Antonio Liguori

The beneficial effects of antioxidant supplementation in enteral feeding in critically ill patients: A prospective, randomized, double-blind, placebo-controlled trial

We investigated whether intervention with antioxidant vitamins C and E in enteral feeding influenced oxidative stress and clinical outcome in critically ill patients. Two-hundred-sixteen patients expected to require at least 10 days of enteral feeding completed the study. One-hundred-five patients received enteral feeding supplemented with antioxidants, and 111 control patients received an isocaloric formula. Plasma lipoper-oxidation (by thiobarbituric acid reactive substances [TBARS] and prostaglandin F2&agr; isoprostane levels), low-density lipoprotein (LDL) oxidizability, and LDL tocopherol content were determined at baseline and at the end of the 10-day period. The clinical 28-day outcome was also assessed. Plasma TBARS and isoprostanes were 5.33 ± 1.26 nM/mL and 312 ± 68 pg/mL, respectively, before treatment and 2.42 ± 0.61 nM/mL and 198 ± 42 pg/mL after intervention (P < 0.01 for both comparisons). Antioxidants improved LDL resistance to oxidative stress by approximately 30% (the lag time before treatment was 87 ±23 min and was 118 ±20 min after treatment; P <0.04). There was a significantly reduced 28-day mortality after antioxidant intervention (45.7% in the antioxidant group and 67.5% in the regular-feeding group; P < 0.05). Isoprostanes may provide a sensitive biochemical marker for dose selection in studies involving antioxidants.

Effect of gestational hypercholesterolaemia on omental vasoreactivity, placental enzyme activity and transplacental passage of normal and oxidised fatty acids

Objective  Maternal hypercholesterolaemia during pregnancy increases lipid peroxidation in mothers and fetuses and programs increased susceptibility to atherosclerosis later in life. The objective of this study was to elucidate the role of the placenta in mediating oxidative stress from mother to offspring.

Long-term treatment with sulfhydryl angiotensin-converting enzyme inhibition reduces carotid intima-media thickening and improves the nitric oxide/oxidative stress pathways in newly diagnosed patients with mild to moderate primary hypertension

BACKGROUND Sulfhydryl angiotensin-converting enzyme (ACE) inhibitors exert antiatherosclerotic effects in preclinical models and antioxidant effects in patients. However, whether ACE inhibitors have any clinically significant antiatherogenic effects remains still debated. OBJECTIVES In mildly hypertensive patients, we evaluated the effect of the sulfhydryl ACE inhibitor zofenopril in comparison with the carboxylic ACE inhibitor enalapril on carotid atherosclerosis (intima-media thickness [IMT] and vascular lumen diameter) and systemic oxidative stress (nitrite/nitrate, asymmetrical dimethyl-l-arginine, and isoprostanes). METHODS In 2001, we started a small prospective randomized clinical trial on 48 newly diagnosed mildly hypertensive patients with no additional risk factors for atherosclerosis (eg, hyperlipidemia, smoke habit, familiar history of atherosclerosis-related diseases or diabetes). Patients were randomly assigned either to the enalapril (20 mg/d, n = 24) or the zofenopril group (30 mg/d, n = 24); the planned duration of the trial was 5 years. Carotid IMT and vascular lumen diameter were determined by ultrasonography for all patients at baseline and at 1, 3, and 5 years. Furthermore, nitrite/nitrate, asymmetrical dimethyl-l-arginine, and isoprostane levels were measured. RESULTS In our conditions, IMT of the right and left common carotid arteries was similar at baseline in both groups (P = NS). Intima-media thickness measurements until 5 years revealed a significant reduction in the zofenopril group but not in the enalapril group (P < .05 vs enalapril-treated group). This effect was coupled with a favorable nitric oxide/oxidative stress profile in the zofenopril group. CONCLUSIONS Long-term treatment with the sulfhydryl ACE inhibitor zofenopril besides its blood pressure-lowering effects may slow the progression of IMT of the carotid artery in newly diagnosed mildly hypertensive patients.

Functional impairment of hematopoietic progenitor cells in patients with coronary heart disease

The circulating form of endothelial progenitors cells (EPCs) are derivated from bone marrow (BM)‐derived hematopoietic stem cells (HSCs). Enhanced mobilization of EPCs was shown to be linked to cardiac diseases. This study investigated whether reduced EPC levels in advanced coronary heart disease (CHD) are secondary to a functional exhaustion of HSCs in the BM or to reduced mobilization. Number and functional properties of EPCs were assessed in 15 healthy controls, and 40 patients with CHD. The colony‐forming unit (CFU) capacity of BM‐derived mononuclear cells and the CD34+ HSC number were examined in four healthy volunteers, and 15 CHD patients. EPC number was reduced in CHD patients (P < 0.01 vs. controls). Moreover, the migratory capacity was significantly impaired in EPCs of CHD patients (P < 0.05 vs. controls). On multivariate analysis, CHD was an independent predictor of functional EPC impairment. CFUs were reduced in CHD patients (59.6 ± 21.2 vs. 75.4 ± 25.8 in controls, P < 0.05). CHD was also predictor of impaired CFU capacity. In this small clinical study, CHD is associated with selective impairment of HSC function in the BM and in the peripheral blood, which may contribute to impairment of cardiac function.

Influence of Maternal Dysmetabolic Conditions During Pregnancy on Cardiovascular Disease

Pathogenic factors associated with maternal hypercholesterolemia, obesity, and diabetic conditions during pregnancy influence fetal development and predispose offspring to cardiovascular disease. Animal models have established cause–effect relationships consistent with epidemiological findings in humans and have demonstrated, in principle, that interventions before or during pregnancy can reduce or prevent pathogenic in utero programming. However, little is known about the mechanisms by which maternal dysmetabolic conditions enhance disease susceptibility in offspring. Identification of these mechanisms is rendered more difficult by the fact that programming effects in offspring may be latent and may require conventional risk factors and inherited genetic co-factors to become clinically manifest. Given the increasing prevalence of maternal risk factors, which is expected to lead to a wave of cardiovascular disease in the coming decades, and the length of prospective studies on developmental programming in humans, greater-than-usual emphasis on experimental models and translational studies is necessary.

Maternal C-reactive protein and developmental programming of atherosclerosis

OBJECTIVE Maternal hypercholesterolemia during pregnancy enhances the susceptibility to atherosclerosis in their offspring by oxidation-dependent mechanisms. The present study investigated whether maternal C-reactive protein (CRP) level, which is an indicator of inflammation and cardiovascular risk, or smoking, which enhances oxidative stress, predict the in utero programming of atherosclerosis. STUDY DESIGN Subsets of patients from the Fate of Early Lesions in Childhood study (156 normocholesterolemic children) were examined at autopsy, classified by maternal cholesterol levels during pregnancy. Maternal CRP level was correlated with maternal cholesterol and aortic atherosclerosis of children. RESULTS CRP level was elevated in hypercholesterolemic mothers and showed significant correlation with atherogenesis in children in univariate and multivariate analysis. However, many hypercholesterolemic mothers did not have elevated CRP levels. Smoking only correlated in univariate analysis. CONCLUSION CRP level during pregnancy is a predictor of increased atherogenesis in children of hypercholesterolemic mothers, albeit a weaker one than maternal cholesterol. In the presence of hypercholesterolemia, maternal smoking does not further enhance atherogenic programming.

Effects of vitamin E and HMG-CoA reductase inhibition on cholesteryl ester transfer protein and lecithin-cholesterol acyltransferase in hypercholesterolemia.

BackgroundThe enzyme lecithin-cholesterol acyl transferase (LCAT) esterifies free cholesterol on highdensity lipoprotein (HDL) and the cholesteryl ester transfer protein (CETP) transfers cholesteryl esters to very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL). Using statins, contradictory findings have been made regarding CETP activity in normolipidemic individuals and in those with familial dysbetatlipoproteinemia. In contrast, LCAT activity appears to be unaffected by simvastatin. Antioxidants have also been proposed for use in anti-atherosclerotic treatment, because the oxidation of LDL may have a key role in the pathophysiology of atherogenesis. ObjectiveTo investigate, in hypercholesterolemic patients, whether a combination of pravastatin with the antioxidant, vitamin E, has greater effects on the activity of CETP and of LCAT than does pravastatin alone. MethodsThis placebo-diet-controlled multicenter trial included 220 hypercholesterolemic patients who were assigned randomly to groups to receive: diet and 20–40 mg pravastatin (n = 52), diet and pravastatin in combination with 100 mg/day vitamin E (100 IU) as DL-α-tocopherol (n = 56), diet and α-tocopherol (n = 60), or diet associated with placebo (n = 52). Plasma LCAT activity was determined using excess exogenous substrate, containing [3H]cholesterol. Plasma CETP activity was measured in the supernatant fraction after precipitation of endogenous apo B-containing lipoproteins with phosphotungstate-Mg2+. The exchange of cholesteryl esters between [14C]cholesteryl esterlabeled LDL and unlabeled HDL was measured during a 16-h incubation, while LCAT was inhibited. ResultsThe addition of pravastatin to the diet induced a significant decrease in plasma CETP activity (P< 0.05); this effect was less evident in the group cotreated with vitamin E. For the first time, it was shown that CETP concentrations increased significantly after vitamin E alone (P< 0.05). No significant differences in the plasma activity of LCAT were observed among the groups. ConclusionsPravastatin reduced CETP activity, but not that of LCAT. Addition of vitamin E prevented the decrease in CETP activity and had no effect on LCAT activity. The mechanism responsible for these effects is unknown, but could involve the prevention of radical-induced damage to CETP by vitamin E. Coronary Artery Dis 9:257–264

“Warm-Up” Phenomenon Detected by Electrocardiographic Ambulatory Monitoring in Adult and Older Patients

OBJECTIVE: Inducing tolerance to myocardial ischemia by repeated brief episodes of ischemia has been called “ischemic preconditioning.” “Warm‐up” phenomenon refers to patients with coronary heart disease improving performance after a first exertion and may represent a clinical counterpart to ischemic preconditioning. The goal of this study was to assess whether the severity of myocardial ischemia would be attenuated by two repeated walking‐induced ischemic episodes in adult and older patients.

Severe Type 2 Diabetes Induces Reversible Modifications of Endothelial Progenitor Cells Which are Ameliorate by Glycemic Control

Background Circulating endothelial progenitors cells (EPCs) play a critical role in neovascularization and endothelial repair. There is a growing evidence that hyperglycemia related to Diabetes Mellitus (DM) decreases EPC number and function so promoting vascular complications. Aim of the Study This study investigated whether an intensive glycemic control regimen in Type 2 DM can increase the number of EPCs and restores their function. Methods Sixty-two patients with Type 2 DM were studied. Patients were tested at baseline and after 3 months of an intensive regimen of glycemic control. The Type 2 DM group was compared to control group of subjects without diabetes. Patients with Type 2 DM (mean age 58.2±5.4 years, 25.6% women, disease duration of 15.4±6.3 years) had a baseline HgA1c of 8.7±0.5% and lower EPC levels (CD34+/KDR+) in comparison to healthy controls (p<0.01). Results The intensive glycemic control regimen (HgA1c decreased to 6.2±0.3%) was coupled with a significant increase of EPC levels (mean of 18%, p<0.04 vs. baseline) and number of EPCs CFUs (p<0.05 vs. baseline). Conclusion This study confirms that number and bioactivity of EPCs are reduced in patients with Type 2 DM and, most importantly, that the intensive glycemic control in Type 2 DM promotes EPC improvement both in their number and in bioactivity.

Histological findings and evidence of lipid conjugated dienes and malonyldialdehyde in human fetal aortas

Recent evidence strongly suggests that peroxidative modification of lipids may play a significant role in atherogenesis. In our present research, we investigated if the oxidative stress mediated by oxygen free radicals was a pathophysiologic condition that occurred in the early stages of human development. Thus the aim of this research was to examine lipid peroxidation in human fetal aortas. Human fetal aortas and proximal iliac arteries (n= 8) were obtained from fetuses aged 7 ± 2 months, immediately after autopsy. Lipids from the initial fatty streak lesions (LFS) and the vessels uninvolved (LUV) were extracted by the chloroform/methanol method. Lipid peroxidation levels were measured by two different methods: determination of lipid conjugate dienes (the spectrum trend was recorded from 320 to 200 nm with a spectrophotometer) and malonyldialdehyde (MDA) content (TBA method). We observed that lipid conjugated dienes were present in LFS, but not in LUV, with a characteristic absorption peak at 233 nm. In addition, MDA levels were significantly higher when the LFS = 3.85 ± 0.91 nmol than when the LUV = O.41 ± 0.12 nmol (p<0.001 versus LUV). The presence of lipid peroxidation in our samples could be mediated by free radical production in the first stages of human development. Thus these data suggest that LFS peroxidation mediated by free radicals occurs in the vascular circulation in the early stages of human development. This could influence the progression of vascular damage and atherosclerotic disease.