Alcohol and Stroke. An Epidemiological Labyrinth

Establishing new approaches for the prevention and treatment of stroke relies on identifying modifiable risk factors that contribute to the development of this complex disease. Mendelian randomization (MR) studies, analogous to naturally occurring randomized trials, can assess causality of potentially modifiable biomarkers and offer new insights into biological pathways. Stroke is the second leading cause of death worldwide and the chief determinant of long-term disability. Stroke is a heterogeneous disease arising from several distinct underlying pathologies and is typically classified as ischemic or hemorrhagic, and further subclassified using imaging data. Ischemic stroke (IS), including its 3 main subtypes: small vessel disease, large vessel disease, and cardioembolic stroke, accounts for ≈80% of stroke and is the result of an interrupted blood supply, leading to localized areas of ischemia in the brain. Small vessel disease may be a consequence of nonatherosclerotic, as well as atherosclerotic, mechanisms that result in an occlusion of the small perforating arteries, whereas large vessel disease results from occlusions or emboli from plaque rupture in larger vessels, such as a carotid artery. Cardioembolic stroke arises typically from emboli from the heart. By contrast, hemorrhagic stroke is a consequence of intracerebral hemorrhage (bleeding into the brain) or subarachnoid hemorrhage (bleeding into the subarachnoid space). These diverse stroke subtypes have distinct underlying pathologies reflecting different risk factor distributions. MR studies, using genetic variants as instrumental variables, afford a powerful approach to assessing causality of risk factors and avoid biases inherent in observational studies, including confounding and reverse causation. This review considers the contribution of MR studies to stroke epidemiology and their relevance to understanding risk factors and new therapeutic targets for stroke. Meta-analyses of large prospective studies have enhanced our knowledge of classical and emerging risk factors for stroke.1–4 Classical risk factors for stroke include nonmodifiable characteristics, …

Objective: To compare complications of surgical clipping and coil embolization in the treatment of unruptured aneurysms. Background: Surgical clipping has been the preferred treatment for unruptured cerebral aneurysms but endovascular coil embolization is an increasingly employed alternative. No direct comparisons of the techniques are available to guide clinical decision making. Methods: We performed a cohort study of patients treated for unruptured cerebral aneurysms at 60 university hospitals from January 1994 through June 1997 using the University HealthSystem Consortium database. The database was validated by chart review from one of the participant universities. The main outcome measures were in-hospital mortality and adverse outcomes, defined as in-hospital deaths and discharges to nursing homes or rehabilitation hospitals. Results: The primary treatment modality was surgical in 2,357 cases and endovascular in 255 cases. Adverse outcomes were significantly more common in surgical cases (18.5%) compared to endovascular cases (10.6%) (p0.002), and the difference was not altered after adjusting for age, sex, race, transfer admissions, emergency room admissions, and year of treatment (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.4 to 3.3; p0.001). In-hospital mortality was also increased in surgical cases (2.3% versus 0.4%; p0.039), but the difference was not significant in the multivariable model (OR 6.3, 95% CI 0.9 to 46.1; p0.07). Length of stay and hospital charges were significantly greater for surgical cases (p0.0001 for each), and these differences were not affected by risk adjustment. Conclusion: Endovascular coil embolization resulted in fewer adverse outcomes than surgery for unruptured cerebral aneurysms treated at the university hospitals studied. Although these results should be seen as preliminary, the magnitude of difference and current predominance of surgery appear to justify a randomized trial.

See related article, pages 2438–2445. Migraine with aura has been consistently associated with increased risk of ischemic stroke.1–3 Most studies suggest that this association is particularly strong for younger women. Although several potential biological mechanisms have been proposed to explain the migraine-stroke association, the precise mechanisms remain unknown. Because migraine is particularly prevalent in an age group in which ischemic stroke, even among migraineurs with aura, is very rare, it seems likely that factors in addition to migraine with aura must be present to lead to an increased risk of stroke. In this issue of Stroke , MacClellan and colleagues4 evaluate several additional features that may help to identify patients with migraine with aura who are at particular increased risk of ischemic stroke. In this population-based case-control study of 386 women aged 15 to 49 with a first- ever ischemic stroke event and 614 age and ethnicity-matched controls, migraine and visual aura symptoms were ascertained using a standardized headache questionnaire. Participants could be classified into patients with probable migraine with visual aura (PMVA), probable migraine without visual aura, and patients without migraine. Compared with nonmigraineurs, …

Proponents of cholesterol as a risk factor for stroke usually support their argument by citing evidence from clinical trials of the beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (“statins”) in reducing stroke risk among people with prior cardiovascular disease. Although such studies may provide some supportive evidence, causation can really only be established between a risk factor and a disease when certain criteria are met.1 These include the criteria that the association between the risk factor and the disease must be temporal and biologically plausible. Although there may be little or no debate about whether cholesterol is a biologically plausible risk factor for stroke or that high cholesterol levels precede (rather than follow) stroke, some of the other criteria are more ambiguous. These other “guidelines for causation” are discussed below: There have been numerous major prospective epidemiological studies of cholesterol and the risk of stroke. However, at best, the …

The association of light to moderate alcohol consumption with risk of ischemic stroke remains uncertain, as are the roles of potentially mediating factors and modification by apolipoprotein E (apoE) genotype. We studied the prospective association of alcohol consumption and risk of ischemic stroke among 4410 participants free of cardiovascular disease at baseline in the Cardiovascular Health Study, a population-based cohort study of older adults from 4 US communities. Participants reported their consumption of alcoholic beverages yearly. During an average follow-up period of 9.2 years, 434 cases of incident ischemic stroke occurred. Compared with long-term abstainers, the multivariate relative risks of ischemic stroke were 0.85 (95% CI, 0.63 to 1.13), 0.75 (95% CI, 0.53 to 1.06), 0.82 (95% CI, 0.51 to 1.30), and 1.03 (95% CI, 0.68 to 1.57) among consumers of <1, 1 to 6, 7 to 13, and > or =14 drinks per week (P quadratic trend 0.06). ApoE genotype appeared to modify the alcohol-ischemic stroke relationship (P interaction 0.08), with generally lower risks among drinkers than abstainers in apoE4-negative participants but higher risks among drinkers than abstainers among apoE4-positive participants. We could not identify candidate mediators among lipid, inflammatory, and prothrombotic factors. In this study of older adults, the association of alcohol use and risk of ischemic stroke was U-shaped, with modestly lower risk among consumers of 1 to 6 drinks per week. However, apoE genotype may modify this association, and even moderate alcohol intake may be associated with an increased risk of ischemic stroke among apoE4-positive older adults.

Patients with recently symptomatic severe carotid stenosis have a high risk of ischemic stroke on medical treatment. The main mechanism of stroke appears to be plaque surface thrombus formation and distal embolism. It is unclear to what extent reduction in blood flow across the stenosis, and the consequent reduction in cerebral perfusion pressure, is also important. Angiographic indices of reduced cerebral perfusion may identify patients at a particularly high risk of stroke who require urgent endarterectomy. The most direct angiographic correlate of poststenotic perfusion pressure is the degree of narrowing of the distal internal carotid artery (ICA) lumen. We sought to develop criteria for the definition of poststenotic narrowing of the ICA and to determine the effect of this and other angiographic characteristics likely to be associated with reduced cerebral perfusion on the risk of ipsilateral ischemic stroke in patients with recently symptomatic carotid stenosis. We studied the carotid angiograms of 3007 patients in the European Carotid Surgery Trial. Poststenotic narrowing of the ICA was defined with use of the ratio of the lumen diameter of the ICA to that of the common carotid artery (CCA). The normal range of the ICA/CCA ratio was defined in 2966 symptomatic or contralateral carotid arteries with 0% to 49% stenosis. Arteries with 70% to 99% symptomatic stenosis and an ICA/CCA ratio below this range were categorized as narrowed. We related the presence of narrowing and other angiographic characteristics to the risk of ipsilateral ischemic stroke on medical treatment. An assessment of the ICA/CCA ratio had good interobserver reproducibility. Poststenotic narrowing of the ICA was defined as an ICA/CCA ratio of <0.42. The 5-year risk of ipsilateral carotid territory ischemic stroke on medical treatment was 8% in patients with 70% to 99% stenosis and narrowing of the ICA versus 25% in patients without narrowing (log rank test, P=0.02). This difference remained after correction for other clinical and angiographic variables (hazard ratio 0.40, 95% CI 0.17 to 0.94, P=0. 03). The other angiographic characteristics did not predict stroke. Poststenotic narrowing of the ICA was associated with a low risk of stroke on medical treatment. This suggests that low flow alone is not usually sufficient to cause ischemic stroke distal to symptomatic carotid stenosis. Poststenotic narrowing may be protective because blood flow distal to the stenosis is insufficient to carry emboli to the brain.

See related article, pages 1078–1083. The metabolic syndrome is a clustering of metabolic abnormalities, which include insulin resistance or diabetes, obesity, hypertension, and dyslipidemia. Although the mechanisms of the underlying abnormalities remain to be clarified, the pathogenesis includes both genetic predisposition and modifiable risk factors such as sedentary lifestyle and dietary intake. Recent estimates suggest that approximately 24% of US adults have the metabolic syndrome.1 In several studies, the metabolic syndrome has been shown to increase the risk of cardiovascular diseases2; however, the strength of its association with stroke is weaker than that for coronary heart disease.3 In the guidelines for the primary prevention of stroke from the American Heart Association/American Stroke Association, the metabolic syndrome is listed as a less–well-documented risk factor.4 But, given the high prevalence of the metabolic syndrome, studying its association with stroke is certainly relevant for 2 reasons: first, to obtain a better etiologic understanding of the causes of stroke; second, to identify individuals at high risk for stroke. This translates into 2 distinct scientific questions: is the metabolic syndrome by itself a risk factor for stroke?; and can we predict which individuals are at increased risk for stroke based on information about the metabolic syndrome? To answer these questions from observational data, one needs 2 distinct model-building strategies that require differences in assumptions of biological associations and statistical considerations.5,6 In this issue of Stroke ,7 Wang and …

Ischemic stroke is an uncommon but devastating complication of myocardial infarction (MI). It is possible that delay in the acute revascularization of these patients influences the risk of peri-MI ischemic stroke independent of size of infarction or residual ventricular function. The influence of the timing and type of revascularization on risk of ischemic stroke in the patient with MI has not previously been assessed. We used the National Registry of Myocardial Infarction 3 and 4 databases to identify 45,997 subjects who received thrombolytic therapy and 47,876 patients who were treated with primary percutaneous transluminal coronary angioplasty for MI. In-hospital ischemic stroke occurred in 248 (0.54%) and 150 (0.31%) patients in the two groups, respectively. Patients were stratified based on time from presentation to initial therapy. A statistically significant linear relationship between time to revascularization therapy and risk of in-hospital ischemic stroke was seen on univariate analysis. A multivariate model incorporating 26 other variables showed thrombolytic therapy within 15 minutes was associated with a lower risk of ischemic stroke (odds ratio, 0.58; 95% CI, 0.36-0.94). Primary angioplasty within 90 minutes of arrival was associated with a nonsignificant trend toward lower stroke risk (odds ratio, 0.68; 95% CI, 0.41-1.12). Interestingly, his benefit of early reperfusion therapy did not appear to be related to improvements in left ventricular function. Risk of in-hospital ischemic stroke with MI is closely tied to the time to revascularization with both thrombolytic and percutaneous transluminal coronary angioplasty therapies. Early revascularization is independently predictive of a lower risk of ischemic stroke, but the mechanism of this does not appear to be related to improved cardiac function. The records of 45,997 subjects who received thrombolytic therapy and 47,876 patients who were treated with primary percutaneous transluminal coronary angioplasty for myocardial infarction were analyzed to determine the relationship between time to revascularization and the occurrence of ischemic stroke. A statistically significant linear relationship between time to revascularization therapy and risk of in-hospital ischemic stroke was seen on univariate analysis. A multivariate model incorporating 26 other variables showed thrombolytic therapy within 15 minutes of presentation was associated with a lower risk of ischemic stroke, and angioplasty within 90 minutes was similarly associated with a nonsignificant trend toward lower stroke risk.

Antioxidants increase the resistance of low-density lipoprotein to oxidation and may thereby reduce risk for atherosclerosis. To determine whether intake of vitamin E, vitamin C, or carotenoids predict risk for total or ischemic stroke. Prospective observational study. The Health Professionals Follow-up Study. 43,738 men 40 to 75 years of age who did not have cardiovascular disease or diabetes. Repeated and validated dietary assessments were done by using a self-administered 131-item food-frequency questionnaire, which included questions on dose and duration of vitamin supplement use. The follow-up period was 8 years. A total of 328 strokes occurred: 210 ischemic, 70 hemorrhagic, and 48 unclassified. After adjustment for age, smoking, hypertension, hypercholesterolemia, body mass index, physical activity, parental history of myocardial infarction, alcohol consumption, and total energy intake, the relative risk for ischemic stroke in the top quintile of vitamin E intake (median, 411 IU/d) compared with the bottom quintile (5.4 IU/d) was 1.18 (95% CI, 0.77 to 1.82). The relative risk for ischemic stroke in the top quintile of vitamin C intake (1167 mg/d) compared with the bottom quintile (95 mg/d) was 1.03 (CI, 0.66 to 1.59). Results for total stroke were similar. Associations of vitamin intake with hemorrhagic stroke were also nonsignificant, but the CIs were wide. Neither dose nor duration of vitamin E or vitamin C supplement use was related to risk for total or ischemic stroke. The relative risk for ischemic stroke was 1.16 (CI, 0.81 to 1.67) in men using 250 IU or more of vitamin E supplementation per day compared with men who used no vitamin E supplements and was 0.93 (CI, 0.60 to 1.45) in men using 700 mg or more of vitamin C supplementation per day compared with men who used no vitamin C supplements. A significant inverse relation between lutein intake and risk for ischemic stroke was seen but was not independent of other dietary factors. Vitamin E and vitamin C supplements and specific carotenoids did not seem to substantially reduce risk for stroke in this cohort. Modest effects, however, cannot be excluded.

OPINION article Front. Neurol., 11 August 2016Sec. Multiple Sclerosis and Neuroimmunology Volume 7 - 2016 | https://doi.org/10.3389/fneur.2016.00128

The role of C-reactive protein (CRP) as a novel plasma marker of atherothrombotic disease is currently under investigation. Previous studies have mostly related CRP to coronary heart disease, were often restricted to a case-control design, and failed to include pertinent risk factors to evaluate the joint and net effect of CRP on the outcome. We related plasma CRP levels to incidence of first ischemic stroke or transient ischemic attack (TIA) in the Framingham Study original cohort. There were 591 men and 871 women free of stroke/TIA during their 1980 to 1982 clinic examinations, when their mean age was 69.7 years. CRP levels were measured by using an enzyme immunoassay on previously frozen serum samples. Analyses were based on sex-specific CRP quartiles. Risk ratios (RRs) were derived, and series of trend analyses were performed. During 12 to 14 years of follow-up, 196 ischemic strokes and TIAs occurred. Independent of age, men in the highest CRP quartile had 2 times the risk of ischemic stroke/TIA (RR=2.0, P=0.027), and women had almost 3 times the risk (RR=2.7, P=0.0003) compared with those in the lowest quartile. Assessment of the trend in risk across quartiles showed unadjusted risk increase for men (RR=1.347, P=0.0025) and women (RR=1.441, P=0.0001). After adjustment for smoking, total/HDL cholesterol, systolic blood pressure, and diabetes, the increase in risk across CRP quartiles remained statistically significant for both men (P=0.0365) and women (P=0.0084). Independent of other cardiovascular risk factors, elevated plasma CRP levels significantly predict the risk of future ischemic stroke and TIA in the elderly.

Background and aimsIndividuals with familial hypercholesterolemia (FH), causing severely elevated LDL-C, are expected to have a higher risk of ischemic stroke. The risk of hemorrhagic stroke and impact of statin use are, however, not known. We aimed to investigate the risk of incident total, ischemic and hemorrhagic stroke in individuals with FH compared to controls, and to explore the association between cumulative statin use and risk of total stroke in FH. MethodsThis prospective cohort study consists of 4186 individuals with genetically verified FH and 82 180 age and sex matched controls followed from 2008 to 2018 for incident stroke. Daily defined doses (DDD) described cumulative statin exposure: 0–5000 DDD (“low”), 5000–10,000 DDD (“intermediate”), and >10 000 DDD (“high”). Results were presented as hazard ratio (95% CI) derived from Cox proportional hazards models. ResultsIndividuals with FH did not have a higher risk of total stroke (1.16 (0.95–1.43) nor ischemic stroke (1.11 (0.88–1.38). Excess risk of hemorrhagic stroke was observed (1.63 (1.07, 2.48) but attenuated after adjusting for antithrombotic medication (1.25 (0.81, 1.93). Among individuals with FH, there was no association between statin use and total stroke for intermediate vs. low DDD [0.69 (0.32, 1.48)] or for high vs. low DDD [0.83 (0.41, 1.67)]. ConclusionsNo significant excess risk of incident total and ischemic stroke in FH, and no difference in total stroke risk among the FH population with low, intermediate, and high statin exposure were observed. The observed relationship between FH and hemorrhagic stroke was no longer significant after adjusting for use of anti-thrombotic medication.

BackgroundsThe risk of stroke is higher among patients with chronic obstructive pulmonary disease (COPD) than among the healthy population. Moreover, women generally have worse long-term stroke outcomes than men.MethodsThe data of 6681 women with COPD (aged ≥ 65 years) registered in Taiwan’s National Health Insurance Research Database were retrospectively analyzed from January 1, 2001 to December 31, 2011. After 1:1 propensity score matching, the patients were divided into vaccinated and unvaccinated groups.ResultsIn total, 5102 women were enrolled. The vaccinated group had a significantly lower risk of total, hemorrhagic, and ischemic stroke than the unvaccinated group (adjusted hazard ratio [aHR]: 0.60, 95% confidence interval [CI]: 0.54–0.67; aHR: 0.59, 95% CI: 0.43–0.83; and aHR: 0.59, 95% CI: 0.52–0.68, respectively). A lower risk of stroke was observed among the women aged 65–74 and ≥75 years, and the association was dose-dependent in all types of stroke (aHR: 1.08, 95% CI: 0.92–1.26; aHR: 0.70, 95% CI: 0.60–0.82; and aHR: 0.32, 95% CI: 0.26–0.38 for those vaccinated 1, 2 to 3, and ≥4 times, respectively, during the follow-up period). Women with a CHA2DS2-VASc score (conditions and characteristics included congestive heart failure, hypertension, diabetes, stroke, vascular disease, age, and sex) of 2–3 and ≥4 had a significantly lower risk of ischemic stroke while receiving more vaccinations. A smaller significant lower risk of hemorrhagic stroke after more than 4 times of vaccination was noted in the women with a CHA2DS2-VASc score of ≥4. Both interrupted and non-interrupted vaccination was associated with lower risk of stroke occurrence.ConclusionInfluenza vaccination is associated with a lower risk of total, hemorrhagic, and ischemic stroke among women with COPD, and the association is dose-dependent. However, the findings may be limited by unmeasurable confounders. Further investigations on this subject are warranted.

Association between statin adherence and the risk of stroke among South Korean adults with hyperlipidemia

Stroke is a major cause of death in the United States. The association between alcohol consumption and ischemic stroke (IS) remains controversial. We used data collected on participants in the Framingham Study to assess the association between total alcohol intake and type of alcoholic beverage and development of IS, overall and according to age. A total of 196 men and 245 women developed IS during three 10-year follow-up periods. In the categories of never drinkers, drinkers of 0.1 to 11, 12 to 23, and > or =24 g/d of ethanol (a "typical drink" is approximately 12 g of ethanol), and former drinkers of 0.1 to 11 and > or =12 g/d, crude incidence rates of IS were 6.5, 5.9, 4.9, 5.0, 6.7, and 17.8 cases per 1000 person-years, respectively, for men and 5.9, 4.1, 4.1, 4.3, 8.3, and 7.1, respectively, for women. Overall, compared with never drinkers in a multivariate Cox regression, current alcohol consumption was not related significantly to IS in either sex. Former drinking of > or =12 g/d of alcohol was associated with a 2.4 times higher risk of IS among men but not among women. When stratified by age, alcohol intake was associated with lower risk of IS among subjects aged 60 to 69 years. In beverage-specific analysis, only wine consumption was related to a decreased risk of IS. Our data showed no significant association between total alcohol and IS overall but showed a protective effect of alcohol among subjects aged 60 to 69 years.