Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed-forward loop between LXR and autophagy.

BACKGROUND: Hyperlipidaemia is a major risk factor for cardiovascular disease, and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development. OBJECTIVE: We sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 on subclinical atherosclerosis and the mechanism by which it acts. METHODS: A pan-European cohort of high-risk individuals where carotid intima-media thickness has been assessed was adopted. Human primary monocyte-derived macrophages were prepared from whole blood from individuals recruited by perilipin-2 genotype or from buffy coats from the Karolinska University hospital blood central. RESULTS: The Pro251 variant of perilipin-2 is associated with decreased intima-media thickness at baseline and over 30 months of follow-up. Using human primary monocyte-derived macrophages from carriers of the beneficial Pro251 variant, we show that this variant increases autophagy activity, cholesterol efflux and a controlled inflammatory response. Through extensive mechanistic studies, we demonstrate that increase in autophagy activity is accompanied with an increase in liver-X-receptor (LXR) activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol. CONCLUSIONS: For the first time, we show that perilipin-2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin-2 modulates levels of the LXR ligand 27OH-cholesterol and initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its beneficial effects on subclinical atherosclerosis.

Interval Change in Diffusion and Perfusion MRI Parameters for the Assessment of Pseudoprogression in Cerebral Metastases Treated With Stereotactic Radiation.

OBJECTIVE: Apparent increases in the size of cerebral metastases after stereotactic radiosurgery (SRS) can be caused by pseudoprogression or true disease progression, which poses a diagnostic challenge at conventional MRI. The purpose of this study was to assess whether interval change in DWI and perfusion MRI parameters can differentiate pseudoprogression from progressive disease after treatment with SRS. MATERIALS AND METHODS: Patients with apparent growth of cerebral metastases after SRS treatment who underwent pre- and post-SRS DWI, dynamic susceptibility contrast (DSC)-MRI, and perfusion dynamic contrast-enhanced (DCE)-MRI were retrospectively evaluated. Final assignment of pseudoprogression or progressive disease was determined at 6-month follow-up imaging using the Response Assessment in Neuro-Oncology Brain Metastases criteria. Mean values of apparent diffusion coefficient (ADC), DCE-MRI-derived volume transfer constant (Ktrans), and DSC-MRI-derived relative cerebral blood volume (CBV) from pre- and post-SRS MRI scans were compared between groups using univariate and regression analysis. Fisher exact test was used to compare interval change of imaging biomarkers. RESULTS: Of 102 cerebral metastases evaluated, 32 lesions in 29 patients met our inclusion criteria. The mean duration of follow-up was 7.2 months (range, 6-14 months). Twenty-two lesions were determined as pseudoprogression, and 10 lesions were determined as progressive disease using the Response Assessment in Neuro-Oncology Brain Metastases criteria at 6-month follow-up MRI. The interval change pattern of our imaging parameters matched the expected patterns of treatment response for ADC (23/32 lesions; 72%; p = 0.055; odds ratio, 5.1), Ktrans (24/32 lesions; 75%; p = 0.006; odds ratio, 19.2), and relative CBV (27/32 lesions; 84%; p = 0.001; odds ratio, 25.3). CONCLUSION: Pseudoprogression can be distinguished from disease progression in cerebral metastases treated with SRS via an interval decrease in relative CBV and Ktrans values.

Integrative studies implicate matrix metalloproteinase-12 as a culprit gene for large-artery atherosclerotic stroke.

BACKGROUND: Ischaemic stroke and coronary heart disease are important contributors to the global disease burden and share atherosclerosis as the main underlying cause. Recent evidence from a genome-wide association study (GWAS) suggested that single nucleotide polymorphisms (SNP) near the MMP12 gene at chromosome 11q22.3 were associated with large-vessel ischaemic stroke. Here, we evaluated and extended these results by examining the relationship between MMP12 and atherosclerosis in clinical and experimental studies. METHODS AND RESULTS: Plasma concentrations of MMP12 were measured at baseline in 3394 subjects with high-risk for cardiovascular disease (CVD) using the Olink ProSeek CVD I array. The plasma MMP12 concentration showed association with incident cardiovascular and cerebrovascular events (130 and 67 events, respectively, over 36 months) and carotid intima-media thickness progression (P = 3.6 × 10-5 ). A GWAS of plasma MMP12 concentrations revealed that SNPs rs499459, rs613084 and rs1892971 at chr11q22.3 were independently associated with plasma MMP12 (P < 5 × 10-8 ). The lead SNPs showed associations with mRNA levels of MMP12 and adjacent MMPs in atherosclerotic plaques. MMP12 transcriptomic and proteomic levels were strongly significantly increased in carotid plaques compared with control arterial tissue and in plaques from symptomatic versus asymptomatic patients. By combining immunohistochemistry and proximity ligation assay, we demonstrated that MMP12 localizes to CD68 + macrophages and interacts with elastin in plaques. MMP12 silencing in human THP-1-derived macrophages resulted in reduced macrophage migration. CONCLUSIONS: Our study supports the notion that MMP12 is implicated in large-artery atherosclerotic stroke, functionally by enhancing elastin degradation and macrophage invasion in plaques.

Brachytherapy for Central Serous Chorioretinopathy.

Brachytherapy is widely used for the treatment of choroidal melanoma and has recently been explored for the treatment of wet age-related macular degeneration. We propose the use of low dose radiation via episcleral brachytherapy in refractory cases of central serous chorioretinopathy (CSCR). The pathogenesis of CSCR involves dilatation and hyperpermeability of large choroidal vessels. Low dose radiation can induce intimal proliferation in large choroidal vessels and decrease their hyperpermeability. Concerns about the use of brachytherapy in CSCR include damage to the choriocapillaris or the retinal vessels. This can be addressed with the use of a specialized device through which a very precise and appropriate dose can be delivered. The dose of the radiation delivered decreases exponentially at a depth of approximately 0.5-1.5 mm from the devise-sclera interface. Considering an increased choroidal thickness in cases of CSCR, delivery of a safe dose can be assured.

Interaction between female mating preferences and predation may explain the maintenance of rare males in the pentamorphic fish Poecilia parae.

Variation in mating preferences coupled with selective predation may allow for the maintenance of alternative mating strategies. Males of the South American live-bearing fish Poecilia parae fall in one of five discrete morphs: red, yellow, blue, stripe-coloured tail (parae) and female mimic (immaculata). Field surveys indicate that the red and yellow morphs are the rarest and that their rarity is consistent across years. We explored the role of variable female mating preference and selective predation by visual predators in explaining the rarity of red and yellow males, and more generally, the maintenance of this extreme colour polymorphism. We presented wild-caught P. parae females and Aequidens tetramerus, the most common cichlid predator, with the five male colour morphs in separate trials to determine mating and prey preferences, respectively. We found that a large proportion of females shared a strong preference for the rare carotenoid-based red and yellow males, but a distinct group also preferred the blue and parae morphs. The cichlid predator strongly preferred red and yellow males as prey. Together, these results suggest that the interaction between premating sexual selection favouring and predation acting against the red and yellow morphs may explain their rarity in the wild. The trade-off between sexual and natural selection, accompanied by variation in female mating preferences, may therefore facilitate the maintenance of the striking colour polymorphism in P. parae.

Medulloblastoma with extensive nodularity undergoing post-therapeutic maturation to a gangliocytoma: a case report and literature review.

We present a report of a 12-year-old boy diagnosed with medulloblastoma at 22 months of age. A gross total resection was performed followed by adjuvant systemic chemotherapy due to his young age; however, the tumor recurred locally in the posterior fossa 7 months later. The recurrent tumor was excised and he received craniospinal radiation with a boost given to the posterior fossa followed by high-dose chemotherapy. He remained disease free for approximately 10 years without major neurologic deficit and only mild cognitive impairment. A routine follow-up MRI of the brain revealed an enhancing mass. The patient underwent surgical debulking and pathological examination revealed no residual immature medulloblastoma cells but instead mature ganglion cells, consistent with a gangliocytoma. The apparent maturation of primitive medulloblastoma cells is a rare phenomenon, which may have ensued from the long-term effects of adjuvant therapies inducing advanced cellular maturation.

Ionized or Total Magnesium levels, what should we measure in critical ill patients?

Monitoring and measuring magnesium (Mg) values are essential to prevent the development of numerous complications in perioperative medicine and critically ill patients. Although previous studies suggest that measuring free ionized magnesium (iMg) is more useful for estimating Mg status, clinicians currently rely on measurement of total serum magnesium to determine if supplemental magnesium is needed. In this review, we analyzed the recent literature to decide whether it is better to measure ionized serum Mg or total serum Mg when assessing magnesium status, whether iMg predicts clinical outcome, and what are the difficulties in measuring serum iMg levels in intensive care patients and perioperative medicine.

Markers of inflammation, thrombosis and endothelial activation correlate with carotid IMT regression in stable coronary disease after atorvastatin treatment.

BACKGROUND AND AIMS: MIAMI is a prospective multicenter clinical study designed to investigate the relationship between changes in carotid intima-media thickness (C-IMT) and changes in circulating markers of inflammation, thrombosis and endothelial activation in stable coronary patients treated for 20+/-3.7 months with 20mg/day atorvastatin. METHODS AND RESULTS: Eighty-five subjects had their C-IMT, blood lipids and soluble markers measured at baseline, at the 12th month and at the end of the study. Almost all soluble markers decreased upon treatment except for high-sensitivity C-reactive protein (hs-CRP), interleukin-18 (IL-18), tissue factor pathway inhibitor-free (TFPI-free) and soluble vascular cell adhesion molecules-1 (sVCAM-1) which did not change significantly, and interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and soluble CD40 ligand (sCD40L) which increased. sCD40L, fibrinogen, tissue factor pathway inhibitor-total (TFPI-total), soluble intercellular adhesion molecules-1 (sICAM-1), sE-selectin, interleukin-8 (IL-8) and von Willebrand factor (vWF) changed significantly even after application of the Bonferroni correction for multiple comparisons. Changes in lipids did not correlate with C-IMT regression either when considered singly or when combined in a lipid score. Changes in soluble markers correlated poorly with C-IMT regression when analyzed singly, but strongly when combined in relevant composite scores (inflammation/coagulation score, endothelial activation score, soluble markers score and total score). CONCLUSION: In patients with stable coronary artery disease treated with moderate doses of atorvastatin, carotid IMT regression correlated with changes of inflammation, thrombosis and endothelial activation profiles.

E-selectin and TFPI are associated with carotid intima-media thickness in stable IHD patients: the baseline findings of the MIAMI study.

OBJECTIVE: MIAMI was a prospective multicenter clinical study designed to investigate the relationship between changes in carotid intima-media thickness (C-IMT) and those in the levels of circulating markers of inflammation, thrombosis and endothelial dysfunction. The study was performed in a group of stable coronary patients treated for two years with a moderate dosage of atorvastatin (20mg/day). In this paper the cross-sectional relationship between C-IMT and the same circulating markers of inflammation, thrombosis and endothelial dysfunction measured at baseline was investigated. METHODS: Eighty-five subjects that had not used statins for at least two months were enrolled in the study. At time of enrollment, the levels of vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), E-selectin, interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-alpha, high-sensitivity C-reactive protein (hs-CRP), tissue factor (TF), tissue factor pathway inhibitor (TFPI), von Willebrand factor (vWF), fibrinogen, total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL), and triglycerides were measured, in parallel with C-IMT assessment. RESULTS: In cross-sectional analyses, markers of endothelial perturbation (i.e. E-selectin) and TFPI were more strongly correlated with arherosclerotic burden than markers of inflammation. The baseline picture in this study indicates that E-selectin and TFPI are linked with atherosclerotic burden.

Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study.

BACKGROUND: Carriers of the apolipoprotein A-I(Milano) (apoA-I(M)) mutant present with very low plasma HDL cholesterol and moderate hypertriglyceridemia, apparently not leading to premature coronary heart disease. The objective of this study was to establish whether this high-risk lipid/lipoprotein profile is associated with structural changes in the carotid arteries and heart, indicative of preclinical atherosclerosis. METHODS AND RESULTS: Twenty-one A-I(M) carriers were compared with age- and sex-matched control subjects from the same kindred and with 2 series of matched subjects with primary hypoalphalipoproteinemia (HA). Structural changes in the carotid arteries were defined as the intima-media thickness (IMT) measured by B-mode ultrasound. HA subjects, both recruited among patients attending our Lipid Clinic and blood donors, showed significant thickening of the carotids (average IMT, 0.86+/-0.25 and 0.88+/-0.29 mm, respectively) compared with control subjects (average IMT, 0.64+/-0.12 mm); the apoA-I(M) carriers instead showed normal arterial thickness (average IMT, 0.63+/-0.10 mm). Moreover, a significantly higher prevalence of atherosclerotic plaques was found in patients and blood donors with HA (both 57%) compared with apoA-I(M) carriers (33%) and control subjects (21%). Echocardiographic findings and maximal treadmill ECG did not differ significantly between apoA-I(M) carriers and control subjects, apart from a slight increase in left ventricular end-diastolic dimension in the carriers. CONCLUSIONS: Despite severe HA, carriers of the apoA-I(M) mutant do not show structural changes in the arteries and heart, in contrast to HA subjects, who are characterized by a marked increase in carotid IMT and increased prevalence of atherosclerotic plaques.

Carotid artery intima-media thickness measured by ultrasonography in normal clinical practice correlates well with atherosclerosis risk factors.

BACKGROUND AND PURPOSE: The intima-media thickness (IMT) of extracranial carotid arteries determined by B-mode ultrasound is a measurable index of the presence of atherosclerosis. The ultrasonographic scan protocol and the scan reading techniques used until now to measure IMT are, however, time consuming and require the participation of specialized research centers. In this study we present a cross-sectional study of 963 patients attending the Enrica Grossi Paoletti Center in Milan, Italy, with the aim of assessing whether ultrasonographic measurements of carotid artery in routine clinical practice can yield the same results as those obtained with quantitative methods used until now in clinical trials. METHODS: Maximum and mean maximum IMT of carotid arteries were assessed by B-mode ultrasound with the use of the electronic caliper of the machine in real time. RESULTS: The intraobserver and interobserver variability of IMT of carotid arteries performed with the electronic caliper in real time was similar to that of quantitative processing of frozen images (coefficients of variation of intraobserver and interobserver mean maximum IMT measurements were 4.2% and 7.3%, respectively). Carotid artery IMT thus measured correlated with most of the known atherosclerosis risk factors and discriminated between patients with and without previous history of cardiovascular events. IMT was linearly related to the total number of vascular risk factors both in the whole group and after stratification of patients into 3 age classes. CONCLUSIONS: These observations establish a strong correlation between B-mode imaging of carotid atherosclerosis evaluated in normal clinical practice and data provided by clinical trials and validate this simple reading technique as a means of identifying IMT as another possible risk factor in patients at high risk of vascular disease.

Platelet alpha 2-adrenergic receptors in hypercholesterolemia: relationship between binding studies and epinephrine-induced platelet aggregation.

BACKGROUND: Platelets isolated from patients with hypercholesterolemia are more sensitive in vitro to various aggregating agents, including epinephrine, than those isolated from normocholesterolemic subjects. Increased platelet reactivity is one mechanism that may explain the enhanced risk of thromboembolism in hypercholesterolemia. This study assessed whether platelet hyperreactivity to epinephrine in hypercholesterolemia is associated with higher alpha 2-adrenergic receptor density or affinity for epinephrine. METHODS: Platelet aggregation and binding studies, with use of [3H]yohimbine as ligand, were performed on platelets isolated from 30 patients with type IIa hypercholesterolemia and 23 control subjects. RESULTS: Platelet aggregation in response to epinephrine was significantly higher in patients with hypercholesterolemia than in control subjects. A statistically significantly higher alpha 2-adrenergic receptor density was observed in a subgroup of 13 patients with hypercholesterolemia than in 13 sex- and age-matched control subjects (280 +/- 61 and 230 +/- 49 fmol/mg protein respectively; p < 0.03), but no difference was observed in receptor affinity for the ligand. In these subgroups plasma total and levels of low-density lipoprotein (LDL) cholesterol were inversely correlated with platelet aggregation but directly correlated with platelet receptor density. CONCLUSION: Platelet alpha 2-adrenergic receptor density is increased in hypercholesterolemia and directly correlates with plasma total and levels of LDL cholesterol, providing at least a partial explanation for the enhanced platelet response to epinephrine that is observed in hypercholesterolemia.

Iron-ovotransferrin preparation does not interfere with ciprofloxacin absorption.

Iron supplements can interfere with the bioavailability of a number of drugs, including thyroxine, tetracycline derivatives, penicillamine, methyldopa, levodopa, carbidopa, ciprofloxacin, and the newer fluoroquinolones. A new iron formulation was tested in which iron ions are bound to ovotransferrin, a protein that shares more than an 80% similarity with the sequence of human transferrin and apparently is less likely than the commonly used iron salts to reduce drug absorption. Ciprofloxacin was taken as a model drug, of wide use and restricted range of therapeutic levels, and its absorption was evaluated after the administration of the iron-ovotransferrin complex versus an iron-gluconate formulation in healthy volunteers. At variance with the iron gluconate formulation, which led to a reduction of about 50% of peak serum ciprofloxacin levels (Cmax; 1.0 +/- 0.2 versus 2.4 +/- 0.3 micrograms/ml; p < 0.01) and of the area under the serum concentration-time curve from time 0 to infinity [AUC(0 - infinity); 10.1 +/- 1.1 versus 18.3 +/- 1.0 mg.L-1.hr; p < 0.01], the iron-ovotransferrin complex caused only modest, non significant changes in absorption with a minimal reduction of the AUC[0 - infinity) (17.3 +/- 1.0 versus 18.3 +/- 1.0 mg.L-1.hr; difference not significant) and a nonsignificant decrease in the Cmax (2.2 +/- 0.3 versus 2.4 +/- 0.3 microgram/ml; difference not significant). Iron was also well absorbed from the formulation in the presence of a fatty meal. The very common drug interactions with oral iron preparations can be effectively prevented by the use of the iron-ovotransferrin complex interacting to a minimal extent with a sensitive drug with a reduced margin of efficacy, such as ciprofloxacin.

Glycosylation pattern of platelet glycoprotein IIb and IIIa in type IIa hypercholesterolemia.

The microheterogeneity and polymorphism of platelet membrane glycoproteins IIb and IIIa from hypercholesterolemic type IIA patients and from normolipidemic controls were compared by isoelectric focusing followed by immunological detection. Their size and the extent of glycosylation were investigated by polyacrylamide gel electrophoresis and carbohydrate affinity stain. No qualitative or quantitative differences could be detected, either within each test group or between the two groups. This finding rules out the hypothesis that altered molecular forms of the glycoproteins forming the fibrinogen receptor might be involved in the pathogenesis of platelet hyperaggregability in hypercholesterolemic patients.

Intima-media thickness after pravastatin stabilizes also in patients with moderate to no reduction in LDL-cholesterol levels: the carotid atherosclerosis Italian ultrasound study.

The Carotid Atherosclerosis Italian Ultrasound study (CAIUS), a multicenter, double-blind clinical trial, performed in 305 asymptomatic, moderately hypercholesterolemic patients, clearly demonstrated beneficial effects of pravastatin on the carotid intima-media thickness (IMT) progression. The database of the CAIUS study was examined in order to investigate the presence of a relationship, if any, between the activity of pravastatin on IMT progression rate and its hypocholesterolemic effect. Quantitative B-mode ultrasound imaging was used to quantify the individual mean maximum IMT progression rate in 3 years. In the overall group of patients (placebo and pravastatin) covariance analysis showed that while the variable 'treatment' (0 = placebo, 1 = pravastatin) was significantly related to the reduction of IMT progression (F= 6.6, P = 0.01), the IMT progression did not correlate with the extent of LDL-C lowering (F= 0.00, P = 0.98). To further investigate this issue. the pravastatin treated group was stratified into quartiles of LDL-C reduction. In contrast to what was observed in the placebo group, in which a positive mean IMT progression rate was observed, independent of the extent of LDL-C reduction, no IMT progressionwas observed in any subgroup treated with pravastatin. No significant difference was found among quartiles and no trend could be identified. In conclusion, the effect of pravastatin treatment on carotid IMT progression rate is beneficial; however the CAIUS study demonstrated that lowering LDL-C by itself, does not explain the variability of beneficial changes in IMT.

Effects of smoking regular or light cigarettes on brachial artery flow-mediated dilation.

BACKGROUND AND PURPOSE: To compare the effects of regular cigarettes (RCs) and light cigarettes (LCs) on brachial artery flow-mediated dilation (FMD) and sublingual glyceryl trinitrate-induced dilation (GTN), markers of endothelial dependant and independent function, respectively. METHODS: 206 subjects (age 51.5 ± 12.8 yr, 122 men) had their smoking habits recorded and FMD and GTN measured by B-mode ultrasound. Cigarettes were categorized as RCs or LCs according to their content of tar, nicotine and CO. The chronic effect was assessed in current smokers of RCs (n = 85) or LCs (n = 53) and in never smokers (NS; n = 68). The acute effect was assessed in current smokers by measuring FMD before and 10-min after smoking a single regular (n = 29) or light (n = 51) cigarette. RESULTS: FMD was significantly lower in consumers of RCs (6.26%, 95% C.I. 5.58, 6.94) or LCs (5.59%, 95% C.I. 4.74, 6.45) compared to NS (8.68%, 95% C.I. 7.92, 9.44) (both P < 0.0001), but did not differ (P > 0.05) when compared to each other. GTN was similar in the three groups. Analyses adjusted for clinical confounders and for markers involved in oxidative stress, arginine/nitric oxide pathway, and inflammation provided identical results. Smoking a single cigarette, either regular or light, reduced FMD (-0.88% and -1.17%, respectively, both P < 0.05), without significant difference between cigarette type. RCs and LCs produced analogous chronic and acute effects when FMD was calculated with respect to the last 60 s of the low-flow phase (FMD60s). CONCLUSIONS: LCs impair endothelial-dependant vasodilation as much as RCs. Thus, smoking LCs cannot be considered an alternative to the only safe choice of a complete and permanent smoking cessation.

LDL oxidative modification and carotid atherosclerosis: results of a multicenter study.

OBJECTIVE: Serum LDL conjugated diene concentration is a marker of oxidative modification of LDL. We investigated the relationship between LDL conjugated dienes and cross-sectional subclinical atherosclerosis assessed by carotid IMT in high-risk subjects of a multicenter study. METHODS: Serum LDL conjugated dienes and ultrasonographically assessed carotid intima-media thickness (IMT(mean), IMT(max) and IMT(mean-max)) were available for 553 subjects from Finland, France, Italy, the Netherlands, and Sweden. RESULTS: In multivariate regression analysis, gender (p < 0.001), age (p < 0.001), systolic blood pressure (IMT(mean), p = 0.01; IMT(mean-max), p = 0.05) and serum LDL conjugated dienes (p = 0.02 for both IMT(mean) and IMT(mean-max)) were the strongest determinants of IMT variation, adjusted for study center, ultrasound videotape reader and serum LDL cholesterol. Pack-years of smoking, added into the regression model, did not destroy the significant association between increased serum LDL conjugated dienes and IMT. Ratio of LDL conjugated dienes to LDL particle cholesterol was higher in subjects of Northern recruiting centers than of Southern centers (r = 0.39, p < 0.0001). CONCLUSIONS: There was a cross-sectional association between in vivo increased LDL oxidative modification and subclinical atherosclerosis after adjustment for traditional risk factors. The subjects in Northern countries of Europe had more oxidatively modified lipids per cholesterol in LDL particle than subjects in Southern countries.

The metabolic syndrome predicts carotid intima-media thickness no better than the sum of individual risk factors in a lipid clinic population.

OBJECTIVE: To assess whether the diagnosis 'metabolic syndrome' (MS) predicts the degree of subclinical atherosclerosis better than its component parts or the total number of vascular risk factors (VRFs) in patients attending a lipid clinic. METHODS: Carotid intima-media thickness (C-IMT) was measured by B-mode ultrasound in 1804 patients (56+/-13 years; 52% women). To investigate whether the increased subclinical carotid atherosclerosis often ascribed to MS may be explained by a real interaction between the components or simply by a sum of VRFs, observed C-IMTs were compared with those predicted by the sum of individual components. Values for C-IMT of MS patients were also compared with those of controls matched for number of VRFs or for SCORE predicted risk (SPR). RESULTS: Carotid IMT values were significantly higher in patients with MS (n=362) than in those not so diagnosed (IMT(mean), 1.07+/-0.37 vs. 0.95+/-0.33; IMT(max), 1.98+/-0.93mm vs. 1.67+/-0.82mm, both p<0.0001), but were not higher than those predicted by the sum of individual risk factors. The linear regression lines of the correlations between C-IMT and total number of VRFs overlapped in patients with and without MS. In patients with and without MS matched for age, sex and total number of VRFs, or matched for age, sex and SPR the C-IMT differences disappeared. CONCLUSIONS: In patients attending a lipid clinic, 'metabolic syndrome' appears not to correlate with C-IMT to a greater extent than what is expected from its component parts or from the patient's total number of VRFs.

Non-invasive assessment of unstimulated forearm arterial compliance in human subjects. Impaired vasoreactivity in hypercholesterolaemia.

A study was carried out in order to determine the feasibility and reproducibility of a direct plethysmographic assessment of unstimulated forearm arterial compliance (FAC) in hypercholesterolaemic and normocholesterolaemic subjects. Simultaneous recordings of forearm pulse volume and blood pressure over the whole cardiac cycle are used to establish the pulse volume-blood pressure relationship. FAC was measured on-line by computing the ratio of dV/dP. The area under the curve (FAC(AUC)) of FAC/blood-pressure curve was determined in a standard range of blood pressure (70-130 mmHg). The method was validated by demonstrating its capacity to detect changes in FAC(AUC) induced by nitrate and by muscarinic stimuli. The results show a reduced FAC(AUC) in hypercholesterolaemic patients vs. controls (2.28 +/- 0.8 x 10(-3) vs. 4.12 +/- 1.06 x 10(-3) (mL 100 mL-1 forearm mmHg-1) mmHg; P = 0.0001). The method appears to be highly sensitive to nitrate and muscarinic stimuli. The new technique provides a potentially useful tool to detect and monitor in vivo, without stimulating arterial dilatation, e.g. by acetylcholine infusion, the functional arterial changes in subjects with a major risk factor for arterial disease as well as the effects of dietary/drug treatments.