Established Stroke Risk Factors Research Articles

Gender-Specific Hormonal Profiles: Unveiling the Complex Link to Stroke Risk

Stroke affects women more frequently, suggesting a possible link to sex hormones, yet the evidence for this remains inconclusive. Here, we present a pioneering exploration of the nuanced interplay between genetically predicted sex hormone levels, with a particular focus on testosterone and SHBG, to elucidate their causal relationship with stroke risk. Utilizing Mendelian randomization, we aimed to determine whether SHBG levels causally affect stroke occurrence, with a focus on sex-specific effects and the interplay with established stroke risk factors. We leveraged genetic variants from comprehensive genome-wide association studies (GWAS), which are known to robustly predict levels of total and bioavailable testosterone, SHBG, and cholesterol. Employing a robust statistical approach, we meticulously analyzed published GWAS summary statistics, applying inverse variance weighting and conducting comprehensive sensitivity analyses with state-of-the-art methods such as MR-Egger, weighted median, and MR-PRESSO. Multivariate analyses further addressed potential confounders, including pleiotropic effects and selection bias. Strikingly, our results demonstrate that elevated SHBG levels are robustly associated with a markedly reduced stroke risk in women. In contrast, lower SHBG levels were associated with an increased risk of small-vessel ischemic stroke, potentially due to elevated cholesterol. These novel insights not only highlight the intricate interplay among SHBG, cholesterol, and immune system components in the pathogenesis of stroke but also illuminate avenues for future research aimed at unraveling the underlying biological mechanisms.

The Role of Lipoprotein(a) in Peripheral Artery Disease.

Lipoprotein(a) is a low-density-lipoprotein-like particle that consists of apolipoprotein(a) bound to apolipoprotein(b). It has emerged as an established causal risk factor for atherosclerotic cardiovascular disease, stroke, and aortic valve stenosis through multifactorial pathogenic mechanisms that include inflammation, atherogenesis, and thrombosis. Despite an estimated 20% of the global population having elevated lipoprotein(a) levels, testing remains underutilized due to poor awareness and a historical lack of effective and safe therapies. Although lipoprotein(a) has a strong association with coronary artery disease and cerebrovascular disease, its relationship with peripheral artery disease is less well established. In this article, we review the epidemiology, biology, and pathogenesis of lipoprotein(a) as it relates to peripheral artery disease. We also discuss emerging treatment options to help mitigate major adverse cardiac and limb events in this population.

Alcohol consumption may be a risk factor for cerebrovascular stenosis in acute ischemic stroke and transient ischemic attack

BackgroundAtherosclerosis are well established risk factors for ischemic stroke, however the association between alcohol consumption and atherosclerosis is controversial. This study aims to explore the potential correlation between alcohol consumption and cerebral stenosis in patients with acute ischemic stroke and transient ischemic attack (TIA).MethodsNine hundreds and eighty-eight patients with first acute ischemic stroke attack or TIA were recruited retrospectively. Alcohol consumption was classified into five consumption categories (non-drinkers, occasional drinkers, < 140 g per week [mild drinkers], 140–279 g per week [moderate drinkers], ≥ 280 g per week [heavy drinkers]). Computed tomography angiography (CTA) and digital subtraction angiography (DSA) were utilized to assess the carotid and cerebral artery in all patients. Five-step scale for degree of stenosis was applied: normal (0, 0 points), mild (< 50%, 1 point), moderate (50–69%, 2 points), severe (70–99%, 3 points), and occlusion (100%, 4 points).ResultsThe carotid and cerebral artery stenosis scores were positively correlated with moderate alcohol consumption (B = 1.695, P < 0.001). Compared with nondrinkers, moderate alcohol consumption had significant increasing risk of moderate carotid and cerebral artery stenosis (OR = 4.28, 95% CI: 1.47–12.49, P = 0.008) and severe stenosis (OR = 4.24, 95% CI: 1.55–11.64, P = 0.005) and occlusion (OR = 3.87, 95% CI: 1.65–9.06, P = 0.002). Compared with nondrinkers, heavy alcohol consumption patients had significant higher risk of carotid and cerebral artery occlusion (OR = 2.71, 95% CI: 1.36–5.41, P = 0.005).ConclusionsHigher alcohol consumption may associate with higher risk and more severity of carotid and cerebrovascular stenosis.

Identification of potential biological processes and key genes in diabetes-related stroke through weighted gene co-expression network analysis

BackgroundType 2 diabetes mellitus (T2DM) is an established risk factor for acute ischemic stroke (AIS). Although there are reports on the correlation of diabetes and stroke, data on its pathogenesis is limited. This study aimed to explore the underlying biological mechanisms and promising intervention targets of diabetes-related stroke.MethodsDiabetes-related datasets (GSE38642 and GSE44035) and stroke-related datasets (GSE16561 and GSE22255) were obtained from the Gene Expression omnibus (GEO) database. The key modules for stroke and diabetes were identified by weight gene co-expression network analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes Genomes (KEGG) analyses were employed in the key module. Genes in stroke- and diabetes-related key modules were intersected to obtain common genes for T2DM-related stroke. In order to discover the key genes in T2DM-related stroke, the Cytoscape and protein–protein interaction (PPI) network were constructed. The key genes were functionally annotated in the Reactome database.ResultsBy intersecting the diabetes- and stroke-related crucial modules, 24 common genes for T2DM-related stroke were identified. Metascape showed that neutrophil extracellular trap formation was primarily enriched. The hub gene was granulin precursor (GRN), which had the highest connectivity among the common genes. In addition, functional enrichment analysis indicated that GRN was involved in neutrophil degranulation, thus regulating neutrophil extracellular trap formation.ConclusionsThis study firstly revealed that neutrophil extracellular trap formation may represent the common biological processes of diabetes and stroke, and GRN may be potential intervention targets for T2DM-related stroke.

New-onset as opposed to established atrial fibrillation as a risk factor for incident stroke

BackgroundAtrial fibrillation (AF) is an established risk factor for acute ischemic stroke (AIS). It remains unclear if new-onset AF confers a higher risk of AIS than longer-standing AF. MethodsWe retrospectively analyzed all stroke-free patients who underwent transthoracic echocardiography (TTE) in the Henry Ford Health System between March 6 and September 6, 2016. Incident AIS and new-onset AF were ascertained by the presence of new diagnostic codes in the electronic medical record over a follow-up period of up to 5 years. Cox proportional hazards regression was used to identify risk factors for new-onset AF or AIS. ResultsOf 7310 patients who underwent baseline TTE the mean age was 65 years, 54% were female, 51% were Caucasian, and 46% had left atrial enlargement (LAE). Of at-risk patients, 10.9% developed new-onset AF and 2.9% experienced incident AIS. The risk of new-onset AF among at-risk patients was 3.1 times higher among patients with any degree of LAE compared to those with normal LA size (95% CI 2.6–3.6, P < 0.0001). New-onset AF, more than established AF, in turn had a powerful association with incident AIS. The cumulative 5-year risk of AIS was 3.5% in those without AF, 5.9% in those with established AF prior to TTE, and 20.1% in those with new-onset AF (P < 0.0001). In multivariable analysis new-onset AF had the strongest association with incident AIS (P < 0.0001), followed by increasing age (P = 0.0025), black race (P = 0.0032), and smoking (P = 0.0063). ConclusionsNew-onset AF has a strong relationship with incident AIS. LAE was present in nearly half of stroke-free patients undergoing TTE, and was associated with a significantly higher likelihood of new-onset AF during follow-up. Vigilant cardiac monitoring for AF in individuals with LAE, coupled with the timely initiation of anticoagulation, may be an important strategy for the primary prevention of AF-related stroke.

Is there a temporal relationship between atrial fibrillation and stroke? A review

ImportanceAtrial fibrillation (AF) is an established risk factor for ischaemic stroke. The introduction of continuous cardiac rhythm monitoring devices has enabled detection of brief and asymptomatic episodes of AF.ObservationsThe search...

Association between Urine Albumin-to-creatinine Ratio and Intracranial Atherosclerotic Plaque in Chinese Adults - Results from the PRECISE Study.

Intracranial plaque may cause stroke in the absence of luminal stenosis. Although urine albumin-to-creatinine ratio (ACR) has been proved an established risk factor for cardiovascular disease, stroke and carotid atherosclerosis, little is known on the relationship between urine ACR and intracranial plaque. Subjects with history of stroke or coronary heart disease (CHD) were excluded in the PRECISE study. The intracranial plaque was assessed by vessel wall magnetic resonance imaging (MRI). Subjects were stratified according to ACR tertiles. Logistic regression and ordinal regression were performed to analyze the association between ACR and the presence of intracranial plaque or sum of the stenosis score for each artery. 2962 individuals were included with the mean age of 61.0±6.6 years. The median ACR was 11.7mg/g (interquartile range 7.0-22.0 mg/g), and the mean estimated glomerular filtration rate (eGFR) based on combination of creatinine and cystatin C was 88.5±14.8 ml/min·1.73m2. 495 (16.7%) participants had intracranial plaque. The highest ACR tertile with ACR ＞16.00mg/g was independently associated with the presence of intracranial plaque (OR 1.38, 95% CI: 1.05-1.82, p=0.02) and the odds of higher intracranial plaque burden (common OR 1.39, 95% CI: 1.05-1.83, p=0.02) after adjustment of confounding factors. No significant association was observed between eGFR and intracranial plaque presence or intracranial plaque burden. Among a low-risk community-dwelling population without prior stroke or CHD in China, ACR was independently associated with intracranial plaque presence and plaque burden measured by vessel wall MRI.

Epidemiology and Risk Factors for Stroke in Chronic Kidney Disease: A Narrative Review.

Patients with chronic kidney disease (CKD) have a higher risk ofboth ischemic and hemorrhagic stroke. This association appears to be partly independent from the higher prevalence of established risk factors for stroke in patients with CKD, including hypertension and atrial fibrillation. In the present review we aim to discuss the impact of CKD on the risk of stroke and stroke-related consequences, and explore the pathophysiology underpinning the increased risk of stroke in patients with CKD. We cover the clinical association between renal dysfunction and cerebrovascular disease including stroke, silent brain infarct, cerebral small vessel disease, microbleeds, and white matter hyperintensity, and discuss the underlying mechanisms.

Resolving the Smoking Paradox: No Evidence for Smoking-Induced Preconditioning in Large Vessel Occlusion Stroke

Introduction: Smoking is an established risk factor for stroke. However, several studies have reported a better outcome after stroke for patients who smoke. According to this “smoking paradox” hypothesis, smoking might promote less severe strokes, higher collateral scores, and smaller infarct cores. Methods: In this retrospective study, we screened data of 2,980 acute ischemic stroke patients with MCA-M1 occlusion treated with mechanical thrombectomy. Patients were categorized according to smoking status (current, former, or never). We assessed univariate associations between clinical characteristics and smoking status. Subsequently, we used adjusted regression analysis to evaluate associations of smoking with stroke severity on admission (National Institutes of Health Stroke Scale [NIHSS]; primary endpoint), infarct core volume, and collateral status (secondary endpoints). Results: Out of 320 patients, 19.7% (n = 63) were current smokers and 18.8% (n = 60) were former smokers. Admission NIHSS, reperfusion success, and modified Rankin Scale (mRS) after 3–6 months were similar in all groups. Current smokers were younger, more often male and less likely to have atrial fibrillation compared to former and never smokers. In regression analyses, smoking status was neither associated with admission NIHSS (estimate 0.54, 95% confidence interval [CI]: −1.27–2.35, p = 0.557) nor with collateral status (estimate 0.79, 95% CI: 0.44–1.44, p = 0.447) or infarct core volume (estimate −0.69, 95% CI: −15.15–13.77, p = 0.925 for current vs. never smokers). Conclusion: We could not confirm the smoking paradox. Our results support the fact that smoking causes stroke at a younger age, highlighting the role of smoking as a modifiable vascular risk factor.

Salt-induced maladaptive innate immune memory impedes stroke recovery

Abstract A high salt diet (HSD) is a top risk factor for human mortality. Beyond its heavily implicated role in hypertension, it is now linked to the development of inflammatory diseases before the onset of cardiovascular events. Even after salt reduction, HSD can induce prolonged tissue damage, yet the mechanisms by which HSD induces persistent negative effects on immune system are largely unexplored. While HSD is an established risk factor for stroke, its impact on long-term stroke recovery is unknown. Here, we model two major stroke types, intracerebral hemorrhage, and cerebral ischemia, to investigate how HSD induces unfavorable immune responses and subsequently impacts long-term tissue repair. We found HSD exclusively hampers alternative activation in monocytes-derived macrophages (MDMs) while sparing the major parenchymal macrophage—microglia—in the stroke brain. HSD induces innate immune memory in the hematopoietic stem and progenitor cells through downregulating mitochondrial oxidative phosphorylation and NR4a orphan nuclear receptors expression. This immunological memory was retained in the brain-infiltrating MDMs and restrained their reparative functions. Consequently lead to impaired tissue repair and neurobehavioral recovery during stroke recovery phase. Pharmacological treatment with NR4a1 activator and genetic overexpression of NR4a1 restored MDMs reparative phenotype suppressed by HSD and enabled stroke recovery. These findings establish a new mechanism linking HSD-induced maladaptive innate immune memory to a hindered macrophage alternative activation and delayed tissue recovery. Our data unveil innate immune memory and NR4a1 as potential therapeutic targets for treating HSD-associated diseases.

Abstract P475: Left Ventricular Hypertrophy Prevalence by Electrocardiogram in Patients Presenting With Cerebrovascular Accident

Background: A strong association has been previously suggested between left ventricular hypertrophy (LVH) and stroke. The prevalence of LVH and hypertension, however, differs depending on demographic variables. In light of the most recent hypertension guidelines, more aggressive blood pressure control is called for to achieve the lower goals set forth. This will hopefully translate into lower incidence of LVH and stroke. Objectives: To examine the prevalence of left ventricular hypertrophy in patients receiving an electrocardiogram (EKG) for a diagnosis of stroke, transient ischemic attack, or cerebrovascular accident; all of which will be referred to as CVA. Methods: An EKG database from a university cardiology noninvasive lab was examined for the diagnosis of CVA over a one year period. The EKGs were evaluated for the presence of LVH or atrial fibrillation/flutter. The results were analyzed using Chi square test. Results: There was a total of 14,798 EKGs performed over one year. There were 272 EKGs with a diagnosis of CVA (1.7%); 2364 EKGs (16%) with diagnosis of LVH, and 481 (3.2%) with diagnosis of atrial fibrillation/flutter. Out of the 272 EKGs in patients with CVA diagnosis, there were 174 EKGs in sinus rhythm without LVH (64%), 78 EKGs in sinus rhythm with LVH (29%, P &lt; 0.05), and 20 EKGs in atrial fibrillation or atrial flutter (7.4%, P &lt; 0.05). Discussion: Stroke is a major health problem associated with increased mortality and morbidity. While atrial fibrillation and atrial flutter are well-established causes of stroke and were nearly twice as frequent in CVA patients as the general population in our cohort, LVH by EKG, in the absence of atrial fibrillation/flutter, was also nearly twice as prevalent, underscoring its importance as a potential marker for CVA. Hypertension is a well established risk factor for stroke in addition to cardiovascular events, and is a major cause of LVH on EKG. In our cohort nearly one third of patients with stroke were in sinus rhythm, but had left ventricular hypertrophy by EKG, a prevalence that was nearly four times that of atrial fibrillation/flutter. Since hypertension is the most common cause of left ventricular hypertrophy in our population, this places further significance on hypertension as a major modifiable risk factor and predictor of CVA and cardiovascular disease in general. In light of the most recent hypertension guidelines, aggressive blood pressure management to achieve the newly defined lower limits for a diagnosis of hypertension, with monitoring for signs of left ventricular hypertrophy by EKG, should be emphasized in order to decrease the incidence of stroke and other cardiovascular events.

Abstract WP70: Emergency Department Visits For Hypertensive Urgency And Risk Of Subsequent Stroke

Introduction: Chronic hypertension is an established long-term risk factor for stroke. However, little is known about short-term stroke risk after an episode of acute severe hypertension without evidence of target organ damage (i.e., hypertensive urgency [HU]). We evaluated the short-term risk of stroke after an ED visit with HU resulting in discharge home (treat-and-release). Methods: We performed a case-crossover study using deidentified administrative claims from all nonfederal EDs and hospitals across 11 states. The study cohort comprised patients diagnosed with any stroke (ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage), defined using validated ICD-10 codes, between 2016-2018. We tabulated and compared incident ED visits for HU during case periods (2-week intervals from 0-24 weeks before the index stroke) to control periods (equivalent time periods exactly 1 year earlier). ED visits with HU were ascertained using the ICD-10 code I16.0, which we validated through detailed chart review of 50 patients at our center resulting in a code sensitivity and specificity of 100% and 96%, respectively. We used McNemar’s test for matched data to calculate risk ratios (RRs) for an ED HU visit occurring before stroke. Results: Among 45,063 patients with stroke, 22,417 (50%) were female and 37,577 (83%) had a prior diagnosis of hypertension. There were 201 patients with stroke who had at least one ED visit for HU during the preceding 24 weeks. An ED visit for HU was significantly more common in the 2 weeks before stroke compared to the 2-week control period 1 year earlier (RR, 5.1; 95% CI, 2.4-12.7; p&lt;0.0001). The association between stroke and preceding ED visit for HU decreased in magnitude with increasing temporal distance from stroke and was no longer significant by the 7-8 week period before stroke (Figure 1). Conclusion: Treat-and-release ED visits for HU are associated with a significantly increased short-term risk of stroke.

Genetic loci, rs17817449 and rs6567160, known for obesity and the risk of stroke events among middle-aged and older Chinese people.

Fat Mass and Obesity-Associated (FTO) and the Melanocortin-4 Receptor (MC4R) genes are strongly associated with obesity, an established risk factor for stroke. We aimed to assess the associations between rs17817449 at the FTO and rs6567160 at the MC4R and the risk of stroke events in middle-aged and older Chinese people. Study data were obtained from the Guangzhou Biobank Cohort Study; a total of 148 participants with a self-reported history of stroke and an equal volume of age- and sex-matched participants were selected as the cases and the controls in a case-control study; a total of 13,967 participants at the first follow-up and all participants with fatal stroke (up to April 2021) were included in a retrospective cohort study. Conditional logistic regression and the Cox proportional hazards regression analyses were used to assess the associations of the two genetic loci with the risk of stroke events. After adjusting for age, sex, education, job, smoking, alcohol consumption, body mass index, physical activity, hypertension, diabetes, and dyslipidemia, rs17817449 and rs6567160 shared minor alleles G and C, respectively, in the case-control analyses. The genotypes GG+GT of rs17817449 at the FTO were significantly associated with a decreased risk of fatal stroke occurrence, with fatal all strokes having an adjusted hazard ratio (aHR) of 0.71 (95% confidence intervals (CI) 0.52-0.97, P = 0.04) and fatal ischemic stroke having an aHR of 0.64 (95% CI 0.41-1.00, P = 0.05), when the genotype TT was taken as a reference and a series of multiplicities were adjusted; the risk of fatal all strokes was lowered by dyslipidemia (aHR = 0.63, 95% CI 0.39-1.00, P = 0.05) and non-diabetes (aHR = 0.68, 95% CI 0.46-0.99, P = 0.049) in the retrospective cohort analyses. Significances were observed neither in the associations between rs6567160 and the risk of stroke events nor in an interaction between rs17817449 and rs6567160 in the two-stage analyses. The G allele of rs17817449 at the FTO, not rs6567160 at the MC4R, was associated with a decreased risk of fatal stroke occurrence; its functional role in stroke should be explored in relatively healthy middle-aged to older Chinese people.

Abstract 11930: Ascension Health System Experience With Extended Ambulatory Electrocardiographic Monitoring: Implementation of a Novel Integrated Approach to Better Characterize Disparities in Healthcare

Introduction: Atrial fibrillation (AF) is an established risk factor for stroke, hospitalization and mortality. Whether AF differs by race has not been well characterized in the real world setting due to inherent challenges in linking large datasets across multiple databases. Methods: Extended ambulatory electrocardiographic (AECG) monitoring with Zio XT allows for continuous recording of cardiac rhythm data for up to 14 days in indicated patients. A preliminary dataset from the Ascension Health System electronic health records (EHR) archive on patients prescribed the Zio XT patch was retrospectively analyzed. The study population consisted of 6,293 patients treated at 34 Ascension centers in 6 states between January 2020 and April 2022. Patient EHR data were linked to proprietary device-specific rhythm reports for analyses. Results: Among 6,293 patients in whom EHR data were matched to Zio XT findings, the median (IQR) age was 63 (47, 73) years, 3,816 (60.6%) were female, and 1,038 (16.5%) were non-Caucasian. Median device wear time was 7.2 (5.0, 13.9) days. AF was detected in 749 (11.9%) patients, including 326 (5.2%) with 100% AF. Median AF burden was 37.0% (3.4%, 100%). Older white males had the highest risk of AF events, whereas younger non-white females had the lowest risk (Figure 1). Non-white subgroups demonstrated greater freedom from AF compared to whites. Conclusions: In these preliminary findings, the use of Zio XT for extended AECG monitoring in the Ascension Health System is in predominantly older patients. Patients were racially and geographically diverse, and females were well represented. More than 10% of patients had AF detected during the monitoring period. Despite small sample sizes, differences in AF detection by subgroups demonstrate that a tailored approach to managing AF remains a critically important research question. Linkage of patient EHR data with device-specific outcomes can be a useful approach to address this important unmet need.

Two-year outcomes of patients with atrial fibrillation and heart failure: the ETNA-AF-Europe registry

Abstract Background Heart failure (HF) is an established risk factor for stroke and systemic embolic events (SEE) in subjects with atrial fibrillation (AF), but it is debated whether this risk varies according to left ventricular ejection fraction (LVEF). Methods We investigated the impact of HF in the ETNA-AF-Europe registry, a prospective, multi-centre, post-authorisation, observational study enrolling patients treated with edoxaban for AF in 825 sites from 10 European countries. This 2-year follow-up analysis is based on a data snapshot from 26 October 2020. HF was defined as a) history of HF or b) ischaemic cardiomyopathy or c) EF &amp;lt;40% or d) dyspnoea not due to chronic obstructive pulmonary disease together with ≥1 of the following: ischaemic heart disease, valvular heart disease, or hypertension treated with ≥3 drugs. Patients' characteristics are summarised descriptively and clinical outcomes are reported as annualised event rates. The hazard ratio (HR) with 95% confidence intervals (CI) for the association of HF with the outcomes was assessed in Cox regression models with stepwise variable selection. Results Of the 13,133 patients, 1,854 (14.1%) had HF; LVEF was available for 1,489 (80.3%), and was &amp;lt;40% in 671 (43.9%) and ≥40% in 857 (56.1%). Patients with HF were more often men and slightly older than those without (Table 1). As expected, they also had more cardiovascular (CV) comorbidities and higher CHA2DS2-VASC and, to a lesser extent, HAS-BLED scores (Table 1). At the end of the 2-year follow-up, the rates of ischaemic stroke/transient ischaemic attack (TIA)/SEE, major bleeding, intracranial haemorrhage (ICH), CV death, and all-cause death were higher in patients with than without HF (Figure 1). When patients with HF were categorized according to LVEF, ischaemic stroke/TIA/SEE was more frequent in those with LVEF ≥40% vs those with LVEF &amp;lt;40%. By contrast, more patients with LVEF &amp;lt;40% died due to any as well as CV causes. The rates of major bleeding and ICH were comparable between the two subgroups (Figure 1). Univariable Cox regression analysis confirmed the association of HF with major bleeding (HR 2.01, 95% CI [1.49–2.71]) and all-cause death (2.62 [2.28–3.02]), but not with ischaemic stroke/TIA/SEE (1.06 [0.72–1.55]). The results were consistent when LVEF was taken into account: the HRs for LVEF &amp;lt;40% or LVEF ≥40%, respectively, were 1.60 (0.99–2.60) and 1.55 (1.02–2.38) for major bleeding, 2.11 (1.69–2.63) and 1.59 (1.28–1.97) for all-cause death, and 0.66 (0.31–1.41) and 1.19 (0.71–1.98) for ischaemic stroke/TIA/SEE. Conclusions In this real-world, large cohort of patients with AF on edoxaban, those with HF at baseline faced more ischaemic, bleeding, and death events, and having HF increased the risk of major bleeding and death, with no differences according to LVEF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This research was funded by Daiichi Sankyo Europe.

Advances in Stroke: Genetics, Genomics, Precision Medicine.

Advances in Stroke: Genetics, Genomics, Precision Medicine.

Endogenous H2S targets mitochondria to promote continual phagocytosis of erythrocytes by microglia after intracerebral hemorrhage

Hematoma clearance, which is achieved largely by phagocytosis of erythrocytes in the hemorrhagic brain, limits injury and facilitates recovery following intracerebral hemorrhage (ICH). Efficient phagocytosis critically depends on the capacity of a single phagocyte to phagocytize dead cells continually. However, the mechanism underlying continual phagocytosis following ICH remains unclear. We aimed to investigate the mechanism in this study. By using ICH models, we found that the gasotransmitter hydrogen sulfide (H2S) is an endogenous modulator of continual phagocytosis following ICH. The expression of the H2S synthase cystathionine β-synthase (CBS) and CBS-derived H2S were elevated in brain-resident phagocytic microglia following ICH, which consequently promoted continual phagocytosis of erythrocytes by microglia. Microglia-specific deletion of CBS delayed spontaneous hematoma clearance via an H2S-mediated mechanism following ICH. Mechanistically, oxidation of CBS-derived endogenous H2S by sulfide-quinone oxidoreductase initiated reverse electron transfer at mitochondrial complex I, leading to superoxide production. Complex I-derived superoxide, in turn, activated uncoupling protein 2 (UCP2) to promote microglial phagocytosis of erythrocytes. Functionally, complex I and UCP2 were required for spontaneous hematoma clearance following ICH. Moreover, hyperhomocysteinemia, an established risk factor for stroke, impaired ICH-enhanced CBS expression and delayed hematoma resolution, while supplementing exogenous H2S accelerated hematoma clearance in mice with hyperhomocysteinemia. The results suggest that the microglial CBS-H2S-complex I axis is critical to continual phagocytosis following ICH and can be targeted to treat ICH.

The Controversial Role of HCY and Vitamin B Deficiency in Cardiovascular Diseases

Plasma homocysteine (HCY) is an established risk factor for cardiovascular disease CVD and stroke. However, more than two decades of intensive research activities has failed to demonstrate that Hcy lowering through B-vitamin supplementation results in a reduction in CVD risk. Therefore, doubts about a causal involvement of hyperhomocysteinemia (HHcy) and B-vitamin deficiencies in atherosclerosis persist. Existing evidence indicates that HHcy increases oxidative stress, causes endoplasmatic reticulum (ER) stress, alters DNA methylation and, thus, modulates the expression of numerous pathogenic and protective genes. Moreover, Hcy can bind directly to proteins, which can change protein function and impact the intracellular redox state. As most mechanistic evidence is derived from experimental studies with rather artificial settings, the relevance of these results in humans remains a matter of debate. Recently, it has also been proposed that HHcy and B-vitamin deficiencies may promote CVD through accelerated telomere shortening and telomere dysfunction. This review provides a critical overview of the existing literature regarding the role of HHcy and B-vitamin deficiencies in CVD. At present, the CVD risk associated with HHcy and B vitamins is not effectively actionable. Therefore, routine screening for HHcy in CVD patients is of limited value. However, B-vitamin depletion is rather common among the elderly, and in such cases existing deficiencies should be corrected. While Hcy-lowering with high doses of B vitamins has no beneficial effects in secondary CVD prevention, the role of Hcy in primary disease prevention is insufficiently studied. Therefore, more intervention and experimental studies are needed to address existing gaps in knowledge.

Etiology and Outcome of Ischemic Stroke in Patients With Renal Impairment Including Chronic Kidney Disease

Background and ObjectivesChronic kidney disease is a worldwide public health problem that is recognized as an established risk factor for stroke. It remains unclear whether its distribution and clinical impact are consistent across ischemic stroke subtypes in patients with renal impairment. We examined whether renal impairment was associated with the proportion of each stroke subtype vs ischemic stroke overall and with functional outcomes after each stroke subtype.MethodsStudy participants were 10,392 adult patients with an acute stroke from the register of the Japan Stroke Data Bank, a hospital-based multicenter stroke registration database, between October 2016 and December 2019, whose baseline serum creatinine levels or a dipstick proteinuria result were available. All ischemic strokes were classified according to the Trial of Org 10172 in Acute Stroke Treatment criteria. Unfavorable functional outcome was defined as modified Rankin Scale (mRS) score 3–6 at discharge. Mixed effect logistic regression was used to determine the relationship between the outcomes and the estimated glomerular filtration rate (eGFR), eGFR strata (<45, 45–59, ≥60 mL/min/1.73 m2), or dipstick proteinuria ≥1 adjusted for covariates.ResultsOverall, 2,419 (23%) patients had eGFR 45–59 mL/min/1.73 m2 and 1,976 (19%) had eGFR <45 mL/min/1.73 m2, including 185 patients (1.8%) receiving hemodialysis. Both eGFR 45–59 and eGFR <45 mL/min/1.73 m2 were associated with a higher proportion of cardioembolic stroke (odds ratio [OR], 1.21 [95% CI, 1.05–1.39] and 1.55 [1.34–1.79], respectively) and a lower proportion of small vessel occlusion (0.79 [0.69–0.90] and 0.68 [0.59–0.79], respectively). A similar association with the proportion of these 2 subtypes was proven in the analyses using decreased eGFR as continuous values. Both eGFR <45 mL/min/1.73 m2 and proteinuria were associated with unfavorable functional outcomes in patients with cardioembolic stroke (OR, 1.30 [95% CI, 1.01–1.69] and 3.18 [2.03–4.98], respectively) and small vessel occlusion (OR, 1.44 [1.01–2.07] and 2.08 [1.08–3.98], respectively).DiscussionRenal impairment contributes to the different distributions and clinical effects across specific stroke subtypes, particularly evident in cardioembolic stroke and small vessel occlusion. This possibly indicates shared mechanisms of susceptibility and potentially enhancing pathways.

Genetic Contributors of Incident Stroke in 10,700 African Americans With Hypertension: A Meta-Analysis From the Genetics of Hypertension Associated Treatments and Reasons for Geographic and Racial Differences in Stroke Studies.

Background: African Americans (AAs) suffer a higher stroke burden due to hypertension. Identifying genetic contributors to stroke among AAs with hypertension is critical to understanding the genetic basis of the disease, as well as detecting at-risk individuals. Methods: In a population comprising over 10,700 AAs treated for hypertension from the Genetics of Hypertension Associated Treatments (GenHAT) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) studies, we performed an inverse variance-weighted meta-analysis of incident stroke. Additionally, we tested the predictive accuracy of a polygenic risk score (PRS) derived from a European ancestral population in both GenHAT and REGARDS AAs aiming to evaluate cross-ethnic performance. Results: We identified 10 statistically significant (p < 5.00E-08) and 90 additional suggestive (p < 1.00E-06) variants associated with incident stroke in the meta-analysis. Six of the top 10 variants were located in an intergenic region on chromosome 18 (LINC01443-LOC644669). Additional variants of interest were located in or near the COL12A1, SNTG1, PCDH7, TMTC1, and NTM genes. Replication was conducted in the Warfarin Pharmacogenomics Cohort (WPC), and while none of the variants were directly validated, seven intronic variants of NTM proximal to our target variants, had a p-value <5.00E-04 in the WPC. The inclusion of the PRS did not improve the prediction accuracy compared to a reference model adjusting for age, sex, and genetic ancestry in either study and had lower predictive accuracy compared to models accounting for established stroke risk factors. These results demonstrate the necessity for PRS derivation in AAs, particularly for diseases that affect AAs disproportionately. Conclusion: This study highlights biologically plausible genetic determinants for incident stroke in hypertensive AAs. Ultimately, a better understanding of genetic risk factors for stroke in AAs may give new insight into stroke burden and potential clinical tools for those among the highest at risk.