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BACKGROUND: Circulating plasma proteins are clinically useful biomarkers for stroke risk. We examined the causal links between plasma proteins and stroke risk in individuals of South Asian ancestry. METHODS AND RESULTS: We applied proteome-wide Mendelian randomization and colocalization approaches to understand causality of 2922 plasma proteins on stroke risk in individuals of South Asian ancestry. We obtained genetic instruments (proxies) for plasma proteins from the UK Biobank (N=920). Genome-wide association studies summary data for strokes (N≤11 312) were sourced from GIGASTROKE consortium. Our primary approach involved the Wald ratio or inverse-variance-weighted methods, with statistical significance set at false discovery rate <0.1. Additionally, a Bayesian colocalization approach assessed shared causal variants among proteome, transcriptome, and stroke phenotypes to minimize bias from linkage disequilibrium. We found evidence of a potential causal effect of plasma GP6 (glycoprotein VI) levels on cardioembolic stroke (odds ratio [OR]Wald ratio=2.53 [95% CI, 1.59-4.03]; P=9.2×10-5, false discovery rate=0.059). Generalized Mendelian randomization accounting for correlated single nucleotide polymorphisms (SNPs), with the P value threshold at P<5×10-8 and clumped at r2=0.3, showed consistent direction of effect of GP6 on cardioembolic stroke (ORgeneralized inverse-variance-weighted=2.21 [95% CI, 1.46-3.33]; P=1.6×10-4). Colocalization analysis indicated that plasma GP6 levels colocalize with cardioembolic stroke (posterior probability=91.4%). Multitrait colocalization combining transcriptome, proteome, and cardioembolic stroke showed moderate to strong evidence that these 2 traits colocalize with GP6 expression in the coronary artery and brain tissues (multitrait posterior probability>50%). The potential causal effect of GP6 on cardioembolic stroke was not significant in European populations (ORinverse-variance-weighted=1.08 [95% CI, 0.93-1.26]; P=0.29). CONCLUSIONS: Our joint Mendelian randomization and colocalization analyses suggest that genetically predicted GP6 is potentially causally associated with cardioembolic stroke risk in individuals of South Asian ancestry. As genetic data on individuals of South Asian ancestry increase, future Mendelian randomization studies with larger sample size for plasma GP6 levels should be implemented to further validate our findings. Additionally, clinical studies will be necessary to verify GP6 as a therapeutic target for cardioembolic stroke in South Asians.
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Pueblo Asiatico , Teorema de Bayes , Accidente Cerebrovascular Embólico , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Glicoproteínas de Membrana Plaquetaria , Polimorfismo de Nucleótido Simple , Humanos , Accidente Cerebrovascular Embólico/genética , Accidente Cerebrovascular Embólico/epidemiología , Accidente Cerebrovascular Embólico/sangre , Pueblo Asiatico/genética , Glicoproteínas de Membrana Plaquetaria/genética , Glicoproteínas de Membrana Plaquetaria/metabolismo , Femenino , Masculino , Factores de Riesgo , Persona de Mediana Edad , Predisposición Genética a la Enfermedad , Biomarcadores/sangre , Anciano , Medición de Riesgo/métodosRESUMEN
BACKGROUND AND OBJECTIVES: Obesity is hypothesized to induce a hypercoagulable state that increases stroke risk. The molecular mechanisms underlying this association are largely uncharacterized. We aimed to apply mendelian randomization to identify whether the association of genetically proxied body mass index (BMI) with cardioembolic stroke risk is mediated by changes in levels of circulating coagulation factors. METHODS: Genetic proxies for BMI and levels of circulating coagulation factors were obtained, respectively, from the Genetic Investigation of ANthropometric Traits consortium (n = 694,649) and deCODE cohort (n = 35,559). Genetic associations with cardioembolic stroke risk were obtained from the GIGASTROKE consortium (10,804 cases and 1,234,804 controls). We performed a two-sample mendelian randomization analysis testing the association of genetically proxied BMI with cardioembolic stroke risk, genetically proxied BMI with levels of coagulation factors, and genetically proxied levels of coagulation factors with cardioembolic stroke risk. These estimates were carried forward to mediation and sensitivity analyses. RESULTS: A 1-SD increase in genetically proxied BMI associated with increased cardioembolic stroke risk (OR of cardioembolic stroke per 1-SD of BMI 1.20, 95% CI 1.08-1.33, p = 8.65 × 10-4) with similar findings in statistical sensitivity analyses more robust to the inclusion of pleiotropic variants. Genetically proxied BMI was further associated with increased levels of Factor VII, Factor Xa, Factor XI, and Protein S (all p < 5.9 × 10-6). Of these factors, genetically proxied levels of Factor XI were associated with cardioembolic stroke risk (OR of cardioembolic stroke per 1-SD increase in Factor XI levels 1.32, 1.19-1.46, p = 6.18 × 10-8). The mediated effect of genetically proxied BMI through Factor XI accounted for 26% (6%-49%) of the total effect of BMI on cardioembolic stroke. DISCUSSION: Human genetic data support increased levels of Factor XI as a mechanistic explanation for how obesity increases cardioembolic stroke risk. The clinical relevance of this association warrants further investigation within ongoing clinical trials of Factor XI inhibition.
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Índice de Masa Corporal , Análisis de la Aleatorización Mendeliana , Obesidad , Trombofilia , Humanos , Obesidad/genética , Obesidad/complicaciones , Obesidad/sangre , Obesidad/epidemiología , Trombofilia/genética , Trombofilia/sangre , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/sangre , Femenino , Factores de Coagulación Sanguínea/genética , Masculino , Factores de Riesgo , Accidente Cerebrovascular Embólico/genética , Accidente Cerebrovascular Embólico/epidemiologíaRESUMEN
INTRODUCTION AND AIM: The advances and the wide use of brain imaging have considerably increased the prevalence of silent brain infarctions (SBI). We aim in this study to determine the prevalence of SBI in patients presenting with acute cardioembolic stroke and the predictive cardiovascular risk factors. METHODS: This retrospective study included 267 patients presenting with acute cardioembolic stroke in the emergency and/or neurology departments of the Hassan II University Hospital Center. Clinical, biological and echocardiographic characteristics were recorded. All patients were screened for SBI by brain imaging. RESULTS: The prevalence of SBI in our series was 46%. A group of 203 non-valvular patients and a group of 64 valvular patients were distinguished. In non-valvular group, the average age was 72.97±10.53years. The prevalence of SBI was 45.3%. Forty-four percent of patients with SBI had atrial fibrillation (AF). In multivariate regression analysis, the history of previous stroke, CHA2DS2-VASc Score≥4, enlarged left atrium (LA), the association of AF with enlarged LA and the lability of International Normalized Ratio in patients initially treated with anticoagulants were significantly associated with the occurrence of SBI (P=0.013, P=0.032, P=0.0001, P=0.01, P=0.03, respectively). Territorial location was significantly the most frequent (P=0.007). In valvular group, the average age was 57.19±14.38years. The prevalence of SBI was 48.4%. In multivariate regression analysis, SBI were significantly associated with moderate or severe mitral stenosis (P=0.02) and with the enlarged LA (P=0.02). In all patients, Modified Rankin Scale at 3 months of discharge from the acute stroke was significantly higher (mRS≥3) in patients with SBI (P=0.04). CONCLUSIONS: SBI requires good management of associated cardiovascular risk factors in a population presenting with initial cardioembolic stroke.
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Infarto Encefálico , Accidente Cerebrovascular Embólico , Humanos , Masculino , Femenino , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Prevalencia , Accidente Cerebrovascular Embólico/epidemiología , Accidente Cerebrovascular Embólico/etiología , Accidente Cerebrovascular Embólico/diagnóstico por imagen , Factores de Riesgo , Anciano de 80 o más Años , Infarto Encefálico/epidemiología , Infarto Encefálico/diagnóstico por imagen , Infarto Encefálico/etiología , Enfermedades Asintomáticas , Análisis Multivariante , Fibrilación Atrial/epidemiología , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnósticoRESUMEN
INTRODUCTION: Variations in the left atrial appendage (LAA) morphology are associated with different embolic risk in patients with atrial fibrillation (AF). Data are scarce regarding the association between LAA morphology and Embolic stroke of undetermined source (ESUS). PATIENTS AND METHODS: Using cardiac computed tomography (CCT) scans, LAA morphology was categorized as either chicken wing (CW), cactus, windsock, or cauliflower. Furthermore, we examined the presence of large secondary lobes arising from the main lobe, considering their existence as indicative of a complex LAA morphology. LAA morphologies were compared between ESUS (n = 134) and AF patients (n = 120); and between ESUS patients with (n = 24) and without (n = 110) subsequent AF diagnosis during long-term follow-up. RESULTS: ESUS patients had a significantly higher prevalence of cauliflower morphology compared to AF group (52% vs 34%, respectively, p = 0.01); however, no significant difference was found between the groups when categorizing LAA morphology to either CW or non-CW. ESUS patients had significantly higher prevalence of large secondary lobes compared with AF patients (50% vs 29%, respectively, p = 0.001). When comparing ESUS patients with and without AF diagnosis during follow-up (20-48 months of follow-up, median 31 months), there were no significant differences in the prevalence of the "classical" morphologies, but large secondary lobes were significantly more prevalent among those without subsequent AF diagnosis. CONCLUSION: ESUS patients have a high prevalence of complex LAA morphology, which might be associated with an increased risk for thrombus formation even in the absence of AF.
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Apéndice Atrial , Fibrilación Atrial , Accidente Cerebrovascular Embólico , Humanos , Apéndice Atrial/diagnóstico por imagen , Apéndice Atrial/patología , Femenino , Masculino , Anciano , Fibrilación Atrial/complicaciones , Fibrilación Atrial/epidemiología , Fibrilación Atrial/patología , Fibrilación Atrial/diagnóstico por imagen , Persona de Mediana Edad , Accidente Cerebrovascular Embólico/epidemiología , Accidente Cerebrovascular Embólico/etiología , Accidente Cerebrovascular Embólico/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Anciano de 80 o más Años , Factores de Riesgo , Estudios RetrospectivosRESUMEN
BACKGROUND: The association between hypothyroidism and stroke remains controversial and the association between hypothyroidism and stroke subtypes has not been satisfactorily researched. This study aimed to explore the causal effect of hypothyroidism on the risk of stroke and its subtypes by Mendelian randomization (MR) analysis. METHODS: Single nucleotide polymorphisms (SNPs) were selected from published genome-wide association studies (GWAS) meta-analysis as instrumental variables (IVs) for hypothyroidism. As outcomes, summary GWAS data for stroke and its subtypes were obtained from two other large GWAS meta-analyses, including any stroke (AS), any ischemic stroke (AIS), large vessel stroke (LAS), cardiogenic embolic stroke (CES), small vessel stroke (SVS), and intracranial hemorrhage (ICH). Univariate Mendelian randomization (UVMR) and multivariate Mendelian randomization (MVMR) were used to assess the causal effect of hypothyroidism on stroke and its subtypes. RESULTS: In UVMR, genetically predicted hypothyroidism was significantly associated with LAS (OR = 1.14, 95CI = 1.02-1.27) and SVS (OR = 1.14, 95CI = 1.04-1.25), but not with AS, AIS, CES, and ICH. The results of the MVMR showed that after adjusting for smoking, alcohol consumption, hypertension, diabetes, low-density lipoprotein cholesterol (LDL-c), and body mass index (BMI), the causal association between hypothyroidism and SVS remained significant, while the association between hypothyroidism and LAS became nonsignificant. CONCLUSION: Hypothyroidism is causally associated with risk for LAS and SVS, but not for other stroke subtypes. Hypothyroidism may be an independent risk factor for SVS, and vascular risk factors play an important role in hypothyroidism causing LAS.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Hipotiroidismo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Accidente Cerebrovascular , Humanos , Hipotiroidismo/genética , Hipotiroidismo/epidemiología , Hipotiroidismo/diagnóstico , Factores de Riesgo , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Medición de Riesgo , Fenotipo , Accidente Cerebrovascular Isquémico/genética , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/epidemiología , Femenino , Accidente Cerebrovascular Embólico/genética , Accidente Cerebrovascular Embólico/etiología , Accidente Cerebrovascular Embólico/diagnóstico , Accidente Cerebrovascular Embólico/epidemiología , MasculinoRESUMEN
BACKGROUND: Atrial cardiopathy(AC) and patent foramen ovale (PFO) are two etiologies of embolic strokes of undetermined source (ESUS). We aimed to explore the relationship between them in ESUS. METHODS: A total of 1146 participants were included from January 2019 to June 2022, which included the ESUS group and non-embolic stroke which includes LAA(large arterial atherosclerosis) + SAO(small artery occlusion) group. AC was defined as the presence of at least one of the following: PTFV1(P-wave terminal force in lead V1) > 4000 µV*ms in the electrocardiograms, NT-proBNP(N-terminal probrain natriuretic peptide) > 250 pg/mL in laboratory tests or LAD(left atrial diameter) > 3.8 cm for women and > 4.0 cm for men in cardiac ultrasound. The presence of PFO was assessed by transthoracic echocardiography, transcranial Doppler ultrasound, transesophageal echocardiography or cardiac MRI. PFO was considered pathogenic if the RoPE score was 7 to 10. RESULTS: The prevalence of AC and PFO was higher in the ESUS group than the LAA + SAO group. The prevalence of AC was lower in ESUS patients with pathogenic PFO (37.9%) than those without PFO (68.4%) and with incidental PFO (64.0%) (p = 0.006). The prevalence of pathogenic PFO was lower in ESUS patients with AC than those without AC (6.0% vs. 17.8%, p = 0.006). The AUC(area under the curve) of PTFV1 for predicting ESUS was 0.724 [95%CI (0.686-0.762), p < 0.05)], indicating that PTFV1 the most valuable AC biomarker. CONCLUSIONS: The prevalence of AC is inversely related to the prevalence of pathogenic PFO in ESUS patients. PTFV1 was the most valuable index to predict ESUS among the AC biomarkers.
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Accidente Cerebrovascular Embólico , Foramen Oval Permeable , Cardiopatías , Accidente Cerebrovascular , Masculino , Humanos , Femenino , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/epidemiología , Foramen Oval Permeable/diagnóstico , Foramen Oval Permeable/diagnóstico por imagen , Accidente Cerebrovascular Embólico/diagnóstico por imagen , Accidente Cerebrovascular Embólico/epidemiología , Cardiopatías/diagnóstico por imagen , Cardiopatías/epidemiología , Ecocardiografía , Factores de RiesgoRESUMEN
BACKGROUND: Stroke is a leading cause of death and disability worldwide. Atrial fibrillation (AF) is a common cause of stroke but may not be detectable at the time of stroke. We hypothesized that an AF polygenic risk score (PRS) can discriminate between cardioembolic stroke and noncardioembolic strokes. METHODS: We evaluated AF and stroke risk in 26 145 individuals of European descent from the Stroke Genetics Network case-control study. AF genetic risk was estimated using 3 recently developed PRS methods (LDpred-funct-inf, sBayesR, and PRS-CS) and 2 previously validated PRSs. We performed logistic regression of each AF PRS on AF status and separately cardioembolic stroke, adjusting for clinical risk score (CRS), imputation group, and principal components. We calculated model discrimination of AF and cardioembolic stroke using the concordance statistic (c-statistic) and compared c-statistics using 2000-iteration bootstrapping. We also assessed reclassification of cardioembolic stroke with the addition of PRS to either CRS or a modified CHA2DS2-VASc score alone. RESULTS: Each AF PRS was significantly associated with AF and with cardioembolic stroke after adjustment for CRS. Addition of each AF PRS significantly improved discrimination as compared with CRS alone (P<0.01). When combined with the CRS, both PRS-CS and LDpred scores discriminated both AF and cardioembolic stroke (c-statistic 0.84 for AF; 0.74 for cardioembolic stroke) better than 3 other PRS scores (P<0.01). Using PRS-CS PRS and CRS in combination resulted in more appropriate reclassification of stroke events as compared with CRS alone (event reclassification [net reclassification indices]+=14% [95% CI, 10%-18%]; nonevent reclassification [net reclassification indices]-=17% [95% CI, 15%-0.19%]) or the modified CHA2DS2-VASc score (net reclassification indices+=11% [95% CI, 7%-15%]; net reclassification indices-=14% [95% CI, 12%-16%]) alone. CONCLUSIONS: Addition of polygenic risk of AF to clinical risk factors modestly improves the discrimination of cardioembolic from noncardioembolic strokes, as well as reclassification of stroke subtype. Polygenic risk of AF may be a useful biomarker for identifying strokes caused by AF.
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Fibrilación Atrial , Accidente Cerebrovascular Embólico , Accidente Cerebrovascular , Humanos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/epidemiología , Fibrilación Atrial/genética , Estudios de Casos y Controles , Accidente Cerebrovascular Embólico/epidemiología , Accidente Cerebrovascular Embólico/genética , Accidente Cerebrovascular Embólico/complicaciones , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/genética , Factores de Riesgo , Medición de RiesgoRESUMEN
BACKGROUND: Up to 25% of embolic strokes occur in individuals without atrial fibrillation (AF) or other identifiable mechanisms. OBJECTIVES: This study aims to assess whether left atrial (LA) blood flow characteristics are associated with embolic brain infarcts, independently of AF. METHODS: The authors recruited 134 patients: 44 with a history of ischemic stroke and 90 with no history of stroke but CHA2DS2VASc score ≥1. Cardiac magnetic resonance (CMR) evaluated cardiac function and LA 4-dimensional flow parameters, including velocity and vorticity (a measure of rotational flow), and brain magnetic resonance imaging (MRI) was performed to detect large noncortical or cortical infarcts (LNCCIs) (likely embolic), or nonembolic lacunar infarcts. RESULTS: Patients (41% female; age 70 ± 9 years) had moderate stroke risk (median CHA2DS2VASc = 3, Q1-Q3: 2-4). Sixty-eight (51%) had diagnosed AF, of whom 58 (43%) were in AF during CMR. Thirty-nine (29%) had ≥1 LNCCI, 20 (15%) had ≥1 lacunar infarct without LNCCI, and 75 (56%) had no infarct. Lower LA vorticity was significantly associated with prevalent LNCCIs after adjustment for AF during CMR, history of AF, CHA2DS2VASc score, LA emptying fraction, LA indexed maximum volume, left ventricular ejection fraction, and indexed left ventricular mass (OR: 2.06 [95% CI: 1.08-3.92 per SD]; P = 0.027). By contrast, LA flow peak velocity was not significantly associated with LNCCIs (P = 0.21). No LA parameter was associated with lacunar infarcts (all P > 0.05). CONCLUSIONS: Reduced LA flow vorticity is significantly and independently associated with embolic brain infarcts. Imaging LA flow characteristics may aid identification of individuals who would benefit from anticoagulation for embolic stroke prevention, regardless of heart rhythm.
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Circulación Sanguínea , Infarto Encefálico , Accidente Cerebrovascular Embólico , Atrios Cardíacos , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fibrilación Atrial/epidemiología , Circulación Sanguínea/fisiología , Infarto Encefálico/epidemiología , Accidente Cerebrovascular Embólico/epidemiología , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/fisiopatología , Factores de RiesgoRESUMEN
The Hisayama Study is an ongoing epidemiological study of stroke, coronary artery disease (CAD), and other noncommunicable diseases in a general Japanese population established in 1961. According to the longitudinal data from the Hisayama Study, average levels of systolic blood pressure among hypertensive individuals have decreased with time since 1961. In contrast, the prevalence of metabolic risk factors such as obesity, hypercholesterolemia, and glucose intolerance has increased with time. The incidence rates of ischemic stroke in this population have declined significantly as a result of improvement in hypertension management, but the proportion of atherothrombotic brain infarction (ATBI) and embolic stroke among the total ischemic stroke cases have increased probably due to the increased prevalence of metabolic risk factors and the increased number of patients with atrial fibrillation (AF) with super-aging population. Therefore, a strategy to reduce the risks of ATBI and embolic stroke by comprehensive management of their risk factors is necessary.In this review, we first show the secular trends in the incidence of stroke and the prevalence of its risk factors using the data from the Hisayama Study. Then, the studies for the association of traditional risk factors with stroke development in the Hisayama Study are introduced. Finally, we developed risk prediction models to estimate the absolute risk of atherosclerotic cardiovascular disease (ASCVD; including ATBI and CAD) and AF, that may be used for the stratification of future risk of ATBI and AF-related stroke in clinical practice or health examination.
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Pueblos del Este de Asia , Síndrome Metabólico , Accidente Cerebrovascular , Anciano , Humanos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/epidemiología , Infarto Encefálico/epidemiología , Pueblos del Este de Asia/estadística & datos numéricos , Accidente Cerebrovascular Embólico/complicaciones , Accidente Cerebrovascular Embólico/epidemiología , Hipertensión/complicaciones , Hipertensión/epidemiología , Incidencia , Factores de Riesgo , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Japón/epidemiología , Síndrome Metabólico/epidemiologíaRESUMEN
INTRODUCTION: A patent foramen ovale (PFO) may coexist with other potential embolic sources (PESs) in patients with embolic stroke of undetermined source (ESUS), leading to difficulty in attributing the stroke to either the PFO or other PESs. We aimed to investigate the prevalence and predictors of concomitant PESs in ESUS patients with PFOs. METHODS: A retrospective cohort study was conducted in a tertiary stroke centre. Consecutive patients with ESUS and a concomitant PFO admitted between 2012 and 2021 were included in the study. Baseline characteristics and investigations as a part of stroke workup including echocardiographic and neuroimaging data were collected. PESs were adjudicated by 2 independent neurologists after reviewing the relevant workup. RESULTS: Out of 1,487 ESUS patients, a total of 309 patients who had a concomitant PFO with mean age of 48.8 ± 13.2 years were identified during the study period. The median Risk of Paradoxical Embolism (RoPE) score for the study cohort was 6 (IQR 5-7.5). Of the 309 patients, 154 (49.8%) only had PFO, 105 (34.0%) patients had 1 other PES, 34 (11.0%) had 2 PES, and 16 (5.2%) had 3 or more PES. The most common PESs were atrial cardiopathy (23.9%), left ventricular dysfunction (22.0%), and cardiac valve disease (12.9%). The presence of additional PESs was associated with age ≥60 years (p < 0.001), RoPE score ≤6 (p ≤0.001), and the presence of comorbidities including diabetes mellitus (p = 0.004), hypertension (p≤ 0.001), and ischaemic heart disease (p = 0.011). CONCLUSION: A large proportion of ESUS patients with PFOs had concomitant PESs. The presence of concomitant PESs was associated with older age and a lower RoPE score. Further, large cohort studies are warranted to investigate the significance of the PES and their overlap with PFOs in ESUS.
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Accidente Cerebrovascular Embólico , Embolia Paradójica , Foramen Oval Permeable , Accidente Cerebrovascular , Humanos , Adulto , Persona de Mediana Edad , Foramen Oval Permeable/complicaciones , Foramen Oval Permeable/diagnóstico por imagen , Foramen Oval Permeable/epidemiología , Accidente Cerebrovascular Embólico/epidemiología , Estudios Retrospectivos , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/complicaciones , Comorbilidad , Embolia Paradójica/diagnóstico por imagen , Embolia Paradójica/epidemiología , Embolia Paradójica/etiologíaRESUMEN
Background The potential causes or sources of embolic stroke of undetermined source (ESUS) vary. This study aimed to investigate the main cause of deep ESUS by evaluating nonstenotic intracranial atherosclerotic plaque. Methods and Results We retrospectively screened consecutive patients with unilateral anterior circulation ESUS. After excluding the patients with possible embolism from an extracranial artery such as aortic arch plaque, carotid plaque, and so on, the enrolled patients with ESUS were categorized into 2 groups: deep ESUS and cortical with/without deep ESUS. All patients underwent intracranial high-resolution magnetic resonance imaging to assess the characteristics of nonstenotic intracranial atherosclerotic plaque. Biomarkers of atrial cardiopathy (ie, P-wave terminal force in lead V1 on ECG, NT-proBNP [N-terminal pro-brain natriuretic peptide] and left atrial diameter) were collected. A total of 155 patients with ipsilateral nonstenotic intracranial atherosclerotic plaque were found, with 76 (49.0%) in deep ESUS and 79 (51.0%) in cortical with/without deep ESUS. We found more prevalent plaque in the M1 segment of the middle cerebral artery and the ostia of the perforator, with a smaller remodeling index plaque burden, and less frequent occurrence of complicated plaque in deep ESUS versus cortical with/without deep ESUS. Higher BNP (brain natriuretic peptide) levels and a higher prevalence of atrial cardiopathy in cortical with/without deep ESUS versus deep ESUS. Moreover, the discrimination of vulnerable plaque for predicting ESUS was significantly enhanced after adjusting for or further excluding patients with deep ESUS. Conclusions The current study provides the first high-resolution magnetic resonance imaging evidence that cortical with/without deep ESUS and deep ESUS should be 2 distinct entities and that atherosclerosis, not embolism, might be the main cause of deep ESUS.
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Aterosclerosis , Accidente Cerebrovascular Embólico , Embolia , Cardiopatías , Arteriosclerosis Intracraneal , Embolia Intracraneal , Placa Aterosclerótica , Accidente Cerebrovascular , Humanos , Embolia Intracraneal/diagnóstico por imagen , Embolia Intracraneal/epidemiología , Embolia Intracraneal/etiología , Accidente Cerebrovascular Embólico/epidemiología , Accidente Cerebrovascular Embólico/etiología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/complicaciones , Estudios Retrospectivos , Placa Aterosclerótica/complicaciones , Embolia/complicaciones , Imagen por Resonancia Magnética , Aterosclerosis/complicaciones , Aterosclerosis/diagnóstico por imagen , Cardiopatías/complicaciones , Arteriosclerosis Intracraneal/complicaciones , Arteriosclerosis Intracraneal/diagnóstico por imagen , Factores de RiesgoRESUMEN
BACKGROUND: Embolic stroke of undetermined source (ESUS) accounts for up to 25% of strokes. Understanding risk factors associated with ESUS is important in reducing stroke burden worldwide. However, ESUS patients are younger and present with fewer traditional risk factors. Significant global variation in ESUS populations also exists making the clinical picture of this type of stroke unclear. METHODS AND RESULTS: ESUS patients were pair matched for age, sex, and ethnicity with a group of all other strokes (both n = 331). Exploratory factor analysis was applied in both groups to 14 risk and clinical factors to identify latent factors. In ESUS patients, two latent factors emerged consisting primarily of heart-related variables such as left ventricular wall motion abnormalities, reduced ejection fraction, and increased left atrial volume index, as well as aortic arch atherosclerosis. This is in comparison to the all other strokes group, which was dominated by traditional stroke risk factors. CONCLUSIONS: Our findings support the existence of a unique pattern of risk factors specific to ESUS. We show that LVWMA and corresponding changes in left heart function are a potential source of emboli in these patients. In addition, the clustering of aortic arch atherosclerosis with left heart factors suggests a causal link. Through the application of exploratory factor analysis, this work contributes to a further understanding of stroke mechanisms in ESUS.
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Accidente Cerebrovascular Embólico , Embolia Intracraneal , Accidente Cerebrovascular , Accidente Cerebrovascular Embólico/complicaciones , Accidente Cerebrovascular Embólico/epidemiología , Análisis Factorial , Humanos , Embolia Intracraneal/complicaciones , Embolia Intracraneal/epidemiología , Factores de Riesgo , Accidente Cerebrovascular/complicacionesRESUMEN
AIMS: This study aimed at clarifying the incidence of recurrent stroke and its etiology in patients with embolic stroke of undetermined source (ESUS) and other stroke subtypes in both the acute and chronic periods. METHODS: A total of 645 patients who were admitted with acute ischemic stroke (IS) between March 2015 and August 2019 were enrolled. Among them, 511 patients with ESUS, cardioembolism (CE), large artery atherosclerosis (LAA), or small vessel disease (SVD) were analyzed in this study. After discharge, 391 patients who visited the outpatient clinic were followed up until August 2020. The outcome was stroke recurrence. RESULTS: In the acute admission, recurrence rates were 7.6%, 8.1%, 18.8%, and 2.2% in patients with ESUS, CE, LAA, and SVD, respectively, and there were significant differences between the groups. The subtype of recurrence was almost identical to that of the index stroke. In the outpatient clinic, the annual recurrence rates were 4.4%, 4.3%, 6.0%, and 2.9% in ESUS, CE, LAA, and SVD, respectively, and no difference was observed. Subtypes of recurrence in outpatients with ESUS included ESUS, intracerebral hemorrhage (ICH), and SVD. Patients with ESUS and SVD had a higher risk of ICH during follow-up. CONCLUSIONS: Although the risk of recurrence was comparable between patients with ESUS and CE and intermediate between patients with LAA and SVD, in the acute admission unit, the risk in outpatients was similar among all subtypes. ESUS was the most recurrent stroke subtype in outpatients with ESUS. The risk of hemorrhagic stroke was significant in patients with SVD and ESUS.
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Encéfalo/diagnóstico por imagen , Accidente Cerebrovascular/epidemiología , Anciano , Anciano de 80 o más Años , Accidente Cerebrovascular Embólico/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Japón/epidemiología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Accidente Cerebrovascular/diagnósticoRESUMEN
BACKGROUND: A proportion of patients with embolic stroke of undetermined source have silent atrial fibrillation (AF) or develop AF after the initial evaluation. Better understanding of the risk for development of AF is critical to implement optimal monitoring strategies with the goal of preventing recurrent stroke attributable to underlying AF. The RE-SPECT ESUS trial (Randomized, Double-Blind Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) provides an opportunity to assess predictors for developing AF and associated recurrent stroke. METHODS: RE-SPECT ESUS was a randomized, controlled trial (564 sites, 42 countries) assessing dabigatran versus aspirin for the prevention of recurrent stroke in patients with embolic stroke of undetermined source. Of 5390 patients enrolled and followed for a median of 19 months, 403 (7.5%) were found to develop AF reported as an adverse event or using cardiac monitoring per standard clinical care. Univariable and multivariable regression analyses were performed to define predictors of AF. RESULTS: In the multivariable model, older age (odds ratio for 10-year increase, 1.99 [95% CI, 1.78-2.23]; P<0.001), hypertension (odds ratio, 1.36 [95% CI, 1.03-1.79]; P=0.0304), diabetes (odds ratio, 0.74 [95% CI, 0.56-0.96]; P=0.022), and body mass index (odds ratio for 5-U increase, 1.29 [95% CI, 1.16-1.43]; P<0.001) were independent predictors of AF during the study. In a sensitivity analysis restricted to 1117 patients with baseline NT-proBNP (N-terminal prohormone of brain natriuretic peptide) measurements, only older age and higher NT-proBNP were significant independent predictors of AF. Performance of several published predictive models was assessed, including HAVOC (AF risk score based on hypertension, age ≥75 years, valvular heart disease, peripheral vascular disease, obesity, congestive heart failure, and coronary artery disease) and CHA2DS2-VASc (stroke risk score based on congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, previous stroke, transient ischemic attack or thromboembolism [doubled], vascular disease, age 65 to 74 years, and sex category [female]) scores, and higher scores were associated with higher rates of developing AF. CONCLUSIONS: Besides age, the most important variable, several other factors, including hypertension, higher body mass index, and lack of diabetes, are independent predictors of AF after embolic stroke of undetermined source. When baseline NT-proBNP was available, only older age and elevation of this biomarker were predictive of subsequent AF. Understanding who is at higher risk of developing AF will assist in identifying patients who may benefit from more intense, long-term cardiac monitoring. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.
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Aspirina/administración & dosificación , Fibrilación Atrial , Dabigatrán/administración & dosificación , Accidente Cerebrovascular Embólico , Modelos Cardiovasculares , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Administración Oral , Factores de Edad , Anciano , Fibrilación Atrial/sangre , Fibrilación Atrial/complicaciones , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/epidemiología , Índice de Masa Corporal , Método Doble Ciego , Accidente Cerebrovascular Embólico/sangre , Accidente Cerebrovascular Embólico/epidemiología , Accidente Cerebrovascular Embólico/etiología , Accidente Cerebrovascular Embólico/prevención & control , Femenino , Humanos , Hipertensión/sangre , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Recurrencia , Factores de RiesgoRESUMEN
This concise review of the epidemiology, pathophysiology, evaluation, acute management, and prevention of ischemic stroke targets internists, family practitioners, and emergency physicians who manage patient with stroke.
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Anticoagulantes/uso terapéutico , Accidente Cerebrovascular Isquémico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Trombectomía , Terapia Trombolítica , Accidente Cerebrovascular Embólico/epidemiología , Accidente Cerebrovascular Embólico/fisiopatología , Accidente Cerebrovascular Embólico/prevención & control , Accidente Cerebrovascular Embólico/terapia , Procedimientos Endovasculares , Humanos , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/fisiopatología , Accidente Cerebrovascular Isquémico/prevención & control , Accidente Cerebrovascular Isquémico/terapia , Accidente Cerebrovascular Trombótico/epidemiología , Accidente Cerebrovascular Trombótico/fisiopatología , Accidente Cerebrovascular Trombótico/prevención & control , Accidente Cerebrovascular Trombótico/terapiaRESUMEN
OBJECTIVES: This study assessed the temporal trends in the incidence of ischemic stroke among patients hospitalized with takotsubo cardiomyopathy (TCM) stratified by the subtypes of ischemic stroke (cardioembolic versus thrombotic). Predictors of each stroke subtype, the association with atrial fibrillation (AF), the occurrence of ventricular fibrillation/ventricular tachycardia (VF/VT), cardiogenic shock (CS), in-hospital mortality, length of stay (LOS), and total healthcare cost were also assessed. BACKGROUND: Ischemic stroke in TCM is thought to be primarily cardioembolic from left ventricular mural thromboembolism. Limited data are available on the incidence of thrombotic ischemic stroke in TCM. MATERIALS AND METHODS: We identified 27,970 patients hospitalized with the primary diagnosis of TCM from the 2008 to 2017 National Inpatient Sample, of which 751 (3%) developed ischemic stroke. Of those with ischemic stroke, 571 (76%) had thrombotic stroke while 180 (24%) had cardioembolic stroke. Cochrane armitage test was used to assess the incidence of thrombotic and cardioembolic strokes and multivariate regression was used to identify risk factors associated with each stroke subtype. We compared the incidence of AF, VF/VT, CS, LOS, in-hospital mortality and total cost between hospitalized patients with TCM alone to those with cardioembolic and thrombotic strokes. RESULTS: From 2008 - 2017, the incidence of thrombotic stroke (4.7%-9.5% (p< 0.0001) increased while it was unchanged for cardioembolic stroke (0.5%-0.7% P=0.5). In the multivariate regression, peripheral artery disease, prior history of stroke, and hyperlipidemia were significantly associated with thrombotic stroke, while CS, AF, and Asian race (compared to White race) were associated with cardioembolic stroke. Both cardioembolic and thrombotic strokes were associated with higher odds of IHM, AF, CS, longer LOS and increased cost. Trends in in-hospital mortality and the utilization of thrombolysis, cerebral angiography, and mechanical thrombectomy among patients with TCM and ischemic stroke were unchanged from 2008 to 2017. CONCLUSION: Among patients with TCM and ischemic stroke, thrombotic stroke was more common compared to cardioembolic stroke. Ischemic stroke was associated with poorer outcomes, including higher in-hospital mortality and increased healthcare resource utilization in TCM.
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Accidente Cerebrovascular Embólico/epidemiología , Hospitalización/tendencias , Cardiomiopatía de Takotsubo/epidemiología , Accidente Cerebrovascular Trombótico/epidemiología , Anciano , Anciano de 80 o más Años , Angiografía Cerebral/tendencias , Bases de Datos Factuales , Accidente Cerebrovascular Embólico/diagnóstico , Accidente Cerebrovascular Embólico/mortalidad , Accidente Cerebrovascular Embólico/terapia , Femenino , Costos de la Atención en Salud/tendencias , Mortalidad Hospitalaria/tendencias , Humanos , Incidencia , Pacientes Internos , Tiempo de Internación/tendencias , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Medición de Riesgo , Factores de Riesgo , Cardiomiopatía de Takotsubo/diagnóstico , Cardiomiopatía de Takotsubo/mortalidad , Cardiomiopatía de Takotsubo/terapia , Trombectomía/economía , Trombectomía/mortalidad , Trombectomía/tendencias , Accidente Cerebrovascular Trombótico/diagnóstico , Accidente Cerebrovascular Trombótico/mortalidad , Accidente Cerebrovascular Trombótico/terapia , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVES: Recurrent stroke remains a challenge though secondary prevention is initiated immediately post-stroke. Stroke subtype may determine the risk of recurrent stroke and require specific preventive measures. We aimed to identify subtype-specific stroke recurrence and associated risk factors over time. METHODS AND MATERIALS: A systematic review was performed using PubMed and Embase for studies including adults >18 years, first-ever ischemic stroke in population-based observational studies or registries, documented TOAST-criteria and minimum 1-year follow-up. Meta-analysis on stroke recurrence rate was performed. Final search: November 2019. RESULTS: The search retrieved 26 studies (between 1997 and 2019). Stroke recurrence rate ranged from 5.7% to 51.3%. Recurrent stroke was most frequent in large artery atherosclerosis (LAA) and cardioembolic (CE) stroke with recurrent stroke similar to index stroke subtype. We identified a lower recurrence rate for small vessel occlusion (SVO) stroke with recurrence frequently of another stroke subtype. Based on a meta-analysis the summary proportion recurrence rate of recurrent stroke in studies using TOAST-criteria = 0.12 and = 0.14 in studies using TOAST-like criteria. Hypertension, diabetes mellitus, atrial fibrillation previous transient ischemic attack, and high stroke severity were independent risk factors for recurrence. CONCLUSION: Stroke recurrence rates seem unchanged over time despite the use of secondary prevention. The highest recurrence rate is in LAA and CE stroke eliciting same subtype recurrent stroke. A lower recurrence rate is seen with SVO stroke with a more diverse recurrence pattern. Extensive workup is important in all stroke subtypes - including SVO stroke. Future research needs to identify better preventive treatment and improve compliance to risk factor prevention to reduce stroke recurrence.
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Enfermedades de los Pequeños Vasos Cerebrales/epidemiología , Accidente Cerebrovascular Embólico/epidemiología , Arteriosclerosis Intracraneal/epidemiología , Accidente Cerebrovascular Isquémico/epidemiología , Anciano , Anciano de 80 o más Años , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico , Enfermedades de los Pequeños Vasos Cerebrales/prevención & control , Comorbilidad , Accidente Cerebrovascular Embólico/diagnóstico , Accidente Cerebrovascular Embólico/prevención & control , Femenino , Humanos , Arteriosclerosis Intracraneal/diagnóstico , Arteriosclerosis Intracraneal/prevención & control , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/prevención & control , Masculino , Persona de Mediana Edad , Prevalencia , Pronóstico , Recurrencia , Medición de Riesgo , Factores de Riesgo , Prevención Secundaria , Factores de TiempoRESUMEN
Background We examined sex differences in nonstenotic carotid plaque composition in patients with embolic stroke of undetermined source (ESUS). Methods and Results Patients with anterior circulation ischemic stroke imaged with neck computed tomographic angiography who met criteria for ESUS or had atrial fibrillation were identified. Patients with atrial fibrillation were included as a negative control. Semiautomated plaque quantification software analyzed carotid artery bifurcations. Plaque subcomponent (calcium, intraplaque hemorrhage [IPH], and lipid rich necrotic core) volumes were compared by sex and in paired analyses of plaque ipsilateral versus contralateral to stroke. Multivariate linear regressions tested for associations. Ninety-four patients with ESUS (55% women) and 95 patients with atrial fibrillation (47% women) were identified. Men with ESUS showed significantly higher volumes of calcified plaque (63.9 versus 19.6 mm3, P<0.001), IPH (9.4 versus 3.3 mm3, P=0.008) and a IPH/lipid rich necrotic core ratio (0.17 versus 0.07, P=0.03) in carotid plaque ipsilateral to stroke side than women. The atrial fibrillation cohort showed no significant sex differences in plaque volumes ipsilateral to stroke. Multivariate analyses of the ESUS cohort showed male sex was associated with IPHipsi (ß=0.49; 95% CI, 0.11-0.87) and calciumipsi (ß=0.78; 95% CI, 0.33-1.23). Paired plaque analyses in men with ESUS showed significantly higher calcified plaque (63.9 versus 34.1 mm3, P=0.03) and a trend of higher IPHipsi (9.4 versus 7.5 mm3, P=0.73) and lipid rich necrotic coreipsi (59.0 versus 48.4 mm3, P=0.94) volumes. Conclusions Sex differences in carotid plaque composition in ESUS suggest the possibility of a differential contribution of nonstenosing carotid plaque as a stroke mechanism in men versus women.
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Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/epidemiología , Angiografía por Tomografía Computarizada/métodos , Accidente Cerebrovascular Embólico/epidemiología , Placa Aterosclerótica/epidemiología , Anciano , Anciano de 80 o más Años , Enfermedades de las Arterias Carótidas/complicaciones , Enfermedades de las Arterias Carótidas/diagnóstico , Accidente Cerebrovascular Embólico/etiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Placa Aterosclerótica/complicaciones , Placa Aterosclerótica/diagnóstico , Estudios Retrospectivos , Distribución por Sexo , Factores Sexuales , Estados Unidos/epidemiologíaRESUMEN
INTRODUCTION: Elevated troponin levels are found in a significant number of patients who are diagnosed with acute embolic stroke (AES) after first diagnosed atrial fibrillation (AF). These myocardial injuries, which are known as cardiocerebral infarction (CCI), are potentially caused by coronary embolism and correspond to simultaneous cardiac and cerebral embolisms. However, this severe condition remains poorly understood. In this prospective study, we aimed to investigate the prevalence and the cardiac magnetic resonance (CMR) characteristics of CCI. MATERIALS AND METHODS: Consecutive patients with first diagnosed AF hospitalized for AES in a neurovascular intensive care unit from 2019 to 2020 were included. Troponin Ic kinetic were measured <72 h, MRI and coronary angiography or CT scan were performed <7 days after admission. Patients with significant coronary lesions were excluded. RESULTS: During the study period, 1150 patients with strokes were hospitalized in the neurovascular intensive care unit (ICU). Of these patients, 955 had an ischemic stroke and 97 had a transient ischemic attack. Among the 44 patients with AES and with first diagnosed AF, 34 patients underwent CMR and CMR analysis identified 12 MI. A significant rise in troponin (>0.10 µg/L) was observed in 35% of the total population (12/34 patients). More specifically, a rise was seen in 23% of the AES without MI group, 58% of the AES with MI. In addition, coronary embolism was identified in 3 patients who underwent coronary angiography (3/12) and MI was often (30%) localized in infero-latero-medial and infero-apical segments. Most AES were localized in the superficial sylvian territory. CONCLUSION: We found a high prevalence of CMR-confirmed double embolization sites in the acute phase of an embolic stroke. Further studies are required to better characterize the pathophysiology, clinical course and prognostic value of CCI. Moreover, optimal management strategies, including antiplatelet therapy, remain to be determined.
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Fibrilación Atrial/diagnóstico , Electrocardiografía , Accidente Cerebrovascular Embólico/diagnóstico por imagen , Imagen por Resonancia Cinemagnética , Infarto del Miocardio/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/epidemiología , Biomarcadores/sangre , Angiografía por Tomografía Computarizada , Angiografía Coronaria , Accidente Cerebrovascular Embólico/epidemiología , Femenino , Francia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Valor Predictivo de las Pruebas , Prevalencia , Estudios Prospectivos , Troponina I/sangre , Regulación hacia ArribaRESUMEN
OBJECTIVE: Prevention of recurrent stroke in patients with embolic stroke of undetermined source (ESUS) is challenging. The advent of safer anticoagulation in the form of direct oral anticoagulants (DOACs) has prompted exploration of prophylactic anticoagulation for all ESUS patients, rather than anticoagulating just those with documented atrial fibrillation (AF). However, recent trials have failed to demonstrate a clinical benefit, while observing increased bleeding. We modeled the economic impact of anticoagulating ESUS patients without documented AF across multiple geographies. METHODS: CRYSTAL-AF trial data were used to assess ischaemic stroke event rates in ESUS patients confirmed AF-free after long-term monitoring. Anticipated bleeding event rates (including both minor and major bleeds) with aspirin, dabigatran 150 mg, and rivaroxaban 20 mg were sourced from published meta-analyses, whilst a 30% ischaemic stroke reduction for both DOACs was assumed. Cost data for clinical events and pharmaceuticals were collected from the local payer perspective. RESULTS: Compared with aspirin, dabigatran and rivaroxaban resulted in 17.9 and 29.9 additional bleeding events per 100 patients over a patient's lifetime, respectively. Despite incorporating into our model the proposed 30% reduction in ischaemic stroke risk, both DOACs were cost-additive over patient lifetime, as the costs of bleeding events and pharmaceuticals outweighed cost savings associated with the reduction in ischaemic strokes. DOACs added £5953-£7018 per patient (UK), 6683-7368 (Netherlands), 4933-9378 (Spain), AUD$5353-6539 (Australia) and $26,768-$32,259 (US) of payer cost depending on the agent prescribed. Additionally, in the U.S. patient pharmacy co-payments ranged from $2468-$12,844 depending on agent and patient plan. In all settings, cost-savings could not be demonstrated even when the modelling assumed 100% protection from recurrent ischaemic strokes, due to the very low underlying risk of recurrent ischaemic stroke in this population (1.27 per 100 patient-years). CONCLUSIONS: Anticoagulation of non-AF patients may cause excess bleeds and add substantial costs for uncertain benefits, suggesting a personalised approach to anticoagulation in ESUS patients.