Biomedical subjects

Andrea Mezzetti

Publications and source records attributed to Andrea Mezzetti.

At least 37 records · Page 2Linked to original sources

PubMed2004

Increased expression of transforming growth factor-beta1 as a stabilizing factor in human atherosclerotic plaques.

BACKGROUND AND PURPOSE: Transforming growth factor-beta (TGF-beta) is a growth factor/cytokine involved in vascular remodeling and atherogenesis. Recent studies in apolipoprotein E-deficient mice have demonstrated a pivotal role of TGF-beta in the maintenance of the balance between inflammation and fibrosis in atherosclerotic plaques. Furthermore, inhibition of TGF-beta signaling has been shown to accelerate plaque formation and its progression toward an unstable phenotype in mice. However, if this mechanism is operative also in humans is still unknown. The aim of this study was to characterize the expression of TGF-beta1 in human carotid plaque and to correlate it with the extent of inflammatory infiltration and collagen content with the clinical signs of plaque instability. METHODS: Plaques were obtained from patients undergoing carotid endoarterectomy and divided into symptomatic and asymptomatic according to clinical evidence of recent transient ischemic attack or stroke. Plaques were analyzed for TGF-beta1 expression by Immunocytochemistry, Western, and Northern blotting analysis. Immunocytochemistry was used to identify CD68+ macrophages, CD3 T lymphocytes, HLA-DR+ cells, and alpha-smooth muscle cells. Procollagen and interstitial collagen content were analyzed by immunohistochemistry and Sirius Red staining, respectively. RESULTS: Plaque TGF-beta1 mRNA was increased up to 3-fold in asymptomatic as compared with symptomatic plaques. Plaques from asymptomatic group had fewer (P<0.0001) macrophages and T lymphocytes compared with symptomatic plaques. TGF-beta1 gene was transcriptionally active as demonstrated by increased (P<0.0001) TGF-beta1 protein expression in asymptomatic plaques. Immunohistochemistry showed that TGF-beta was mainly expressed in plaque shoulder and was associated with a comparable increase (P<0.0001) in plaque procollagen and collagen content. CONCLUSIONS: In conclusion, this study demonstrates the higher expression of TGF-beta1 in human asymptomatic lesions and provides evidence that TGF-beta1 may play an important role in the process of plaque stabilization.

Aged↗

PubMed2004

Balance between PGD synthase and PGE synthase is a major determinant of atherosclerotic plaque instability in humans.

OBJECTIVE: Inducible cyclooxygenase (COX-2) catalyzes the first step in prostanoid biosynthesis and is considered a proinflammatory enzyme. COX-2 and type 1 inducible PGE synthase (mPGES-1) have a role in metalloproteinase (MMP) release leading to plaque rupture. In contrast, lipocalin-type PGD synthase (L-PGDS) has been shown to exert antiinflammatory actions. Thus, in this study we investigated whether a shift from a PGDS-oriented to a PGES-oriented profile in arachidonate metabolism leads to inflammatory activation in rupture-prone plaque macrophages. METHODS AND RESULTS: Atherosclerotic plaques were obtained from 60 patients who underwent carotid endarterectomy, symptomatic (n=30) and asymptomatic (n=30) according to evidence of recent transient ischemic attack or stroke. Plaques were analyzed for COX-2, mPGES-1, L-PGDS, PPARgamma, IkappaBalpha, NF-kappaB, and MMP-9 by immunocytochemistry, Western blot, reverse-transcriptase polymerase chain reaction, enzyme immunoassay, and zymography. Prostaglandin E2 (PGE2) pathway was significantly prevalent in symptomatic plaques, whereas PGD2 pathway was overexpressed in asymptomatic ones, associated with NF-kappaB inactivation and MMP-9 suppression. In vitro COX-2 inhibition in monocytes was associated with reduced MMP-9 release only when PGD2 pathway overcame PGE2 pathway. CONCLUSIONS: These results suggest that COX-2 may have proinflammatory and antiinflammatory properties as a function of expression of downstream PGH2 isomerases, and that the switch from L-PGDS to mPGES-1 in plaque macrophages is associated with cerebral ischemic syndromes, possibly through MMP-induced plaque rupture.

Arachidonic Acid↗

PubMed2004

A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke.

CONTEXT: Myocardial infarction (MI) and ischemic stroke are thought to be caused by matrix digestion by metalloproteinases (MMPs) leading to rupture of atherosclerotic plaques. Production of macrophage MMP-2 and MMP-9 is induced by cyclooxygenase 2 (COX-2) and prostaglandin E(2) synthesis. Although COX-2 expression may be genetically determined, the relation between COX-2 polymorphisms and the risk of MI and stroke is unclear. OBJECTIVE: To investigate the relationship between the -765G-->C polymorphism of the COX-2 gene and clinically evident plaque rupture. DESIGN, SETTING, AND PARTICIPANTS: Prospective, matched case-control study conducted between March 2002 and October 2003 among 864 patients with first MI or atherothrombotic ischemic stroke and 864 hospitalized controls. The groups were matched for age, sex, body mass index, smoking, hypertension, hypercholesterolemia, and diabetes. The -765G-->C variant of the COX-2 gene was genotyped by restriction endonuclease digestion of polymerase chain reaction products. MAIN OUTCOME MEASURES: Presence of the -765G-->C polymorphism of the COX-2 gene; COX-2, MMP-2, and MMP-9 expression and activity in plaques and in peripheral monocytes; urinary 6-keto PGF1alpha (marker of endothelial prostacyclin); and endothelium-dependent and -independent forearm blood flow vasodilation. RESULTS: The prevalence of -765GC was 2.41 times higher among controls than among cases (43.3% vs 17.9%; P<.001). The prevalence of -765CC homozygosity was 5.81 times higher (6.4% vs 1.1%; P =.04). Among participants carrying the -765GC and -765CC genotypes, the prevalence ratios for MI or stroke were 0.48 (95% CI, 0.36-0.68) and 0.33 (95% CI, 0.24-0.55), respectively. Expression of COX-2 and MMPs was significantly lower in atherosclerotic plaques from participants carrying the -765C allele, while the -765G-->C polymorphism did not affect endothelial prostacyclin biosynthesis or endothelium-dependent vasodilation in vivo. In subgroup analyses (n = 224 cases), serum high-sensitivity C-reactive protein was significantly lower in patients carrying the -765C allele (mean [SD], 0.78 [0.1] vs 2.56 [0.4] mg/L; P =.04). CONCLUSIONS: We found that the -765G-->C polymorphism of the COX-2 gene is associated with a decreased risk of MI and stroke. Detection of this genotype may be useful for predicting genetic risk of MI and stroke.

Arteriosclerosis↗

PubMed2004

Blockade of the angiotensin II type 1 receptor stabilizes atherosclerotic plaques in humans by inhibiting prostaglandin E2-dependent matrix metalloproteinase activity.

BACKGROUND: Clinical trials have demonstrated that agents that inhibit the angiotensin II pathway confer benefit beyond the reduction of blood pressure alone. However, the molecular mechanism underlying this effect has yet to be investigated. Recently, we have demonstrated enhanced expression of inducible cyclooxygenase (COX) and prostaglandin (PG)E2-dependent synthase (COX-2/mPGES-1) in human symptomatic plaques and provided evidence that it is associated with metalloproteinase (MMP)-induced plaque rupture. Thus, the aim of this study was to characterize the effect of the angiotensin II type 1 (AT1) receptor antagonist irbesartan on the inflammatory infiltration and expression of COX-2/mPGES-1 and MMPs in human carotid plaques. METHODS AND RESULTS: Seventy patients with symptomatic carotid artery stenosis were randomized to irbesartan (300 mg/d) or chlorthalidone (50 mg/d) for 4 months before endarterectomy. Plaques were subjected to analysis of COX-1, COX-2, mPGES-1, MMP-2, and MMP-9, angiotensin II, AT(1), AT2, and collagen content by immunocytochemistry, Western blot, and reverse-transcriptase polymerase chain reaction, whereas zymography was used to detect MMP activity. Immunohistochemistry was also used to identify CD68+ macrophages, CD3+ T lymphocytes, smooth muscle cells (SMCs), and HLA-DR+ inflammatory cells. Plaques from the irbesartan group had fewer (P<0.0001) macrophages, T lymphocytes, and HLA-DR+ cells; less (P<0.0001) immunoreactivity for COX-2/mPGES-1 and MMPs; reduced (P<0.0001) gelatinolytic activity; and increased (P<0.0001) collagen content. It is worth noting that COX-2/mPGES-1 inhibition was observed after incubation in vitro with irbesartan but not with the selective AT2 blockade PD123,319. CONCLUSIONS: This study demonstrates that irbesartan decreases inflammation and inhibits COX-2/mPGES-1 expression in plaque macrophages, and this effect may in turn contribute to plaque stabilization by inhibition of MMP-induced plaque rupture.

Aged↗

PubMed2004

Cardiovascular and renal events in uncomplicated mild hypertensive patients with sustained and white coat hypertension.

BACKGROUND: The prognostic value of white coat hypertension (WCH) in uncomplicated patients with mild hypertension is not yet completely clear. We investigated cardiovascular outcomes in patients with mild hypertension and without left ventricular hypertrophy, diabetes mellitus, and associated cardiovascular and renal disease, with sustained hypertension (SH) and WCH. METHODS: The occurrence of fatal and nonfatal cardiovascular events was evaluated in 1038 patients with mild hypertension and 241 normotensive subjects. The presence of WCH was defined as clinic hypertension and daytime blood pressure <135/85 mm Hg. RESULTS: During follow-up (4.5 +/- 2.3 years, range 0.5 to 9.2 years) the event rates per 100 patient-years in subjects with normotension, WCH, and SH were 0.27, 0.38, and 1.39, respectively. After adjustment for other covariates, Cox regression analysis showed that SH was an independent predictor of cardiovascular events (SH versus WCH, RR 5.17, 95% CI 2.04 to 13.1, P = 0 .001), whereas there was no significant difference between normotension and WCH (normotension versus WCH, RR 0.93, 95% CI 0.22 to 3.98, P = .92). At the end of follow-up, drug therapy was less frequent and intensive in WCH than in SH. CONCLUSIONS: In this study of individuals with mild hypertension and without left ventricular hypertrophy, diabetes mellitus, and associated cardiovascular and renal disease, subjects with WCH, despite less frequent and intensive drug therapy, had a significantly better prognosis than those with sustained hypertension.

Adult↗

PubMed2004

Prognostic value of left ventricular concentric remodeling in uncomplicated mild hypertension.

BACKGROUND: The prognostic value of left ventricular (LV) concentric remodeling in essential hypertension, and particularly in uncomplicated mild hypertension, is not yet completely clear. We investigated cardiovascular outcome in uncomplicated mild hypertensive patients with normal LV geometry and LV concentric remodeling. METHODS: The occurrence of fatal and nonfatal cardiovascular events was evaluated in 1088 uncomplicated mild hypertensive patients, 751 with normal LV geometry (LV mass index <125 g/m(2) in men and <110 g/m(2) in women and relative wall thickness <0.45) and 337 with LV concentric remodeling (LV mass index <125 g/m(2) in men and <110 g/m(2) in women and relative wall thickness >/=0.45). RESULTS: During follow-up (4.74 +/- 2.4 years, range 0.5 to 9.7 years) the event rates per 100 patient-years in subjects with normal LV geometry and LV concentric remodeling were 0.69 and 1.87, respectively. After adjustment for other covariates, Cox regression analysis showed that LV concentric remodeling (LV concentric remodeling versus normal LV geometry, RR 1.78, 95% CI 1.02 to 3.1, P < .05) was an independent predictor of cardiovascular events. CONCLUSION: In a population with uncomplicated mild hypertension, patients with LV concentric remodeling have a worse prognosis than those with normal LV geometry.

Adult↗

PubMed2004

[New insights on the molecular mechanisms of type-1 angiotensin II receptor blockers and their contribution to atherosclerotic plaque stabilization].

Clinical trials have demonstrated that agents inhibiting the angiotensin II pathway confer benefit beyond the reduction of blood pressure alone. However, the molecular mechanism underlying this effect has yet to be investigated. Recently, we have demonstrated enhanced expression of inducible COX and PGE synthase (COX-2/mPGES-1) in human symptomatic plaques, and provided evidence that it is associated with plaque rupture induced by metalloproteinases (MMPs), proteolytic enzymes of matrix structural components. In a recent study, we hypothesized that angiotensin II could promote plaque instability through induction of the COX-2/mPGES-1 pathway. We analyzed atherosclerotic plaques from symptomatic patients who were randomized to treatment with irbesartan (300 mg/die) or chlortalidone (50 mg/die) for 4 months before endarterectomy. We found that plaques from the irbesartan group had reduced inflammatory infiltration, less immunoreactivity for COX-2/mPGES-1 and MMPs, reduced gelatinolytic activity and increased collagen content. It is worth noting that COX-2/mPGES-1 inhibition was observed after incubation in vitro with irbesartan but not with the selective AT2 blockade PD123,319. These findings suggest that AT1 receptor blockers could represent a novel form of therapy for plaque stabilization in patients with atherosclerotic disease.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2003

Preprocedural level of soluble CD40L is predictive of enhanced inflammatory response and restenosis after coronary angioplasty.

BACKGROUND: Inflammation plays a pathogenic role in the development of restenosis after percutaneous transluminal coronary angioplasty (PTCA). CD40-CD40L interaction is involved in the pathogenesis of atherosclerosis; however, its role in the pathophysiology of restenosis is still unclear. We tested the hypothesis that soluble CD40L (sCD40L) may be involved in the process of restenosis and that it exerts its effect by triggering a complex group of inflammatory reactions on endothelial and mononuclear cells. METHODS AND RESULTS: We studied 70 patients who underwent PTCA and who had repeated angiograms at 6-month follow-up. Plasma sCD40L was measured before and 1, 5, 15, and 180 days after PTCA, whereas plasma soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, E-selectin, and monocyte chemoattractant protein (MCP)-1 were measured before and 24 hours after PTCA. Furthermore, the release of adhesion molecules and MCP-1 and the ability to repair an injury in endothelial cells, as well as the generation of O2- in monocytes, were analyzed in vitro after stimulation with serum from patients or healthy control subjects. Restenosis occurred in 18 patients (26%). Restenotic patients had preprocedural sCD40L significantly higher than patients with favorable outcomes (2.13+/-0.3 versus 0.87+/-0.12 ng/mL, P<0.0001). Elevated sCD40L at baseline was significantly correlated with adhesion molecules and MCP-1 generation after PTCA and with lumen loss at 6-month follow-up. Furthermore, high sCD40L was directly associated in vitro with adhesion molecules and MCP-1 generation and impaired migration in endothelial cells and with enhanced O2- generation in monocytes. CONCLUSIONS: We conclude that increased sCD40L is associated with late restenosis after PTCA. This may provide an important biochemical link between restenosis and aspirin-insensitive platelet activation. These results provide a rationale for studies with new antiplatelet treatments in patients who underwent PTCA.

Angioplasty, Balloon, Coronary↗

PubMed2003

The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control.

BACKGROUND: RAGE (receptor for advanced glycation end products [AGEs]) plays a role in diabetic atherosclerosis. Recently, we have demonstrated enhanced expression of cyclooxygenase-2 and PGE synthase-1 (COX-2/mPGES-1) in human symptomatic plaques, and provided evidence that it is associated with metalloproteinase (MMP)-induced plaque rupture. However, the specific transmembrane signaling pathway(s) influencing plaque COX-2/mPGES-1 expression is unknown. The aim of this study was to characterize RAGE expression in human plaques and to correlate it with the inflammatory infiltration, COX-2/mPGES-1 and MMP expression, and with clinical evidence of diabetes. METHODS AND RESULTS: Plaques obtained from 60 patients undergoing carotid endarterectomy were divided into diabetic and nondiabetic according to clinical evidence of type 2 diabetes. Plaques were subjected to analysis of RAGE, NF-kappaB, COX-2/mPGES-1, MMP-2 and MMP-9, lipid and oxidized LDL (oxLDL) content, and collagen content by immunohistochemistry and Western blot, whereas zymography was used to detect MMP activity. Immunohistochemistry was used to identify CD68+ macrophages, CD3+ T-lymphocytes, smooth muscle cells (SMCs), and HLA-DR+ inflammatory cells. Diabetic plaques had more (P<0.0001) macrophages, T-lymphocytes, and HLA-DR+ cells, more (P<0.0001) immunoreactivity for RAGE, activated NF-kappaB, COX-2/mPGES-1, and MMPs, increased (P<0.0001) gelatinolytic activity, reduced (P<0.0001) collagen content, and increased (P<0.0001) lipid and oxLDL content. Interestingly, RAGE, COX-2/mPGES-1, and MMP expression was linearly correlated with plasma level of HbA1c. CONCLUSIONS: In conclusion, this study demonstrates in humans that RAGE overexpression is associated with enhanced inflammatory reaction and COX-2/mPGES-1 expression in diabetic plaque macrophages, and this effect may contribute to plaque destabilization by inducing culprit metalloproteinase expression.

Aged↗

PubMed2003

Suppression of the functionally coupled cyclooxygenase-2/prostaglandin E synthase as a basis of simvastatin-dependent plaque stabilization in humans.

BACKGROUND: The clinical benefits of statins are attributed to changes in plaque composition that lead to reduced metalloproteinase (MMP) activity and plaque stabilization. However, the molecular mechanism of this effect is unclear. Recently, we demonstrated enhanced expression of isoforms of inducible cyclooxygenase (COX) and PGE synthase (COX-2/mPGES) in human symptomatic plaque and provided evidence that this is associated with MMP-induced plaque rupture. The aim of this study was to characterize the effect of simvastatin on inflammatory infiltration and the expression of COX-2/mPGES and MMPs in human carotid plaques. METHODS AND RESULTS: Seventy patients with symptomatic carotid artery stenosis were randomized to the American Heart Association Step 1 diet plus simvastatin (40 mg/d) or the American Heart Association Step 1 diet alone for 4 months before endarterectomy. Plaques were subjected to analysis of COX-1, COX-2, mPGES, MMP-2 and MMP-9, lipid and oxidized LDL (oxLDL) content, and collagen content by immunocytochemistry, Western blot, and reverse transcription-polymerase chain reaction, whereas zymography was used to detect MMP activity. Immunocytochemistry was also used to identify CD68+ macrophages, CD3+ T-lymphocytes, smooth muscle cells (SMCs), and HLA-DR+ inflammatory cells. Plaques from the simvastatin group had fewer (P<0.0001) macrophages, T-lymphocytes, and HLA-DR+ cells; less (P<0.0001) immunoreactivity for COX-2/mPGES and MMPs; reduced (P<0.0001) gelatinolytic activity; increased (P<0.0001) collagen content; and reduced (P<0.0001) lipid and oxLDL content. Interestingly, COX-2/mPGES inhibition by simvastatin was completely reversed by mevalonate in vitro. CONCLUSIONS: This study demonstrates that simvastatin decreases inflammation and inhibits COX-2/mPGES expression in plaque macrophages, and this effect in turn may contribute to plaque stabilization by inhibition of MMP-induced plaque rupture.

Aged↗

PubMed2003

Modulation of aspirin-insensitive eicosanoid biosynthesis by 6-methylprednisolone in unstable angina.

BACKGROUND: The evidence that inflammation plays a pivotal role in the pathophysiology of acute coronary syndromes prompted us to investigate the effects of glucocorticoid treatment on leukotriene (LT) C4 and thromboxane (TX) A2 biosynthesis in unstable angina. METHODS AND RESULTS: Urinary LTE4 and 11-dehydro-TXB2 were significantly higher in 12 patients with unstable angina than in 12 patients with stable angina and 12 patients with nonischemic chest pain. Furthermore, we randomized the unstable angina patients to receive intravenous 6-methylprednisolone (6-MP; 1 mg/kg BID for 2 days) or matching placebo and collected 12 consecutive 6-hour urine samples before and during the infusions. LTE4 excretion showed a time-dependent decrease in the 6-MP group but did not decrease during placebo. Furthermore, during myocardial ischemia, LTE4 was significantly higher before 6-MP infusion than during steroid therapy. In contrast, 11-dehydro-TXB2 did not differ significantly during 6-MP versus placebo. Myocardial ischemia elicited by stress test in the stable angina patients was not accompanied by any change in LTE4 and 11-dehydro-TXB2, thus ruling out a role of ischemia per se in the induction of increased eicosanoid production. CONCLUSIONS: Increased production of vasoactive LT and TX may occur in unstable angina despite conventional antithrombotic and antianginal treatment. Glucocorticoids can suppress LTC4 biosynthesis in the short term and may provide an interesting tool to explore the pathophysiological significance of inflammatory cell activation in this setting.

Adult↗

PubMed2003

Relationship between musculoskeletal symptoms and blood markers of oxidative stress in patients with chronic fatigue syndrome.

In 21 patients with chronic fatigue syndrome (CFS) versus 20 normal subjects, we investigated the oxidant/antioxidant balance and its correlation with muscle symptoms. Patients versus controls showed significantly: lower Lag Phase and Vitamin E (Vit E) concentrations in plasma and low-density lipoproteins (LDL), higher LDL thiobarbituric acid reactive substances (TBARS), higher fatigue and lower muscle pain thresholds to electrical stimulation. A significant direct linear correlation was found between fatigue and TBARS, thresholds and Lag Phase, thresholds and Vit E in plasma and LDL. A significant inverse linear correlation was found between fatigue and Lag Phase, fatigue and Vit E, thresholds and TBARS. Increased oxidative stress and decreased antioxidant defenses are related to the extent of symptomatology in CFS, suggesting that antioxidant supplementation might relieve muscle symptoms in the syndrome.

Adult↗

PubMed2003

Effect of a standardized grape seed extract on low-density lipoprotein susceptibility to oxidation in heavy smokers.

The aim of our study was to evaluate the effect of a standardized formulation of a polyphenolic extract of grapes (Leucoselect-Phytosome [LP]) on low-density lipoprotein (LDL) susceptibility to oxidation in a group of heavy smokers. A randomized, double-blind, crossover study was undertaken in 24 healthy male heavy smokers, aged > or = 50 years. Enrolled subjects were given 2 capsules twice daily for 4 weeks (phase 1). Each capsule contained 75 mg of a grape procyanidin extracts and soy-phosphatidlcholine or placebo consisiting of 75 mg lactose and soy-phosphatidlcholine. A wash out period of 3 weeks was then followed by 4 weeks of the opposite treatment (phase 2). Blood samples were taken at baseline and at the end of each phase and assayed for plasma lipids and LDL susceptibility to oxidation. Compliance was good, and no adverse effects were recorded. Subjects did not show significant modification of total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C) and LDL-C during LP treatment. Among oxidative indices, thiobarbituric acid reactive substances (TBARS) concentration was significantly reduced in subjects taking LP (-14.7% +/- 21.1% v +5.0% +/- 18.1%, P <.01), and the lag phase prolonged (+15.4% +/- 24.4% v -0.1% +/- 16.0%, P <.05) compared with placebo and basal values. The antioxidant potential of grape seed extract polyphenols may prove effective in a model of oxidative stress (smoking); however more investigational data are needed before use in wider clinical settings.

Antioxidants↗

PubMed2002

Low-density lipoprotein level reduction by the 3-hydroxy-3-methylglutaryl coenzyme-A inhibitor simvastatin is accompanied by a related reduction of F2-isoprostane formation in hypercholesterolemic subjects: no further effect of vitamin E.

BACKGROUND: Both statins and vitamin E, by reducing the rate of lipid peroxidation, may interfere with oxidative stress, but the impact of their combination is unknown. METHODS AND RESULTS: We randomized 43 hypercholesterolemic patients (21 men, 22 women, age 63+/-11 years) to either simvastatin, to achieve >20% reduction of total cholesterol, or simvastatin plus 600 mg/d vitamin E for 2 months. Patients were then crossed over to the alternative treatment. Lipid parameters documented patients' compliance to simvastatin, whereas plasma levels of vitamin E documented compliance and absorption of vitamin E. We assessed urinary excretion of the isoprostane 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) as an in vivo index of oxidative stress at baseline and after each month of therapy. 8-Iso-PGF(2alpha) was significantly reduced by simvastatin, from 361+/-148 pg/mg creatinine (mean+/-SD) at baseline to 239+/-124 pg/mg creatinine after 1 month. The addition of vitamin E did not reduce such levels any further (256+/-125 after 1 month). Linear regression analysis showed a weak inverse relationship of 8-iso-PGF(2alpha) with vitamin E levels but a much stronger relationship with LDL cholesterol (R(2)=0.162; P<0.001). CONCLUSIONS: In hypercholesterolemic patients, LDL cholesterol is a major correlate of oxidative stress. Concomitant with LDL cholesterol reduction, simvastatin causes a drastic reduction of oxidative stress to a level that is not further reduced by the addition of vitamin E. Results of clinical trials with vitamin E may have been hampered by inadequate knowledge of the background level of lipid peroxidation, which is a major determinant of vitamin E bioactivity.

Antioxidants↗

PubMed2002

Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy.

BACKGROUND: Hypercholesterolemia is associated with inflammation and the prothrombotic state. CD40-CD40 ligand (CD40L) interactions promote a prothrombotic response in nucleated cells. The aim of this study was to characterize the in vivo expression of soluble CD40L (sCD40L) in hypercholesterolemia, to correlate it with the extent of the prothrombotic state, and to investigate whether it may be modified by statins. METHODS AND RESULTS: We studied 80 hypercholesterolemic patients and 80 matched healthy subjects. Hypercholesterolemic subjects had enhanced levels of sCD40L, factor VIIa (FVIIa), and prothrombin fragment 1+2 (F1+2) compared with healthy subjects. sCD40L correlated with total cholesterol and LDL cholesterol. Moreover, sCD40L was positively associated with in vivo platelet activation, as reflected by plasma P-selectin and urinary 11-dehydro-thromboxane B2, and with procoagulant state, as reflected by FVIIa and F1+2. Inhibition of cholesterol biosynthesis by pravastatin or cerivastatin was associated with comparable, significant reductions in sCD40L, FVIIa, and F1+2. CONCLUSIONS: This study suggests that sCD40L may represent the molecular link between hypercholesterolemia and the prothrombotic state and demonstrates that statin therapy may significantly reduce sCD40L and the prothrombotic state.

CD40 Ligand↗

PubMed2002

Endothelial function in sustained and white coat hypertension.

BACKGROUND: Endothelial dysfunction is a frequent finding in essential hypertension. The aim of this study was to assess endothelial function, by evaluating circulating nitric oxide metabolites, nitrate plus nitrite (NOx), and endothelium-dependent vasodilation (EDD), in white coat hypertension in comparison with sustained hypertension and normotension. METHODS: We selected 22 sustained hypertensive, 22 white coat hypertensive, and 22 normotensive subjects matched for age, gender, body mass index, and occupation. Women were also matched for menopausal status. Subjects with smoking habit, dyslipidemia, and diabetes mellitus were excluded from the study. White coat hypertension was defined as clinical hypertension and daytime ambulatory blood pressure (BP) <135/85 mm Hg. Groups received for 2 days a low-nitrate diet before obtaining blood samples for laboratory measurements. The NOx levels were measured by using the Griess reagent after enzymatic conversion of all nitrate to nitrite. Subjects also underwent brachial artery study by ultrasonography to evaluate EDD and endothelium-independent vasodilation. RESULTS: White coat hypertensive subjects had significantly higher levels of NOx than sustained hypertensive patients (30.8 +/- 12 v 22 +/- 8.5 micromol/L, P <.05) and significantly higher EDD (7.8% +/- 3.1% v 4.6% +/- 3.0%, P <.05). No significant difference was observed between white coat hypertensive and normotensive subjects regarding these parameters. Endothelium-independent vasodilation was not significantly different among sustained hypertensives, white coat hypertensives, and normotensives (18% +/- 4.2% v 18.3% +/- 3.9% v 18.6% +/- 4.8%, respectively, P = not significant). CONCLUSIONS: Our data suggest that middle-aged white coat hypertensive subjects without other cardiovascular risk factors do not show endothelial dysfunction in contrast with sustained hypertensive patients.

Adult↗

PubMed2002

Genetic factors associated with the absence of atherosclerosis in octogenarians.

BACKGROUND: Atherosclerosis (ATS) is a common age-related disease of large arteries. The prevalence of older subjects with vascular successful aging (VaSA), defined as the absence of clinical symptoms and instrumental signs of ATS, is low in Western countries. The possible contribution of genetics to the VaSA phenomenon is not known. METHODS: We investigated the distribution of four genetic polymorphisms (angiotensin converting enzyme [ACE], methylenetetrahydrofolate reductase [MTHFR], apolipoprotein E [apo E], and paraoxonase [PON] genes) in 30 subjects with VaSA, 30 subjects with moderate carotid atherosclerosis (ATS group), and 161 controls with a negative history for cardiovascular disease. Clinical examination; ultrasonographic examination of carotid, vertebral, abdominal aortic, iliac, and femoral arteries; and electrocardiogram were performed. RESULTS: The frequency of PON 192 B allele was lower in VaSA patients (13%) compared with ATS patients (37%) and controls (46%) ( p =.06 and.006, respectively); B/B homozygotes were 27% in the ATS group, 12% in controls, and 0% in the VaSA group. The frequency of the MTHFR thermolable + allele was higher in VaSA (0.51) compared with ATS (0.39) and controls (0.40) (VaSA vs C, p =.006). No differences in the distribution of ACE I/D and apo E alleles emerged between the three groups. CONCLUSIONS: The low prevalence of the PON 192 B allele in the VaSA subjects suggests that this polymorphism might have an important role in VaSA, probably by hydrolyzing lipid peroxides and thus preventing low-density lipoprotein from undergoing the oxidative modification. This finding further supports the oxidative hypothesis of ATS.

Aged↗

PubMed2002

Heart rate in hypertensive patients treated with ACE inhibitors and long-acting dihydropyridine calcium antagonists.

Rapid heart rate (HR) has been reported to be a predictor of cardiovascular morbidity and mortality in hypertensive patients. The aim of this study was to evaluate the effect of ACE inhibitors and long-acting dihydropyridine calcium antagonists on clinic and ambulatory HR in patients with essential hypertension. We selected 292 hypertensive patients treated with ACE inhibitors and 198 hypertensive patients treated with dihydropyridine calcium antagonists. Groups were balanced for age, gender, body mass index, baseline blood pressure (BP) and HR, treatment duration and occupation. Patients had been submitted to clinic evaluation and noninvasive monitoring of BP and HR at baseline and during chronic therapy. Clinic and ambulatory BP were significantly and similarly reduced in patients treated with ACE inhibitors and calcium antagonists. Globally, clinic and 24-h HR were significantly reduced in patients treated with ACE inhibitors and remained unchanged in those treated with calcium antagonists. When patients were grouped according to baseline clinic HR (< 65 beats/min, 65-74 beats/min, 75-84 beats/min, and >85 beats/min), ACE inhibitors did not significantly change HR in subjects with baseline clinic HR <74 beats/min but significantly reduced clinic, 24-h, daytime and nighttime HR in those with baseline HR >75 beats/min and particularly in those with baseline HR >85 beats/min. Calcium antagonists did not significantly change clinic, 24-h, daytime and nighttime HR in various subgroups. Our study shows that ACE inhibitors reduce both clinic and ambulatory HR in hypertensive patients with faster HR, who seem to be at higher risk, and that long-acting dihydropyridine calcium antagonists do not induce significant changes in HR during chronic treatment (neither decrease nor increase). Whether this aspect is associated with a better prognostic impact of ACE inhibitors in essential hypertension should be determined in prospective studies.

Angiotensin-Converting Enzyme Inhibitors↗