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Silent coronary artery disease (CAD) is one of the manifestations of heart disease that particularly affects subjects with type 2 diabetes mellitus (T2DM). From a clinical point of view, silent CAD represents a constant challenge for the diabetologist, who has to decide whether a patient could or could not be screened for this disease. In the present narrative review, several aspects of silent CAD are considered: the epidemiology of the disease, the associated risk factors, and main studies conducted, in the last 20 years, especially aimed to demonstrate the usefulness of the screening of silent CAD, to improve cardiovascular outcomes in type 2 diabetes.

Background This cross-sectional study aimed to identify actionable factors to improve LDL-cholesterol target achievement and overcome underuse of lipid-lowering treatments in high- or very-high-cardiovascular risk patients. Methods We evaluated healthcare records of 934,332 subjects from North-Italy, including subjects with available lipid profile and being on statin treatments up to December 2018. A 6-month-period defined adherence with proportion-of-days-covered ≥ 80%. Treatment was classified as high-intensity-statin (HIS) + ezetimibe, HIS-alone, non-HIS (NHIS) + ezetimibe or NHIS alone. Results We included 27,374 subjects without and 10,459 with diabetes. Among these, 30% and 36% were on secondary prevention, respectively. Adherence was high (78–100%) and increased with treatment intensity and in secondary prevention. Treatment intensity increased in secondary prevention, but only 42% were on HIS. 2019-guidelines LDL-cholesterol targets were achieved in few patients and more often among those with diabetes (7.4% vs. 10.7%, p Conclusions Among patients on statin treatment and high adherence, only a small proportion of patients achieved LDL-cholesterol targets. Late initiation of high-intensity treatments, particularly among those with misperceived low-risk (e.g., female subjects or those with high HDL-cholesterol), appears as pivotal factors needing to be modified to improve CVD prevention.

Background Patients with type 2 diabetes (T2DM) have a prothrombotic state that needs to be fully clarified; microparticles (MPs) have emerged as mediators and markers of this condition. Thus, we investigate, in vivo, in T2DM either with good (HbA1c ≤ 7.0%; GGC) or poor (HbA1c > 7.0%; PGC) glycemic control, the circulating levels of MPs, and in vitro, the molecular pathways involved in the release of MPs from platelets (PMP) and tested their pro-inflammatory effects on THP-1 transformed macrophages. Methods In 59 T2DM, and 23 control subjects with normal glucose tolerance (NGT), circulating levels of CD62E+, CD62P+, CD142+, CD45+ MPs were determined by flow cytometry, while plasma levels of ICAM-1, VCAM-1, IL-6 by ELISA. In vitro, PMP release and activation of isolated platelets from GGC and PGC were investigated, along with their effect on IL-6 secretion in THP-1 transformed macrophages. Results We found that MPs CD62P+ (PMP) and CD142+ (tissue factor-bearing MP) were significantly higher in PGC T2DM than GGC T2DM and NGT. Among MPs, PMP were also correlated with HbA1c and IL-6. In vitro, we showed that acute thrombin exposure stimulated a significantly higher PMP release in PGC T2DM than GGC T2DM through a more robust activation of PAR-4 receptor than PAR-1 receptor. Treatment with PAR-4 agonist induced an increased release of PMP in PGC with a Ca2+-calpain dependent mechanism since this effect was blunted by calpain inhibitor. Finally, the uptake of PMP derived from PAR-4 treated PGC platelets into THP-1 transformed macrophages promoted a marked increase of IL-6 release compared to PMP derived from GGC through the activation of the NF-kB pathway. Conclusions These results identify PAR-4 as a mediator of platelet activation, microparticle release, and inflammation, in poorly controlled T2DM.

Objective The lipid profile represents a driver of cardiovascular risk in type 2 diabetes. The effect of chronic insulin therapy on cholesterol levels is unclear. We aim to evaluate the effect of basal insulin on lipid profile compared to other classes of antihyperglycemic agents in type 2 diabetic patients. Design We performed a meta-analysis of randomized controlled trials reporting changes of lipid parameters in type 2 diabetic patients randomly assigned to basal insulin or other classes of anti-hyperglycemic agents. Results The levels of total (TC) and low-density lipoprotein cholesterol (LDL-C) appeared to be significantly reduced by therapies with glucagon-like peptide-1 receptor agonists (GLP-1RA) in comparison to basal insulin (mean difference [MD] –3.80; 95% CI [–6.30 to –1.30] mg/dL, P Conclusions GLP-1RA were superior to basal insulin in the control of TC and LDL-C. Basal insulin effectively reduced serum triglycerides. TZD led to improvement in HDL-C. DPP4-I and standard therapy did not have any significant effect on lipid levels.

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In 2020, the Sars-Cov-2 pandemic is causing a huge and dramatic impact on healthcare systems worldwide. During this emergency, fragile patients suffering from other comorbidities, especially patients susceptible to or affected by cardiovascular disease, are the ones most exposed to the poorer outcomes. Therefore, it is still mandatory to continue to strictly adhere to the rules of cardiovascular prevention. This document aims to provide all doctors with simple and clear recommendations in order to spread useful messages to the widest number of subjects in order to continue the battle against cardiovascular diseases even in times of pandemic.

Context: Acromegaly is a systemic disease characterized by persistent bone pathology and excess cardiovascular mortality. Despite multiple concomitant risk factors, atherosclerosis does not seem to be accelerated in acromegaly. Objective: To compare the levels of circulating myeloid calcifying cells (MCCs), which promote ectopic calcification and inhibit angiogenesis, in individuals with and without acromegaly. Design: Cross-sectional case-control study. Setting: Tertiary ambulatory referral endocrinology center. Patients: 44 acromegalic patients (25 active; 19 inactive), 44 control subjects matched by age, sex, risk factors, and medications, and 8 patients cured of acromegaly. Intervention: MCCs were measured using flow cytometry based on the expression of osteocalcin (OC) and bone alkaline phosphatase (BAP) on monocytes and circulating CD34+ stem cells. Main Outcome Measure: Differences in MCCs between patients and controls. Results: OC+BAP+ MCCs were severely reduced in acromegalic compared with control patients (0.17% ± 0.02% vs 1.00% ± 0.24%; P < 0.001), as were the total OC+ and BAP+ monocytic cells. Patients with inactive acromegaly and those cured of acromegaly displayed persistently reduced levels of MCCs. In the controls, but not acromegalic patients, MCCs were increased in the presence of diabetes or cardiovascular disease. A direct correlation was noted between MCCs and parathyroid hormone (r = 0.61; P < 0.0001), supporting a link between bone biology and MCCs. Conclusions: In patients with acromegaly, the levels of MCCs are reduced and remain low, even years after a complete cure. This finding might be related to low atherosclerotic calcification and the persistence of bone pathology after acromegaly remission or cure.

Background Complication screening is recommended for patients with type 2 diabetes (T2D), but the optimal screening intensity and schedules are unknown. In this study, we evaluated whether intensive versus standard complication screening affects long-term cardiovascular outcomes. Methods In this observational study, we included 368 T2D patients referred for intensive screening provided as a 1-day session of clinical–instrumental evaluation of diabetic complications, followed by dedicated counseling. From a total of 4906 patients, we selected control T2D patients who underwent standard complication screening at different visits, by 2:1 propensity score matching. The primary endpoint was the 4p-MACE, defined as cardiovascular mortality, or non-fatal myocardial infarction, stroke, or heart failure. The Cox proportional regression analyses was used to compare outcome occurrence in the two groups, adjusted for residual confounders. Results 357 patients from the intensive screening group (out of 368) were matched with 683 patients in the standard screening group. Clinical characteristics were well balanced between the two groups, except for a slightly higher prevalence of microangiopathy in the intensive group (56% vs 50%; standardized mean difference 0.11, p = 0.1). Median follow-up was 5.6 years. The adjusted incidence of 4p-MACE was significantly lower in the intensive versus standard screening group (HR 0.70; 95% CI 0.52–0.95; p = 0.02). All components of the primary endpoint had nominally lower rates in the intensive versus standard screening group, which was particularly significant for heart failure (HR 0.43; 95% CI 0.22–0.83; p = 0.01). Conclusion Among T2D patients attending a specialist outpatient clinic, intensive complication screening is followed by better long-term cardiovascular outcomes. No significant effect was noted for cardiovascular and all-cause mortality and the benefit was mainly driven by a reduced rate of hospitalization for heart failure.

Background and aims Cardiovascular outcome trials have documented a strong benefit of sodium glucose cotransporter-2 inhibitors (SGLT2i) on the risk of hospitalization for heart failure (HF) in patients with type 2 diabetes (T2D) with or without established cardiovascular disease or prior history of HF. The mechanisms, however, are not entirely clear. We aimed to evaluate whether treatment with SGLT2i affected cardiac function using impedance cardiography (ICG) in a randomized placebo-controlled trial. Materials and methods Thirty-three patients with T2D were randomized to receive blind dapagliflozin 10 mg or matching placebo for 12-week on top of their ongoing glucose lowering medication regimen. Cardiac function was evaluated by resting ICG at baseline and at the end of the 12-week treatment period. ICG is a non-invasive technology based on the continuous measurement of thoracic electrical conductivity to process a cardiodynamic parameters related to fluid content, blood flow, cardiac function, and circulatory function. We also evaluated changes in glycaemic control, blood pressure, and body weight. Results Thirty-one patients completed the study, 1 was excluded because ICG data was missing. Patients included in the final analysis were on average 63.4-year-old, with a known diabetes duration of 14.1 years and a baseline HbA1c of 8.2% (66 mmol/mol). 63.3% of patients had established cardiovascular disease (symptomatic or asymptomatic) and 36.7% had microangiopathy, but none had a prior history of HF. After 12 weeks, patients randomized to dapagliflozin, as compared to those randomized to placebo, showed improvements in HbA1c (− 1.2%; 13 mmol/mol), systolic blood pressure (− 3.7 mmHg), and body weight (− 3.3 kg). Based on ICG, in both groups, we detected no significant change in parameters of blood flow (stroke volume, cardiac output, cardiac index), systolic function (ejection fraction, acceleration and velocity indexes, systolic time ratio), circulatory function (systemic vascular resistance index), and fluid status (thoracic fluid content) after treatment. Conclusion This is the first study exploring cardiac effects of SGLT2i using ICG in T2D. We observed no change in cardiac function parameters estimated by ICG in T2D patients who received dapagliflozin versus placebo for 12 weeks. Trial registration ClinicalTrial.gov NCT02327039. Registered 30 December 2014

Current evidence shows that cholesterol management either reduces the likelihood of cardiovascular disease (CVD) or slows down its progression. Hence, it is important that all health professionals make appropriate use of all the available intervention strategies to control risk factors: from dietary improvement and positive lifestyle changes to the use of functional foods, food supplements, and drugs. This review examines the effect of the most frequently occurring cholesterol-lowering substances in functional foods or in supplements across Europe, namely plant sterols and stanols, monacolin K found in red yeast rice, berberine and beta-glucans. We conclude that currently available supplements and functional foods can effectively reduce plasma LDL cholesterol levels by about 5 to 25%, either alone or in combination. Suitable candidates for these products are mainly individuals at low absolute cardiovascular risk at a young age or according to classic algorithms. Of note, despite being freely available for purchase, these products should be used following shared agreement between the caring physician and the patient ("concordance").

Patients with type 2 diabetes mellitus die most frequently from cardiovascular disease. Metabolic control is mandatory both for preventing long-term complications and for reducing the negative effects of the exposure of the other risk factors. In this article, we will describe the most commonly used glucose-lowering agents, the pathophysiological mechanisms underlying their cardiovascular protection, the available evidence-based data for this protection, and the contraindications and potential adverse effects.

Background The risk of diabetic complications is modified by genetic and epigenetic factors. p66Shc drives the hyperglycaemic cell damage and its deletion prevents experimental diabetic complications. We herein tested whether p66Shc expression in peripheral blood mononuclear cells (PBMCs) predicts adverse outcomes in people with diabetes. Methods In a cohort of 100 patients with diabetes (16 type 1 and 84 type 2), we quantified baseline p66Shc expression in PBMCs by quantitative PCR. Patients were extensively characterized for demographics, anthropometrics, biochemical data, prevalence of complications, and medications. With a pseudo-prospective design, we retrieved cardiovascular death, major adverse cardiovascular events (MACE), and new occurrence of micro- or macroangiopathy during follow-up. Results At baseline, patients were on average 60 year old, with 10-year diabetes duration, and overall poor glycaemic control (HbA1c 7.8%). Patients with high versus low p66Shc expression (based on median value) had very similar baseline characteristics. Average p66Shc expression did not differ by presence/absence of complications. During a median 5.6-year follow-up, the primary endpoint of cardiovascular death or MACE occurred in 22 patients, but no relation was detected between cardiovascular outcomes and p66Shc expression. In patients who developed new complications at follow-up, baseline p66Shc was significantly higher, especially for macroangiopathy. The incidence of new macroangiopathy was > 3-times higher in patients with high versus those with low baseline p66Shc expression. Conclusions p66Shc expression in PBMCs was not associated with prevalent diabetic complications but predicted new onset of complications, especially macroangiopathy, although no relation with hard cardiovascular endpoints was detected.

Aims Atherosclerosis is an inflammatory disease wherein cholesterol-loaded macrophages play a major role. MicroRNAs and microparticles propagate inflammatory pathways and are involved in cardiovascular disease. We aimed to screen and validate circulating microRNAs correlated with atherosclerosis development in humans, and to dissect the molecular mechanisms associated with atherogenesis using in vitro and in vivo approaches. Methods and results A panel of 179 secreted microRNAs was screened in plasma samples of patients with and without atherosclerosis, and validated cross-sectionally and prospectively in patients followed for up to 11 years. miR-30c-5p was inversely correlated with total and LDL cholesterol, carotid intimal media thickness (CIMT), presence and future development of plaques. Using a human macrophage line and in vitro gene silencing strategies, we found that miR-30c-5p was downregulated by oxidized LDL (oxLDL) via the scavenger receptor CD36 and inhibition miR processing by Dicer. In turn, miR-30c-5p downregulation was responsible for the effects of oxLDL on macrophage IL-1β release, caspase-3 expression, and apoptosis. miR-30c-5p loaded into microparticles was uptaken by macrophages and regulated target genes, like caspase-3, at transcriptional level. To establish the relevance of this pathway on endothelial damage as the earliest step of atherogenesis, we show that systemic miR-30c-5p knockdown induced caspase-3 and impaired endothelial healing after carotid injury in C57Bl/6 J mice. Conclusions With an unbiased screening of secreted microRNAs, we identify reduction of miR-30c-5p in microparticles as a promoter of early atherosclerosis, by conveying pro-inflammatory pro-apoptotic signals and impairing endothelial healing. Therefore, stimulation of miR-30c-5p is a candidate direct anti-atherosclerotic therapy.

Aims To re-analyse data from a previous retrospective study on 127 555 patients, in which we showed that dipeptidyl peptidase-4 (DPP-4) inhibitor therapy was associated with a lower risk of hospitalization for HF (HHF) than sulphonylurea (SU) therapy, in order to evaluate intraclass differences among DPP-4 inhibitors and SUs. Methods We included patients with type 2 diabetes (T2D) initiating DPP-4 inhibitor or SU therapy, alone or in combination with metformin. Patients undergoing intraclass switch, those with a previous HHF, those receiving insulin treatment, and those with

Aims The cost-effectiveness of screening for silent coronary heart disease (CHD) in type 2 diabetes (DM2) is still debated. Methods We applied a diagnostic algorithm for silent CHD detection, in a cohort of 102 asymptomatic DM2 subjects (57 ± 7 years), attending 5 Italian outpatient clinics, to verify its predictive value. The risk of silent CHD was calculated considering classical risk factors, and presence of microangiopathy/macroangiopathy. Patients were divided in 3 groups, i.e. group 1: normal ECG and low silent CHD risk; group 2: abnormal ECG, irrespective of silent CHD risk; group 3: high silent CHD risk, irrespective of ECG. To group 2 and 3, a functional test was recommended and performed in 78% of patients. Results Silent CHD prevalence was similar in group 2 and 3 (25 vs. 17% respectively; p = 0.495). However, evaluating the entire cohort, a significant higher prevalence of silent CHD was observed in subjects with abnormal vs. normal ECG (23 vs. 4%; P = 0.004), but not in subjects with high vs. low pre-test silent CHD risk (14 vs. 9%; p = 0.472). Conclusions An abnormal ECG was a strong, independent predictor of silent CHD (OR 8.9; CI 1.27–62.5; p = 0.028) in DM2. Therefore, a functional stress testing should be considered in DM2 patients with ECG abnormalities.

Background Microparticles (MPs) are vesicular structures shed from endothelial or circulating blood cells, after activation or apoptosis, and can be considered markers of vascular damage. We aimed to determine the levels of circulating MPs, their content of miRNA-126-3p and 5p, and their relationship with early endothelial activation/damage, in patients with different degree of glucose tolerance. Methods CD62E+, CD62P+, CD142+, CD45+ circulating MPs, their apoptotic (AnnexinV+) fractions, and miRNA-126 expression were determined in 39 prediabetic (PreDM), 68 type 2 diabetic (T2DM), and 53 control (NGT) subjects, along with main anthropometric and biochemical measurements. MPs were analysed by flow cytometry. miRNA-126 was measured by quantitative real-time PCR. Plasma antioxidant capacity was determined by electronic spin resonance; ICAM-1, and VCAM-1 by ELISA. Results Activated endothelial cell-derived MPs (CD62E+) were significantly increased in PreDM and T2DM in comparison to NGT (p

Monocyte-macrophages (MoMas) play a major role in atherosclerosis. In mice, hypercholesterolemia increases pro-inflammatory monocytes that promote plaque growth, but whether this is true also in humans in unknown. We herein analyzed monocyte subsets and MoMa phenotypes in familiar (FH, n = 22) and non-familiar (NFH, n = 20) hypercholesterolemic compared with normocholesterolemic (CTRL, n = 20) patients. We found that FH and NFH had higher circulating pro-inflammatory CD68(+)CCR2(+) M1 MoMas than CTRL, while anti-inflammatory CX3CR1(+)CD163(+)/CD206(+) M2 MoMas were reduced only in NFH. As a result, the M1/M2 polarization balance was increased in FH and, more markedly in NFH. M1 MoMas and the M1/M2 polarization ratio were directly correlated to pre-treatment LDL cholesterol levels and strongly associated with the presence of atherosclerotic plaques. In conclusion, we show for the first time that human hypercholesterolemia is associated with a pro-inflammatory imbalance of circulating monocytic cells, which can predispose to the development of atherosclerosis.

Dipeptidyl peptidases 4 (DPP4) inhibitors are a new class of oral anti-hyperglycemic drugs for the treatment of type 2 diabetes (T2DM). They are also called "incretins" because they act by inhibiting the degradation of endogenous incretin hormones, in particular GLP-1, that mediates their main metabolic effects. DPP4 is an ubiquitous protease that regulates not only glucose and lipid metabolism, but also exhibits several systemic effects at different site levels. DPP4 inhibition improves endothelial function, reduces the pro-oxidative and the pro-inflammatory state, and exerts renal effects. These actions are mediated by different DPP4 ligands, such as cytokines, growth factors, neuotransmitters etc. Clinical and experimental studies have demonstrated that DPP4 inhibitors are efficient in protecting cardiac, renal and vascular systems, through antiatherosclerotic and vasculoprotective mechanisms. For these reasons DDP4 inhibitors are thought to be "cardiovascular protective" as well as anti-diabetic drugs. Clinical trials aimed to demonstrate the efficacy of DPP4 inhibitors in reducing cardiovascular events, independent of their anti-hyperglycemic action, are ongoing. These trials will also give necessary information on their safety.

Based on the knowledge that matrix metalloproteinases (MMPs) and S100A8/A9 synergistically work in causing PDAC-associated type 2 diabetes mellitus (T2DM), we verified whether tissue and blood MMP8, MMP9, S100A8 and S100A9 expression might help in distinguishing PDAC among diabetics.Relative quantification of MMP8, MMP9, S100A8 and S100A9 mRNA was performed in tissues obtained from 8 PDAC, 4 chronic pancreatitis (ChrPa), 4 non-PDAC tumors and in PBMCs obtained from 30 controls, 43 T2DM, 41 ChrPa, 91 PDAC and 33 pancreatic-biliary tract tumors.T2DM was observed in PDAC (66%), in pancreatic-biliary tract tumors (64%) and in ChrPa (70%). In diabetics, with or without PDAC, MMP9 tissue expression was increased (p0.05). Both MMPs increased in PDAC and MMP9 increased also in pancreatic-biliary tract tumors PBMCs. In diabetics, MMP9 was independently associated with PDAC (p=0.025), but failed to enhance CA 19-9 discriminant efficacy. A highly reduced S100A9 expression, found in 7 PDAC, was significantly correlated with a reduced overall survival (p=0.015).An increased expression of tissue and blood MMP9 reflects the presence of PDAC-associated diabetes mellitus. This finding fits with the hypothesized role of MMPs as part of the complex network linking cancer to diabetes.

Upon activation, neutrophils undergo histone citrullination by protein arginine deiminase-4 (PAD4), exocytosis of chromatin and enzymes as neutrophil extracellular traps (NETs), and death. In diabetes, neutrophils are primed to release NETs and die by NETosis. Although this process is a defense against infection, NETosis can damage tissue. Therefore, we examined the effect of NETosis on the healing of diabetic foot ulcers (DFU). Using proteomics, we found that NET components were enriched in non-healing human DFU. In an independent validation cohort, a high concentration of neutrophil elastase in the wound was associated with infection and a subsequent worsening of the ulcer. NET components (elastase, histones, NGAL, and proteinase-3) were elevated in the blood of patients with DFU. Circulating elastase and proteinase-3 were associated with infection, and serum elastase predicted delayed healing. Neutrophils isolated from the blood of DFU patients showed an increased spontaneous NETosis but an impaired inducible NETosis. In mice, skin PAD4 activity was increased by diabetes, and FACS detection of histone citrullination, together with intravital microscopy showed that NETosis occurred in the bed of excisional wounds. PAD4 inhibition by Cl-amidine reduced netting neutrophils and rescued wound healing in diabetic mice. Cumulatively, these data suggest that NETosis delays DFU healing. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Diabetes is an established risk factor for erectile dysfunction (ED). The pathophysiology of ED in diabetic men is multifactorial, but it mainly involves a vascular disorder related to a reduction of endothelial function. Recently, several studies have correlated ED risk factors with vitamin D deficiency. In this study, we evaluate the relationship between 25-hydroxyvitamin D [25(OH)D] levels, erectile dysfunction, and vascular disease, in type 2 diabetes mellitus men (T2DM). In this observational study, 92 T2DM males (58.83 ± 9.73 years) underwent medical history collection, International Index of Erectile Function (IIEF-5) questionnaire, that allows the identification and grading of DE, physical examination, biochemical/hormonal blood tests, and penile echo-color Doppler ultrasonography. T2DM patients with lower 25(OH)D levels (25 nmol/l) showed higher penile IMT (p 0.05), waist circonference (p 0.05), glucose concentrations (p 0.05), and lower IIEF-5 score (p 0.005), testosterone concentrations (p 0.05), and cavernous peak systolic velocity (PSV) (p 0.05), compared to patients with 25(OH)D50 nmol/l. 25(OH)D levels were directly correlated with IIEF-5 (R = 0.39; p = 0.0001), testosterone (R = 0.24; p = 0.02), and PSV (R = 0.24; p = 0.04) and inversely with waist (R = -0.33; p = 0.002), HbA1c (R = -0.22; p = 0.03), triglyceride (R = -0.21; p = 0.06), and penile IMT (R = -0.30; p = 0.009). At multivariate analysis, 25(OH)D deficiency remained an independent predictor of DE. We demonstrate a significant association between 25(OH)D deficiency and erectile dysfunction in T2DM men. This association may be due to the influence of 25(OH)D deficiency on cardiovascular risk factor (glycaemia, HDL cholesterol, and triglycerides), testosterone plasma levels and endothelial dysfunction.

Aims The hyperglycemic hyperosmolar syndrome (HHS) is a life-threatening diabetic complication. We aimed to portrait the short and long term outcome after a HHS episode and to describe features associated with increased early mortality. Methods We collected data from consecutive HHS cases, defined based on rigorous glucose and osmolality criteria. We retrieved anthropometric measures, history of diabetes, other cardiovascular risk factors and chronic co-morbidity. Clinical and biochemical parameters were recorded at admission, after 24 h and at discharge. We assessed incidence of complications, as well as short (≤30 days) and long term mortality. Results Patients were about 80-year old. Fifty-one cases were included, characterized by severe hyperglycemia (55.5 mosm/L) and hyperosmolality (385 mosm/L). Thirty-three percent developed at least one complication. Short term mortality was 16%; lower Glasgow Coma Scale, higher plasma glucose and mild acidosis were predictive of short term mortality. The long term mortality (median follow-up 1.27 years) was not significantly different from historical mortality data after hypoglycemic coma. Conclusion In this study, early mortality of HHS was 16% and some clinical features at presentation were predictive of an adverse short term outcome. Long term survival after a HHS episode did not appear to be severely impaired.

Background: In the postprandial state, insulin regulates metabolic and cardiovascular responses. In insulin resistance, the insulin action is impaired at both levels. However, postprandial hemodynamic responses are poorly characterized in this setting. Objective: We investigated fasting and postprandial cardiac and vascular hemodynamic responses in subjects with and without insulin resistance. Design: Sixty-six atherosclerosis-free, healthy volunteers were studied in a fasted state and � 180 min after ingestion of a mixed meal. The insulin sensitivity index was determined by using a minimal model analysis; hemodynamic response was monitored by using continuous impedance cardiography that allowed a reliable beat-to-beat noninvasive evaluation of stroke volume, cardiac contractility, and several derived variables. Results: Subjects were divided into insulin-resistant (IR; n = 33) and insulin-sensitive (IS; n = 33) groups. After fasting, IR subjects had significantly higher values of systolic and diastolic blood pressures and the systemic vascular resistance index (SVRI) than did IS subjects. In the postprandial state, acute vasodilatation was comparable and synchronous (at 30 min) in IR and IS subjects (P = 0.209), but subsequent vascular tone recovery (30‐180 min) was significantly impaired in IR subjects (P = 0.018), even after adjustment for age and sex (P = 0.031). Hemodynamic dysregulation was directly correlated with metabolic disturbances in the postprandial state. In basal and postprandial states, hemodynamic variables related to cardiac function were not significantly different in IR and IS subjects. Conclusions: IR subjects had a worse fasting vascular performance than did IS subjects. In the postprandial phase, insulin resistance was associated with a shorter duration of vasodilatation in the absence of an altered cardiac performance. Peripheral hemodynamic alterations in fasting and postprandial states may have a negative effect on cardiovascular performance in IR patients. Am J Clin Nutr 2011;93:926‐33.

Type 2 diabetes is characterized by a two- to fourfold increased risk of cardiovascular disease. This is generally attributed to the adverse effects of hyperglycemia and oxidative stress on vascular biology. It has also been shown that patients with prediabetic conditions, such as impaired fasting glucose and impaired glucose tolerance, are at increased risk of cardiovascular disease as well (1). This result suggests that abnormalities in carbohydrate metabolism form a continuum that progressively worsens cardiovascular health; the first step of the adverse sequence of events that leads to the atherosclerotic process is thought to be endothelial dysfunction (2). Vascular endothelial cells play a major role in maintaining cardiovascular homeostasis. In addition to providing a physical barrier between the vessel wall and lumen, the endothelium secretes a number of mediators that regulate platelet aggregation, coagulation, fibrinolysis, and vascular tone. The term “endothelial dysfunction” refers to a condition in which the endothelium loses its physiological properties: the tendency to promote vasodilation, fibrinolysis, and anti-aggregation. Endothelial cells secrete several mediators that can alternatively mediate either vasoconstriction, such as endothelin-1 and thromboxane A2, or vasodilation, such as nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor. NO is the major contributor to endothelium-dependent relaxation in conduit arteries, whereas the contribution of endothelium-derived hyperpolarizing factor predominates in smaller resistance vessels. In patients with diabetes, endothelial dysfunction appears to be a consistent finding; indeed, there is general agreement that hyperglycemia and diabetes lead to an impairment of NO production and activity. The endothelium has a limited intrinsic capacity of self-repair, being built up by terminally differentiated cells with a low proliferative potential. That is why endothelial repair is accomplished through the contribution of circulating cells, namely endothelial progenitor cells (EPCs), in physiological and pathological conditions. In this review, we will outline the mechanisms of endothelial dysfunction …

Objectives Metabolic syndrome (MetS) associates with endothelial dysfunction and a high risk of cardiovascular events and death. Circulating progenitor cells have been shown to contribute to endothelial homeostasis and repair . We aimed to test whether progenitor cell count is an independent event predictor and modifies cardiovascular risk associated with MetS. Methods On the basis of the expression of CD34, CD133 and KDR, 6 phenotypes of progenitor cells were counted using flow cytometry in 214 subjects with and without MetS. We recorded classical risk factors and MetS components, cumulative risk estimates, and high-sensitive C-reactive protein. Subjects were followed-up for a median of 34 months to collect total events, cardiovascular events and all-cause mortality. Results In the Cox proportional hazards regression analyses, we found that, unlike other phenotypes, reduced CD34+ cells predicted cardiovascular and total events and death, independently of all potential confounders. Remarkably, a low CD34+ cell count significantly increased the risk associated with MetS, as shown by synergy indexes. Conclusion The level of circulating CD34+ cells is a novel independent risk biomarker and modulates outcomes in the MetS, suggesting that generic progenitor cells have a role in disease development or progression over the long-term.

OBJECTIVE The presence of carotid plaques is associated with future cardiovascular events, with local plaque composition being an independent outcome predictor. We examined the association between ultrasonographically determined carotid plaque calcification and incident major adverse cardiovascular events (MACE) and death in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS We enrolled 581 patients with T2D who underwent routine carotid ultrasonography. Plaques were classified as echolucent (lipid rich), heterogenous, and echogenic (calcific). We collected demographic, anthropometric, and clinical data at baseline and followed the patients for up to 9 years. RESULTS Plaques were detected in 81.8% of the patients (echolucent in 16.4%, heterogenous in 43.2%, and echogenic in 22.2%). During follow-up (4.3 ± 0.1 years), 58 deaths (27 cardiovascular) and 236 fatal and nonfatal MACE occurred. In univariate analyses, presence versus absence of any carotid plaque was associated with incident MACE, and the hazard ratio (95% CI) progressively increased from echolucent (1.97 [0.93–3.44]), to heterogeneous (3.10 [2.09–4.23]), to echogenic (3.71 [2.09–5.59]) plaques. Compared with echolucent plaques, echogenic plaques were associated with incident MACE independently from confounders. This association was attenuated after adjusting for the degree of stenosis, but in patients with stenosis ≤30%, echogenic plaque type still predicted total and atherosclerotic MACE, even after further adjusting for mean intima-media thickness. CONCLUSIONS In T2D, carotid plaque calcification predicts MACE, especially in patients with a low degree of stenosis. The biology of atherosclerotic calcification in diabetes needs to be further elucidated to understand the basis of this association.

Background and Purpose— Disruption of the endothelial layer is the first step in the atherogenic process. Experimental studies have shown that endothelial progenitor cells (EPCs) are involved in endothelial homeostasis and repair. Conversely, EPC depletion has been demonstrated in the setting of established atherosclerotic diseases. With this background, we evaluated whether variations in the number of EPCs are associated with subclinical atherosclerosis in healthy subjects. Methods— Carotid intima-media thickness (IMT), high-sensitive C-reactive protein (hsCRP), levels of circulating EPCs, and cardiovascular risk were compared in 137 healthy subjects. Six subpopulations of progenitor cells were determined by flow cytometry on the basis of the surface expression of CD34, CD133, and KDR antigens: CD34 + , CD133 + , CD34 + CD133 + , CD34 + KDR + , CD133 + KDR + , and CD34 + CD133 + KDR + . Results— Among different antigenic profiles of EPCs, only CD34 + KDR + cells were significantly reduced in subjects with increased IMT. Specifically, CD34 + KDR + cells were inversely correlated with IMT, even after adjustment for hsCRP and 10-year Framingham risk and independently of other cardiovascular parameters. Conclusions— Depletion of CD34 + KDR + EPCs is an independent predictor of early subclinical atherosclerosis in healthy subjects and may provide additional information beyond classic risk factors and inflammatory markers.

Aims Vascular endothelial cells play a major role in maintaining cardiovascular homeostasis in health. Diabetes mellitus (DM) substantially impairs the vasodilating properties of the endothelium and leads to endothelial dysfunction, which can thus be considered the first step in the progression of cardiovascular disease. The aim of the present study is to illustrate possible mechanisms responsible for endothelial dysfunction in DM. Data synthesis We have shown that NADPH oxidase gene expression is increased in circulating lymphomonocytes from patients with DM, and that this increased gene expression is dependent upon metabolic control. Hyperglycemia can mediate its adverse effects through the activation of protein kinase C. We have shown an increase in membrane-associated PKC beta 2 activity in monocytes from patients with DM. This activity was reduced by 40% in the euglycemic condition. Finally, we show a reduction of the circulating endothelial progenitor cells, a subset of bone marrow-derived endothelial-oriented stem cells, which can give rise to mature endothelial cells. Conclusion Endothelial dysfunction, the initial step of the atherosclerotic process, is reversible. Thus, major efforts should be made to control not only hyperglycemia but also the other risk factors for cardiovascular disease, in order to prevent the onset of all these processes that eventually leads the diabetic patient to premature death.

OBJECTIVES We sought to establish whether a reduction in endothelial progenitor cells (EPCs) has a putative role in peripheral vascular disease (PVD) of type 2 diabetic patients. BACKGROUND Peripheral vascular disease is a common and severe complication of diabetes mellitus. Impaired collateralization of diabetic vasculopathy has been extensively shown, but causes leading to its pathogenesis are not fully understood. Recently, EPCs have been found to contribute to vascular repair and angiogenesis. Diabetes has been associated with low levels of circulating EPCs, but no data are available in the literature on the relationship between EPCs and PVD in diabetes. METHODS Flow cytometric analysis was used to quantify circulating progenitor cells (CPCs, CD34+) and EPCs (CD34+KDR+) in 51 patients and 17 control subjects. RESULTS The CPCs and EPCs from diabetic patients were reduced by 33% and 40%, respectively, compared with healthy subjects (p < 0.001). An inverse correlation was found between the number of EPCs and the values of fasting glucose (r = -0.49, p = 0.006). Peripheral vascular disease was associated with a 47% reduction in EPCs (p < 0.0001) and EPC levels directly correlated with the ankle-brachial index (r = 0.70, p = 0.01). The subgroup of diabetic patients with PVD also had reduced CPCs by 32% (p = 0.037), whereas patients with ischemic foot lesions had the lowest levels of both EPCs and CPCs (p = 0.02). CONCLUSIONS Our data demonstrate decreased EPC levels in diabetic patients and, for the first time, show that PVD is associated with an extensively low number of EPCs. Depletion of circulating EPCs in diabetic patients may be involved in the pathogenesis of peripheral vascular complications.

BACKGROUND No data are available on the relationship between myocardial perfusion and left ventricular (LV) function in type 1 diabetes mellitus (T1DM), which may constitute a factor explaining the progressive contractile dysfunction to the overt phase of diabetic cardiomyopathy. HYPOTHESIS This study was undertaken to test whether myocardial perfusion abnormalities are present at rest and during exercise and whether they are related to contractile dysfunction in T1DM. METHODS Twenty-two patients with T1DM, aged 32 +/- 8.3 years, without macro- or microvascular complications, and 10 controls, aged 31 +/- 3 years, were studied. Left ventricular function and myocardial perfusion were assessed by two-dimensional and myocardial contrast echocardiography at rest and during handgrip (HG). RESULTS Fourteen patients with T1DM showed a decline in LV ejection fraction (LVEF) during HG (Group 1) while 8 had a normal response (Group 2). Both basal myocardial blood volume (MBV) and velocity (beta) were normal in T1DM. During exercise, MBV and beta increased and were associated with an increase in myocardial blood flow (MBF) in controls. In T1DM, beta did not change and MBV increased only in Group 2, while this increase was not observed in Group 1 (controls: 14.9 +/- 2.3 vs. Group 1: 7.6 +/- 1.6, p < 0.001; and vs. Group 2: 10.2 +/- 2.8, p < 0.001), beta (0.86 +/- 0.12 vs. 0.68 +/- 0.14, p < 0.001; and vs. 0.67 +/- 0.15, p < 0.001). A correlation between the ratio exercise MBF/resting MBF and LVEF at peak exercise in T1DM was observed (r = 0.805, p < 0.001). CONCLUSIONS A large proportion of patients with T1DM exhibit abnormalities in myocardial adaptable capacity to match an acute overload, which are related to a defective increase in myocardial perfusion.

Moderate alcohol (ETOH) intake has been associated with a significant reduction in risk for infarction among general populations. In this study, we assessed the effects of low-dose ETOH (40 g over 3-h period as vodka) on the interaction between glucose (G), insulin, and lactate (L) during the insulin-modified frequently sampled i.v. glucose tolerance test (FSIGT) (0.3 U/kg body weight between 20-25 min) in eight normal volunteers. In the control (C) study, water was administered. An insulin-independent two-compartment model was used to describe G and L kinetics. Insulin sensitivity (S(I)) was significantly higher in the ETOH study than in the C study (2.49 +/- 0.52 vs. 0.92 +/- 0.20 10(-4) min(-1)microU(-1)ml, C vs. ETOH; P = 0.0391). No significant differences were observed in G effectiveness (0.029 +/- 0.004 vs. 0.033 +/- 0.004 min(-1)). Blood L levels were higher during FSIGT when ETOH was administered [area under the curve (AUC), 201 plus minus 16 vs. 123 +/- 23 mmol/liter in 240 min; P = 0.0001]. The dynamic analysis of blood L concentrations showed that ETOH also significantly decreased L clearance (0.0016 +/- 0.0011 vs. 0.0029 +/- 0.0002 min(-1); P = 0.0156), whereas no difference was observed for the fractional conversion of the rate of G disappearance to L (0.0033 +/- 0.0012 vs. 0.0031 +/- 0.0005 min(-1)). ETOH decreased baseline plasma FFA concentration; AUC of FFA was markedly reduced with ETOH (65 +/- 14 vs. 109 plus minus 17 mmol/liter in 240 min; P = 0.0063) and inversely correlated with S(I) (r = 0.693; P = 0.0029). The amount of C-peptide in 240 min as well as the amounts before and after insulin administration were not different between the two tests. We concluded that G and L kinetics derived from FSIGT shows that moderate ETOH intake: 1) improves insulin action; 2) decreases L clearance; and 3) does not affect beta cell function. Because ETOH at moderate doses has a marked antilipolytic action, it might improve insulin action by improving substrate competition. The present findings suggest that moderate alcohol consumption in the diet should not be discouraged.

Type 2 diabetes (T2D) is characterized by low HDL cholesterol (HDL-C) and HDL dysfunction. We herein tested whether lowering HbA1c affects HDL-C and reverse cholesterol transport (RCT). Forty-two uncontrolled T2D patients initiating basal insulin were included. HbA1c, HDL-C and RCT were assessed at baseline and after 6 months. At baseline, HDL-C and RCT were directly correlated (r = 0.50; p 0.001). After 6 months of insulin therapy, HbA1c dropped from 8.8 ± 0.16% to 7.1 ± 0.1%, while average HDL-C and RCT did not change. Follow-up HDL-C and RCT were still correlated (r = 0.31; p = 0.033) and ΔHDL-C correlated with ΔRCT (r = 0.32; p = 0.029). ΔHbA1c correlated with ΔHDL-C (r = 0.43, p = 0.001), but not with ΔRCT. In patients with ΔHbA1c above the median value (1.3%), HDL-C (but not RCT) increased significantly. In conclusion, glucose control correlates with increased HDL-C, but not with improved RCT. Thus, persistent HDL dysfunction despite improved HbA1c and HDL-C can contribute to residual cardiovascular risk in T2D.

Incretin-based therapy became recently available as antihyperglycemic treatment for patients with type 2 diabetes (T2DM). Incretin therapy comprises glucagon-like peptide receptor agonists (GLP-1RA) and dipeptidyl-peptidase 4 inhibitors (DPP4-I): these classes of drugs not only have the ability to reduce blood glucose, but also can exert several cardioprotective effects. They have been shown to positively influence some risk factors for cardiovascular disease (CVD), to improve endothelial function, and to directly affect cardiac function. For these reasons incretins are considered not only antidiabetic drugs, but also cardiovascular effective. The first clinical trials aimed to demonstrate the safety of DPP4 inhibitors have been recently published: their clinical significance will be discussed in light of the prior experimental findings.

Acromegaly increases cardiovascular risk, possibly due to the high prevalence of classical risk factors. However, in vitro studies show a protective role of GH/IGF-1 on the endothelium.The objective of the study was to investigate circulating endothelial progenitor cells (EPCs), a marker of vascular regeneration, in acromegalic patients and how they are affected by acromegaly treatment.This was a cross-sectional case-control and observational study.The study was conducted at a tertiary ambulatory referral endocrinology center.Forty-three acromegalic patients (26 active; 17 inactive) and 43 control subjects matched by age, gender, and degree of glucose tolerance participated in the study.Circulating EPCs were quantified by flow cytometry based on the expression of CD34, CD133, and kinase insert domain-containing receptor (KDR). Nine patients with active acromegaly were reevaluated after 24 weeks of treatment with somatostatin analogs (SSAs).Differences in EPC levels between patients and controls were measured.Acromegalic patients showed a significant reduction of the total CD34(+)KDR(+) EPC population compared with controls, which was more evident in patients without diabetes or hypertension. More definite CD34(+)CD133(+)KDR(+) EPCs were reduced in patients with active compared with those with inactive acromegaly and compared with controls. The number of CD34(+)CD133(+)KDR(+) EPCs correlated with IGF-1 levels (r = -0.45; P.001), fasting plasma glucose (r = -0.40; P = .004), and the homeostasis model assessment index of insulin resistance (r = -0.32; P = .026). CD34(+)CD133(+)KDR(+) EPCs increased 2-fold after SSA treatment.Acromegalic patients have a reduced endothelial regenerative capacity, possibly due to activation of the GH/IGF-1, rather than concomitant risk factors. Treatment with SSAs can restore immature EPCs to normal levels.

OBJECTIVE Vasculoprotective endothelial progenitor cells (EPCs) are regulated by stromal-derived factor-1α (SDF-1α) and are reduced in type 2 diabetes. Because SDF-1α is a substrate of dipeptidyl-peptidase-4 (DPP-4), we investigated whether the DPP-4 inhibitor sitagliptin modulates EPC levels in type 2 diabetic patients. RESEARCH DESIGN AND METHODS This was a controlled, nonrandomized clinical trial comparing 4-week sitagliptin (n = 16) versus no additional treatment (n = 16) in addition to metformin and/or secretagogues in type 2 diabetic patients. We determined circulating EPC levels and plasma concentrations of SDF-1α, monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and nitrites/nitrates. RESULTS There was no difference in clinical baseline data between the sitagliptin and control arms. After 4 weeks, as compared with control subjects, patients receiving sitagliptin showed a significant increase in EPCs and SDF-1α and a decrease in MCP-1. CONCLUSIONS Sitagliptin increases circulating EPCs in type 2 diabetic patients with concomitant upregulation of SDF-1α. This ancillary effect of DPP-4 inhibition might have potential favorable cardiovascular implications.

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β superfamily, has been recently described as a soluble rejuvenation factor for the heart, muscle, and brain. In fact, GDF11 declines in aged mice, while its replenishment improves vascular, brain, muscle, and cardiac function (1–3). As type 2 diabetes (T2D) increases with age and is characterized by accelerated aging (4), we cross-sectionally explored the effects of age, diabetes, and vascular disease on plasma GDF11 concentrations. The study was approved by the local ethics committee and conducted in accordance with the principles of the Declaration of Helsinki. Plasma GDF11 concentrations were measured by ELISA (MBS2502734, MyBioSource) in a previously described cohort of T2D patients and age- and sex-matched control subjects without diabetes (5). As the distribution of GDF11 concentrations was skewed, it was log-transformed before statistical analyses. On average, plasma GDF11 concentrations were higher in T2D patients than …

Diabetes compromises the bone marrow (BM) microenvironment and reduces the number of circulating CD34+ cells. Diabetic autonomic neuropathy (DAN) may impact the BM, because the sympathetic nervous system is prominently involved in BM stem cell trafficking. We hypothesize that neuropathy of the BM affects stem cell mobilization and vascular recovery after ischemia in patients with diabetes. We report that, in patients, cardiovascular DAN was associated with fewer circulating CD34+ cells. Experimental diabetes (streptozotocin-induced and ob/ob mice) or chemical sympathectomy in mice resulted in BM autonomic neuropathy, impaired Lin−cKit+Sca1+ (LKS) cell and endothelial progenitor cell (EPC; CD34+Flk1+) mobilization, and vascular recovery after ischemia. DAN increased the expression of the 66-kDa protein from the src homology and collagen homology domain (p66Shc) and reduced the expression of sirtuin 1 (Sirt1) in mice and humans. p66Shc knockout (KO) in diabetic mice prevented DAN in the BM, and rescued defective LKS cell and EPC mobilization. Hematopoietic Sirt1 KO mimicked the diabetic mobilization defect, whereas hematopoietic Sirt1 overexpression in diabetes rescued defective mobilization and vascular repair. Through p66Shc and Sirt1, diabetes and sympathectomy elevated the expression of various adhesion molecules, including CD62L. CD62L KO partially rescued the defective stem/progenitor cell mobilization. In conclusion, autonomic neuropathy in the BM impairs stem cell mobilization in diabetes with dysregulation of the life-span regulators p66Shc and Sirt1.

Although there are different mechanistic theories for aging,[1][1] endothelial dysfunction (ED) is a rather neglected player in the aging process. A maladaptive insulin/IGF-1-like signaling (IIS) has a remarkable importance in proaging mechanisms, and insulin has direct effects on ED.[2][2]

OBJECTIVE Diabetes mellitus (DM) increases cardiovascular risk, at least in part, through shortage of vascular regenerative cells derived from the bone marrow (BM). In experimental models, DM causes morphological and functional BM alterations, but information on BM function in human DM is missing. Herein, we sought to assay mobilization of stem and proangiogenic cells in subjects with and without DM. RESEARCH DESIGN AND METHODS In a prospective trial (NCT01102699), we tested BM responsiveness to 5 μg/kg human recombinant granulocyte colony–stimulating factor (hrG-CSF) in 24 individuals with DM (10 type 1 and 14 type 2) and 14 individuals without DM. Before and 24 h after hrG-CSF, we quantified circulating stem/progenitor cells and total and differential white blood cell counts. We also evaluated in vivo the proangiogenic capacity of peripheral blood mononuclear cells using the Matrigel plug assay. RESULTS In response to hrG-CSF, levels of CD34+ cells and other progenitor cell phenotypes increased in subjects without DM. Patients with DM had significantly impaired mobilization of CD34+, CD133+, and CD34+CD133+ hematopoietic stem cells and CD133+KDR+ endothelial progenitors, independently of potential confounders. The in vivo angiogenic capacity of peripheral blood mononuclear cells significantly increased after hrG-CSF in control subjects without DM, but not in patients with DM. DM was also associated with the inability to upregulate CD26/DPP-4 on CD34+ cells, which is required for the mobilizing effect of granulocyte colony–stimulating factor. CONCLUSIONS Stem and proangiogenic cell mobilization in response to hrG-CSF is impaired in DM, possibly because of maladaptive CD26/DPP-4 regulation. These alterations may hamper tissue repair and favor the development of cardiovascular complications.

The metabolic syndrome (MS) is characterized by chronic inflammation. We aimed to determine the association of white blood cell (WBC) count with prevalence and development of the MS and its components in the general population. A cohort of 1,329 subjects from the local working population aged 41.3 ± 7.5 years and recruited since 2000–2008 was followed up for 4.0 ± 1.2 years. WBC count and MS components were determined at baseline and follow-up. To determine whether WBC predicted incident MS, we used a logistic regression analysis adjusted for demographics, baseline variables that define MS components, smoke, medications, and follow-up duration. Cross-sectionally in the whole population, WBC count increased in parallel with the number of MS components in the same individual, and the presence of each component was associated with higher WBC count. Baseline WBC count was significantly higher in subjects with prevalent MS. Among subjects without MS at baseline, those who developed MS had significantly higher WBC than those who did not develop MS at follow-up. Development of each MS component was associated with increased WBC count. WBC count remained significantly associated with MS development after correction for several potential confounders (OR for 1 SD increase in WBC 1.26; 95 % CI 1.01–1.58). In conclusion, elevated WBC is intimately linked to the prevalence and future development of the MS in a young population of working subjects.

The metabolic syndrome (MS), a predisposing condition for cardiovascular disease, presents disturbances in hemodynamics; impedance cardiography (ICG) can assess these alterations. In subjects with MS, the morphology of the pulses present in the ICG time series is more irregular/complex than in normal subjects. Therefore, the aim of the present study was to quantitatively assess the complexity of ICG times series in 53 patients, with or without MS, through a nonlinear analysis algorithm, the approximate entropy, a method employed in recent years for the study of several biological signals, which provides a scalar index, ApEn. We correlated ApEn computed from ICG times series data during fasting and postprandial phase with the presence of alterations in the parameters defining MS [Adult Treatment Panel (ATP) III (Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C; National Heart, Lung, and Blood Institute; American Heart Association. Circulation 109: 433–438, 2004) and the International Diabetes Federation (IDF) definition]. Results show that ApEn was significantly higher in subjects with MS compared with those without (1.81 ± 0.09 vs. 1.65 ± 0.13; means ± SD; P = 0.0013, with ATP III definition; 1.82 ± 0.09 vs. 1.67 ± 0.12; P = 0.00006, with the IDF definition). We also demonstrated that ApEn increase parallels the number of components of MS. ApEn was then correlated to each MS component: mean ApEn values of subjects belonging to the first and fourth quartiles of the distribution of MS parameters were statistically different for all parameters but HDL cholesterol. No difference was observed between ApEn values evaluated in fasting and postprandial states. In conclusion, we identified that MS is characterized by an increased complexity of ICG signals: this may have a prognostic relevance in subjects with this condition.

Aims: We investigated the prevalence of the myocyte enhancer factor (MEF)2A exon 11 deletion, a putative coronary artery disease (CAD) susceptibility gene, in patients referred for coronary angiography.Methods and results: In total, 1079 consecutive patients referred for coronary angiography in the GENICA Study were genotyped and 301 low-risk subjects were used as controls. One patient with early onset three vessels CAD, carrying the MEF2A deletion was found in the GENICA Study cohort and none in the control group.Conclusion: In a cohort of patients undergoing coronary angiography for suspected CAD the MEF2A exon 11 deletion occurred in 0.09%.

We hypothesize that type 2 diabetic patients with different phenotypes may show different response to incretin-based therapies. Therefore, we tested whether the presence of metabolic syndrome (MS) influences glycemic response to these drugs. We prospectively followed 211 patients, treated with the GLP-1 analog exenatide (n = 102) or a DPP-4 inhibitor (n = 109) for at least 4 months. Treatment was decided on clinical grounds. We collected baseline data (age, sex, BMI, waist, systolic and diastolic blood pressure, lipid profile, data on diabetic complications and concomitant treatment) and HbA1c at subsequent visits. Patients were divided into groups according to the presence/absence of MS. Compared to patients on exenatide, patients on DPP-4 inhibitors were older and had lower BMI, waist, diastolic blood pressure, fasting plasma glucose, and HbA1c. At means of baseline values, HbA1c reduction was similar in patients treated with exenatide or DPP-4 inhibitors. Patients on exenatide showed significantly higher HbA1c reduction if they had MS (−1.55 ± 0.22%; n = 88) than if they had not (−0.34 ± 0.18%; P = 0.002). Conversely, patients on DPP-4 inhibitors showed significantly lower HbA1c reduction if they had MS (−0.60 ± 0.12%; n = 73) than if they had not (−1.50 ± 0.24%; P < 0.001). Type of MS definition (ATP-III, IDF or WHO) poorly influenced these trends. The interaction between type of therapy (exenatide vs. DPP-4 inhibitors) and MS remained significant after adjusting for age, baseline HbA1c, BMI, and concomitant medications. In conclusion, the presence of MS appears to modify the response to incretin-based therapies. Given the non-randomized nature of this study, these data need to be replicated.

OBJECTIVE Reduction of bone marrow–derived circulating progenitor cells has been proposed as a novel mechanism of cardiovascular disease in type 2 diabetes. The present study was designed to describe the extent and potential mechanisms of progenitor cell reduction during the natural history of type 2 diabetes. RESEARCH DESIGN AND METHODS We identified 425 individuals, divided into seven categories according to carbohydrate metabolism status (normal glucose tolerance [NGT], impaired fasting glucose, impaired glucose tolerance [IGT], and newly diagnosed type 2 diabetes) and diabetes duration (0–9, 10–19, and ≥20 years). These categories were examined as ideally describing the natural history of type 2 diabetes development and progression. We measured CD34+ and CD34+KDR+ progenitor cells by flow cytometry. We also evaluated progenitor cells in 20 coupled bone marrow and peripheral blood samples and examined progenitor cell apoptosis in 34 subjects. RESULTS In comparison to NGT, CD34+ cells were significantly reduced in IGT and had a first nadir in newly diagnosed type 2 diabetes and a second nadir after 20 years of diabetes. Statistical adjustment for possible confounders confirmed that CD34+ cell counts are deeply reduced at time of diagnosis, that they partially recover during the subsequent 0–19 years, and that they dip again after ≥20 years. A similar, but less consistent, trend was detected for CD34+KDR+ cells. Peripheral blood CD34+ cells were directly correlated with bone marrow CD34+ cells and inversely correlated with CD34+ cell apoptosis. CONCLUSIONS Circulating progenitor cell reduction marks the clinical onset of type 2 diabetes. Both defective mobilization and increased apoptosis may account for this phenomenon. While a partial recovery occurs during subsequent years, bone marrow reserve seems exhausted in the long term.

Purpose: This study aimed to assess vascular endothelial function in patients with ocular hypertension (OHT) or primary open-angle glaucoma (POAG) by measuring: (a) endothelium-dependent flow-mediated vasodilation (FMD) of the brachial artery, and (b) circulating endothelial progenitor cells, which are believed to support the integrity of the vascular endothelium. Methods: We enrolled 25 patients with OHT, 23 with POAG and 26 control subjects, all of whom were aged

BACKGROUND: Circulating progenitor cells (CPC) contribute to the homeostasis of the vessel wall, and a reduced CPC count predicts cardiovascular morbidity and mortality. We tested the hypothesis that CPC count improves cardiovascular risk stratification and that this is modulated by low-grade inflammation. METHODOLOGY/PRINCIPAL FINDINGS: We pooled data from 4 longitudinal studies, including a total of 1,057 patients having CPC determined and major adverse cardiovascular events (MACE) collected. We recorded cardiovascular risk factors and high-sensitive C-reactive protein (hsCRP) level. Risk estimates were derived from Cox proportional hazard analyses. CPC count and/or hsCRP level were added to a reference model including age, sex, cardiovascular risk factors, prevalent CVD, chronic renal failure (CRF) and medications. The sample was composed of high-risk individuals, as 76.3% had prevalent CVD and 31.6% had CRF. There were 331 (31.3%) incident MACE during an average 1.7+/-1.1 year follow-up time. CPC count was independently associated with incident MACE even after correction for hsCRP. According to C-statistics, models including CPC yielded a non-significant improvement in accuracy of MACE prediction. However, the integrated discrimination improvement index (IDI) showed better performance of models including CPC compared to the reference model and models including hsCRP in identifying MACE. CPC count also yielded significant net reclassification improvements (NRI) for CV death, non-fatal AMI and other CV events. The effect of CPC was independent of hsCRP, but there was a significant more-than-additive interaction between low CPC count and raised hsCRP level in predicting incident MACE. CONCLUSIONS/SIGNIFICANCE: In high risk individuals, a reduced CPC count helps identifying more patients at higher risk of MACE over the short term, especially in combination with a raised hsCRP level.

The expanding diabetic epidemic and the high risk of cardiovascular events in diabetic patients suggest that screening heart disease in this population is an important issue. Nonetheless, the advisability of large-scale screening in asymptomatic individuals with diabetes is debated, because available techniques are expensive and have suboptimal diagnostic accuracy. Moreover, all diabetic patients should be treated aggressively as if they all had a positive screening test, because diabetes could be considered a coronary risk equivalent. In this article, we underline the importance of an early diagnosis of coronary artery disease and heart failure in diabetic patients, suggesting that positive screening tests have significant implications in clinical management.

Background Cardiovascular risk factors cluster in the metabolic syndrome (MS), but it is not known whether the risk associated with the syndrome is higher than the sum of its parts. In this study, we explored the relationship between clustering cardiometabolic risk factors and carotid intima-media thickness (c-IMT). Methods and results Cardiovascular parameters and c-IMT were determined in 240 middle-aged healthy participants, divided into groups according to their number of MS components. Higher number of MS components were associated with higher mean c-IMT. Analysis of synergy revealed that c-IMT increase at component clustering fitted an additive model. Redefinition of cutpoints for MS traits, optimized to detect high c-IMT, did not improve the interaction between components. When metabolic factors were rendered independent, a synergistic interaction between factors in increasing the likelihood of having a high c-IMT was detected. Synergic as well was the interaction between metabolic factors with other risk factors that are not consequence of insulin resistance, such as low-density lipoprotein-cholesterol level and smoking habit. Conclusion A stepwise approach reveals that the lack of synergy in the interactions between MS components is attributable to their mutual interdependence, possibly owing to the common pathophysiological background. Indeed, if MS is a unique clinical entity, it should be no more than the sum of its parts.

Vascular endothelium plays a major role in maintaining cardiovascular homeostasis. Nitric oxide is the most powerful vasodilating compound. Diabetes disrupts endothelial integrity through an increased oxidative stress. Recent evidence indicates that there is a strong interaction between diabetes, the secretory proteins of adipocytes, called adipokines, and endothelium. Endothelial dysfunction may precede the development of overt DM, and a prolonged and repeated exposure to postprandial hyperglycemia may play an important role in the development of atherosclerosis, even in those who have normal fasting plasma glucose levels.