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Objective. To evaluate the prognostic value of glomerular hyperfiltration on long-term kidney-related outcomes and mortality in subjects with diabetes. Methods. We retrospectively analyzed 21-year longitudinal data from 314 patients with long-standing type 2 or type 1 diabetes. Glomerular hyperfiltration was identified based on the age- and sex-specific distribution of the glomerular filtration rate measured by 99mTc-DTPA dynamic renal scintigraphy (mGFR). The primary outcome was a composite of doubling of serum creatinine, end-stage kidney disease (ESKD), or cardiorenal death. The kidney-specific outcome was a composite of doubling of serum creatinine, ESKD, or renal death. Results. Over a median of 21.0 years, the primary composite outcome occurred in 25 (39.7%), 24 (38.1%), and 46 (24.5%) participants with high (H-mGFR, n=63), low (L-mGFR, n=63), or normal glomerular filtration (N-mGFR, n=188), respectively. Compared with N-mGFR, the hazard ratio [95% confidence interval] for the primary composite outcome was 2.09 [1.25–3.49] in H-mGFR and 1.81 [1.05–3.16] in L-mGFR. The hazard ratio for the kidney-specific composite outcome was 4.95 [2.21–11.09] in H-mGFR and 3.81 [1.70–8.56] in L-mGFR. The hazard ratios for doubling of serum creatinine and cardiorenal death were 4.86 [2.18–10.90] and 2.18 [1.24–3.83] in H-mGFR, respectively, and 4.04 [1.77–9.20] and 2.26 [1.27–4.01] in L-mGFR. Conclusions. Glomerular hyperfiltration, similar to hypofiltration, increases the combined risk of worsening kidney function and mortality from cardiovascular or renal causes in patients with diabetes. These findings encourage the active screening of these patients to optimize risk stratification and treatment of subclinical kidney disease.

The severity of the atherosclerotic burden is hardly quantifiable in subjects at high cardiovascular (CV) risk under intensive pharmacological therapy. Several molecules have been proposed as circulating biomarkers of atherosclerosis, but none has emerged as clinically meaningful.Circulating proteins involved in inflammation, plaque remodeling, smooth muscle cell migration, apoptosis and endothelial activity were measured by Proximity Extension Assay in the SUMMIT study cohort (n = 1500), including patients with type 2 diabetes (66%) and established CV disease (50%), who underwent ultrasound assessment of carotid atherosclerosis with total plaque area quantification.In patients with evidence of carotid artery atherosclerosis (n = 1174), seven biomarkers were identified as the more closely related to atherosclerosis extension. Compared with a multivariable model including major traditional CV risk factors, the percentage gain of explained variability in total plaque area was the greatest (33%) after inclusion of CD40 receptor (CD40R) ligand, followed by PDGF (30%), CD40R (26%), EGF (22%), CXCL1 (15%), HBEGF and MMP-17 (both 11%). The relationship of total plaque area with CD40R, PDGF was hyperbolic. In the whole study cohort, including subjects without carotid plaques, CD40R was the strongest predictor of the presence and extension of carotid atherosclerosis. Subjects in the third CD40R tertile had a more than two-fold greater atherosclerotic burden compared with lower CD40R tertiles, despite an only marginally higher load of CV risk factors.CD40R stands among an extended set of plausible atherosclerosis-related biomarkers as the most powerful predictor of carotid atherosclerosis burden in a high CV risk cohort.

Background Type 2 diabetes mellitus (T2D) increases the risk of incident heart failure (HF), whose earliest fingerprint is effort intolerance (i.e. impaired peak oxygen consumption, or VO2peak). In the uncomplicated T2D population, however, the prevalence of effort intolerance and the underpinning mechanistic bases are uncertain. Leveraging the multiparametric characterization allowed by imaging-cardiopulmonary exercise testing (iCPET), the aim of this study is to quantify effort intolerance in T2D and to dissect the associated cardiopulmonary alterations. Methods Eighty-eight adults with well-controlled and uncomplicated T2D and no criteria for HF underwent a maximal iCPET with speckle tracking echocardiography, vascular and endothelial function assessment, as well as a comprehensive biohumoral characterization. Effort intolerance was defined by a VO2peak below 80% of maximal predicted oxygen uptake. Results Forty-eight patients (55%) had effort intolerance reaching a lower VO2peak than T2D controls (16.5 ± 3.2 mL/min/kg, vs 21.7 ± 5.4 mL/min/kg, p 2/work slope (9.9 ± 1.2 vs 11.2 ± 1.4, p 2peak above 80%. Diastolic function, vascular resistance, endothelial function, biohumoral exams, right heart and pulmonary function indices did not differ between the two groups. Conclusions Effort intolerance and reduced VO2peak is a severe and highly prevalent condition in uncomplicated, otherwise asymptomatic T2D. It results from a major defect in skeletal muscle oxygen extraction coupled with a subtle myocardial systolic dysfunction.

Heart failure (HF) is a complex clinical syndrome characterized by different etiologies and a broad spectrum of cardiac structural and functional abnormalities. Current guidelines suggest a classification based on left ventricular ejection fraction (LVEF), distinguishing HF with reduced (HFrEF) from preserved (HFpEF) LVEF. HF should also be thought of as a continuous range of conditions, from asymptomatic stages to clinically manifest syndrome. The transition from one stage to the next is associated with a worse prognosis. While the rate of HF-related hospitalization is similar in HFrEF and HFpEF once clinical manifestations occur, accurate knowledge of the steps and risk factors leading to HF progression is still lacking, especially in HFpEF. Precise hemodynamic and metabolic characterization of patients with or at risk of HF may help identify different disease trajectories and risk factors, with the potential to identify specific treatment targets that might offset the slippery slope towards overt clinical manifestations. Exercise can unravel early metabolic and hemodynamic alterations that might be silent at rest, potentially leading to improved risk stratification and more effective treatment strategies. Cardiopulmonary exercise testing (CPET) offers valuable aid to investigate functional alterations in subjects with or at risk of HF, while echocardiography can assess cardiac structure and function objectively, both at rest and during exercise (exercise stress echocardiography [ESE]). The purpose of this narrative review was to summarize the potential advantages of using an integrated CPET-ESE evaluation in the characterization of both subjects at risk of developing HF and patients with stable HF.

The association between type 2 diabetes mellitus (T2DM) and heart failure (HF) is well established. Early in the course of the diabetic disease, some degree of impaired exercise capacity (a powerful marker of health status with prognostic value) can be frequently highlighted in otherwise asymptomatic T2DM subjects. However, the literature is quite heterogeneous, and the underlying pathophysiologic mechanisms are far from clear. Imaging-cardiopulmonary exercise testing (CPET) is a non-invasive, provocative test providing a multi-variable assessment of pulmonary, cardiovascular, muscular, and cellular oxidative systems during exercise, capable of offering unique integrated pathophysiological information. With this review we aimed at defying the cardiorespiratory alterations revealed through imaging-CPET that appear specific of T2DM subjects without overt cardiovascular or pulmonary disease. In synthesis, there is compelling evidence indicating a reduction of peak workload, peak oxygen assumption, oxygen pulse, as well as ventilatory efficiency. On the contrary, evidence remains inconclusive about reduced peripheral oxygen extraction, impaired heart rate adjustment, and lower anaerobic threshold, compared to non-diabetic subjects. Based on the multiparametric evaluation provided by imaging-CPET, a dissection and a hierarchy of the underlying mechanisms can be obtained. Here we propose four possible integrated pathophysiological mechanisms, namely myocardiogenic, myogenic, vasculogenic and neurogenic. While each hypothesis alone can potentially explain the majority of the CPET alterations observed, seemingly different combinations exist in any given subject. Finally, a discussion on the effects -and on the physiological mechanisms-of physical activity and exercise training on oxygen uptake in T2DM subjects is also offered. The understanding of the early alterations in the cardiopulmonary response that are specific of T2DM would allow the early identification of those at a higher risk of developing HF and possibly help to understand the pathophysiological link between T2DM and HF.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: The purpose of this review is to examine the benefits and harms of pharmacological intervention acting directly or indirectly on the cardiovascular system to treat aortic root and valve disease, versus placebo.

Aims We evaluated the impact of echocardiographic epicardial adipose tissue (EAT) on cardiovascular haemodynamics, metabolic profile and prognosis in heart failure (HF) using combined cardiopulmonary-echocardiography exercise stress. Methods and results We analysed EAT thickness of HF patients with reduced (HFrEF, n = 205) and preserved (HFpEF, n = 188) ejection fraction, including 44 controls. HFpEF patients displayed the highest EAT, while HFrEF patients had lower values than controls. EAT showed an inverse correlation with natriuretic peptides, troponin T and C-reactive protein in HFrEF, while having a direct association with troponin T and C-reactive protein in HFpEF. EAT was independently associated with peak oxygen consumption (VO2 ) and peripheral extraction (AVO2 diff), regardless of body mass index. EAT was inversely correlated with peak VO2 and AVO2 diff in HFpEF, while a direct association was observed in HFrEF, where lower EAT values were associated with worse left ventricular systolic dysfunction. In HFpEF, increased EAT was related to right ventriculo-arterial (tricuspid annular plane systolic excursion/systolic pulmonary artery pressure) uncoupling. After 21 months of follow-up, 146 HF hospitalizations and 34 cardiovascular deaths were recorded in the HF population. Cox multivariable analysis supported an independent differential role of EAT in HF cohorts (interaction P = 0.01): higher risk of adverse events for increasing EAT in HFpEF [hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.04-1.37] and for decreasing EAT in HFrEF (HR 0.75, 95% CI 0.54-0.91). Conclusion In HFpEF, EAT accumulation is associated with worse haemodynamic and metabolic profile, also affecting survival. Conversely, lower EAT values imply higher left ventricular dysfunction, global functional impairment and adverse prognosis in HFrEF.

Background Increased epicardial adipose tissue (EAT) thickness correlates with metabolic syndrome, insulin resistance, microvascular dysfunction and enhanced pericardial restraint. Purpose We measured echocardiographic EAT thickness in heart failure (HF) patients with reduced (HFrEF) or preserved (HFpEF) ejection fraction to determine whether EAT could bear prognostic significance at clinical follow-up. Methods We prospectively enrolled 393 consecutive HF outpatients (205 HFrEF, 188 HFpEF) referred to our hospital due to dyspnoea and/or effort intolerance. We performed a resting clinical and biohumoral evaluation, followed by combined cardiopulmonary-echocardiography exercise stress. A composite of cardiovascular death and HF-related hospitalization was chosen as endpoint during follow-up. Results Patients with HFpEF displayed higher EAT thickness (median 8 mm, interquartile range [IQR] 4–12 mm) than HFrEF (median 3 mm, IQR 2–6 mm; p Conclusion EAT accumulation is more marked in HFpEF than HFrEF and carries different prognostic meanings in the two subsets. In HFpEF, EAT thickening portends adverse outcome, which may be due to increased mechanical restraint and secretion of pro-inflammatory and pro-atherogenic adipokines. In HFrEF, greater EAT thickness seems to have a protective role, while EAT thinning is associated with a worse prognosis, likely reflecting a catabolic state (i.e. cardiac cachexia). Larger studies will clarify whether EAT is a bystander or an active player in the different HF phenotypes. Funding Acknowledgement Type of funding sources: None. Figure 1

Background Epicardial adipose tissue (EAT) acts as a paracrine organ and could exert direct mechanical compression on the myocardium. Purpose We investigated the impact of echocardiographic EAT thickness on metabolic profile and cardiovascular hemodynamics at rest and during exercise in heart failure (HF) patients with reduced (HFrEF) and preserved (HFpEF) ejection fraction Methods We prospectively enrolled 393 consecutive HF outpatients (205 HFrEF, 188 HFpEF) referred to the our hospital due to dyspnoea and/or effort intolerance. We performed a resting clinical and biohumoral evaluation, followed by combined cardiopulmonary-echocardiography exercise stress. The protocol also included 44 healthy controls. Results Patients with HFpEF displayed the greatest EAT thickness (median 8 mm, interquartile range [IQR] 4–12 mm), while those with HFrEF had thinner EAT (median 3 mm, IQR 2–6 mm) than controls (median 5 mm, IQR 3–7 mm; p The analysis of cardiac mechanics revealed that thinner EAT was associated with worse left ventricle systolic dysfunction (average S') and remodeling (3D left ventricle mass) in HFrEF. In HFpEF, increased EAT was related to more severe left atrio-ventricular (left atrium reservoir strain/left ventricle global longitudinal strain) and right ventriculo-arterial (tricuspid annular plane systolic excursion/systolic pulmonary artery pressure) coupling (Figure 2). Conclusion In HFpEF, EAT accumulation is associated with worse hemodynamic and metabolic profile. In HFrEF, conversely, EAT thinning portends more severe LV dysfunction and impaired global functional capacity. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Background: Abnormal circadian blood pressure (BP) patterns and reduced heart rate variability (HRV) are established risk factors for cardiovascular events in diabetic patients. However, studies assessing all-cause mortality associated with altered BP patterns and HRV in diabetes are limited by follow-up periods of less than 10 years. Methods: We examined a cohort of 349 patients with type 2 diabetes ( n =284) or type 1 diabetes ( n =65) recruited in Pisa (Italy) from 1999 and followed-up for 21 years, all with available 24-hour ambulatory BP and HRV monitoring. Dipping, non-dipping and reverse dipping status were defined as a ≥10% decline, Results: After 6,251 person-years of follow-up (median follow-up 21.0 [14.0-21.0] years, 183 [52%] women, age 57.1±11.9 y, BMI 29.4±5.9 kg/m 2 , HbA1c 8.6±2.1%), a total of 136 (39%) deaths occurred. Compared with dippers (n=166), non-dippers (n=144) and reverse dippers (n=39) showed progressively higher prevalence of cardiac autonomic neuropathy (11%, 16% and 31%, respectively), low HRV (45% vs 53% vs 62%), 24-hour hypertension (40%, 60% and 67%), isolated nocturnal hypertension (5%, 27% and 49%), postural hypotension (14%, 26% and 43%), and lower prevalence of white-coat hypertension (31%, 17% and 13%). Reverse dippers and non-dippers had progressively lower mean overall survival (OS) compared with dippers (16.1±5.3 years, 17.5±5.3 years and 18.6±4.6 years, respectively). Reverse dippers also showed an increased risk of all-cause mortality after adjustment for age, sex, BMI, office SBP, plasma glucose, and diabetes duration and type (HR 2.3 [1.4-3.8]). Patients with low HRV had reduced mean OS than those with high HRV (16.9±5.5 and 18.8±4.4, respectively) but similar adjusted risk (HR 1.3 [0.9-1.9]). No significant interactions emerged between BP patterns, HRV and diabetes type on OS. Conclusions: Non-dipping and reverse dipping BP patterns are associated with an increased prevalence of cardiac autonomic neuropathy and reduced survival probability in diabetic patients over a 21-year follow-up, with reverse dipping more than doubling the adjusted risk of all-cause mortality.

The impressive results of recent clinical trials with glucagon-like peptide-1 receptor agonists (GLP-1Ra) and sodium glucose transporter 2 inhibitors (SGLT-2i) in terms of cardiovascular protection prompted a huge interest in these agents for heart failure (HF) prevention and treatment. While both classes show positive effects on composite cardiovascular endpoints (i.e. 3P MACE), their actions on the cardiac function and structure, as well as on volume regulation, and their impact on HF-related events have not been systematically evaluated and compared. In this narrative review, we summarize and critically interpret the available evidence emerging from clinical studies. While chronic exposure to GLP-1Ra appears to be essentially neutral on both systolic and diastolic function, irrespective of left ventricular ejection fraction (LVEF), a beneficial impact of SGLT-2i is consistently detectable for both systolic and diastolic function parameters in subjects with diabetes with and without HF, with a gradient proportional to the severity of baseline dysfunction. SGLT-2i have a clinically significant impact in terms of HF hospitalization prevention in subjects at high and very high cardiovascular risk both with and without type 2 diabetes (T2D) or HF, while GLP-1Ra have been proven to be safe (and marginally beneficial) in subjects with T2D without HF. We suggest that the role of the kidney is crucial for the effect of SGLT-2i on the clinical outcomes not only because these drugs slow-down the time-dependent decline of kidney function and enhance the response to diuretics, but also because they attenuate the meal-related anti-natriuretic pressure (lowering postprandial hyperglycemia and hyperinsulinemia and preventing proximal sodium reabsorption), which would reduce the individual sensitivity to day-to-day variations in dietary sodium intake. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-021-01385-5.

Background SARS-CoV-2 infection is associated with a wide spectrum of neurological complications, including encephalitis. Most cases showed features consistent with a central nervous system (CNS) cytokine-mediated damage. However, few cases arguing for an autoimmune mechanism have been described, mainly as single reports or sparse in large case series involving other CNS manifestations. In this paper, we described a case of definite autoimmune limbic encephalitis (LE) COVID-19 related and reviewed the existing literature on other reported cases. Case report Two weeks after the onset of COVID-19 infection, a 74-year-old woman presented with subacute confusion and focal motor seizures with impaired awareness, starting from left temporal region. Cerebrospinal fluid analysis revealed hyperproteinorrachia. Brain MRI showed bilateral T2/FLAIR hyperintensities in both hippocampi and total body PET/TC scan revealed hypermetabolism in basal ganglia bilaterally. A diagnosis of autoimmune LE was made. Thus, high dose corticosteroids and antiseizure medications were started, with a marked improvement of neurological conditions. Literature review We systematically reviewed the literature to identify all well-documented cases of definite autoimmune LE (according to Graus criteria) in patients with COVID-19 infection, identifying other five cases exhibiting a good response to immunomodulating therapy. Conclusion A very limited number of autoimmune LE have been described until now. It is important to monitor neurological symptoms in COVID-19 patients and to consider the possibility of an autoimmune LE, in particular when altered mental status and seizures appear late in the disease course. This allows to promptly start the appropriate treatments and avoid unnecessary delays., Highlights • A limited number of autoimmune LE covid-19 related have been described until now. • A specific focus on autoimmune limbic encephalitis covid-19-related is lacking. • It ​is important to consider the possibility of covid-19 related limbic encephalitis to promptly start appropriate treatments.

Since 1985, the thiazolidinedione pioglitazone has been widely used as an insulin sensitizer drug for type 2 diabetes mellitus (T2DM). Although fluid retention was early recognized as a safety concern, data from clinical trials have not provided conclusive evidence for a benefit or a harm on cardiac function, leaving the question unanswered. We reviewed the available evidence encompassing both in vitro and in vivo studies in tissues, isolated organs, animals and humans, including the evidence generated by major clinical trials. Despite the increased risk of hospitalization for heart failure due to fluid retention, pioglitazone is consistently associated with reduced risk of myocardial infarction and ischemic stroke both in primary and secondary prevention, without any proven direct harm on the myocardium. Moreover, it reduces atherosclerosis progression, in-stent restenosis after coronary stent implantation, progression rate from persistent to permanent atrial fibrillation, and reablation rate in diabetic patients with paroxysmal atrial fibrillation after catheter ablation. In fact, human and animal studies consistently report direct beneficial effects on cardiomyocytes electrophysiology, energetic metabolism, ischemia–reperfusion injury, cardiac remodeling, neurohormonal activation, pulmonary circulation and biventricular systo-diastolic functions. The mechanisms involved may rely either on anti-remodeling properties (endothelium protective, inflammation-modulating, anti-proliferative and anti-fibrotic properties) and/or on metabolic (adipose tissue metabolism, increased HDL cholesterol) and neurohormonal (renin–angiotensin–aldosterone system, sympathetic nervous system, and adiponectin) modulation of the cardiovascular system. With appropriate prescription and titration, pioglitazone remains a useful tool in the arsenal of the clinical diabetologist.

Postprandial hyperglycemia interferes with vascular reactivity and is a strong predictor of cardiovascular disease. Macronutrient preloads reduce postprandial hyperglycemia in subjects with impaired glucose tolerance (IGT) or type 2 diabetes (T2D), but the effect on endothelial function is unknown. Therefore, we examined whether a protein/lipid preload can attenuate postprandial endothelial dysfunction by lowering plasma glucose responses in subjects with IGT/T2D. Endothelial function was assessed by the reactive hyperemia index (RHI) at fasting, 60 min and 120 min during two 75 g oral glucose tolerance tests (OGTTs) preceded by either water or a macronutrient preload (i.e., egg and parmesan cheese) in 22 volunteers with IGT/T2D. Plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, free fatty acids, and amino acids were measured through each test. RHI negatively correlated with fasting plasma glucose. During the control OGTT, RHI decreased by 9% and its deterioration was associated with the rise in plasma glucose. The macronutrient preload attenuated the decline in RHI and markedly reduced postprandial glycemia. The beneficial effect of the macronutrient preload on RHI was proportional to the improvement in glucose tolerance and was associated with the increase in plasma GLP-1 and arginine levels. In conclusion, a protein/lipid macronutrient preload attenuates glucose-induced endothelial dysfunction in individuals with IGT/T2D by lowering plasma glucose excursions and by increasing GLP-1 and arginine levels, which are known regulators of the nitric oxide vasodilator system.

AIMS: Chronic kidney dysfunction (CKD) and persistent congestion influence heart failure prognosis, but little is known about the role of inflammation in this association. We assessed the relationship between inflammatory biomarkers, persistent congestion and CKD and their prognostic implications in patients with acute heart failure. METHODS: We enrolled 97 hospitalised patients (mean age: 66 ±â€Š12 years, ejection fraction: 30 ±â€Š8%) with acute heart failure. Before discharge, congestion was assessed using a heart failure scoring system on the basis of Framingham criteria. Circulating levels of high-sensitivity C-reactive protein, TGF-s-1, IL-1, IL-6, IL-10, TNF-α, soluble tumour necrosis factor receptor type 1 and 2 were measured. Patients were divided into four groups according to the presence of CKD (estimated glomerular filtration rate

Despite the longstanding and widespread use of statins, they are used quite inefficiently in everyday clinical practice. This might be because of a lack of robust evidence or the wide variety of different guidelines that are frequently changed. Using data from clinical trials and some simple mathematical modeling, we sought to expand upon the relation between low-density lipoprotein cholesterol (LDL-C) control and cardiovascular risk to offer a firm basis for independent decision making in everyday clinical practice. Analysis of the dose–response curves of different statins indicated that doubling the dose will provide a

Several studies reported acute symptomatic seizures as a possible neurological complication of COVID-19 pneumonia. Apart from metabolic imbalances, hypoxia, and fever, other ictogenic mechanisms are likely related to an immune-mediated damage. The same mechanisms are shared by other respiratory viruses. Since neurotropic properties of SARS-CoV-2 have been questioned, we investigated whether SARS-CoV-2 has a similar ictogenic potential to other respiratory non-neurotropic viruses. We conducted a retrospective study identifying 1141 patients with SARS-CoV-2 pneumonia and 146 patients with H1N1/H3N2 pneumonia. We found a similar prevalence of seizures in the two viral pneumonia (1.05% with SARS-CoV-2 vs 2.05% with influenza; p = 0.26). We detailed clinical, electroencephalographic, and neuroradiological features of each patient, together with the hypothesized pathogenesis of seizures. Previous epilepsy or pre-existing predisposing conditions (i.e., Alzheimer’s disease, stroke, cerebral neoplasia) were found in one-third of patients that experienced seizures, while two-thirds of patients had seizures without known risk factors other than pneumonia in both groups. The prevalence of pre-existing predisposing conditions and disease severity indexes was similar in SARS-CoV-2 and H1N1/H3N2 pneumonia, thus excluding they could act as potential confounders. Considering all the patients with viral pneumonia together, previous epilepsy (p

Eating protein before carbohydrate reduces postprandial glucose excursions by enhancing insulin and glucagon-like peptide-1 (GLP-1) secretion in type 2 diabetes (T2D). We tested the hypothesis that this insulinotropic effect depends on the elevation of plasma amino acids (AA) after the digestion of food protein. In 16 T2D patients, we measured plasma AA levels through the course of two 75-g oral glucose tolerance tests (OGTT) preceded by either 500-ml water or a high-protein nutrient preload (50-g Parmesan cheese, one boiled egg, and 300-ml water). Changes in beta cell function were evaluated by measuring and modelling plasma glucose, insulin, and C-peptide through the OGTT. Changes in incretin hormone secretion were assessed by measuring plasma GLP-1. Plasma AA levels were 24% higher after the nutrient preload (p

Produced as a tissue defence response to hypoxia and inflammation, growth differentiation factor-15 (GDF-15) is elevated in people receiving metformin treatment. To gain insight into the relationship of GDF-15 with metformin and major cardiovascular risk factors, we analysed the data from the SUMMIT cohort (n = 1438), a four-centre, nested, case-control study aimed at verifying whether biomarkers of atherosclerosis differ according to the presence of type 2 diabetes and cardiovascular disease. While in univariate analysis, major cardiovascular risk factors, with the exception of gender and cholesterol, increased similarly and linearly across GDF-15 quartiles, the independent variables associated with GDF-15, both in participants with and without diabetes, were age, plasma creatinine, N-terminal pro-brain natriuretic peptide, diuretic use, smoking exposure and glycated haemoglobin. In participants with diabetes, metformin treatment was associated with a 40% rise in GDF-15 level, which was independent of the other major factors, and largely explained their elevated GDF-15 levels. The relatively high GDF-15 bioavailability might partly explain the protective cardiovascular effects of metformin.

Background/aims: \ud Uncertainty still exists on the earliest beta-cell defects at the bases of the type 2 diabetes. We assume that this depends on the inaccurate distinction between fasting and post-load glucose homeostasis and aim at providing a description of major beta-cell functions across the full physiologic spectrum of each condition.\ud \ud Methods: \ud In 1320 non-diabetic individuals we performed an OGTT with insulin secretion modeling and a euglycemic insulin clamp, coupled in subgroups to glucose tracers and IVGTT; 1038 subjects underwent another OGTT after 3.5 years. Post-load glucose homeostasis was defined as mean plasma glucose above fasting levels (δOGTT). The analysis was performed by two-way ANCOVA.\ud \ud Results: \ud Fasting plasma glucose (FPG) and δOGTT were weakly related variables (stβ = 0.12) as were their changes over time (r = −0.08). Disruption of FPG control was associated with an isolated and progressive decline (approaching 60%) of the sensitivity of the beta-cell to glucose values within the normal fasting range. Disruption of post-load glucose control was characterized by a progressive decline (approaching 60%) of the slope of the full beta-cell vs glucose dose-response curve and an early minor (30%) decline of potentiation. The acute dynamic beta-cell responses, neither per se nor in relation to the degree of insulin resistance appeared to play a relevant role in disruption of fasting or post-load homeostasis. Follow-up data qualitatively and quantitatively confirmed the results of the cross-sectional analysis.\ud \ud Conclusion: \ud In normal subjects fasting and post-load glucose homeostasis are largely independent, and their disruption is sustained by different and specific beta-cell defects.

Background Asymptomatic left ventricular (LV) dysfunction is highly prevalent in type 2 diabetes patients. Unlike the other hypoglycemic drugs, SGLT2 inhibitors have shown potential benefits for reducing cardiovascular death and risk factors, aside from lowering plasma glucose levels. With this study we aim at determining whether the treatment with empagliflozin is associated with an improvement in LV functions in diabetic patients with asymptomatic LV dysfunction against Sitagliptin, which is presumably neutral on myocardial function. To determine changes in LV systolic and diastolic functions we will use speckle-tracking echocardiography, a novel sensitive, non-invasive, bedside method allowing the calculation of LV global longitudinal strain (GLS), an index of myocardial deformability, as well as 3D echocardiography, which allows a better evaluation of LV volumes and mass. Methods The EMPA-HEART trial will be a phase III, open label, active-controlled, parallel groups, single centre, exploratory study conducted in Pisa, Italy. A cohort of 75 diabetic patients with normal LV systolic (2D-Echo EF > 50%) and renal (eGFR sec MDRD > 60 ml/min/1.73 mq) functions and no evidence of valvular and/or ischemic heart disease will be randomized to either Empagliflozin 10 mg/die or Sitagliptin 100 mg/die. The primary outcome is to detect a change in GLS from baseline to 1 and 6 months after treatment initiation. The secondary outcomes include changes from baseline to 6 months in 3-D Echocardiography EF, left atrial volume and E/E′, VO2max as measured at cardiopulmonary test, cardiac autonomic function tests (R–R interval during Valsalva manoeuvre, deep-breathing, lying-to-standing), and the determination of a set of plasma biomarkers aimed at studying volume, inflammation, oxidative stress, matrix remodelling, myocyte strain and injury. Discussion SGLT2 inhibitors might affect myocardial functions through mechanisms acting both directly and indirectly on the myocardium. The set of instrumental and biohumoral tests of our study might actually detect the presence and entity of empagliflozin beneficial effects on the myocardium and shed light on the mechanisms involved. Further, this study might eventually provide information to design a clinical strategy, based on echocardiography and/or biomarkers, to select the patients who might benefit more from this intervention. Trial registration EUDRACT Code 2016-0022250-10

Background Metformin, the eldest and most widely used glucose lowering drug, is likely to be effective also on cardiac and vascular disease prevention. Nonetheless, uncertainty still exists with regard to its effects on the cardiovascular system as a whole and specifically on the myocardium, both at the organ and cellular levels. Methods We reviewed the available data on the cardiac and vascular effects of metformin, encompassing both in vitro, either tissue or isolated organ, and in vivo studies in experimental animals and humans, as well as the evidence generated by major clinical trials. Results At the cellular level metformin’s produces both AMP-activated kinase (AMPK) dependent and independent effects. At the systemic level, possibly also through other pathways, this drug improves endothelial function, protects from oxidative stress and inflammation, and from the negative effects of angiotensin II. On the myocardium it attenuates ischemia-reperfusion injury and prevents adverse remodeling induced by humoral and hemodynamic factors. The effects on myocardial cell metabolism and contractile function being not evident at rest or in more advanced stages of cardiac dysfunction, could be relevant during transient ischemia, during an acute increase in workload and in the early stages of diabetic/hypertensive cardiomyopathy as confirmed by few small clinical trials and some observational studies. The overall evidence emerging from both clinical trials and real world registry is in favor of a protective effect of metformin with respect to both coronary events and progression to heart failure. Conclusions Given this potential, its efficacy and its safety (and also its low cost) metformin remains the central pillar of the therapy of diabetes.

A remarkable example of coordination between IGOs to deal with corruption and fraud in public procurement is the “Agreement for the Mutual Enforcement of Debarment Decisions” signed by the World Bank and the main regional Multilateral Development Banks (MDBs) in 2010. This article will try to examine the characteristics of the MDBsʼ cross debarment agreement and its significance for the MDBs that adhered to it in terms of the process of harmonization that resulted from it. Secondly, the article discusses the potential benefits and challenges connected to the extension of this agreement to other MDBs or to other initiatives that have been initiated in parallel to, or in imitation of, the MDBsʼ cross debarment agreement.

Reverse remodeling (R2) in non-ischemic dilated cardiomyopathy (NIDCM) is associated with reduced morbidity, improved quality of life and survival. There is still scarce knowledge on predictors of R2, relevant for guide to treatment and device implantation. We aimed to identify predictors of R2