Mosaic Loss of Chromosome Y Is Associated With Functional Outcome After Ischemic Stroke.

BACKGROUND: Mosaic loss of chromosome Y (LOY) is associated with cardiovascular and neurodegenerative diseases in men, and genetic predisposition to LOY is associated with poor poststroke outcome. We, therefore, tested the hypothesis that LOY itself is associated with functional outcome after ischemic stroke. METHODS: The study comprised male patients with ischemic stroke from the cohort studies SAHLSIS2 (Sahlgrenska Academy Study on Ischemic Stroke Phase 2; n=588) and LSR (Lund Stroke Register; n=735). We used binary logistic regression to analyze associations between LOY, determined by DNA microarray intensity data, and poor 3-month functional outcome (modified Rankin Scale score, >2) in each cohort separately and combined. Patients who received recanalization therapy were excluded from sensitivity analyses. RESULTS: LOY was associated with about 2.5-fold increased risk of poor outcome in univariable analyses (P<0.001). This association withstood separate adjustment for stroke severity and diabetes in both cohorts but not age. In sensitivity analyses restricted to the nonrecanalization group (n=987 in the combined cohort), the association was significant also after separate adjustment for age (odds ratio, 1.6 [95% CI, 1.1-2.4]) and when additionally adjusting for stroke severity and diabetes (odds ratio, 1.6 [95% CI, 1.1-2.5]). CONCLUSIONS: We observed an association between LOY and poor outcome after ischemic stroke in patients not receiving recanalization therapy. Future studies on LOY and other somatic genetic alterations in larger stroke cohorts are warranted.

Fibroblast growth factor 23 is associated with risk of intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Fibroblast growth factor 23 (FGF23) is an osteogenic hormone associated with chronic kidney disease and is an emerging risk factor for several cardiovascular diseases. The association of FGF23 with stroke is unclear. The aim of this study was to investigate the association of FGF23 with incident intracerebral hemorrhage (ICH). METHODS: This was a nested case-control study of 220 ICH cases and 244 age- and sex-matched controls from the population-based Malmö Diet and Cancer Study (n = 28,449). Incident ICH cases were ascertained using national registers and classified by bleeding location. Logistic regression was used to study the association of plasma levels of FGF23 with incident ICH, adjusting for potential ICH risk factors. Subgroup analyses were performed for lobar and non-lobar ICH, fatal ICH, ICH with large volume and ICH with poor functional outcome, respectively. RESULTS: Higher FGF23 levels at baseline were significantly associated with incident ICH. After multivariable adjustment, the odds ratio for the association with all ICH was 1.84 (95% confidence interval [CI] 1.25-2.71, p = 0.002) per doubling of FGF23 concentration. For lobar and non-lobar ICH, odds ratios were 1.73 (95% CI 1.04-2.87, p = 0.035) and 2.13 (95% CI 1.32-3.45, p = 0.002), respectively. FGF23 was also significantly associated with fatal ICH, ICH with large volume and ICH with poor functional outcome. CONCLUSIONS: Higher FGF23 was associated with incident ICH in this nested case-control study. Further studies are required to explore whether the association is causal.

Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke: Meta-Analysis of Population-Based Studies Involving 17 180 Individuals.

Rationale: Proinflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of MCP-1 (monocyte chemoattractant protein-1) in atherosclerosis and stroke. However, data from large-scale observational studies are lacking. Objective: To determine whether circulating levels of MCP-1 are associated with risk of incident stroke in the general population. Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke during a mean follow-up interval of 16.3 years (280 522 person-years at risk; 1435 incident stroke events). We applied Cox proportional-hazards models and pooled hazard ratios (HRs) using random-effects meta-analyses. After adjustments for age, sex, race, and vascular risk factors, higher MCP-1 levels were associated with increased risk of any stroke (HR per 1-SD increment in ln-transformed MCP-1, 1.07; 95% CI, 1.01-1.14). Focusing on stroke subtypes, we found a significant association between baseline MCP-1 levels and higher risk of ischemic stroke (HR, 1.11 [1.02-1.21]) but not hemorrhagic stroke (HR, 1.02 [0.82-1.29]). The results followed a dose-response pattern with a higher risk of ischemic stroke among individuals in the upper quartiles of MCP-1 levels as compared with the first quartile (HRs, second quartile: 1.19 [1.00-1.42]; third quartile: 1.35 [1.14-1.59]; fourth quartile: 1.38 [1.07-1.77]). There was no indication for heterogeneity across studies, and in a subsample of 4 studies (12 516 individuals), the risk estimates were stable after additional adjustments for circulating levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein). Conclusions: Higher circulating levels of MCP-1 are associated with increased long-term risk of stroke. Our findings along with genetic and experimental evidence suggest that MCP-1 signaling might represent a therapeutic target to lower stroke risk.Visual Overview: An online visual overview is available for this article.

Association of TIM-1 (T-Cell Immunoglobulin and Mucin Domain 1) With Incidence of Stroke.

OBJECTIVE: The aim of this study was to investigate if there is a causal relationship between circulating levels of TIM-1 (T-cell immunoglobulin and mucin domain 1) and incidence of stroke. Approach and Results: Plasma TIM-1 was analyzed in 4591 subjects (40% men; mean age, 57.5 years) attending the Malmö Diet and Cancer Study. Incidence of stroke was studied in relation to TIM-1 levels during a mean of 19.5 years follow-up. Genetic variants associated with TIM-1 (pQTLs [protein quantitative trait loci]) were examined, and a 2-sample Mendelian randomization analysis was performed to explore the role of TIM-1 in stroke using summary statistics from our pQTLs and the MEGASTROKE consortium. A total of 416 stroke events occurred during follow-up, of which 338 were ischemic strokes. After risk factor adjustment, TIM-1 was associated with increased incidence of all-cause stroke (hazards ratio for third versus first tertile, 1.44 [95% CI, 1.10-1.87]; P for trend, 0.004), and ischemic stroke (hazards ratio, 1.42 [95% CI, 1.06-1.90]; P for trend, 0.011). Nineteen independent lead SNPs, located in three genomic risk loci showed significant associations with TIM-1 (P<5×10-8). A 2-sample Mendelian Randomization analysis suggested a causal effect of TIM-1 on stroke (ß=0.083, P=0.0004) and ischemic stroke (ß=0.102, P=7.7×10-5). CONCLUSIONS: Plasma level of TIM-1 is associated with incidence of stroke. The genetic analyses suggest that this could be a causal relationship.

Comparison of risk factors for ischemic stroke and coronary events in a population-based cohort.

BACKGROUND: Although coronary events (CE) and ischemic stroke share many risk factors, there are also some important differences. The aim of this paper was to assess the association of risk factors in relation to incident CE and ischemic stroke and to evaluate the heterogeneity in patterns of risk factors between the two outcomes. METHOD: Traditional risk factors and inflammatory markers associated with coronary events and ischemic stroke were measured in the Malmö Diet and Cancer Cohort (MDCS, n = 26 519), where a total of 2270 incident ischemic stroke and 3087 incident CE occurred during a mean follow up time 19 ± 6 years, and in relation to inflammatory markers in the cardiovascular sub-cohort (MDC-CV, n = 4795). Cox regression analysis was used to obtain hazard ratios. A modified Lunn-McNeil competing risk analysis was conducted to assess the significance of any differences in risk profiles of these outcomes. RESULTS: Most cardiovascular risk factors were associated both with incident CE and ischemic stroke. However, current smoking, ApoB, low ApoA1, male sex and education level of ≤ 9 years of schooling were preferentially associated with CE compared to ischemic stroke. Conversely, age showed a stronger association with ischemic stroke than with CE. CONCLUSION: CE and ischemic stroke have broadly similar risk factors profiles. However, there are some important differential associations, as well as substantial differences in the magnitude of the association. These could reflect the distinct biology of atherogenesis in different vascular beds. The difference in the determinants highlights the importance of looking at CE and ischemic stroke, two manifestations of cardiovascular disease, separately.

Blood cadmium concentration and risk of subarachnoid haemorrhage.

BACKGROUND: Cadmium is a toxic metal and exposure is mainly from diet and tobacco smoke. Cadmium is accumulated in blood vessels and may reduce synthesis of procollagen and inhibit proliferation of vascular smooth muscle cells. High blood cadmium has been associated with increased risk of myocardial infarction, stroke and unruptured intracranial aneurysms. We examined whether blood cadmium increase the risk of subarachnoid haemorrhage (SAH). METHODS: The Malmö Diet and Cancer cohort (n = 28,449) was examined in 1991-1996 and blood samples were taken. Incidence of SAH was followed up to 2014. Cadmium was measured in stored blood samples from incident SAH cases and matched controls (n = 93 vs n = 276) and odds ratio (OR) for SAH was assessed in a nested case control design. RESULTS: Subjects with cadmium concentration in the highest quartile had increased risk of SAH compared to those in the first quartile (OR: 3.22, 95%CI: 1.67-6.22). However, after adjusting for smoking, results were weakened and non-significant (OR: 1.57, 95%CI: 0.51-4.80). CONCLUSIONS: Cadmium concentration was associated with increased risk of SAH but this association was largely explained by smoking. Whether cadmium in tobacco may contribute to the vascular pathology and increased risk of SAH in smokers should be further studied.

High Serum Level of Matrix Metalloproteinase-7 Is Associated With Increased Risk of Spontaneous Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Increased degradation of the extracellular matrix in the arterial wall by matrix metalloproteinases (MMPs) may be an important mechanism in the pathogenesis of intracranial aneurysms and subarachnoid hemorrhage (SAH). MMP-2 and MMP-9 have been suggested to be involved in matrix degradation preceding SAH. We studied serum levels of MMP-1, -2, -3, -7, -9, -10, and -12 and the risk of incident SAH. METHODS: A nested case-control study within the population-based cohort, Malmö Diet and Cancer study, was performed including incident cases of spontaneous SAH (n=79) and controls matched by age, sex, and follow-up time (n=232). MMPs were measured in serum from the baseline examination in 1991 to 1996. MMPs were compared between cases and controls, using conditional logistic regression adjusting for risk factors. RESULTS: Baseline levels of MMP-7, MMP-10, and MMP-12 were significantly higher in incident SAH cases compared with controls. Odds ratios (95% confidence interval) for SAH per 1 SD increase of MMP-7, MMP-10, and MMP-12 were 1.78 (1.31-2.41), 1.45 (1.11-1.91), and 1.53 (1.17-2.01), respectively. After adjustment for SAH risk factors, MMP-7 was still significantly associated with SAH (odds ratio: 1.64; 95% confidence interval: 1.19-2.27; P=0.0026), whereas associations for MMP-10 and MMP-12 were attenuated and nonsignificant. We did not find any association between high serum levels of MMP-2 or MMP-9 and SAH risk. CONCLUSIONS: High serum level of MMP-7 was associated with increased risk of incident spontaneous SAH, independently of the main risk factors for SAH. High serum levels of MMP-2 and MMP-9 did not predict SAH risk.

FADD (Fas-Associated Protein With Death Domain), Caspase-3, and Caspase-8 and Incidence of Ischemic Stroke.

Background and Purpose- Apoptosis has been implicated in atherosclerosis and plaque rupture. This population-based study examined the relationship between 3 markers of apoptosis, that is, FADD (Fas-associated protein with death domain), caspase-3, and caspase-8, and incidence of ischemic stroke. Methods- The study population included 4356 participants from the MDCS (Malmö Diet and Cancer Study) cardiovascular cohort, without a history of stroke. Incidence of ischemic stroke was followed by linkages to local and national registers. Cox proportional hazards regression was used to assess the incidence of ischemic stroke in relation to quartiles of FADD, caspase-3, and caspase-8, adjusted for potential confounders. Results- During a mean follow-up period of 19.5±4.9 years, a total of 321 (7.4%) participants were diagnosed with incident ischemic stroke. Individuals with high levels of FADD and caspase-8 had a significantly increased risk of ischemic stroke, after adjustment for potential confounders. The multivariable-adjusted hazard ratios for Q4 versus Q1-Q3 of FADD and caspase-8 were 1.49 (95% CI, 1.18-1.87; P<0.01) and 1.77 (95% CI, 1.41-2.22; P<0.001), respectively. The hazard ratios per 1-SD increment of FADD and caspase-8 were 1.27 (95% CI, 1.14-1.41) and 1.31 (95% CI, 1.18-1.45), respectively. No association was observed for caspase-3 with ischemic stroke. Conclusions- Elevated levels of FADD and caspase-8, but not caspase-3, are associated with increased incidence of ischemic stroke.

Genome wide association study identifies two loci associated with cadmium in erythrocytes among never-smokers.

BACKGROUND: Cadmium is a non-essential toxic metal with multiple adverse health effects. Exposure in the general population occurs by smoking and diet. Cadmium in erythrocytes is a valid biomarker of exposure and body burden of cadmium. OBJECTIVES: We aimed to identify genetic variants related to concentrations of cadmium in erythrocytes. METHODS: Erythrocyte cadmium was analyzed in 4432 individuals (1728 never smokers) from the Swedish population-based Malmö Diet and Cancer cohort. Genotyping was performed using the Illumina HumanOmniExpressExome Bead chip with genome-wide coverage. Genome wide analyses were performed in the whole sample and in never smokers. RESULTS: No single nucleotide polymorphism (SNP) reached a genome-wide significant association with erythrocyte cadmium in the whole sample. However, in never smokers, 14 variants showed genome-wide significant relationships with erythrocyte cadmium after adjusting for age and sex. Thirteen variants were in linkage disequilibrium on chromosome 8q13.3 in the XKR9 and LACTB2 genes. The lead SNP on 8q13.3 was rs12681420 (minor allele G, minor allele frequency [MAF] = 0.46, ß: -0.11, P = 3.48 × 10-11), an intron variant within the XKR9 gene. The other significant locus, rs17574271 (minor allele C, MAF = 0.09, ß: 0.17, P = 6.18 × 10-9), was an intron variant within the DLGAP1 gene at chromosome 18p11.31. CONCLUSION: This genome-wide study of never smokers from the general population identified two independent regions related to erythrocyte cadmium. The strongest locus covers the XKR9 and LACTB2 genes, which both could have related functions in cadmium absorption and metabolism. Replication studies are needed to confirm the findings and mechanisms should be further investigated.

Tumor Necrosis Factor Receptor 1 and 2 Are Associated With Risk of Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Raised plasma concentrations of tumor necrosis factor receptors (TNFR) have been linked to arterial stiffness, cerebral microbleeds, and vascular events. The aim of this study was to investigate the association of circulating levels of TNFR1 and TNFR2 with risk for future intracerebral hemorrhage (ICH). METHODS: The population-based MDCS cohort (Malmö Diet and Cancer Study; n=28 449) was conducted in 1991 to 1996. A nested case-control study was performed in the MDCS, including 220 cases who experienced ICH during the follow-up period (mean age at inclusion 62 years, 48% men) and 244 matched controls. Of the 220 ICH cases, 68 died within 28 days. Conditional logistic regression was used to study the association between plasma levels of TNFR1 and TNFR2 and incident ICH, adjusting for known ICH risk factors. RESULTS: Concentrations of both TNFR1 and TNFR2 were significantly higher in subjects who developed ICH during the follow-up. The associations remained after adjustment for ICH risk factors (TNFR1: odds ratio [OR], 2.28; 95% confidence interval [CI], 1.26-4.11; P=0.006; TNFR2: OR, 1.77; CI, 1.16-2.70; P=0.008). ORs were somewhat higher for nonlobar ICH (3.04; CI, 1.29-7.14 and 2.39; CI, 1.32-4.32, respectively) than for lobar ICH (2.03; CI, 0.93-4.41 and 1.35; CI, 0.78-2.37, respectively). TNFR1 and TNFR2 were also associated with increased risk of fatal ICH (TNFR1: OR, 4.42; CI, 1.67-11.6; TNFR2: OR, 2.90; CI, 1.50-5.58) and with poor functional outcome according to the modified Rankin Scale. CONCLUSIONS: High plasma levels of TNFR1 and TNFR2 were associated with incident ICH, most clearly with ICH of nonlobar location. The results suggest that tumor necrosis factor-mediated inflammation could be associated with vascular changes preceding ICH.

Serum Potassium Is Positively Associated With Stroke and Mortality in the Large, Population-Based Malmö Preventive Project Cohort.

BACKGROUND AND PURPOSE: Low serum potassium is associated with stroke in populations with cardiovascular disease, hypertension, and diabetes mellitus but has not been studied in a mainly healthy population. We aimed to study the relation between serum potassium and incident stroke and mortality in the Malmö Preventive Project, a large cohort with screening in early mid-life and follow-up >25 years. METHODS: Serum potassium measurements and covariates were available in 21 353 individuals (79% men, mean age 44 years). Mean follow-up time was 26.9 years for stroke analyses and 29.3 years for mortality analyses. There were 2061 incident stroke events and 8709 deaths. Cox regression analyses adjusted for multiple stroke risk factors (age, sex, height, weight, systolic blood pressure, fasting blood glucose, serum sodium, current smoking, prevalent diabetes mellitus, prevalent coronary artery disease, and treatment for hypertension) were fitted. RESULTS: There was an independent, linear association between serum potassium, per mmol/L increase, and both stroke (hazard ratio, 1.33; 95% confidence interval, 1.17-1.52; P<0.0001) and mortality (hazard ratio, 1.20; 95% confidence interval, 1.13-1.28; P<0.0001). This was significant in subjects both older and younger than the median age (46.5 years), and there was evidence of an interaction with serum sodium. The association was positive and significant for both ischemic stroke and intracerebral hemorrhage and in both hypertensive and normotensive subjects. CONCLUSIONS: Serum potassium, measured in early mid-life, was linearly associated with both incidence of ischemic stroke and intracerebral hemorrhage and all-cause mortality. An interaction with serum sodium implies that factors related to electrolyte balance and incident hypertension may be mediating factors.

Eosinophil Cationic Protein, Carotid Plaque, and Incidence of Stroke.

BACKGROUND AND PURPOSE: ECP (eosinophil cationic protein) is a marker of eosinophil activity and degranulation, which has been linked to atherosclerosis and cardiovascular disease. We examined the relationship between ECP, carotid plaque, and incidence of stroke in a prospective population-based cohort. METHODS: The subjects participated in the Malmö Diet and Cancer Study between 1991 and 1994. A total of 4706 subjects with no history of stroke were included (40% men; mean age, 57.5 years). Carotid plaque was determined by B-mode ultrasound of the right carotid artery. Incidence of stroke was followed up during a mean period of 16.5 years in relation to plasma ECP levels. RESULTS: Subjects in the third tertile (versus first tertile) of ECP tended to have higher prevalence of carotid plaque (odds ratio: 1.18; 95% confidence interval: 1.003-1.39; P=0.044 after multivariate adjustments). A total of 258 subjects were diagnosed with ischemic stroke (IS) during follow-up. ECP was associated with increased incidence of IS after risk factor adjustment (hazard ratio, 1.57; 95% confidence interval: 1.13-2.18; for third versus first tertile; P=0.007). High ECP was associated with increased risk of IS in subjects with carotid plaque. The risk factor-adjusted hazard ratio for IS was 1.86 (95% confidence interval: 1.32-2.63) in subjects with carotid plaque and ECP in the top tertile, compared with those without plaque and ECP in the first or second tertiles. CONCLUSIONS: High ECP is associated with increased incidence of IS. The association between ECP and IS was also present in the subgroup with carotid plaque.

Incidence of stroke and stroke subtypes in chronic obstructive pulmonary disease.

It is uncertain whether the incidence of stroke is increased in patients with chronic obstructive pulmonary disease (COPD), and whether COPD is associated with all subtypes of stroke (i.e. ischemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage). We evaluated the association between COPD and incidence of stroke in a nation-wide cohort study. All individuals between 40 and 84 years of age, hospitalised for COPD between 1987 and 2003 in Sweden were identified in the Swedish hospital discharge register. For each COPD patient (n = 103,419), one reference individual was randomly selected from the general population matched for year of birth, sex and county of residence. After excluding subjects with prior stroke, incidence rates during 10 years follow-up were calculated. Hazard ratios (HR) for stroke comparing COPD patients with reference subjects were estimated using Cox regression adjusting for demographics and comorbidities. Incidence of all-cause stroke (n events = 17,402) was significantly increased in COPD patients compared to reference individuals (HR 1.24, 95 % CI 1.19-1.28), especially during the first 2 years after COPD diagnosis (HR 1.46, 1.37-1.55). Incidences of ischemic stroke (HR 1.20, 1.15-1.25), intracerebral haemorrhage (HR 1.29, 1.16-1.43) and subarachnoid haemorrhage (HR 1.46, 1.16-1.85) were all increased in COPD patients. Incidences of all stroke subtypes are increased in COPD, especially during the first years after COPD diagnosis. The association was independent of several comorbidities, although residual confounding from smoking and hypertension cannot be excluded. A global evaluation of stroke risk factors seems warranted in patients with COPD.

Fibroblast Growth Factor 23 and Incidence of Subarachnoid Hemorrhage: Nested Case-Control Study.

BACKGROUND AND PURPOSE: Fibroblast growth factor 23 (FGF23) is a hormone with regulatory effects on mineral metabolism and arterial calcification. We aimed to study the association between FGF23 and risk of incident subarachnoid hemorrhage (SAH) in a nested case-control study. METHODS: FGF23 was analyzed in stored blood samples from incident SAH cases (n=79) and control subjects (n=232), participating in the prospective, population-based Malmö Diet and Cancer Study. The association between FGF23 and SAH was studied using conditional logistic regression. RESULTS: High FGF23 was associated with incident SAH. In the highest compared with the lowest quartile of FGF23, the odds ratio for SAH was 3.28 (95% confidence interval, 1.34-8.00), P for trend=0.006, after adjustment for SAH risk factors. CONCLUSIONS: High FGF23 was associated with increased risk of incident SAH in subjects from the general population. Further studies should elucidate whether FGF23 is a causal risk factor for SAH, or could be used in risk prediction.

Leukocyte count and incidence of subarachnoid haemorrhage: a prospective cohort study.

BACKGROUND: Subarachnoid haemorrhage (SAH) is a devastating disease, in the majority of cases caused by a rupture of an arterial intracranial aneurysm. The effect of systemic low-grade inflammation on incidence of SAH is not known. The purpose of this study was to evaluate the relationship between leukocyte count, a marker of systemic inflammation, and incidence of SAH in a large cohort study. METHODS: Leukocyte count and other cardiovascular risk factors were measured in 19,794 individuals (17,083 men and 2,711 women, mean age 44 years) participating in a health screening program between 1974 and 1981. Incidence of SAH in relation to baseline leukocyte concentration was studied during a mean follow-up of 27 years in participants free from previous stroke. RESULTS: Ninety-five participants had a SAH, corresponding to an incidence of 22 per 100,000 in women and 17 per 100,000 in men. The hazard ratio for SAH per one standard deviation (2.01 × 109 cells/L) increase of leukocyte concentration was 1.26 (95% CI 1.05-1.53, p = 0.014) after adjustment for several potential confounding factors including smoking. In sensitivity analysis, there was a significant association in smokers but not in non-smokers. CONCLUSIONS: High leukocyte count at baseline was associated with increased incidence of SAH, although this relationship might be restricted to smokers. The results support the view that low-grade systemic inflammation could be involved in the pathogenesis of SAH, or constitute an early risk marker for the disease.

What decides the suspicion of acute coronary syndrome in acute chest pain patients?

BACKGROUND: Physicians assessing chest pain patients in the emergency department (ED) base the likelihood of acute coronary syndrome (ACS) mainly on ECG, symptom history and blood markers of myocardial injury. Among these, the ECG has been stated to be the most important diagnostic tool. We aimed to analyze the relative contributions of these three diagnostic modalities to the ED physicians' evaluation of ACS likelihood in clinical practice. METHODS: 1151 consecutive ED chest pain patients were prospectively included. The ED physician's subjective assessment of the patient's likelihood of ACS (obvious ACS, strong, vague or no suspicion of ACS), the symptoms and the ECG were recorded on a special form. The ED TnT value was retrieved from the medical records. Frequency tables and logistic regression models were used to evaluate the contributions of the diagnostic tests to the level of ACS suspicion. RESULTS: Symptoms determined whether the physician had any suspicion of ACS (odds ratio, OR 526 for symptoms typical compared to not suspicious of ACS) since neither ECG nor TnT contributed significantly (ORs not significantly different from 1) to this assessment. ACS was suspected in only one in ten patients with symptoms not suspicious of ACS. Symptoms were also more important (OR 620 for typical symptoms) than ECG (OR 31 for ischemic ECG) and TnT (OR 3.4 for a positive TnT) for the assessment of obvious ACS/strong suspicion versus vague/no suspicion. Of the patients with ST-elevation on ECG, 71% were considered to have an obvious ACS, as opposed to only 6% of those with symptoms typical of ACS and 10% of those with a positive TnT. CONCLUSION: The ED physicians used symptoms as the most important assessment tool and applied primarily the symptoms to determine the level of ACS suspicion and to rule out ACS. The ECG was primarily used to rule in ACS. The TnT level played a minor role for the assessment of ACS likelihood. Further studies regarding ACS prediction based on symptoms may help improve decision-making in ED patients with possible ACS.

Age at Menopause and the Risk of Stroke: Observational and Mendelian Randomization Analysis in 204 244 Postmenopausal Women.

Background Observational studies have shown that women with an early menopause are at higher risk of stroke compared with women with a later menopause. However, associations with stroke subtypes are inconsistent, and the causality is unclear. Methods and Results We analyzed data of the UK Biobank and EPIC-CVD (European Prospective Investigation Into Cancer and Nutrition-Cardiovascular Diseases) study. A total of 204 244 postmenopausal women without a history of stroke at baseline were included (7883 from EPIC-CVD [5292 from the subcohort], 196 361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD, 5.8), and pooled mean age at menopause was 47.8 years (SD, 6.2). Over a median follow-up of 12.6 years (interquartile range, 11.8-13.3), 6770 women experienced a stroke (5155 ischemic strokes, 1615 hemorrhagic strokes, 976 intracerebral hemorrhages, and 639 subarachnoid hemorrhages). In multivariable adjusted observational Cox regression analyses, the pooled hazard ratios per 5 years younger age at menopause were 1.09 (95% CI, 1.07-1.12) for stroke, 1.09 (95% CI, 1.06-1.13) for ischemic stroke, 1.10 (95% CI, 1.04-1.16) for hemorrhagic stroke, 1.14 (95% CI, 1.08-1.20) for intracerebral hemorrhage, and 1.00 (95% CI, 0.84-1.20) for subarachnoid hemorrhage. When using 2-sample Mendelian randomization analysis, we found no statistically significant association between genetically proxied age at menopause and risk of any type of stroke. Conclusions In our study, earlier age at menopause was related to a higher risk of stroke. We found no statistically significant association between genetically proxied age at menopause and risk of stroke, suggesting no causal relationship.

Lung function as a risk factor for subarachnoid hemorrhage: a prospective cohort study.

BACKGROUND AND PURPOSE: The etiology of subarachnoid hemorrhage (SAH) is poorly understood. Reduced lung function, expressed as low forced expiratory volume in 1 second (FEV(1)) and low forced vital capacity (FVC), is a predictor of cardiovascular disease, but whether reduced lung function is a risk factor for SAH is not known. The association between lung function and incidence of SAH was investigated in a prospective cohort study. METHODS: Between 1974 and 1992, 20 534 men and 7237 women (mean age, 44 years) were examined in a health screening program including spirometry. The incidence of SAH was studied during a mean follow-up of 26 years in relation to age- and height-standardized FEV(1), FVC, and FEV(1)/FVC. RESULTS: One hundred forty-five subjects had a SAH (18.3 per 100 000 person-years in men and 26.5 per 100 000 person-years in women). The hazard ratio for SAH in the lowest compared to the highest quartile of FEV(1) and FEV(1)/FVC was 2.24 (95% CI, 1.32-3.81; P for trend=0.014) and 1.92 (95% CI, 1.14-3.23; P for trend=0.003), respectively, after adjustment for several confounding factors including smoking and hypertension. The results persisted when analysis was restricted to nonsmokers. FVC showed no significant association with incidence of SAH. CONCLUSIONS: Baseline lung function, expressed as low FEV(1) or FEV(1)/FVC, is a risk factor for SAH, independently of smoking.

Ability of risk scores to predict a low complication risk in patients admitted for suspected acute coronary syndrome.

BACKGROUND: When acute coronary syndrome (ACS) cannot be ruled out, emergency department (ED) patients with chest pain are admitted for in-hospital observation because of the risk of complications such as arrhythmia and acute heart failure. A study was undertaken to compare the ability of three risk prediction models to identify patients at a very low risk of complications. METHODS: 559 consecutive patients with chest pain presenting to the ED and admitted for a suspicion of ACS were prospectively included. Predefined in-hospital complications were recorded and the risk predictions of the Global Registry of Acute Coronary Events (GRACE) risk score, the Freedom-from-Events (FFE) risk score and the Goldman rule were compared using receiver operating characteristics (ROC) curves. RESULTS: Of the 559 patients, 140 had ACS and 32 had at least one complication. The GRACE score was superior to the FFE score in predicting the risk of complications (area under ROC curve 0.76 (95% CI 0.68 to 0.85) vs 0.69 (95% CI 0.60 to 0.79), p=0.021) whereas the Goldman rule (area under ROC curve 0.60; 95% CI 0.49 to 0.72) was inferior to both the GRACE and FFE scores. With the GRACE score set to a negative predictive value of 100% (95% CI 96% to 100%), 108 patients (19.3%) at almost no risk of complications could have been correctly identified in the ED. CONCLUSION: The GRACE and FFE scores are able to predict low complication risks in patients with chest pain admitted for suspected ACS, but only the GRACE score may be able to identify a significant number of patients at almost no risk of complications. A larger multicentre study is needed to confirm the possibility of using the GRACE score to identify patients suitable for assessment without monitoring.