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Background: To quantify the decline in recurrent major cardiovascular events (MCVE) risk in patients with clinically manifest vascular disease between 1996 and 2014 and to assess whether the improvements in recurrent MCVE-risk can be explained by reduced prevalence of risk factors, more medication use and less subclinical atherosclerosis., Methods and Results: The study was conducted in the Second Manifestations of ARTerial disease (SMART) cohort in patients entering the cohort in the period 1996-2014. The prevalence of risk factors and subclinical atherosclerosis was measured at baseline. Incidence rates per 100person-years for recurrent MCVE (including stroke, myocardial infarction, retinal bleeding, retinal infarction, terminal heart failure, sudden death, fatal rupture of abdominal aneurysm) were calculated, stratified by the year of study enrolment. For the attributable risk of changes in risk factors, risk factor treatment, and subclinical atherosclerosis on the incidence rates of recurrent MCVE, adjusted rate ratios were estimated with Poisson regression. 7216 patients had a median follow-up of 6.5years (IQR 3.4-9.9). The crude incidence of recurrent MCVE declined by 53% between 1996 and 2014 (from 3.68 to 1.73 events per 100person-years) and by 75% adjusted for age and sex. This improvement in vascular prognosis was 36% explained by changes in risk factors, medication use and subclinical atherosclerosis., Conclusion: The risk of recurrent MCVE in patients with clinically manifest vascular disease has strongly declined in the period between 1996 and 2014. This is only partly attributable to lower prevalence of risk factors, improved medication use and less subclinical atherosclerosis., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To assess the cost-effectiveness of an internet-based, nurse-led vascular risk factor management programme in addition to usual care compared with usual care alone in patients with a clinical manifestation of a vascular disease., Design: Cost-effectiveness analysis alongside a randomised controlled trial (the Internet-based vascular Risk factor Intervention and Self-management (IRIS) study)., Setting: Multicentre trial in a secondary and tertiary healthcare setting., Participants: 330 patients with a recent clinical manifestation of atherosclerosis in the coronary, cerebral, or peripheral arteries and with ≥2 treatable vascular risk factors not at goal., Intervention: The intervention consisted of a personalised website with an overview and actual status of patients' vascular risk factors, and mail communication with a nurse practitioner via the website for 12 months. The intervention combined self-management support, monitoring of disease control and pharmacotherapy., Main Outcome Measures: Societal costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness., Results: Patients experienced equal health benefits, that is, 0.86 vs 0.85 QALY (intervention vs usual care) at 1 year. Adjusting for baseline differences, the incremental QALY difference was -0.014 (95% CI -0.034 to 0.007). The intervention was associated with lower total costs (€4859 vs €5078, difference €219, 95% CI -€2301 to €1825). The probability that the intervention is cost-effective at a threshold value of €20,000/QALY, is 65%. At mean annual cost of €220 per patient, the intervention is relatively cheap., Conclusions: An internet-based, nurse-led intervention in addition to usual care to improve vascular risk factors in patients with a clinical manifestation of a vascular disease does not result in a QALY gain at 1 year, but has a small effect on vascular risk factors and is associated with lower costs., Trial Registration Number: NCT00785031., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Hemoglobin and hematocrit are important determinants of blood viscosity and arterial oxygen content and may therefore influence cerebral blood flow (CBF). We examined cross-sectional and prospective associations of hemoglobin and hematocrit with CBF in 569 patients with manifest arterial disease (mean age 57 ± 10 years) with available data on magnetic resonance angiography to measure parenchymal CBF. Mean (SD) parenchymal CBF at baseline was 52.3 (9.8) mL/min/100 mL and decreased with 1.5 (11.0) mL/min/100 mL after on average 3.9 years of follow-up. Linear regression analyses showed that greater hemoglobin and hematocrit values were associated with lower baseline parenchymal CBF and more decline in parenchymal CBF over time, independent of cardiovascular risk factors, use of antiplatelet drugs, anticoagulants, or diuretics, and brain measures: adjusted mean differences (95% confidence interval [CI]) in decline in parenchymal CBF between patients in the lower and upper quartiles of hemoglobin and hematocrit were -2.48 (95% CI -3.70 to -1.25) and -3.69 (95% CI -5.45 to -1.94) mL/min/100 mL. Higher hemoglobin and hematocrit were associated with lower baseline parenchymal CBF and a greater decline in parenchymal CBF over time, possibly as a result of physiological compensating mechanisms., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: We aimed to examine the cross-sectional and prospective relationship between leisure time physical activity, brain MRI abnormalities and cognitive performance in patients with vascular disease., Methods: Within the SMART-MR study, 1.5 T MRI of the brain and neuropsychological examinations were performed at baseline (n = 1232) and after 3.9 ± 0.4 years follow-up (n = 663). Automatic brain segmentation was used to quantify intracranial (ICV), total brain, ventricular, and white matter lesion (WML) volumes. Brain infarcts were rated visually. Level of physical activity was expressed in metabolic equivalents (MET) hours p/week. With linear regression analysis we examined associations of level of physical activity with brain MRI measures and with cognitive performance, adjusted for potential confounders. For the association with brain infarcts relative risks (RR) were calculated with Poisson regression., Results: At baseline, an increase in physical activity of one SD (39.7 METh/w) was significantly associated with larger total brain volume (B = 0.20% of ICV; 95% CI 0.06; 0.33%). A trend was found for the association of physical activity with smaller ventricular volume (B = -0.04% of ICV; 95% CI -0.09; 0.02%) and with a decreased risk for brain infarcts (RR = 0.91, 95% CI: 0.82-1.02). No association was found with smaller WML volume (B = -0.02% of ICV; 95% CI -0.07; 0.04%). No associations with change in brain structures over time were observed. Also, no associations between physical activity and cognitive performance or cognitive decline were found., Conclusion: These data suggest that leisure time physical activity does not have a significant contribution in preventing or slowing down brain abnormalities and cognitive decline in this cohort of middle-aged individuals already burdened with vascular disease., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

We examined the association between brain atrophy and vascular brain lesions (i.e., white matter lesions [WMLs] or brain infarcts), alone or in combination, with decline in memory and executive functioning over 4 years of follow-up in 448 patients (57 ± 9.5 years) with symptomatic atherosclerotic disease from the Second Manifestations of ARTerial disease--Magnetic Resonance SMART-MR study. Automated brain segmentation was used to quantify volumes of total brain, ventricles, cortical gray matter, and WMLs on 1.5-T magnetic resonance imaging (MRI). Brain infarcts were rated visually. WML volume was associated with significant decline in z score of executive functioning. No independent associations between MRI measures and memory decline were found. Significant declines in z scores of memory performance and of executive functioning were observed in patients with a combination of severe atrophy (upper quartile) and most vascular brain lesions (upper quartile) compared with those with minimal atrophy (lowest quartile) and fewest vascular brain lesions (lowest quartile). Our findings suggest that in patients with symptomatic atherosclerotic disease, the combination of brain atrophy and WMLs or brain infarcts accelerates cognitive decline over 4 years., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: We investigated whether plasma ferritin levels through the pro-inflammatory effects of free iron are associated with adipose tissue dysfunction in a relevant population of patients with manifest vascular disease who would potentially benefit the most from further aetiological insights., Materials and Methods: In a cohort of 355 patients with vascular diseases, the association between plasma ferritin and adiponectin levels was quantified using linear regression analysis. Interleukin-6 and adiponectin levels were measured in medium from pre-adipocytes and adipocytes after incubation with increasing concentrations of Fe(III)-citrate and after co-incubation with iron chelators or radical scavengers., Results: Increasing ferritin plasma concentrations were not related to plasma adiponectin levels in patients without (β -0·13; 95% CI -0·30 to 0·04) or with the metabolic syndrome (β -0·04; 95% CI -0·17 to 0·10). Similar results were found in patients who developed a new cardiovascular event in the follow-up period. In vitro, incubation with increasing concentrations of Fe(III)-citrate-induced inflammation in pre-adipocyte cultures as witnessed by increased IL-6 secretion at 30 μm Fe(III)-citrate vs. control (500 ± 98 pg/mL vs. 194 ± 31 pg/mL, P = 0·03). Co-incubation of pre-adipocytes with iron chelators or radical scavengers prevented this inflammatory response. Incubation of adipocytes with 30 μm Fe(III)-citrate did not influence adiponectin secretion compared with control., Conclusions: In patients with vascular disease, there is no association between plasma ferritin and adiponectin levels. In vitro, free iron induces an inflammatory response in pre-adipocytes, but not in adipocytes. This response was blocked by co-incubation with iron chelators or radical scavengers. Adiponectin secretion by adipocytes was not influenced by free iron., (© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Aim: Diabetes mellitus (DM) is associated with brain atrophy and vascular brain lesions. Cardiovascular disease is a key determinant in this association. We assessed whether DM increased the rate of progression of brain atrophy, vascular brain lesions, and cognitive decline in patients with symptomatic atherosclerotic disease., Methods: In 663 patients (58±10years) from the SMART-MR study (n=89 with DM), 1.5T MRI and neuropsychological examination were performed at baseline and after 3.9±0.4years follow-up., Results: Repeated measures ANCOVA (adjusted for age, sex, and vascular risk factors) showed that patients with DM had smaller total brain volume (mean differences as percentage of intracranial volume (ICV) [95% CI]: -1.36% [-1.81; -0.91]), smaller gray matter volume (-1.23% [-1.85; -0.61]), larger ventricular volume (0.32% [0.14; 0.49]), and larger white matter lesion volume (0.31% [0.09; 0.53]) than patients without DM. Patients with DM had accelerated increase in ventricular volume over time compared with patients without DM (mean differences ventricular volume as percentage of ICV: 0.32% [0.25; 0.39] vs. 0.17% [0.15; 0.19]; p-interaction DM×time<0.01). Poisson regression showed that patients with DM had an increased risk for incident brain infarcts (relative risk [95% CI]: 1.62 [1.04; 2.53]). Patients with and without DM had similar performance on cognition., Conclusions: DM on top of existing symptomatic atherosclerotic disease is associated with increased brain atrophy and vascular brain lesion load that proceed at a slightly higher rate than in patients without DM., (© 2013 Elsevier B.V. All rights reserved)

Background and Aims: Plasma aldosterone has been associated with all-cause and cardiovascular mortality in high-risk cardiovascular populations, including patients with heart failure, myocardial infarction and high-risk coronary artery disease (CAD) patients. In the present study, we evaluated the association of plasma aldosterone levels with vascular events in a large prospective cohort of stable CAD patients recruited in an outpatient setting. Moreover, we investigated the relationship between aldosterone and atherosclerotic burden., Methods and Results: Baseline plasma aldosterone levels were measured in 2699 subjects with CAD (mean age 60 ± 10 years, 82% male). During a median follow-up of 4.7 years, 308 (11%) patients died, of which 203 were from a vascular cause. Vascular endpoints of myocardial infarction, ischemic stroke or vascular death occurred in 355 (13%) patients. Multivariable Cox regression analysis was performed, adjusting for multiple confounders. Aldosterone (median 96 pg/mL, interquartile range 70-138 pg/mL, normal range 58-362 pg/mL) was independently associated with major vascular events (hazard ratio (HR) 1.56, 95% confidence interval (CI) 1.13-2.15) and vascular mortality (HR 1.95, 95% CI 1.27-3.00). By multivariable regression analysis, aldosterone was also associated with the presence of atherosclerosis in additional vascular territories (cerebrovascular disease and/or peripheral artery disease) (p=0.026)., Conclusions: In patients with stable coronary artery disease, plasma aldosterone is independently associated with the risk of major vascular events and vascular mortality and with atherosclerotic burden., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Introduction: More insights in the etiopathogenesis of thrombi could be helpful in the treatment of patients with acute ischemic stroke. The aim of our study was to determine the relationship between presence of a hyperdense vessel sign and thrombus density with different stroke subtypes., Methods: We included 123 patients with acute ischemic anterior circulation stroke and a visible occlusion on CT-angiography caused by cardioembolism (n = 53), large artery atherosclerosis (n = 55), or dissection (n = 15). Presence or absence of a hyperdense vessel sign was assessed and thrombus density was measured in Hounsfield Units (HU) on non-contrast 1 mm thin slices CT. Subsequently, occurrence of hyperdense vessel sign and thrombus density (absolute HU and rHU (=HU thrombus/HU contralateral)) were related with stroke subtypes., Results: The presence of hyperdense vessel signs differed significantly among subtypes and was found in 45, 64 and 93 % of patients with cardioembolism, large artery atherosclerosis and dissection, respectively (p = 0.003). The mean HU and rHU (+95 % CI) of the thrombi in all vessels were respectively 56.1 (53.2-59.0) and 1.39 (1.33-1.45) in cardioembolism, 64.6 (62.2-66.9) and 1.59 (1.54-1.64) in large artery atherosclerosis and 76.4 (73.0-79.8) and 1.88 (1.79-1.97) in dissection (p < 0.0001). We found the same significant ranking order in the density of thrombi with hyperdense vessel signs (mean HU and rHU (+95 % CI), respectively): cardioembolism 61.3 (57.4-65.3) and 1.49 (57.4-65.3); large artery atherosclerosis 67.3 (64.9-69.7) and 1.65 (1.58-1.71); dissection 76.4 (72.6-80.1) and 1.89 (1.79-1.99, p < 0.0001)., Conclusion: Presence of a hyperdense vessel sign and thrombus density are related to stroke subtype.

Background: Although the overall average 10-year cardiovascular risk for patients with manifest atherosclerosis is considered to be more than 20%, actual risk for individual patients ranges from much lower to much higher. We investigated whether information on metabolic syndrome (MetS) or its individual components improves cardiovascular risk stratification in these patients., Design and Methods: We conducted a prospective cohort study in 3679 patients with clinical manifest atherosclerosis from the Secondary Manifestations of ARTerial disease (SMART) study. Primary outcome was defined as any cardiovascular event (cardiovascular death, ischemic stroke or myocardial infarction). Three pre-specified prediction models were derived, all including information on established MetS components. The association between outcome and predictors was quantified using a Cox proportional hazard analysis. Model performance was assessed using global goodness-of-fit fit (χ(2)), discrimination (C-index) and ability to improve risk stratification., Results: A total of 417 cardiovascular events occurred among 3679 patients with 15,102 person-years of follow-up (median follow-up 3.7 years, range 1.6-6.4 years). Compared to a model with age and gender only, all MetS-based models performed slightly better in terms of global model fit (χ(2)) but not C-index. The Net Reclassification Index associated with the addition of MetS (yes/no), the dichotomous MetS-components or the continuous MetS-components on top of age and gender was 2.1% (p = 0.29), 2.3% (p = 0.31) and 7.5% (p = 0.01), respectively., Conclusions: Prediction models incorporating age, gender and MetS can discriminate between patients with clinical manifest atherosclerosis at the highest vascular risk and those at lower risk. The addition of MetS components to a model with age and gender correctly reclassifies only a small proportion of patients into higher- and lower-risk categories. The clinical utility of a prediction model with MetS is therefore limited.

Objective: Chronic exposure to high levels of angiotensin-converting enzyme (ACE) might increase the risk of hypertensive cardiovascular events. However, little data are available on the association of direct measures of ACE activity with vascular risk and disease. We examined whether serum ACE levels were associated with the risk of recurrent vascular events., Methods: Within the SMART-MR study, a prospective cohort study among patients with symptomatic atherosclerotic disease, analyses were performed in 950 patients (mean age 58 ± 10 years) without use of ACE-inhibitors or angiotensin II receptor blockers. At baseline, participants underwent a vascular screening and serum ACE levels (U/L) were measured. Patients were followed for recurrent vascular events, including vascular death, ischemic stroke, and ischemic coronary heart disease (CHD)., Results: After a mean follow up of 7.2 years (range 0.2-10.1 years), we documented 55 cases of vascular death, 33 cases of ischemic stroke, and 77 cases of ischemic CHD. Multivariable Cox-regression models showed that higher baseline ACE levels were associated with an increased risk of ischemic stroke and CHD; HR's (95%CI) were 1.7 (1.0-2.7) and 1.8 (1.2-2.9). High ACE particularly increased risk of stroke in patients with high blood pressure (defined as >140/90 mmHg) (HR = 4.8; 95%CI 1.0-19.4). This relation was independent of several confounders including use of antihypertensive medication. Serum ACE was not significantly associated with risk of vascular death., Conclusion: Our results suggest that in a population with high vascular risk, higher serum ACE levels contribute to an increased risk of ischemic stroke and CHD events., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Lower self-rated health status has been associated with worse prognosis in patients with coronary artery disease (CAD). We investigated the influence of self-rated physical and mental health status on the risk of future vascular events and mortality for various locations of symptomatic atherosclerotic disease and asymptomatic disease., Design: Patients with CAD (n = 2547), cerebrovascular disease (n = 1061), peripheral arterial disease (PAD; n = 648), abdominal aortic aneurysm (AAA; n = 272) and asymptomatic atherosclerotic disease (n = 1933) were followed for a median of 4 years for the occurrence of a new vascular event or death. Self-rated health status was assessed with the Short Form-36 physical and mental component summary scales. Cox regression models were used to estimate associations between health status and vascular events and death, adjusted for age, sex, vascular risk factors and intima-media thickness., Results: In the total population, lower self-rated physical health status (per 10-point decrease) increased the risk of vascular events [hazard ratio (HR) = 1.37, 95% confidence interval (CI) 1.24-1.52], and all-cause (HR = 1.45, 95% CI 1.29-1.63) and vascular mortality (HR = 1.40, 95% CI 1.20-1.64). A 10-point decrease in mental health status was associated with a modest increase in the risk of vascular events (HR = 1.19, 95% CI 1.08-1.32), and all-cause (HR = 1.19, 95% CI 1.05-1.34) and vascular mortality (HR = 1.28, 95% CI 1.09-1.49). Risk estimates of physical and mental health status were highest in patients with asymptomatic atherosclerotic disease and lowest in those with PAD., Conclusions: Poorer self-rated physical and mental health status increases the risk of vascular events and mortality in a broad population of patients with symptomatic and asymptomatic atherosclerotic disease., (© 2012 The Association for the Publication of the Journal of Internal Medicine.)

Objective: To investigate whether an internet based, nurse led vascular risk factor management programme promoting self management on top of usual care is more effective than usual care alone in reducing vascular risk factors in patients with clinically manifest vascular disease., Design: Prospective randomised controlled trial., Setting: Multicentre trial in secondary and tertiary healthcare setting., Participants: 330 patients with a recent clinical manifestation of atherosclerosis in the coronary, cerebral, or peripheral arteries and with at least two treatable risk factors not at goal., Intervention: Personalised website with an overview and actual status of patients' risk factors and mail communication via the website with a nurse practitioner for 12 months; the intervention combined self management support, monitoring of disease control, and drug treatment., Main Outcome Measures: The primary endpoint was the relative change in Framingham heart risk score after 1 year. Secondary endpoints were absolute changes in the levels of risk factors and the differences between groups in the change in proportion of patients reaching treatment goals for each risk factor., Results: Participants' mean age was 59.9 (SD 8.4) years, and most patients (n=246; 75%) were male. After 1 year, the relative change in Framingham heart risk score of the intervention group compared with the usual care group was -14% (95% confidence interval -25% to -2%). At baseline, the Framingham heart risk score was higher in the intervention group than in the usual care group (16.1 (SD 10.6) v 14.0 (10.5)), so the outcome was adjusted for the separate variables of the Framingham heart risk score and for the baseline Framingham heart risk score. This produced a relative change of -12% (-22% to -3%) in Framingham heart risk score for the intervention group compared with the usual care group adjusted for the separate variables of the score and -8% (-18% to 2%) adjusted for the baseline score. Of the individual risk factors, a difference between groups was observed in low density lipoprotein cholesterol (-0.3, -0.5 to -0.1, mmol/L) and smoking (-7.7%, -14.9% to -0.4%). Some other risk factors tended to improve (body mass index, triglycerides, systolic blood pressure, renal function) or tended to worsen (glucose concentration, albuminuria)., Conclusion: An internet based, nurse led treatment programme on top of usual care for vascular risk factors had a small effect on lowering vascular risk and on lowering of some vascular risk factors in patients with vascular disease., Trial Registration: Clinical trials NCT00785031.

Objective: A relationship between depression and mortality has been well established, but underlying mechanisms remain unclear. We investigated the influence of cerebral small vessel disease (CSVD), characterized by white matter lesions (WMLs) and lacunar infarcts, on the relationship between mood mortality during 6 years follow-up., Methods: Mood problems were assessed with the mental component summary of the 36-item Short-Form Medical Outcomes Study in 1110 patients with symptomatic atherosclerotic disease (mean age 59 years). Volumetric WML estimates were obtained with 1.5-T magnetic resonance imaging; lacunar infarcts were scored visually. Cox regression models were adjusted for age, sex, vascular risk, physical functioning, antidepressants and infarcts. We adjusted for CSVD to examine whether it may be an intermediate or confounding factor. Second, we added interaction terms to investigate whether associations differed between patients with CSVD (absent/present)., Results: Patients in the lowest quartile of mental functioning, representing most severe mood problems, were at higher, although not significant, risk of death (hazard ratio [HR] = 1.47, 95% confidence interval [CI] = 0.94-2.30) compared with patients in higher quartiles. Adjustment for CSVD did not change this association. Lacunar infarcts, not WML, modified the association of mood problems with mortality (p value for interaction = .01); mood problems strongly increased the risk of mortality in patients with lacunar infarcts (HR = 2.75, 95% CI = 1.41-5.38) but not in those without it (HR = 0.78, 95% CI = 0.39-1.57)., Conclusions: Patients with lacunar infarcts may be especially vulnerable for the effect of mood problems on mortality.

Abdominal obesity is characterized by sympathetic nerve activation (SNA), probably mediated by elevated insulin and leptin levels. Resting heart rate (RHR) is a marker of sympathetic tone, and independently associated with cardiovascular events and death in various populations. We investigated and quantified the relation between visceral adipose tissue (VAT) and RHR in patients with vascular disease. In 3,723 patients with manifest vascular disease, visceral and subcutaneous fat tissue was measured with ultrasonography. RHR was obtained from an electrocardiogram (ECG). The association between quartiles of VAT and RHR was quantified using linear regression analysis with adjustments for potential confounding factors. Separate analyses were performed for men and women and for location of vascular disease. Visceral fat was categorized into sex-pooled quartiles (Q) ranging from 2.7-8.0 cm in Q1 (reference) to 9.4-20.6 cm in Q4. High visceral fat thickness was associated with increased RHR, in men (Q4 vs. Q1, β = 4.36; 95% confidence interval (CI) = 3.11-5.61) and women (β = 1.48; 95% CI = -0.70 to 3.66), after full adjustment. Waist circumference and BMI had a significant relation with RHR in men (β = 3.51; 95% CI = 2.21-4.81 and β = 2.80; 95% CI = 1.51-4.08, respectively) but these relations were smaller and not significant in women (β = 0.71; 95% CI = -1.44 to 2.85 and β = 0.24; 95% CI = -1.90 to 2.37, respectively). There was no relation between subcutaneous fat and RHR in men and women. The relation between visceral fat and RHR was similar in patients with different locations of vascular diseases. Increased visceral fat is associated with increased RHR in male and female patients with vascular disease, independent of the location.

Background: The 'vascular depression' hypothesis states that brain changes located in frontal-subcortical pathways increase vulnerability for specific depressive symptom profiles, but studies examining locations of small-vessel and degenerative changes with individual symptoms are scarce. We examined whether location and progression of white-matter lesions (WMLs), lacunar infarcts and atrophy were associated with motivational and mood symptoms in patients with symptomatic atherosclerotic disease., Method: In 578 patients [63 (s.d.=8) years] of the Second Manifestations of ARTerial disease (SMART)-Medea study, volumes of WMLs and atrophy and visually rated infarcts were obtained with 1.5 T magnetic resonance imaging at baseline and after 3.9 (s.d.=0.4) years' follow-up. Depressive symptoms were assessed with Patient Health Questionnaire-9 at follow-up and categorized into motivational and mood symptoms., Results: Regression analyses adjusted for age, gender, education, Mini-Mental State Examination, physical functioning, antidepressant use and vascular risk factors showed that location in mainly deep white-matter tracts and progression of WMLs were associated with symptoms of anhedonia, concentration problems, psychomotor retardation and appetite disturbance. Lacunar infarcts in deep white matter were associated with greater motivational [Incidence rate ratio (IRR) 1.7, 95% confidence interval (CI) 1.2-2.4] and mood (IRR 1.7, 95% CI 1.1-2.6) sumscores, and with symptoms of psychomotor retardation, energy loss and depressed mood; lacunar infarcts in the thalamus were associated with psychomotor retardation only. Cortical atrophy was associated with symptoms of anhedonia and appetite disturbance. Excluding patients with major depression did not materially change the results., Conclusions: Our findings suggest that disruption of frontal-subcortical pathways by small-vessel lesions leads to a symptom profile that is mainly characteristic of motivational problems, also in the absence of major depression.

The underlying pathology of lacunar infarcts, white matter lesions and also of microbleeds is poorly understood. We assessed whether the presence of lacunar infarcts, white matter lesions or microbleeds on MRI was associated with a decrease in cerebrovascular reactivity, and assessed whether this association was similar for lacunar infarcts, white matter lesions and microbleeds. BOLD-fMRI scan with breath-holding at 7 T and anatomical scans at 1.5 T were available in 49 patients with atherosclerotic disease from the Second Manifestations of ARTerial disease (SMART) study. Microbleeds and lacunar infarcts were scored visually and volumetric assessment of white matter lesions was performed on the 1.5 T scan. The percentage of voxels with a significant signal change on breath-holding and the whole brain signal change were calculated as measures of cerebrovascular reactivity. The mean percentage of voxels with a significant signal change was 25.1% (SD 6.6) and the mean percentage whole brain signal change was 1.20% (SD 0.51). Age, gender, and diastolic blood pressure were significantly associated with cerebrovascular reactivity. Cerebrovascular reactivity was lower with increasing age, lower in females compared to males and lower with lower diastolic blood pressure. ANCOVA showed that patients with microbleeds (n=18) had a significantly lower whole brain signal change than patients without microbleeds, with a mean difference of -0.36% (95% CI -0.64 to 0.07), independent of age, sex, systolic and diastolic blood pressure and non-lacunar infarcts. No significant associations were found for presence of lacunar infarcts or white matter lesion volume with whole brain signal change or percentage of voxels with a significant signal change. The results show that presence of microbleeds is associated with an impaired cerebrovascular reactivity in patients with atherosclerotic disease, whereas no significant association was found for the presence of lacunar infarcts or white matter lesions in our study., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background and Purpose: Cerebral small vessel disease may be related to vascular and nonvascular pathology. We assessed whether lacunar infarcts and white matter lesions on MRI increased the risk of vascular and nonvascular death and future vascular events in patients with atherosclerotic disease., Methods: Brain MRI was performed in 1309 patients with atherosclerotic disease from the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study. Infarcts were scored visually and volumetric assessment of white matter lesion was performed. Patients were followed for a median of 4.5 years (range, 0.2 to 7.1 years) for death, ischemic stroke, and ischemic cardiac complications., Results: Cox regression models showed that presence of lacunar infarcts (n=229) increased the risk of vascular (hazard ratio, 2.6; 95% CI, 1.4 to 4.9) and nonvascular death (hazard ratio, 2.7; 95% CI, 1.3 to 5.3), adjusted for age, sex, vascular risk factors, nonlacunar infarcts, and white matter lesion. These risks were similar for patients with silent lacunar infarcts. White matter lesion volume (relative to total intracranial volume) increased the risk of vascular death (hazard ratio per milliliter increase, 1.03; 95% CI, 1.01 to 1.05) and white matter lesions in the upper quintile compared with lower quintiles increased risk of ischemic stroke (hazard ratio, 2.6; 95% CI, 1.3 to 4.9)., Conclusions: Cerebral small vessel disease, with or without a history of cerebrovascular disease, is associated with increased risk of death and ischemic stroke in patients with atherosclerotic disease.

Our understanding of the development and progression of atherosclerosis has increased substantially over the past decades. A significant role for the renin-angiotensin-aldosterone system (RAAS) in this process has gained appreciation in recent years. Preclinical and clinical studies have associated components of the RAAS with various cardiovascular disease conditions. Classically known for its contribution to hypertension, dysregulation of the system is now also believed to promote vascular inflammation, fibrosis, remodeling, and endothelial dysfunction, all intimately related to atherosclerosis. The reduction in cardiovascular mortality and morbidity, as seen with the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, supports the concept that RAAS is involved in the pathogenesis of atherosclerotic disease. However, the underlying molecular mechanisms of the pathophysiology remain to be completely understood. Evidence points toward additional benefit from therapeutic approaches aiming at more complete inhibition of the system and the possible utility of renin or aldosterone in the prediction of cardiovascular outcome. This review will summarize the current knowledge from clinical studies regarding the presumptive role of renin and aldosterone in the prediction and management of patients with atherosclerosis. For this purpose, a literature search was performed, focusing on available clinical data regarding renin or aldosterone and cardiovascular outcome., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Aims: To assess the effect of various measures of adiposity and of metabolic risk factors, both separately and in combination, on the risk of future Type 2 diabetes in patients with manifest vascular diseases., Methods: This was a prospective cohort study in 2924 patients (mean age 59 ± 12 years) with manifest atherosclerosis. Metabolic risk factors were defined according to National Cholesterol Education Program criteria for the metabolic syndrome. Incidence of Type 2 diabetes was assessed by questionnaire and subsequent verification., Results: During a median follow-up of 4.9 years (range 3.0-7.6 years) there were 178 cases (6.1%) of incident Type 2 diabetes. An increase with 1 sd waist circumference showed a strong association with incident Type 2 diabetes in both men (hazard ratio 2.45, 95% CI 1.97-3.04) and women (hazard ratio 1.77, 95% CI 1.38-2.26). Compared with patients with normal (i.e. below the National Cholesterol Education Program criteria for abdominal adiposity) waist circumference and < 3 metabolic risk factors, both patients with normal waist circumference and ≥ 3 metabolic risk factors and patients with high (i.e. above the National Cholesterol Education Program criteria for abdominal adiposity) waist circumference and < 3 metabolic risk factors had an increased risk of Type 2 diabetes (hazard ratio 2.44, 95% CI 1.37-4.36 and hazard ratio 3.61, 95% CI 2.23-5.85, respectively). Patients with both high waist circumference and ≥ 3 metabolic risk factors had the highest risk of developing Type 2 diabetes (hazard ratio 10.76, 95% CI 6.95-16.64)., Conclusions: In patients with manifest atherosclerosis, both presence of ≥ 3 metabolic risk factors and presence of a high waist circumference alone are associated with increased risk for developing Type 2 diabetes. The combined presence of ≥ 3 metabolic risk factors and high waist circumference, which is present in 15% of patients, is associated with a 10-fold increased risk of future Type 2 diabetes. To identify patients with manifest atherosclerosis at the highest risk of developing Type 2 diabetes, fat distribution in combination with metabolic risk factors should be considered., (© 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.)

Objective: High homocysteine level is a risk factor for atherosclerosis and has been associated with lacunar infarcts (LIs), white matter lesions (WML) and cognitive dysfunction. It is unclear whether homocysteine is associated with cerebral small vessel disease (cSVD) on top of pre-existent atherosclerosis. We evaluated the association between homocysteine and cSVD in a large cohort of patients with symptomatic atherosclerotic disease., Methods: Within the SMART-MR study, a prospective cohort study of patients with symptomatic atherosclerotic disease, we estimated cross-sectional associations of total plasma homocysteine (THCY) and hyperhomocysteinemia (HHCY) with WML volume and presence of LI, using automated brain segmentation in MRIs of 1232 patients and cognitive function in 763 patients. WML were expressed as a logarithmic transformed percentage of total brain volume., Results: Linear regression analyses adjusted for age, sex, vascular risk factors and extent of atherosclerosis showed that THCY and HHCY were significantly associated with larger WML volumes (B=0.01%: 95% CI 0.002-0.02%, and B=0.21%: 95% CI 0.04-0.39%). Increasing THCY was significantly associated with an increased risk of LIs (OR 1.04, 95% CI 1.01-1.07, per 1 μmol). Moreover, HHCY was associated with worse cognitive function (B=-0.12: 95% CI -0.22 to -0.01)., Conclusion: In patients with symptomatic atherosclerotic disease, higher homocysteine levels are associated with higher WML volume, presence of LI and slightly worse cognitive function., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Long-term exposure to hypercalcaemia and hyperphosphataemia leads to media calcification and predicts mortality in patients with end-stage renal disease (ESRD). It is debatable whether this exposure is only a risk factor for arteriosclerosis, or also for superimposed atherosclerosis. Calcium-phosphate exposure is difficult to quantify, because it is variable in time and exerts its deleterious effects only after prolonged presence., Methods: In 90 dialysis patients, calcium and phosphate values from the complete dialysis period were collected. From three-month averages, measures for calcium-phosphate exposure were derived after exclusion of transplant periods. Calcium-phosphate exposure was then related to intima-media thickness (IMT) and to ankle-brachial index (ABI) as markers of early atherosclerosis., Results: Calcium-phosphate exposure was quantified in three ways using 1670 patient-quarters (i.e. three-months periods) covering 93% of the time on dialysis: averaged calcium-phosphate exposure, percentage of time with above-reference values, and burden of hypercalcaemia/hyperphosphataemia represented by this percentage multiplied by months on dialysis. No association was found with IMT. Patients with increased, not decreased, ABI had higher calcium-phosphate exposure throughout dialysis treatment: hyperphosphataemia burden was 31 (19 to 43) months for patients with ABI between 0.90 and 1.40 and 79 (58 to 100) months for patients with ABI >1.40 or incompressible ankle arteries (p<0.001)., Conclusion: These findings do not support the hypothesis that calcium-phosphate exposure leads to atherosclerotic changes on top of arteriosclerosis in ESRD, and confirm its role in causing arteriosclerotic damage leading to increased arterial stiffness and incompressible ankle arteries. The used tool for quantifying calcium-phosphate exposure is easy to apply and can properly weigh the complete exposure during ESRD.

Background: Obesity is related to the development of vascular diseases and metabolic complications. Low grade inflammation is a key feature of central obesity, characterized by elevated plasma levels of C-reactive protein (CRP). We hypothesize that visceral adipose tissue contributes to systemic concentrations of CRP., Methods: In 2410 patients (1729 men and 681 women) with vascular diseases, subcutaneous and visceral fat masses were analyzed with ultrasonography. Metabolic parameters and CRP were measured in a fasting state. The association between fat measurements and plasma CRP was quantified using linear regression analysis. CRP levels were logarithmically transformed. Adjustments were made for age, smoking, type 2 diabetes mellitus, insulin resistance (HOMA-IR) and medication use., Results: Visceral fat was categorized into quartiles (Q) ranging from 3.2 to 7.8 cm in Q1 (reference) to 11.0-19.8 cm in Q4 in men and 2.7-6.0 cm in Q1 (reference) to 9.0-17.4 cm in Q4 in women. beta-coefficients gradually increased across the quartiles from 0.07 (0.01-0.13) in Q2 to 0.25 (0.19-0.31) in Q4 in men and 0.17 (0.07-0.26) in Q2 to 0.42 (0.32-0.52) in Q4 in women, indicating 0.25 and 0.42 mg/l higher logarithmically transformed (log)CRP levels in Q4 compared to Q1 in respectively men and women. Per standard deviation increase of visceral fat, logCRP levels increased with 0.10 mg/l (0.07-0.12) in men and with 0.11 (0.15-0.19) in women. Likewise, in separate analyses waist circumference and body mass index showed a positive, but weaker association with logCRP levels across quartiles (in men: beta 0.21 (0.15-0.27) in Q4 for waist circumference and beta 0.23 (0.17-0.30) in Q4 for body mass index; in women: beta 0.32 (0.22-0.42) in Q4 for waist circumference and beta 0.32 (0.22-0.42) in Q4 for body mass index). In men subcutaneous fat was not associated with logCRP (beta-coefficients relative to Q1: -0.01 (-0.07 to -0.05), -0.01 (-0.07 to -0.05) and 0.05 (-0.01 to -0.11) in Q2 to Q4 respectively)., Conclusions: In conclusion, visceral fat thickness is the strongest contributor to the systemic CRP concentrations in patients with vascular diseases., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Low blood pressure (BP) has been related to increased risk of brain atrophy. As brain hypoperfusion might be a marker for impaired cerebral autoregulation, the risk of brain atrophy may be especially increased if BP is low in combination with brain hypoperfusion. We examined whether low BP was associated with brain atrophy and whether this association was stronger in patients with lower parenchymal cerebral blood flow (CBF), as an indicator of brain perfusion., Methods: Within the Second Manifestations of ARTerial disease-Magnetic Resonance study, a cohort study among 1309 patients with atherosclerotic disease, cross-sectional analyses were performed in 965 patients (mean age 58 +/- 10 years) with available BP and CBF measures. Parenchymal CBF was measured with magnetic resonance angiography and was expressed per 100 ml brain volume. Brain segmentation was used to quantify cortical gray matter volume and ventricular volume (% of intracranial volume)., Results: Linear regression analyses, adjusted for age, sex, and vascular risk factors showed that the association of systolic BP and pulse pressure, but not diastolic BP, with cortical gray matter volume was modified by parenchymal CBF (P interaction <0.05). In patients with lower parenchymal CBF, but not in those with high parenchymal CBF, lower systolic BP and pulse pressure (per SD decrease) were associated with reduced cortical gray matter volume: beta (95% confidence interval) -0.29% (-0.63; 0.00) and -0.34% (-0.69; -0.01)., Conclusion: Our findings suggest that lower BP by itself is not sufficient to induce brain atrophy; however, lower SBP and lower pulse pressure in combination with lower parenchymal CBF increased the risk for cortical atrophy.

Aims: Modification of vascular risk factors is effective in reducing mortality and morbidity in patients with symptomatic atherosclerosis; however, it is difficult to achieve and maintain. The aim of the Risk management in Utrecht and Leiden Evaluation (RULE) study was to assess risk factor status after referral in patients with established vascular disease or type 2 diabetes who took part in the multidisciplinary hospital-based vascular screening programme, Second Manifestations of ARTerial disease, compared with a group who did not participate in such a programme., Methods and Results: Patients with type 2 diabetes, coronary artery disease, cerebrovascular disease or peripheral arterial disease referred by general practitioners to the medical specialist at the University Medical Center (UMC) Utrecht (a setting with a vascular screening programme of systematic screening of risk factors followed by treatment advice) and the Leiden UMC (a setting without such a screening programme), were enrolled in the study. Blood pressure, levels of lipids, glucose and creatinine, weight, waist circumference and smoking status were measured in patients 12-18 months after referral to the two hospitals. A total of 604 patients were treated in the setting with a vascular screening programme and 566 in the setting without such a programme; 70% of all patients were male, with a mean age of 61 +/- 10 years. Amongst screened patients, systolic blood pressure [2.5 mmHg, 95% confidence interval (CI) 0.3-4.6] and the level of LDL cholesterol (0.3 mmol L(-1), 95% CI 0.2-0.4) were lower compared with the group that received usual care, after a median of 16 months from referral., Conclusion: Systematic screening of risk factors, followed by evidence-based, tailored treatment advice contributed to slightly better risk factor reduction in patients with established vascular disease or type 2 diabetes. However, a large proportion of patients did not reach the treatment goals according to (inter)national guidelines. Systematic screening of vascular risk factors alone is not enough for adequate risk factor management in high-risk patients.

Background: It has frequently been hypothesized that high levels of glucocorticoids have deleterious effects on the hippocampus and increase risk for cognitive decline and dementia, but no large-scale studies in humans have examined the direct relation between hippocampal volumes and hypothalamic-pituitary-adrenal axis activity., Methods: Cross-sectional analyses within the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART)-Medea study, an ancillary study to the SMART-MR study on brain changes on magnetic resonance imaging (MRI) among patients with arterial disease. In 575 patients (mean age 62 +/- 9 years), diurnal cortisol rhythm was assessed with six saliva samples, collected at awakening; at 30, 45, and 60 min thereafter; and at 10 pm and 11 pm. A low dose of dexamethasone (.5 mg) was administered at 11 pm, and saliva was sampled the next morning at awakening. Volumetric measurements of the hippocampus were performed on a three-dimensional fast field echo T1-weighted scan with isotropic voxels., Results: Mean total relative hippocampal volume was 6.0 +/- .7 mL. Linear regression analyses, adjusted for age, sex, vascular risk factors, and global brain atrophy showed that participants with higher evening levels and higher awakening levels after dexamethasone had smaller hippocampal volumes [B per SD (4.2) increase = -.09 mL; 95% confidence interval -.15 to -.03 mL and B per SD (2.5) increase = -.07 mL; 95% confidence interval -.13 to -.01 mL, respectively]. The awakening response was not significantly associated with hippocampal volumes., Conclusions: In this population, higher evening cortisol levels and reduced suppression after dexamethasone were associated with smaller hippocampal volumes, independent of total brain volume. The cortisol response after awakening was not associated with hippocampal volume.

Objective: To estimate brain volumes, white matter lesion (WML) volume and asymptomatic infarcts on MRI in a large cohort of patients with atherosclerotic disease., Methods: Within the SMART-MR (Second Manifestations of ARTerial disease-Magnetic Resonance) study, a prospective cohort study on determinants and course of brain changes on MRI, cross-sectional analyses were performed in 1044 patients (mean age 58+/-10 years, 80% male) with coronary artery disease, cerebrovascular disease, peripheral arterial disease, or abdominal aortic aneurysm. Brain segmentation was used to quantify volumes of cortical gray matter, white matter, sulcal and ventricular cerebrospinal fluid, and WML. All volumes were expressed relative to intracranial volume. Brain infarcts were rated visually and distinctions were made between cortical infarcts, large subcortical infarcts, lacunar infarcts, and infarcts in the cerebellum and brainstem., Results: With older age a nonlinear (quadratic) decrease in total brain volume was observed and a nonlinear increase in ventricular volume and WML. Cortical gray matter volume showed a linear decrease with age and was stronger in men than in women. WML volumes also increased more strongly in men than in women, while ventricular volume decrease showed no sex difference. Silent brain infarcts were present in 14% of men and women, and increased to 24% of subjects aged 65 years or older., Conclusion: In a population with atherosclerotic diseases, decrease in brain volumes with increasing age is comparable with findings from the general population. However, vascular pathology on MRI, as indicated by white matter lesions and silent brain infarcts may be more common., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: Most previous studies on determinants of left ventricular (LV) mass have used echocardiography, which is less accurate than cardiac MRI (CMR). Furthermore, studies that used CMR to study the determinants of LV mass were performed in the general population. However, determinants may differ between those with and without previous symptomatic events. We studied the relation between atherosclerotic risk factors and LV mass in subjects free from cardiac disease, yet with and without atherosclerotic disease elsewhere., Methods: A CMR was performed in 531 hypertensive subjects with clinically manifest extra-cardiac atherosclerotic disease or marked risk factors for atherosclerosis. In all subjects information on atherosclerotic risk factors was collected. Multivariable linear regression was used to study the relation of risk factors with LV mass. Interaction was evaluated with multiplicative interaction terms., Results: Overall, male gender, weight, height, systolic blood pressure, albuminuria, current smoking, and a history of abdominal aortic aneurysm (AAA) were related to an increased LV mass. In subjects without a history of symptomatic atherosclerotic disease, gender, weight, height and systolic blood pressure were related to LV mass. In addition to these risk factors, albuminuria, current smoking and a history of AAA were related to LV mass in subjects with a history of symptomatic atherosclerotic disease., Conclusion: Our study points towards differences in risk factor relations across populations with and without symptomatic atherosclerotic disease. The observed relationship between cardiovascular risk factors and LV mass re-emphasizes the importance of adequate treatment of modifiable risk factors in the prevention of cardiovascular disease., (Copyright (c)2008 Elsevier Ireland Ltd. All rights reserved.)

Background: It is unclear whether the metabolic syndrome (MetS) increases risk of cognitive dysfunction beyond the level expected from its individual components. We examined the association of MetS with cognitive dysfunction and assessed whether MetS increased risk of cognitive dysfunction more than that of the sum of its individual components., Methods: Data on 823 participants were used from the SMART-study, a cohort study among patients with atherosclerotic disease. MetS was defined according to the NCEP-ATPIII-criteria. Neuropsychological tests assessing memory, executive, and visuospatial functioning were performed. Regression analyses were performed to assess the association of MetS and its individual components with cognitive dysfunction. To examine whether MetS increased risk of cognitive dysfunction beyond its individual components we tested whether there was interaction on an additive scale by calculating the relative excess risk due to interaction (RERI)., Results: MetS was associated with increased risk of memory (OR 2.0, 95% CI 1.1-3.3) and visuospatial dysfunction (OR 2.3, 95% CI 1.4-2.7) but not with executive dysfunction. However, risk of memory and visuospatial dysfunction for having all MetS components was not greater than that of the sum of the individual components (RERI 0.2 and -0.9)., Conclusions: In this population, MetS is related to increased risk of cognitive dysfunction but not more than that of the sum of its individual components., (Copyright 2009 S. Karger AG, Basel.)

Background: Increased blood pressure generally is associated with kidney function decrease. We evaluated the rate of kidney function decrease, the effect of blood pressure on kidney function deterioration, and the possible interaction with albuminuria in patients with vascular disease., Study Design: Prospective cohort study., Setting & Participants: 745 patients with vascular disease from the Second Manifestations of Arterial Disease (SMART) Study., Factors: Blood pressure, hypertension presence, albuminuria (albumin-creatinine ratio > 27 mg/g)., Outcomes: Rate of kidney function decrease, calculated from the difference between 2 estimated glomerular filtration rate (eGFR) values divided by the individual follow-up time., Measurements: Participants underwent vascular screening at baseline and after a mean follow-up of 4.5 +/- 1.0 years. Rate of kidney function decrease was expressed as annual decrease in eGFR. Linear regression analysis was used to evaluate the relation between blood pressure and eGFR decrease., Results: Mean baseline eGFR was 79.3 +/- 16.3 mL/min/1.73 m(2), and mean annual decrease in eGFR was 1.00 +/- 2.71 mL/min/1.73 m(2). In 35% of patients, eGFR was stable during follow-up. Albuminuria was present in 100 patients (median albumin-creatinine ratio, 58 mg/g). In patients without albuminuria, age-, sex-, and baseline eGFR-adjusted annual eGFR decrease was 0.86 mL/min/1.73 m(2), whereas this was 1.89 mL/min/1.73 m(2) in patients with albuminuria (P < 0.05). In the presence of albuminuria, higher blood pressure was associated with greater eGFR decrease (beta = 1.29; 95% CI, 0.73-1.85 for systolic blood pressure and beta = 3.86; 95% CI, 2.34-5.38 for hypertension presence). In patients without albuminuria, no association was found between blood pressure and kidney function decrease (beta = 0.15; 95% CI, -0.05 to 0.36 for systolic blood pressure and beta = 0.12; 95% CI, -0.28 to 0.52 for hypertension presence; P for interaction term < 0.05)., Limitations: Participants might reflect a healthier subgroup of patients with vascular disease. Creatinine was measured only twice., Conclusions: Kidney function decrease in patients with vascular disease is considerable. Blood pressure is a strong risk factor for eGFR decrease in patients with vascular disease and albuminuria.

Background: High concentrations of high density lipoprotein-cholesterol (HDL-c) are associated with lower cardiovascular risk, but it is not known whether this is also the case in the presence of intensive low density lipoprotein-cholesterol (LDL-C) therapy. In this study, we determined the relationship between HDL-c and new non-fatal or fatal vascular events in patients with various manifestations of clinical evident vascular disease and evaluated whether this relationship is modified by LDL-c levels., Materials and Methods: Prospective single centre, cohort study of 3837 patients with a history or recent diagnosis of clinical manifest vascular disease (coronary, cerebrovascular, peripheral arterial disease or abdominal aortic aneurysm) The relationship between HDL-c quintiles and time to a new event (myocardial infarction, ischaemic stroke, vascular death) was quantified with Cox-regression models and adjusted for potential confounders (age, gender, body mass index, type 2 diabetes, triglycerides, smoking, use of alcohol and lipid-lowering therapy). Effect modification of LDL-c was assessed with interaction terms., Results: During a median follow up of 3.3 (range 0.1-9.5) years, a total of 465 first new events occurred. Compared with the lowest quintile, the upper quintile of HDL-c levels was associated with a lower risk for new events; Hazard Ratio 0.61 (95% CI 0.43-0.86) irrespective of the localisation of vascular disease and use of lipid-lowering medication. Higher HDL-c levels were associated with comparably lower risks for vascular events in patients with LDL-c levels above and below 2.5 mmol L(-1) (P-values for interaction > 0.05)., Conclusions: Patients with various clinical manifestations of vascular diseases in the highest HDL-c quintile have a lower risk for vascular events compared with patients in the lowest HDL-c quintile. Further, the current results expand the evidence by showing that also in a cohort of patients with various localisations of clinical evident vascular disease, in which statins were widely used, higher HDL-c levels confer a lower risk for developing new vascular events, irrespective of the localisation of vascular disease, use of lipid-lowering medication and plasma LDL-c concentration.

Risk reduction in patients with clinically manifest vascular disease focuses on preventing new vascular events and not on prevention of type 2 diabetes. However, given the common pathophysiological pathways involved in the development of atherosclerosis and type 2 diabetes, it is probable that people with atherosclerotic vascular disease have an elevated risk of type 2 diabetes. The present prospective cohort study investigated the incidence of type 2 diabetes and the effect of the presence of metabolic syndrome on the incidence of type 2 diabetes in 4,022 patients with clinically manifest atherosclerosis, included in the study from September 1996 to June 2006. Patients who died (n=456), who were lost to follow-up (n=84) and those with diabetes at baseline (n=558) were excluded, leaving 2,924 patients for analysis. The incidence of diabetes was assessed by questionnaire (self-reported diabetes). During 13,726 person-years of follow-up (median follow-up 4.3 years, range 2.4-7.0 years), there were 152 type 2 diabetes cases (5.2%), corresponding to an incidence rate of 11.1 (95% CI 9.4-13.0) per 1,000 person-years. Patients with metabolic syndrome were at increased risk of incident type 2 diabetes compared to those without metabolic syndrome, with an adjusted hazard ratio of 5.7 (95% CI 3.7-8.9) for Revised National Cholesterol Education Program, 6.0 (4.1-9.0) for National Cholesterol Education Program and 4.0 (2.7-6.1) for International Diabetes Federation definitions of metabolic syndrome. Of all metabolic syndrome components, abdominal obesity was most strongly associated with incident type 2 diabetes (94% higher risk of type 2 diabetes for 1 standard deviation (11.3 cm) increase in waist circumference). In conclusion, patients with manifest atherosclerosis are at high risk of developing type 2 diabetes. Metabolic syndrome identifies those at the highest risk and is an easy to use clinical tool. Abdominal obesity is a strong individual predictor of type 2 diabetes. Patients with manifest atherosclerosis and metabolic syndrome may derive particular benefit from lifestyle interventions focusing on weight reduction.

Objective: Recent reports of animal models have shown that growth factors have stimulating effect on brain perfusion via the development of blood vessels. However, studies on the effect of growth factors on brain perfusion in humans are lacking. The aim of our study was to prospectively investigate in humans the relation between growth factors and brain perfusion., Methods: We analyzed circulating levels of vascular endothelial growth factor (VEGF), granulocyte-macrophage colony-stimulating growth factor (GM-CSF), tumor necrosis factor alpha (TNFalpha) and basic fibroblast growth factor (bFGF) in 121 consecutive patients (99 men and 22 women, age 58+/-10 years) who were enrolled in a prospective cohort study of patients with symptomatic atherosclerotic disease. In all patients regional cerebral blood flow (rCBF; in mL/min/100g) measurements were performed with arterial spin labeling magnetic resonance imaging. Cerebrovascular risk factors were assessed by means of a questionnaire and physical, ultrasonographic and laboratory examination., Results: Increasing levels of TNFalpha were significantly associated with a higher rCBF (beta=7.0; 95% confidence interval 0.7; 13.9), independent of the presence of cerebrovascular risk factors. No significant association was found for VEGF, GM-CSF and bFGF., Conclusions: Increasing levels of TNFalpha are associated with increased rCBF, independent of the presence of cerebrovascular risk factors.

Purpose: To prospectively investigate which cerebrovascular risk factors are related to regional cerebral blood flow (rCBF), as measured noninvasively with arterial spin-labeling (ASL) magnetic resonance (MR) imaging, in a large group of patients with symptomatic atherosclerotic disease., Materials and Methods: Ethics committee approval and informed consent were obtained. One hundred thirty consecutive patients (107 men, 23 women; mean age, 58 years +/- 10 [standard deviation]) with symptomatic atherosclerotic disease were included in the study. Cerebrovascular risk factors (body mass index, carotid artery stenosis, diabetes mellitus, hyperhomocysteinemia, hyperlipidemia, hypertension, and smoking) were assessed by means of a questionnaire and physical, ultrasonographic, and laboratory examinations. The control group consisted of 10 subjects (eight men, two women; mean age, 58 years +/- 15) without symptomatic atherosclerotic disease. rCBF measurements were performed with ASL MR imaging. The effects of the individual cerebrovascular risk factors on the rCBF were assessed by using linear regression analysis., Results: Hypertension was significantly associated with higher rCBF (adjusted beta = 6.5 mL/min/100 g; 95% confidence interval: 1.4 mL/min/100 g, 11.7 mL/min/100 g). Hyperhomocysteinemia was significantly related to lower rCBF (adjusted beta = -7.4 mL/min/100 g; 95% confidence interval: -12.7 mL/min/100 g, -2.1 mL/min/100 g). No significant associations between rCBF and the other cerebrovascular risk factors were found., Conclusion: In patients with symptomatic atherosclerotic disease, hypertension is related to higher rCBF and hyperhomocysteinemia is related to lower rCBF., (RSNA, 2007)

Aims: Patients with Type 2 diabetes and coronary heart disease (CHD) have an excess cardiovascular risk. The relationship of both other sites [cerebrovascular disease, peripheral arterial disease (PAD)] and the extent of clinically evident cardiovascular disease (CVD) with the occurrence of new cardiovascular events have not been investigated previously in patients with diabetes. We aimed to quantify this relationship and to assess the additional influence of atherosclerotic burden., Methods: From 1996 to 2005, 776 patients with Type 2 diabetes with (n = 458) and without (n = 318) clinically evident CVD were followed prospectively for cardiovascular events (cardiovascular death, non-fatal ischaemic stroke or myocardial infarction). CVD was classified according to the site (cerebrovascular disease, CHD, PAD); the extent of atherosclerosis was expressed as the number of affected sites. Carotid intima-media thickness and albuminuria were used as markers of atherosclerotic burden., Results: Compared with patients with diabetes without CVD, the hazard ratio (HR) for a cardiovascular event was 3.8 (95% confidence interval 1.7, 8.5), adjusted for age, gender and potential confounders, in those with cerebrovascular disease, 4.3 (1.9, 9.5) in those with CHD, and 4.6 (2.1, 10.2) in those with PAD. Findings were similar after additional adjustment for atherosclerotic burden. Adjusted HR was 3.4 (1.6, 6.9) for patients with diabetes with one affected site and 6.6 (3.0, 14.3) for those with two or more sites., Conclusions: Patients with Type 2 diabetes and cerebrovascular disease, CHD or PAD have strongly increased risks for future cardiovascular events which are comparable. This risk increases markedly with the number of different cardiovascular sites affected and is irrespective of atherosclerotic burden.

Background: Extra domain A (EDA), splice-variant of fibronectin, is a Toll-like receptor 4 (Tlr4) ligand. Recently, EDA has been demonstrated to enhance atherogenesis in mice but human data on the role of EDA in atherosclerotic disease are lacking. We hypothesized that EDA is associated with unstable plaque phenotypes and that plasma EDA could serve as biomarker for atherosclerosis., Methods: EDA levels were assessed in carotid endarterectomy specimen (206 patients) and related with plaque phenotype. In a second patient cohort, systemic EDA levels in atherosclerotic patients (73 patients) were compared to risk-factor matched controls (68 patients)., Results: EDA plaque levels were associated with characteristics of stable plaques; more smooth muscle cells (P=0.003), more collagen (P=0.071) and less fat (P=0.023). Concomitantly, asymptomatic patients showed higher EDA values in the plaque compared to symptomatic patients (P=0.004). EDA plasma levels did not differ between atherosclerotic patients versus controls (P=0.134)., Conclusion: EDA plaque levels are higher in asymptomatic patients and are associated with a stable plaque phenotype. EDA is not a plasma marker for atherosclerotic disease. These results suggest that local presence of endogenous Tlr4 ligand EDA is not associated with in an unstable plaque phenotype in humans.

Objective: Reticulon-4/Nogo (Nogo-B) protects mouse arteries from lumen loss by reducing smooth muscle cell (SMC) migration and intimal thickening. Our goal was to determine plaque and circulating levels of Nogo-B in atherosclerotic and control subjects. Therefore, we studied the relationships between local Nogo-B, plaque characteristics, and clinical data in patients undergoing carotid endarterectomy., Methods and Results: Western blot analysis showed that endarterectomy specimens from the femoral (n=19) and carotid arteries (n=145) contained significantly less Nogo-B than nonatherosclerotic mammary arteries (n=8; P<0.003) and aortas (n=15; P=0.03). Immunohistochemistry revealed that in atherosclerotic lesions, Nogo-B was expressed by macrophage/foam cells, SMC rich, and neo-vascularized areas. Atheromatous plaques (>40% fat content) showed a significant reduction in Nogo-B expression (P=0.002). Nogo-B expression levels were significantly lower in patients with more than 90% of carotid stenosis (P=0.04) or restenotic lesions after prior carotid intervention (duplex; P=0.01). In contrast, plasmatic levels of Nogo-B (soluble Nogo-B) did not differ between atherosclerotic subjects (n=68) and risk-factor matched controls (n=63; P=0.5)., Conclusion: Our findings suggest that local reduction of Nogo-B in atherosclerotic tissue might contribute to plaque formation and/or instability triggering luminal narrowing. In contrast, plasma Nogo-B levels are not associated with clinically manifested atherosclerotic disease.

Objectives: To assess whether the validity of endothelial function measurement by flow-mediated dilatation (FMD) is affected by local brachial artery stiffness (distensibility coefficient; DC) and arterial wall thickness (intima-media thickness, IMT)., Background: FMD measurement relies on assessment of arterial diameter change. Increased IMT and decreased DC might physically limit dilatation of the brachial artery in spite of healthy endothelium., Methods: DC, IMT and FMD of the brachial artery were simultaneously measured in 349 patients with advanced atherosclerosis or cardiovascular risk factors. The relations between FMD and age, and FMD and current smoking were regarded as a proxy for the relation between FMD and true endothelial function., Results: The relations between FMD and age, and FMD and smoking, were significantly modified by brachial artery DC. No modification was found for IMT. The interaction terms were statistically significant (p=0.03 and 0.04, respectively). The relation between FMD and age, and FMD and smoking was progressively more pronounced in patients with more elastic arteries., Conclusion: The results of our study indicate that increased arterial stiffness may interfere with valid measurement of FMD and that patients with stiff arteries may be considered for exclusion from analyses involving FMD to ensure its validity.

Objectives. Albuminuria and decreased estimated glomerular filtration rate (eGFR) are associated with increased cardiovascular risk, but do not necessarily coexist and have different pathophysiological mechanisms. This study aims to evaluate separate and combined effects of decreased eGFR and albuminuria on the occurrence of vascular diseases and mortality in patients with vascular disease. Design. Prospective cohort study. Setting. University Medical Center Utrecht, the Netherlands. Subjects and main outcome measures. 2600 patients with vascular disease were followed for vascular events, vascular and all-cause mortality. Cox regression analysis was used to calculate hazard ratios (HRs) according to eGFR (MDRD) and albuminuria (albumin-to-creatinine ratio >3 mg mmol−1). Results. In this population, 14.0% had albuminuria, 15.6% had eGFR <60 ml min−1 1.73 m−2 and 5.2% had both. Nonalbuminuric decreased eGFR and albuminuria with normal eGFR generated moderately increased risks on all outcomes. eGFR <60 ml min−1 1.73 m−2 without albuminuria mainly influenced the risk of vascular events (HR 1.50; 1.05–2.15) whilst albuminuria with eGFR ≥60 ml min−1 1.73 m−2 principally affected all-cause mortality (HR 1.53; 1.04–2.26). The combination of eGFR <60 ml min−1 1.73 m−2 and albuminuria was associated with an increased risk for vascular events (HR 2.27; 1.54–3.34), vascular mortality (HR 2.22; 1.40–3.52) and all-cause mortality (HR 1.84; 1.25–2.69). Comparable results were found in additional analyses amongst 759 diabetic patients. Conclusions. The combination of decreased eGFR with albuminuria is associated with the highest risks of vascular events, vascular and all-cause mortality in patients with vascular diseases. To adequately estimate vascular risk associated with impaired renal function, both eGFR and urinary albumin should be considered. [ABSTRACT FROM AUTHOR]

Abstract Background Renal size and function reflect the health of the kidney. These parameters are associated with age, gender and body weight. The kidneys are also influenced by micro- and macrovascular diseases. Atherosclerotic markers and risk factors may influence the age-related changes of renal size and function. Methods Data of 1056 patients who entered the SMART-study (Second Manifestations of ARTerial disease) were used to assess the effect of atherosclerosis on the relationship between age and renal size and function and to study the effect of atherosclerosis on renal size and function. Patients who were newly referred to the hospital with manifestations of vascular disease were screened for asymptomatic atherosclerosis with noninvasive tests. The carotid intima-media thickness (IMT) and albuminuria were used as estimates for the atherosclerotic burden. Renal size was defined as the mean pole-to-pole length of both kidneys measured by ultrasonography. Renal function was represented by serum creatinine. Results Intima-media thickness was a significant effect modifier of the age-renal size relationship (P = 0·041). The increase of serum creatinine with age was more pronounced in the highest tertile of IMT (P = 0·048). Renal size decreased equally with age in patients with and without hypertension or diabetes mellitus (DM). The same held true for the age-renal function relationship. Albuminuria and DM were independent predictors of renal size and function. Conclusion Atherosclerosis accelerates the decrease of renal size and the increase of serum creatinine with age. Renal size and function are determined by albuminuria and DM. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To study whether calcifications in breast arteries, as seen on mammograms, predict future development of coronary artery calcifications. Methods: We studied 499 women, aged 49–70 years, participating in a breast cancer screening program and investigated whether arterial calcifications in the breast (BAC) are associated with coronary arterial calcifications (CAC) after 9 years follow-up. Mammograms were reviewed for the presence of BAC. CAC was assessed by multi slice computed tomography (MSCT). With logistic regression analysis the independent effect of various risk factors on BAC and CAC was measured. Results: BAC was present in 58 of 499 women (12%) and CAC score>0 was present in 262 of 499 women (53%). BAC was strongly associated with CAC (OR 3.2, 95% CI 1.71–6.04) and this remained significant after adjustment for age at baseline and the duration of follow-up (OR 2.1, 95% CI 1.10–4.23). Most CV risk factors were associated with CAC but not with BAC. Only parity was significantly associated with both increased CAC (OR 2.1, 95% CI 1.21–3.60) and increased BAC (OR 5.3, 95% CI 1.23–22.43). Breastfeeding was associated with BAC (OR 3.4, 95% CI 1.40–8.23) but not with CAC (OR 1.3, 95% CI 0.84–1.93). Conclusion: Breast arterial calcifications are predictive of subsequent development of calcifications in the coronary arteries. [Copyright &y& Elsevier]