Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD) and type 2 diabetes (T2D), respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) = 1.31, P = 1.2 x 10(-12)) and intracranial aneurysm (OR = 1.29, P = 2.5 x 10(-6)), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases.

Background and Purpose-The cellular mechanisms of degeneration and repair preceding rupture of the saccular cerebral artery aneurysm wall need to be elucidated for rational design of growth factor or drug-releasing endovascular devices. Methods-Patient records, preoperative vascular imaging studies, and the snap-frozen fundi resected after microsurgical clipping from 66 aneurysms were studied. Immunostainings for markers of smooth muscle cell (SMC) phenotype, proliferation, and inflammatory cell subtypes and TUNEL reaction were performed. Results-Unruptured (24) and ruptured (42) aneurysms had similar dimensions (median diameter in unruptured 6 mm; median in ruptured 7 mm; Pϭ0.308). We identified 4 basic types of aneurysm wall that associated with rupture: (1) endothelialized wall with linearly organized SMCs (17/66; 42% ruptured), (2) thickened wall with disorganized SMCs (20/66; 55% ruptured), (3) hypocellular wall with either myointimal hyperplasia or organizing luminal thrombosis (14/66; 64% ruptured), and (4) an extremely thin thrombosis-lined hypocellular wall (15/66; 100% ruptured). Apoptosis, de-endothelialization, luminal thrombosis, SMC proliferation, and T-cell and macrophage infiltration associated with rupture. Furthermore, macrophage infiltration associated with SMC proliferation, and both were increased in ruptured aneurysms resected Ͻ12 hours from rupture, suggesting that these were not just reactive changes. Conclusions-Before rupture, the wall of saccular cerebral artery aneurysm undergoes morphological changes associated with remodeling of the aneurysm wall. Some of these changes, like SMC proliferation and macrophage infiltration, likely reflect ongoing repair attempts that could be enhanced with pharmacological therapy.

Saccular intracranial aneurysms (sIA) are pouch-like pathological dilatations of intracranial arteries that develop when the cerebral artery wall becomes too weak to resist hemodynamic pressure and distends. Some sIAs remain stable over time, but in others mural cells die, the matrix degenerates, and eventually the wall ruptures, causing life-threatening hemorrhage. The wall of unruptured sIAs is characterized by myointimal hyperplasia and organizing thrombus, whereas that of ruptured sIAs is characterized by a decellularized, degenerated matrix and a poorly organized luminal thrombus. Cell-mediated and humoral inflammatory reaction is seen in both, but inflammation is clearly associated with degenerated and ruptured walls. Inflammation, however, seems to be a reaction to the ongoing degenerative processes, rather than the cause. Current data suggest that the loss of mural cells and wall degeneration are related to impaired endothelial function and high oxidative stress, caused in part by luminal thrombosis. The aberrant flow conditions caused by sIA geometry are the likely cause of the endothelial dysfunction, which results in accumulation of cytotoxic and pro-inflammatory substances into the sIA wall, as well as thrombus formation. This may start the processes that eventually can lead to the decellularized and degenerated sIA wall that is prone to rupture.

Background and Purpose-This prospective study was conducted to compare the outcomes of surgical clipping and endovascular treatment in acute (Ͻ72 hours) aneurysmal subarachnoid hemorrhage (SAH). Methods-One hundred nine consecutive patients were randomly assigned to either surgical (nϭ57) or endovascular (nϭ52) treatment. Clinical and neuropsychological outcome was assessed at 3 and 12 months after treatment; MRI of the brain was performed at 12 months. Follow-up angiography was scheduled after clipping and 3 and 12 months after endovascular treatment. Results-One year postoperatively, 43/41 (surgical/endovascular) patients had good or moderate recovery, 5/4 had severe disability or were in a vegetative state, and 9/7 had died (NS) according to intention to treat.

Saccular intracranial aneurysms (IAs) are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with ∼832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with IA in the combined data set, including intervals near RBBP8 on 18q11.2 (OR=1.22, P=1.1×10-12), STARD13/KL on 13q13.1 (OR=1.20, P=2.5×10-9) and a gene-rich region on 10q24.32 (OR=1.29, P=1.2×10-9). We also confirmed prior associations near SOX17 (8q11.23-q12.1; OR=1.28, P=1.3×10-12) and CDKN2A/B (9p21.3; OR=1.31, P=1.5×10-22). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting proliferation and senescence of progenitor cell populations that are responsible for vascular formation and repair.

The likelihood of rupture of unruptured intracranial aneurysms that were less than 10 mm in diameter was exceedingly low among patients in group 1 and was substantially higher among those in group 2. The risk of morbidity and mortality related to surgery greatly exceeded the 7.5-year risk of rupture among patients in group 1 with unruptured intracranial aneurysms smaller than 10 mm in diameter.

Stroke is the world’s third leading cause of death. One cause of stroke, intracranial aneurysm, affects ~2% of the population and accounts for 500,000 hemorrhagic strokes annually in midlife (median age 50), most often resulting in death or severe neurological impairment1. The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24-1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm2-5. Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells6-8, suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role9. These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.

Internal carotid BBAs are rare, small, and difficult to treat endovascularly, with only 2 of 14 patients successfully treated with coil placement. The BBAs rupture easily during surgery (ruptured in 6 of 11 surgical cases). Intraoperative aneurysm rupture invariably led to ICA trap ligation. Sacrifice of the ICA within 48 hours of an SAH led to very poor outcome, even in patients with adequate collateral capacity on preoperative angiograms, probably because of vasospasm-induced compromise of the cerebral collaterals.