70 research outputs found
Validation of plasma fibrinogen as a marker of carotid atherosclerosis in subjects free of clinical cardiovascular disease
BACKGROUND AND OBJECTIVES: Fibrinogen has been found to be an independent risk factor for cardiovascular disease. The aim of this study was to validate the measurement of plasma fibrinogen as a marker of subclinical atherosclerosis in a series of asymptomatic subjects (n=519, median age 55.5 years, 80% men).
DESIGN AND METHODS: All individuals had a complete clinical examination, lipid profile (cholesterol and its high and low density lipoprotein fractions and triglycerides), global vascular risk assessment (PROCAM), and B-mode ultrasonography of the carotid arteries to determine the intima-media thickness (IMT) and the presence of atheroma plaques. C-reactive protein (CRP), and von Willebrand factor (vWF) were also measured in all subjects as markers of inflammation/endothelial damage.
RESULTS: In the univariate model, a positive relationship was found between plasma fibrinogen concentration and carotid IMT (p<0.001). Fibrinogen concentration also correlated positively with age (p<0.001), systolic blood pressure (p<0.001), smoking (p<0.05), diabetes (p<0.05), PROCAM (p<0.001), CRP and vWF (p<0.001). In the multivariate analysis, the association of fibrinogen with carotid IMT remained significant (p=0.008) after adjustment for all parameters analyzed.
INTERPRETATION AND CONCLUSIONS: In a population sample of adults without clinically overt atherosclerotic disease, elevated fibrinogen levels was related to carotid IMT independently of a wide range of important confounding variables. Plasma fibrinogen may represent a systemic marker of carotid atherosclerosis
Superoxide dismutase in patients with chronic hepatitis C virus infection
It has been reported that hepatitis C virus (HCV) may cause oxidative stress in infected cells. Patients with chronic hepatitis C exhibit an increased production of tumor necrosis factor-alpha (TNF alpha), a cytokine that can produce oxidative stress by stimulating the generation of reactive oxygen species (ROS). Cell defense against ROS includes overexpression of Mn-superoxide dismutase (SOD), an inducible mitochondrial enzyme. To investigate cell defense against oxidative stress in HCV infection, we analyzed Mn-SOD mRNA in liver and in peripheral blood mononuclear cells (PBMC) from patients with chronic hepatitis C. Mn-SOD expression in PBMC was significantly increased in patients with HCV infection. Patients with sustained virological and biochemical response after therapy showed significantly lower Mn-SOD than patients with positive viremia. By contrast, Mn-SOD expression was not enhanced in the liver of patients with chronic hepatitis C. The values of Mn-SOD mRNA did not correlate with TNF alpha mRNA expression, viral load, or liver disease activity. Our results indicate that in HCV infection an induction of Mn-SOD was present in PBMC but absent in the liver, suggesting that this organ could be less protected against oxidative damage. Oxidative stress could participate in the pathogenesis of HCV infection
RelaciĂłn entre las fases precoces de la enfermedad renal y el sĂndrome metabĂłlico
Advanced kidney disease is a major health problem
due to its association with high cardiovascular morbidity and mortality. Early
recognition of advanced kidney disease is the mainstay to avoid its progression.
Since metabolic syndrome and insulin resistance are risk factors for both
cardiovascular and advanced kidney disease, we investigated the relationship of
early kidney disease (EKD) with metabolic syndrome and insulin resistance, and
their association with surrogate markers of arteriosclerosis. METHODS: We studied
1498 subjects. Insulin resistance was defined as HOMA >/=3.7 mmol (muU)/L(2) and
EKD as stages 1 and 2 of the NKF-KDOQI. Carotid intima-media thickness was used
as a surrogate marker of arteriosclerosis. RESULTS: The presence of one trait of
metabolic syndrome was associated with an odds ratio (OR) for EKD of 2.3 (95%
confidence interval [CI], 1.18-4.48) that increased to 6.72 (95% CI, 3.56-13.69)
in subjects with the syndrome. All the traits of the syndrome except low level of
high-density lipoproteins showed an increased OR for EKD. Increasing HOMA was
also directly correlated with higher OR for EKD, being as high as 3.89 (95% CI,
1.99-7.59) for subjects in the fourth quartile. Subjects with the syndrome plus
EKD showed an increased intima-media thickness compared with those without kidney
disease. CONCLUSIONS: Insulin resistance and all metabolic syndrome traits except
low level of high-density lipoproteins were significantly associated with an
increased OR for EKD. Both metabolic syndrome and EKD were independently and
additively related to the presence of surrogate markers of arteriosclerosis
Protective effect of the G-765C COX-2 polymorphism on subclinical atherosclerosis and inflammatory markers in asymptomatic subjects with cardiovascular risk factors
BACKGROUND: Cyclooxygenase (COX)-2, a key regulatory enzyme in prostanoid synthesis, plays an important role in inflammatory processes. The -765G>C COX-2 polymorphism has been associated with lower promoter activity in vitro and reduced levels of C-reactive protein (CRP) in atherosclerotic carriers of the C allele. However, its pathophysiological relevance in vivo has not been fully elucidated.
METHODS AND RESULTS: We assessed the -765G>C polymorphism and COX-2 expression in 220 asymptomatic subjects free of cardiovascular disease, in relation to global vascular risk, carotid intima-media thickness (IMT), and inflammatory markers (fibrinogen, C-reactive protein [CRP], von Willebrand factor [vWF] and interleukin-6 [IL-6]). Genotype frequencies were: CC (7.7%), CG (34.5%), GG (57.7%). Among hypercholesterolemic subjects (n=140), C allele carriers had lower COX-2 expression (p<0.05), reduced carotid IMT (p<0.01) and diminished levels of inflammatory markers CRP, vWF and IL-6 (p<0.05), as compared to GG homozygous subjects. The association between carotid IMT and COX-2 polymorphism remained significant after adjusting for cardiovascular risk factors and inflammatory markers (p=0.008).
CONCLUSIONS: In asymptomatic hypercholesterolemic subjects the C allele of -765G>C COX-2 polymorphism was associated with lower COX-2 expression, and reduced subclinical atherosclerosis and systemic inflammation compared with GG homozygous, thus conferring atherosclerosis protection in this cardiovascular risk population
NADPH OxidaseâDependent Superoxide Production Is Associated With Carotid Intima-Media Thickness in Subjects Free of Clinical Atherosclerotic Disease
ObjectiveâOxidative stress plays a critical role in the pathogenesis of atherosclerosis. The NADPH oxidase constitutes the
main source of superoxide in phagocytic and vascular cells. This study aimed to investigate the levels of NADPH
oxidaseâmediated superoxide production in phagocytic cells and the association between phagocytic superoxide
production and carotid intima-media thickness (IMT), a surrogate marker of asymptomatic atherosclerosis.
Methods and ResultsâNADPH oxidaseâmediated superoxide production was determined by a chemiluminescence assay
using lucigenin and associated with IMT for 184 asymptomatic subjects free of overt clinical atherosclerotic disease.
Compared with individuals in the lowest tertile of superoxide production, those in the upper tertile ( 20 counts/sec)
showed significantly higher IMT (P 0.05). In correlation analysis, a positive relationship was found between
superoxide production and carotid IMT. Superoxide production also correlated positively (P 0.05) with body mass
index (BMI). In multivariate analysis, the association of superoxide production with carotid IMT remained significant
after adjustment for age, sex, systolic blood pressure, BMI, triglycerides, glucose, and smoking.
ConclusionsâIn a population sample of adults without clinically overt atherosclerotic disease, increased NADPH oxidase
activity was associated with enhanced carotid IMT, suggesting a relationship between phagocytic NADPH oxidaseâ
mediated oxidative stress and the development of atherosclerosis
Increased phagocytic nicotinamide adenine dinucleotide phosphate oxidaseâdependent superoxide production in patients with early chronic kidney disease
Background. Oxidative stress has been implicated in the
pathogenesis of atherosclerosis that develops in patients with
advanced chronic kidney disease (CKD). This study was
designed to investigate whether a relationship exists between
phagocytic nicotinamide adenine dinucleotide phosphate
(NADPH) oxidaseâdependent superoxide anion (âąO2
â) production
and subclinical atherosclerosis in patients with early
CKD.
Methods. Superoxide production was assayed by chemiluminescence
under baseline and stimulated conditions on mononuclear
cells obtained from asymptomatic patients with stage 1
to 2 CKD (N = 22) and healthy controls (N = 21). Ultrasonographic
determination of carotid intima-media thickness (IMT)
was used to assess the presence of atherosclerosis.
Results. Although there were no differences in baseline âąO2
â
production between controls and patients, the âąO2
â production
in phorbol myristate acetateâstimulated mononuclear cells was
increased (P < 0.05) in patients compared with controls. The
phorbol myristate acetateâinduced âąO2
â production was completely
abolished by apocynin, a specific inhibitor of NADPH
oxidase. A direct correlation (r = 0.441, P < 0.05) was found
between plasma insulin levels and NADPH oxidaseâmediated
âąO2
â production in patients. Carotid IMT was higher (P <
0.005) in patients than in controls. CarotidIMTvalues above the
upper normal limit in controls were found in 70% and 40% of
patients with increased or normal NADPH oxidaseâmediated
âąO2
â production, respectively.
Conclusion. Generation of âąO2
â that is mainly dependent on
NADPH oxidase is abnormally enhanced in patients with early
CKD. It is suggested that this alteration could be related to the
development of subclinical atherosclerosis in these patients
Hyperhomocysteinemia in liver transplant recipients: prevalence and multivariate analysis of predisposing factors.
Liver transplant recipients have an increased risk for cardiovascular disease
because of a high incidence of obesity, arterial hypertension, diabetes mellitus,
and hyperlipidemia. Hyperhomocysteinemia has been found to be an important risk
factor for cardiovascular disease in large studies. Fasting serum levels of
homocysteine were measured in 105 liver transplant recipients, and
hyperhomocysteinemia was defined as a fasting serum homocysteine level greater
than 13 micromol/L. Patients with versus without hyperhomocysteinemia were
compared. The possible association of hyperhomocysteinemia with age, sex, cause
of liver disease, time elapsed since liver transplantation, immunosuppressive
therapy, folic acid level, liver function test results, renal function, and other
cardiovascular risk factors was investigated. Patients with serum homocysteine
levels greater than 15 micromol/L were treated with folic acid, 10 mg/d, and
serum homocysteine levels were measured again 1 to 3 months later in 10 patients.
Hyperhomocysteinemia was detected in 28 patients (27%). In univariate analysis,
it was associated with hepatitis C virus infection, treatment with mycophenolate
mofetil, and greater serum levels of alkaline phosphatase, gamma-glutamyl
transpeptidase, urea, and creatinine. In multivariate analysis, only greater
serum levels of creatinine (P =.006) were associated with hyperhomocysteinemia.
Treatment with folic acid resulted in a decrease in fasting serum homocysteine
levels in 9 of the 10 patients tested (P =.01). Hyperhomocystinemia, associated
with renal dysfunction, is a frequent finding in liver transplant recipients.
Treatment with folic acid may reduce fasting homocysteine levels
Functional Effect of the p22phox -930A/G Polymorphism on p22phox Expression and NADPH Oxidase Activity in Hypertension
Oxidative stress induced by superoxide is implicated in hypertension. NADPH oxidase is the main source of
superoxide in phagocytic and vascular cells, and the p22phox subunit is involved in NADPH oxidase activation. Recently
we reported an association of 930A/G polymorphism in the human p22phox gene promoter with hypertension. This study
was designed to investigate the functional role of this polymorphism in hypertension. We thus investigated the
relationships between the 930A/G polymorphism and p22phox expression and NADPH oxidaseâmediated superoxide
production in phagocytic cells from 70 patients with essential hypertension and 70 normotensive controls. Genotyping
of the polymorphism was performed by restriction fragment length polymorphism. NADPH oxidase activity was
determined by chemiluminescence assays, and p22phox mRNA and protein expression was measured by Northern and
Western blotting, respectively. Compared with hypertensive subjects with the AA/AG genotype, hypertensive subjects
with the GG genotype exhibited increased (P 0.05) phagocytic p22phox mRNA (1.26 0.06 arbitrary unit [AU] versus
0.99 0.03 AU) and protein levels (0.58 0.05 AU versus 0.34 0.04 AU) and enhanced NADPH oxidase activity
(1998 181 counts/s versus 1322 112 counts/s). No differences in these parameters were observed among genotypes
in normotensive cells. Transfection experiments on vascular smooth muscle cells showed that the A-to-G substitution
of this polymorphism produced an increased reporter gene expression in hypertensive cells. Nitric oxide production, as
assessed by measurement of serum nitric oxide metabolites, was lower in GG hypertensive subjects than in AA/AG
hypertensive subjects. In conclusion, these results suggest that hypertensive subjects carrying the GG genotype of the
p22phox 930A/G polymorphism are highly exposed to NADPH oxidase-mediated oxidative stress
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