Valentina Sedda

Plasma Total Cysteine and Cardiovascular Risk Burden: Action and Interaction

We hypothesized that redox analysis could provide sensitive markers of the oxidative pathway associated to the presence of an increasing number of cardiovascular risk factors (RFs), independently of type. We classified 304 subjects without cardiovascular disease into 4 groups according to the total number of RFs (smoking, hypertension, hypercholesterolaemia, hyperhomocysteinaemia, diabetes, obesity, and their combination). Oxidative stress was evaluated by measuring plasma total and reduced homocysteine, cysteine (Cys), glutathione, cysteinylglycine, blood reduced glutathione, and malondialdehyde. Twenty-seven percent of subjects were in group 0 RF, 26% in 1 RF, 31% in 2 RF, and 16% in ≥3 RF. By multivariable ordinal regression analysis, plasma total Cys was associated to a higher number of RF (OR = 1.068; 95% CI = 1.027–1.110, P = 0.002). Total RF burden is associated with increased total Cys levels. These findings support a prooxidant effect of Cys in conjunction with RF burden, and shed light on the pathophysiologic role of redox state unbalance in preclinical atherosclerosis.

Plasma glutathione levels are independently associated with γ-glutamyltransferase activity in subjects with cardiovascular risk factors

To investigate whether GGT (γ-glutamyltransferase) is associated to specific redox patterns. GGT, total and reduced aminothiols and malondialdehyde, were measured in 150 subjects (83 males, 48 (39–56) years), with none, one or more risk factors. By univariable analysis GGT was positively associated with age (p =0.001), male gender (p <0.001), risk factor number (p <0.001), ACE-inhibitors (p =0.008), anti-platelet agents (p =0.029), atherothrombotic events (p =0.001), glucose (p =0.013), malondialdehyde (p =0.029), plasma total cysteine (p =0.046) and inversely associated with plasma total glutathione (p =0.001). By multivariable analysis only male gender (p <0.001), risk factor number (p <0.001) and glutathione (p <0.001) were independently associated with GGT activity. These findings suggest that an ongoing redox imbalance, in terms of decreased plasma glutathione, is associated with raised GGT activity in subjects with a greater risk factor burden.

Effect of homocysteine lowering by 5-methyltetrahydrofolate on redox status in hyperhomocysteinemia.

The endothelial dysfunction induced by hyperhomocysteinemia can be reversed by 5-methyltetrahydrofolate (5-MTHF) via homocysteine (Hcy) lowering. An additive antioxidant action of 5-MTHF has been suggested to ameliorate endothelial dysfunction through increased nitric oxide production and superoxide radical scavenging, independent of Hcy lowering. The aim of the study was to assess whether 5-MTHF affects the redox state in hyperhomocysteinemia. We examined the effect of 3 months of oral 5-MTHF treatment (15 mg/day) on the redox pattern in 48 hyperhomocysteinemic subjects compared to 24 untreated hyperhomocysteinemic subjects. By analysis of variance with repeated measures in the 72 subjects, 5-MTHF markedly decreased plasma total Hcy (p-tHcy; P=0.0001) and blood-total glutathione (GSH; b-tGSH; P=0.002). By multivariate linear regression in the treated subjects, p-tHcy changes from baseline to 3 months (adjusted by baseline p-tHcy levels) correlated only with changes in reduced cysteinylglycine (P=0.001). The effects of treatment on Hcy lowering and GSH metabolism were greater in medium than in moderate hyperhomocysteinemia. In conclusion, high-dose 5-MTHF treatment for 3 months ensures marked Hcy lowering to normal values even in subjects with high Hcy levels, and should be the treatment of choice in medium hyperhomocysteinemia. Furthermore, 5-MTHF shows a favorable interaction with GSH metabolism.

Methionine challenge paradoxically induces a greater activation of the antioxidant defence in subjects with hyper- vs. normohomocysteinemia

To determine whether hyperhomocysteinemia induced post-methionine loading (PML) is associated with different response in the aminothiol redox state and oxidative stress vs. normohomocysteinemia, we assessed PML plasma thiols, vitamins, free malondialdehyde (MDA), and blood reduced glutathione (GSH) in 120 consecutive subjects (50 [35–56] years, 83 males), divided into two groups according to PML plasma total Hcy < 35 μM (Group 1, n = 65) or ≥ 35 μM (Group 2, n = 55). In the group as a whole, plasma reduced cysteine and cysteinylglycine, blood reduced GSH (all p for time = 0.0001) and plasma total GSH (p for time = 0.001) increased from baseline to PML. MDA values were unchanged. Group 1 and 2 differed in blood reduced GSH (p for group = 0.004, higher in Group 2), and MDA levels (p for group = 0.024, lower in Group 2). The oxidative stress induced by methionine challenge seems to be opposed by scavenger molecules activation, namely GSH, and lipid peroxidation does not increase. This mechanism paradoxically appears to be more efficient in hyperhomocysteinemic subjects.

Effects of Sapropterin on Endothelium-Dependent Vasodilation in Patients With CADASIL A Randomized Controlled Trial

Background and Purpose— Cerebral autosomal–dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare autosomal dominant disorder caused by NOTCH3 mutations, is characterized by vascular smooth muscle and endothelial cells abnormalities, altered vasoreactivity, and recurrent lacunar infarcts. Vasomotor function may represent a key factor for disease progression. Tetrahydrobiopterin, essential cofactor for nitric oxide synthesis in endothelial cells, ameliorates endothelial function. We assessed whether supplementation with sapropterin, a synthetic tetrahydrobiopterin analog, improves endothelium-dependent vasodilation in CADASIL patients. Methods— In a 24-month, multicenter randomized, double-blind, placebo-controlled trial, CADASIL patients aged 30 to 65 years were randomly assigned to receive placebo or sapropterin 200 to 400 mg BID. The primary end point was change in the reactive hyperemia index by peripheral arterial tonometry at 24 months. We also assessed the safety and tolerability of sapropterin. Analysis was done by intention-to-treat. Results— The intention-to-treat population included 61 patients. We found no significant difference between sapropterin (n=32) and placebo (n=29) in the primary end point (mean difference in reactive hyperemia index by peripheral arterial tonometry changes 0.19 [95% confidence interval, −0.18, 0.56]). Reactive hyperemia index by peripheral arterial tonometry increased after 24 months in 37% of patients on sapropterin and in 28% on placebo; however, after adjustment for age, sex, and clinical characteristics, improvement was not associated with treatment arm. The proportion of patients with adverse events was similar on sapropterin and on placebo (50% versus 48.3%); serious adverse events occurred in 6.3% versus 13.8%, respectively. Conclusions— Sapropterin was safe and well-tolerated at the average dose of 5 mg/kg/day, but did not affect endothelium-dependent vasodilation in CADASIL patients. Clinical Trial Registration— URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2007-004370-55.

PO20-618 EFFECTIVENESS OF A DIETETIC SUPPLEMENTATION IN IMPROVING LIPID PANEL IN DYSLIPIDEMIC SUBJECTS

total (b)cysteine (p = 0.001) and VitE/cholesterol (p = 0.0001). At T2 lower values of oxidant total (p)cysteine (T2 vs all p < 0.05), HDL/cholesterol (T2 vs all p < 0.0001) and LDL (T2 vs all p < 0.01) were found; conversely, antioxidants total and reduced (p)glutathione (T2 vs T0 p = 0.005 and T2 vs all, p < 0.05, respectively), VitE/cholesterol (T2 vs all, p < 0.0001) and HDL (T2 vs all, p < 0.0001) increased. No significant changes were found for other parameters. Conclusions: Four weeks of FerroSuper improved the redox pattern as demonstrated by higher content of antioxidants bcysteine and VitE/ch. Additionally, the sinergic action of the composition, positively affects homocysteine levels. Prolonged periods greatly improved the redox state; indeed, a beneficial redistribution of cholesterol among lipoprotein fractions, with a significant increase in HDL and a reduction in LDL was found.