Abstracts of literature

Stroke ranks as the third leading cause of death in the United States. It is now estimated that there are more than 700 000 incident strokes annually and 4.4 million stroke survivors.1 2 The economic burden of stroke was estimated by the American Heart Association to be $51 billion (direct and indirect costs) in 1999.3 Despite the advent of treatment of selected patients with acute ischemic stroke with tissue plasminogen activator and the promise of other experimental therapies, the best approach to reducing the burden of stroke remains prevention.4 5 High-risk or stroke-prone individuals can be identified and targeted for specific interventions.6 This is important because epidemiological data suggest a substantial leveling off of prior declines in stroke-related mortality and a possible increase in stroke incidence.7 8 The Stroke Council of the American Heart Association formed an ad hoc writing group to provide a clear and concise overview of the evidence regarding various established and potential stroke risk factors. The writing group was chosen based on expertise in specific subject areas, and it used literature review, reference to previously published guidelines, and expert opinion to summarize existing evidence and formulate recommendations (Table 1⇓). View this table: Table 1. Levels of Evidence and Grading of Recommendations As given in Tables 2 through 4⇓⇓⇓, risk factors or risk markers for a first stroke were classified according to potential for modification (nonmodifiable, modifiable, or potentially modifiable) and strength of evidence (well documented, less well documented).5 The tables give the estimated prevalence, population attributable risk, relative risk, and risk reduction with treatment for each factor when known. Population attributable risk reflects the proportion of ischemic strokes in the population that can be attributed to a particular risk factor and is given by the formula 100×[prevalence(relative risk−1)/prevalence(relative risk−1)+1]). …

Abstracts of literature

Racial/ethnic differences have been documented in the relationship between obstructive sleep apnea (OSA) and stroke incidence, yet racial differences in OSA symptoms or treatment and their relationship with stroke incidence are underexplored and may contribute to stroke disparities. We comprehensively examined OSA symptoms and their relationships to stroke incidence by race/ethnicity. Data were collected from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, a population-based cohort of Black and White individuals in the United States. Participants free from a stroke diagnosis at baseline were included. Participants self-reported the following: (1) snoring; (2) daytime sleepiness; (3) provider-diagnosed sleep apnea (PDSA); and (4) treatment for PDSA using positive airway pressure (PAP). OSA risk was categorized as high or low based on the Berlin Sleep Questionnaire. Incident stroke was defined as first occurrence of stroke over an average of 12 (SD 3.9) years of follow-up. We report the relationships between snoring, OSA risk, PDSA, PAP therapy use, and incident stroke by race/ethnicity using Cox proportional hazards models after adjusting for demographic and socioeconomic factors and stroke risk factors. Among the 22,192 participants (mean age [SD] 64.2[9.1] years), 38.1% identified as Black. Overall, snoring was not associated with incident stroke (hazard ratio [HR] 0.98, 95% CI 0.85-1.13). However, among White individuals but not Black individuals, high OSA risk and PDSA were associated with incident stroke (HR 1.22, 95% CI 1.01-1.47; HR 1.33, 95% CI 1.04-1.70, respectively). PAP therapy use among those with PDSA (compared with non-PDSA) was associated with incident stroke in White individuals (HR 1.38, 95% CI 1.05-1.80). PAP therapy use among those with PDSA (compared with those with PDSA without PAP therapy use) was associated with reduced risk of incident stroke in Black (HR 0.39, 95% CI 0.17-0.91) but not White (HR 0.63, 95% CI 0.37-1.10) individuals. White individuals with high OSA risk and those with PDSA with or without PAP therapy use were at increased incident stroke risk, whereas Black individuals reporting PDSA and PAP had reduced incident stroke risk relative to those not using PAP. Future research is needed to understand the mechanisms underlying racial differences in OSA and stroke such as differences in assessment modes and treatment.

Reduced lung function has been shown to be a significant predictor of non-fatal ischaemic heart disease, and of mortality due to cardiovascular disease. Fewer studies have analysed the relationship between lung function and risk of fatal or non-fatal stroke. The present study presents results on the relation between forced expiratory volume in one second (FEV1) and risk of incident and fatal first-ever stroke. The analyses are based on prospective cohort data from 12 878 eligible men and women aged 45-84 years, who participated in the first health examination of the Copenhagen City Heart Study in 1976-1978. The subjects were followed from day of entry until 31 December 1993. During that period 808 first-ever strokes occurred of which 153 were fatal within 28 days. Risk of incident and fatal stroke was estimated by means of Cox hazard regression. The analyses included adjustment for potential confounders: sex, age, smoking, inhalation, body mass index, systolic blood pressure, triglycerides, physical activity in leisure time, education, diabetes mellitus, and antihypertensive treatment. We found an inverse association between FEV1 and risk of first-time stroke. For each 10% decrease in FEV1 in percentage of expected, the relative risk (RR) increased 1.05 (95% CI : 1.00-1.09, P = 0.03). This represents an approximately 30% higher risk of stroke in the group of people with the lowest lung function as compared to the group with the highest lung function. The association between lung function and risk of fatal stroke resembled that of risk of incident stroke (fatal and non-fatal). The RR was 1.11 (95% CI : 1.03-1.19) for each 10% decrease in FEV1 in percentage of expected. This represents approximately a doubling of the risk between the highest and lowest lung function groups. This study shows that reduced lung function measured in percentage of predicted FEV1 is a predictor of first-time stroke and fatal stroke independent of smoking and inhalation. The high risk of fatal first-ever stroke in the group of people with low lung function may be of significance in both the design and interpretation of clinical trials.

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, …

Many patients with severe obstructive sleep apnea (OSA) do not complain of excessive daytime sleepiness (EDS), possibly due to increased sympathetic nervous activity (SNA) and accompanying heightened alertness. We hypothesized that in patients with OSA, those without subjective EDS (Epworth Sleepiness Scale, ESS score < 11) would have higher very low frequency (VLF) heart rate variability (HRV) during sleep, reflecting greater sympathetic heart rate modulation than patients with an ESS score ≥ 11. Patients with severe OSA (AHI ≥ 30: 26 with and 65 without heart failure) were divided into those with and without EDS. Heart rate (HR) signals were acquired in stage 2 sleep during periods of recurrent apneas and hypopneas and submitted to coarse graining spectral analysis, which extracts harmonic, neurally mediated contributions to HRV from total spectral power. Because the apnea-hyperpnea cycle entrains muscle SNA at VLF (0 to 0.04 Hz), VLF power was our principal between-group comparison. Subjects without EDS had higher harmonic VLF power (944 ± 839 vs 447 ± 461 msec(2), p = 0.003) than those with EDS, irrespective of the presence or absence of heart failure (1218 ± 944 vs 426 ± 299 msec(2), p = 0.043, and 1029 ± 873 vs 503 ± 533 msec(2), p = 0.003, respectively). ESS scores correlated inversely with VLF power in all (r = -0.294, p = 0.005) and in heart failure subjects (r = -0.468, p = 0.016). Patients with severe OSA but without EDS have higher VLF-HRV than those with EDS. This finding suggests that patients with severe OSA but without EDS have greater sympathetic modulation of HRV than those with EDS that may reflect elevated adrenergically mediated alertness. Taranto Montemurro L; Floras JS; Picton P; Kasai T; Alshaer H; Gabriel JM; Bradley TD. Relationship of heart rate variability to sleepiness in patients with obstructive sleep apnea with and without heart failure.

African Americans and individuals of African ancestry have a higher risk of stroke compared with non-Hispanic white individuals. Identifying the source of this disparity could provide an opportunity for clinical stroke risk stratification and more targeted therapy. Whether sickle cell trait (SCT) is an indicator of increased risk of ischemic stroke among African Americans is still unclear. To examine whether SCT is associated with a higher risk of incident ischemic stroke among African Americans. This meta-analysis assessed the association of SCT with the risk of incident ischemic stroke. Four large, prospective, population-based studies with African American cohorts were assessed: Jackson Heart Study (September 1, 2005, through December 31, 2012), Multi-Ethnic Study of Atherosclerosis (July 1, 2002, through December 31, 2012), Reasons for Geographic and Racial Differences in Stroke (January 1, 2003, through December 31, 2014), and Women's Health Initiative (October 1, 1998, through December 31, 2012). Using a Cox proportional hazards regression model adjusted for major stroke risk factors, this study estimated the hazard ratio for incident ischemic stroke associated with SCT. Data analysis was performed from July 10, 2016, to February 2, 2017. Participants' SCT status determined by polymerase chain reaction assay genotyping or a combination of whole-exome sequencing and imputation. Incident ischemic stroke. This meta-analysis included 19 464 African American individuals (1520 with SCT, 17 944 without SCT, and 620 with ischemic stroke) from 4 studies, with a mean (SD) age of 60.0 (13.0) years (5257 [27.0%] men and 14 207 [73.0%] women). No differences were found in the distribution of risk factors for ischemic stroke comparing participants with and those without SCT at study visit 1 in each cohort. The crude incidence of ischemic stroke was 2.9 per 1000 person-years (95% CI, 2.2-4.0 per 1000 person-years) among those with SCT and 3.2 per 1000 person-years (95% CI, 2.7-3.8 per 1000 person-years) among those without SCT. After stroke risk factors were adjusted for, the hazard ratio of incident ischemic stroke independently associated with SCT in the meta-analysis of all 4 cohorts was 0.80 (95% CI, 0.47-1.35; P = .82). The results of the meta-analysis were similar to those of individual cohorts, in which the results were also similar. Sickle cell trait may not be associated with incidence of ischemic stroke among African Americans. The results of this study suggest performing a more thorough clinical evaluation of a stroke patient with SCT rather than assuming that SCT is the etiologic factor for the stroke.

Microalbuminuria, a marker of both kidney disease and endothelial dysfunction, may be associated with global vascular risk, but the nature and magnitude of the link between microalbuminuria and incident stroke has not been clearly defined. The purpose of this study was to assess the consistency and strength of the association of microalbuminuria with risk of stroke in prospective studies using meta-analysis. We conducted a systematic search of electronic databases and bibliographies for studies reporting a multivariate-adjusted estimate, represented as relative risk with 95% CI, of the association between microalbuminuria and stroke risk. Studies were excluded if a majority of study participants had established kidney disease or pre-eclampsia. Estimates were combined using a random-effect model. We identified 12 studies, with a total of 48 596 participants and 1263 stroke events. Overall, presence of microalbuminuria was associated with greater stroke risk (relative risk, 1.92; 95% CI, 1.61 to 2.28; P < 0.001) after adjustment for established cardiovascular risk factors. There was evidence of significant heterogeneity in the magnitude of the association across studies (P for heterogeneity < 0.001, I² = 68%), which was partially explained by differences in study population, microalbuminuria definition, and different microalbuminuria-related risk among stroke subtypes. However, in stratified analyses, microalbuminuria was associated with increased risk of subsequent stroke in all subgroups (general population, diabetics, those with known stroke). Microalbuminuria is strongly and independently associated with incident stroke risk. Future studies should explore whether microalbuminuria is just a risk marker or a modifiable risk factor for stroke.

Background: Depression is a risk factor for stroke, yet most studies of this association have been conducted in white populations. We investigated the association between depressive symptoms and long-term stroke risk in a community-based cohort of African Americans. Methods: We used data from the Jackson Heart Study to investigate the association of depressive symptoms at baseline (between 2000 and 2004) with incident stroke risk over 9 years of follow-up. We classified depressive symptoms using the Centers for Epidemiologic Studies Depression (CES-D) scale. We used Kaplan-Meier estimates and Cox proportional hazards models to assess stroke risk using 3 exposure variables: any depressive symptoms (CES-D score ≥ 16); minor (score 16 to less than 21) vs major depression (score ≥ 21); and CES-D score per 1 SD increase. Models were adjusted for a stroke risk score and behavioral risk factors. Results: Of 3309 participants without a history of stroke and with complete CES-D information, 738 (22.3%) had depressive symptoms at baseline. The rate of incident stroke was higher among patients with depressive symptoms than among those without (2.8% vs 2.2%; P = .15). Depressive symptoms at baseline were not associated with greater stroke risk in unadjusted or adjusted models (Table). Major depressive symptoms were associated with a twofold greater unadjusted stroke risk compared with no depressive symptoms. However, this association was not significant after multivariable adjustment. Conclusions: In a community-based cohort of African Americans, depressive symptoms were not associated with a greater risk of incident stroke after adjustment for other risk factors.

The relevance between circulating metabolites and vascular events remains controversial and comprehensive studies are lacking. We sought to investigate the prospective associations of plasma metabolomics with risks of incident stroke, ischemic stroke (IS), hemorrhagic stroke (HS), and myocardial infarction (MI). Within the UK Biobank cohort, 249 circulating metabolites were measured in 90 438 participants without baseline vascular diseases. Cox proportional hazards regressions were applied to estimate adjusted hazard ratios (HRs) for per 1 standard deviation increment in metabolites. The least absolute shrinkage and selection operator algorithm was used for selecting metabolite subsets. During a median of 9.0 years of follow-up, we documented 833 incident stroke and 1256 MI cases. Lipid constituents, comprising cholesterol, cholesteryl esters, free cholesterol, phospholipids, and total lipids, in very low- (VLDL), intermediate- (IDL), and low-density lipoprotein (LDL) particles were positively associated with MI risk (HR=1.12 to 1.36; 95% CI=1.06 to 1.44), while in high-density lipoprotein (HDL) particles showed inverse associations (HR=0.68 to 0.81; 95% CI=0.63 to 0.87). Similar association pattern with MI was also observed for VLDL, IDL, LDL, and HDL particles themselves. In contrast, triglycerides within all lipoproteins, including most HDL particles, were positively associated with MI risk (HR=1.14 to 1.28; 95% CI=1.08 to 1.35) and, to a slightly lesser extent, with stroke and IS. Unsaturation of fatty acids and albumin were inversely associated with risks of stroke, IS, and MI. In contrast, the linear association for HS is absent. When combining multiple metabolites, the metabolite risk score captured a drastically elevated risk of all vascular events, about twice that of any single metabolite. Taken together, circulating metabolites showed remarkably widespread associations with incident MI, but substantially weakened associations with risks of stroke and its subtypes. Exhaustive metabolomics profiling may shed light on vascular risk prediction and, in turn, guide pertinent strategies of intervention and treatment.

From 1965 to 1968, the Honolulu Heart Program began following 8,006 men in a prospective study of cardiovascular disease. At the time of study enrollment, an estimate of current 24-hour habitual physical activity was collected from each subject. On the basis of a calculated physical activity index, subjects were classified as being inactive, partially active, or active. This report examines the relation between the levels of physical activity and stroke that occurred among 7,530 of the men over 22 years of follow-up. Risk of stroke was examined separately in younger (45-54 years) middle-aged men and older (55-68 years) middle-aged men. Among the older men, those who were inactive or partially active experienced a three- to fourfold excess incidence of hemorrhagic stroke as compared with active men (p < 0.01). There was a two- to threefold excess of intracerebral hemorrhage in men who were inactive or partially active as compared with those who were active (p < 0.05). An excess of subarachnoid hemorrhage was observed in inactive older men, with only one event occurring in those who were active (p < 0.05). After exclusion of subjects with hypertension, diabetes mellitus, and left ventricular hypertrophy, the relative risk of hemorrhagic stroke for inactive men versus active men was 3.7 (95% confidence interval (CI) 1.3-10.4). In older men who did not smoke cigarettes, the relative risk of thromboembolic stroke among inactive men versus active men was 2.8 (95% CI 1.2-6.7), and when partially active older men were compared with those who were active, the relative risk was 2.4 (95% CI 1.0-5.7). These findings persisted after control for the residual effects of systolic blood pressure and other risk factors for stroke. Benefits of physical activity in reducing the risk of thromboembolic stroke were not observed in men who smoked cigarettes. The authors conclude that physical activity may be important in reducing the risk of stroke, particularly among nonsmoking men in older middle age.

APOL1 renal risk variants are strongly associated with chronic kidney disease in Black adults, but reported associations with cardiovascular disease (CVD) have been conflicting. We examined associations of APOL1 with incident coronary heart disease (n=323), ischemic stroke (n=331), and the composite CVD outcome (n=500) in 10 605 Black participants of the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Primary analyses compared individuals with APOL1 high-risk genotypes to APOL1 low-risk genotypes in Cox proportional hazards models adjusted for CVD risk factors and African ancestry. APOL1 high-risk participants were younger and more likely to have albuminuria at baseline than APOL1 low-risk participants. The risk of incident stroke, coronary heart disease, or composite CVD end point did not significantly differ by APOL1 genotype status in multivariable models. The association of APOL1 genotype with incident composite CVD differed by diabetes mellitus status (Pinteraction=0.004). In those without diabetes mellitus, APOL1 high-risk genotypes associated with greater risk of incident composite CVD (hazard ratio, 1.67; 95% confidence interval, 1.12-2.47) compared with those with APOL1 low-risk genotypes in multivariable adjusted models. This latter association was driven by ischemic strokes (hazard ratio, 2.32; 95% confidence interval, 1.33-4.07), in particular, those related to small vessel disease (hazard ratio, 5.10; 95% confidence interval, 1.55-16.56). There was no statistically significant association of APOL1 genotypes with incident CVD in subjects with diabetes mellitus. The APOL1 high-risk genotype was associated with higher stroke risk in individuals without but not those with chronic kidney disease in fully adjusted models. APOL1 high-risk status is associated with CVD events in community-dwelling Black adults without diabetes mellitus.

Background: Major differences between women and men exist in the clinical presentation, medical care, and prognosis and outcomes of stroke. We assessed the sex-specific association of major risk factors and the risk of incident stroke, including its major subtypes, among women and men. Methods: Between 2006-10, the UK Biobank recruited over 500,000 participants aged 40-69 years across the UK. During 9 years of follow-up, 4,662 (44% women) cases of stroke were recorded among 471,971 (56% women) individuals without a history of cardiovascular disease at baseline. Cox regression models yielded adjusted hazard ratios (HRs), and women-to-men ratios of HRs (RHR), for stroke associated with seven risk factors. Results: The incidence rate per 10,000 person years was 8.66 (8.29; 9.04) in women and 13.96 (13.44; 14.50) in men for any stroke; 6.06 (5.75; 6.38) in women and 11.35 (10.88; 11.84) in men for ischaemic stroke, and 1.56 (1.41; 1.73) in women and 2.23 (2.02; 2.45) in men for haemorrhagic stroke. The magnitude of the relationship between increases in indices of blood pressure, body anthropometry, and lipid levels, diabetes mellitus, and atrial fibrillation and the risk of any stroke was similar between men and women. Hypertension (stage 2), current smoking, and a low socioeconomic status, respectively, were associated with a greater HR of any stroke in women than men; the RHRs were 1.36 (1.26; 1.47), 1.18 (1.02; 1.36), and 1.17 (1.03; 1.33). Diabetes was associated with a higher HR of ischaemic stroke in women than men (RHR: 1.25 [1.00; 1.56]). Atrial fibrillation was associated with a higher HR of haemorrhagic stroke in women than men (RHR: 2.80 [1.07; 7.36]). The incidence of stroke was higher among men than women for all risk factors, except type 1 diabetes and atrial fibrillation (haemorrhagic stroke only). Conclusion: Several risk factors are more strongly associated with the risk of any stroke or stroke subtypes in women compared with men. Despite this, the incidence of stroke in the presence of risk factors generally remains higher among men than women.

To explore the dose-response relationship between the Metabolic Score of Insulin Resistance (METS-IR), uric acid (UA) and the risk of stroke incidence, the mediating role of C-reactive protein (CRP) in the above relationship, as well as the joint effect of METS-IR and UA on the risk of stroke incidence. Participants from the CHARLS study were included in this cohort study. Logistic regression models were used to estimate the odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the associations of METS-IR and UA with the risk of incident stroke. The dose-response relationships of METS-IR and UA with stroke risk were assessed by restricted cubic spline regression. The mediation models were employed to estimate the potential mediating effects of CRP on the associations of METS-IR and UA with stroke risk. Logistic regression analysis was carried out to analyse the association of stroke and MRTS-IR combined with UA. During a 9-year follow-up from 2011 to 2018, 570 incident cases of stroke were documented among 7,343 total participants. Per interquartile range increases in METS-IR and UA were associated with the increased risk of incident stroke, with the OR (95% CI) of 1.61 (1.44, 1.80) and 1.18 (1.05, 1.32) respectively. A dose-response function showed that METS-IR had a nonlinear relationship (P for nonlinear=0.047) and UA had a linear relationship (P for nonlinear=0.247) with the stroke risk. CRP had significant mediated effects on the associations of METS-IR and UA with stroke risk, and the proportion of mediation was 9.01% and 26.34% respectively (all P < 0.05). The results of joint effect showed that participants with high levels of METS-IR and UA had the highest increased risk of stroke compared to the participants with low levels of METS-IR and UA. METS-IR and UA levels were positively associated with an increased risk of stroke onset, and CRP mediated these relationships. Improving insulin sensitivity and regulating CRP and uric acid levels may be important for preventing the risk of stroke occurrence.

<i>Stroke</i> : Highlights of Selected Articles