Risk Of aSAH Research Articles

Dietary factors and the incidence of intracranial aneurysms: a Mendelian randomization research

ABSTRACT Background Intracranial aneurysms (IAs) pose a significant threat to morbidity and mortality, yet their etiology remains inadequately comprehended. The present study employs Mendelian randomization (MR) to investigate the relationship among dietary elements with IAs, encompassing unruptured intracranial aneurysms (uIA) as well as aneurysmal subarachnoid hemorrhage (aSAH). Methods The current study employed a double-sample MR test utilizing genome-wide association study (GWAS) summary data from the IEU and IAs’ meta-analysis to investigate the genetically predicted consumption levels of various dietary factors using GWAS data. Causation was assessed by techniques of MR-Egger, weighted mode, and median, as well as IVW. To guarantee the accuracy of the results, pleiotropy and heterogeneity evaluations were also carried out. Results The findings of the study indicate a positive correlation between the intake of alcohol, lamb/mutton, and pork with the risk of IAs (IVW all p < 0.05). Conversely, a negative correlation was observed regarding dried fruit consumption and the risk of aSAH (IVW p < 0.05). There was only scant evidence supporting the association between alcohol intake frequency and an elevated risk of uIA (IVW method p < 0.05). The MR analysis outcomes were authenticated by the MR-PRESSO method and were deemed reliable. Furthermore, sensitivity calculations, such as pleiotropy and homogeneity test, leave-one-out evaluation, and funnel charts, validated the robustness of the results. Conclusions The findings suggest that reducing alcohol, lamb/mutton, and pork intake, and increasing dried fruit intake may be potential strategies for the prevention of IAs and aSAH. Additional research is necessary to validate these outcomes and elucidate the underlying mechanisms.

Causal relationships between gut microbiota and Aneurysmal Subarachnoid Hemorrhage: A Bidirectional Mendelian Randomization Study

Background and PurposeAneurysmal Subarachnoid Hemorrhage (aSAH) poses a significant health burden globally, necessitating a deeper understanding of its etiology and potential preventive strategies. Recent research has suggested a possible link between gut microbiota composition and the risk of vascularity, prompting investigation into this association using Mendelian Randomization (MR) analysis. Here, we aimed to elucidate the causal relationship between gut microbiota composition and aSAH risk utilizing MR analysis. MethodsWe employed four distinct MR methodologies, including inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode, to assess the causal nexus between gut microbiota composition and aSAH risk. Genetic instrumental variables (IVs) associated with gut microbiome composition were selected from a comprehensive multiethnic genome-wide association study (GWAS) involving 18,473 individuals across diverse geographic regions. Sensitivity analyses were conducted to detect potential heterogeneity and pleiotropy. ResultsOur Mendelian Randomization (MR) analyses unveiled a substantial and statistically significant causal relationship between gut microbiota composition and the risk of Aneurysmal Subarachnoid Hemorrhage (aSAH). Employing the Inverse Variance Weighted (IVW) method, we observed negative associations between aSAH and specific taxonomic levels of gut microbiota. Specifically, the IVW approach identified significant associations with one order, Victivallales (PIVW=0.047, OR: 0.78, 95 % CI: 0.62-0.99), one family, Porphyromonadaceae (PIVW=0.03, OR: 0.64, 95 % CI: 0.43-0.95), one class, Lentisphaeria (PIVW=0.047, OR: 0.78, 95 % CI: 0.62-0.99), and three genera: Bilophila (PIVW=0.02, OR: 0.68, 95 % CI: 0.50-0.93), Fusicatenibacter (PIVW=0.04, OR: 0.69, 95 % CI: 0.49-0.98), and Ruminococcus1 (PIVW=0.01, OR: 0.51, 95 % CI: 0.32-0.84). These findings were consistent across various MR methodologies, underscoring the robustness of our results. Sensitivity analyses further validated the stability of our findings, with no evidence of heterogeneity or pleiotropy detected. ConclusionOur study provides compelling evidence supporting a causal relationship between gut microbiota composition and the risk of aSAH. These findings underscore the potential therapeutic implications of modulating gut microbiota to prevent and manage aSAH. Further research is warranted to explore the underlying mechanisms and develop targeted interventions aimed at mitigating aSAH risk through gut microbiota modulation.

Genetic evidence for the causal association of neuroticism with intracranial aneurysms: A Mendelian randomization study

ObjectiveThe aim of this study was to assess the potential causal relationship between neuroticism and 12 neuroticism items with intracranial aneurysms (IAs) and aneurysmal subarachnoid hemorrhage (aSAH) using a two-sample Mendelian randomization (MR) approach. MethodsStudy data were obtained from the Genome-Wide Association Study (GWAS) pooled dataset, and we extracted summary statistics for neuroticism, 12 neuroticism items, and IAs, which were categorized into ruptured and unruptured aneurysms (IA), aSAH, and unruptured IAs (uIA). Single nucleotide polymorphisms (SNPs) were used as instrumental variables (IVs) to explore the causal relationship between exposure and outcome using five Mendelian randomization methods, with Inverse variance weighted (IVW) as the primary study method. Horizontal multiple validity tests, sensitivity analyses, and inverse MR ensured the stability of the results. ResultsThe two-sample MR showed a genetically predictive association between neuroticism and IA [odds ratio (OR) = 1.16; 95 % confidence interval (95 % CI): 1.04–1.30; p = 0.009], aSAH (OR = 1.17; 95 % CI: 1.03–1.33; p = 0.013) and uIA (OR = 1.30; 95 % CI: 1.07–1.59; p = 0.009) were all genetically predictive of association. Ivw showed a positive association between 5 neuroticism items and IA risk, 5 neuroticism items and aSAH risk as well as no genetically predictive association between neuroticism items and uIA. Sensitivity analysis and inverse MR confirmed the robustness of the results. ConclusionOur Mendelian randomization analysis demonstrated genetic causality between neuroticism and neuroticism items with intracranial aneurysms, aneurysmal subarachnoid hemorrhage, and unruptured intracranial aneurysms, and further studies are needed to confirm these results and explore potential mechanisms of action.

Sex differences in risk factor relationships with subarachnoid haemorrhage and intracranial aneurysms: A Mendelian Randomisation study.

The prevalence of intracranial aneurysms (IAs) and incidence of aneurysmal subarachnoid haemorrhage (aSAH) is higher in women than in men. Although several cardiometabolic and lifestyle factors have been related to the risk of IAs or aSAH, it is unclear whether there are sex differences in causal relationships of these risk factors. The aim of this study was to determine sex differences in causal relationships between cardiometabolic and lifestyle factors and risk of aSAH and IA. We conducted a sex-specific two-sample Mendelian randomisation study using summary-level data from genome-wide association studies. We analysed low-density lipoprotein cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides, non-HDL-C, total cholesterol, fasting glucose, systolic and diastolic blood pressure, smoking initiation, and alcohol use as exposures, and aSAH and IA (i.e., aSAH and unruptured IA combined) as outcomes. We found statistically significant sex differences in the relationship between genetically proxied non-HDL-C and aSAH risk, with odds ratios (ORs) of 0.72 (95% confidence interval 0.58, 0.88) in women and 1.01 (0.77, 1.31) in men (P-value for sex difference 0.044). Moreover, genetic liability to smoking initiation was related to a statistically significantly higher risk of aSAH in men compared to women (P-value for sex difference 0.007) with ORs of 3.81 (1.93, 7.52) and 1.12 (0.63, 1.99), respectively, and to a statistically significantly higher IA risk in men compared to women (P-value for sex difference 0.036) with ORs of 3.58 (2.04, 6.27) and 1.61 (0.98, 2.64), respectively. In addition, higher genetically proxied systolic and diastolic blood pressure were related to a higher risk of aSAH and IA in both women and men. Higher genetically proxied non-HDL-C was related to a lower risk of aSAH in women compared to men. Moreover, genetic liability to smoking initiation was associated with a higher risk for aSAH and IA in men compared to women. These findings may help improve understanding of sex differences in the development of aSAH and IA.

Causal relationship between mitochondrial-associated proteins and cerebral aneurysms: a Mendelian randomization study.

Cerebral aneurysm is a high-risk cerebrovascular disease with a poor prognosis, potentially linked to multiple factors. This study aims to explore the association between mitochondrial-associated proteins and the risk of cerebral aneurysms using Mendelian randomization (MR) methods. We used GWAS summary statistics from the IEU Open GWAS project for mitochondrial-associated proteins and from the Finnish database for cerebral aneurysms (uIA, aSAH). The association between mitochondrial-associated exposures and cerebral aneurysms was evaluated using MR-Egger, weighted mode, IVW, simple mode and weighted median methods. Reverse MR assessed reverse causal relationship, while sensitivity analyses examined heterogeneity and pleiotropy in the instrumental variables. Significant causal relationship with cerebral aneurysms were confirmed using FDR correction. Through MR analysis, we identified six mitochondrial proteins associated with an increased risk of aSAH: AIF1 (OR: 1.394, 95% CI: 1.109-1.752, p = 0.0044), CCDC90B (OR: 1.318, 95% CI: 1.132-1.535, p = 0.0004), TIM14 (OR: 1.272, 95% CI: 1.041-1.553, p = 0.0186), NAGS (OR: 1.219, 95% CI: 1.008-1.475, p = 0.041), tRNA PusA (OR: 1.311, 95% CI: 1.096-1.569, p = 0.003), and MRM3 (OR: 1.097, 95% CI: 1.016-1.185, p = 0.0175). Among these, CCDC90B, tRNA PusA, and AIF1 demonstrated a significant causal relationship with an increased risk of aSAH (FDR q < 0.1). Three mitochondrial proteins were associated with an increased risk of uIA: CCDC90B (OR: 1.309, 95% CI: 1.05-1.632, p = 0.0165), tRNA PusA (OR: 1.306, 95% CI: 1.007-1.694, p = 0.0438), and MRM3 (OR: 1.13, 95% CI: 1.012-1.263, p = 0.0303). In the reverse MR study, only one mitochondrial protein, TIM14 (OR: 1.087, 95% CI: 1.004-1.177, p = 0.04), showed a causal relationship with aSAH. Sensitivity analysis did not reveal heterogeneity or pleiotropy. The results suggest that CCDC90B, tRNA PusA, and MRM3 may be common risk factors for cerebral aneurysms (ruptured and unruptured), while AIF1 and NAGS are specifically associated with an increased risk of aSAH, unrelated to uIA. TIM14 may interact with aSAH. Our findings confirm a causal relationship between mitochondrial-associated proteins and cerebral aneurysms, offering new insights for future research into the pathogenesis and treatment of this condition.

Prescribed Drug Use and Aneurysmal Subarachnoid Hemorrhage Incidence: A Drug-Wide Association Study.

Current benefits of invasive intracranial aneurysm treatment to prevent aneurysmal subarachnoid hemorrhage (aSAH) rarely outweigh treatment risks. Most intracranial aneurysms thus remain untreated. Commonly prescribed drugs reducing aSAH incidence may provide leads for drug repurposing. We performed a drug-wide association study (DWAS) to systematically investigate the association between commonly prescribed drugs and aSAH incidence. We defined all aSAH cases between 2000 and 2020 using International Classification of Diseases codes from the Secure Anonymised Information Linkage databank. Each case was matched with 9 controls based on age, sex, and year of database entry. We investigated commonly prescribed drugs (>2% in study population) and defined 3 exposure windows relative to the most recent prescription before index date (i.e., occurrence of aSAH): current (within 3 months), recent (3-12 months), and past (>12 months). A logistic regression model was fitted to compare drug use across these exposure windows vs never use, controlling for age, sex, known aSAH risk factors, and health care utilization. The family-wise error rate was kept at p < 0.05 through Bonferroni correction. We investigated exposure to 205 commonly prescribed drugs between 4,879 aSAH cases (mean age 61.4, 61.2% women) and 43,911 matched controls. We found similar trends for lisinopril and amlodipine, with a decreased aSAH risk for current use (lisinopril odds ratio [OR] 0.63, 95% CI 0.44-0.90, amlodipine OR 0.82, 95% CI 0.65-1.04) and an increased aSAH risk for recent use (lisinopril OR 1.30, 95% CI 0.61-2.78, amlodipine OR 1.61, 95% CI 1.04-2.48). A decreased aSAH risk in current use was also found for simvastatin (OR 0.78, 95% CI 0.64-0.96), metformin (OR 0.58, 95% CI 0.43-0.78), and tamsulosin (OR 0.55, 95% CI 0.32-0.93). By contrast, an increased aSAH risk was found for current use of warfarin (OR 1.35, 95% CI 1.02-1.79), venlafaxine (OR 1.67, 95% CI 1.01-2.75), prochlorperazine (OR 2.15, 95% CI 1.45-3.18), and co-codamol (OR 1.31, 95% CI 1.10-1.56). We identified several drugs associated with aSAH, of which 5 drugs (lisinopril and possibly amlodipine, simvastatin, metformin, and tamsulosin) showed a decreased aSAH risk. Future research should build on these signals to further assess the effectiveness of these drugs in reducing aSAH incidence. This study provides Class III evidence that some commonly prescribed drugs are associated with subsequent development of aSAH.

Sex differences in risk factor relationships with subarachnoid haemorrhage and intracranial aneurysms: A Mendelian Randomisation study.

The prevalence of intracranial aneurysms (IAs) and incidence of aneurysmal subarachnoid haemorrhage (aSAH) is higher in women than in men. Although several cardiometabolic and lifestyle factors have been related to the risk of IAs or aSAH, it is unclear whether there are sex differences in causal relationships of these risk factors. The aim of this study was to determine sex differences in causal relationships between cardiometabolic and lifestyle factors and risk of aSAH and IA. We conducted a sex-specific two-sample Mendelian randomisation study using summary-level data from genome-wide association studies. We analysed low-density lipoprotein cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides, non-HDL-C, total cholesterol, fasting glucose, systolic and diastolic blood pressure, smoking initiation, and alcohol use as exposures, and aSAH and IA (i.e., aSAH and unruptured IA combined) as outcomes. We found statistically significant sex differences in the relationship between genetically proxied non-HDL-C and aSAH risk, with odds ratios (ORs) of 0.72 (95% confidence interval 0.58, 0.88) in women and 1.01 (0.77, 1.31) in men (P-value for sex difference 0.044). Moreover, genetic liability to smoking initiation was related to a statistically significantly higher risk of aSAH in men compared to women (P-value for sex difference 0.007) with ORs of 3.81 (1.93, 7.52) and 1.12 (0.63, 1.99), respectively, and to a statistically significantly higher IA risk in men compared to women (P-value for sex difference 0.036) with ORs of 3.58 (2.04, 6.27) and 1.61 (0.98, 2.64), respectively. In addition, higher genetically proxied systolic and diastolic blood pressure were related to a higher risk of aSAH and IA in both women and men. Higher genetically proxied non-HDL-C was related to a lower risk of aSAH in women compared to men. Moreover, genetic liability to smoking initiation was associated with a higher risk for aSAH and IA in men compared to women. These findings may help improve understanding of sex differences in the development of aSAH and IA.

The association between hematologic traits and aneurysm-related subarachnoid hemorrhage: a two-sample mendelian randomization study.

Several hematologic traits have been suggested to potentially contribute to the formation and rupture of intracranial aneurysms (IA). The purpose of this study is to explore the causal association between hematologic traits and the risk of IA. To explore the causal association between hematologic traits and the risk of IA, we employed two-sample Mendelian randomization (MR) analysis. Two independent summary-level GWAS data were used for preliminary and replicated MR analyses. The inverse variance weighted (IVW) method was employed as the primary method in the MR analyses. The stabilities of the results were further confirmed by a meta-analysis. In the preliminary MR analysis, hematocrit, hemoglobin concentration (p = 0.0047), basophil count (p = 0.0219) had a suggestive inverse causal relationship with the risk of aneurysm-associated subarachnoid hemorrhage (aSAH). The monocyte percentage of white cells (p = 0.00956) was suggestively positively causally correlated with the risk of aSAH. In the replicated MR analysis, only the monocyte percentage of white cells (p = 0.00297) remained consistent with the MR results in the preliminary analysis. The hematocrit, hemoglobin concentration, and basophil count no longer showed significant causal relationship (p > 0.05). Meta-analysis results further confirmed that only the MR result of monocyte percentage of white cells reached significance in the random effect model and fixed effect model. None of the 25 hematologic traits was causally associated with the risk of unruptured intracranial aneurysms (uIA). This study revealed a suggestive positive association between the monocyte percentage of white cells and the risk of aSAH. This finding contributes to a better understanding that monocytes/macrophages could participate in the risk of aSAH.

Causal Associations Between Gut Microbiota and Cerebrovascular Diseases

BackgroundNumerous studies suggest that the gut microbiota closely linked to cerebrovascular diseases, such as IA and aSAH. Nevertheless, the confirmation of a definitive causal connection between gut microbiota, IA, and aSAH is still pending. The aim of our research is to explore the potential bidirectional causality among them. MethodsThis bidirectional Mendelian Randomization (MR) study used single nucleotide polymorphisms (SNPs) linked to gut microbiota, IA, and aSAH from Genome-Wide Association Studies. The Inverse Variance Weighted (IVW) method was used to explore causality. To assess the robustness of the result, sensitivity analyses were further performed, including weighted-median method, MR-Egger regression, Maximum-likelihood method, MR pleiotropy residual sum and outlier (MR-PRESSO) test and leave-one-out analysis. ResultsIn the IVW method, the family Porphyromonadaceae (OR 0.63; 95% CI 0.47-0.85; P: 0.002) and genus Bilophila (OR 0.66; 95% CI 0.50-0.86; P: 0.002) showed a significant negative association with the risk of IA. Similarly, the genus Bilophila (OR: 0.68; 95% CI: 0.50-0.93; P: 0.017) and genus Ruminococcus1 (OR: 0.48; 95% CI: 0.30-0.78; P: 0.003) were linked to reduced risk of aSAH. The sensitivity analysis yielded similar outcomes in the IVW approach. Through the adoption of reverse MR analysis, a potential correlation between IA and decreased abundance of genus Ruminococcus1 was identified (OR 0.94; 95% CI 0.90-0.99; P 0.024). ConclusionsThis Mendelian randomization analysis investigated the causal associations between gut microbiota, IA, and aSAH risks. The findings expanded current knowledge of the microbiota-gut-brain axis and offered novel perspectives on preventing and managing these conditions.

Prediction of aneurysmal subarachnoid hemorrhage in comparison with other stroke types using routine care data.

Aneurysmal subarachnoid hemorrhage (aSAH) can be prevented by early detection and treatment of intracranial aneurysms in high-risk individuals. We investigated whether individuals at high risk of aSAH in the general population can be identified by developing an aSAH prediction model with electronic health records (EHR) data. To assess the aSAH model's relative performance, we additionally developed prediction models for acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) and compared the discriminative performance of the models. We included individuals aged ≥35 years without history of stroke from a Dutch routine care database (years 2007-2020) and defined outcomes aSAH, AIS and ICH using International Classification of Diseases (ICD) codes. Potential predictors included sociodemographic data, diagnoses, medications, and blood measurements. We cross-validated a Cox proportional hazards model with an elastic net penalty on derivation cohorts and reported the c-statistic and 10-year calibration on validation cohorts. We examined 1,040,855 individuals (mean age 54.6 years, 50.9% women) for a total of 10,173,170 person-years (median 11 years). 17,465 stroke events occurred during follow-up: 723 aSAH, 14,659 AIS, and 2,083 ICH. The aSAH model's c-statistic was 0.61 (95%CI 0.57-0.65), which was lower than the c-statistic of the AIS (0.77, 95%CI 0.77-0.78) and ICH models (0.77, 95%CI 0.75-0.78). All models were well-calibrated. The aSAH model identified 19 predictors, of which the 10 strongest included age, female sex, population density, socioeconomic status, oral contraceptive use, gastroenterological complaints, obstructive airway medication, epilepsy, childbirth complications, and smoking. Discriminative performance of the aSAH prediction model was moderate, while it was good for the AIS and ICH models. We conclude that it is currently not feasible to accurately identify individuals at increased risk for aSAH using EHR data.

Lower incidence of diabetes mellitus in patients with aneurysmal subarachnoid hemorrhage: a large case–control study with propensity score matching

Background and purposeDiabetes mellitus (DM) is a well-established cardiovascular risk factor for atherosclerotic disease; however, its effect on the risk of rupture of intracranial aneurysms remains controversial. Herein, we aimed to perform a case–control study to investigate the relationship between DM and aneurysmal subarachnoid hemorrhage (aSAH).MethodsWe retrospectively reviewed the data of patients with ruptured or unruptured aneurysms who were treated between 2013 and 2023. Univariate and multivariate analyses were performed. Propensity score matching (PSM) analysis was conducted to evaluate the relationship between DM and risk of aSAH.ResultsA total of 4,787 patients with 5,768 intracranial aneurysms were included. Among them, 2,957 (61.8%) were females, 1765 (36.9%) had ruptured aneurysms, and 531 (11.1%) presented with DM. Female sex, current drinking, and hypercholesterolemia were associated with a higher risk of aSAH, whereas old age, former smoking, and DM were associated with a lower risk of aSAH in multivariate analysis (p &amp;lt; 0.05). The incidence of DM (13.4%, 406/3022) in the unruptured group was higher than that in the ruptured group (7.1%, 125/1765) (odds ratio, 0.55; 95% confidence interval, 0.444–0.680) (p &amp;lt; 0.001). After propensity score matching, 530 patients with DM were successfully matched, and DM was still associated with a lower risk of aSAH (odds ratio, 0.24; 95% confidence interval, 0.185–0.313) (p &amp;lt; 0.001).ConclusionPatients with aSAH have a lower incidence of DM, however, this case-cohort study could not establish a causal relationship. A prospective and large study with long-term follow-up is warranted to establish a causal relationship.

Mood swings are causally associated with intracranial aneurysm subarachnoid hemorrhage: A Mendelian randomization study.

Mood swings have been observed in patients with intracranial aneurysm (IA), but it is still unknown whether mood swings can affect IA. To explore the causal association between mood swings or experiencing mood swings and IA through a two-sample Mendelian randomization (MR) study. Summary-level statistics of mood swings, experiencing mood swings, IA, aneurysm-associated subarachnoid hemorrhage (aSAH), and non-ruptured IA (uIA) were collected from the genome-wide association study. Two-sample MR and various sensitivity analyses were employed to explore the causal association between mood swings or experiencing mood swings and IA, or aSAH, or uIA. The inverse-variance weighted method was used as the primary method. Genetically determined mood swings (odds ratio [OR]=5.23, 95% confidence interval (95%CI): 1.65-16.64, p=.005) and experiencing mood swings (OR=2.50, 95%CI: 1.37-4.57, p=.003) were causally associated with an increased risk of IA. Mood swings (OR=5.67, 95%CI: 1.40-23.04, p=.015) and experiencing mood swings were causally associated with the risk of aSAH (OR=2.91, 95%CI: 1.47-5.75, p=.002). Neither mood swings (OR=1.95, 95%CI: .31-12.29, p=.478) nor experiencing mood swings (OR=1.20, 95%CI: .48-3.03, p=.693) were associated with uIA. Mood swings and experiencing mood swings increased the risk of IA and aSAH incidence. These results suggest that alleviating mood swings may reduce IA rupture incidence and aSAH incidence.

Unlike severe periodontitis, caries does not associate with intracranial aneurysms or aneurysmal subarachnoid hemorrhage

PurposePeriodontal diseases and caries are common oral diseases that predispose to tooth loss if untreated. In this study, we investigated whether loss of teeth or caries associate with intracranial aneurysm (IA) pathology similar to periodontal diseases.MethodsA total of 166 patients with either IA or aneurysmal subarachnoid hemorrhage (aSAH) underwent oral examination in Kuopio University Hospital and Tampere University Hospital. Findings were compared to geographically matched controls acquired from cross-sectional Health2000 survey. This study consisted of three sequential steps. First, we compared the number of missing teeth and prevalence of caries in IA and aSAH patients and geographically matched control population, second step was a multivariate analysis including other risk factors, and third step was a 13-year follow-up of the Health2000 survey participants with missing teeth or caries at baseline.ResultsLoss of teeth did not significantly differ between IA patients and controls. In logistic regression model adjusted for known risk factors and demographic data, 1–4 caries lesions (OR: 0.40 95%Cl 0.2–0.9, p = 0.031) was associated with lack of IAs, while age (OR: 1.03 95%Cl 1.01.1 p = 0.024), current smoking (OR: 2.7 95%Cl 1.4–5.1, p = 0.003), and severe periodontitis (OR: 5.99 95%Cl 2.6–13.8, p < 0.001) associated to IA formation. In the cox-regression, severe periodontitis at baseline increased the risk of aSAH (HR: 14.3, 95%Cl 1.5–135.9, p = 0.020) during a 13-year follow-up, while caries or missing teeth did not.ConclusionUnlike severe periodontitis, caries does not increase the risk of IAs and aSAHs. However, cariogenic bacteria may participate to IA pathology by disseminating to circulation via inflamed gingival tissue.

Associations Between Drug Treatments and the Risk of Aneurysmal Subarachnoid Hemorrhage: a Systematic Review and Meta-analysis.

There is increasing interest in drug therapy for preventing aneurysmal subarachnoid hemorrhage (aSAH). We aimed to comprehensively evaluate the association between drug use and the risk of aSAH. We searched PubMed and Scopus from the databases' inception until December 2021. Observational studies reporting the association between any drug therapy and aSAH were included. The odds ratios (ORs) for each drug used in aSAH were meta-analyzed with a random-effect model. According to the systematic review, 25 observational studies were eligible for the present study. Four therapeutic purpose-based classes (e.g., lipid-lowering agents) and 14 mechanism-based classes (e.g., statins) were meta-analyzed. Anti-hypertensive agents (OR, 0.50; 95% confidence interval [95% CI], 0.33-0.74), statins (OR, 0.55; 95% CI, 0.35-0.85), biguanides (OR, 0.57; 95% CI, 0.34-0.96), and acetylsalicylic acid (ASA) (OR, 0.62; 95% CI, 0.41-0.94) were inversely associated with the risk of aSAH. Non-ASA non-steroidal anti-inflammatory drugs (OR, 1.73; 95% CI, 1.07-2.79), selective cyclooxygenase-2 inhibitors (OR, 2.04; 95% CI, 1.24-3.35), vitamin K antagonists (OR, 1.50; 95% CI, 1.18-1.91), and dipyridamole (OR, 1.77; 95% CI, 1.23-2.54) were positively associated with the incidence of aSAH. There was also a trend toward a positive association between glucocorticoids (OR, 1.38; 95% CI, 0.97-1.94) and aSAH. The present study suggests that anti-hypertensive agents, statins, biguanides, and ASA are candidate drugs for preventing aSAH. By contrast, several drugs (e.g., anti-thrombotic drugs) may increase the risk of aSAH. Thus, the indications of these drugs in patients with intracranial aneurysms should be carefully determined.

Genetically predicted tobacco consumption and risk of intracranial aneurysm: a Mendelian randomization study.

Several observational studies have suggested that tobacco consumption is a risk factor for intracranial aneurysms (IAs). We here genetically predict the causal association between specific smoking features and biomarkers for smokers and IA risk. The Mendelian randomization (MR) analysis considered summary statistics from the largest current genome-wide association studies of smoking and IA. The inverse-variance weighted (IVW) method, weighted median method, MR-RAPS, and multiple variants Mendelian randomization (MVMR) were performed to estimate the effect of different smoking features and drinking in IA. We observed significant causal effects of smoking on the risk of both aneurysmal subarachnoid hemorrhage (aSAH) and unruptured IA (uIA). The ORs of IAs based on the IVW method were 1.890 (95% CI 1.486-2.405) of ever smoking regularly. MVMR analysis afforded odds ratios of 1.685 (95% CI 1.136-2.501). In the further subgroup analysis, a similar causal relationship was observed in aSAH. Moreover, our analyses suggested that higher blood cotinine level and cadmium increases aSAH risk, and ORs were 1.235 (95%CI 1.009-1.186) and 1.235 (95%CI 1.046-1.458), respectively. Our study suggests that ever smoking regularly is associated with the IA risk, which includes both uIA and aSAH. Besides, higher blood cadmium and cotinine level may increases IA and aSAH risk. Thus, tobacco control should be promoted as primordial prevention for IAs, and screening for patients with a smoking history is emphasized.

Sex Hormones and Risk of Aneurysmal Subarachnoid Hemorrhage: A Mendelian Randomization Study.

Background:The risk of aneurysmal subarachnoid hemorrhage (aSAH) is increased in postmenopausal women compared with men of similar age, suggesting a role for sex hormones. We aimed to explore whether sex hormones, and age at menarche/menopause have a causal effect on aSAH risk by conducting a 2-sample MR study (Mendelian randomization).Methods:We obtained sex-specific genetic instruments for serum estradiol, bioavailable testosterone (BioT), SHBG (sex hormone-binding globulin), and age at menarche/menopause from genome-wide association studies. The associated sex-specific aSAH risk was estimated with inverse-variance weighted MR analyses with various statistical sensitivity analyses. Multivariable and cluster MR analyses were performed for BioT and SHBG to account for a genetic and phenotypic correlation between the 2 exposures. The clusters represented (1) single-nucleotide polymorphisms primarily increasing SHBG, with secondary decreasing effects on BioT, and (2) single-nucleotide polymorphisms affecting BioT without affecting SHBG.Results:Univariable MR analyses showed an 18% increased aSAH risk among women per 1-SD increase in genetically determined SHBG levels (odds ratio, 1.18 [95% CI, 1.05–1.34]; P=0.007). Suggestive evidence was identified for a 27% decreased risk of aSAH among women per 1-SD increase in BioT (odds ratio, 0.73 [95% CI, 0.55–0.95]; P=0.02). The latter association disappeared in cluster analysis when only using SHBG-independent variants. MR analyses with variants from the cluster with primary SHBG effects and secondary (opposite) BioT-effects yielded a statistically significant association (odds ratio, 1.21 [95% CI, 1.05–1.40]; P=0.008). No other causal associations were identified.Conclusions:Genetic predisposition to elevated serum levels of SHBG, with secondary lower serum BioT levels, is associated with an increased aSAH risk among women, suggesting that SHBG and BioT causally elevate aSAH risk. Further studies are required to elucidate the underlying mechanisms and their potential as an interventional target to lower aSAH incidence.

Cumulative Time of Cigarette Smoking Is Associated with a Greater Risk of Aneurysmal Subarachnoid Hemorrhage and Younger Age at Presentation: A Nationwide Observation Study

Smoking is known to be associated with an increased risk of intracranial aneurysm rupture; however, the risk in smokers stratified by age, sex, and aneurysm location is not clear. A retrospective study of all aneurysmal subarachnoid hemorrhage (aSAH) cases in Australia between 2008 and 2018 was conducted. The relative risk of aSAH in smokers compared with nonsmokers was calculated on the basis of nationwide smoking statistics and was stratified according to sex, age group, and aneurysm location. Out of 12,915 aSAH patients, 3249 (25.2%) were active smokers. Across both men and women, smoking increased the risk of aSAH by 2.4× in 30- to 39-year-olds (95% CI 2.1-2.7), 2.4× in 40- to 49-year-olds (95% CI 2.2-2.7), 2.3× in 50- to 59-year-olds (95% CI 2.1-2.4), and 1.8× in 60- to 69-year-olds (95% CI 1.7-2.0) with less of an effect in smokers younger than 30 years (RR: 1.2, 95% CI 1.0-1.5) and older than 70 years (RR: 1.0, 95% CI 0.9-1.2). Compared with a nonsmoker younger than 30 years old, the relative risk of aSAH increased by an average of 7.2 for every decade spent smoking in women and an average of 4.0 for every decade spent smoking in men. Additionally, smokers were 5.2× more likely to present before 50 years of age. Smoking increased the risk of aSAH by 2-fold between the ages of 30 and 60. Smokers experienced aSAH at younger ages.

Association of Reproductive Life Span and Age at Menopause With the Risk of Aneurysmal Subarachnoid Hemorrhage.

Subarachnoid hemorrhage from cerebral aneurysm remains a devastating disease with high mortality and morbidity. Cerebral aneurysm and its rupture are more prevalent in postmenopausal women and have been postulated to be hormonally influenced. The goal of this study was to investigate the associations of female-specific factors, including reproductive life span, age at menarche, and age at menopause, with the incidence of aneurysmal subarachnoid hemorrhage (aSAH) in women. Participants in the Nurses' Health Study were followed up from 1980 or the time of reaching menopause until 2018. Only women with natural menopause or surgical menopause due to bilateral oophorectomy were included. Reproductive life span was defined by subtracting the age at menarche from the age at menopause. Multivariable-stratified proportional hazards models were used to study reproductive life span, age at menarche, and age at menopause with the incidence of aSAH. Multivariable models were adjusted for age, race, smoking, hysterectomy, hypertension, hyperlipidemia, body mass index, hormone therapy use, oral contraceptive use, and parity. A total of 97,398 postmenopausal women with reproductive life span data were included; 138 participants developed aSAH, which was confirmed on medical record review by a physician. A shorter reproductive life span (≤35 years) was associated with a 2-fold higher incidence of aSAH after multivariable adjustment (hazard ratio [HR] 2.0 [95% CI 1.4-2.8]). Early age at menopause (age <45 years) was similarly associated with a higher risk of aSAH (HR 2.1 [95% CI 1.4-3.1]), but age at menarche was not. Use of oral contraceptives and postmenopausal hormone therapy was not associated with the incidence of aSAH. An earlier age at menopause and a shorter reproductive life span duration (≤35 years) were associated with a higher risk of incident aSAH in women. No associations were noted for age at menarche, parity, oral contraceptive use, or postmenopausal therapy use.

Development and Validation of Scoring Indication of Surgical Clipping and Endovascular Coiling for Aneurysmal Subarachnoid Hemorrhage from the Post Hoc Analysis of Japan Stroke Data Bank.

There are no scoring methods for optimal treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). We developed a scoring model to predict clinical outcomes according to aSAH risk factors using data from the Japan Stroke Data Bank (JSDB). Of 5344 patients initially registered in the JSDB, 3547 met the inclusion criteria. Patients had been diagnosed with aSAH and treated with surgical clipping or endovascular coiling between 1998 and 2013. We performed multivariate logistic regression for poor outcomes at discharge, indicated by a modified Rankin Scale (mRS) score >2, and in-hospital mortality for both treatment methods. Based on each risk factor, we developed a scoring model assessing its validity using another dataset of our institution. In the surgical clipping group, scoring criteria for aSAH were age >72 years, history of more than once stroke, World Federation of Neurological Societies (WFNS) grades II–V, aneurysmal size >15 mm, and vertebrobasilar artery (VBA) aneurysm location. In the endovascular coiling group, scoring criteria were age >80 years, history of stroke, WFNS grades III–V, computed tomography (CT) Fisher group 4, and aneurysmal location in the middle cerebral artery (MCA) and anterior cerebral artery (ACA). The rates of poor outcome of mRS score >2 in an isolated dataset using these scoring criteria were significantly correlated with our model’s scores, so this scoring model was validated. This scoring model can help in the more objective treatment selection in patients with aSAH.

Meteorological Variation Is a Predisposing Factor for Aneurismal Subarachnoid Hemorrhage: A 5-Year Multicenter Study in Fuzhou, China

The climatic characteristics of aneurysmal subarachnoid hemorrhage (aSAH) have been reported, but consensus has not yet been reached. It is of great significance to elucidate the relationships between meteorological variation and aSAH in regions with specific climate patterns. We analyzed the occurrence of aSAH in the capital city of Fujian Province, China, through a multicenter, 5-year study, and aimed to reveal the meteorological influences on aSAH in the coastal city of eastern Fujian under the subtropical marine monsoon condition. A total of 2555 consecutive patients with aSAH in Fuzhou were collected using specialized stroke admission database from January 2013 to December 2017. Meteorological parameters including temperature, atmospheric pressure, and humidity were obtained from China Surface Meteorological Station during the same period. Poisson regression was used to explore the association between meteorological parameters and aSAH to calculate the incidence rate ratios (IRRs) with corresponding 95% confidence intervals (CIs). Generalized additive model analysis further revealed the nonlinear relationships between weather and aSAH. Daily minimum temperature (IRR 0.976, 95% CI 0.958-0.996) and maximum pressure (IRR 1.022, 95% CI 1.001-1.042) were independently correlated with the onset of aSAH. Low temperature (below 16°C) and excessive atmospheric pressure (above 1008 hPa) increased the risk of aSAH. In addition, March in spring and December in winter were the 2 ictus peaks in Fuzhou throughout the year. Cold and excessive atmospheric pressure are triggers for the occurrence of aSAH; March in spring and December in winter are the predominant onset periods in Fuzhou.