Stroke : Highlights of Selected Articles

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. 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. 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. High ECP is associated with increased incidence of IS. The association between ECP and IS was also present in the subgroup with carotid plaque.

The purpose of this longitudinal follow-up study was to investigate the risk of ischemic stroke nationwide in patients with seropositive rheumatoid arthritis (RA) and controls who were matched in age and sex. Patient data were collected from the National Health Insurance Service (NHIS) Health Screening (HEALS) cohort. Using the International Classification of Diseases code M05 (seropositive RA), with a prescription of any disease-modifying anti-rheumatic drug (DMARD), RA was identified. A total of 2,765 patients and 13,825 control subjects were included in our study. The 12-year incidence of ischemic stroke in each group was calculated using the Kaplan-Meier method. The risk ratio of ischemic stroke was estimated using Cox proportional hazards regression. Sixty-four patients (2.31%) in the seropositive RA group and 512 (3.70%) in the control group experienced ischemic stroke (P < 0.001) during the follow-up period. The hazard ratio of ischemic stroke in the seropositive RA group was 1.32 (95% confidence interval (CI), 1.02-1.73) after adjusting for age and sex. The adjusted hazard ratio of ischemic stroke in the seropositive RA group was 1.40 (95% CI, 1.07-1.82) after adjusting for demographics and comorbid medical disorders. According to the subgroup analysis, the hazard ratios of ischemic stroke risks in the female and hypertensive subgroups were 1.44 (95% CI, 1.05-1.97) and 1.66 (95% CI, 1.16-2.38), respectively. In the non-diabetes and non-dyslipidemia subgroups, the corresponding hazard ratios of ischemic stroke were 1.47 (95% CI, 1.11-1.95) and 1.43 (95% CI, 1.07-1.91). Seropositive RA patients have an increased risk of ischemic stroke. In female, hypertension, non-diabetes, and non-dyslipidemia RA subgroups, even without the traditional risk factors for stroke (except for hypertension), increased the risk, which could be potentially attributed to RA.

VIM (vimentin) is a cytoskeletal intermediate filament protein, which has been linked to atherosclerosis and thrombosis; both are important causes of stroke. We examined the relationship between circulating VIM and incidence of stroke, and if carotid plaque could modify the association in a prospective population-based cohort. This prospective study was based on the Malmö Diet and Cancer Cohort. A total of 4688 participants (39.7% men; mean age, 57.6 years) were examined and blood samples were collected between 1991 and 1994. Incidence of stroke was followed up to 2018. Cox' proportional hazards regression was used to assess the relationship between VIM and stroke. During a mean follow-up of 22.0 years, a total of 528 subjects were diagnosed with stroke, among which 434 were ischemic stroke. Participants in the highest quartile (vs 1st quartile) had 1.34× higher risk of total stroke (95% CI, 1.03-1.74) and 1.47× higher of ischemic stroke (95% CI, 1.10-1.98) after adjustment for potential confounders. A significant interaction was found between carotid plaque and VIM with respect to incidence of both total stroke and ischemic stroke (P=0.041 and 0.011, respectively). After stratifying by carotid plaque, high VIM had stronger association with stroke in participants with carotid plaque, especially for the risk of ischemic stroke (adjusted hazard ratio,1.66 [95% CI, 1.23-2.25] for quartile 4 versus quartile 1 to 3). VIM is positively associated with the incidence of stroke, especially in individuals with carotid plaque. Further studies are needed to confirm the observed associations.

For decades, it has been suggested that small dense low-density lipoprotein (sdLDL) may be particularly atherogenic. High levels of sdLDL are associated with an increased risk of ischemic heart disease; however, the association of sdLDL with ischemic stroke has not been explored in a large prospective study on the general population. We tested the hypothesis that high sdLDL cholesterol levels are associated with an increased risk of ischemic stroke. This prospective study included 38,319 individuals from the Copenhagen General Population Study with fresh sample measurements of sdLDL cholesterol. Median follow-up time was 3.1 years. We observed 302 and 74 ischemic and hemorrhagic strokes from baseline in 2013 to 2017 to the end of follow-up in 2018. For comparison, we included estimates for large buoyant LDL cholesterol and total LDL cholesterol. Higher levels of sdLDL cholesterol were log-linearly associated with increased risk of ischemic stroke. Compared with individuals with sdLDL cholesterol in the lowest tertile (≤0.60 mmol/l; ≤23 mg/dl) the multivariable adjusted hazard ratio for ischemic stroke was 1.79 (95% confidence interval=1.31-2.43) for the highest tertile (≥0.86 mmol/l; ≥33 mg/dl). Multivariable adjusted hazard ratios for ischemic stroke per 1 mmol/l (38.7mg/dl) higher levels were 1.69 (1.28-2.22) for sdLDL cholesterol, 0.95 (0.78-1.16) for large buoyant LDL cholesterol, and 1.08 (0.93-1.25) for total LDL cholesterol. Hazard ratios were similar when further adjusting for body mass index (BMI) and diabetes mellitus in the biological pathway in combination with related lipids and lipoproteins. Higher sdLDL cholesterol levels were robustly associated with increased risk of ischemic stroke. ANN NEUROL 2023;93:952-964.

ObjectivesLarge differences exist in the burden of cardiovascular disease (CVD) between Russia and Western European countries including Norway. Obesity prevalence may contribute to the differences. We investigated whether difference in the level of adiposity, assessed using body mass index and waist-to-hip ratio(WHR), could explain intercountry differences in the burden of carotid plaque, a measure of atherosclerosis, in the populations.DesignCross-sectional analysis. Logistic and linear regression models were used.SettingWe used population-based cross-sectional Know Your Heart (KYH) study in Russia and the Tromsø 7 study (Tromsø 7) in Norway.Participants3262 and 1800 men and women aged 40–69 years in KYH and Tromsø 7, respectively.Primary and secondary outcomeThe presence of carotid plaques and plaque score assessed using ultrasound.ResultsThe presence of carotid plaques and plaque score were higher in KYH than Tromsø 7 regardless of age group and sex. A positive association between carotid plaque burden and adiposity was found (OR of having at least one plaque per SD in WHR 1.18 (95% CI 1.06 to 1.31) for men; 1.15 (1.06 to 1.25) for women)) adjusted for age, smoking and education in a pooled analysis of the two studies. There was little evidence of the interaction between study and adiposity. These effects did not differ between the two studies. However, neither adiposity nor CVD risk factors (smoking, systolic blood pressure, cholesterol, glycosylated haemoglobin) explained the higher carotid plaque burden in KYH compared with Tromsø 7.ConclusionAdiposity, especially abdominal adiposity, is a risk factor for carotid plaque in Russia and Norway, although neither adiposity nor established CVD risk factors explained the higher plaque burden in Russia. To reduce the CVD burden in Russia, beyond prevention and treatment of adiposity, further research is required to understand why Russia has a high burden of atherosclerosis.

We examined the relationship of carotid artery lesions (CALs), with and without acoustic shadowing (AS), to incident ischemic stroke events in the Atherosclerosis Risk in Communities study cohort. The study population consisted of 13 123 men and women aged 45 to 64 years, and free of stroke, examined during 1986-1989. Over an average follow-up time of 8.0 years, 226 incident ischemic stroke cases (thromboembolic brain infarctions) were identified and classified by a standardized protocol. Three levels of exposure were defined on the basis of the presence of B-mode ultrasound-detected CALs and AS in a 3-cm segment of the carotid arteries centered at the bifurcation. The hazard ratio for ischemic stroke adjusted for age, ethnicity, and study site for women with a CAL without AS, compared with those without a CAL, was 1.92 (95% CI, 1.23, 3.01), and the hazard ratio comparing those with a CAL with AS with those without a CAL was 4.01 (95% CI, 2.28, 7.06). The corresponding hazard ratios for men were 1.99 (95% CI, 1.36, 2.91) and 2.23 (95% CI, 1.32, 3.79). Although adjustment for diabetes, hypertension medication, systolic blood pressure, left ventricular hypertrophy score, fibrinogen, von Willebrand factor antigen, and smoking status attenuated these associations somewhat, when compared with no evidence of CALs, CALs with AS remained statistically significant predictors of ischemic stroke in women, while CALs without AS were predictive of ischemic stroke in men. B-mode ultrasound-detected CALs and AS serve as markers of atherosclerosis and thus are predictive of ischemic stroke.

Circulating biomarkers and ischemic stroke risk in adults with atrial fibrillation taking anticoagulation: the Reasons for Geographic And Racial Differences in Stroke study.

To explore the usefulness of carotid ultrasound examination as a marker of aging and predictor of disability among older people. Carotid ultrasound, measuring carotid intima media thickness (CIMT) and recording the presence of plaques, was carried out in 152 adults aged 29-59 years (47 women) and in 107 older adults aged 61-88 years (86 women). In all, clinical routine laboratory parameters and lymphocyte telomere length as T/S ratio were measured. Among older adults, 12-min walk, timed up and go, hand grip and quadriceps strength were determined. CIMT was significantly higher among older people and T/S ratio was significantly higher in young women. Carotid plaques were found in one adult and 17 older people. A multiple regression analysis accepted age, systolic blood pressure and T/S ratios as independent predictors of CIMT (R(2) = 0.51). Among older people, a logistic regression accepted age and the presence of carotid plaques as significant predictors of a 12-min walk speed below 1 m/s. An abnormal 12-min walk as an indicator of functional decline among older people is associated with the presence of carotid artery plaques. CIMT is independently associated with age.

BackgroundSeveral studies have reported that chronic rhinosinusitis (CRS) increases the risk of stroke. The aim of this study is to elucidate the putative association between CRS and stroke (ischemic or hemorrhagic) using large population-based national health insurance data.MethodsUsing the national cohort study from the Korean Health Insurance Review and Assessment Service, CRS patients (n = 22,959) and control participants (n = 91,836) were selected and matched at a rate of 1:4 (age, sex, income, region, hypertension, diabetes, and dyslipidemia). A Cox-proportional hazard model was used to analyze the hazard ratio (HR) of CRS for hemorrhagic stroke and ischemic stroke. We divided the participants according to age and gender for the subgroup analysis.ResultsThe HR for hemorrhagic and ischemic stroke was significantly increased in the CRS patients compared to that in the controls (adjusted HR = 2.43, 95% confidence interval [CI] = 2.10–2.80 for hemorrhagic stroke; adjusted HR = 1.76, 95% CI = 1.61–1.92 for ischemic stroke) after adjusting for age, sex, income, region of residence, hypertension, diabetes, dyslipidemia, ischemic heart disease, migraine, chronic kidney disease, depression, sleep disorder, and chronic obstructive pulmonary disorder. In the subgroup analysis, the HR of hemorrhagic stroke was significantly increased in the CRS group regardless of age and gender. The HR of ischemic stroke was also significantly increased in all subgroups of the CRS group.ConclusionCRS consistently increased the risk of ischemic and hemorrhagic stroke regardless of age and gender.

Remote ischemic preconditioning is neuroprotective in models of acute cerebral ischemia. We tested the effect of prehospital rPerC as an adjunct to treatment with intravenous alteplase in patients with acute ischemic stroke. Open-label blinded outcome proof-of-concept study of prehospital, paramedic-administered rPerC at a 1:1 ratio in consecutive patients with suspected acute stroke. After neurological examination and MRI, patients with verified stroke receiving alteplase treatment were included and received MRI at 24 hours and 1 month and clinical re-examination after 3 months. The primary end point was penumbral salvage, defined as the volume of the perfusion-diffusion mismatch not progressing to infarction after 1 month. Four hundred forty-three patients were randomized after provisional consent, 247 received rPerC and 196 received standard treatment. Patients with a nonstroke diagnosis (n=105) were excluded from further examinations. The remaining patients had transient ischemic attack (n=58), acute ischemic stroke (n=240), or hemorrhagic stroke (n=37). Transient ischemic attack was more frequent (P=0.006), and National Institutes of Health Stroke Scale score on admission was lower (P=0.016) in the intervention group compared with controls. Penumbral salvage, final infarct size at 1 month, infarct growth between baseline and 1 month, and clinical outcome after 3 months did not differ among groups. After adjustment for baseline perfusion and diffusion lesion severity, voxelwise analysis showed that rPerC reduced tissue risk of infarction (P=0.0003). Although the overall results were neutral, a tissue survival analysis suggests that prehospital rPerC may have immediate neuroprotective effects. Future clinical trials should take such immediate effects, and their duration, into account. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00975962.

To investigate whether benzbromarone or allopurinol use is associated with the risk of ischemic stroke among individuals aged 20-84years with hyperuricemia or gout. We conducted a retrospective cohort study utilizing 2006 to 2024 records from the TriNetX network. Individuals aged 20-84years who used benzbromarone or allopurinol were included. To form the benzbromarone and allopurinol groups, individuals were matched 1:1 based on demographic and clinical comorbidities. The unadjusted risk ratio was estimated using the Compare Outcomes module in TriNetX. Additionally, a Cox proportional hazards regression model was applied to the unmatched cohort to estimate the adjusted hazard ratio, controlling for demographic and clinical comorbidities. After matching, each group included 26,510 individuals. Over a maximum 15-year follow-up period, the cumulative incidence of ischemic stroke was 1.375% in the benzbromarone group and 1.179% in the allopurinol group. The unadjusted risk ratio was 1.166 (95% CI: 1.003-1.355). The adjusted hazard ratio from the Cox model was 1.296 (95% CI: 1.129-1.488; P = 0.0002), indicating a statistically significant increased risk of ischemic stroke associated with benzbromarone use compared to allopurinol. Benzbromarone use was associated with a higher long-term risk of ischemic stroke compared to allopurinol among individuals aged 20-84years with hyperuricemia or gout. Key Points What is known: • Benzbromarone and allopurinol are two commonly prescribed urate-lowering therapies for hyperuricemia and gout. • The association between these medications and the risk of ischemic stroke remains uncertain. What is new here: • In this study, benzbromarone use was associated with a significantly higher risk of ischemic stroke compared to allopurinol use. • The adjusted hazard ratio for ischemic stroke was 1.296 (95% CI: 1.129-1.488, P = 0.0002) for benzbromarone versus allopurinol. Translational impact: • These findings suggest that benzbromarone may carry a higher long-term ischemic stroke risk than allopurinol, which could inform clinical decision-making in urate-lowering therapy selection.

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.

Objectives: Renal dysfunction is associated with increased risk of cardiovascular disease and is an independent predictor of stroke and systemic embolism. Nonvalvular atrial fibrillation (NVAF) patients with renal dysfunction may face a particularly high risk of thromboembolism and bleeding. The current retrospective cohort study was designed to assess the impact of renal function on ischemic stroke and major bleeding rates in NVAF patients in the real-world setting (outside a clinical trial).Methods: Medical claims and Electronic Health Records were retrieved retrospectively from Optum’s Integrated Claims–Clinical de-identified dataset from May 2011 to August 2014. Patients with NVAF treated with warfarin (2468) or rivaroxaban (1290) were selected. Each treatment cohort was stratified by baseline estimated creatinine clearance (eCrCl) levels. Confounding adjustments were made using inverse probability of treatment weights (IPTWs). Incidence rates and hazard ratios of ischemic stroke and major bleeding events were calculated for both cohorts.Results: Overall, patients treated with rivaroxaban had an ischemic stroke incidence rate of 1.9 per 100 person-years (PY) while patients treated with warfarin had a rate of 4.2 per 100 PY (HR = 0.41 [0.21–0.80], p = .009). Rivaroxaban patients with an eCrCl below 50 mL/min (N = 229) had an ischemic stroke rate of 0.8 per 100 PY, while the rate for the warfarin cohort (N = 647) was 6.0 per 100 PY (HR = 0.09 [0.01–0.72], p = .02). For the other renal function levels (i.e. eCrCl 50–80 and ≥80 mL/min) HRs indicated no statistically significant differences in ischemic stroke risks. Bleeding events did not differ significantly between cohorts stratified by renal function.Conclusions: Ischemic stroke rates were significantly lower in the overall NVAF population for rivaroxaban vs. warfarin users, including patients with eCrCl below 50 mL/min. For all renal function groups, major bleeding risks were not statistically different between treatment groups.

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.

Whether endogenous sex hormones are associated with ischemic stroke (IS) is unclear. We tested the hypothesis that extreme concentrations of endogenous sex hormones are associated with risk of IS in the general population. Adult men (n = 4615) and women (n = 4724) with measurements of endogenous sex hormones during the 1981-1983 examination of the Copenhagen City Heart Study, Denmark, were followed for up to 29 years for incident IS, with no loss to follow-up. Mediation analyses assessed whether risk of IS was mediated through potential mediators. Present and previous findings were summarized in meta-analyses. Plasma total testosterone and total estradiol were measured by competitive immunoassays. Diagnosis of IS was ascertained from the national Danish Patient Registry and the national Danish Causes of Death Registry and verified by experienced neurologists. During follow-up, 524 men and 563 women developed IS. Men with testosterone concentrations ≤10th percentile compared to the 11th-90th percentiles had a hazard ratio for IS of 1.34 (95% confidence interval, 1.05-1.72); 21% of this risk was mediated by body mass index (P = .002) and 14% by hypertension (P = .02). In accordance with this, the corresponding hazard ratio was 1.46 (1.09-1.95) in overweight/obese and hypertensive men. The corresponding hazard ratio in the meta-analysis was 1.43 (1.21-1.70). Other extreme concentrations of testosterone or estradiol were not associated with risk of IS in men or women. Extremely low endogenous testosterone concentrations were associated with high risk of IS in men, a risk mediated in part by body mass index and hypertension. Whether or not low testosterone is a causal factor for IS or merely a biomarker of poor metabolic health is still not known.