11ß-hydroxysteroid dehydrogenase type 2 polymorphisms and activity in a Chilean essential hypertensive and normotensive cohort.

BACKGROUND: 11ß-hydroxysteroid dehydrogenase type 2 enzyme (11ß-HSD2) inactivates cortisol (F) to cortisone (E); its impairment is associated with hypertension. We reported that 15.7% of the Chilean essential hypertensives possessed a high F/E ratio suggesting a partial deficit in 11ß-HSD2 activity. It has been reported that the G534A(Glu178/Glu) polymorphism in the HSD11B2 gene is associated with hypertension. Investigate the frequency of the G534A polymorphism and its correlation with the glucocorticoid profile in Chilean essential hypertensive and normotensive subjects. METHODS: Essential hypertensive outpatients (n = 232) and normotensive subjects (n = 74) were recruited. A change in the AluI restriction enzyme digest pattern, caused by the presence of the G534A polymorphism, was utilized to screen DNA isolated from leukocytes within the cohort before confirmation by sequencing. Plasma renin activity (PRA), serum aldosterone, F, and E were measured by radioimmunoassay. Urinary tetrahydrocortisol (THF), 5α-tetrahydrocortisol (5α-THF), and tetrahydrocortisone (THE) were measured by gas chromatography-mass spectrometry. RESULTS: G534A polymorphism frequency was similar between hypertensive patients (19 of 232; 8.2%) and normotensive subjects (7 of 74; 9.5%). When categorized by presence or absence of the G534A polymorphism, no significant differences in the serum F/E ratio or other measured biochemical variables were detected. Despite a previous report that the G534A polymorphism is associated with a neighboring C468A (Thr156/Thr) polymorphism, analysis within our cohort showed that only one patient in each group presented with this double polymorphism. CONCLUSIONS: We report the frequency of the G534A polymorphism in the Spanish-Amerindian population. No correlation was detected between this polymorphism and the presence of hypertension and biochemical parameters in this Chilean cohort.

Increased urinary glucocorticoid metabolites are associated with metabolic syndrome, hypoadiponectinemia, insulin resistance and ß cell dysfunction.

Metabolic syndrome (MetS) may have increased cortisol (F) production caused by 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) in liver and adipose tissue and/or by HPA axis dysregulation. F is then mainly metabolized by liver reductases into inactive tetrahydrometabolites (THMs). We measured THM levels in patients with or without MetS and evaluate the correlation between THMs and anthropometric and biochemical parameters. We recruited 221 subjects, of whom 130 had MetS by ATP III. We evaluated F, cortisone (E), adipokines, glucose, insulin and lipid profiles as well as urinary (24h) F, E and THM levels. ß Cell function was estimated by the HOMA Calculator. We observed that patients with MetS showed higher levels of THMs, HOMA-IR and leptin and lower levels of adiponectin and HOMA-ß but no differences in F and E in plasma or urine. THM was associated with weight (r = +0.44, p<0.001), waist circumference (r = +0.38, p<0.01), glycemia (r = +0.37, p<0.01), and triglycerides (r = +0.18, p=0.06) and negatively correlated with adiponectin (r = -0.36, p<0.001), HOMA-ß (r = -0.21, p<0.001) and HDL (r = -0.29, p<0.01). In a logistic regression model, THM levels were associated with hypertension, hyperglycemia and dyslipidemia. We conclude that MetS is associated with increased urinary THMs but not with F and E levels in plasma or urine. Increased levels of THM, reflecting the daily cortisol production subsequently metabolized, are correlated with hypoadiponectinemia, hypertension, dyslipidemia, insulin resistance and ß cell dysfunction. A subtle increased in glucocorticoid production may further account for the phenotypic and biochemical similarities observed in central obesity and Cushing's syndrome.

Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women.

OBJECTIVE: In hyperandrogenic women, hyperinsulinaemia amplifies 17 α-hydroxycorticosteroid intermediate response to ACTH, without alterations in serum cortisol or androgen response to stimulation. The aim of the study is to assess whether acute hyperinsulinaemia determines absolute changes in either basal or ACTH-stimulated adrenal steroidogenesis in these subjects. DESIGN AND METHODS: Twelve young hyperandrogenic women were submitted in two separate days to an 8 h hyperinsulinaemic (80  mU/m² × min) euglycaemic clamp, and to an 8 h saline infusion. In the second half of both the protocols, a 4 h ACTH infusion (62.5  µg/h) was carried out. Serum cortisol, progesterone, 17 α-hydroxyprogesterone (17-OHP), 17 α-hydroxypregnenolone (17-OHPREG), DHEA and androstenedione were measured at basal level and during the protocols. Absolute adrenal hormone secretion was quantified by measuring C19 and C21 steroid metabolites in urine collected after the first 4 h of insulin or saline infusion, and subsequently after 4 h of concurrent ACTH infusion. RESULTS: During insulin infusion, ACTH-stimulated 17-OHPREG and 17-OHP were significantly higher than during saline infusion. No significant differences in cortisol and androgens response to ACTH were found between the protocols. Nevertheless, urinary excretion of ACTH-stimulated C19 and C21 steroid metabolites was significantly higher during hyperinsulinaemia than at basal insulin levels (both P < 0.005). Changes in steroid metabolites molar ratios suggested stimulation by insulin of 5 α-reductase activity. CONCLUSIONS: These in vivo data support the hypothesis that insulin acutely enhances ACTH effects on both the androgen and glucocorticoid pathways.

11ß-Hydroxysteroid dehydrogenase type-2 and type-1 (11ß-HSD2 and 11ß-HSD1) and 5ß-reductase activities in the pathogenia of essential hypertension.

Cortisol availability is modulated by several enzymes: 11ß-HSD2, which transforms cortisol (F) to cortisone (E) and 11ß-HSD1 which predominantly converts inactive E to active F. Additionally, the A-ring reductases (5α- and 5ß-reductase) inactivate cortisol (together with 3α-HSD) to tetrahydrometabolites: 5αTHF, 5ßTHF, and THE. The aim was to assess 11ß-HSD2, 11ß-HSD1, and 5ß-reductase activity in hypertensive patients. Free urinary F, E, THF, and THE were measured by HPLC-MS/MS in 102 essential hypertensive patients and 18 normotensive controls. 11ß-HSD2 enzyme activity was estimated by the F/E ratio, the activity of 11ß-HSD1 in compare to 11ß-HSD2 was inferred by the (5αTHF + 5ßTHF)/THE ratio and 5ß-reductase activity assessed using the E/THE ratio. Activity was considered altered when respective ratios exceeded the maximum value observed in the normotensive controls. A 15.7% of patients presented high F/E ratio suggesting a deficit of 11ß-HSD2 activity. Of the remaining 86 hypertensive patients, two possessed high (5αTHF + 5ßTHF)/THE ratios and 12.8% had high E/THE ratios. We observed a high percentage of alterations in cortisol metabolism at pre-receptor level in hypertensive patients, previously misclassified as essential. 11ß-HSD2 and 5ß-reductase decreased activity and imbalance of 11ß-HSDs should be considered in the future management of hypertensive patients.

Cigarette smoking blocks the protective expression of Nrf2/ARE pathway in peripheral mononuclear cells of young heavy smokers favouring inflammation.

Cigarette smoking is an important risk factor for atherosclerosis, a chronic inflammatory disease. However the underlying factors of this effect are unclear. It has been hypothesized that water-soluble components of cigarette smoke can directly promote oxidative stress in vasculature and blood cells. Aim of this study was to study the relationship between oxidative stress and inflammation in a group of young smokers. To do this we evaluated: 1) the oxidation products of phospholipids (oxPAPC) in peripheral blood mononuclear cells (PBMC); 2) their role in causing PBMC reactive oxygen species (ROS) generation and changes in GSH; 3) the expression of the transcription factor NF-E2-related factor 2 (Nrf2) and of related antioxidant genes (ARE); 4) the activation of NF-kB and C-reactive protein (CRP) values. We studied 90 healthy volunteers: 32 non-smokers, 32 moderate smokers (5-10 cigarettes/day) and 26 heavy smokers (25-40 cigarettes/day). OxPAPC and p47phox expression, that reasonably reflects NADPH oxidase activity, were higher in moderate smokers and heavy smokers than in non-smokers (p<0.01), the highest values being in heavy smokers (p<0.01). In in vitro studies oxPAPC increased ROS generation via NADPH oxidase activation. GSH in PBMC and plasma was lower in moderate smokers and heavy smokers than in non-smokers (p<0.01), the lowest values being in heavy smokers (p<0.01). Nrf2 expression in PBMC was higher in moderate smokers than in non-smokers (p<0.01), but not in heavy smokers, who had the highest levels of NF-kB and CRP (p<0.01). In in vitro studies oxPAPC dose-dependently increased NF-kB activation, whereas at the highest concentrations Nrf2 expression was repressed. The small interference (si) RNA-mediated knockdown of NF-kappaB/p65 increased about three times the expression of Nrf2 stimulated with oxPAPC. Cigarette smoke promotes oxPAPC formation and oxidative stress in PBMC. This may cause the activation of NF-kB that in turn may participate in the negative regulation of Nrf2/ARE pathway favouring inflammation.

Preliminary evidence for cell membrane amelioration in children with cystic fibrosis by 5-MTHF and vitamin B12 supplementation: a single arm trial.

BACKGROUND: Cystic fibrosis (CF) is one of the most common fatal autosomal recessive disorders in the Caucasian population caused by mutations of gene for the cystic fibrosis transmembrane conductance regulator (CFTR). New experimental therapeutic strategies for CF propose a diet supplementation to affect the plasma membrane fluidity and to modulate amplified inflammatory response. The objective of this study was to evaluate the efficacy of 5-methyltetrahydrofolate (5-MTHF) and vitamin B12 supplementation for ameliorating cell plasma membrane features in pediatric patients with cystic fibrosis. METHODOLOGY AND PRINCIPAL FINDINGS: A single arm trial was conducted from April 2004 to March 2006 in an Italian CF care centre. 31 children with CF aged from 3 to 8 years old were enrolled. Exclusion criteria were diabetes, chronic infections of the airways and regular antibiotics intake. Children with CF were supplemented for 24 weeks with 5-methyltetrahydrofolate (5-MTHF, 7.5 mg /day) and vitamin B12 (0.5 mg/day). Red blood cells (RBCs) were used to investigate plasma membrane, since RBCs share lipid, protein composition and organization with other cell types. We evaluated RBCs membrane lipid composition, membrane protein oxidative damage, cation content, cation transport pathways, plasma and RBCs folate levels and plasma homocysteine levels at baseline and after 24 weeks of 5-MTHF and vitamin B12 supplementation. In CF children, 5-MTHF and vitamin B12 supplementation (i) increased plasma and RBC folate levels; (ii) decreased plasma homocysteine levels; (iii) modified RBC membrane phospholipid fatty acid composition; (iv) increased RBC K(+) content; (v) reduced RBC membrane oxidative damage and HSP70 membrane association. CONCLUSION AND SIGNIFICANCE: 5-MTHF and vitamin B12 supplementation might ameliorate RBC membrane features of children with CF. TRIAL REGISTRATION: ClinicalTrials.gov NCT00730509.

Urinary cortisol to cortisone metabolites ratio in prednisone-treated and spontaneously hypertensive patients.

OBJECTIVE AND METHODS: Prednisone and its active metabolite prednisolone, both substrates for 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), may represent a pharmacological challenge for the enzyme. The aim of the present work was to define the possible role of abnormal cortisol/cortisone handling, as revealed by an urinary tetrahydrocortisol + allotetrahydrocortisol (THFs)/tetrahydrocortisone (THE) ratio between 1.5 and 3.0, by measuring urinary cortisol and cortisone metabolites in: normotensive individuals (n = 100) who received 7-8 mg/day of oral prednisone and were then followed for development of hypertension; essential hypertensive (EH) participants from primary care (n = 103); and EH hypertensive patients referred to the Hypertension Unit (n = 141). RESULTS: About one-third (14 out of 47, 30%) of glucorticoid-treated patients who developed hypertension showed a THFs/THE ratio >1.5, which was seen in 3% (n = 3) and 14% (n = 19) of primary and tertiary care hypertensive patients, respectively. A THFs/THE ratio >1.5 was associated with a 3.8-fold incremental risk of hypertension after glucocorticoid therapy, regardless of duration and intensity of prednisone therapy. CONCLUSIONS: A number of EH patients and glucocorticoid-treated participants shared a similar phenotype, characterized by both arterial hypertension and elevated urinary THFs/THE ratio. Such a phenotype is more common in severely, rather than in mildly, hypertensive patients.

Correlation between homocysteine plasma levels and nailfold videocapillaroscopic patterns in systemic sclerosis.

The aim of the study is to investigate the relationship between microangiopathy as assessed by nailfold videocapillaroscopy (NVC) and plasma level of homocysteine (Hcy) in systemic sclerosis (SSc). As known, Hcy is a nonessential amino acid that interferes with normal properties of a vascular tree. Sixty patients affected by SSc (4 men and 56 women, mean age 54.6) underwent the determination of plasma Hcy level; at the same time, NVC was performed. Hcy level was also determined in 30 sex- and age-matched controls. In patients affected by SSc the plasma Hcy level was significantly higher than in healthy controls (11.8 and 6.5 micromol/l, respectively; p < 0.001). A significant correlation was found between plasma Hcy concentration and the pattern of NVC with a progressive increase from early to active and above all to late pattern (10.7, 11.8, and 17.4 micromol/l, respectively; p < 0.001). Subjects with high Hcy level (i.e., >75th percentile of Hcy level in controls and in patients considered altogether) were mostly represented in the scleroderma patients with late nailfold videocapillaroscopic pattern; the crude odds ratio was 9.0 (significant; 95% CI from 2.1 to 38.8). In conclusion, Hcy plasma level is related to microvascular involvement in patients affected by SSc; the concentration increases with the progression of the nailfold videocapillaroscopic pattern. Hyperhomocysteinemia may represent an aggravating factor among the complex mechanisms involved in scleroderma damage contributing to the injury of endothelium.

Hyperhomocysteinemia and mortality after coronary artery bypass grafting.

BACKGROUND: The independent prognostic impact, as well as the possible causal role, of hyperhomocysteinemia (HHcy) in coronary artery disease (CAD) is controversial. No previous study specifically has addressed the relationship between HHcy and mortality after coronary artery bypass grafting (CABG) surgery. The aim of this study is to evaluate the prognostic impact of HHcy after CABG surgery. METHODOLOGY AND PRINCIPAL FINDINGS: We prospectively followed 350 patients who underwent elective CABG between May 1996 and May 1999. At baseline, fasting total homocysteine (tHcy) levels were measured in all participants, and a post-methionine loading (PML) test was performed in 77.7% of them (n = 272). After a median follow-up of 58 months, 33 patients (9.4%) had died, 25 because of cardiovascular events. HHcy, defined by levels higher than the 90th percentile (25.2 micromol/L) of the population's distribution, was significantly associated to total and cardiovascular mortality (P = 0.018 [log-rank test 5.57]; P = 0.002 [log-rank test 9.76], respectively). The PML test had no prognostic value. After multiple adjustment for other univariate predictors by Cox regression, including statin therapy (the most powerful predictor in uni-/multivariate analyses), high-sensitivity C Reactive Protein (hs-CRP) levels, and all known major genetic (MTHFR 677C-->T polymorphism) and non-genetic (B-group vitamin status and renal function) tHcy determinants, HHcy remained an independent prognostic factor for mortality (HRs: 5.02, 95% CIs 1.88 to 13.42, P = 0.001). CONCLUSIONS: HHcy is an important prognostic marker after CABG, independent of modern drug therapy and biomarkers.

Acute hyperhomocysteinemia induces a reduction in arterial distensibility and compliance.

OBJECTIVE: The aim of the study was to evaluate the effects of acute hyperhomocysteinemia on distensibility and compliance of large peripheral arteries. Isoprostanes generation and antioxidant vitamins were used to assess the role of oxidative stress. DESIGN: A cross-over, double-blind study on distensibility (DC: distensibility coefficient) and compliance (CC: cross-sectional compliance) of common femoral and brachial arteries was performed in 12 healthy young male volunteers by means of a wall track system before and 4 h after a single oral methionine (100 mg/kg) or placebo administration. The effects of methionine load were investigated also after oral administration of vitamin C (1g/day) and vitamin E (800 mg/day) for 8 consecutive days. RESULTS: Oral methionine induced a significant increase in plasmatic levels of homocysteine. Distensibility and compliance of brachial and femoral arteries were significantly reduced after methionine load in comparison to placebo. This acute impairment of arterial wall mechanical properties was associated to endothelial dysfunction, since altered flow-dependent vasodilatation (P < 0.05 versus placebo) was observed in the same arterial districts. A significant increase in urinary 8-iso-prostaglandin F2alpha was observed after methionine. Pretreatment with vitamins C and E prevented the effects of methionine on femoral and brachial arteries as well as on urinary 8-iso-prostaglandin F2alpha excretion. CONCLUSIONS: Hyperhomocysteinemia seems responsible for altered arterial wall elasticity and for endothelial dysfunction. A pivotal role can be attributed to oxidative stress.

Low plasma vitamin B-6 concentrations and modulation of coronary artery disease risk.

BACKGROUND: Low concentrations of pyridoxal-5'-phosphate (PLP), the active metabolite of vitamin B-6, are associated with high C-reactive protein (CRP) concentrations. Both low PLP and elevated inflammatory markers, such as high-sensitivity CRP (hs-CRP) and fibrinogen, are related to higher risk of coronary artery disease (CAD). OBJECTIVES: The objectives were to evaluate the relation between PLP and acute-phase reactants in affecting CAD risk and to estimate the risk of CAD related to low plasma PLP, either alone or in combination with high concentrations of acute-phase reactants and other classic risk factors for CAD. DESIGN: A case-control study was conducted with 742 participants: 475 with severe multivessel CAD and 267 free from coronary atherosclerosis (CAD-free). We measured plasma PLP, fibrinogen, hs-CRP, and serum lipid concentrations and all major biochemical CAD risk factors, including total homocysteine. RESULTS: A significant, inverse, graded relation was observed between PLP and both hs-CRP and fibrinogen (P < 0.001). The prevalence of PLP concentrations in the lower half of the population (<50th percentile: 36.3 nmol/L) was significantly higher among CAD patients than among CAD-free subjects (P < 0.001). The odds ratio for CAD risk related to low PLP concentrations after adjustments for the major classic CAD risk factors, including hs-CRP and fibrinogen, was 1.89 (95% CI: 1.18, 3.03; P = 0.008). The CAD risk as a result of low PLP was additive when considered in combination with elevated hs-CRP concentrations or with an increased ratio of LDL to HDL. CONCLUSION: Low plasma PLP concentrations are inversely related to major markers of inflammation and independently associated with increased CAD risk.

Determinants of platelet activation in human essential hypertension.

Experimental data suggest that oxidative stress might be enhanced in hypertension and contribute to platelet activation. We hypothesized that both oxidative stress and platelet activation could be related to the clinical characteristics of hypertensive patients. The urinary excretion of 11-dehydrothromboxane (TX) B2, reflecting in vivo platelet activation, was measured in 75 patients with mild to severe essential hypertension and 75 pair-matched, healthy controls. The urinary excretion of 8-iso-prostaglandin (PG) F2alpha was determined as an index of in vivo lipid peroxidation. Urinary 11-dehydro-TXB2 was significantly higher in essential hypertensives compared with controls. Although no statistically significant difference in urinary 8-iso-PGF2alpha was observed between patients and controls, plasma vitamin C was lower and plasma homocysteine higher in hypertensive patients than in controls. Both urinary 11-dehydro-TXB2 and 8-iso-PGF2alpha were higher in patients with advanced hypertensive retinopathy compared with patients without retinopathy. Multivariate linear regression analysis identified urinary 8-iso-PGF2alpha, plasma fibrinogen, homocysteine, and vitamin E as the only variables independently correlated with urinary 11-dehydro-TXB2. Logistic regression analysis showed that high urinary 8-iso-PGF2alpha, plasma fibrinogen, and homocysteine, as well as low plasma vitamin E, advanced retinopathy, elevated diastolic blood pressure, and the absence of antihypertensive treatment, were predictors of high urinary 11-dehydro-TXB2. We demonstrated increased oxidative stress and persistent platelet activation in essential hypertensives with advanced vascular lesions. These findings might help identify hypertensive patients who are at increased risk of cardiovascular events and who might benefit from long-term antiplatelet therapy.

The interaction between MTHFR 677 C-->T genotype and folate status is a determinant of coronary atherosclerosis risk.

The 677 C-->T polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene interacts with folate status in determining elevated total plasma levels of homocysteine, a risk factor for coronary atherosclerotic disease (CAD). The present study had the following goals: 1) to define the 677 C-->T genotype-specific threshold values of both plasma and RBC folate, associated with hyperhomocysteinemia (>15 micro mol/L); and 2) to determine the risk of CAD among subjects with levels of folate below the genotype-specific threshold considered at risk for hyperhomocysteinemia. We examined 655 subjects, with (433) or without (222) angiographically documented CAD. The MTHFR 677 C-->T genotype-specific threshold values of plasma folate corresponded to the 40th, 30th and 10th percentile in the TT, CT and CC genotype, respectively. A multivariate logistic regression analysis showed that the risk of CAD among subjects with plasma folate levels below the genotype-specific thresholds was 1.6 (95% CI, 1.04-2.46). Similar results were obtained when RBC folate was considered as a measure of folate status (odds ratio = 1.8, 95% CI, 1.03-3.15). A gene-nutrient interaction that defines a higher risk for CAD is determined by folate levels below specific thresholds, which differ depending on the MTHFR 677 C-->T genotype.

Homocysteine plasma concentration is related to severity of lung impairment in scleroderma.

OBJECTIVE: To investigate the correlation between plasma concentration of total homocysteine and pulmonary involvement in patients with limited or diffuse scleroderma (systemic sclerosis, SSc). METHODS: Seventy-one patients with scleroderma were divided into 3 groups based on pulmonary involvement: Group A comprised patients without lung involvement (9 cases); Group B patients with lung involvement of mild and moderate stages (44 cases); and Group C patients with lung involvement of severe stage and endstage (18 cases). At the time of evaluation of lung involvement all patients underwent determination of plasma homocysteine concentration. Homocysteine concentration was also measured in 30 healthy controls homogeneous for sex and age. RESULTS: In patients with scleroderma the homocysteine concentration was significantly higher than in controls (11.1 and 6.9 micromol/l, respectively; p < 0.001). We found a significant association between plasma homocysteine concentration and severity of lung involvement that was not modified by correction for age, time from the diagnosis, type of scleroderma pattern, and serum creatinine and folate levels. Homocysteine concentration progressively increases in scleroderma patients with more severe pulmonary involvement. Subjects with high homocysteine concentration (i.e., > or = 75th percentile of homocysteine concentration in patients with scleroderma without lung involvement) were mostly present in the group with the greatest lung involvement. CONCLUSION: High level of homocysteinemia is associated with an increased risk of pulmonary disease in patients with scleroderma. We hypothesize that hyperhomocysteinemia may worsen injury of the endothelium, a key lesion in scleroderma disease, favoring the development of lung involvement. Our data support the hypothesis that homocysteine could be involved in the pathogenetic process of scleroderma pulmonary involvement.

Glucose-induced alterations of intracellular ionized magnesium in human lymphocytes.

The intracellular ionic content of human erythrocytes may be altered by hyperglycaemia. Despite this, very little is known about the cellular mechanisms linking glucose and cellular magnesium homeostasis. We measured intracellular ionized magnesium in human lymphocytes, by means of a fluorimetric technique, total intracellular magnesium by means of atomic absorption spectrophotometry and intracellular ATP by means of HPLC. The incubation of lymphocytes with D-glucose in the absence of insulin was followed by a significant decrease in intracellular ionized magnesium; this effect did not occur when the cells were incubated with L-glucose. The effect of glucose on intracellular ionized magnesium was blocked by amphotericin B and the EC(50) of the effect of glucose on intracellular ionized magnesium was about 5 mmol/l of glucose. The increase of intracellular ionized magnesium in cells incubated in the absence of glucose was followed by a decrease in intracellular ATP. In a Na(+)-free medium the decrease of intracellular ionized magnesium in the presence of glucose was still present and the incubation of lymphocytes with glucose did not modify total intralymphocyte magnesium. By selective permeabilization of cell membranes, we established that glucose could not increase compartmentalized intracellular ionized magnesium. Our data supports the hypothesis that glucose per se induces a substantial decrease in intracellular ionized magnesium, which is probably due to an augmented binding of intracellular ionized magnesium to cellular ATP.

Biochemical and genetic markers of iron status and the risk of coronary artery disease: an angiography-based study.

BACKGROUND: Iron may promote coronary atherosclerotic disease (CAD) by increasing lipid peroxidation. Studies on biochemical or genetic markers of body iron stores as risk factors for CAD have yielded conflicting results. METHODS: We studied 849 individuals with a clear-cut definition of the CAD phenotype, i.e., with (CAD; n = 546) or without (CAD-free; n = 303) angiographically documented disease. We determined serum ferritin, as a biochemical estimate of iron stores, and the C282Y mutation in the HFE gene, i.e., the main cause of hemochromatosis in Caucasians. The relationships of ferritin with serum markers of either inflammation [C-reactive protein (CRP)] or lipid peroxidation (malondialdehyde) were also investigated. RESULTS: Mean ferritin concentrations were slightly higher in CAD vs CAD-free individuals, but this difference disappeared after adjusting for sex and CRP. Ferritin was significantly correlated with CRP (Spearman's test, rho = 0.129; P <0.001). Heterozygotes for Cys282Tyr were 4.8% among the CAD group and 6.6% among the CAD-free group (P = 0.26). The prevalence of high concentrations of stored iron, defined as ferritin concentrations above the sex-specific upper quintiles of the control distribution, was also similar in the two groups. There was a higher prevalence of "iron depletion" in CAD-free vs CAD females (20% vs 8.8%, respectively), but this difference disappeared after adjustment for age and other cardiovascular risk factors (odds ratio, 0.66; 95% confidence interval, 0.21-2.08). No differences in iron markers were found in CAD patients with or without myocardial infarction. CONCLUSIONS: Our results do not support a role for biochemical or genetic markers of iron stores as predictors of the risk of CAD or its thrombotic complications.