Manfredi Tesauro

Ghrelin Improves Endothelial Function in Patients With Metabolic Syndrome

Background— Metabolic syndrome importantly accelerates the atherosclerotic process, the earliest event of which is endothelial dysfunction. Ghrelin, a gastric peptide with cardiovascular actions, has been shown to inhibit proatherogenic changes in experimental models. This study therefore investigated whether ghrelin administration might beneficially affect endothelial function in metabolic syndrome. Methods and Results— Endothelium-dependent and -independent vasodilator responses to intra-arterial infusion of increasing doses of acetylcholine and sodium nitroprusside (SNP), respectively, were assessed by strain-gauge plethysmography before and after local administration of human ghrelin (200 &mgr;g/min). During saline, the vasodilator response to acetylcholine was significantly blunted (P=0.008) in patients with metabolic syndrome (n=12, 5 female) compared with controls (n=12, 7 female), whereas the vasodilator response to SNP was not different between groups (P=0.68). In patients with metabolic syndrome, basal plasma ghrelin was significantly lower than in controls (P=0.02). In these patients, ghrelin infusion markedly increased intravascular concentrations of the peptide (P<0.001) and resulted in a potentiation of the vasodilator response to acetylcholine (P=0.001 versus saline) but not to SNP (P=0.22). This effect was likely related to enhanced nitric oxide bioavailability because, in a group of patients with metabolic syndrome (n=6, 2 female), ghrelin had no effect on the vasodilator response to acetylcholine (P=0.78 versus saline) after nitric oxide inhibition by NG-monomethyl-l-arginine. Conclusions— These findings indicate that ghrelin reverses endothelial dysfunction in patients with metabolic syndrome by increasing nitric oxide bioactivity, thereby suggesting that decreased circulating levels of the peptide, such as those found in these patients, might play a role in the pathobiology of atherosclerosis.

Short-term treatment with atorvastatin reduces platelet CD40 ligand and thrombin generation in hypercholesterolemic patients

BACKGROUND Soluble CD40L (sCD40L), a substance that maximally reflects in vivo platelet activation, is increased in patients with hypercholesterolemia. We investigated the relation between sCD40L and platelet CD4OL in hypercholesterolemic patients before and after a short-term treatment with atorvastatin. METHODS AND RESULTS Collagen-induced platelet CD40L and plasma levels of sCD40L and prothrombin fragment F1+2, a marker of thrombin generation, were investigated in 30 hypercholesterolemic patients and 20 healthy subjects. Hypercholesterolemic patients were then randomized to either diet (n=15; group A) or atorvastatin 10 mg/d (group B); the aforementioned variables were measured at baseline and after 3 days of treatment. Compared with referents, hypercholesterolemic patients showed higher values of platelet CD40L (P<0.005), sCD40L (P<0.005), and F1+2 (P<0.003). Platelet CD40L was significantly correlated with sCD40L (P<0.001), and the latter was significantly correlated with F1+2 (P<0.001). The intervention trial showed no changes in group A but a significant decrease in platelet CD40L (P<0.01), sCD40L (P<0.002), and F1+2 (P<0.03) in group B. In vitro studies demonstrated that cholesterol enhanced platelet CD40L and CD40L-mediated clotting activation by human monocytes; also, atorvastatin dose-dependently inhibited platelet CD40L expression and clotting activation by CD40L-stimulated monocytes. CONCLUSIONS This study shows that, in hypercholesterolemia, platelet overexpression of CD40L may account for enhanced plasma levels of sCD40L and F1+2. Atorvastatin exerts a direct antithrombotic effect via inhibition of platelet CD40L and CD40L-mediated thrombin generation, independently of its cholesterol-lowering effect.

Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome

CONTEXT Hesperidin, a citrus flavonoid, and its metabolite hesperetin may have vascular actions relevant to their health benefits. Molecular and physiological mechanisms of hesperetin actions are unknown. OBJECTIVE We tested whether hesperetin stimulates production of nitric oxide (NO) from vascular endothelium and evaluated endothelial function in subjects with metabolic syndrome on oral hesperidin therapy. DESIGN, SETTING, AND INTERVENTIONS: Cellular mechanisms of action of hesperetin were evaluated in bovine aortic endothelial cells (BAEC) in primary culture. A randomized, placebo-controlled, double-blind, crossover trial examined whether oral hesperidin administration (500 mg once daily for 3 wk) improves endothelial function in individuals with metabolic syndrome (n = 24). MAIN OUTCOME MEASURE We measured the difference in brachial artery flow-mediated dilation between placebo and hesperidin treatment periods. RESULTS Treatment of BAEC with hesperetin acutely stimulated phosphorylation of Src, Akt, AMP kinase, and endothelial NO synthase to produce NO; this required generation of H(2)O(2). Increased adhesion of monocytes to BAEC and expression of vascular cell adhesion molecule-1 in response to TNF-α treatment was reduced by pretreatment with hesperetin. In the clinical study, when compared with placebo, hesperidin treatment increased flow-mediated dilation (10.26 ± 1.19 vs. 7.78 ± 0.76%; P = 0.02) and reduced concentrations of circulating inflammatory biomarkers (high-sensitivity C-reactive protein, serum amyloid A protein, soluble E-selectin). CONCLUSIONS Novel mechanisms for hesperetin action in endothelial cells inform effects of oral hesperidin treatment to improve endothelial dysfunction and reduce circulating markers of inflammation in our exploratory clinical trial. Hesperetin has vasculoprotective actions that may explain beneficial cardiovascular effects of citrus consumption.

Arterial stiffness as an independent predictor of longitudinal changes in cognitive function in the older individual

Background Cognitive decline significantly contributes to disability in older individuals. We previously demonstrated cross-sectionally that arterial stiffness [pulse wave velocity (PWV)] was associated with memory loss independently of traditional cardiovascular risk factors and of neuroimaging findings in older individuals without prior stroke. The present study aimed to evaluate PWV as a predictor of longitudinal changes in cognitive function in older individuals reporting memory problems. Participants and methods We studied 102 older individuals (mean age 79 ± 6 years; 31 men, 71 women) reporting memory problems. PWV was measured noninvasively by Complior. Traditional cardiovascular risk factor levels were measured. Global cognitive function was measured by the Mini-Mental State Examination (MMSE) (maximum score = 30) at baseline and at follow-up visit. Cerebral computed tomography evaluated the presence of microvascular damage or cortical atrophy. Individuals with prior stroke or atrial fibrillation were excluded. Results The baseline MMSE was 22.9 ± 5.5; 61% were hypertensive, 26.8% diabetic, 9.4% smokers, 10.5% taking statins, and 21.1% taking nitrates. The average PWV was 13.5 ± 2.2 m/s. After a median follow-up of 12 months, the average per-year decline in MMSE was 2.9 points or 12.1%. Multiple regression models showed that PWV independently predicted cognitive decline (model R2 = 0.50). PWV was the single strongest predictor of cognitive decline, explaining 15.2% of the total variance (each 1 m/s increase in PWV was associated with an average 0.74 per-year decrease in MMSE score, P < 0.001). Conclusion In older individuals, arterial stiffness (PWV) is a strong predictor of loss in cognitive function, independent of age, sex, education, and traditional cardiovascular risk factors.

Oxidative Stress in Diabetes: Implications for Vascular and Other Complications

In recent decades, oxidative stress has become a focus of interest in most biomedical disciplines and many types of clinical research. Increasing evidence shows that oxidative stress is associated with the pathogenesis of diabetes, obesity, cancer, ageing, inflammation, neurodegenerative disorders, hypertension, apoptosis, cardiovascular diseases, and heart failure. Based on these studies, an emerging concept is that oxidative stress is the “final common pathway” through which the risk factors for several diseases exert their deleterious effects. Oxidative stress causes a complex dysregulation of cell metabolism and cell–cell homeostasis; in particular, oxidative stress plays a key role in the pathogenesis of insulin resistance and β-cell dysfunction. These are the two most relevant mechanisms in the pathophysiology of type 2 diabetes and its vascular complications, the leading cause of death in diabetic patients.

Human obesity and endothelium-dependent responsiveness

Obesity is an ongoing worldwide epidemic. Besides being a medical condition in itself, obesity dramatically increases the risk of development of metabolic and cardiovascular disease. This risk appears to stem from multiple abnormalities in adipose tissue function leading to a chronic inflammatory state and to dysregulation of the endocrine and paracrine actions of adipocyte‐derived factors. These, in turn, disrupt vascular homeostasis by causing an imbalance between the NO pathway and the endothelin 1 system, with impaired insulin‐stimulated endothelium‐dependent vasodilation. Importantly, emerging evidence suggests that the vascular dysfunction of obesity is not just limited to the endothelium, but also involves the other layers of the vessel wall. In particular, obesity‐related changes in medial smooth muscle cells seem to disrupt the physiological facilitatory action of insulin on the responsiveness to vasodilator stimuli, whereas the adventitia and perivascular fat appear to be a source of pro‐inflammatory and vasoactive factors that may contribute to endothelial and smooth muscle cell dysfunction, and to the pathogenesis of vascular disease. While obesity‐induced vascular dysfunction appears to be reversible, at least in part, with weight control strategies, these have not proved sufficient to prevent the metabolic and cardiovascular complication of obesity on a large scale. While a number of currently available drugs have shown potentially beneficial vascular effects in patients with obesity and the metabolic syndrome, elucidation of the pathophysiological mechanisms underlying vascular damage in obese patients is necessary to identify additional pharmacologic targets to prevent the cardiovascular complications of obesity, and their human and economic costs.

Fish oil supplementation improves endothelial function in normoglycemic offspring of patients with type 2 diabetes

OBJECTIVE Offspring of patients with type 2 diabetes (OPDs) exhibits endothelial dysfunction (ED) associated with a chronic inflammatory state. N-3 polyunsaturated fatty acids (n-3 PUFA) may have antioxidant and anti-inflammatory properties that are beneficial for cardiovascular and metabolic health. Therefore, in the present study, we tested the hypothesis that dietary supplementation with fish oil rich in n-3 PUFA may improve ED in otherwise healthy OPDs. METHODS AND DESIGN A double-blind, placebo-controlled trial was conducted with 50 OPDs. Participants were randomized to treatment with either placebo or n-3 PUFA (2g/day) for 12 weeks. Before and after treatment we evaluated endothelial function (using flow-mediated dilation (FMD) of the brachial artery), circulating inflammatory markers (adiponectin, TNF-alpha, and high sensitivity-CRP), and insulin resistance (QUICKI). RESULTS No significant changes were observed in study outcomes in subjects treated with placebo. By contrast, when compared with baseline values, subjects treated with n-3 PUFA had significant improvement in FMD (9.1+/-5.8% vs. 11.7+/-4.4%, p=0.02) that was accompanied by decreased plasma triglycerides (117+/-73mg/dl vs. 86+/-44mg/dl, p=0.001) and TNF-alpha levels (8.9+/-2.3pg/ml vs. 6.8+/-2.7pg/ml, p=0.001), and a trend towards increased plasma adiponectin levels (7.8+/-4.5microg/ml vs. 9.5+/-5.1microg/ml, p=0.09). When data were analyzed by multiple regression analysis, decreased TNF-alpha after treatment with n-3 PUFA predicted increased FMD. CONCLUSION Dietary supplementation with n-3 PUFA significantly improved endothelial function and reduced pro-inflammatory markers in OPDs. Thus, fish oil consumption may have beneficial cardiovascular and metabolic health effects in otherwise healthy subjects predisposed to diabetes and its vascular complications.

Decreased plasma adiponectin concentration in major depression.

Adiponectin is the most abundant adipose-derived plasma protein. Recently adiponectin levels have been linked to most variables of metabolic syndrome and conventional risk factors for cardiovascular disease. However, its relation with major depression is yet unclear. We evaluated plasma adiponectin levels in 32 first-episode drug-naïve major depression (DSM-IV-TR) patients without conventional risk factors for cardiovascular disease and 32 matched healthy subjects. Major depression patients displayed lower adiponectin plasma levels compared to controls (P<0.01). Adiponectin significantly correlated with depression severity, as assessed by HAM-D (rho=0.83, P<0.001). This study shows decreased plasma adiponectin concentrations in major depression patients and relates adiponectinemia reduction to major depression severity.

Obesity, blood vessels and metabolic syndrome.

Obesity is rising worldwide at an alarming rate and so is the incidence of obesity‐related disorders, such as the metabolic syndrome, type 2 diabetes and cardiovascular diseases. The obesity‐dependent vascular damage appears to be derived from a variety of changes in the adipose tissue, leading to a chronic inflammatory state and dysregulation of adipocyte‐derived factors. This, in turn, impairs vascular homeostasis by determining an unbalance between the protective effect of the nitric oxide pathway and the unfavourable action of the endothelin‐1 system. In addition, hyperinsulinemia and insulin resistance contribute to vascular dysfunction because the opposing endothelium‐dependent vasodilating and vasoconstrictor effects of insulin are shifted towards a predominant vasoconstriction in patients with obesity. Importantly, emerging evidence suggests that the vascular dysfunction of obesity is not only limited to the endothelium but also involves the other layers of the vessel wall. In particular, obesity‐related changes in vascular smooth muscle seem to disrupt the physiological facilitatory action of insulin on the responsiveness to vasodilator stimuli, whereas the adventitia and the perivascular fat appear to be a source of proinflammatory and vasoactive factors that may contribute to endothelial and smooth muscle cell dysfunction and to the pathogenesis of vascular disease.

Metabolic and cardiovascular effects of ghrelin

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is synthesized as a preprohormone and then proteolytically processed to yield a 28-amino acid peptide. This peptide was originally reported to induce growth hormone release; large evidence, however, has indicated many other physiological activities of ghrelin, including regulation of food intake and energy balance, as well as of lipid and glucose metabolism. Ghrelin receptors have been detected in the hypothalamus and the pituitary, but also in the cardiovascular system, where ghrelin exerts beneficial hemodynamic activities. Ghrelin administration acutely improves endothelial dysfunction by increasing nitric oxide bioavailability and normalizes the altered balance between endothelin-1 and nitric oxide within the vasculature of patients with metabolic syndrome. Other cardiovascular effects of ghrelin include improvement of left ventricular contractility and cardiac output, as well as reduction of arterial pressure and systemic vascular resistance. In addition, antinflammatory and antiapoptotic actions of ghrelin have been reported both in vivo and in vitro. This review summarizes the most recent findings on the metabolic and cardiovascular effects of ghrelin through GH-dependent and -independent mechanisms and the possible role of ghrelin as a therapeutic molecule for treating cardiovascular diseases.