ANDREA NATALI | University of Pisa (original) (raw)

Papers by ANDREA NATALI

Journal of the American Society of Echocardiography, 2021

Background: Cardiopulmonary exercise testing (CPET) represents the gold standard to estimate peak... more Background: Cardiopulmonary exercise testing (CPET) represents the gold standard to estimate peak oxygen consumption (VO 2) noninvasively. To improve the analysis of the mechanisms behind effort intolerance, we examined whether exercise stress echocardiography measurements relate to directly measured peak VO 2 during exercise in a large cohort of patients within the heart failure (HF) spectrum. Methods: We performed a symptom-limited graded ramp bicycle CPET exercise stress echocardiography in 30 healthy controls and 357 patients: 113 at risk of developing HF (American College of Cardiology/American Heart Association stage A-B) and 244 in HF stage C with preserved (HFpEF, n = 101) or reduced ejection fraction (HFrEF, n = 143). Results: Peak VO 2 significantly decreased from controls (23, 21.7-29.7 mL/kg/minute; median, interquartile range) to stage A-B (18, 15.4-20.7 mL/kg/minute) and stage C (HFpEF: 13.6, 11.8-16.8 mL/kg/minute; HFrEF: 14.2, 10.7-17.5 mL/kg/minute). A regression model to predict peak VO 2 revealed that peak left ventricular (LV) systolic annulus tissue velocity (S 0), peak tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (right ventricle-pulmonary artery coupling), and low-load left atrial (LA) reservoir strain/E/e' (LA compliance) were independent predictors, in addition to peak heart rate, stroke volume, and workload (adjusted R 2 = 0.76, P < .0001). The model was successfully tested in subjects with atrial fibrillation (n = 49) and with (n = 224) and without (n = 163) beta-blockers (all P < .01). Peak S 0 showed the highest accuracy in predicting peak VO 2 < 10 mL/kg/minute (cut point # 7.5 cm/sec, area under the curve = 0.92, P < .0001) and peak VO 2 > 20 mL/kg/minute (cut point > 12.5 cm/sec, area under the curve = 0.84, P < .0001) in comparison with the other cardiac variables of the model (P < .05). Conclusions: Peak VO 2 is directly related to measures of LV systolic function, LA compliance, and right ventricle-pulmonary artery coupling, in addition to heart rate and stroke volume and independently of workload, age, and sex. The evaluation of cardiac mechanics may provide more insights into the causes of effort intolerance in subjects from HF stages A-C.

DOAJ (DOAJ: Directory of Open Access Journals), Dec 31, 2011

Conservation Science in Cultural Heritage, Jul 1, 2007

Conservation Science in Cultural Heritage, Dec 30, 2013

the two book series' "I beni culturali e l'ambiente", and "La formazione e la ricerca nel settore... more the two book series' "I beni culturali e l'ambiente", and "La formazione e la ricerca nel settore dei beni culturali e ambientali" and the historical-technical Journal "Conservation Science in Cultural Heritage". He is the author of more than 370 publications in national and international journals and of 22 volumes covering various subjects and sectors, such as commodities, technology and environment, focusing in particular on the field of cultural and environmental heritage. Chiara Matteucci has a degree and is a specialized technician-diagnostician at the Department of Cultural Heritage of the Alma Mater Studiorum University of Bologna. She works extensively in the field of analytical-diagnostic investigations involving artifacts from different areas of interest: artistic-historical, archaeological, archival-library and music. Her work is carried out in the Diagnostic Laboratory for Cultural Heritage in the

DOAJ (DOAJ: Directory of Open Access Journals), 2008

Conservation Science in Cultural Heritage, Jul 7, 2008

Diabetologia, 2019

Aims/hypothesis Experimental studies suggest that the fatty acid palmitoleate may act as an adipo... more Aims/hypothesis Experimental studies suggest that the fatty acid palmitoleate may act as an adipocyte-derived lipid hormone (or 'lipokine') to regulate systemic metabolism. We investigated the relationship of circulating palmitoleate with insulin sensitivity, beta cell function and glucose tolerance in humans. Methods Plasma NEFA concentration and composition were determined in non-diabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study cohort at baseline (n = 1234) and after a 3 year follow-up (n = 924). Glucose tolerance, insulin secretion and beta cell function were assessed during an OGTT. Whole-body insulin sensitivity was measured by a hyperinsulinaemic-euglycaemic clamp (M/I) and OGTT (oral glucose insulin sensitivity index [OGIS]). The liver insulin resistance index was calculated using clinical and biochemical data. Body composition including fat mass was determined by bioelectrical impedance. Results Circulating palmitoleate was proportional to fat mass (r = 0.21, p < 0.0001) and total NEFA levels (r = 0.19, p < 0.0001). It correlated with whole-body insulin sensitivity (M/I: standardised regression coefficient [std. β] = 0.16, p < 0.0001), liver insulin resistance (std. β = −0.14, p < 0.0001), beta cell function (potentiation: std. β = 0.08, p = 0.045) and glucose tolerance (2 h glucose: std. β = −0.24, p < 0.0001) after adjustment for age, sex, BMI, adiposity and other NEFA. High palmitoleate concentrations prevented the decrease in insulin sensitivity associated with excess palmitate (p = 0.0001). In a longitudinal analysis, a positive independent relationship was observed between changes in palmitoleate and insulin sensitivity over time (std. β = 0.07, p = 0.04). Conclusions/interpretation We demonstrated that plasma palmitoleate is an independent determinant of insulin sensitivity, beta cell function and glucose tolerance in non-diabetic individuals. These results support the role of palmitoleate as a beneficial lipokine released by adipose tissue to prevent the negative effects of adiposity and excess NEFA on systemic glucose metabolism.

European Heart Journal, 2020

Background and purpose CD40 and CD40 ligand (CD40L) are costimulatory molecules and members of th... more Background and purpose CD40 and CD40 ligand (CD40L) are costimulatory molecules and members of the TNF receptor superfamily well known for their involvement in inflammatory and autoimmune diseases. This study uses two large human cohorts – the SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) and the Carotid Plaque Imaging Project (CPIP) – to explore the potential of plasma or intra-plaque expression of CD40 and CD40L as biomarkers and to locally affect plaque stability. Methods Proximity Extension Assay (PEA) technique was used to measure soluble CD40 and CD40L (sCD40 and sCD40L) in plasma from 1437 subjects from the SUMMIT cohort, the majority of which (80%) with pre-existing cardiovascular disease, and in atherosclerotic plaque homogenates from 199 subjects of the CPIP cohort undergoing carotid endarterectomy. The Mann-Whitney U test was used to compare groups and Spearman's rank correlation/the Chi-square test was used to a...

Nature Communications, 2021

The hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperg... more The hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04–1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09–1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulate...

Journal of Stroke, 2021

Background and Purpose CD40 and CD40 ligand (CD40L) are costimulatory molecules of the tumor necr... more Background and Purpose CD40 and CD40 ligand (CD40L) are costimulatory molecules of the tumor necrosis factor receptor superfamily and well known for their involvement in inflammatory diseases: atherosclerotic mouse models with disrupted CD40 signalling develop lesions of reduced size with a more stable plaque profile. This study investigated the potential of plasma and intraplaque levels of CD40 and CD40L as markers for cardiovascular disease (CVD) in humans and their association with plaque stability.Methods Soluble CD40 and CD40L (sCD40L) were measured in plasma in 1,437 subjects from The SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) cohort. Intra-plaque levels of sCD40 and sCD40L were measured in atherosclerotic plaque homogenates from 199 subjects of the Carotid Plaque Imaging Project (CPIP) cohort. Results Both plasma sCD40 and sCD40L levels were elevated in individuals with prevalent stroke, while sCD40 levels also were h...

Cardiovascular Diabetology, 2019

Background: The relationship between dyslipidemia, inflammation and CV organ damage in type 2 dia... more Background: The relationship between dyslipidemia, inflammation and CV organ damage in type 2 diabetes mellitus (T2DM) is complex. Insulin resistance and inflammatory cytokines interleukins (ILs) increase plasma triglycerides (TG). ILs also up-regulate expression of matrix-metalloproteinases (MMPs) that, together with TG, decrease high density lipoprotein cholesterol (HDL) levels. High TG, low HDL, increased ILs and MMPs trigger structural and functional changes in different parts of cardiovascular (CV) system. To understand better the role of lipids and inflammation in CV organ damage, the present study investigated the interrelationships between lipids, ILs and MMPs, as well as the associations of lipids, ILs and MMPs with various CV measures, both in diabetic and non-diabetic population (nonT2DM). Methods: In T2DM patients (N = 191) and nonT2DM subjects (N = 94) were assessed carotid intima-media thickness (cIMT) and inter-adventitial diameter (IADiam), carotid wave speed (ccaWS), carotid-femoral pulse wave velocity (cfPWV), left ventricular (LV) mass, LV systolic (s′) and early diastolic (e′) longitudinal velocities of mitral annulus, together with glycemic control, lipid profile, IL-6, IL-18 and MMP-12. Results: T2DM patients, as compared to nonT2DM subjects, had significantly higher plasma levels of IL-6, IL-18, MMP-12 and lower HDL (P < 0.05-0.0001). They had also higher cIMT, IADiam, ccaWS, cfPWV and LV mass, and lower e′ velocity (P < 0.005-0.0001). Both in T2DM patients and nonT2DM subjects, MMP-12 increased with IL-6 (r = 0.43 and 0.39; P < 0.0001) and IL-18 (r = 0.32 and 0.42; P < 0.0001), and HDL decreased with MMP-12 (r = − 0.29 and − 0.42; P < 0.0001). In both populations, MMP-12 was directly associated with IADiam, ccaWS, cfPWV and LV mass (r = 0.42, 0.32, 0.26 and 0.29; P < 0.0001 in T2DM patients, and r = 0.39, 0.28, 0.32 and 0.27; P < 0.01-0.0001 in nonT2DM subjects). In multivariate analysis, MMP-12 remained independently related to IADiam, ccaWS, cfPWV and LV mass in T2DM patients, and to IADiam only in nonT2DM subjects. Conclusions: This cross-sectional study demonstrated a direct association between ILs and MMP-12, as well as an inverse association between MMP-12 and HDL, both in T2DM patients and in nonT2DM subjects. In T2DM patients, who had higher levels of ILs and MMP-12, the latter was independently related to several structural and functional markers of preclinical CV organ damage.

Journal of Internal Medicine, 2015

Background-There is a need to develop and validated surrogate markers of cardiovascular disease (... more Background-There is a need to develop and validated surrogate markers of cardiovascular disease (CVD) in diabetes. The macrovascular changes associated with diabetes include an aggravated atherosclerosis, increased arterial stiffness and endothelial dysfunction. In the present study we aimed to determine which of these factors are most effective at identifying patients who have a clinically manifest cardiovascular event. Methods and results-We measured carotid intima media thickness (IMT), ankle-brachial pressure index (ABPI), pulse wave velocity (PWV) and endothelial function assessed by the reactive hyperemia index (RHI) in a cohort of 458 subjects with type 2 diabetes (T2D) and CVD (myocardial infarction, stroke or lower extremity arterial disease), 527 subjects with T2D but no clinically manifest CVD and 515 non-T2D subjects with or without CVD. Carotid IMT and ABPI demonstrated independent association with the presence of clinical CVD in T2D, while assessment of PWV and RHI provide limited independent additive information. Measurement of IMT in the bulb provided a better discrimination of the presence of CVD in T2D than measurement of IMT in the common carotid artery. The most important factors associated with increased carotid IMT in T2D were age, diabetes duration, systolic blood pressure, impaired renal function and increased arterial stiffness, whereas no or only weak independent associations were found with metabolic factors and endothelial dysfunction. Conclusions-Our findings demonstrate that measures of atherosclerotic burden show the best association with clinically manifest CVD in T2D. They also show that vascular changes not directly related to known metabolic risk factors are of importance in atherosclerosis and CVD in T2D. A better understanding of these mechanisms will be of critical importance for development of more effective preventive cardiovascular therapies in diabetes.

Nutrition, Metabolism and Cardiovascular Diseases, 2014

Background and Aims-We have previously shown that the anti-inflammatory and antioxidant functions... more Background and Aims-We have previously shown that the anti-inflammatory and antioxidant functions of HDL are impaired in T2D patients. In this study, we examined whether HDL from T2D patients contains elevated levels of oxidized fatty acids and whether those levels correlate with cardiovascular disease (CVD). Methods and Results-HETEs and HODEs on HDL were determined by LC-MS/MS in 40 non-diabetic controls (ND), 40 T2D without CVD (D + CVD −) and 38 T2D with known history of CVD (D + CVD +). HDL oxidant index was evaluated by a cell-free assay using dichlorofluorescein. Twenty-six randomly selected subjects from the three groups underwent coronary calcium score evaluation (CAC). Major cardiovascular risk factors were similar among the groups. HETEs and HODEs content were significantly increased in HDL from D + CVD + when compared to D + CVD − and ND patients. HDL oxidant index was not different among the three groups; however, it was significantly higher in patients with CAC score >100 when compared to patients with CAC score <100. Conclusion-Patients with D + CVD − and D + CVD + are characterized by a severe, graded enrichment of oxidized fatty acids on HDL. In the present study, a loss of HDL function (as

Hypertension, 1994

Hyperinsulinemia, insulin resistance, or both have been described in patients with essential hype... more Hyperinsulinemia, insulin resistance, or both have been described in patients with essential hypertension. Previous work from our laboratory has shown that in hypertensive patients with microalbuminuria, dyslipidemia and abnormal patterns in the diurnal variations of blood pressure are frequently associated. Whether hyperinsulinemia and microalbuminuria are directly related has not been determined. To test this possibility, we measured the plasma insulin response to an oral glucose load in 25 patients with or without microalbuminuria and 20 normotensive control subjects. Serum lipid profile and 24-hour ambulatory blood pressure were obtained. In the hypertensive patients as a group, the plasma insulin response to glucose (evaluated as the insulin area under the curve) was significantly enhanced compared with a group of 20 normotensive healthy control subjects (46,311 +/- 3745 and 27,557 +/- 2563 pmol/L x 2 hours, P < .01). When the hypertensive patients were subdivided according ...

Hypertension, 1988

Atrial natriuretic factor (ANF) may be physiopathologically involved in several clinical conditio... more Atrial natriuretic factor (ANF) may be physiopathologically involved in several clinical conditions including human hypertension. However, few data are available regarding this putative hormone and its relationship to aldosterone, blood pressure, and vascular responsiveness to alpha-adrenergic receptor stimulation in primary aldosteronism, a volume-expanded, low-renin model of human hypertension. For this reason, the behavior of supine and upright plasma ANF as related to aldosterone, blood pressure, and forearm alpha-adrenergic sensitivity (plethysmographic technique) to intra-arterial norepinephrine infusion was studied in eight patients with primary aldosteronism (five with adenomas, three with hyperplasia) before and at the end of two sequential 1-week low (20 mmol/day) and high sodium (200 mmol/day) diet periods. Basal, predict ANF concentrations decreased and increased after low and high sodium intakes, respectively. Furthermore, highly significant postural ANF decrements afte...

Diabetes, 2011

OBJECTIVE Previous studies have found that high insulin sensitivity predicts weight gain; this as... more OBJECTIVE Previous studies have found that high insulin sensitivity predicts weight gain; this association has not been confirmed. Our aim was to systematically analyze metabolic predictors of spontaneous weight changes. RESEARCH DESIGN AND METHODS In 561 women and 467 men from the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort (mean age 44 years, BMI range 19–44 kg/m2, 9% impaired glucose tolerance) followed up for 3 years, we measured insulin sensitivity (by a euglycemic clamp) and β-cell function (by modeling of the C-peptide response to oral glucose and by acute insulin response to intravenous glucose). RESULTS Insulin sensitivity was similar in weight gainers (top 20% of the distribution of BMI changes), weight losers (bottom 20%), and weight stable subjects across quartiles of baseline BMI. By multiple logistic or linear regression analyses controlling for center, age, sex, and baseline BMI, neither insulin sensitivity nor any β-cell function...

Diabetes, 2007

OBJECTIVE—To quantitate the separate impact of obesity and hyperlycemia on the incretin effect (i... more OBJECTIVE—To quantitate the separate impact of obesity and hyperlycemia on the incretin effect (i.e., the gain in β-cell function after oral glucose versus intravenous glucose). RESEARCH DESIGN AND METHODS—Isoglycemic oral (75 g) and intravenous glucose administration was performed in 51 subjects (24 with normal glucose tolerance [NGT], 17 with impaired glucose tolerance [IGT], and 10 with type 2 diabetes) with a wide range of BMI (20–61 kg/m2). C-peptide deconvolution was used to reconstruct insulin secretion rates, and β-cell glucose sensitivity (slope of the insulin secretion/glucose concentration dose-response curve) was determined by mathematical modeling. The incretin effect was defined as the oral-to-intravenous ratio of responses. In 8 subjects with NGT and 10 with diabetes, oral glucose appearance was measured by the double-tracer technique. RESULTS—The incretin effect on total insulin secretion and β-cell glucose sensitivity and the GLP-1 response to oral glucose were sign...

Atherosclerosis, 2008

To study whether telmisartan, an angiotensin II (AII) receptor blocker (ARB), modulates endotheli... more To study whether telmisartan, an angiotensin II (AII) receptor blocker (ARB), modulates endothelial inflammation and oxidative cell damage induced by AII-independent stimuli in cultured human umbilical vein endothelial cell (HUVEC)s. Endothelial inflammation, as reflected by increased VCAM-1 and ICAM-1 expression (ELISA), was induced by TNF-alpha, an inflammatory cytokine, and cell damage (COMET and MTT assay) by hydrogen peroxide, a reactive oxygen species. Losartan, another ARB, its active metabolites (EXP-3174, EXP-3179), dexamethasone, a synthetic steroid, and pyrrolidine dithiocarbamate (PDTC), an anti-oxidant, were the controls. The contribution of PPAR-gamma agonism was assessed through synthetic PPAR-gamma agonists and antagonists and the antagonism for AII-type 1 receptor-mediated stimuli by evaluating the interference against cell death induced by AII (MTT assay), a pro-apoptotic peptide that induces oxidative stress. The in vitro scavenging properties for oxyradicals were quantified by the TOSC assay. Telmisartan and PDTC reduced TNF-alpha-stimulated VCAM-1 in a concentration-dependent manner while losartan, EXP-3174, EXP-3179 and dexamethasone were ineffective. All compounds did not modify ICAM-1 expression. PPAR-gamma agonists or antagonists did not interfere with the effect of telmisartan. Both ARBs antagonized AII-induced cell death but only telmisartan reduced hydrogen peroxide-induced cell damage. Telmisartan scavenged selectively hydroxyl radicals without affecting peroxyl radicals and peroxynitrite. Telmisartan modulates pleiotropically TNF-alpha induced VCAM-1 expression and oxidative damage in vascular endothelium, possibly by acting as a hydroxyl radical scavenger. Those anti-inflammatory and antioxidant properties may contribute to the therapeutic effect, although the applicability of these data to the clinical situations has to be verified.