Hyperglycemia and insulin resistance are key players in the development of atherosclerosis and its complications. A large body of evidence suggest that metabolic abnormalities cause overproduction of ...reactive oxygen species (ROS). In turn, ROS, via endothelial dysfunction and inflammation, play a major role in precipitating diabetic vascular disease. A better understanding of ROS-generating pathways may provide the basis to develop novel therapeutic strategies against vascular complications in this setting. Part I of this review will focus on the most current advances in the pathophysiological mechanisms of vascular disease: (i) emerging role of endothelium in obesity-induced insulin resistance; (ii) hyperglycemia-dependent microRNAs deregulation and impairment of vascular repair capacities; (iii) alterations of coagulation, platelet reactivity, and microparticle release; (iv) epigenetic-driven transcription of ROS-generating and proinflammatory genes. Taken together these novel insights point to the development of mechanism-based therapeutic strategies as a promising option to prevent cardiovascular complications in diabetes.
In part II of this review, we describe the epidemiology and clinical consequences of vascular disease in patients with diabetes, and discuss the efficacy of risk factor modification and antiplatelet ...treatment. Specifically, evidence-based cardiovascular therapies are discussed through novel clinical insights on management of hyperglycaemia, hypertension, dyslipidaemia as well as platelet dysfunction. Recent trends in the incidence and outcomes of vascular disease in diabetes suggest that timely and effective implementation of therapies is making a favourable impact.
Recent randomized trials suggest that intensive glycaemic control fails to reduce heart failure-related events in patients with diabetes. The molecular cues underlying persistent myocardial damage ...despite normoglycaemia restoration remain elusive. MicroRNAs (miRNAs), a class of small non-coding RNAs, orchestrate transcriptional programs implicated in adverse cardiac remodelling. The present study investigates whether miRNAs participate to hyperglycaemic memory in the diabetic heart.
miRNA landscape was assessed by Mouse miRNome miRNA PCR Arrays in left ventricular specimens collected from 4-month-old streptozotocin-induced diabetic mice, with or without intensive glycaemic control by slow-release insulin implants. A dysregulation of 316 out of 1008 total miRNAs was observed in the diabetic hearts when compared with controls. Of these, 209 were up-regulated and 107 were down-regulated by >2.0-fold. Interestingly enough, the expression of 268 of those miRNAs remained significantly altered in diabetic mice even after subsequent normoglycaemia. Ingenuity pathway analysis revealed that dysregulated miRNAs were implicated in myocardial signalling networks triggering apoptosis (miR-320b, miR-378, miR-34a), fibrosis (miR-125b, miR-150, miR-199a, miR-29b, miR30a), hypertrophic growth (miR-1, miR-150, miR-199a, miR-133a, miR-214, miR-29a, miR-125b, miR-221, miR-212), autophagy (miR-133a, miR-221, miR-212, miR30a), oxidative stress (miR-221, miR-146a, miR-34a, miR-210, miR-19b, miR-125b, miR27a, miR-155), and heart failure (miR-423, miR-499, miR-199a), respectively.
Glycaemic control is not able to rescue hyperglycaemia-induced alterations of miRNA landscape in the diabetic heart. These findings may provide novel insights to understand why diabetic cardiomyopathy progresses despite normalization of blood glucose levels.
The coexistence of type 2 diabetes mellitus (T2DM) and heart failure (HF), either with reduced (HFrEF) or preserved ejection fraction (HFpEF), is frequent (30–40% of patients) and associated with a ...higher risk of HF hospitalization, all‐cause and cardiovascular (CV) mortality. The most important causes of HF in T2DM are coronary artery disease, arterial hypertension and a direct detrimental effect of T2DM on the myocardium. T2DM is often unrecognized in HF patients, and vice versa, which emphasizes the importance of an active search for both disorders in the clinical practice. There are no specific limitations to HF treatment in T2DM. Subanalyses of trials addressing HF treatment in the general population have shown that all HF therapies are similarly effective regardless of T2DM. Concerning T2DM treatment in HF patients, most guidelines currently recommend metformin as the first‐line choice. Sulphonylureas and insulin have been the traditional second‐ and third‐line therapies although their safety in HF is equivocal. Neither glucagon‐like preptide‐1 (GLP‐1) receptor agonists, nor dipeptidyl peptidase‐4 (DPP4) inhibitors reduce the risk for HF hospitalization. Indeed, a DPP4 inhibitor, saxagliptin, has been associated with a higher risk of HF hospitalization. Thiazolidinediones (pioglitazone and rosiglitazone) are contraindicated in patients with (or at risk of) HF. In recent trials, sodium–glucose co‐transporter‐2 (SGLT2) inhibitors, empagliflozin and canagliflozin, have both shown a significant reduction in HF hospitalization in patients with established CV disease or at risk of CV disease. Several ongoing trials should provide an insight into the effectiveness of SGLT2 inhibitors in patients with HFrEF and HFpEF in the absence of T2DM.
Abstract
Endothelial cells (ECs) are sentinels of cardiovascular health. Their function is reduced by the presence of cardiovascular risk factors, and is regained once pathological stimuli are ...removed. In this European Society for Cardiology Position Paper, we describe endothelial dysfunction as a spectrum of phenotypic states and advocate further studies to determine the role of EC subtypes in cardiovascular disease. We conclude that there is no single ideal method for measurement of endothelial function. Techniques to measure coronary epicardial and micro-vascular function are well established but they are invasive, time-consuming, and expensive. Flow-mediated dilatation (FMD) of the brachial arteries provides a non-invasive alternative but is technically challenging and requires extensive training and standardization. We, therefore, propose that a consensus methodology for FMD is universally adopted to minimize technical variation between studies, and that reference FMD values are established for different populations of healthy individuals and patient groups. Newer techniques to measure endothelial function that are relatively easy to perform, such as finger plethysmography and the retinal flicker test, have the potential for increased clinical use provided a consensus is achieved on the measurement protocol used. We recommend further clinical studies to establish reference values for these techniques and to assess their ability to improve cardiovascular risk stratification. We advocate future studies to determine whether integration of endothelial function measurements with patient-specific epigenetic data and other biomarkers can enhance the stratification of patients for differential diagnosis, disease progression, and responses to therapy.
Type 2 diabetes mellitus (T2DM) is a metabolic condition with an elevated impact on cardiovascular (CV) risk. The innovative therapeutic approaches for T2DM - incretin-based therapies (IBTs), ...including glucagon-like peptide 1 (GLP-1) receptor agonists, have become popular and more widely used in recent years. The available scientific data from clinical studies and clinical practice highlights their beyond glucose-lowering effects, which is achieved without any increase in hypoglycaemia. The former effects include reduction in body weight, lipids, blood pressure, inflammatory markers, oxidative stress, endothelial dysfunction, and subclinical atherosclerosis, thus reducing and potentially preventing CV events. In fact, the introduction of IBTs is one of the key moments in the history of diabetes research and treatment. Such therapeutic strategies allow customization of antidiabetic treatment to each patient's need and therefore obtain better metabolic control with reduced CV risk. The aim of the present paper is to provide a comprehensive overview of the effects of GLP-1RA on various cardiometabolic markers and overall CV risk, with particular attention on recent CV outcome studies and potential mechanisms. In particular, the effects of liraglutide on formation and progression of atherosclerotic plaque and mechanisms explaining its cardioprotective effects are highlighted.
•GLP-1 receptor agonists favourably modulate cardio-metabolic risk factors.•Liraglutide and semaglutide also reduced cardiovascular events.•Liraglutide seems to reduce the formation and the progression of atherosclerosis.
Cardiovascular outcome trials in patients with type 2 diabetes at high cardiovascular risk have led to remarkable advances in our understanding of the effectiveness of GLP-1 receptor agonists and ...SGLT2 inhibitors to reduce cardiorenal events. In 2019, the American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD), and European Society of Cardiology (ESC) published updated recommendations for the management of such patients. We are concerned that ongoing discussions focusing on the differences between the endocrinologists' consensus report from the ADA and EASD and cardiologists' guidelines from the ESC are contributing to clinical inertia, thereby effectively denying evidence-based treatments advocated by both groups to patients with type 2 diabetes and cardiorenal disease. A subset of members from the writing groups of the ADA-EASD consensus report and the ESC guidelines was convened to emphasise where commonalities exist and to propose an integrated framework that encompasses the views incorporated in management approaches proposed by the ESC and the ADA and EASD. Coordinated action is required to ensure that people with type 2 diabetes, cardiovascular disease, heart failure, or chronic kidney disease are treated appropriately with an SGLT2 inhibitor or GLP-1 receptor agonist. In our opinion, this course should be initiated independent of background therapy, current glycaemic control, or individualised treatment goals.
Systematic paraaortic and bilateral pelvic lymphadenectomy is the standard of a comprehensive surgical staging in presumed early epithelial ovarian cancer, but no prospective randomized evidence ...suggests a possible therapeutic value. Moreover, this procedure is associated with potential severe morbidity. The Sentinel Lymph Nodes in Early-Stage Ovarian Cancer trial is a prospective study designed to test whether sentinel node detection can accurately predict nodal status in a cohort of women with early epithelial ovarian cancer.
We here present the results of the first part of the Sentinel Lymph Nodes in Early-Stage Ovarian Cancer trial, regarding the feasibility of the sentinel lymph node technique and the preliminary findings regarding its safety and accuracy.
The Sentinel Lymph Nodes in Early-Stage Ovarian Cancer trial is a prospective, phase II, single-arm study included patients with presumed stages I–II epithelial ovarian cancer planned for immediate or delayed minimally invasive comprehensive staging. The ovarian pedicle is injected with 2 mL of a 1.25 mg/mL indocyanine green solution. The pelvic and lumboaortic retroperitoneum is then accessed and inspected to identify and remove sentinel nodes. After sentinel node procedure, staging is completed including systematic pelvic and paraaortic lymphadenectomy. Assuming a sensitivity of 98.5% in predicting positive sentinel lymph nodes at histology, a pathological lymph node prevalence of 14.2%, a precision of estimate (ie, the maximum marginal error) d = 5%, a type I error α = 0.05, a sample size of 160 patients is needed to test the general hypothesis. Here we present the preliminary results on the first 31 patients enrolled.
Thirty-one patients were included. Sentinel node was identified in 21 patients (detection rate, 67.7%). The detection rate was significantly higher in women undergoing immediate vs delayed staging (88.9% vs 41.7%, P = .003). Four patients had positive nodes. In all the patients with lymphatic dissemination, a positive sentinel node was identified (sensitivity, 100%; false-negative rate, 0%; negative predictive value, 100%). One (3.2%) intra- and 2 (6.5%) postoperative grade I complications occurred.
Our data show that the detection of sentinel node in early epithelial ovarian cancer is low when patients are submitted to delayed-staging surgery. However, sentinel node procedure is feasible and has the potential to provide reliable and useful information on nodal status and may allow the avoidance of systematic lymphadenectomy in the majority of patients.
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