An elevated ankle-brachial index is not a valid proxy for peripheral medial arterial calcification

BACKGROUND AND AIMS: The ankle brachial index (ABI) is often used as a proxy for medial arterial calcification (MAC) in studies investigating MAC as a cardiovascular risk factor, but evidence supporting this hypothesis is sparse. This study aims to investigate the use of an elevated ABI as proxy for MAC, as visualized with computed tomography (CT). METHODS: Cross-sectional data of 718 participants with, or at risk of cardiovascular disease was used. The ABI was calculated using cutoffs >1.4 and > 1.3. The presence of MAC was assessed in the crural and femoral arteries by CT imaging. Modified Poisson regression was used to assess the association between an elevated ABI and the presence of MAC, and test characteristics were calculated. RESULTS: MAC was found in 25.0% of participants. An ABI >1.4 was found in 8.7% of participants, of whom 45.2% had MAC. An elevated ABI was significantly associated with the presence of MAC (RR 1.74, CI: 1.26-2.40). However, poor positive specific agreement (23.3%, CI: 13.9-34.3), sensitivity (15.7%, CI: 10.4-21.1) and positive predictive value (45.2%, CI: 32.8-57.5) were found. Despite good specificity (93.6%, CI: 91.6-95.7) the area under the receiving operator curve remained poor (54.7%, CI: 51.8-57.6). Negative specific agreement (84.5%, CI: 81.4-87.0) and negative predictive value (77.0%, CI: 73.7-80.2) were acceptable. CONCLUSIONS: An elevated ABI is insufficient to serve as a true diagnostic proxy for MAC. Studies that have drawn conclusions on the association between MAC and cardiovascular disease, solely based on the ABI, are likely to underestimate the found effects

Intimal and medial calcification in relation to cardiovascular risk factors

PURPOSE: To assess specific risk factors and biomarkers associated with intimal arterial calcification (IAC) and medial arterial calcification (MAC). METHODS: We conducted a cross-sectional study in patients with or at risk of vascular disease from the SMART study(n = 520) and the DCS cohort(n = 198). Non-contrast computed tomography scanning of the lower extremities was performed and calcification in the femoral and crural arteries was scored as absent, predominant IAC, predominant MAC or indistinguishable. Multinomial regression models were used to assess the associations between cardiovascular risk factors and calcification patterns. Biomarkers for inflammation, calcification and vitamin K status were measured in a subset of patients with IAC(n = 151) and MAC(n = 151). RESULTS: Femoral calcification was found in 77% of the participants, of whom 38% had IAC, 28% had MAC and 11% were scored as indistinguishable. The absolute agreement between the femoral and crural arteries was high(69%). Higher age, male sex, statin use and history of coronary artery disease were associated with higher prevalences of femoral IAC and MAC compared to absence of calcification. Smoking and low ankle-brachial-index (ABI) were associated with higher prevalence of IAC and high ABI was associated with less IAC. Compared to patients with IAC, patients with MAC more often had diabetes, have a high ABI and were less often smokers. Inactive Matrix-Gla Protein was associated with increased MAC prevalence, while osteonectin was associated with decreased risk of MAC, compared to IAC. CONCLUSIONS: When femoral calcification is present, the majority of the patients have IAC or MAC throughout the lower extremity, which have different associated risk factor profiles

Metabolic syndrome and risk of incident heart failure in non-diabetic patients with established cardiovascular disease

BACKGROUND: In patients with established cardiovascular disease (CVD), the relation between metabolic syndrome (MetS) and incident heart failure (HF) in the absence of diabetes mellitus (DM) is largely unknown. This study assessed this relation in non-diabetic patients with established CVD. METHODS: Patients from the prospective UCC-SMART cohort with established CVD, but without DM or HF at baseline were included (n = 4653). MetS was defined according to the Adult Treatment Panel III criteria. Insulin resistance was quantified using the homeostasis model of insulin resistance (HOMA-IR). The outcome was a first hospitalization for HF. Relations were assessed using Cox proportional hazards models adjusted for established risk factors: age, sex, prior myocardial infarction (MI), smoking, cholesterol, and kidney function. RESULTS: During a median follow-up of 8.0 years, 290 cases of incident HF were observed (0.81/100 person years). MetS was significantly related to an increased risk of incident HF independent of established risk factors (hazard ratio [HR] 1.32; 95% confidence interval [CI] 1.04-1.68, HR per criterion 1.17; 95% CI 1.06-1.29), as was HOMA-IR (HR per standard deviation [SD] 1.15; 95% CI 1.03-1.29). Of the individual MetS components, only higher waist circumference independently increased the risk of HF (HR per SD 1.34; 95% CI 1.17-1.53). Relations were independent of the occurrence of interim DM and MI, and were not significantly different for HF with reduced vs preserved ejection fraction. CONCLUSION: In CVD patients without a current diagnosis of DM, MetS and insulin resistance increase the risk of incident HF independent of established risk factors

The relation between healthy lifestyle changes and decrease in systemic inflammation in patients with stable cardiovascular disease

Background and aims: Pharmacological lowering of inflammation has proven effective in reducing recurrent cardiovascular event rates. Aim of the current study is to evaluate lifestyle changes (smoking cessation, weight loss, physical activity level increase, alcohol moderation, and a summary lifestyle improvement score) in relation to change in plasma C-reactive protein (CRP) concentration in patients with established cardiovascular disease. Methods: In total, 1794 patients from the UCC-SMART cohort with stable cardiovascular disease and CRP levels ≤10 mg/L, who returned for a follow-up study visit after median 9.9 years (IQR 5.4–10.8), were included. The relation between changes in smoking status, weight, physical activity, alcohol consumption, a summary lifestyle improvement score and change in plasma CRP concentration was evaluated with linear regression analyses. Results: Smoking cessation was related to a 0.40 mg/L decline in CRP concentration (β-coefficient −0.40; 95%CI -0.73,-0.07). Weight loss (per 1SD = 6.4 kg) and increase in physical activity (per 1 SD = 48 MET hours per week) were related to a decrease in CRP concentration (β-coefficients −0.25; 95%CI -0.33,-0.16 and −0.09; 95%CI -0.17,-0.01 per SD). Change in alcohol consumption was not related to CRP difference. Every point higher in the summary lifestyle improvement score was related to a decrease in CRP concentration of 0.17 mg/L (β-coefficient −0.17; 95%CI -0.26,-0.07). Conclusions: Smoking cessation, increase in physical activity, and weight loss are related to a decrease in CRP concentration in patients with stable cardiovascular disease. Patients with the highest summary lifestyle improvement score have the most decrease in CRP concentration. These results may indicate that healthy lifestyle changes contribute to lowering systemic inflammation, potentially leading to a lower cardiovascular risk in patients with established cardiovascular disease

White matter hyperintensity shape is associated with cognitive functioning - the SMART-MR study

White matter hyperintensity (WMH) shape has been associated with the severity of the underlying brain pathology, suggesting it is a potential neuroimaging marker of WMH impact on brain function. In 563 patients with vascular disease (58 ± 10 years), we examined the relationship between WMH volume, shape, and cognitive functioning. WMH volume and shape were automatically determined on 1.5T brain MRI data. Standardized linear regression analyses estimated the association between WMH volume and shape (concavity index, solidity, convexity, fractal dimension, and eccentricity) and memory and executive functioning, adjusted for age, sex, educational level, and reading ability. Larger WMH volumes were associated with lower executive functioning Z-scores (b (95%-CI): -0.09 (-0.17;-0.01)). Increased shape complexity of periventricular/confluent WMH associated with lower executive functioning (concavity index +1SD: -0.13 (-0.20;-0.06); solidity -1SD: -0.09 (-0.17;-0.02)) and lower memory function (fractal dimension +1SD: -0.10 (-0.18;-0.02)). Of note, the association between concavity index and executive functioning was independent of WMH volume (-0.12 (-0.19;-0.04)). Our results suggest that WMH shape contains additional information about WMH burden, not otherwise captured by WMH volume

Psychosocial factors and hippocampal subfields: The Medea-7T study

Specific subfields within the hippocampus have shown vulnerability to chronic stress, highlighting the importance of looking regionally within the hippocampus to understand the role of psychosocial factors in the development of neurodegenerative diseases. A systematic review on psychosocial factors and hippocampal subfield volumes was performed and showed inconsistent results, highlighting the need for future studies to explore this relationship. The current study aimed to explore the association of psychosocial factors with hippocampal (subfield) volumes, using high-field 7T MRI. Data were from the Memory Depression and Aging (Medea)-7T study, which included 333 participants without dementia. Hippocampal subfields were automatically segmented from T2-weighted images using ASHS software. Generalized linear models accounting for correlated outcomes were used to assess the association between subfields (i.e., entorhinal cortex, subiculum, Cornu Ammonis [CA]1, CA2, CA3, dentate gyrus, and tail) and each psychosocial factor (i.e., depressive symptoms, anxiety symptoms, childhood maltreatment, recent stressful life events, and social support), adjusted for age, sex, and intracranial volume. Neither depression nor anxiety was associated with specific hippocampal (subfield) volumes. A trend for lower total hippocampal volume was found in those reporting childhood maltreatment, and a trend for higher total hippocampal volume was found in those who experienced a recent stressful life event. Among subfields, low social support was associated with lower volume in the CA3 (B = −0.43, 95% CI: −0.72; −0.15). This study suggests possible differential effects among hippocampal (subfield) volumes and psychosocial factors

Association of White Matter Hyperintensity Markers on MRI and Long-term Risk of Mortality and Ischemic Stroke: The SMART-MR Study

OBJECTIVE: To determine whether white matter hyperintensity (WMH) markers on MRI are associated with long-term risk of mortality and ischemic stroke. METHODS: We included consecutive patients with manifest arterial disease enrolled in the Second Manifestations of Arterial Disease-Magnetic Resonance (SMART-MR) study. We obtained WMH markers (volume, type, and shape) from brain MRI scans performed at baseline using an automated algorithm. During follow-up, occurrence of death and ischemic stroke was recorded. Using Cox regression, we investigated associations of WMH markers with risk of mortality and ischemic stroke, adjusting for demographics, cardiovascular risk factors, and cerebrovascular disease. RESULTS: We included 999 patients (59 ± 10 years; 79% male) with a median follow-up of 12.5 years (range 0.2-16.0 years). A greater periventricular or confluent WMH volume was independently associated with a greater risk of vascular death (hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.13-1.47) for a 1-unit increase in natural log-transformed WMH volume and ischemic stroke (HR 1.53, 95% CI 1.26-1.86). A confluent WMH type was independently associated with a greater risk of vascular (HR 1.89, 95% CI 1.15-3.11) and nonvascular death (HR 1.65, 95% CI 1.01-2.73) and ischemic stroke (HR 2.83, 95% CI 1.36-5.87). A more irregular shape of periventricular or confluent WMH, as expressed by an increase in concavity index, was independently associated with a greater risk of vascular (HR 1.20, 95% CI 1.05-1.38 per SD increase) and nonvascular death (HR 1.21, 95% CI 1.03-1.42) and ischemic stroke (HR 1.28, 95% CI 1.05-1.55). CONCLUSIONS: WMH volume, type, and shape are associated with long-term risk of mortality and ischemic stroke in patients with manifest arterial disease

The role of cognitive and brain reserve in memory decline and atrophy rate in mid and late-life: The SMART-MR study

OBJECTIVE: Investigate associations of cognitive and brain reserve with trajectories of memory decline in mid-life and late-life, and whether the relationship of memory decline with atrophy differs as a function of reserve. METHODS: Participants were 989 Dutch middle-aged to older adults from the SMART-MR prospective cohort, followed up to 12 years with up to 3 measurements of memory and brain MRI. Education and Dutch National Adult Reading Test (DART) were used as proxies of cognitive reserve, and intracranial volume (ICV) and baseline brain parenchymal fraction (BPF) for brain reserve. Univariate growth curve models analyzed associations of reserve with memory decline, and multiple-group bivariate growth curve models tested the longitudinal brain-memory relationship as a function of reserve. Models were additionally stratified by mid-life and late-life. RESULTS: Higher DART, education, and BPF were related to a slower rate of memory decline, particularly in late-life, but ICV was not. A positive covariance indicated that an individual who undergoes atrophy also undergoes memory decline-this relationship did not differ across cognitive or brain reserve, but was not present in mid-life. Memory declined slower than brain volume, yet rates were more similar in the low DART, education, and BPF groups. DISCUSSION: Higher cognitive (DART, education) and brain reserve (BPF) work protectively in longitudinal memory change. ICV is an inappropriate proxy of brain reserve, failing to show any association with memory performance at baseline or over time. Deconstructing relationships of reserve capacities with longitudinal cognitive and brain outcomes may identify focus areas with potential for intervention

Reduced parenchymal cerebral blood flow is associated with greater progression of brain atrophy: The SMART-MR study

Global cerebral hypoperfusion may be involved in the aetiology of brain atrophy; however, long-term longitudinal studies on this relationship are lacking. We examined whether reduced cerebral blood flow was associated with greater progression of brain atrophy. Data of 1165 patients (61 ± 10 years) from the SMART-MR study, a prospective cohort study of patients with arterial disease, were used of whom 689 participated after 4 years and 297 again after 12 years. Attrition was substantial. Total brain volume and total cerebral blood flow were obtained from magnetic resonance imaging scans and expressed as brain parenchymal fraction (BPF) and parenchymal cerebral blood flow (pCBF). Mean decrease in BPF per year was 0.22% total intracranial volume (95% CI: -0.23 to -0.21). Mean decrease in pCBF per year was 0.24 ml/min per 100 ml brain volume (95% CI: -0.29 to -0.20). Using linear mixed models, lower pCBF at baseline was associated with a greater decrease in BPF over time (p = 0.01). Lower baseline BPF, however, was not associated with a greater decrease in pCBF (p = 0.43). These findings indicate that reduced cerebral blood flow is associated with greater progression of brain atrophy and provide further support for a role of cerebral blood flow in the process of neurodegeneration

Carotid Artery Stenosis and Progression of Hemispheric Brain Atrophy: The SMART-MR Study

INTRODUCTION: It has been hypothesized that carotid artery stenosis (CAS) may lead to greater atrophy of subserved brain regions; however, prospective studies on the impact of CAS on progression of hemispheric brain atrophy are lacking. We examined the association between CAS and progression of hemispheric brain atrophy. METHODS: We included 654 patients (57 ± 9 years) of the SMART-MR study, a prospective cohort study of patients with manifest arterial disease. Patients had baseline CAS duplex measurements and a 1.5T brain MRI at baseline and after 4 years of follow-up. Mean change in hemispheric brain volumes (% of intracranial volume [ICV]) was estimated between baseline and follow-up for left-sided and right-sided CAS across three degrees of stenosis (mild [≤29%], moderate [30-69%], and severe [≥70%]), adjusting for demographics, cerebrovascular risk factors, and brain infarcts. RESULTS: Mean decrease in left and right hemispheric brain volumes was 1.15% ICV and 0.82% ICV, respectively, over 4 years of follow-up. Severe right-sided CAS, compared to mild CAS, was associated with a greater decrease in volume of the left hemisphere (B = -0.49% ICV, 95% CI: -0.86 to -0.13) and more profoundly of the right hemisphere (B = -0.90% ICV, 95% CI: -1.27 to -0.54). This pattern was independent of cerebrovascular risk factors, brain infarcts, and white matter hyperintensities on MRI, and was also observed when accounting for the presence of severe bilateral CAS. Increasing degrees of left-sided CAS, however, was not associated with greater volume loss of the left or right hemisphere. CONCLUSIONS: Our data indicate that severe (≥70%) CAS could represent a risk factor for greater ipsilateral brain volume loss, independent of cerebrovascular risk factors, brain infarcts, or white matter hyperintensities on MRI. Further longitudinal studies in other cohorts are warranted to confirm this novel finding