Mucosal lactoferrin response to genital tract infections is associated with iron and nutritional biomarkers in young Burkinabé women.

BACKGROUND/OBJECTIVES: The iron-binding affinity of vaginal lactoferrin (Lf) reduces iron available to genital pathogens. We describe host reproductive, nutritional, infection and iron biomarker profiles affecting vaginal Lf concentration in young nulliparous and primigravid women in Burkina Faso. SUBJECTS/METHODS: Vaginal eluates from women who had participated in a randomized, controlled periconceptional iron supplementation trial were used to measure Lf using a competitive double-sandwich ELISA. For this analysis samples from both trial arms were combined and pregnant and non-pregnant cohorts compared. Following randomization Lf was measured after 18 months (end assessment) for women remaining non-pregnant, and at two antenatal visits for those becoming pregnant. Associations between log Lf levels and demographic, anthropometric, infection and iron biomarker variables were assessed using linear mixed models. RESULTS: Lf samples were available for 712 non-pregnant women at end assessment and for 303 women seen at an antenatal visit. Lf concentrations of pregnant women were comparable to those of non-pregnant, sexually active women. Lf concentration increased with mid-upper-arm circumference, (P = 0.047), body mass index (P = 0.018), Trichomonas vaginalis (P < 0.001) infection, bacterial vaginosis (P < 0.001), serum C-reactive protein (P = 0.048) and microbiota community state types III/IV. Adjusted Lf concentration was positively associated with serum hepcidin (P = 0.047), serum ferritin (P = 0.018) and total body iron stores (P = 0.042). There was evidence that some women maintained persistently high or low Lf concentrations from before, and through, pregnancy. CONCLUSION: Lf concentrations increased with genital infection, higher BMI, MUAC, body iron stores and hepcidin, suggesting nutritional and iron status influence homeostatic mechanisms controlling vaginal Lf responses.

Iron uptake by ZIP8 and ZIP14 in human proximal tubular epithelial cells.

In patients with iron overload disorders, increasing number of reports of renal dysfunction and renal iron deposition support an association between increased iron exposure and renal injury. In systemic iron overload, elevated circulating levels of transferrin-bound (TBI) and non-transferrin-bound iron (NTBI) are filtered to the renal proximal tubules, where they may cause injury. However, the mechanisms of tubular iron handling remain elusive. To unravel molecular renal proximal tubular NTBI and TBI handling, human conditionally immortalized proximal tubular epithelial cells (ciPTECs) were incubated with 55Fe as NTBI and fluorescently labeled holo-transferrin as TBI. Ferrous iron importers ZIP8 and ZIP14 were localized in the ciPTEC plasma membrane. Whereas silencing of either ZIP8 or ZIP14 alone did not affect 55Fe uptake, combined silencing significantly reduced 55Fe uptake compared to control (p < 0.05). Furthermore, transferrin receptor 1 (TfR1) and ZIP14, but not ZIP8, colocalized with early endosome antigen 1 (EEA1). TfR1 and ZIP14 also colocalized with uptake of fluorescently labeled transferrin. Furthermore, ZIP14 silencing decreased 55Fe uptake after 55Fe-Transferrin exposure (p < 0.05), suggesting ZIP14 could be involved in early endosomal transport of TBI-derived iron into the cytosol. Our data suggest that human proximal tubular epithelial cells take up TBI and NTBI, where ZIP8 and ZIP14 are both involved in NTBI uptake, but ZIP14, not ZIP8, mediates TBI-derived iron uptake. This knowledge provides more insights in the mechanisms of renal iron handling and suggests that ZIP8 and ZIP14 could be potential targets for limiting renal iron reabsorption and enhancing urinary iron excretion in systemic iron overload disorders.

Variable workup calls for guideline development for type 2A hereditary haemochromatosis.

BACKGROUND: Type 2A hereditary haemochromatosis (type 2A HH) is a rare iron-loading disorder caused by mutations in the HFE2 gene, which encodes the HJV protein. We present characteristics, treatment and follow-up of subjects diagnosed with type 2A HH in the Netherlands to increase awareness of the disease and its treatment, and to define knowledge gaps. METHODS: We collected clinical, biochemical and genetic data from seven patients (two female; five probands) from six families genetically diagnosed with type 2A HH at the Expertise Center for Iron Disorders, Radboud University Medical Centre between 2006 and 2016. RESULTS: The five probands presented with heterogeneous complaints between the ages of 19 and 39. One of two patients with delayed clinical diagnosis developed hypogonadism and Y. enterocolitica sepsis. Diagnostic workup and follow-up varied. When assessed, elevated transferrin saturation (79-98%), ferritin (1400-6200 µg/l) and severely elevated liver iron levels were found, and in all subjects, phlebotomies were initiated. One subject was switched to erythrocytapheresis. Target ferritin levels varied. Despite long-term iron depletion, two subjects developed clinical complications. Sanger sequencing revealed two pathogenic HFE2 variants (homozygous or compound heterozygous) for the five families of Dutch descent and one new pathogenic variant in the family of non-Dutch descent. CONCLUSION: Three genetic variants caused type 2A HH in six families. Clinical diagnosis was delayed in two subjects. We observed variance in presentation, workup, follow-up and treatment. We found new complications in long-term iron-depleted patients. We recommend research and guidelines for optimal workup, follow-up and treatment of type 2A HH.

Inhibition of Nrf2 alters cell stress induced by chronic iron exposure in human proximal tubular epithelial cells.

Iron can catalyze reactive oxygen species (ROS) formation, causing cellular injury. In systemic iron overload, renal tubular epithelial cells are luminally exposed to high iron levels due to glomerular filtration of increased circulating iron. Reports of tubular dysfunction and iron deposition in ß-thalassemia major support an association between increased chronic iron exposure and renal tubular injury. In acute iron exposure, Nuclear factor-erythroid 2-related factor 2 (Nrf2) may protect from iron-induced injury, whereas chronic renal stress may lead to Nrf2 exhaustion. We studied the cytotoxic mechanisms of chronic iron exposure using human conditionally immortalized proximal tubular epithelial cells (ciPTECs). Long-term iron exposure resulted in iron accumulation, cytosolic ROS formation and increased heme oxygenase 1 (HMOX-1) mRNA expression (all p < 0.001). This was accompanied by nuclear translocation of Nrf2 and induction of its target protein NQO1, which both could be blocked by the Nrf2 inhibitor trigonelline. Interestingly, iron and trigonelline incubation reduced ROS production, but did not affect HMOX-1 mRNA levels. Moreover, ferritin protein and CHOP mRNA expression were induced in combined iron and trigonelline incubated cells (p < 0.05). Together, these findings suggest that chronic iron exposure induces oxidative stress and that exhaustion of the antioxidant Nrf2 pathway may lead to renal injury.

Biochemical Effects on the Liver of 1 Month of Alcohol Abstinence in Moderate Alcohol Consumers.

SHORT SUMMARY: : In this study in healthy moderate alcohol consumers, we observe that one month of alcohol abstinence results in decreased gamma-glutamyl transferase levels, which return to baseline levels after resumption of alcohol consumption.

TFR2-related haemochromatosis in the Netherlands: a cause of arthralgia in young adulthood.

BACKGROUND: Type 3 hereditary haemochromatosis (HH) is a rare iron overload disorder caused by variants in the transferrin 2 receptor (TFR2) gene. We aim to present characteristics of patients diagnosed with TFR2-HH in the Netherlands, in order to increase knowledge and awareness of this disease. METHODS: We collected clinical, biochemical and genetic data from four patients from three families diagnosed with HH type 3 in the Netherlands between 2009 and 2016. RESULTS: Three women and one man diagnosed with HH type 3 presented with arthralgia and elevated ferritin levels and transferrin saturation (TSAT) at ages 25-41 years. The hepcidin/ferritin ratio as measured in three patients was low. Liver iron content in two patients as assessed by MRI or liver biopsy was highly increased (250 and 362.7 µmol iron/g dry weight, respectively, reference < 35 µmol/g). DNA analysis revealed four different TFR2 pathogenic variants: one nonsense, one splicing and two missense variants, of which three are novel. Phlebotomy decreased the serum iron parameters but did not relieve the arthralgia. CONCLUSION: In patients with a combination of elevated TSAT and ferritin in the absence of anaemia, and after exclusion of HFE-related HH, rare forms of HH should be considered. In these cases, presentation with arthralgia in young adulthood, low hepcidin/ferritin ratio and/or liver iron content > 100 µmol/g form an indication for analysis of the TFR2 gene. Although type 3 HH is extremely rare, awareness of the disease among physicians is important in order to achieve an early diagnosis and prevent complications, such as liver damage.

Live high, train low - influence on resting and post-exercise hepcidin levels.

The post-exercise hepcidin response during prolonged (>2 weeks) hypoxic exposure is not well understood. We compared plasma hepcidin levels 3 h after exercise [6 × 1000 m at 90% of maximal aerobic running velocity (vVO2max )] performed in normoxia and normobaric hypoxia (3000 m simulate altitude) 1 week before, and during 14 days of normobaric hypoxia [196.2 ± 25.6 h (median: 200.8 h; range: 154.3-234.8 h) at 3000 m simulated altitude] in 10 well-trained distance runners (six males, four females). Venous blood was also analyzed for hepcidin after 2 days of normobaric hypoxia. Hemoglobin mass (Hbmass ) was measured via CO rebreathing 1 week before and after 14 days of hypoxia. Hepcidin was suppressed after 2 (Cohen's d = -2.3, 95% confidence interval: [-2.9, -1.6]) and 14 days of normobaric hypoxia (d = -1.6 [-2.6, -0.6]). Hepcidin increased from baseline, 3 h post-exercise in normoxia (d = 0.8 [0.2, 1.3]) and hypoxia (d = 0.6 [0.3, 1.0]), both before and after exposure (normoxia: d = 0.7 [0.3, 1.2]; hypoxia: d = 1.3 [0.4, 2.3]). In conclusion, 2 weeks of normobaric hypoxia suppressed resting hepcidin levels, but did not alter the post-exercise response in either normoxia or hypoxia, compared with the pre-exposure response.

Safety, pharmacokinetics and pharmacodynamics of the anti-hepcidin Spiegelmer lexaptepid pegol in healthy subjects.

BACKGROUND AND PURPOSE: Anaemia of chronic disease is characterized by impaired erythropoiesis due to functional iron deficiency, often caused by excessive hepcidin. Lexaptepid pegol, a pegylated structured l-oligoribonucleotide, binds and inactivates hepcidin. EXPERIMENTAL APPROACH: We conducted a placebo-controlled study on the safety, pharmacokinetics and pharmacodynamics of lexaptepid after single and repeated i.v. and s.c. administration to 64 healthy subjects at doses from 0.3 to 4.8 mg·kg(-1) . KEY RESULTS: After treatment with lexaptepid, serum iron concentration and transferrin increased dose-dependently. Iron increased from approximately 20 µmol·L(-1) at baseline by 67% at 8 h after i.v. infusion of 1.2 mg·kg(-1) lexaptepid. The pharmacokinetics showed dose-proportional increases in peak plasma concentrations and moderately over-proportional increases in systemic exposure. Lexaptepid had no effect on hepcidin production or anti-drug antibodies. Treatment with lexaptepid was generally safe and well tolerated, with mild and transient transaminase increases at doses ≥2.4 mg·kg(-1) and with local injection site reactions after s.c. but not after i.v. administration. CONCLUSIONS AND IMPLICATIONS: Lexaptepid pegol inhibited hepcidin and dose-dependently raised serum iron and transferrin saturation. The compound is being further developed to treat anaemia of chronic disease.

Hepcidin in chronic kidney disease: not an anaemia management tool, but promising as a cardiovascular biomarker.

Hepcidin is a key regulator of iron homeostasis and plays a role in the pathogenesis of anaemia of chronic disease. Its levels are increased in patients with chronic kidney disease (CKD) due to diminished renal clearance and an inflammatory state. Increased hepcidin levels in CKD patients are supposed to be responsible for functional iron deficiency in these patients and contribute to renal anaemia and resistance to erythropoiesis-stimulating agents. Therefore, hepcidin was purported to be useful as a management tool guiding treatment of renal anaemia. Furthermore, since hepcidin is associated with iron accumulation in macrophages in the vessel wall inducing oxidative stress and atherosclerosis, it has been speculated that hepcidin might function as a biomarker of cardiovascular disease. In this descriptive review, the merits of hepcidin with respect to its role in the pathophysiology of renal anaemia in CKD patients, its presumptive role as a practical diagnostic tool guiding management of renal anaemia, and its possible usefulness as a prognostic biomarker will be discussed.

Donation intensity and metabolic syndrome in active whole-blood donors.

BACKGROUND AND OBJECTIVES: Increased iron and metabolic syndrome (MetS) go hand in hand. Frequent blood donation depletes iron stores. This study investigates whether high-intensity blood donation is associated with lower MetS prevalence compared with low-intensity blood donation, and whether iron acts as an intermediary factor. MATERIALS AND METHODS: A random sample of 422 male and 211 female active whole-blood donors ≥45 years of age was included in a cross-sectional study. Lipids, glucose and iron parameters were measured after overnight fasting. MetS was defined according to the joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention. Three groups of donation intensity were created by sex-specific tertiles of donation frequency per year and duration of donor career. RESULTS: MetS was present in 22·9% of donors. Prevalence of MetS was 1·46 (95% confidence interval [CI]: 0·93-2·30) times higher in men with high donation intensity, whereas in women MetS prevalence was 2·14 (95% CI: 0·94-4·86) times higher in donors with high donation intensity compared with those with low donation intensity. In men, increased prevalence of MetS was mainly associated with higher ferritin, whereas high hepcidin predominantly affected MetS prevalence in women. CONCLUSION: High-intensity blood donation is not associated with a decreased prevalence of MetS. In men and women, different iron parameters are associated with MetS prevalence. The temporal relationship between blood donation, iron and MetS, and gender differences herein need to be explored in future research.

X-linked sideroblastic anaemia due to ALAS2 mutations in the Netherlands: a disease in disguise.

BACKGROUND: X-linked sideroblastic anaemia (XLSA; OMIM#300751) is the most common inherited form of sideroblastic anaemia and is associated with several mutations in the erythroid specific 5-aminolevulinate synthase gene (ALAS2). This gene encodes for aminolevulinic acid synthase 2 (ALAS2), the catalytic enzyme involved in the first en rate-limiting step of haem biosynthesis.1-3 The disorder is characterised by mostly mild hypochromic microcytic anaemia with bone marrow ring sideroblasts. Even untransfused patients with mild or no anaemia are at risk for severe systemic iron overload due to ineffective erythropoiesis. To date, 61 different ALAS2 mutations have been reported in 120 families with XLSA. Descriptions of molecularly confirmed case series from the Netherlands, however, are lacking. METHODS: We reviewed age of presentation, clinical and biochemical features, ALAS₋2 defects and treatment characteristics of 15 Dutch patients from 11 unrelated families diagnosed with XLSA. RESULTS AND CONCLUSIONS: In one family a novel pathogenic c.1412G>A (p.Cys471Tyr) mutation was found. All other families shared the previously described c.1355G>A (p.Arg452His) mutation. Haplotype analysis in seven probands with the p.Arg452His mutation strongly suggests that six of them were ancestrally related. Nevertheless, their phenotype was very different. Our patients illustrate the phenotypical heterogeneity in the presentation of XLSA patients, the effectiveness of treatment regimens and the various pitfalls associated with the diagnosis, follow-up and treatment of the disease. A timely diagnosis avoids unnecessary investigations and allows adequate treatment that can prevent systemic iron load with subsequent severe life-threatening complications. Therefore, we suggest considering XLSA in both male and female patients with unexplained iron overload and÷or (mild) microcytic anaemia, also at older age.

Iron metabolism in the pathogenesis of iron-induced kidney injury.

In the past 8 years, there has been renewed interest in the role of iron in both acute kidney injury (AKI) and chronic kidney disease (CKD). In patients with kidney diseases, renal tubules are exposed to a high concentration of iron owing to increased glomerular filtration of iron and iron-containing proteins, including haemoglobin, transferrin and neutrophil gelatinase-associated lipocalin (NGAL). Levels of intracellular catalytic iron may increase when glomerular and renal tubular cells are injured. Reducing the excessive luminal or intracellular levels of iron in the kidney could be a promising approach to treat AKI and CKD. Understanding the role of iron in kidney injury and as a therapeutic target requires insight into the mechanisms of iron metabolism in the kidney, the role of endogenous proteins involved in iron chelation and transport, including hepcidin, NGAL, the NGAL receptor and divalent metal transporter 1, and iron-induced toxic effects. This Review summarizes emerging knowledge, which suggests that complex mechanisms of iron metabolism exist in the kidney, modulated directly or indirectly by cellular iron content, inflammation, ischaemia and oxidative stress. The potential exists for prevention and treatment of iron-induced kidney injury by customized iron removal or relocation, aided by detailed insight into the underlying pathological mechanisms.

Blood lipid levels and prostate cancer risk; a cohort study.

It has been hypothesized that blood lipid levels might be associated with prostate cancer risk. The aim of the present study was to evaluate the association between serum total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and prostate cancer risk in a cohort study among 2842 Dutch men. By the end of follow-up, 64 incident cases of prostate cancer were identified. Serum total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides were evaluated as potential risk factors for prostate cancer using multivariable Cox proportional hazards regression models. These analyses were restricted to men who never used cholesterol-lowering drugs (2118 men, 43 cases). Higher total and higher LDL cholesterol were significantly associated with an increased risk of prostate cancer (hazards ratios (HR) and 95% confidence interval (CI) per mmol l(-1) were 1.39 (95% CI 1.03-1.88) and 1.42 (95% CI 1.00-2.02), respectively). Similar results were observed for aggressive prostate cancer, whereas for non-aggressive prostate cancer a significant association with HDL cholesterol was found (HR 4.28, 95% CI 1.17-15.67). The results of this study suggest that blood lipid levels may influence risk of prostate cancer. However, the exact roles of different cholesterol fractions on prostate cancer aggressiveness should be further evaluated.

Need for early recognition and therapeutic guidelines of congenital sideroblastic anaemia.

We present a patient with iron overload, who was initially diagnosed with hereditary haemochromatosis. Family analysis, however, established that the iron overload was secondary to congenital sideroblastic anaemia. The patient died of a hepatocellular carcinoma, likely a complication of iron overload, despite phlebotomies. Increased awareness, as well as development of evidence-based clinical guidelines, is required for timely diagnosis and adequate treatment.

Serum ferritin levels are associated with vascular damage in patients with nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Increased ferritin and body iron stores are frequently observed in nonalcoholic fatty liver disease (NAFLD), associated with heightened susceptibility to vascular damage. Conflicting data have been reported on the role of iron in atherosclerosis, with recent data suggesting that excess iron induces vascular damage by increasing levels of the hormone hepcidin, which would determine iron trapping into macrophages, oxidative stress, and promotion of transformation into foam cells. Aim of this study was to investigate the relationship between iron status and cardiovascular damage in NAFLD. METHODS AND RESULTS: Vascular damage was evaluated by common carotid arteries intima-media thickness (CC-IMT) measurement and plaque detection by ecocolor-doppler ultrasonography in 506 patients with clinical and ultrasonographic diagnosis of NAFLD, hemochromatosis gene (HFE) mutations by restriction analysis in 342 patients. Serum hepcidin-25 was measured by time-of-flight mass spectrometry in 143 patients. At multivariate analysis CC-IMT was associated with systolic blood pressure, glucose, LDL cholesterol, abdominal circumference, age, and ferritin (p=0.048). Carotid plaques were independently associated with age, ferritin, glucose, and hypertension. Ferritin reflected iron stores and metabolic syndrome components, but not inflammation or liver damage. Hyperferritinemia was associated with increased vascular damage only in patients with HFE genotypes associated with hepcidin upregulation by iron stores (p<0.0001), and serum hepcidin-25 was independently associated with carotid plaques (p=0.05). CONCLUSION: Ferritin levels, reflecting iron stores, are independent predictors of vascular damage in NAFLD. The mechanism may involve upregulation of hepcidin by increased iron stores in patients not carrying HFE mutations, and iron compartmentalization into macrophages.

Apolipoprotein B, non-HDL cholesterol and LDL cholesterol for identifying individuals at increased cardiovascular risk.

BACKGROUND: To compare apolipoprotein B (apoB), non-high-density lipoprotein-cholesterol (non-HDL-c) and low-density lipoprotein-cholesterol (LDL-c) for identifying individuals with a deteriorated cardiovascular (CV) risk profile, including a panel of subclinical atherosclerosis measurements and prevalent cardiovascular disease (CVD) in a Dutch population-based cohort. METHODS: Clinical and biochemical measurements and a panel of noninvasive parameters of subclinical atherosclerosis were determined in 1517 individuals, aged 50-70 years. RESULTS: Both men and women with increasing levels of apoB and non-HDL-c were more obese, had higher blood pressure and fasting glucose levels, and a more atherogenic lipid profile. Furthermore, compared to the reference group (composed of those with apoB, non-HDL-c and LDL-c levels in the bottom quartiles), participants with high apoB and high non-HDL-c levels had a lower ankle-brachial index at rest (-3.5% and -3.1%, respectively) and after exercise (-6.3% and -4.7%, respectively), a thicker near wall (+4.8% and +4.2%, respectively), far wall (both +6.2%), and mean intima-media thickness (+5.7% and +5.3%, respectively) and more plaques (+54.2% and +54.3%, respectively). In addition, they also showed increased stiffness parameters (e.g. pulse wave velocity both +3.6%). Less clear differences in CV risk profile and subclinical atherosclerosis parameters were observed when participants were stratified by LDL-c level. Furthermore, apoB but not LDL-c detected prevalent CVD, and non-HDL-c only detected prevalent CVD in men. The discriminatory power for prevalent CVD expressed as area under the receiver operating characteristic curve was 0.60 (P < 0.001) for apoB, 0.57 (P = 0.001) for non-HDL-c and 0.54 (P = 0.108) for LDL-c. CONCLUSION: Our data support the use of first apoB and secondly non-HDL-c above LDL-c for identifying individuals from the general population with a compromised CV phenotype.

Effect of body mass index reduction on serum hepcidin levels and iron status in obese children.

Iron deficiency has been linked to obesity. Hepcidin is the main regulator of iron homeostasis and is higher in obese children compared to controls. To gain insight into the link between obesity and hepcidin, we performed an intervention study in 15 obese children. These children were subjected to a 6-month weight loss program and underwent physical examination and iron status and absorption as well as hepcidin, interleukin-6 and leptin serum levels evaluation at baseline and after the weight loss program. After the program all children reduced their body mass index standard deviation score (BMI SDS) of at least 0.5. We observed a significant decrease in hepcidin (P=0.003) and leptin levels (P=0.005), and a significant increase in iron absorption (P=0.02). A direct correlation between the measure of hepcidin and leptin reduction was observed and this correlation appeared significant (r²=0.33, P=0.003) when adjusted for interleukin-6 and BMI SDS variations. In conclusion, we have shown that, in obese children, BMI reduction is associated with hepcidin reduction, potentially improving iron status and absorption. Implications of these findings could be considered in the management of obese children with poor iron status.

Impact of waist circumference versus adiponectin level on subclinical atherosclerosis: a cross-sectional analysis in a sample from the general population.

OBJECTIVE: Waist circumference is a clinical marker of obesity and an established risk factor for cardiovascular (CV) disease. Adiponectin, an adipocyte-derived hormone and new biomarker of obesity, was recently proposed as the missing link between obesity and increased cardiovascular risk. We evaluated waist and adiponectin in a middle-aged population-based cohort to compare the impact of both obesity-markers on subclinical atherosclerosis, in relation to other CV risk factors. DESIGN, SETTING & SUBJECTS: Seven noninvasive measurements of atherosclerosis (NIMA), as surrogate markers of (subclinical) atherosclerosis, were determined in 1517 participants of the Nijmegen Biomedical Study, aged 50-70 years, who were drawn from the Dutch community. RESULTS: Both men and women with a high waist (M >104 cm; F >95 cm) showed increased pulse wave velocity (PWV) (M: +9.4%; F: +8.3%) and thicker intima-media thickness (IMT) (M: +7.3%; F: +4.3%) and women also showed increased plaque thickness (+16.6%). After adjustment for other CV risk factors both men and women showed increased IMT (M: +4.8%; F: +2.8%) and men also showed increased PWV (+9.6%). Both men and women with a low adiponectin level (M <2.2 mg L(-1); F <3.5 mg L(-1)) showed a decreased ankle-brachial index after exercise (M: -9.5%; F: -3.9%) and increased IMT (M: +3.7%; F: +3.6%) and women also showed increased PWV (+6.8%), but after adjustment for other CV risk factors low adiponectin level was no longer associated with deteriorated outcomes of NIMA. CONCLUSIONS: Waist circumference showed independent associations with noninvasive measurements of subclinical atherosclerosis, whereas the association of adiponectin level with subclinical atherosclerosis was not independent of other CV risk factors. Prospective studies are needed to elucidate, if the atherogenic effect of a low adiponectin level is mediated by other CV risk factors and not by low adiponectin level intrinsically.

Brachial artery diameter is related to cardiovascular risk factors and intima-media thickness.

BACKGROUND: Previous reports showed inconsistent results about the potential role of flow-mediated dilatation (FMD) in cardiovascular(CV) risk prediction. Few data are available about the role of nitroglycerin-mediated dilatation (NMD), but recently, brachial artery diameter(BAD) appeared to have predictive value in CV risk prediction.We determined the relation of FMD, BAD and NMD with known CV risk factors and intima-media thickness (IMT), a well-established surrogate marker of atherosclerosis, in a community-based population, the Nijmegen Biomedical Study (NBS). MATERIALS AND METHODS: FMD, BAD and NMD were measured in the brachial, and IMT in the common carotid artery ultrasononically in 337 participants, aged 50-70 years. Traditional clinical and biochemical parameters were determined. RESULTS: Both FMD and NMD were not correlated with most CV risk factors or prevalent CVD. However, both IMT and BAD did show significant correlations with CV risk factors. In accordance, both IMT and BAD were significantly correlated with prevalent CVD (r=0.62 and r=-0.37, respectively) . Furthermore, FMD was not correlated with IMT and did hardly (R2=1.1%) improve the prediction of IMT by CV risk factors in regression analysis. However, both BAD and NMD did correlate with IMT (r=-0.29 and r=0.25, respectively). CONCLUSION: In our study, FMD and NMD were not related to known CV risk factors and prevalent CVD, and FMD was not correlated with IMT, a surrogate marker of atherosclerosis. Most intriguingly, BAD was significantly correlated with some CV risk factors, prevalent CVD and IMT. So, BAD is a potential valuable tool in CV risk prediction in middle-aged low-risk populations, whereas FMD is not.