studied 6919 adults aged 20-70 years, including 985 with diabetes and 5934 without diabetes. The eGFR slope was determined based on repeated measurements of eGFR through linear mixed-effects models. A multivariable Cox proportional hazard model was employed to evaluate the association between eGFR slope, both in continuous and categorical form, and the risk of CVD.<br /><b>Results</b><br />The slopes of eGFR exhibited a bell-shaped distribution, with a mean (standard deviation (SD)) of -0.63 (0.13) and - 0.70 (0.14) ml/min per 1.73 m<sup>2</sup> per year in individuals with and without diabetes, respectively. During a median follow-up of 8.22 years, following the 9-year eGFR slope ascertainment period, a total of 551 CVD events (195 in patients with diabetes) were observed. Among individuals with diabetes, a steeper decline in eGFR slope was significantly associated with a higher risk of CVD events, even after adjusting for baseline eGFR, demographic factors, and traditional risk factors for CVD; slopes of (-1.05 to -0.74) and (-0.60 to -0.52) were associated with 2.12 and %64 higher risks for CVD, respectively, compared with a slope of (-0.51 to 0.16). Among individuals without diabetes, the annual eGFR slope did not show a significant association with the risk of CVD.<br /><b>Conclusion</b><br />Monitoring the eGFR slope may serve as a potential predictor of CVD risk in individuals with diabetes.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 04 Oct 2023; 22:270</small></div>

<div><h4>Chronic kidney outcomes associated with GLP-1 receptor agonists versus long-acting insulins among type 2 diabetes patients requiring intensive glycemic control: a nationwide cohort study.</h4><i>Peng ZY, Yang CT, Lin WH, Yao WY, Ou HT, Kuo S</i><br /><b>Background</b><br />Effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus long-acting insulins (LAIs) on preventing progressive chronic kidney outcomes is uncertain for type 2 diabetes (T2D) patients requiring intensive glycemic control. This study aimed to evaluate comparative effectiveness of GLP-1RA versus LAI therapies on progressive chronic kidney outcomes among patients having poor glycemic control and requiring these injectable glucose-lowering agents (GLAs).<br /><b>Methods</b><br />7279 propensity-score-matched pairs of newly stable GLP-1RA and LAI users in 2013-2018 were identified from Taiwan\'s National Health Insurance Research Database and followed until death or 12/31/2019 (intention-to-treat). Subdistributional hazard model was utilized to assess the comparative effectiveness on a composite renal outcome (i.e., renal insufficiency [eGFR < 15 mL/min/1.73 m<sup>2</sup>], dialysis-dependent end-stage renal disease [ESRD], or renal death) and its individual components. Sensitivity analyses with the as-treated scenario, PS weighting, high-dimensional PS techniques, using cardiovascular diseases (CVDs) as positive control outcomes, and interaction testing were performed.<br /><b>Results</b><br />In primary analyses, subdistribution hazard ratios (95% CIs) for initiating GLP-1RAs versus LAIs for the composite renal outcome, renal insufficiency, dialysis-dependent ESRD, and renal death were 0.39 (0.30-0.51), 0.43 (0.32-0.57), 0.29 (0.20-0.43), and 0.28 (0.15-0.51), respectively. Sensitivity analysis results were consistent with the primary findings. CVD history and the medication possession ratio of prior oral GLAs possessed modification effects on GLP-1RA-associated kidney outcomes.<br /><b>Conclusion</b><br />Using GLP-1RAs versus LAIs was associated with kidney benefits in T2D patients requiring intensive glycemic control and potentially at high risk of kidney progression. GLP-1RAs should be prioritized to patients with CVDs or adherence to prior oral GLAs to maximize kidney benefits.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 04 Oct 2023; 22:272</small></div>

<div><h4>Timing of SGLT2i initiation after acute myocardial infarction.</h4><i>von Lewinski D, Kolesnik E, Aziz F, Benedikt M, ... Siller-Matula J, Sourij H</i><br /><b>Background</b><br />Pharmacological post-MI treatment is routinely initiated at intensive/cardiac care units. However, solid evidence for an early start of these therapies is only available for dual platelet therapy and statins, whereas data on beta blockers and RAAS inhibitors are heterogenous and mainly limited to STEMI and heart failure patients. Recently, the EMMY trial provided the first evidence on the beneficial effects of SGLT2 inhibitors (SGLT2i) when initiated early after PCI. In patients with type 2 diabetes mellitus, SGLT2i are considered \"sick days drugs\" and it, therefore, remains unclear if very early SGLT2i initiation following MI is as safe and effective as delayed initiation.<br /><b>Methods and results</b><br />The EMMY trial evaluated the effect of empagliflozin on NT-proBNP and functional and structural measurements. Within the Empagliflozin group, 22 (9.5%) received early treatment (< 24 h after PCI), 98 (42.2%) within a 24 to < 48 h window (intermediate), and 111 (48.1%) between 48 and 72 h (late). NT-proBNP levels declined by 63.5% (95%CI: - 69.1; - 48.1) in the early group compared to 61.0% (- 76.0; - 41.4) in the intermediate and 61.9% (- 70.8; - 45.7) in the late group (n.s.) within the Empagliflozin group with no significant treatment groups-initiation time interaction (p<sub>int</sub> = 0.96). Secondary endpoints of left ventricular function (LV-EF, e/e`) as well as structure (LVESD and LVEDD) were also comparable between the groups. No significant difference in severe adverse event rate between the initiation time groups was detected.<br /><b>Conclusion</b><br />Very early administration of SGLT2i after acute myocardial infarction does not show disadvantageous signals with respect to safety and appears to be as effective in reducing NT-proBNP as well as improving structural and functional LV markers as initiation after 2-3 days.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 30 Sep 2023; 22:269</small></div>

<div><h4>Elevated high-sensitivity C-reactive protein levels increase the risk of new-onset cardiac conduction disorders.</h4><i>Wu L, Wu M, Zhao D, Chen S, ... Miao C, Hong J</i><br /><b>Background</b><br />Previous studies have reported that inflammatory responses can promote the onset of cardiovascular diseases; however, its association with cardiac conduction disorders remains unclear. The present community-based cohort study aimed to elucidate the effects of inflammatory responses on the risk of developing cardiac conduction disorders.<br /><b>Methods</b><br />After the exclusion of participants failing to meet the inclusion criteria, 86,234 eligible participants (mean age: 50.57 ± 11.88 years) were included. The participants were divided into high-sensitivity C-reactive protein (hsCRP)  ≤  3 mg/L, and hsCRP > 3 mg/L groups based on hsCRP values. Multivariate Cox proportional hazard model was used to analyze the relationship between inflammatory responses and various cardiac conduction disorders.<br /><b>Results</b><br />After adjusting for confounding factors, we observed that compared with the hsCRP ≤ 3 mg/L group, the hsCRP > 3 mg/L group exhibited increased risks of atrioventricular block (hazard ratio [HR]:1.64, 95%confidence interval [CI] 1.44-1.87) and left (HR:1.25, 95% CI 1.07-1.45) and right bundle branch block (HR:1.31, 95% CI 1.17-1.47). Moreover, the risk of various cardiac conduction disorders increased for every 1 standard deviation increase in log (hsCRP). The restricted cubic spline function confirmed a linear relationship between log (hsCRP) and the risk of developing cardiac conduction disorders (All nonlinearity P > 0.05).<br /><b>Conclusions</b><br />High hsCRP levels are an independent risk factor for cardiac conduction disorders, and hsCRP levels are dose-dependently associated with the risk of conduction disorders. Our study results may provide new strategies for preventing cardiac conduction disorders.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 30 Sep 2023; 22:268</small></div>

<div><h4>Yearly attained adherence to Mediterranean diet and incidence of diabetes in a large randomized trial.</h4><i>Martínez-González MA, Montero P, Ruiz-Canela M, Toledo E, ... Castañer O, Salas-Salvadó J</i><br /><b>Background</b><br />Several large observational prospective studies have reported a protection by the traditional Mediterranean diet against type 2 diabetes, but none of them used yearly repeated measures of dietary intake. Repeated measurements of dietary intake are able to improve subject classification and to increase the quality of the assessed relationships in nutritional epidemiology. Beyond observational studies, randomized trials provide stronger causal evidence. In the context of a randomized trial of primary cardiovascular prevention, we assessed type 2 diabetes incidence according to yearly repeated measures of compliance with a nutritional intervention based on the traditional Mediterranean diet.<br /><b>Methods</b><br />PREDIMED (\'\'PREvención con DIeta MEDiterránea\'\') was a Spanish trial including 7447 men and women at high cardiovascular risk. We assessed 3541 participants initially free of diabetes and originally randomized to 1 of 3 diets: low-fat diet (n = 1147, control group), Mediterranean diet supplemented with extra virgin olive (n = 1154) or Mediterranean diet supplemented with mixed nuts (n = 1240). As exposure we used actual adherence to Mediterranean diet (cumulative average), yearly assessed with the Mediterranean Diet Adherence Screener (scoring 0 to 14 points), and repeated up to 8 times (baseline and 7 consecutive follow-up years). This score was categorized into four groups: < 8, 8-< 10, 10- < 12, and 12-14 points. The outcome was new-onset type 2 diabetes.<br /><b>Results</b><br />Multivariable-adjusted hazard ratios from time-varying Cox models were 0.80 (95% confidence interval, 0.70-0.92) per + 2 points in Mediterranean Diet Adherence Screener (linear trend p = .001), and 0.46 (0.25-0.83) for the highest (12-14 points) versus the lowest (< 8) adherence. This inverse association was maintained after additionally adjusting for the randomized arm. Age- and sex-adjusted analysis of a validated plasma metabolomic signature of the Mediterranean Diet Adherence Screener (constituted of 67 metabolites) in a subset of 889 participants also supported these results.<br /><b>Conclusions</b><br />Dietary intervention trials should quantify actual dietary adherence throughout the trial period to enhance the benefits and to assist results interpretation. A rapid dietary assessment tool, yearly repeated as a screener, was able to capture a strong inverse linear relationship between Mediterranean diet and type 2 diabetes. Trial registration ISRCTN35739639.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 29 Sep 2023; 22:262</small></div>

<div><h4>Association of cardio-renal biomarkers and mortality in the U.S.: a prospective cohort study.</h4><i>Yang F, Wang M, Chen Y, Wu J, Li Y</i><br /><b>Objective</b><br />Diabetes poses a significant threat to human health. There is a lack of large-scale cohort studies to explore the association between mortality risk and indicators beyond blood glucose monitoring in diabetic populations.<br /><b>Methods</b><br />Multivariable Cox proportional hazards regression models were performed to investigate the association of 13 blood biomarkers with mortality risk in the National Health and Nutrition Examination Survey (NHANES) and biomarker levels were log-transformed and correlated with mortality.<br /><b>Results</b><br />During a median follow-up of 7.42 years, 1783 diabetic patients were enrolled. Compared to traditional risk factors, the addition of hs-cTnT, hs-cTnI, NT-proBNP, creatinine, cystatin C, and β-2 microglobulin biomarkers increased the predictive ability for all-cause mortality by 56.4%, 29.5%, 38.1%, 18.8%, 35.7%, and 41.3%, respectively. However, the inclusion of blood glucose monitoring had no impact on the prediction of all-cause mortality. Compared with the 1st quartiles of creatinine and Cystatin C, the risk of diabetes mortality were higher in the highest quartiles (HR: 5.16, 95% CI: 1.87-14.22; HR: 10.06, 95% CI: 4.20-24.13).<br /><b>Conclusions</b><br />In the diabetic population, elevated plasma levels of hs-cTnT, hs-cTnI, NT-proBNP, creatinine, cystatin C, and β-2 microglobulin serve as robust and straightforward predictors of long-term mortality compared to blood glucose levels and HbA1c values. Creatinine and cystatin C stand out as more precise markers for predicting diabetes mortality prior to blood glucose monitoring.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 29 Sep 2023; 22:265</small></div>

<div><h4>Association of triglyceride-glucose index trajectory and frailty in urban older residents: evidence from the 10-year follow-up in a cohort study.</h4><i>Yuan Y, Chen S, Lin C, Huang X, ... Huang F, Zhu P</i><br /><b>Background</b><br />Frailty is an age-related geriatric syndrome that leads to a series of clinically negative events. A better understanding of the factors associated with frailty assists in preventing its progression. The triglyceride-glucose (TyG) index, a simple alternative index of insulin resistance, has not yet been proven to be associated with frailty. The present study aimed to investigate the association between the TyG index and its trajectory with frailty from a cross-sectional, retrospective and prospective level based on an ongoing cohort.<br /><b>Methods</b><br />This longitudinal study included 1,866 older residents from the \"Fujian prospective aging cohort\" (ChiCTR 2,000,032,949). The TyG index was calculated as ln [fasting triglyceride (mg/dL) ╳ fasting plasma glucose (mg/dL)/2] and group-based trajectory model (GBTM) was applied to identify the trajectory of TyG index. The association between different trajectory groups of TyG index with frailty risk were estimated using multinomial logistic regression analysis.<br /><b>Results</b><br />In the cross-sectional analysis, the highest quartile of the TyG index was associated with an increased risk of frailty (TyG index Q4 vs. Q1, OR = 1.50, 95% CI 1.00-2.25, P = 0.048). Restricted cubic splines demonstrated an increasing trend for TyG index and frailty risk. During a follow-up of ten years, three distinct trajectories of the TyG index were identified: low-stable (n = 697, 38.3%), moderate-stable (n = 910, 50.0%) and high-stable (n = 214, 11.7%). Compared with those in the stable-low group of TyG index trajectory, the ORs (95% CI) of prefrailty and frailty risk were 1.79 (95% CI 1.11-2.88) and 2.17 (95% CI 1.01-3.88) for the high-stable group, respectively (P = 0.017 and P = 0.038). In the subgroup analysis, the association of the high-stable trajectory of TyG and frailty status were only observed in subjects with BMI ≥ 24 kg/m<sup>2</sup>. Prospectively, the highest quartile of the TyG index was associated with a 2.09-fold significantly increased risk of one-year ADL/IADL decline (P = 0.045).<br /><b>Conclusions</b><br />The present study suggests a potential role for a high and sustainable level of TyG index in the risk of frailty. The trajectories of the TyG index can help to identify older individuals at a higher risk of frailty who deserve primitive preventive and therapeutic approaches.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 29 Sep 2023; 22:264</small></div>

<div><h4>Temporal trends and outcomes of heart transplantation in Spain (2002-2021): propensity score matching analysis to compare patients with and without type 2 diabetes.</h4><i>Lopez-de-Andres A, Jiménez-García R, Hernández-Barrera V, Carabantes-Alarcon D, ... de-Miguel-Yanes JM, Cuadrado-Corrales N</i><br /><b>Background</b><br />The impact of Type 2 Diabetes (T2D) on the outcomes of heart transplantation (HT) has not yet been clearly established. The objectives of this study were to examine the trends in the prevalence of T2D among individuals who underwent a HT in Spain from 2002 to 2021, and to compare the clinical characteristics and hospitalization outcomes between HT recipients with and without T2D.<br /><b>Methods</b><br />We used the national hospital discharge database to select HT recipients aged 35 and older. The International Classification of Diseases, Ninth and Tenth Revisions (ICD-9 and ICD-10) were used to identify patients with and without T2D. We also recorded comorbidities, complications of HT, and procedures. Propensity score matching (PSM) and Cox regression were used to analyze the effect of T2D on in-hospital mortality (IHM).<br /><b>Results</b><br />Between 2002 and 2021, a total of 4429 HTs (T2D, 19.14%) were performed in Spain. The number of HTs in patients with T2D decreased from 2002 to 2005 (n = 171) to 2014-2017 (n = 154), then rose during 2018-2021 (n = 186). Complications of HT increased in patients with and without T2D over the study period (26.9% and 31.31% in 2002-2005 vs. 42.47% and 45.01% in 2018-2021, respectively). The results of the PSM showed that pneumonia and Gram-negative bacterial infections were less frequent in patients with T2D and that these patients less frequently required hemodialysis, extracorporeal membrane oxygenation (ECMO), and tracheostomy. They also had a shorter hospital stay and lower IHM than patients without diabetes. The variables associated with IHM in patients with T2D were hemodialysis and ECMO. IHM decreased over time in people with and without T2D. The Cox regression analysis showed that T2D was associated with lower IHM (HR 0.77; 95% CI 0.63-0.98).<br /><b>Conclusions</b><br />The number of HTs increased in the period 2018-2021 compared with 2002-2005 in patients with and without T2D. Over time, complications of HT increased in both groups studied, whereas IHM decreased. The presence of T2D is associated with lower IHM.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 29 Sep 2023; 22:266</small></div>

<div><h4>High triglyceride-glucose (TyG) index is associated with poor prognosis of heart failure with preserved ejection fraction.</h4><i>Zhou Q, Yang J, Tang H, Guo Z, ... Hua X, Tang YD</i><br /><b>Background</b><br />The impact of insulin resistance on the prognosis of heart failure with preserved ejection fraction (HFpEF) remains unknown. This study aimed to investigate the association between the triglyceride-glucose (TyG) index, an easily calculated marker of insulin resistance, and the long-term prognosis of HFpEF.<br /><b>Methods</b><br />A total of 823 patients with HFpEF were enrolled in the study. The TyG index was determined using the formula ln(fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2). The primary endpoint was all-cause death. The secondary endpoints were cardiovascular (CV) death and heart failure (HF) rehospitalization. Restricted cubic spline, multivariate Cox proportional hazard models, and competing risk models were used for analyses.<br /><b>Results</b><br />During a median follow-up period of 3.16 years, 147 (17.8%) all-cause deaths, 139 (16.8%) CV deaths, and 222 (27.0%) HF rehospitalizations occurred. Restricted cubic spline analysis revealed a J-shaped association between the TyG index and the mortality and rehospitalization rates. In the multivariate Cox proportional hazard models, compared with those in the lowest TyG index tertile, patients in the highest tertile exhibited the greatest susceptibility to all-cause death (HR 1.53, 95% CI 1.19-1.98) and CV death (HR 1.52, 95% CI 1.19-1.96). In the competing risk model, a significant association between the TyG index and HF rehospitalization was observed (HR 1.31, 95% CI, 1.07-1.61).<br /><b>Conclusion</b><br />A high TyG index is associated with an increased risk of mortality and rehospitalization in patients with HFpEF. The TyG index may serve as a promising prognostic marker for patients with HFpEF.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 29 Sep 2023; 22:263</small></div>

<div><h4>The neutrophil-lymphocyte ratio as a risk factor for all-cause and cardiovascular mortality among individuals with diabetes: evidence from the NHANES 2003-2016.</h4><i>Dong G, Gan M, Xu S, Xie Y, Zhou M, Wu L</i><br /><b>Background</b><br />Evidence regarding the neutrophil-lymphocyte ratio (NLR) and mortality risk in diabetes patients is scarce. This study investigated the relationship of the NLR with all-cause and cardiovascular mortality risk in diabetes patients.<br /><b>Methods</b><br />Diabetes patients (n = 3251) from seven National Health and Nutrition Examination Survey (NHANES) cycles (2003-2016) were included in this study. The cause of death and mortality status of the participants were obtained from National Death Index records. Restricted cubic spline (RCS) was used to visualize the association of the NLR with mortality risk. The maximally selected rank statistics method (MSRSM) was used to determine the optimal NLR cutoff value corresponding to the most significant association with survival outcomes. Weighted multivariable Cox regression models and subgroup analyses were adopted to assess the association of the NLR with all-cause and cardiovascular mortality. Time-dependent receiver operating characteristic curve (ROC) analysis was conducted to evaluate the accuracy of the NLR in predicting survival outcomes.<br /><b>Results</b><br />During a median follow-up of 91 months (interquartile range, 55-131 months), 896 (27.5%) of the 3251 diabetes patients died, including 261 (8.0%) with cardiovascular deaths and 635 (19.5%) with noncardiovascular deaths. The RCS regression analysis showed a positive linear association between the NLR and all-cause and cardiovascular mortality (both p > 0.05 for nonlinearity) in diabetes patients. Participants were divided into higher (> 3.48) and lower (≤ 3.48) NLR groups according to the MSRSM. In the multivariable-adjusted model, compared with participants with a lower NLR, those with a higher NLR had a significantly higher risk of both all-cause (HR 2.03, 95% confidence interval (CI) 1.64-2.51, p < 0.0001) and cardiovascular mortality (HR 2.76, 95% CI 1.84-4.14, p < 0.0001). The association was consistent in subgroup analyses based on age, sex, smoking status, drinking status, and hypertension, with no significant interaction between the aforementioned characteristics and the NLR (p interaction > 0.05). The time-dependent ROC curve showed that the areas under the curve of the 1-, 3-, 5-, and 10-year survival rates were 0.72, 0.66, 0.64, and 0.64 for all-cause mortality and 0.69, 0.71, 0.69 and 0.65, respectively, for cardiovascular mortality.<br /><b>Conclusion</b><br />An elevated NLR is independently associated with increased all-cause and cardiovascular mortality in diabetes patients.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 29 Sep 2023; 22:267</small></div>

<div><h4>Prevalence of atherosclerosis in individuals with prediabetes and diabetes compared to normoglycaemic individuals-a Swedish population-based study.</h4><i>Östgren CJ, Otten J, Festin K, Angerås O, ... Söderberg S, Sundström J</i><br /><b>Background</b><br />Patients with type 2 diabetes have an increased risk of death and cardiovascular events and people with diabetes or prediabetes have been found to have increased atherosclerotic burden in the coronary and carotid arteries. This study will estimate the cross-sectional prevalence of atherosclerosis in the coronary and carotid arteries in individuals with prediabetes and diabetes, compared with normoglycaemic individuals in a large population-based cohort.<br /><b>Methods</b><br />The 30,154 study participants, 50-64 years, were categorized according to their fasting glycaemic status or self-reported data as normoglycaemic, prediabetes, and previously undetected or known diabetes. Prevalence of affected coronary artery segments, severity of stenosis and coronary artery calcium score (CACS) were determined by coronary computed tomography angiography. Total atherosclerotic burden was assessed in the 11 clinically most relevant segments using the Segment Involvement Score and as the presence of any coronary atherosclerosis. The presence of atherosclerotic plaque in the carotid arteries was determined by ultrasound examination.<br /><b>Results</b><br />Study participants with prediabetes (n = 4804, 16.0%) or diabetes (n = 2282, 7.6%) had greater coronary artery plaque burden, more coronary stenosis and higher CACS than normoglycaemic participants (all, p < 0.01). Among male participants with diabetes 35.3% had CACS ≥ 100 compared to 16.1% among normoglycaemic participants. For women, the corresponding figures were 8.9% vs 6.1%. The prevalence of atherosclerosis in the coronary arteries was higher in participants with previously undetected diabetes than prediabetes, but lower than in patients with known diabetes. The prevalence of any plaque in the carotid arteries was higher in participants with prediabetes or diabetes than in normoglycaemic participants.<br /><b>Conclusions</b><br />In this large population-based cohort of currently asymptomatic people, the atherosclerotic burden in the coronary and carotid arteries increased with increasing degree of dysglycaemia. The finding that the atherosclerotic burden in the coronary arteries in the undetected diabetes category was midway between the prediabetes category and patients with known diabetes may have implications for screening strategies and tailored prevention interventions for people with dysglycaemia in the future.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 27 Sep 2023; 22:261</small></div>

<div><h4>Microvesicle-associated and circulating microRNAs in diabetic dyslipidemia: miR-218, miR-132, miR-143, and miR-21, miR-122, miR-155 have biomarker potential.</h4><i>Nemecz M, Stefan DS, Comarița IK, Constantin A, ... Guja C, Georgescu A</i><br /><b>Background</b><br />Circulating MicroRNAs (miRNAs) carried by microvesicles (MVs) have various physiological and pathological functions by post-transcriptional regulation of gene expression being considered markers for many diseases including diabetes and dyslipidemia. We aimed to identify new common miRNAs both in MVs and plasma that could be predictive biomarkers for diabetic dyslipidemia evolution.<br /><b>Methods</b><br />For this purpose, plasma from 63 participants in the study (17 type 2 diabetic patients, 17 patients with type 2 diabetes and dyslipidemia, 14 patients with dyslipidemia alone and 15 clinically healthy persons without diabetes or dyslipidemia) was used for the analysis of circulating cytokines, MVs, miRNAs and MV-associated miRNAs.<br /><b>Results</b><br />The results uncovered three miRNAs, miR-218, miR-132 and miR-143, whose expression was found to be significantly up-regulated in both circulating MVs and plasma from diabetic patients with dyslipidemia. These miRNAs showed significant correlations with important plasma markers, representative of this pathology. Thus, MV/plasma miR-218 was negatively correlated with the levels of erythrocyte MVs, plasma miR-132 was positively connected with MV miR-132 and negatively with uric acid and erythrocyte plasma levels, and plasma miR-143 was negatively related with creatinine levels and diastolic blood pressure. Also, three miRNAs common to MV and plasma, namely miR-21, miR-122, and miR-155, were identified to be down-regulated and up-regulated, respectively, in diabetic dyslipidemia. In addition, MV miR-21 was positively linked with cholesterol plasma levels and plasma miR-21 with TNFα plasma levels, MV miR-122 was negatively correlated with LDL-c levels and plasma miR-122 with creatinine and diastolic blood pressure and positively with MV miR-126 levels, MV miR-155 was positively associated with cholesterol and total MV levels and negatively with HDL-c levels, whereas plasma miR-155 was positively correlated with Il-1β plasma levels and total MV levels and negatively with MV miR-223 levels.<br /><b>Conclusions</b><br />In conclusion, miR-218, miR-132, miR-143, and miR-21, miR-122, miR-155 show potential as biomarkers for diabetic dyslipidemia, but there is a need for more in-depth studies. These findings bring new information regarding the molecular biomarkers specific to diabetic dyslipidemia and could have important implications for the treatment of patients affected by this pathology.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 25 Sep 2023; 22:260</small></div>

<div><h4>Machine learning in precision diabetes care and cardiovascular risk prediction.</h4><i>Oikonomou EK, Khera R</i><br /><AbstractText>Artificial intelligence and machine learning are driving a paradigm shift in medicine, promising data-driven, personalized solutions for managing diabetes and the excess cardiovascular risk it poses. In this comprehensive review of machine learning applications in the care of patients with diabetes at increased cardiovascular risk, we offer a broad overview of various data-driven methods and how they may be leveraged in developing predictive models for personalized care. We review existing as well as expected artificial intelligence solutions in the context of diagnosis, prognostication, phenotyping, and treatment of diabetes and its cardiovascular complications. In addition to discussing the key properties of such models that enable their successful application in complex risk prediction, we define challenges that arise from their misuse and the role of methodological standards in overcoming these limitations. We also identify key issues in equity and bias mitigation in healthcare and discuss how the current regulatory framework should ensure the efficacy and safety of medical artificial intelligence products in transforming cardiovascular care and outcomes in diabetes.</AbstractText><br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 25 Sep 2023; 22:259</small></div>

<div><h4>Association between the atherogenic index of plasma and adverse long-term prognosis in patients diagnosed with chronic coronary syndrome.</h4><i>Alifu J, Xiang L, Zhang W, Qi P, ... Abdu FA, Che W</i><br /><b>Background</b><br />The Atherogenic Index of Plasma (AIP) is a newly identified biomarker associated with lipid metabolism, demonstrating significant prognostic capabilities in individuals diagnosed with cardiovascular disease. However, its impact within the context of chronic coronary syndromes (CCS) remains unexplored. Thus, the present investigation sought to examine the potential association between AIP levels and long-term clinical outcomes in patients diagnosed with CCS.<br /><b>Methods</b><br />A total of 404 patients diagnosed with CCS and who underwent coronary angiography were included in this study. The AIP index was calculated as log (triglycerides / high-density lipoprotein-cholesterol). The patients were categorized into four groups based on their AIP values: Q1 (< -0.064), Q2 (-0.064 to 0.130), Q3 (0.130 to 0.328), and Q4 (> 0.328). The occurrence of major adverse cardiovascular events (MACE) was monitored during the follow-up period for all patients. Cox regression analysis and Kaplan-Meier curve analysis were employed to examine the relationship between AIP and MACE. Furthermore, ROC analysis was utilized to determine the optimal cut-off value of AIP for predicting clinical MACE.<br /><b>Results</b><br />During the median 35 months of follow-up, a total of 88 patients experienced MACE. Notably, the group of patients with higher AIP values (Q4 group) exhibited a significantly higher incidence of MACE compared to those with lower AIP values (Q1, Q2, and Q3 groups) (31.7% vs. 16.8%, 15.7%, and 23.0% respectively; P = 0.023). The Kaplan-Meier curves illustrated those patients in the Q4 group had the highest risk of MACE relative to patients in the other groups (log-rank P = 0.014). Furthermore, the multivariate Cox regression analysis demonstrated that individuals in the Q4 group had a 7.892-fold increased risk of MACE compared to those in the Q1 group (adjusted HR, 7.892; 95% CI 1.818-34.269; P = 0.006). Additionally, the ROC curve analysis revealed an optimal AIP cut-off value of 0.24 for predicting clinical MACE in patients with CCS.<br /><b>Conclusion</b><br />Our data indicate, for the first time, that AIP is independently associated with poor long-term prognosis in patients suffering from CCS. The optimal AIP cut-off value for predicting clinical MACE among CCS patients was 0.24.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 21 Sep 2023; 22:255</small></div>

<div><h4>Diabetes- versus smoking-related thrombo-inflammation in peripheral artery disease.</h4><i>Alnima T, Meijer RI, Spronk HMH, Warlé M, Cate HT</i><br /><AbstractText>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.</AbstractText><br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 21 Sep 2023; 22:257</small></div>

<div><h4>Subclinical left ventricular deformation and microvascular dysfunction in T2DM patients with and without peripheral neuropathy: assessed by 3.0 T cardiac magnetic resonance imaging.</h4><i>Li XM, Shi R, Shen MT, Yan WF, ... Guo YK, Yang ZG</i><br /><b>Background</b><br />Diabetic peripheral neuropathy (DPN) has been shown to be independently associated with cardiovascular events and mortality. This study aimed to evaluate changes in left ventricular (LV) microvascular perfusion and myocardial deformation in type 2 diabetes mellitus (T2DM) patients with and without DPN, as well as to investigate the association between myocardial perfusion and LV deformation.<br /><b>Methods</b><br />Between October 2015 and July 2022, one hundred and twenty-three T2DM patients without DPN, fifty-four patients with DPN and sixty age‑ and sex‑matched controls who underwent cardiovascular magnetic resonance imaging were retrospectively analyzed. LV myocardial perfusion parameters at rest, including upslope, time to maximum signal intensity (TTM), max signal intensity (max SI), and myocardial strains, including global radial, circumferential and longitudinal strain (GRS, GCS and GLS, respectively), were calculated and compared among the groups with One‑way analysis of variance. Univariable and multivariable linear regression analyses were performed to explore the independent factors influencing LV myocardial perfusion indices and LV strains in diabetes.<br /><b>Results</b><br />The LV GLS, upslope and max SI were significantly deteriorated from controls, through patients without DPN, to patients with DPN (all P < 0.001). Compared with controls, TTM was increased and LV GRS and GCS were decreased in both patient groups (all P < 0.05). Multivariable regression analyses considering covariates showed that DPN was independently associated with reduced upslope, max SI and LV GLS (β = - 0.360, - 2.503 and 1.113, p = 0.021, 0.031 and 0.010, respectively). When the perfusion indices upslope and max SI were included in the multivariable analysis for LV deformation, DPN and upslope (β = 1.057 and - 0.870, p = 0.020 and 0.018, respectively) were significantly associated with LV GLS.<br /><b>Conclusion</b><br />In patients with T2DM, there was more severe LV microvascular and myocardial dysfunction in patients with complicated DPN, and deteriorated subclinical LV systolic dysfunction was associated with impaired myocardial circulation.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 21 Sep 2023; 22:256</small></div>

<div><h4>Cumulative exposure to high remnant-cholesterol concentrations increases the risk of cardiovascular disease in patients with hypertension: a prospective cohort study.</h4><i>Wu W, Chen G, Wu K, Zheng H, ... Wu S, Chen Y</i><br /><b>Background</b><br />The relationship of cumulative remnant-cholesterol (Cum-RC) concentration with the risk of cardiovascular disease (CVD) in patients with hypertension remains unclear.<br /><b>Methods</b><br />We studied data for 28,698 individuals for whom three consecutive total cholesterol, high-density lipoprotein-cholesterol (HDL-C), and triglyceride concentrations were available, and who did not have CVD (14,349 with hypertension and 14,349 without), that was collected between 2006 and 2010. Participants with hypertension were placed into four groups based on Cum-RC quartile: a Q1 group (< 26.40 mg/dl), a Q2 group (26.40-39.56 mg/dl), a Q3 group (39.57-54.65 mg/dl), and a Q4 group (≥ 54.66 mg/dl). Cox proportional hazards models were used to evaluate the relationship between Cum-RC and the risk of CVD.<br /><b>Results</b><br />Over a median 10.9 (interquartile range, 10.5-11.3) years, 1,444 participants with hypertension developed CVD. After adjustment for multiple potential confounding factors, and compared with the Q1 Cum-RC group of the participants with hypertension, the adjusted hazard ratios for CVD for the Q2-Q4 groups were 1.07(0.92,1.26), 1.08(0.91,1.28), and 1.26(1.03,1.54) (P = 0.0405); those for myocardial infarction were 1.51(1.00,2.31), 2.02(1.22,3.27), and 2.08(1.41,3.28) (P < 0.0001); and those for ischemic stroke were 1.02(0.84,1.24), 1.04(0.86,1.25), and 1.29(1.02,1.62), respectively (P = 0.0336). However, no significant relationship was found between Cum-RC and the risk of hemorrhage stroke. At the same Cum-RC, the risk of CVD was significantly higher in participants with hypertension than in those without.<br /><b>Conclusions</b><br />A consistently high remnant-cholesterol concentration increases the risk of CVD in individuals with hypertension. Therefore, the achievement of blood pressure and RC concentration targets should help reduce the risk of CVD in individuals with hypertension.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 21 Sep 2023; 22:258</small></div>

<div><h4>Changes in the triglyceride glucose-body mass index estimate the risk of stroke in middle-aged and older Chinese adults: a nationwide prospective cohort study.</h4><i>Huo RR, Zhai L, Liao Q, You XM</i><br /><b>Background</b><br />Stroke was reported to be highly correlated with the triglyceride glucose-body mass index (TyG-BMI). Nevertheless, literature exploring the association between changes in the TyG-BMI and stroke incidence is scant, with most studies focusing on individual values of the TyG-BMI. We aimed to investigate whether changes in the TyG-BMI were associated with stroke incidence.<br /><b>Methods</b><br />Data were obtained from the China Health and Retirement Longitudinal Study (CHARLS), which is an ongoing nationally representative prospective cohort study. The exposures were changes in the TyG-BMI and cumulative TyG-BMI from 2012 to 2015. Changes in the TyG-BMI were classified using K-means clustering analysis, and the cumulative TyG-BMI was calculated as follows: (TyG-BMI<sub>2012</sub> + TyG-BMI<sub>2015</sub>)/2 × time (2015-2012). Logistic regressions were used to determine the association between different TyG-BMI change classes and stroke incidence. Meanwhile, restricted cubic spline regression was applied to examine the potential nonlinear association of the cumulative TyG-BMI and stroke incidence. Weighted quantile sum regression was used to provide a comprehensive explanation of the TyG-BMI by calculating the weights of FBG, triglyceride-glucose (TG), and BMI.<br /><b>Results</b><br />Of the 4583 participants (mean [SD] age at baseline, 58.68 [9.51] years), 2026 (44.9%) were men. During the 3 years of follow-up, 277 (6.0%) incident stroke cases were identified. After adjusting for potential confounders, compared to the participants with a consistently low TyG-BMI, the OR for a moderate TyG-BMI with a slow rising trend was 1.01 (95% CI 0.65-1.57), the OR for a high TyG-BMI with a slow rising trend was 1.62 (95% CI 1.11-2.32), and the OR for the highest TyG-BMI with a slow declining trend was 1.71 (95% CI 1.01-2.89). The association between the cumulative TyG-BMI and stroke risk was nonlinear (P<sub>association</sub> = 0.017; P<sub>nonlinearity</sub> = 0.012). TG emerged as the primary contributor when the weights were assigned to the constituent elements of the TyG-BMI (weight<sub>2012</sub> = 0.466; weight<sub>2015</sub> = 0.530).<br /><b>Conclusions</b><br />Substantial changes in the TyG-BMI are independently associated with the risk of stroke in middle-aged and older adults. Monitoring long-term changes in the TyG-BMI may assist with the early identification of individuals at high risk of stroke.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 16 Sep 2023; 22:254</small></div>

<div><h4>Insulin resistance, kidney outcomes and effects of the endothelin receptor antagonist atrasentan in patients with type 2 diabetes and chronic kidney disease.</h4><i>Smeijer JD, Kohan DE, Rossing P, Correa-Rotter R, ... Ju W, Lambers Heerspink HJ</i><br /><b>Background</b><br />Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes and associated with the presence of chronic kidney disease (CKD). Experimental studies suggest that endothelin-1 increases IR. We assessed the association between IR and cardio-renal outcomes and the effect of the selective endothelin receptor antagonist atrasentan on IR in patients with type 2 diabetes and CKD.<br /><b>Methods</b><br />We used data from the RADAR and SONAR trials that recruited participants with type 2 diabetes and CKD [eGFR 25-75 mL/min/1.73 m², urine albumin-to-creatinine ratio of 300-5000 mg/g]. IR was calculated using the homeostatic model assessment (HOMA-IR). The association between HOMA-IR and the pre-specified cardio-renal outcomes was assessed using multivariable Cox proportional hazards regression, and effects of atrasentan on HOMA-IR by a linear mixed effect model.<br /><b>Results</b><br />In the SONAR trial, each log-unit increase in HOMA-IR was associated with an increased risk of the composite cardio-renal outcome [hazard ratio 1.32 (95%CI 1.09,1.60; p = 0.004)], kidney outcome [hazard ratio 1.30 (95%CI 1.00,1.68; p-value = 0.048)], and the kidney or all-cause mortality outcome [hazard ratio 1.25 (95%CI 1.01,1.55; p-value = 0.037)]. After 12 weeks treatment in the RADAR trial (N = 123), atrasentan 0.75 mg/day and 1.25 mg/day compared to placebo reduced HOMA-IR by 19.1 (95%CI -17.4, 44.3) and 26.7% (95%CI -6.4, 49.5), respectively. In the SONAR trial (N = 1914), atrasentan 0.75 mg/day compared to placebo reduced HOMA-IR by 9.6% (95%CI 0.6, 17.9).<br /><b>Conclusions</b><br />More severe IR is associated with increased risk of cardio-renal outcomes. The endothelin receptor antagonist atrasentan reduced IR.<br /><b>Trial registration</b><br />RADAR trial (Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan): NCT01356849. SONAR trial (The Study Of Diabetic Nephropathy With AtRasentan) NCT01858532.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 16 Sep 2023; 22:251</small></div>

<div><h4>Temporal trends in chronic complications of diabetes by sex in community-based people with type 2 diabetes: the Fremantle Diabetes Study.</h4><i>Davis WA, Davis TME</i><br /><b>Background</b><br />Whether recent reductions in cardiovascular disease (CVD) events and mortality in type 2 diabetes apply equally to both sexes is largely unknown. The aim of this study was to characterize temporal changes in CVD events and related outcomes in community-based male and female Australian adults with type 2 diabetes or without known diabetes.<br /><b>Methods</b><br />Participants from the longitudinal observational Fremantle Diabetes Study Phases I (FDS1; n = 1291 recruited 1993-1996) and II (FDS2; n = 1509 recruited 2008-2011) and four age-, sex- and postcode-matched individuals without diabetes (FDS1 n = 5159; FDS2 n = 6036) were followed for first myocardial infarction, stroke, heart failure hospitalization, lower extremity amputation, CVD death and all-cause mortality. Five-year incidence rates (IRs) for males versus females in FDS1 and FDS2 were calculated, and IR ratios (IRRs) derived.<br /><b>Results</b><br />The FD1 and FDS2 participants were of mean age 64.0 and 65.4 years, respectively, and 48.7% and 51.8% were males. For type 2 diabetes, IRRs for all endpoints were 11-62% lower in FDS2 than FDS1 for both sexes. For participants without diabetes, IRRs were 8-56% lower in FDS2 versus FDS1 apart from stroke in females (non-significantly 41% higher). IRRs for males versus females across FDS phases were not significantly different for participants with type 2 diabetes or those without diabetes (P-values for male * FDS2 interaction ≥ 0.0.083 adjusted for age). For risk factors in participants with type 2 diabetes, greater improvements between FDS1 and FDS2 in smoking rates in males were offset by a greater reduction in systolic blood pressure in females.<br /><b>Conclusions</b><br />The incidence of chronic complications in Australians with type 2 diabetes and without diabetes has fallen similarly in both sexes over recent decades, consistent with comparably improved overall CVD risk factor management.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 16 Sep 2023; 22:253</small></div>

<div><h4>Plasma metabolite profiles associated with the World Cancer Research Fund/American Institute for Cancer Research lifestyle score and future risk of cardiovascular disease and type 2 diabetes.</h4><i>Rios S, García-Gavilán JF, Babio N, Paz-Graniel I, ... Hu FB, Salas-Salvadó J</i><br /><b>Background</b><br />A healthy lifestyle (HL) has been inversely related to type 2 diabetes (T2D) and cardiovascular disease (CVD). However, few studies have identified a metabolite profile associated with HL. The present study aims to identify a metabolite profile of a HL score and assess its association with the incidence of T2D and CVD in individuals at high cardiovascular risk.<br /><b>Methods</b><br />In a subset of 1833 participants (age 55-80y) of the PREDIMED study, we estimated adherence to a HL using a composite score based on the 2018 Word Cancer Research Fund/American Institute for Cancer Research recommendations. Plasma metabolites were analyzed using LC-MS/MS methods at baseline (discovery sample) and 1-year of follow-up (validation sample). Cross-sectional associations between 385 known metabolites and the HL score were assessed using elastic net regression. A 10-cross-validation procedure was used, and correlation coefficients or AUC were assessed between the identified metabolite profiles and the self-reported HL score. We estimated the associations between the identified metabolite profiles and T2D and CVD using multivariable Cox regression models.<br /><b>Results</b><br />The metabolite profiles that identified HL as a dichotomous or continuous variable included 24 and 58 metabolites, respectively. These are amino acids or derivatives, lipids, and energy intermediates or xenobiotic compounds. After adjustment for potential confounders, baseline metabolite profiles were associated with a lower risk of T2D (hazard ratio [HR] and 95% confidence interval (CI): 0.54, 0.38-0.77 for dichotomous HL, and 0.22, 0.11-0.43 for continuous HL). Similar results were observed with CVD (HR, 95% CI: 0.59, 0.42-0.83 for dichotomous HF and HR, 95%CI: 0.58, 0.31-1.07 for continuous HL). The reduction in the risk of T2D and CVD was maintained or attenuated, respectively, for the 1-year metabolomic profile.<br /><b>Conclusions</b><br />In an elderly population at high risk of CVD, a set of metabolites was selected as potential metabolites associated with the HL pattern predicting the risk of T2D and, to a lesser extent, CVD. These results support previous findings that some of these metabolites are inversely associated with the risk of T2D and CVD.<br /><b>Trial registration</b><br />The PREDIMED trial was registered at ISRCTN ( http://www.isrctn.com/ , ISRCTN35739639).<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 16 Sep 2023; 22:252</small></div>

<div><h4>Serum branch-chained amino acids are increased in type 2 diabetes and associated with atherosclerotic cardiovascular disease.</h4><i>Moreno-Vedia J, Llop D, Rodríguez-Calvo R, Plana N, ... Masana L, Ibarretxe D</i><br /><b>Background:</b><br/>and aim</b><br />Circulating biomarkers of metabolic and cardiovascular diseases can help in the early detection and prevention of those diseases. Using proton nuclear magnetic resonance (1H-NMR), we aimed to study the plasma levels of low-molecular-weight metabolites (LMWMs) in a cohort of 307 patients with metabolic diseases to assess their relationships with type-2 diabetes (T2D) and incident atherosclerotic cardiovascular disease (ASCVD).<br /><b>Methods</b><br />We conducted a cross-sectional and prospective study. We included 307 patients attending the Lipid Unit of our University Hospital for the treatment of the following metabolic disturbances and associated disorders: T2D (73.9%), obesity (58.7%), and hypertension (55.1%). 1H-NMR was used to study the plasma levels of 13 LMWMs. LMWM serum concentrations were evaluated in patients with and without T2D. and the correlations with several parameters and their associations with T2D were analyzed. The association between LMWM levels at baseline and the development of ASCVD in patients with T2D after 10 years of follow-up was also evaluated.<br /><b>Results</b><br />Among the LMWMs measured, the branched-chain amino acids (BCAAs) valine, leucine and isoleucine showed a positive association with several clinical and lipid-related biochemical parameters and inflammatory markers (p < 0.05). Likewise, these three BCAAS were associated with diabetes even after adjusting for covariates (p < 0.05). During the follow-up period of 10 years, 29 of the 185 patients with diabetes at baseline (15.68%) developed ASCVD. After adjusting for clinical covariates, baseline levels of valine and alanine were associated with the development of ASCVD (p < 0.05).<br /><b>Conclusion</b><br />Overall, our results indicated that plasma levels of LMWMs measured by 1H-NMR could be potential biomarkers associated with T2D. Moreover, alanine and valine can help in the early detection of the cardiovascular risk associated with this metabolic disease.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 14 Sep 2023; 22:249</small></div>

<div><h4>Inflammation and oxidative stress markers in type 2 diabetes patients with Advanced Carotid atherosclerosis.</h4><i>Ménégaut L, Laubriet A, Crespy V, Leleu D, ... Steinmetz E, Masson D</i><br /><b>Background</b><br />Type 2 diabetes mellitus (T2DM) is a major global health issue and a significant risk factor for atherosclerosis. Atherosclerosis in T2DM patients has been associated with inflammation, insulin resistance, hyperglycemia, dyslipidemia, and oxidative stress. Identifying molecular features of atherosclerotic plaques in T2DM patients could provide valuable insights into the pathogenesis of the disease.<br /><b>Methods</b><br />The MASCADI (Arachidonic Acid Metabolism in Carotid Stenosis Plaque in Diabetic Patients) study aimed to investigate the increase of 2-arachidonoyl-lysophatidylcholine (2-AA-LPC) in carotid plaques from T2DM and control patients and to explore its association with plaque vulnerability as well as with blood and intra-plaque biomarkers altered during diabetes.<br /><b>Results</b><br />In a population of elderly, polymedicated patients with advanced stage of atherosclerosis, we found that T2DM patients had higher systemic inflammation markers, such as high-sensitivity C-reactive protein (hsCRP) and IL-1β, higher levels of oxysterols, increased triglyceride levels, and decreased HDL levels as compared to control patients. Furthermore, 2-AA-LPC was significantly enriched in plaques from diabetic patients, suggesting its potential role in diabetic atherosclerosis. Interestingly, 2-AA-LPC was not associated with systemic markers related to diabetes, such as hsCRP, triglycerides, or HDL cholesterol. However, it was significantly correlated with the levels of inflammatory markers within the plaques such as lysophospholipids and 25-hydroxycholesterol, strengthening the link between local inflammation, arachidonic acid metabolism and diabetes.<br /><b>Conclusion</b><br />Our study is in line with a key role for inflammation in the pathogenesis of diabetic atherosclerosis and highlights the involvement of 2-AA-LPC. Further research is needed to better understand the local processes involved in the alteration of plaque composition in T2DM and to identify potential therapeutic targets.<br /><b>Trial registration</b><br />The MASCADI was registered on ClinicalTrials.gov (clinical registration number: NCT03202823).<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 14 Sep 2023; 22:248</small></div>

<div><h4>Unlocking the potential of microRNAs: machine learning identifies key biomarkers for myocardial infarction diagnosis.</h4><i>Samadishadlou M, Rahbarghazi R, Piryaei Z, Esmaeili M, ... Bani F, Kavousi K</i><br /><b>Background</b><br />MicroRNAs (miRNAs) play a crucial role in regulating adaptive and maladaptive responses in cardiovascular diseases, making them attractive targets for potential biomarkers. However, their potential as novel biomarkers for diagnosing cardiovascular diseases requires systematic evaluation.<br /><b>Methods</b><br />In this study, we aimed to identify a key set of miRNA biomarkers using integrated bioinformatics and machine learning analysis. We combined and analyzed three gene expression datasets from the Gene Expression Omnibus (GEO) database, which contains peripheral blood mononuclear cell (PBMC) samples from individuals with myocardial infarction (MI), stable coronary artery disease (CAD), and healthy individuals. Additionally, we selected a set of miRNAs based on their area under the receiver operating characteristic curve (AUC-ROC) for separating the CAD and MI samples. We designed a two-layer architecture for sample classification, in which the first layer isolates healthy samples from unhealthy samples, and the second layer classifies stable CAD and MI samples. We trained different machine learning models using both biomarker sets and evaluated their performance on a test set.<br /><b>Results</b><br />We identified hsa-miR-21-3p, hsa-miR-186-5p, and hsa-miR-32-3p as the differentially expressed miRNAs, and a set including hsa-miR-186-5p, hsa-miR-21-3p, hsa-miR-197-5p, hsa-miR-29a-5p, and hsa-miR-296-5p as the optimum set of miRNAs selected by their AUC-ROC. Both biomarker sets could distinguish healthy from not-healthy samples with complete accuracy. The best performance for the classification of CAD and MI was achieved with an SVM model trained using the biomarker set selected by AUC-ROC, with an AUC-ROC of 0.96 and an accuracy of 0.94 on the test data.<br /><b>Conclusions</b><br />Our study demonstrated that miRNA signatures derived from PBMCs could serve as valuable novel biomarkers for cardiovascular diseases.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 11 Sep 2023; 22:247</small></div>

<div><h4>Endogenous estradiol contributes to vascular endothelial dysfunction in premenopausal women with type 1 diabetes.</h4><i>Simon AB, Derella CC, Blackburn M, Thomas J, ... Saad KM, Harris RA</i><br /><b>Background</b><br />Endogenous estrogen is cardio-protective in healthy premenopausal women. Despite this favorable action of estrogen, animal models depict a detrimental effect of estradiol on vascular function in the presence of diabetes. The present study sought to determine the role of endogenous estradiol on endothelial function in women with type 1 diabetes.<br /><b>Method</b><br />32 women with type 1 diabetes (HbA<sub>1c</sub> = 8.6 ± 1.7%) and 25 apparently healthy women (HbA<sub>1c</sub> = 5.2 ± 0.3%) participated. Flow-mediated dilation (FMD), a bioassay of nitric-oxide bioavailability and endothelial function was performed during menses (M) and the late follicular (LF) phase of the menstrual cycle to represent low and high concentrations of estrogen, respectively. In addition, a venous blood sample was collected at each visit to determine circulating concentrations of estradiol, thiobarbituric acid reactive substances (TBARS), and nitrate/nitrite (NOx), biomarkers of oxidative stress and nitric oxide, respectively. Data were collected in (1) 9 additional women with type 1 diabetes using oral hormonal birth control (HBC) (HbA<sub>1c</sub> = 8.3 ± 2.1%) during the placebo pill week and second active pill week, and (2) a subgroup of 9 demographically matched women with type 1 diabetes not using HBC (HbA<sub>1c</sub> = 8.9 ± 2.1%).<br /><b>Results</b><br />Overall, estradiol was significantly increased during the LF phase compared to M in both type 1 diabetes (Δestradiol = 75 ± 86 pg/mL) and controls (Δestradiol = 71 ± 76 pg/mL); however, an increase in TBARS was only observed in patients with type 1 diabetes (ΔTBARS = 3 ± 13 µM) compared to controls (ΔTBARS = 0 ± 4 µM). FMD was similar (p = 0.406) between groups at M. In addition, FMD increased significantly from M to the LF phase in controls (p = 0.024), whereas a decrease was observed in type 1 diabetes. FMD was greater (p = 0.015) in patients using HBC compared to those not on HBC, independent of menstrual cycle phase.<br /><b>Conclusion</b><br />Endogenous estradiol increases oxidative stress and contributes to endothelial dysfunction in women with diabetes. Additionally, HBC use appears to be beneficial to endothelial function in type 1 diabetes.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 07 Sep 2023; 22:243</small></div>

<div><h4>Implication of diabetic status on platelet reactivity and clinical outcomes after drug-eluting stent implantation: results from the PTRG-DES consortium.</h4><i>Jeon KH, Jeong YH, Chae IH, Kim BK, ... Suh JW, PTRG-DES Consortium Investigators</i><br /><b>Background</b><br />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.<br /><b>Methods</b><br />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.<br /><b>Results</b><br />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 Hb<sub>A1c</sub> 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 [HR<sub>adj</sub>]: 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 (HR<sub>adj</sub>: 1.507; 95% CI: 1.193-1.902; P < 0.001).<br /><b>Conclusion</b><br />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.<br /><b>Clinical trial registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov . Unique identifier: NCT04734028.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 07 Sep 2023; 22:245</small></div>

<div><h4>Triglyceride-glucose index and heart failure: a systematic review and meta-analysis.</h4><i>Khalaji A, Behnoush AH, Khanmohammadi S, Ghanbari Mardasi K, ... Vinciguerra C, Cannavo A</i><br /><b>Background</b><br />Insulin resistance (IR) is a major metabolic disorder observed in heart failure (HF) and is tightly associated with patients\' poor prognosis. The triglyceride-glucose index (TyG) has been proposed as a surrogate marker of IR in HF. Yet, whether TyG is a reliable clinical marker is still under debate. Hence, we aimed to respond to this relevant question via a systematic review and meta-analysis of existing studies.<br /><b>Methods</b><br />A systematic search was conducted in PubMed, Embase, Scopus, and Web of Science to find studies investigating the TyG index in patients with HF or its association with the incidence of HF. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were pooled through random-effect meta-analysis. HRs were calculated using TyG as a continuous variable (1 unit increase) and by comparing the group with the highest TyG to the lowest TyG group.<br /><b>Results</b><br />Thirty studies, involving 772,809 participants, were included in this systematic review. Meta-analysis of seven studies comparing the highest-TyG to the lowest-TyG group showed a significantly increased risk of HF in the former group (HR 1.21, 95% CI 1.14 to 1.29, P < 0.01). The same result was found when pooling the HRs for a one-unit increase in the TyG index (HR 1.17, 95% CI 1.08 to 1.26). Similarly, a more elevated TyG index was associated with a higher incidence of HF in patients with type 2 diabetes or coronary artery disease. Additionally, the incidence of adverse events (readmission and mortality) in patients with HF was associated with TyG.<br /><b>Conclusion</b><br />Our findings support the TyG index as a valuable marker to assess the risk of HF incidence in different populations and as a prognostic marker in patients with HF. Further studies should be conducted to confirm these associations and investigate the clinical utility of the TyG index.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 07 Sep 2023; 22:244</small></div>

<div><h4>BMI-based obesity classification misses children and adolescents with raised cardiometabolic risk due to increased adiposity.</h4><i>Zapata JK, Azcona-Sanjulian MC, Catalán V, Ramírez B, ... Frühbeck G, Gómez-Ambrosi J</i><br /><b>Objective</b><br />To assess how inaccurately the body mass index (BMI) is used to diagnose obesity compared to body fat percentage (BF%) measurement and to compare the cardiometabolic risk in children and adolescents with or without obesity according to BMI but with a similar BF%.<br /><b>Methods</b><br />A retrospective cross-sectional investigation was conducted including 553 (378 females/175 males) white children and adolescents aged 6-17 years, 197 with normal weight (NW), 144 with overweight (OW) and 212 with obesity (OB) according to BMI. In addition to BMI, BF% measured by air displacement plethysmography, as well as markers of cardiometabolic risk had been determined in the existing cohort.<br /><b>Results</b><br />We found that 7% of subjects considered as NW and 62% of children and adolescents classified as OW according to BMI presented a BF% within the obesity range. Children and adolescents without obesity by the BMI criterion but with obesity by BF% exhibited higher blood pressure and C-reactive protein (CRP) in boys, and higher blood pressure, glucose, uric acid, CRP and white blood cells count, as well as reduced HDL-cholesterol, in girls, similar to those with obesity by BMI and BF%. Importantly, both groups of subjects with obesity by BF% showed a similarly altered glucose homeostasis after an OGTT as compared to their NW counterparts.<br /><b>Conclusions</b><br />Results from the present study suggest increased cardiometabolic risk factors in children and adolescents without obesity according to BMI but with obesity based on BF%. Being aware of the difficulty in determining body composition in everyday clinical practice, our data show that its inclusion could yield clinically useful information both for the diagnosis and treatment of overweight and obesity.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 04 Sep 2023; 22:240</small></div>

<div><h4>Relationship between cumulative exposure to triglyceride-glucose index and heart failure: a prospective cohort study.</h4><i>Zheng H, Chen G, Wu K, Wu W, ... Wu S, Chen Y</i><br /><b>Background</b><br />High triglyceride-glucose index (TyG) is a major risk factor for heart failure, but the long-term effect of high TyG index on the risk of developing heart failure remains unclear. Therefore, we aimed to determine the relationship between the cumulative exposure to TyG index and the risk of heart failure.<br /><b>Methods</b><br />A total of 56,149 participants from the Kailuan Study, who participated in three consecutive health examinations in 2006, 2008, and 2010 and had no history of heart failure or cancer were recruited for this study. The cumulative TyG index was calculated as the weighted sum (value × time) of the mean TyG index for each time interval. The participants were placed into quartiles based on their cumulative TyG index. The study ended on December 31, 2020, and the primary outcome was new-onset heart failure during the follow-up period. In addition, a Cox proportional hazards regression model and a restricted cubic spline analysis were used to further evaluate the relationship between cumulative TyG index and the risk of heart failure.<br /><b>Results</b><br />During a median follow-up period of 10.04 years, a total of 1,312 new heart failure events occurred. After adjustment for potential confounding factors, the Cox regression analysis showed that the hazard ratios (95% confidence intervals) for the risk of heart failure in the Q2, Q3, and Q4 groups were 1.02 (0.83,1.25), 1.29 (1.07,1.56) and 1.40 (1.15,1.71), respectively, vs. the Q1 group. The subgroup analysis showed a significant interaction between cumulative TyG index and BMI or waist circumference, but there was no interaction between age, sex and cumulative TyG index. The restricted cubic spline analysis showed a dose-response relationship between cumulative TyG index and the risk of heart failure. In addition, the sensitivity analysis generated results that were consistent with the primary results.<br /><b>Conclusions</b><br />High cumulative TyG index is associated with a higher risk of heart failure. Thus, the TyG index may be useful for the identification of individuals at high risk of heart failure. The present findings emphasize the importance of the long-term monitoring of the TyG index in clinical practice.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 04 Sep 2023; 22:239</small></div>

<div><h4>Ethnic differences in the association between age at diagnosis of diabetes and the risk of cardiovascular complications: a population-based cohort study.</h4><i>Ke C, Stukel TA, Thiruchelvam D, Shah BR</i><br /><b>Background</b><br />We examined ethnic differences in the association between age at diagnosis of diabetes and the risk of cardiovascular complications.<br /><b>Methods</b><br />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.<br /><b>Results</b><br />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.<br /><b>Conclusions</b><br />There are important ethnic differences in the association between age at diagnosis and risk of cardiovascular complications.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 04 Sep 2023; 22:241</small></div>

<div><h4>Causal associations between type 1 diabetes mellitus and cardiovascular diseases: a Mendelian randomization study.</h4><i>Liu Z, Wang H, Yang Z, Lu Y, Zou C</i><br /><b>Background</b><br />The presence of type 1 diabetes mellitus (T1DM) has been demonstrated to pose an increased risk for developing cardiovascular diseases (CVDs). However, the causal relationships between T1DM and CVDs remain unclear due to the uncontrolled confounding factors and reverse causation bias of the observational studies.<br /><b>Methods</b><br />Summary statistics of T1DM and seven CVDs from the largest available genome-wide association studies (GWAS) of European ancestry and FinnGen biobank were extracted for the primary MR analysis, and the analysis was replicated using UK biobank (UKBB) for validation. Three complementary methods: inverse variance weighted (IVW), weighted median, and MR-Egger were used for the MR estimates. The potential pleiotropic effects were assessed by MR-Egger intercept and MR-PRESSO global test. Additionally, multivariable MR (MVMR) analysis was performed to examine whether T1DM has independent effects on CVDs with adjustment of potential confounding factors. Moreover, a two-step MR approach was used to assess the potential mediating effects of these factors on the causal effects between T1DM and CVDs.<br /><b>Results</b><br />Causal effects of T1DM on peripheral atherosclerosis (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.02-1.10; p = 0.002)] and coronary atherosclerosis (OR = 1.03, 95% CI: 1.01-1.05; p = 0.001) were found. The results were less likely to be biased by the horizontal pleiotropic effects (both p values of MR-Egger intercept and MR-PRESSO Global test > 0.05). In the following MVMR analysis, we found the causal effects of T1DM on peripheral atherosclerosis and coronary atherosclerosis remain significant after adjusting for a series of potential confounding factors. Moreover, we found that hypertension partly mediated the causal effects of T1DM on peripheral atherosclerosis (proportion of mediation effect in total effect: 11.47%, 95% CI: 3.23-19.71%) and coronary atherosclerosis (16.84%, 95% CI: 5.35-28.33%). We didn\'t find significant causal relationships between T1DM and other CVDs, including heart failure (HF), coronary artery disease (CAD), atrial fibrillation (AF), myocardial infarction (MI) and stroke. For the reverse MR from CVD to T1DM, no significant causal relationships were identified.<br /><b>Conclusion</b><br />This MR study provided evidence supporting the causal effect of T1DM on peripheral atherosclerosis and coronary atherosclerosis, with hypertension partly mediating this effect.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 02 Sep 2023; 22:236</small></div>

<div><h4>Left ventricular remodeling response to SGLT2 inhibitors in heart failure: an updated meta-analysis of randomized controlled studies.</h4><i>Carluccio E, Biagioli P, Reboldi G, Mengoni A, ... Bardelli G, Ambrosio G</i><br /><b>Background</b><br />Randomized controlled trials (RCTs) reported contrasting results about reverse left ventricular remodeling (LVR) after sodium-glucose co-transporter-2 inhibitors (SGLT2i) therapy in patients with heart failure (HF).<br /><b>Methods and results</b><br />We performed a metanalysis of RCTs of SGLT2i administration in HF outpatients published until June 2022 searching four electronic databases. The protocol has been published in PROSPERO. Primary LVR outcome was change in absolute LV end-diastolic (LVEDV) and end-systolic volume (LVESV) from baseline to study endpoint. Secondary outcomes included changes in LVEDV and LVESV indexed to body surface area, LV Mass index (LVMi), LV ejection fraction (LVEF), and N-terminal pro-B-type natriuretic peptide (NTproBNP). Mean differences (MDs) with 95% CIs were pooled. A total of 9 RCTs (1385 patients) were analyzed. All of them reported data on LVEF. Six trials reported data on LVESV and LVEDV (n = 951); LVMi was available in 640. SGLT2i treatment significantly reduced LVEDV [MD= -10.59 ml (-17.27; -3.91), P = 0.0019], LVESV [MD= -8.80 ml (-16.91; -0.694), P = 0.0334], and LVMI [MD= -5.34 gr/m2 (-9.76; -0.922), P = 0.0178], while LVEF significantly increased [MD = + 1.98% (0.67; 0.306), P = 0.0031]. By subgroup analysis, the beneficial effects of SGLT2i on LVEF did not differ by imaging method used, time to follow-up re-evaluation, or HF phenotype. Reduction in LV volumes tended to be greater in HF with reduced EF (HFrEF) than in those with preserved EF (HFpEF), while the opposite was observed for LVMi.<br /><b>Conclusions</b><br />Treatment with SGLT2i significantly reversed cardiac volumes, improving LV systolic function and LV mass, particularly in HFrEF patients.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 02 Sep 2023; 22:235</small></div>

<div><h4>Association between the insulin resistance and all-cause mortality in patients with moderate and severe aortic stenosis: a retrospective cohort study.</h4><i>Huang R, Xu X, Xu C, Zhang S, ... Liao X, Zhuang X</i><br /><b>Background</b><br />The triglyceride-glucose (TyG) index is a reliable surrogate marker of insulin resistance (IR). However, whether the TyG index has prognostic value in patients with moderate to severe aortic stenosis (AS) remains unclear.<br /><b>Methods</b><br />This study enrolled 317 patients with moderate to severe AS at the First Affiliated Hospital of Sun Yat-Sen University. The patients were grouped according to the cut-off value of the TyG index. Cox regression with Firth\'s penalized maximum likelihood method and restricted cubic splines regression were conducted to assess the association between the TyG index and all-cause mortality. The added value of the TyG index included in the traditional risk factors model for outcome prediction was also analyzed.<br /><b>Results</b><br />Among 317 patients (mean age 67.70 years, 62.8% male), there was 84 all-cause mortality during a median 38.07 months follow-up. After fully adjusting for confounders, a per-unit increase in the TyG index was associated with a 62% higher all-cause mortality risk (HR 1.622, 95% CI 1.086-2.416, p = 0.018). The restricted cubic splines regression model revealed a linear association between the TyG index and the risk of all-cause mortality (p for nonlinearity = 0.632). The addition of the TyG index in the basic risk model has an incremental effect on the prediction of mortality [C-statistic change from 0.755 to 0.768; continuous net reclassification improvement (95% CI): 0.299 (0.051-0.546), p = 0.017; integrated discrimination improvement: 0.017 (0.001-0.033), p = 0.044].<br /><b>Conclusions</b><br />Higher IR assessed by the TyG index was associated with a higher risk of all-cause mortality in patients with moderate and severe AS.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 02 Sep 2023; 22:238</small></div>

<div><h4>The role of oxidative stress in diabetes mellitus-induced vascular endothelial dysfunction.</h4><i>An Y, Xu BT, Wan SR, Ma XM, ... Xu Y, Jiang ZZ</i><br /><AbstractText>Diabetes mellitus is a metabolic disease characterized by long-term hyperglycaemia, which leads to microangiopathy and macroangiopathy and ultimately increases the mortality of diabetic patients. Endothelial dysfunction, which has been recognized as a key factor in the pathogenesis of diabetic microangiopathy and macroangiopathy, is characterized by a reduction in NO bioavailability. Oxidative stress, which is the main pathogenic factor in diabetes, is one of the major triggers of endothelial dysfunction through the reduction in NO. In this review, we summarize the four sources of ROS in the diabetic vasculature and the underlying molecular mechanisms by which the pathogenic factors hyperglycaemia, hyperlipidaemia, adipokines and insulin resistance induce oxidative stress in endothelial cells in the context of diabetes. In addition, we discuss oxidative stress-targeted interventions, including hypoglycaemic drugs, antioxidants and lifestyle interventions, and their effects on diabetes-induced endothelial dysfunction. In summary, our review provides comprehensive insight into the roles of oxidative stress in diabetes-induced endothelial dysfunction.</AbstractText><br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 02 Sep 2023; 22:237</small></div>

<div><h4>Microvascular endothelial dysfunction in skin is associated with higher risk of heart failure with preserved ejection fraction in women with type 2 diabetes: the Hoorn Diabetes Care System Cohort.</h4><i>Canto ED, van Deursen L, Hoek AG, Elders PJM, ... Eringa EC, Beulens JWJ</i><br /><b>Background</b><br />Microvascular dysfunction plays a crucial role in complications of type 2 diabetes and might contribute to heart failure with preserved ejection fraction (HFpEF), a disease that disproportionally affects women. We aimed to investigate if presence and degree of microvascular dysfunction (MVD) in skin relates to markers of left ventricular diastolic dysfunction (LVDD) and HFpEF risk in adults with type 2 diabetes, and whether sex modifies this association.<br /><b>Methods</b><br />We recruited 154 participants (50% women) from the Hoorn Diabetes Care System Cohort, a prospective cohort study, for in vivo evaluation of skin MVD, echocardiography and blood sampling. MVD was assessed by laser speckle contrast analysis combined with iontophoresis of insulin, acetylcholine and sodium nitroprusside (SNP). We performed a cross-sectional analysis of the association between perfusion responses and echocardiographic and clinical markers of LVDD and the H2FPEF score by multivariable linear regression analysis adjusted for confounders. Sex was evaluated as a potential effect modifier and the analysis was stratified.<br /><b>Results</b><br />Mean age was 67 ± 6y, mean HbA1c 7.6 ± 1.3%. Women were more frequently obese (54.5 vs. 35.1%), had higher NT-proBNP plasma levels (80, IQR:34-165 vs. 46, 27-117 pg/ml) and E/E\'(13.3 ± 4.3 vs. 11.4 ± 3.0) than men. Eleven women and three men were diagnosed with HFpEF, and showed lower perfusion response to insulin than those without HFpEF. A lower perfusion response to insulin and acetylcholine was associated with higher HFpEF risk in women, but not men (10% decreased perfusion response was associated with 5.8% [95%CI: 2.3;9.4%] and 5.9% [1.7;10.1%] increase of the H2FPEF score, respectively). A lower perfusion response to SNP was associated with higher pulmonary arterial systolic pressure in men while a lower perfusion response to acetylcholine associated with higher LV mass index in women and with worse LV longitudinal strain in the total population. No significant associations were found between perfusion responses and conventional LVDD markers.<br /><b>Conclusions</b><br />Impaired microvascular responses to insulin and acetylcholine in skin confers a higher risk of HFpEF in women with type 2 diabetes. In vivo measures of systemic MVD could represent novel risk markers for HFpEF, opening new avenues for the prevention of HFpEF in type 2 diabetes.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 01 Sep 2023; 22:234</small></div>

<div><h4>Sex-specific associations between adipokine profiles and carotid-intima media thickness in the Cameron County Hispanic Cohort (CCHC).</h4><i>Kim D, Memili A, Chen HH, Highland HM, ... North KE, Gutierrez AD</i><br /><b>Background</b><br />Adipokines are hormones secreted from adipose tissue and are associated with cardiometabolic diseases (CMD). Functional differences between adipokines (leptin, adiponectin, and resistin) are known, but inconsistently reported associations with CMD and lack of studies in Hispanic populations are research gaps. We investigated the relationship between subclinical atherosclerosis and multiple adipokine measures.<br /><b>Methods</b><br />Cross-sectional data from the Cameron County Hispanic Cohort (N = 624; mean age = 50; Female = 70.8%) were utilized to assess associations between adipokines [continuous measures of adiponectin, leptin, resistin, leptin-to-adiponectin ratio (LAR), and adiponectin-resistin index (ARI)] and early atherosclerosis [carotid-intima media thickness (cIMT)]. We adjusted for sex, age, body mass index (BMI), smoking status, cytokines, fasting blood glucose levels, blood pressure, lipid levels, and medication usage in the fully adjusted linear regression model. We conducted sexes-combined and sex-stratified analyses to account for sex-specificity and additionally tested whether stratification of participants by their metabolic status (metabolically elevated risk for CMD as defined by having two or more of the following conditions: hypertension, dyslipidemia, insulin resistance, and inflammation vs. not) influenced the relationship between adipokines and cIMT.<br /><b>Results</b><br />In the fully adjusted analyses, adiponectin, leptin, and LAR displayed significant interaction by sex (p < 0.1). Male-specific associations were between cIMT and LAR [β(SE) = 0.060 (0.016), p = 2.52 × 10<sup>-4</sup>], and female-specific associations were between cIMT and adiponectin [β(SE) = 0.010 (0.005), p = 0.043] and ARI [β(SE) = - 0.011 (0.005), p = 0.036]. When stratified by metabolic health status, the male-specific positive association between LAR and cIMT was more evident among the metabolically healthy group [β(SE) = 0.127 (0.015), p = 4.70 × 10<sup>-10</sup>] (p for interaction by metabolic health < 0.1). However, the female-specific associations between adiponectin and cIMT and ARI and cIMT were observed only among the metabolically elevated risk group [β(SE) = 0.014 (0.005), p = 0.012 for adiponectin; β(SE) = - 0.015 (0.006), p = 0.013 for ARI; p for interaction by metabolic health < 0.1].<br /><b>Conclusion</b><br />Associations between adipokines and cIMT were sex-specific, and metabolic health status influenced the relationships between adipokines and cIMT. These heterogeneities by sex and metabolic health affirm the complex relationships between adipokines and atherosclerosis.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 31 Aug 2023; 22:231</small></div>

<div><h4>Association between the triglyceride glucose (TyG) index and the risk of acute kidney injury in critically ill patients with heart failure: analysis of the MIMIC-IV database.</h4><i>Yang Z, Gong H, Kan F, Ji N</i><br /><b>Background</b><br />Insulin resistance (IR) can be effectively assessed using the dependable surrogate biomarker triglyceride-glucose (TyG) index. In various critical care contexts, like contrast-induced acute kidney injury (AKI), an elevated TyG index has demonstrated a robust correlation with the incidence of AKI. Nonetheless, the potential of the TyG index to predict AKI in critically ill patients with heart failure (HF) remains uncertain.<br /><b>Methods</b><br />A cohort of participants was non-consecutively selected from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database and divided into quartiles based on their TyG index values. The incidence of AKI was the primary outcome. The secondary endpoint was in-hospital mortality within both the whole study population and the subset of AKI patients. The use of the renal replacement therapy (RRT) which represented the progression of AKI severity was also included as a secondary endpoint representing renal outcome. A restricted cubic splines model and Cox proportional hazards models were utilized to evaluate the association of TyG index with the risk of AKI in patients with HF in a critical condition. Kaplan-Meier survival analysis was employed to estimate primary and secondary endpoint disparities across groups differentiated by their TyG index.<br /><b>Results</b><br />This study included a total of 1,393 patients, with 59% being male. The incidence of AKI was 82.8%. Cox proportional hazards analyses revealed a significant association between TyG index and the incidence of AKI in critically ill patients with HF. The restricted cubic splines model illustrated the linear relationship between higher TyG index and increased risk of AKI in this specific patient population. Furthermore, the Kaplan-Meier survival analyses unveiled statistically significant differences in the use of RRT across the subset of AKI patients based on the quartiles of the TyG index.<br /><b>Conclusions</b><br />The results highlight the TyG index as a robust and independent predictor of the incidence of AKI and poor renal outcome in patients with HF in a critical condition. However, further confirmation of causality necessitates larger prospective studies.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 31 Aug 2023; 22:232</small></div>

<div><h4>Empagliflozin is associated with lower cardiovascular risk compared with dipeptidyl peptidase-4 inhibitors in adults with and without cardiovascular disease: EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study results from Europe and Asia.</h4><i>Vistisen D, Carstensen B, Elisabetta P, Lanzinger S, ... EMPRISE EU, East Asia Study Group</i><br /><b>Background</b><br />Studies that have reported lower risk for cardiovascular outcomes in users of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) are limited by residual cofounding and lack of information on prior cardiovascular disease (CVD). This study compared risk of cardiovascular events in patients within routine care settings in Europe and Asia with type 2 diabetes (T2D) initiating empagliflozin compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) stratified by pre-existing CVD and history of heart failure (HF).<br /><b>Methods and results</b><br />Adults initiating empagliflozin and DPP-4i in 2014-2018/19 from 11 countries in Europe and Asia were compared using propensity score matching and Cox proportional hazards regression to assess differences in rates of primary outcomes: hospitalisation for heart failure (HHF), myocardial infarction (MI), stroke; and secondary outcomes: cardiovascular mortality (CVM), coronary revascularisation procedure, composite outcome including HHF or CVM, and 3-point major adverse cardiovascular events (MACE: MI, stroke and CVM). Country-specific results were meta-analysed and pooled hazard ratios (HR) with 95% confidence intervals (CI) from random-effects models are presented. In total, 85,244 empagliflozin/DPP4i PS-matched patient pairs were included with overall mean follow-up of 0.7 years. Among those with pre-existing CVD, lower risk was observed for HHF (HR 0.74; 95% CI 0.64-0.86), CVM (HR 0.55; 95% CI 0.38-0.80), HHF or CVM (HR 0.57; 95% CI 0.48-0.67) and stroke (HR 0.79; 95% CI 0.67-0.94) in patients initiating empagliflozin vs DPP-4i. Similar patterns were observed among patients without pre-existing CVD and those with and without pre-existing HF.<br /><b>Conclusion</b><br />These results from diverse patient populations in routine care settings across Europe and Asia demonstrate that initiation of empagliflozin compared to DPP-4i results in favourable cardioprotective effects regardless of pre-existing CVD or HF status.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 31 Aug 2023; 22:233</small></div>

<div><h4>Triglyceride-glucose index in the prediction of adverse cardiovascular events in patients without diabetes mellitus after coronary artery bypass grafting: a multicenter retrospective cohort study.</h4><i>Wu Z, Xie L, Guo D, Chen S, ... Zang D, Yang J</i><br /><b>Background</b><br />The triglyceride-glucose (TyG) index has been evaluated as a reliable surrogate for insulin resistance (IR) and has been proven to be a predictor of poor outcomes in patients with cardiovascular diseases. However, data are lacking on the relationship of the TyG index with prognosis in nondiabetic patients who underwent coronary artery bypass grafting (CABG). Thus, the purpose of our current study was to investigate the potential value of the TyG index as a prognostic indicator in patients without diabetes mellitus (DM) after CABG.<br /><b>Methods</b><br />This multicenter, retrospective cohort study involving 830 nondiabetic patients after CABG from 3 tertiary public hospitals from 2014 to 2018. Kaplan-Meier survival curve analysis was conducted followed by the log-rank test. Cox proportional hazards regression models were used to explore the association between the TyG index and major adverse cardiovascular events (MACEs). The incremental predictive power of the TyG index was evaluated with C-statistics, continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI).<br /><b>Results</b><br />An incrementally higher TyG index was associated with an increasingly higher cumulative incidence of MACEs (log-rank test, p < 0.001). The hazard ratio (95% CI) of MACEs was 2.22 (1.46-3.38) in tertile 3 of the TyG index and 1.38 (1.18-1.62) per SD increase in the TyG index. The addition of the TyG index yielded a significant improvement in the global performance of the baseline model [C-statistic increased from 0.656 to 0.680, p < 0.001; continuous NRI (95% CI) 0.269 (0.100-0.438), p = 0.002; IDI (95% CI) 0.014 (0.003-0.025), p = 0.014].<br /><b>Conclusions</b><br />The TyG index may be an independent factor for predicting adverse cardiovascular events in nondiabetic patients after CABG.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 30 Aug 2023; 22:230</small></div>

<div><h4>Long-term cardiovascular outcomes of biodegradable polymer drug eluting stents in patients with diabetes versus non-diabetes mellitus: a meta-analysis.</h4><i>Wang H, Zu Q, Tang H, Lu M, Chen R, Yang Z</i><br /><b>Background</b><br />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.<br /><b>Methods</b><br />Cochrane central, MEDLINE (Subset PubMed), EMBASE, Web of Science, http://www.<br /><b>Clinicaltrials</b><br />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.<br /><b>Results</b><br />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.<br /><b>Conclusions</b><br />Diabetes mellitus was an independent risk factor associated with long term adverse cardiovascular outcomes following PCI with BP-DES.<br /><br />© 2023. BioMed Central Ltd., part of Springer Nature.<br /><br /><small>Cardiovasc Diabetol: 29 Aug 2023; 22:228</small></div>