Juha Hernesniemi

The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm

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 × 10−12) and intracranial aneurysm (OR = 1.29, P = 2.5 × 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.

Remodeling of Saccular Cerebral Artery Aneurysm Wall Is Associated With Rupture: Histological Analysis of 24 Unruptured and 42 Ruptured Cases

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; P=0.308). 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 <12 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.

Natural history of brain arteriovenous malformations: a long-term follow-up study of risk of hemorrhage in 238 patients.

OBJECTIVELong-term follow-up studies in patients with brain arteriovenous malformations (AVM) have yielded contradictory results regarding both risk factors for rupture and annual rupture rate. We performed a long-term follow-up study in an unselected, consecutive patient population with AVMs admitted to the Department of Neurosurgery at Helsinki University Central Hospital between 1942 and 2005. METHODSPatients with untreated AVMs were followed from admission until death, occurrence of AVM rupture, initiation of treatment, or until the end of 2005. Patients with at least 1 month of follow-up were included in further analysis. Annual and cumulative incidence rates of AVM rupture as well as several potential risk factors for rupture were analyzed using Kaplan-Meier life table analyses and Cox proportional hazards regression models. RESULTSWe identified 238 patients with a mean follow-up period of 13.5 years (range, 1 month–53.1 years). The average annual risk of hemorrhage from AVMs was 2.4%. The risk was highest during the first 5 years after diagnosis, decreasing thereafter. Risk factors predicting subsequent AVM hemorrhage in univariate analysis were young age, previous rupture, deep and infratentorial locations, and exclusively deep venous drainage. Previous rupture, large AVM size, and infratentorial and deep locations were independent risk factors according to multivariate models. CONCLUSIONAccording to this long-term follow-up study, AVMs with previous rupture and large size, as well as with infratentorial and deep locations have the highest risk of subsequent hemorrhage. This risk is highest during the first few years after diagnosis but remains significant for decades.

Outcomes of Early Endovascular Versus Surgical Treatment of Ruptured Cerebral Aneurysms A Prospective Randomized Study

Background and Purpose This prospective study was conducted to compare the outcomes of surgical clipping and endovascular treatment in acute (<72 hours) aneurysmal subarachnoid hemorrhage (SAH). Methods One hundred nine consecutive patients were randomly assigned to either surgical (n=57) or endovascular (n=52) 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. Patients with good clinical recovery did not differ in their neuropsychological test scores. Symptomatic vasospasm (OR 2.47; 95% CI 1.45 to 4.19;P <0.001), poorer Hunt and Hess grade (OR 2.50; 95% CI 1.31 to 4.75;P =0.005), need for permanent shunt (OR 8.90; 95% CI 1.80 to 44.15;P =0.008), and larger size of the aneurysm (OR 1.22; 95% CI 1.02 to 1.45;P =0.032) independently predicted worsened clinical outcome regardless of the treatment modality. In MRI, superficial brain retraction deficits (P <0.001) and ischemic lesions in the territory of the ruptured aneurysm (P =0.025) were more frequent in the surgical group. Kaplan-Meier analysis (mean±SD follow-up 39±18 months) revealed equal survival in both treatment groups. No late rebleedings have occurred. Conclusions One-year clinical and neuropsychological outcomes seem comparable after early surgical and endovascular treatment of ruptured intracranial aneurysms. The long-term efficacy of endovascular treatment in preventing rebleeding remains open.

Genome-wide association study of intracranial aneurysm identifies three new risk loci

Saccular intracranial aneurysms 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 intracranial aneurysms in the combined dataset, including intervals near RBBP8 on 18q11.2 (odds ratio (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-CDKN2B (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 the proliferation and senescence of progenitor-cell populations that are responsible for vascular formation and repair.

Susceptibility loci for intracranial aneurysm in European and Japanese populations

Stroke is the worlds 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 mid-life (median age 50), most often resulting in death or severe neurological impairment. 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 aneurysm. Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells, suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role. These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.

Impact of early surgery on outcome after aneurysmal subarachnoid hemorrhage. A population-based study.

Background and Purpose Population-based patient materials have not been used earlier in assessing the effects of neurosurgical treatment on survival and functional outcome of subarachnoid hemorrhage. Moreover, the proportion of all subarachnoid hemorrhage patients who might be candidates for neurosurgical treatment has not been estimated. Methods We compared the survival and functional outcome of two population-based patient materials from Central Finland in 1976 through 1978 (n=146) and 1980 through 1987 (n=351). The most important basic characteristics of both materials were similar. In the 1970s, only patients aged <60 years with carotid territory aneurysms were operated on after an interval of 2 weeks from the bleeding. In the 1980s, early surgery was attempted, and the other exclusion criteria were abandoned. Allocation to medical or surgical treatment was not randomized. Results During the 1970s, only 14% of the patients had surgical treatment, with a median delay of 15 days after the bleeding; in the 1980s, the corresponding figures were 46% and 4 days. Despite these fundamental changes in the treatment policy, the survival up to 3 years in the 1980s was only marginally improved compared with the 1970s. Conversely, the functional outcome at 4 years after the bleeding was significantly better in the 1980s than the 1970s, with 82% and 64% of the survivors, respectively, being independent in the activities of daily living (P=.002). We estimated that 60% of all patients with subarachnoid hemorrhage might be candidates for neurosurgical treatment, provided that there are no delays in admission or evaluation. Conclusions An active treatment policy of subarachnoid hemorrhage including early surgery only marginally improves survival, but the quality of life of the survivors is significantly better. Only 60% of all patients in the population with subarachnoid hemorrhage can, at least theoretically, benefit from surgical treatment. (Stroke. 1993;24:1649-1654.)

Saccular intracranial aneurysm: pathology and mechanisms

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.

Blood blister–like aneurysms of the internal carotid artery trunk causing subarachnoid hemorrhage: treatment and outcome

OBJECT The object of this study was to evaluate cases of subarachnoid hemorrhage (SAH) from ruptured blood blister-like aneurysms (BBAs) of the internal carotid artery (ICA) trunk. METHODS The authors performed a single-center, retrospective study. Data analyzed were patient age, sex, Hunt and Hess grade, Fisher grade, time from SAH to hospitalization, aneurysm size and location, collateral capacity of the circle of Willis, time from hospitalization to aneurysm repair, type of aneurysm repair, complications, and Glasgow Outcome Scale (GOS) score at follow-up. RESULTS A total of 211 patients suffered SAH from ICA aneurysms. Of these, 14 patients (6.6%) had ICA trunk BBAs; 6 men and 8 women. The median age was 47.8 years (range 29.9-67.7 years). The Hunt and Hess grade was IV or V in 7 cases, and SAH was Fisher Grade 3 + 4 in 6. All aneurysms were small (< 1 cm), without relation to vessel bifurcations, and usually located anteromedially on the ICA trunk. Three patients were treated with coil placement and 11 with clip placement. Of the 7 patients in whom the ICA was preserved, only 1 had poor outcome (GOS Score 2). In contrast, cerebral infarcts developed in all patients treated with ICA sacrifice, directly postoperatively in 2 and after delay in 5. Six patients died, 1 survived in poor condition (GOS Score 3; p < 0.001). CONCLUSIONS 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.

Microscope-integrated near-infrared indocyanine green videoangiography during surgery of intracranial aneurysms: the Helsinki experience.

BACKGROUND Microscope-integrated near-infrared indocyanine green videoangiography (ICG-VA) is a new method of intraoperative blood flow assessment. The objective of this study was to evaluate the reliability of this technique in the evaluation of neck residuals and patency of branches after microneurosurgical clipping of intracranial aneurysms (IAs). METHODS During a period of 14 months, between November 2005 and December 2006, 289 patients with intracranial aneurysms were operated on in our institution. Intraoperative ICG-VA was performed during microneurosurgical clipping of 239 IAs in 190 patients. Postoperative computed tomography and computed tomography angiography (CTA) were performed for all patients. Intraoperative interpretation of ICG-VA in assessing the neck residual or the patency of vessels after clipping of each single aneurysm were recorded and correlated with postoperative CTA and/or digital subtraction angiography. RESULTS Postoperative imaging studies revealed no incomplete occlusions of aneurysm domes. Unexpected neck residuals were observed in 14 aneurysms (6%). There were no parent artery occlusions. Unexpected branch occlusions including both major and minor branching arteries were observed in 15 aneurysms (6%). CONCLUSIONS Indocyanine green videoangiograph is a simple and fast method of blood flow assessment with acceptable reliability. Indocyanine green videoangiograph can provide real-time information to assess blood flow in vessels of different size as well as the occlusion of the aneurysm. Intraoperative assessment of blood flow in the perforating branches is one of the most important advantages. In selected cases such as giant, complex, and deep-sited aneurysms or when the quality of image in ICG-VA is not adequate, other methods of intraoperative blood flow assessment should be considered.