Chiara Pecchioli

Plasma Ghrelin in Anorexia, Bulimia, and Binge-Eating Disorder: Relations with Eating Patterns and Circulating Concentrations of Cortisol and Thyroid Hormones

The present study was designed to investigate the relations between plasma ghrelin concentrations, eating patterns, and circulating concentrations of cortisol and thyroid hormones in women with anorexia nervosa, bulimia nervosa, and binge-eating disorder. The patterns of disordered eating behavior were assessed using the Eating Attitudes Test (EAT-26) and the Bulimia Test-Revised (BULIT-R). In women with eating disorders, but not in healthy control women, plasma ghrelin concentrations were negatively correlated with body mass index (BMI) and plasma concentrations of thyreotropin (TSH), free T3 and free T4, and positively correlated with plasma concentrations of cortisol. The ghrelin concentrations of women with binge-eating and purging behavior were significantly lower than those of women with anorexia nervosa, restricting type, and there was a negative relation between the frequency and severity of binge-eating and purging behavior, as measured by the BULIT-R total score, and ghrelin concentrations. In a multivariate regression model controlling for the confounding effects of body mass index (BMI) and age, higher ghrelin concentrations were correlated with lower BULIT-R total scores. The results of this study did not confirm the hypothesis advanced in previous studies that ghrelin concentrations are higher in patients with binge-eating/purging forms of eating disorders. Based on these data, we suggest that, in women with eating disorders, ghrelin concentrations best reflect nutritional status rather than specific patterns of disordered eating behavior.

Metabolomics signature improves the prediction of cardiovascular events in elderly subjects

AIMS Age is one of the most important determinants of cardiovascular health, therefore the management of cardiovascular diseases (CVD) in elderly people entails great challenge. A possible explanation of vascular senescence process is the mitochondrial damage and dysfunction. We hypothesized that metabolomic profiling would identify biomarkers predicting major cardiovascular events (MACEs) in elderly people, improving the clinical standard cardiovascular risk factors. METHODS AND RESULTS Targeted-mass-spectrometry-based profiling of 49 metabolites was performed in a group of very old participants (n = 67, mean age = 85 ± 3 years) with a high rate of previous CVD (68%). Principal Component Analysis, Random Survival Forest analysis and Cox proportional hazards regression modeling were used to evaluate the relation between the metabolite factors and recurring MACEs. We tested discrimination ability and reclassification of clinical and metabolomic models. At follow-up (median = 3.5 years), 17 MACEs occurred (5 cardiovascular deaths, 1 nonfatal myocardial infarction, 7 nonfatal strokes and 4 peripheral artery surgeries) (incidence = 7.3% person-years). Metabolite factor 1, composed by medium- and long-chain acylcarnitines, and factor 7 (alanine) were independently associated with MACEs, after adjustment for clinical CV covariates [HR = 1.77 (95%CI = 1.11-2.81, p = 0.016) and HR = 2.18 (95%CI = 1.17-4.07, p = 0.014), respectively]. However, only factor 1 significantly increases the prediction accuracy of the Framingham Recurring-Coronary-Heart-Disease-Score, with a significant improvement in discrimination (integrated discrimination improvement = 7%, p = 0.01) and correctly reclassifying 41% of events and 37% of non-events resulting in a cNRI = 0.79 (p = 0.005). CONCLUSIONS Aging mitochondrial dysfunction evaluated by metabolomic profiling is associated with MACEs, independently of standard predictors.

Pioglitazone improves endothelial and adipose tissue dysfunction in pre-diabetic CAD subjects

OBJECTIVE To investigate the effect of pioglitazone on endothelial and adipose tissue dysfunction in newly detected IGT patients with CAD. METHODS AND DESIGN Participants (n=25) were randomized to treatment with either placebo or pioglitazone (30 mg/day) for 12 weeks. Before and after treatment we evaluated endothelial function (flow-mediated dilation--FMD--of the brachial artery), circulating adipose and inflammatory markers (adiponectin isoforms, TNF-alpha, and high sensitivity-CRP), and insulin sensitivity (euglycemic hyperinsulinemic clamp). RESULTS No significant changes were observed in subjects (n=12) treated with placebo. By contrast, subjects (n=13) treated with pioglitazone had significant improvement in FMD (10.8±5.3 vs 13.3±3.6%, p<0.01), accompanied by increased high molecular weight adiponectin (HMW-Ad) (1.7±1.2 vs 4.8±3.6 μg/ml, p<0.05) and decreased TNF-alpha (4.3±1.9 vs 3.2±1.2 pg/ml, p<0.05) associated to an increased glucose disposal (4.8±1.9 vs 5.4±2.0 mg kg(-1) min(-1), p<0.05). A multiple regression analysis indicated that increasing of HMW-Ad after pioglitazone predicted increased FMD. CONCLUSION Pioglitazone significantly improves endothelial and adipose tissue dysfunction in pre-diabetic patients with CAD.

Occult impaired glucose regulation in patients with atherosclerosis is associated to the number of affected vascular districts and inflammation

OBJECTIVE The role of inflammatory adipokines has clear mechanistic effects in the promotion of both DM2 and cardiovascular diseases (CVDs), but it is unknown to what extent atherosclerosis-related inflammation might promote defects of glucose metabolism. The purpose of this study was to test the hypothesis that in subjects with atherosclerotic vascular disease and no previous medical record of type 2 diabetes mellitus (DM2), the diagnosis of occult impaired glucose regulation (IGR) is related to the severity of atherosclerosis, measured as the single or combined presence of an history of coronary artery disease (CAD), carotid atherosclerosis (Car-ATS) and peripheral artery disease (PAD). METHODS In a population of 551 subjects (440 men and 111 women) with a previous history of atherosclerosis, we investigated the presence of IGR (including both impaired glucose tolerance and DM2). To test the correlation between conventional and non-conventional risk factors for cardiovascular disease and diabetes we used logistic and regression analysis models. RESULTS IGR was more prevalent in patients with a documented vascular disease in two or three vessel districts compared with patients with only one symptomatic district (p=0.016). Among classic risk factors we found that waist circumference was correlated neither to IGR nor to symptomatic vascular disease extension. By contrast, adiponectin level was independently associated to vascular and glucose regulation status (p=0.012 and p<0.001, respectively). CONCLUSION In subjects affected by atherosclerotic vascular diseases, the presence of impaired glucose regulation is associated to the number of vascular districts affected and to a reduced adiponectin level.

A score including ADAM17 substrates correlates to recurring cardiovascular event in subjects with atherosclerosis

OBJECTIVE Atherosclerosis disease is a leading cause for mortality and morbidity. The narrowing/rupture of a vulnerable atherosclerotic plaque is accountable for acute cardiovascular events. However, despite of an intensive research, a reliable clinical method which may disclose a vulnerable patient is still unavailable. APPROACH AND RESULTS We tested the association of ADAM17 (A Disintegrin and Metallo Protease Domain 17) circulating substrates (sICAM-1, sVCAM-1, sIL6R and sTNFR1) with a second major cardiovascular events [MACEs] (cardiovascular death, peripheral artery surgeries, non-fatal myocardial infarction and non-fatal stroke) in 298 patients belonging to the Vascular Diabetes (AVD) study. To evaluate ADAM17 activity we create ADAM17 score through a RECPAM model. Finally we tested the discrimination ability and the reclassification of clinical models. At follow-up (mean 47 months, range 1-118 months), 55 MACEs occurred (14 nonfatal MI, 14 nonfatal strokes, 17 peripheral artery procedures and 10 cardiovascular deaths) (incidence = 7.8% person-years). An increased risk for incident events was observed among the high ADAM17 score individuals both in univariable (HR 19.20, 95% CI 15.82-63.36, p < 0.001) and multivariable analysis (HR 3.42, 95% CI 1.55-7.54, p < 0.001). Finally we found that ADAM17 score significantly increases the prediction accuracy of the Framingham Recurring-Coronary-Heart-Disease-Score, with a significant improvement in discrimination (integrated discrimination improvement = 9%, p = 0.012) and correctly reclassifying 10% of events and 41% of non-events resulting in a cNRI = 0.51 (p = 0.005). CONCLUSION We demonstrated a positive role of ADAM17 activity to predicting CV events. We think that an approach that targets strategies beyond classic cardiovascular risk factors control is necessary in individuals with an established vascular atherosclerosis.

C-peptide: A predictor of cardiovascular mortality in subjects with established atherosclerotic disease

Aim: Insulin resistance and type 2 diabetes are independent risk factors for cardiovascular diseases. Levels of C-peptide are increased in these patients and its role in the atherosclerosis progression was studied in vitro and in vivo over the past years. To evaluate the possible use of C-peptide as cardiovascular biomarkers, we designed an observational study in which we enrolled patients with mono- or poly-vascular atherosclerotic disease. Methods: We recruited 431 patients with stable atherosclerosis and performed a yearly follow-up to estimate the cardiovascular and total mortality and cardiovascular events. Results: We performed a mean follow-up of 56 months on 268 patients. A multivariate Cox analysis showed that C-peptide significantly increased the risk of cardiovascular mortality [Hazard Ratio: 1.29 (95% confidence interval: 1.02−1.65, p < 0.03513)] after adjustment for age, sex, diabetes treatment, estimated glomerular filtration rate and known diabetes status. Furthermore, levels of C-peptide were significantly correlated with metabolic parameters and atherogenic factors. Conclusion: C-peptide was associated with cardiovascular mortality independently of known diabetes status in a cohort of patients with chronic atherosclerotic disease. Future studies using C-peptide into a reclassification approach might be undertaken to consider its potential as a cardiovascular disease biomarker.

Brachial flow-mediated dilation predicts glycemia worsening in normoglycemic young subjects

Endothelial dysfunction (ED) is a common feature of type 2 diabetes (T2D) and cardiovascular disorders. ED is early detectable in subjects with either strong diabetes familiarity or cardiovascular risk factors who may develop overt diabetes later [1–4]. Brachial flow-mediated dilatation (b-FMD) is a marker of in vivo endothelial dysfunction, and it is a simple no invasive method for identifying patients at risk of CV disease. Nevertheless, to our knowledge, a clear link between impaired endothelium-dependent vasodilation in vivo and hyperglycemia spillover has never been reported. To this purpose, we report here the relationship between fasting glycaemia values analyzed 10 years later and baseline endothelial dysfunction assessment in a group of normoglycemic subjects with and without familiarity for T2D [1–3].

A1c value for diabetes diagnosis in subjects with established cardiovascular disease

The prevalence of type 2 diabetes (DM2) is increasing at an alarming rate, and the early detection and intervention in DM2 are now considered one of the most important public health agendas. Currently, there are three different available methods for early DM2 diagnosis. First, fasting plasma glucose (FPG) is simple, easy, inexpensive and widely available to general population. The diagnostic cutoff point is 126 mg/dl and over. Second, the 2-h plasma glucose after oral glucose tolerance test (OGTT), whose diagnostic limit for DM2 is C200 mg/dl (2 h-post load glucose, 2-hPG). Actually, the OGTT is not common in clinical practice, because it may be difficult to perform and costs and demands on participants’ time may be excessive. Although the lack of reproducibility is documented in some reports, evidence suggests that an increased 2-h PG during an OGTT is a better predictor of both all-cause mortality and cardiovascular mortality or morbidity than the FPG [1]. Third and last, A1c. It is an indirect measure of mean blood glucose over the previous 2–3 months, does not require fasting and is more reproducible than FPG because of less biological variability and less pre-analytic instability. A1c values C 48 mmol/mol (6.5 %) have been chosen to detect diabetes. This cutoff point derives from a review of studies that examined the association of A1c values with incidence of retinopathy, a specific microvascular complication of diabetes [1]. Although DM2 retinopathy among patients is a precocious complication, it is much less prevalent than cardiovascular disease [1]. Consistently, a different A1c threshold for DM2 diagnosis might have been chosen if the outcome considered had been established cardiovascular disease (eCVD) rather than retinopathy. Since A1c was accepted as a new diagnostic tool forDM2, several studies have been performed to evaluate its accuracy across different ethnic groups and populations [2, 3], but less data are available for subjects with a high risk of DM2, such those with eCVD [2, 4]. The purpose of this study was to investigate whether A1c is suitable to detect silent diabetes in two different groups of high-risk patients, compared to OGTT: the first Managed by Antonio Secchi.

2-hydroxycaproate predicts cardiovascular mortality in patients with atherosclerotic disease

BACKGROUND AND AIMS We aimed to identify novel biomarkers for cardiovascular mortality through a non-targeted metabolomics approach in patients with established atherosclerotic disease from the Tor Vergata Atherosclerosis Registry (TVAR). METHODS We compared the serum baseline metabolome of 19 patients with atherosclerosis suffering from cardiovascular death during follow-up with the baseline serum metabolome of 20 control patients matched for age, gender, body mass index (BMI) and atherosclerotic disease status, who survived during the observation period. RESULTS Three metabolites were significantly different in the cardiovascular mortality (CVM) group compared to controls: 2-hydroxycaproate, gluconate and sorbitol. 2-hydroxycaproate (otherwise known as alpha hydroxy caproate) was also significantly correlated with time to death. The metabolites performed better when combined together rather than singularly on the identification of CVM status. CONCLUSIONS Our analysis led to identify few metabolites potentially amenable of translation into the clinical practice as biomarkers for specific metabolic changes in the cardiovascular system in patients with established atherosclerotic disease.