RISK FACTORS FOR MEDIAL AND INTIMAL INTRACRANIAL INTERNAL CAROTID ARTERY CALCIFICATION IN MEN AND WOMEN WITH CARDIOVASCULAR DISEASE. THE UCC-SMART STUDY.

INTRODUCTION: Calcifications of the intracranial internal carotid artery (iICA) can lead to an increased risk for stroke. Two types of iICA calcification are known: those affecting the tunica intima or the tunica media. In extracranial arteries, risk factors and calcification patterns are different in women and men, but little is known regarding the iICA. In this study we aimed to identify sex-specific risk profiles and medications associated to intimal and medial iICA calcification in patients with cardiovascular disease (CVD). METHODS: Participants of the UCC-SMART cohort undergoing a non-contrast head CT within six months from the study inclusion were considered (n=475). Intimal or medial iICA calcification pattern was assessed using a previously histology-validated method. Sex-stratified associations between calcification pattern and cardiovascular risk factors, laboratory parameters, and medication use were calculated using Poisson regression analysis with robust standard errors. RESULTS: 204 women and 271 men (age range 24-79 years) were included. 45.4% of men and 34.8% of women showed intimal iICA calcification, while 28.4% of men and 24.0% of women showed medial iICA calcification. Minimal or no iICA calcification was observed in 26.2% of men and in 41,2% of women (reference group). Older age was associated with both calcification patterns in women and men. In women, use of vitamin K antagonists and lipid lowering drugs were associated to medial calcification, while systolic blood pressure and glucose levels were associated to intimal calcification. In men, current smoking was associated to intimal calcification. CONCLUSIONS: Women and men with CVD show differences in risk profiles and medication use associated to intimal and medial iCA calcification.

Intracranial arteriosclerosis and the risk of dementia: A population-based cohort study.

BACKGROUND: The impact of intracranial arteriosclerosis on dementia remains largely unclear. METHODS: In 2339 stroke-free and dementia-free participants (52.2% women, mean age 69.5 years) from the general population, we assessed intracranial carotid artery calcification (ICAC) and vertebrobasilar artery calcification (VBAC) as proxy for arteriosclerosis. Associations with dementia were assessed using Cox models. In addition, indirect effects through cerebral small vessel disease (cSVD) and subcortical brain structure volumes were assessed using causal mediation analyses. RESULTS: During a median of 13.4 years (25th-75th percentiles 9.9-14.5) of follow-up, 282 participants developed dementia. Both ICAC presence (hazard ratio [HR]: 1.53, 95% confidence interval [CI]: 1.00-2.32]) and volume (HR per standard deviation: 1.19, 95% CI: 1.01-1.40) increased dementia risk. For VBAC, severe calcifications increased dementia risk (HR for third vs first volume tertile: 1.89, 95% CI: 1.00-3.59). These effects were mediated partly through increased cSVD (percentage mediated for ICAC: 13% and VBAC: 24%). DISCUSSION: Intracranial arteriosclerosis increases the risk of dementia.

Intracranial atherosclerosis in pseudoxanthoma elasticum: A case-control study.

BACKGROUND AND AIMS: Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by systemic calcification of elastin fibers. Additionally, PXE is associated with an increased risk of stroke. It has been hypothesized that this may be caused by accelerated (intracranial) atherogenesis, as a consequence of specific genetic mutations underlying PXE. Hence, we compared the distribution and burden of intracranial atherosclerosis between PXE patients and healthy controls. METHODS: Fifty PXE patients and 40 age-and-sex-matched healthy controls (without previous ischemic cerebrovascular disease) underwent 3T MRI to visualize atherosclerotic intracranial vessel wall lesions (VWLs). We compared the presence and burden of VWLs (total and for the anterior cerebral, middle cerebral, intracranial internal carotid, posterior cerebral, and basilar arteries separately) between PXE patients and healthy controls using logistic (presence versus absence) and negative binomial regression models (VWL count) adjusted for relevant confounders. All regressions included group (PXE patients vs. healthy controls) as independent variable. RESULTS: We found that 34 (68.0%) PXE patients and 28 (70.0%) healthy controls had a VWL (odds ratio for presence 1.06 [95%CI 0.38-2.91]). In addition, the total burden of VWLs was similar between PXE patients (68 VWLs) and healthy controls (73 VWLs, incidence rate ratio for count 0.81 [95%CI 0.55-1.20]). Findings were similar when analyses were stratified for artery. CONCLUSIONS: The distribution and burden of intracranial atherosclerosis were similar between PXE patients and healthy controls. This implies PXE and its underlying mutations do not involve increased (intracranial) atherogenesis and that vascular calcification or other mechanisms explains the increased stroke risk in PXE.

Morphological Subtypes of Intracranial Internal Carotid Artery Arteriosclerosis and the Risk of Stroke.

BACKGROUND: Accumulating evidence highlights the existence of distinct morphological subtypes of intracranial carotid arteriosclerosis. So far, little is known on the prevalence of these subtypes and subsequent stroke risk in the general population. We determined the prevalence of morphological subtypes of intracranial arteriosclerosis and assessed the risk of stroke associated with these subtypes. METHODS: Between 2003 and 2006, 2391 stroke-free participants (mean age 69.6, 51.7% women) from the population-based Rotterdam Study underwent noncontrast computed tomography to visualize calcification in the intracranial carotid arteries as a proxy for intracranial arteriosclerosis. Calcification morphology was evaluated according to a validated grading scale and categorized into intimal, internal elastic lamina (IEL), or mixed subtype. Follow-up for stroke was complete until January 1, 2016. We used multivariable Cox regression to assess associations of each subtype with incident stroke. RESULTS: The prevalence of calcification was 82% of which 39% had the intimal subtype, 48% IEL subtype, and 13% a mixed subtype. During a median follow-up of 10.4 years, 155 participants had a stroke. All 3 subtypes were associated with a higher risk of stroke (adjusted hazard ratio [95% CI] for intimal: 2.11 [1.07-4.13], IEL: 2.66 [1.39-5.11], and mixed subtype 2.57 [1.18-5.61]). The association of the IEL subtype with stroke was strongest among older participants. The association of the intimal subtype with stroke was noticeably stronger in women than in men. CONCLUSIONS: Calcification of the IEL was the most prevalent subtype of intracranial arteriosclerosis. All 3 subtypes were associated with an increased risk of stroke, with noticeable age and sex-specific differences.

Risk factors for calcification of the vertebrobasilar arteries in cardiovascular patients referred for a head CT, the SMART study.

BACKGROUND AND PURPOSE: Vertebrobasilar artery calcification (VBAC) has been associated with increased stroke occurrence. Little is known on VBAC risk factors, especially for patients with cardiovascular disease. We aimed to assess risk factors associated with VBAC in a cohort of cardiovascular patients referred for a head computed tomography (CT) scan. MATERIALS AND METHODS: All patients who underwent a clinically indicated, unenhanced, thin slice head CT 6 months before or after inclusion in the SMART study were included. CTs were assessed for presence of VBAC (dichotomously). Relative risks of the associations of age, sex, diabetes mellitus (DM), obesity, body mass index, estimated glomerular filtration rate, hypertension, hyperlipidemia, use of lipid lowering medication, smoking status, high sensitivity C-reactive protein, ankle-brachial index (ABI; ≤0.90, ≥1.30, continuous), internal carotid artery stenosis ≥70%, and carotid intima-media thickness (IMT) with VBAC were estimated using Poisson regression analysis with robust standard errors, adjusted for age and sex. RESULTS: Of the 471 patients included (57% male, median age 58 [interquartile range 47-63]), 117 (24.8%) showed VBAC. Presence of VBAC was associated with older age (RR per 10 years=1.70 [95%CI 1.46-1.99]), DM (RR=1.45 [95%CI 1.03-2.06]), obesity (RR=1.53 [95%CI 1.10-2.12]), ABI ≤0.90 (RR=1.57 [95%CI 1.02-2.41]), and an increased carotid IMT (RR=2.60 per mm [95%CI 1.20-5.62]). Other measurements were not associated with VBAC. CONCLUSIONS: We identified several markers associated with VBAC in patients with cardiovascular disease referred for a head CT. Future investigation into the relationship between VBAC and stroke is warranted to determine the potential of VBAC in stroke prevention.

Intracranial Arterial Calcification: Prevalence, Risk Factors, and Consequences: JACC Review Topic of the Week.

Intracranial large and small arterial calcifications are a common incidental finding on computed tomography imaging in the general population. Here we provide an overview of the published reports on prevalence of intracranial arterial calcifications on computed tomography imaging and histopathology in relation to risk factors and clinical outcomes. We performed a systematic search in Medline, with a search filter using synonyms for computed tomography scanning, (histo)pathology, different intracranial arterial beds, and calcification. We found that intracranial calcifications are a frequent finding in all arterial beds with the highest prevalence in the intracranial internal carotid artery. In general, prevalence increases with age. Longitudinal studies on calcification progression and intervention studies are warranted to investigate the possible causal role of calcification on clinical outcomes. This might open up new therapeutic directions in stroke and dementia prevention and the maintenance of the healthy brain.