Non-invasive Measurements Of Atherosclerosis Research Articles

Iron and hepcidin as risk factors in atherosclerosis: what do the genes say?

BackgroundPrevious reports suggested a role for iron and hepcidin in atherosclerosis. Here, we evaluated the causality of these associations from a genetic perspective via (i) a Mendelian randomization (MR) approach, (ii) study of association of atherosclerosis-related single nucleotide polymorphisms (SNPs) with iron and hepcidin, and (iii) estimation of genomic correlations between hepcidin, iron and atherosclerosis.ResultsAnalyses were performed in a general population sample. Iron parameters (serum iron, serum ferritin, total iron-binding capacity and transferrin saturation), serum hepcidin and genome-wide SNP data were available for N = 1,819; non-invasive measurements of atherosclerosis (NIMA), i.e., presence of plaque, intima media thickness and ankle-brachial index (ABI), for N = 549. For the MR, we used 12 iron-related SNPs that were previously identified in a genome-wide association meta-analysis on iron status, and assessed associations of individual SNPs and quartiles of a multi-SNP score with NIMA. Quartile 4 versus quartile 1 of the multi-SNP score showed directionally consistent associations with the hypothesized direction of effect for all NIMA in women, indicating that increased body iron status is a risk factor for atherosclerosis in women. We observed no single SNP associations that fit the hypothesized directions of effect between iron and NIMA, except for rs651007, associated with decreased ferritin concentration and decreased atherosclerosis risk. Two of six NIMA-related SNPs showed association with the ratio hepcidin/ferritin, suggesting that an increased hepcidin/ferritin ratio increases atherosclerosis risk. Genomic correlations were close to zero, except for hepcidin and ferritin with ABI at rest [−0.27 (SE 0.34) and −0.22 (SE 0.35), respectively] and ABI after exercise [−0.29 (SE 0.34) and −0.30 (0.35), respectively]. The negative sign indicates an increased atherosclerosis risk with increased hepcidin and ferritin concentrations.ConclusionsOur results suggest a potential causal role for hepcidin and ferritin in atherosclerosis, and may indicate that iron status is causally related to atherosclerosis in women.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0246-4) contains supplementary material, which is available to authorized users.

Serum Hepcidin Is Associated With Presence of Plaque in Postmenopausal Women of a General Population

Iron and the iron regulatory hormone hepcidin, major determinant of body iron distribution, are hypothesized to play a role in cardiovascular disease. Here, we assess the associations of hepcidin as well as ferritin, iron, total iron-binding capacity, and transferrin saturation (ie, iron parameters) with noninvasive measurements of atherosclerosis in men and women of a population-based cohort. We included 766 participants of the Nijmegen Biomedical Study aged 46 to 67 years for whom serum measurements of hepcidin, iron parameters, and noninvasive measurements of atherosclerosis were available. Noninvasive measurements of atherosclerosis were presence of plaque, ankle-brachial index, and intima-media thickness. We performed multivariable logistic and linear regression analyses using quartiles of hepcidin and iron parameters. Analyses were stratified by sex and adjusted for several demographic, clinical, and biochemical determinants, including traditional risk factors of cardiovascular disease based on the Framingham risk score. Hepcidin and the hepcidin/ferritin ratio, reflecting hepcidin expression relative to iron stores, were significantly associated with the presence of plaque in women (adjusted odds ratios for quartile 4 versus quartile 1 [95% confidence intervals] of 3.07 [1.36-6.90] and 2.31 [1.03-5.18], respectively). The hepcidin/ferritin ratio was significantly and negatively associated with ankle-brachial index at rest in men and women (adjusted β for quartile 4 versus quartile 1 [95% confidence intervals] of -0.03 [-0.07 to 0.00] and -0.04 [-0.06 to -0.01], respectively). Our results suggest that the body iron distribution as determined by hepcidin affects the development of atherosclerosis in women.

Association between Metabolic Components and Subclinical Atherosclerosis in Korean Adults

BackgroundMany studies have attempted to develop relatively simple and easy noninvasive measurements of atherosclerosis (NIMA), and each NIMA assesses different atherosclerotic properties. We, therefore, investigated the association between metabolic syndrome (MetS) components and different NIMAs.MethodsThis study included 1,132 Korean subjects over 20 years of age who had visited a Health Promotion Center in Korea. Carotid injury (increased carotid intima-media thickness or plaques) was evaluated by ultrasonography and arterial stiffness by brachial-ankle pulse wave velocity. The MetS components were assessed according to the Asian criteria of the American Heart Association/National Heart, Lung, and Blood Institute.ResultsBoth arterial stiffness and carotid injury gradually deteriorated with increase in the number of MetS components. Arterial stiffness and carotid injury were associated with different MetS components, each of which had varying impact. After adjustment for all possible confounders such as age, sex, and lifestyle, elevated blood pressure (BP) was found to have the strongest association with arterial stiffness, whereas central obesity, impaired fasting plasma glucose, and elevated BP had comparable connection with carotid atherosclerosis.ConclusionIndividual MetS components were related with subclinical atherosclerosis in different ways. Elevated BP showed the strongest association with arterial stiffness, while central obesity, impaired fasting plasma glucose, and elevated BP showed good correlation with carotid atherosclerosis.

Application and validation of a diagnostic algorithm for the atherogenic apoB dyslipoproteinemias

We applied a diagnostic algorithm using apolipoprotein B (apoB) in combination with triglycerides (TG) and total cholesterol to determine the prevalence of dyslipoproteinemias in the general population. We also characterized the overall cardiovascular (CV) risk profiles, including arterial structure and function as measured with a panel of noninvasive parameters. Clinical and biochemical characteristics and noninvasive measurements of atherosclerosis (NIMA) were determined in 1517 individuals, aged 50-70 years. In general, all dyslipoproteinemias were characterized by a worse CV risk profile and deteriorated outcomes of NIMA compared to those with normal apolipoprotein B (< 1·2 g L(-1)) and TG (< 1·5 mM) levels. The prevalence of hyperapoB-hyperTG was 15·1%, and these individuals showed the most abnormal atheroma-related parameters: reduced ankle-brachial-index at rest (-3·5%) and after exercise (-9·8%), increased intima-media thickness (+5·5%) and more carotid plaques (+39·1%). The prevalence of normoapoB-hyperTG because of increased VLDL was 18·1% and 2·3% because of increased chylomicrons and VLDL, and in these groups, the parameters related to stiffness (e.g. pulse-wave-velocity +7·6% and +5·2%, respectively) were most abnormal. Adjustment for apolipoprotein B (apoB) reduced differences in NIMA in the hyperapoB-hyperTG group, whereas adjustment for TG reduced differences in NIMA in the normoapoB-hyperTG group. The overall prevalence of dyslipoproteinemias according to the algorithm was approximately 40% in the Dutch population. The different dyslipoproteinemias showed a less favourable CV risk profile and deteriorated NIMA parameters, reflecting increased subclinical atherosclerosis. Furthermore, different effects on different NIMA parameters were observed in the different dyslipoproteinemias.

Impact of waist circumference versus adiponectin level on subclinical atherosclerosis

Abstract. Holewijn S, den Heijer M, van Tits LJ, Swinkels DW, Stalenhoef AFH, de Graaf J (Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands). Impact of waist circumference versus adiponectin level on subclinical atherosclerosis. A cross‐sectional analysis in a sample from the general population. J Intern Med 2010; 267:588–598.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 &amp; 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 &gt;104 cm; F &gt;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 &lt;2.2 mg L−1; F &lt;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.

The Metabolic Syndrome and Its Traits as Risk Factors for Subclinical Atherosclerosis

The metabolic syndrome (MetS) indicates an increased cardiovascular risk. The objective of the present study was to determine the impact of the MetS and its individual traits on subclinical atherosclerosis, as measured with six noninvasive measurements of atherosclerosis (NIMA) in a 50- to 70-yr-old Dutch population-based cohort. Furthermore, we determined the impact of three different definitions of the MetS. We performed NIMA in 1517 participants of the Nijmegen Biomedical Study. The MetS was defined by definitions of the National Cholesterol Education Program, International Diabetes Federation, and the World Health Organization. Participants with the MetS (National Cholesterol Education Program) were characterized by increased subclinical atherosclerosis compared with participants without any trait of the MetS, as reflected by lower ankle-brachial index at rest [percent change (95% confidence interval), M: -5.2% (-9; -1), F: -3.1% (-6; -1)] and after exercise [M: -7.7% (-17;+2), F: -6.6% (-11; -2)], higher augmentation index [M: +4.8% (+3; +7), F: +1.9% (+4; +18)], increased pulse wave velocity [M: +22.8% (+15;+32), F: +20.5% (+14; +28)], increased intima-media thickness [M: +9.3% (+5; +13), F: +6.9% (+3; +11)], and thicker plaques [M: +17.6% (-2; +41), F: +26.6% (+5; +53)]. Most intriguingly, the number of traits was strongly associated with the severity of subclinical atherosclerosis because all NIMA gradually deteriorated with increasing number of traits present; NIMA were already deteriorated when one or two traits were present and further deteriorated when four or five traits of the MetS were present. Similar result were found when International Diabetes Federation and World Health Organization definitions of the MetS were used. For cardiovascular risk prediction, it is more important to take into account the presence of each individual trait and the number of traits of the MetS than to diagnose the presence of the MetS.

Variation in non-invasive measurements of vascular function in healthy volunteers during daytime

Although it is often recommended to standardize the time of day when performing non-invasive measurements of vascular function, the exact influence of the time of day on the outcome of IMT (intima-media thickness), PWV (pulse wave velocity), AIX (augmentation index) and FMD (flow-mediated dilatation) measurements has not been reported before. Nineteen healthy volunteers visited our department on two different occasions: the first visit was at 09:00 hours after an overnight fast, and the second visit was at 14:00 hours after a standardized breakfast. Non-invasive measurements of atherosclerosis were performed twice at 09:00 hours and once on the second visit at 14:00 hours. Measurement of IMT, PWV, AIX and FMD was reproducible according to the method of Bland and Altman. The absolute difference between repeated measurements at 09:00 hours showed no significant difference compared with the absolute difference between 09:00 and 14:00 hours for IMT (0.029+/-0.014 compared with 0.021+/-0.014 mm; P = 0.27), PWV (0.63+/-0.50 compared with 0.75+/-0.74 m/s; P = 0.52), AIX (4.0+/-4.0 compared with 5.5+/-5.2%; P = 0.35) and FMD (3.8+/-3.7 compared with 4.2+/-2.9%; P = 0.70). In conclusion, our results show that, in healthy volunteers during the daytime, IMT, PWV, AIX and FMD outcomes are not confounded by variation in the exact time of the examination as long as other (exogenous) conditions, including food intake, smoking and intake of alcohol, are carefully controlled for.

W17-P-019 Variation of non-invasive measurements of atherosclerosis in healthy volunteers during daytime

W17-P-019 Variation of non-invasive measurements of atherosclerosis in healthy volunteers during daytime

Interrelationship between non-invasive measurements of atherosclerosis: flow-mediated dilation of brachial artery, carotid intima-media thickness and pulse wave velocity

Flow-mediated dilation (FMD) of the brachial artery, carotid intima-media thickness (IMT) and pulse wave velocity (PWV) have been shown to be good surrogate markers of clinical atherosclerosis. We determined the interrelation between these measurements, and examined whether their combination would be of clinical significance. One hundred and thirty-five consecutive subjects (79 women/56 men) were enrolled, including 110 patients with risk factors for atherosclerosis, and 33 patients with atherosclerotic disease such as coronary heart disease, stroke or arteriosclerosis obliterans. IMT and plaque formation of the carotid artery and FMD of the brachial artery were assessed using ultrasonography. Brachial-ankle PWV (baPWV) was measured using an automated device (form ABI/PWV, Colin). Age, FMD, IMT and PWV were significantly correlated with each other. Multivariate analysis revealed an independent correlation between the parameters except for FMD, and all four parameters were independently correlated with each other in subjects <70 years. Next, we classified the subjects by tertile according to the values of FMD, IMT and PWV. Each of the worst tertiles was associated with a higher prevalence of atherosclerotic disease and carotid plaques compared to the other tertiles. Moreover, subjects with the worst tertiles of all three measurements had a markedly higher prevalence of atherosclerotic disease and carotid plaques. These results suggest that FMD, IMT and PWV are related to each other, but the combination of these measurements will be of stronger clinical relevance.

Noninvasive methods for evaluation of atherosclerosis in man

Accelerated atherosclerosis is known to occur in diabetes mellitus, but the exact mechanisms for this adverse consequence are unknown. Prospective determination of each patient's state of atherosclerosis coupled with serial comparisons between patients could be used to clarify relationships between insulin levels and growth rates of atherosclerotic lesions. Noninvasive measurements of atherosclerosis that are now feasible are phonoangiography, continuous-wave and pulsed Doppler ultrasound imaging, reflected beta-mode ultrasound imaging, computed axial tomography, and nuclear magnetic resonance imaging. An interesting new application of ultrasound beta-mode imaging for the estimation of localized arterial wall stiffness is described.