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Aims: To analyze the association between chronic SGLT2-I treatment and development of contrast-induced acute kidney injury (CI-AKI) in diabetic patients with acute myocardial infarction (AMI) undergoing PCI., Methods: Multicenter international registry of consecutive patients with type 2 diabetes mellitus (T2DM) and AMI undergoing PCI between 2018 and 2021. The study population was stratified by the presence of chronic kidney disease (CKD) and anti-diabetic therapy at admission (SGLT2-I versus non-SGLT2-I users)., Results: The study population consisted of 646 patients: 111 SGLT2-I users [28 (25.2%) with CKD] and 535 non-SGLT2-I users [221 (41.3%) with CKD]. The median age was 70 [61-79] years. SGLT2-I users exhibited significantly lower creatinine values at 72 h after PCI, both in the non-CKD and CKD stratum. The overall rate of CI-AKI was 76 (11.8%), significantly lower in SGLT2-I users compared to non-SGLT2-I patients (5.4% vs 13.1%, p = 0.022). This finding was also confirmed in patients without CKD (p = 0.040). In the CKD cohort, SGLT2-I users maintained significantly lower creatinine values at discharge. The use of SGLT2-I was an independent predictor of reduced rate of CI-AKI (OR 0.356; 95%CI 0.134-0.943, p = 0.038)., Conclusion: In T2DM patients with AMI, the use of SGLT2-I was associated with a lower risk of CI-AKI, mostly in patients without CKD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: Type 2 diabetes mellitus (T2DM) and heart failure are closely related entities and together determine an increased risk of mortality compared to patients suffering from only one of these diseases. Sodium-glucose co-transporter type 2 inhibitors (SGLT-2i) have shown favorable effects on cardiovascular system, particularly on heart failure. Aim of this study is to verify whether in individuals with T2DM and heart failure with reduced ejection fraction (HFrEF) treated with SGLT-2i, echocardiographic signs of favorable reverse remodeling follow longitudinal observation., Methods: 31 subjects with T2DM and HFrEF were finally included. All individuals performed clinical visit, medical history, blood sampling and echocardiography at time 0' and at the end of 6 months of follow-up on SGLT-2i treatment., Results: After 6 months follow-up, left ventricular ejection fraction (LVEF), global work index (GWI), global work efficiency (GWE), global longitudinal strain (GLS), left atrial expansion index (LAEI) and total left atrial emptying fraction (TLAEF), tricuspid annular plane systolic excursion (TAPSE), septal thickness (St), pulmonary artery systolic pressures (PASP) and TAPSE/PASP ratio significantly improved., Conclusions: Despite the lack of a favorable effect on cardiac remodeling, SGLT-2i treatment significantly improved LV systolic and diastolic function, left atrial (LA) reservoir and total emptying function, RV systolic function and pulmonary artery pressure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aim: miRNA-21 is a crucial regulator of developing cardiac diseases, but its role is still controversial, and therefore it is necessary to clarify, at cardiac level, its involvement in high glucose induced-acute and chronic cardiac damage., Methods: Human ventricular cardiac myoblasts AC16, treated and not with miRNA-21 inhibitor, were exposed to high glucose for 2 and 7 days, and the expression of damage markers were investigated. Further, cardiac energetic metabolism was evaluated by measuring both the expression of glucose transporters and lipids regulators., Results: Short-term high glucose treatment induced a significant increase in miRNA-21 expression (p < 0.05) that was associated with an increase in hydrogen ion flux and energy potential dissipation without any change in energy production or increase in genes expression involved in cellular damage. miRNA-21 reduction observed (p < 0.05) at 7 days of high glucose treatment, induced the activation of damage pathways and compromised mitochondrial function (p < 0.05)., Conclusion: In human cardiomyocytes, the abundance of miRNA-21 takes part in first defense mechanism against cardiac insult and its cardioprotective effect depends on time of exposure to injury. Moreover, miRNA-21 regulates mitochondrial respiration and the ability of cells to select the most appropriate substrate for ATP production in given environment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

A hyperglycemic state, also in non-diabetic subjects, may be associated with acute coronary syndrome (ACS). Aim of this review is to describe the pathophysiologic association between ACS and hyperglycemic state, the protective mechanisms of a tight glycaemic control in ACS on CV outcomes, and the supporting clinical evidence. Several mechanisms may be responsible of a poor CV outcome in subjects with hyperglycemia during ACS. Endothelial NAPDH oxidase-2 (NOX2) activation in response to high glucose alters the balance between Raf/MAPK-dependent vasoconstriction and PI3K/Akt-dependent vasodilation in favour of constriction. Hyperglycaemia induces an overproduction of superoxide by the mitochondrial electron transport chain through different molecular mechanisms. Moreover, hyperglycaemia increases the size of the infarct by causing myocardial cell death through apoptosis and reducing the collateral blood flow. High FFA concentrations lead to toxicity mechanisms in acutely ischemic myocardium. On the other hand, a tight glycaemic control in ACS exerts a cardioprotective action by anti-inflammatory and anti-apoptotic mechanisms, anti-oxidative stress, endothelium protection, FFA reduction, anti-glucotoxic effect, IR and cardiac fuel metabolisms improvement, heart stem cells protection and reduced activation of adrenergic system. Unfortunately, the clinical studies supporting the above pathophysiological background are few and sometimes controversial, more likely due the risk of hypoglycemia linked to the insulin therapy generally used during ACS. Intriguingly, GLP-1 RA and SGLT2i, demonstrated highly effective in the cardiovascular prevention in high-risk subjects without the risk of hypoglycemia, might keep this cardioprotective effect even in acute conditions such as ASC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: We examined the association of the coronary thrombus microbiota and relative metabolites with major adverse cardiovascular events (MACE) in hyperglycemic patients with ST segment elevation myocardial infarction (STEMI)., Background: Hyperglycemia during STEMI may affect both development and progression of coronary thrombus via gut and thrombus microbiota modifications., Methods: We undertook an observational cohort study of 146 first STEMI patients treated with primary percutaneous coronary intervention (PPCI) and thrombus-aspiration (TA). Patients were clustered, based on admission blood glucose levels, in hyperglycemic (≥140 mg/dl) and normoglycemic (<140 mg/dl). We analyzed gut and thrombus microbiota in all patients. Moreover, we assessed TMAO, CD40L and von Willebrand Factor (vWF) in coronary thrombi. Cox regressions were used for the association between Prevotellaspp. and TMAO terziles and MACE. MACE endpoint at 1 year included death, re-infarction, unstable angina., Results: In fecal and thrombus samples, we observed a significantly different prevalence of both Prevotellaspp. and Alistipesspp. between patients with hyperglycemia (n = 56) and those with normal glucose levels (n = 90). The abundance of Prevotella increased in hyperglycemic vs normoglycemic patients whereas the contrary was observed for Alistipes. Interestingly, in coronary thrombus, the content of Prevotella was associated with admission blood glucose levels (p < 0.01), thrombus dimensions (p < 0.01), TMAO, CDL40 (p < 0.01) and vWF (p < 0.01) coronary thrombus contents. Multivariate Cox-analysis disclosed a reduced survival in patients with high levels of Prevotella and TMAO in coronary thrombus as compared to patients with low levels of Prevotella and TMAO, after 1-year follow up., Conclusions: Hyperglycemia during STEMI may increase coronary thrombus burden via gut and thrombus microbiota dysbiosis characterized by an increase of Prevotella and TMAO content in thrombi., Clinical Trial Registration: NCT03439592. September 30, 2016. Ethic Committee Vanvitelli University: 268/2016., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Metformin represents a striking example of a "historical nemesis" of a drug. About 40 years after its marketing in Europe, once demonstrated its efficacy and safety, metformin was registered also in the U.S. A few years later, it has become a mainstay in T2DM treatment, according to all international Scientific Societies guidelines. Today, despite the advent of new innovative drugs, metformin still persists as a first-choice drug in T2DM. This success is largely justified. In fact, over the years, also positive effects on health increased. In particular, evidence has been accumulated on a beneficial impact against many other aging-related morbidities (obesity, metabolic syndrome, cardiovascular disease, cancer, cognitive decline and mortality). This literature review describes preclinical and clinical evidence favoring the "anti-aging" therapeutic potential of metformin outside of T2DM. The rationale to the use of metformin as part of a combined therapy in a variety of clinical settings, allowing for a reduction of the chemotherapy dose in cancer patients, has also been discussed. In particular, the focus was on metformin action on RAS/RAF/MAPK pathway. In the end, the real challenge for metformin could be to fully demonstrate beneficial effects on health even in non-diabetic subjects., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Metformin, the first choice drug for type 2 diabetes treatment in all stages of therapy, and one of the most widely prescribed anti-hyperglycemic agents worldwide, represents a rare example of an old drug which continues to display new beneficial effects in various fields. However, lactic acidosis (LA) persists as a serious adverse effect. LA incidence is low and is not necessarily determined by the administration of metformin. Unfortunately, the concern for this complication has negatively affected the drug use, particularly in chronic kidney disease, which may impair drug excretion, and in congestive heart failure and chronic liver disease, which may promote lactate accumulation. This review describes how not only these historical contraindications have been considerably scaled back, though rather a recent large body of evidence supports a protective effect of biguanide on kidney, heart and liver and, maybe, against lactic acidosis itself. It is worthy to slow down both contraindications and precautions to metformin use, not to deprive a significant number of diabetic patients, as those with kidney, heart and liver comorbidities, from its potential benefits, and not to hamper in the near future the putative advantages in a wide spectrum of conditions outside of diabetes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Study Hypothesis: Cardiac autonomic dysfunction might lead to higher vaso vagal syncope (VVS) recurrence rate in type 2 diabetes mellitus (T2DM) patients vs. non diabetics patients., Background: VVS recurrence might be due to alterations of autonomic system function, as assessed by heart rate variability (HRV). To date, in this study we investigated the correlation between HRV alterations and VVS recurrence at 12 months of follow up in T2DM vs. non T2DM patients., Materials and Methods: In a prospective multicenter study we studied a propensity score matching (PSM) analysis of 121 T2DM vs. 121 non T2DM patients affected by VVS., Results: T2DM vs. non T2DM patients had at baseline a higher rate of HRV dysfunction, and this was linked to higher rate of VVS recurrence at 12 months of follow up (p < 0.05). Blood pressure alterations and lower LF/HF ratio were linked to higher rate of all cause syncope recurrence, and of vasodepressor, cardio inhibitory, and mixed syncope recurrence (p < 0.05). Anti hypertensive drug therapies increased the number of vasodepressor and mixed syncope events (p < 0.05); alterations of heart rate increased syncope recurrence and mixed syncope recurrence events (p < 0.05). Finally, T2DM was linked to higher rate of VVS recurrence, and specifically of vasodepressor and mixed VVS recurrence (p < 0.05)., Conclusions: T2DM patients have alterations of the autonomic nervous system, as result of cardiac autonomic neuropathy. However, T2DM diagnosis and autonomic dysfunction assessed by HRV alterations predicted VVS recurrence., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: To assess the correlation between diabetic retinopathy (DR) and potential risk factors, as well as the relationship between DR and the other complications of diabetes, in a real-life population of type 2 diabetes patients recruited in several centres in Italy., Methods: The NO BLIND is a cross-sectional, multicentre, observational study, which involved nine public outpatient clinics in Italy. The patients were assessed for eligibility from November 2016 till November 2017. Those enrolled underwent standard fundus oculi exam. Clinical and laboratory data were also collected., Results: 2068 T2DM underwent fundus oculi exam. 435 received diagnosis of diabetic retinopathy (21%). Diabetic retinopathy was independently associated with HDL cholesterol (O.R.: 1.042; 95% C.I.: 1.012-1.109; p = 0.004), Albumin Excretion Rate (AER) (O.R.: 1.001; 95% C.I.: 1.000-1.002; p = 0.034) and GFR (O.R.: 1.159; 95% C.I.: 1.039-1.294; p = 0.008). HDL cholesterol values were hence split in two classes according to a potential cut-off (40 mg/dL), as defined by the ROC curve. Following analysis confirmed the association between DR and high HDL values (p = 0.032). Somatic neuropathy and diabetic ulcer were independently related with DR (p < 0.001 and p = 0.012, respectively)., Conclusions: A novel relationship between high HDL cholesterol and DR was observed., (Copyright © 2019 Elsevier B.V. All rights reserved.)