- Email: [email protected]
65 INFLUENCE OF VISCERAL FAT ON METABOLIC PROFILE AND EARLY VASCULAR DAMAGE IN DYSLIPIDEMIC PATIENTS
S50
Nutrition, Metabolism & Cardiovascular Diseases (2008) S35–S65
63 ANTIOXIDANT CAPACITY OF CIRCULATING ENDOTHELIAL PROGENITOR CELLS (EPCS) AND CIGARETTE SMOKING G. Mandraffino, A. Alibrandi, M. La Scala, C. Saitta, M.A. Sardo, S. Campo, F. Napoli, A. Saitta. Dipartimento di medicina interna e terapia medica, Policlinico universitario, Messina, Italy E-mail: giuseppemandraffi[email protected] Endothelial progenitor cells (EPCs) have been suggested to contribute to ongoing endothelial maintenance and repair. Decreased levels of circulating EPCs associated with increased formation of oxygen reactive species (ROS) have been reported in smoker subjects, however, the effects of cigarette smoking (CS) on EPCs remain to be clarified. In the present study we investigated the effects of CS on the levels of ROS and expression of manganese superoxide dismutase (MnSOD), catalase (CAT) and glutathione peroxidase type 1 (GPX-1)-mRNA in EPCs isolated from peripheral blood of 36 healthy cigarette smokers and 26 nonsmokers controls. Furthermore, we valuated the relationship between circulating EPCs and the plasma levels of CRP and endogenously NO-derived product nitrite/nitrate. In smokers the expression of MnSOD-mRNA was significantly higher (p < 0.001), whereas the expression of CAT and GPx-1-mRNA was lower (p < 0.001) than controls. The amount of ROS was more elevated in smokers (p < 0.001); by contrast the number of EPCs was reduced respect to controls (p < 0.001). A strong correlation between circulating EPCs and levels of CRP (rs = 0.939, p < 0.001), fibrinogen (rs = 0.632, p < 0.001) and nitrite/nitrate (rs= 0.880, p < 0.001) was observed. EPCs were also correlated with the amount of ROS (rs = 0.832, p < 0.001) and with the expression of MnSOD (rs = 0.859, p < 0.001), CAT (rs =0.926, p < 0.001) and GPx-1 (rs =0.927, p < 0.001) -mRNA. Moreover, significant correlations were observed between the levels of CRP, fibrinogen, nitrite/nitrate, and the expression of MnSOD (rs= 0.892, p < 0.001; rs= 0.688, p < 0.001; rs = 0.821, p < 0.001, respectively), CAT (rs =-0.907, p < 0.001; rs = 0.656, p < 0.001; rs= 0.844, p < 0.005, respectively), and GPx1-mRNA (rs = 0.863, p < 0.001; rs = 0.585, p < 0.001; rs= 0.863, p < 0.001). The correlation panel showed significant values between ROS and MnSODmRNA (rs= 0.827, p < 0.001), and between ROS and both CAT (rs = 0.795, p < 0.001), and GPx-1 (rs= 0.745, p < 0.001). Additionally, dependence analysis indicated that CS influenced positively the levels of CRP (p < 0.001), fibrinogen (p < 0.001) and ROS (p < 0.001) and negatively the levels of HDL-C (p < 0.05) and nitrite/nitrate (p < 0.001), according to the intensity of smoke exposure. Multivariate regression model for EPC, showed that circulating EPCs number depends on GPx-1 expression (p < 0.001), CRP (p < 0.001) and HDL-C (p < 0.005) plasma concentrations. Taken together our findings provide evidence for a new effect of smoke exposure involving the expression of EPCs antioxidant enzymes. Furthermore, they indicate that in smokers the inflammatory state and molecules may play a role in modulating EPCs levels and antioxidant enzymes. 64 THE ATHEROGENIC LIPOPROTEIN PHENOTYPE AND LDL SIZE AND SUBCLASSES IN WOMEN WITH GESTATIONAL DIABETES M. Rizzo1 , K. Berneis2 , A.E. Altinova3 , I. Pepe1 , L. Manna1 , G. Di Fede1 , M. Arslan3 , G.A. Spinas2 , G.B. Rini1 . 1 Department of Clinical Medicine and Emerging Diseases, University of Palermo, Italy, 2 Clinics for Endocrinology, Diabetes & Clinical Nutrition, University Hospital Zurich, Switzerland, 3 Department of Endocrinology and Metabolism, Gazi University, Faculty of Medicine, Ankara, Turkey E-mail: [email protected] Objective: Women with gestational diabetes are more likely to develop type-2 diabetes and cardiovascular diseases after pregnancy; yet, the exact type of their lipid alterations is still not fully clear. We investigated in women with gestational diabetes low-density lipoproteins (LDL) size and all seven subclasses, as well as the “atherogenic-lipoprotein-phenotype” (ALP, e.g. concomitant presence of elevated triglycerides, reduced HDL-cholesterol and increased small dense LDL). Design and Methods: In 27 women with gestational diabetes and 23 healthy pregnant women matched for age, weeks of gestation and body mass index (as controls) we measured plasma lipids and LDL size and subclasses by gradient gel electrophoresis between 24th and 28th weeks of gestation. Results: Although no significant differences were found in all plasma lipids, compared to controls women with gestational diabetes showed lower LDL size (p = 0.0007) due to reduced LDL-I (p = 0.0074) and increased LDL-IVA (p = 0.0146) and -IVB (p < 0.0001) subclasses. Correlation analysis revealed that fasting glucose, HOMA and glycated haemoglobin were inversely correlated with LDL-I and positively with LDL-IVA and -IVB (all p < 0.05). No prevalence of ALP was found in both groups due to high HDL-cholesterol levels, while elevated small, dense LDL were more prevalent in women with gestational diabetes than controls (33% vs 4%, p = 0.0107). Conclusions: Beyond plasma lipids, increased levels of small, dense LDL seem to be common in women with gestational diabetes. Yet, whether these findings affect the atherogenic process and the clinical endpoints in this category of subjects remains to be determined by future prospective studies.
65 INFLUENCE OF VISCERAL FAT ON METABOLIC PROFILE AND EARLY VASCULAR DAMAGE IN DYSLIPIDEMIC PATIENTS M.R. Mannarino, R. Helou, D. Covelli, G. Pucci, G. Schillaci, M. Pirro. Internal Medicine, Angiology and Arteriosclerosis Diseases. University of Perugia, Italy E-mail: [email protected] Aim: Visceral fat accumulation may induce metabolic disorders such as atherogenic dyslipidemia, hyperglycemia and hypertension and is associated with accelerated atherosclerosis and increased cardiovascular risk. Assessment of general fat and abdominal fat by traditional anthropometric measures, like BMI and waist circumference, often gives an approximate and sometimes unreliable estimate of visceral fat deposition. Conversely, ultrasonography has been suggested as a novel and reliable non-invasive technique to quantify visceral fat. Whether ultrasound-estimated visceral fat has an influence on metabolic profile and early markers of atherosclerosis, like arterial stiffness and endothelial dysfunction, above that of BMI and waist circumference is still unknown. Methods: Visceral fat area (VFA) was measured in seventy-five dyslipidemic patients by ultrasonography as follows: [VFA] = 9.008 + 1.191×[distance between the internal surface of the abdominal muscle and the splenic vein (mm)] + 0.978×[distance between the internal surface of the abdominal muscle and the posterior wall of the aorta at the umbilicus (mm)] + 3.644×[thickness of the fat layer of the posterior right renal wall (mm)]. All patients underwent measurement of aortic pulse wave velocity (aPWV) as an index of arterial stiffness and brachial flow-mediated vasodilation (FMV) as a measure of endothelial function. Results: VFA was positively correlated with plasma triglycerides (r = 0.502, p 0.001) and glucose (r = 0.459, p = 0.002) and negatively with HDL cholesterol levels (r = 0.434, p = 0.003). VFA above the median value (170 cm2 ) was associated with higher triglycerides and lower HDL in both patients with BMI 27.0 and BMI > 27.0. Significant correlations were found between visceral fat area and aPWV (r = 0.38; p = 0.004), and FMV (r = 0.370; p = 0.01). Similarly, BMI and waist circumferences were significant positive correlates of aPWV (r = 0.345, p = 0.009; r = 0.399, p = 0.002, respectively). Multivariate analysis including alternatively BMI, waist circumference and VFA as independent variables, along with significant covariates of aPWV (e.g. age, systolic blood pressure), showed that only visceral fat area was able to predict an increased aPWV (beta = 0.23, p = 0.04). Similarly, multivariate analysis including FMV as dependent variable and age, systolic blood pressure, LDL cholesterol, smoking status and either waist circumference or VFA as independent variables showed that VFA (beta = 0.39, p = 0.03) but not waist circumference was a significant predictor of FMV variability. Forcing both VFA and waist circumference in the multivariate model, confirmed VFA as a significant FMV negative covariate (beta = 0.70, p = 0.03). Conclusions: Among dyslipidemic patients increased visceral fat area estimated by ultrasound is a major determinant of multiple unfavourable metabolic abnormalities. Moreover, expansion of visceral fat depots contributes to arterial stiffness and reduced flow mediated vasodilation, over and above the deleterious influence of traditional measures of general and abdominal adiposity like BMI and waist circumference. Hence, a selective measurement of visceral fat may help to identify those dyslipidemic patients with a more deteriorated metabolic profile and a more compromised arterial function. 66 RESIDUAL PLATELET REACTIVITY ON DUAL ANTIPLATELET TREATMENT IS ASSOCIATED WITH ISCHEMIC EVENTS IN PATIENTS WITH ACUTE CORONARY SYNDROME: FROM A BIOLOGICAL TO A CLINICAL ENTITY R. Marcucci, A. Cordisco, A.M. Gori, B. Giusti, R. Paniccia, E. Antonucci, N. Maggini, G.F. Gensini, R. Abbate. Dipartimento di Area Critica Medico Chirurgica, Universit` a di Firenze, Italy E-mail: rossella.marcucci@unifi.it A dual antiplatelet regimen of aspirin plus clopidogrel is the standard treatment of patients with acute coronary syndromes (ACS) undergoing pecutaneous coronary revascularization (PCI) with stent implantation. A growing body of evidence, obtained in chronic cardiovascular patients as well as in ACS, is demonstrating that the biological entity of the residual platelet reactivity (RPR) despite dual antiplatelet treatment is associated with an increased risk of aderse cardiovascular events. This is the largest prospective study planned to demonstrate the clinical impact of RPR by different agonists (arachidonic acid AA, ADP and collagen) on the occurrence of major adverse coronary events in the setting of ACS. We have enrolled 1112 ACS patients (961 M/151 F; age: 69 (39 94) yrs) undergoing PCI on dual antiplatelet therapy. RPR has been defined as maximal platelet aggregation by 1 mM arachidonic acid ,10 mM ADP >70% and 2 mg/mL collagen 56% on venous blood samples obtained within 24 hrs from PCI. At a median follow-up of 8 months (1 48) MACE, including cardiac death, myocardial infarction (MI) and target lesion revascularization (TLR) for symptomatic restenosis, were recorded in 202 patients (18.1%): 24 (2.1%) cardiac deaths, 55 (4.9%) MI and 147 (13.2%) TLR. At univariate analysis, RPR by ADP was significantly associated with cardiac death [OR 4.09 (1.7 9.5), p < 0.001] and MI [OR 1.98 (1.01 3.8), p < 0.05] whereas RPR by AA and collagen were significantly associated with MI [OR 2.6 (1.5 4.6), p < 0.001 and OR 2.09 adjusted for (1.05 4.1), p < 0.05, respectively]. At multivariate analysis
Nutrition, Metabolism & Cardiovascular Diseases (2008) S35–S65
63 ANTIOXIDANT CAPACITY OF CIRCULATING ENDOTHELIAL PROGENITOR CELLS (EPCS) AND CIGARETTE SMOKING G. Mandraffino, A. Alibrandi, M. La Scala, C. Saitta, M.A. Sardo, S. Campo, F. Napoli, A. Saitta. Dipartimento di medicina interna e terapia medica, Policlinico universitario, Messina, Italy E-mail: giuseppemandraffi[email protected] Endothelial progenitor cells (EPCs) have been suggested to contribute to ongoing endothelial maintenance and repair. Decreased levels of circulating EPCs associated with increased formation of oxygen reactive species (ROS) have been reported in smoker subjects, however, the effects of cigarette smoking (CS) on EPCs remain to be clarified. In the present study we investigated the effects of CS on the levels of ROS and expression of manganese superoxide dismutase (MnSOD), catalase (CAT) and glutathione peroxidase type 1 (GPX-1)-mRNA in EPCs isolated from peripheral blood of 36 healthy cigarette smokers and 26 nonsmokers controls. Furthermore, we valuated the relationship between circulating EPCs and the plasma levels of CRP and endogenously NO-derived product nitrite/nitrate. In smokers the expression of MnSOD-mRNA was significantly higher (p < 0.001), whereas the expression of CAT and GPx-1-mRNA was lower (p < 0.001) than controls. The amount of ROS was more elevated in smokers (p < 0.001); by contrast the number of EPCs was reduced respect to controls (p < 0.001). A strong correlation between circulating EPCs and levels of CRP (rs = 0.939, p < 0.001), fibrinogen (rs = 0.632, p < 0.001) and nitrite/nitrate (rs= 0.880, p < 0.001) was observed. EPCs were also correlated with the amount of ROS (rs = 0.832, p < 0.001) and with the expression of MnSOD (rs = 0.859, p < 0.001), CAT (rs =0.926, p < 0.001) and GPx-1 (rs =0.927, p < 0.001) -mRNA. Moreover, significant correlations were observed between the levels of CRP, fibrinogen, nitrite/nitrate, and the expression of MnSOD (rs= 0.892, p < 0.001; rs= 0.688, p < 0.001; rs = 0.821, p < 0.001, respectively), CAT (rs =-0.907, p < 0.001; rs = 0.656, p < 0.001; rs= 0.844, p < 0.005, respectively), and GPx1-mRNA (rs = 0.863, p < 0.001; rs = 0.585, p < 0.001; rs= 0.863, p < 0.001). The correlation panel showed significant values between ROS and MnSODmRNA (rs= 0.827, p < 0.001), and between ROS and both CAT (rs = 0.795, p < 0.001), and GPx-1 (rs= 0.745, p < 0.001). Additionally, dependence analysis indicated that CS influenced positively the levels of CRP (p < 0.001), fibrinogen (p < 0.001) and ROS (p < 0.001) and negatively the levels of HDL-C (p < 0.05) and nitrite/nitrate (p < 0.001), according to the intensity of smoke exposure. Multivariate regression model for EPC, showed that circulating EPCs number depends on GPx-1 expression (p < 0.001), CRP (p < 0.001) and HDL-C (p < 0.005) plasma concentrations. Taken together our findings provide evidence for a new effect of smoke exposure involving the expression of EPCs antioxidant enzymes. Furthermore, they indicate that in smokers the inflammatory state and molecules may play a role in modulating EPCs levels and antioxidant enzymes. 64 THE ATHEROGENIC LIPOPROTEIN PHENOTYPE AND LDL SIZE AND SUBCLASSES IN WOMEN WITH GESTATIONAL DIABETES M. Rizzo1 , K. Berneis2 , A.E. Altinova3 , I. Pepe1 , L. Manna1 , G. Di Fede1 , M. Arslan3 , G.A. Spinas2 , G.B. Rini1 . 1 Department of Clinical Medicine and Emerging Diseases, University of Palermo, Italy, 2 Clinics for Endocrinology, Diabetes & Clinical Nutrition, University Hospital Zurich, Switzerland, 3 Department of Endocrinology and Metabolism, Gazi University, Faculty of Medicine, Ankara, Turkey E-mail: [email protected] Objective: Women with gestational diabetes are more likely to develop type-2 diabetes and cardiovascular diseases after pregnancy; yet, the exact type of their lipid alterations is still not fully clear. We investigated in women with gestational diabetes low-density lipoproteins (LDL) size and all seven subclasses, as well as the “atherogenic-lipoprotein-phenotype” (ALP, e.g. concomitant presence of elevated triglycerides, reduced HDL-cholesterol and increased small dense LDL). Design and Methods: In 27 women with gestational diabetes and 23 healthy pregnant women matched for age, weeks of gestation and body mass index (as controls) we measured plasma lipids and LDL size and subclasses by gradient gel electrophoresis between 24th and 28th weeks of gestation. Results: Although no significant differences were found in all plasma lipids, compared to controls women with gestational diabetes showed lower LDL size (p = 0.0007) due to reduced LDL-I (p = 0.0074) and increased LDL-IVA (p = 0.0146) and -IVB (p < 0.0001) subclasses. Correlation analysis revealed that fasting glucose, HOMA and glycated haemoglobin were inversely correlated with LDL-I and positively with LDL-IVA and -IVB (all p < 0.05). No prevalence of ALP was found in both groups due to high HDL-cholesterol levels, while elevated small, dense LDL were more prevalent in women with gestational diabetes than controls (33% vs 4%, p = 0.0107). Conclusions: Beyond plasma lipids, increased levels of small, dense LDL seem to be common in women with gestational diabetes. Yet, whether these findings affect the atherogenic process and the clinical endpoints in this category of subjects remains to be determined by future prospective studies.
65 INFLUENCE OF VISCERAL FAT ON METABOLIC PROFILE AND EARLY VASCULAR DAMAGE IN DYSLIPIDEMIC PATIENTS M.R. Mannarino, R. Helou, D. Covelli, G. Pucci, G. Schillaci, M. Pirro. Internal Medicine, Angiology and Arteriosclerosis Diseases. University of Perugia, Italy E-mail: [email protected] Aim: Visceral fat accumulation may induce metabolic disorders such as atherogenic dyslipidemia, hyperglycemia and hypertension and is associated with accelerated atherosclerosis and increased cardiovascular risk. Assessment of general fat and abdominal fat by traditional anthropometric measures, like BMI and waist circumference, often gives an approximate and sometimes unreliable estimate of visceral fat deposition. Conversely, ultrasonography has been suggested as a novel and reliable non-invasive technique to quantify visceral fat. Whether ultrasound-estimated visceral fat has an influence on metabolic profile and early markers of atherosclerosis, like arterial stiffness and endothelial dysfunction, above that of BMI and waist circumference is still unknown. Methods: Visceral fat area (VFA) was measured in seventy-five dyslipidemic patients by ultrasonography as follows: [VFA] = 9.008 + 1.191×[distance between the internal surface of the abdominal muscle and the splenic vein (mm)] + 0.978×[distance between the internal surface of the abdominal muscle and the posterior wall of the aorta at the umbilicus (mm)] + 3.644×[thickness of the fat layer of the posterior right renal wall (mm)]. All patients underwent measurement of aortic pulse wave velocity (aPWV) as an index of arterial stiffness and brachial flow-mediated vasodilation (FMV) as a measure of endothelial function. Results: VFA was positively correlated with plasma triglycerides (r = 0.502, p 0.001) and glucose (r = 0.459, p = 0.002) and negatively with HDL cholesterol levels (r = 0.434, p = 0.003). VFA above the median value (170 cm2 ) was associated with higher triglycerides and lower HDL in both patients with BMI 27.0 and BMI > 27.0. Significant correlations were found between visceral fat area and aPWV (r = 0.38; p = 0.004), and FMV (r = 0.370; p = 0.01). Similarly, BMI and waist circumferences were significant positive correlates of aPWV (r = 0.345, p = 0.009; r = 0.399, p = 0.002, respectively). Multivariate analysis including alternatively BMI, waist circumference and VFA as independent variables, along with significant covariates of aPWV (e.g. age, systolic blood pressure), showed that only visceral fat area was able to predict an increased aPWV (beta = 0.23, p = 0.04). Similarly, multivariate analysis including FMV as dependent variable and age, systolic blood pressure, LDL cholesterol, smoking status and either waist circumference or VFA as independent variables showed that VFA (beta = 0.39, p = 0.03) but not waist circumference was a significant predictor of FMV variability. Forcing both VFA and waist circumference in the multivariate model, confirmed VFA as a significant FMV negative covariate (beta = 0.70, p = 0.03). Conclusions: Among dyslipidemic patients increased visceral fat area estimated by ultrasound is a major determinant of multiple unfavourable metabolic abnormalities. Moreover, expansion of visceral fat depots contributes to arterial stiffness and reduced flow mediated vasodilation, over and above the deleterious influence of traditional measures of general and abdominal adiposity like BMI and waist circumference. Hence, a selective measurement of visceral fat may help to identify those dyslipidemic patients with a more deteriorated metabolic profile and a more compromised arterial function. 66 RESIDUAL PLATELET REACTIVITY ON DUAL ANTIPLATELET TREATMENT IS ASSOCIATED WITH ISCHEMIC EVENTS IN PATIENTS WITH ACUTE CORONARY SYNDROME: FROM A BIOLOGICAL TO A CLINICAL ENTITY R. Marcucci, A. Cordisco, A.M. Gori, B. Giusti, R. Paniccia, E. Antonucci, N. Maggini, G.F. Gensini, R. Abbate. Dipartimento di Area Critica Medico Chirurgica, Universit` a di Firenze, Italy E-mail: rossella.marcucci@unifi.it A dual antiplatelet regimen of aspirin plus clopidogrel is the standard treatment of patients with acute coronary syndromes (ACS) undergoing pecutaneous coronary revascularization (PCI) with stent implantation. A growing body of evidence, obtained in chronic cardiovascular patients as well as in ACS, is demonstrating that the biological entity of the residual platelet reactivity (RPR) despite dual antiplatelet treatment is associated with an increased risk of aderse cardiovascular events. This is the largest prospective study planned to demonstrate the clinical impact of RPR by different agonists (arachidonic acid AA, ADP and collagen) on the occurrence of major adverse coronary events in the setting of ACS. We have enrolled 1112 ACS patients (961 M/151 F; age: 69 (39 94) yrs) undergoing PCI on dual antiplatelet therapy. RPR has been defined as maximal platelet aggregation by 1 mM arachidonic acid ,10 mM ADP >70% and 2 mg/mL collagen 56% on venous blood samples obtained within 24 hrs from PCI. At a median follow-up of 8 months (1 48) MACE, including cardiac death, myocardial infarction (MI) and target lesion revascularization (TLR) for symptomatic restenosis, were recorded in 202 patients (18.1%): 24 (2.1%) cardiac deaths, 55 (4.9%) MI and 147 (13.2%) TLR. At univariate analysis, RPR by ADP was significantly associated with cardiac death [OR 4.09 (1.7 9.5), p < 0.001] and MI [OR 1.98 (1.01 3.8), p < 0.05] whereas RPR by AA and collagen were significantly associated with MI [OR 2.6 (1.5 4.6), p < 0.001 and OR 2.09 adjusted for (1.05 4.1), p < 0.05, respectively]. At multivariate analysis