Biological Signatures of Asymptomatic Extra- and Intracranial Atherosclerosis

Abstract

Background and Purpose-Intracranial atherosclerotic disease (ICAD) remains a challenge for stroke primary and secondary prevention. Molecular pathways involved in the development of ICAD from its asymptomatic stages are largely unknown. In our population-based study, we aimed to compare the risk factor and biomarker profiles associated with intracranial and extracranial asymptomatic cerebral atherosclerosis. Methods-The Asymptomatic Intracranial Atherosclerosis (AsIA) study cohort includes a random sample population of 933 white subjects Ͼ50 years with a moderate to high vascular risk (based on REGICOR score) and without a history of stroke (64% males; mean age, 66 years). Carotid and intracranial atherosclerosis were screened by cervical and transcranial color-coded Duplex ultrasound, being moderate to severe stenoses confirmed by MR angiography. We registered clinical and anthropometric data and created a biobank with blood samples at baseline. A panel of biomarkers involved in atherothrombogenesis was determined: C-reactive protein, asymmetric-dimethylarginine, resistin, and plasminogen activator inhibitor-1. Insulin resistance was quantified by Homeostasis Model Assessment index. Results-After multinomial regression analyses, male sex, hypertension, smoking, and alcoholic habits were independent risk factors of isolated extracranial atherosclerotic disease. Diabetes and metabolic syndrome conferred a higher risk for ICAD than for extracranial atherosclerotic disease. Moreover, metabolic syndrome and insulin resistance were independent risk factors of moderate to severe ICAD but were not risk factors of moderate to severe extracranial atherosclerotic disease. Regarding biomarkers, asymmetric-dimethylarginine was independently associated with isolated ICAD and resistin with combined ICAD-extracranial atherosclerotic disease. Conclusions-Our

Heritability and Genome-Wide Association Analyses of Intracranial Carotid Artery Calcification

“…These differences in genetic contribution to the development of calcification in different vessel beds shed light on the previously reported variation in atherosclerotic burden across various vessel beds. 7,8,24 In addition to its high heritability, we also identified multiple genome-wide significant variants for ICAC at 2 loci. The first locus, on which we found 28 variants that were associated with ICAC, was located on chromosome 9, near the CKDN2a/CKDN2b genes.…”

Stroke Caused by Atherosclerosis of the Major Intracranial Arteries

“…Hypertension, diabetes mellitus, and age were independently associated with both symptomatic and asymptomatic ICAD on TCD in Korean, Japanese and Caucasian patients 29,30,31 . In a Spanish cohort, diabetes and metabolic syndrome conferred a higher risk for ICAD than extracranial atherosclerotic disease in asymptomatic patients 32 . The association between diabetes mellitus and ICAD is partly mediated by coexistent hypertension and hyperlipidemia 33 .…”

Distinct Roles of Endothelial Dysfunction and Inflammation in Intracranial Atherosclerotic Stroke

“…Therefore, the progression of intracranial atherosclerosis and the development of clinical events may be determined by different factors in patients with intracranial atherosclerosis. Several recent studies investigated possible novel risk factors of intracranial macroangiopathy, which include endothelial dysfunction, asymmetric dimethylarginine (ADMA) [11,] and the inflammatory marker, lipoprotein-associated phospholipase A2 (Lp-PLA 2 ) [12,13]. …”