Mechanisms of Hypercoagulability Driving Stroke Risk in Obesity: A Mendelian Randomization Study.

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.

Embolic Stroke of Undetermined Source: New Data and New Controversies on Cardiac Monitoring and Anticoagulation.

Embolic strokes of undetermined source (ESUS) represent 9%-25% of all ischemic strokes. Based on the suspicion that a large proportion of cardioembolic sources remain undetected among embolic stroke of undetermined source patients, it has been hypothesized that a universal approach of anticoagulation would be better than aspirin for preventing recurrent strokes. However, 4 randomized controlled trials (RCTs), with different degrees of patient selection, failed to confirm this hypothesis. In parallel, several RCTs consistently demonstrated that prolonged cardiac monitoring increased atrial fibrillation detection and anticoagulation initiation compared with usual care in patients with ESUS, and later in individuals with ischemic stroke of known cause (e.g., large or small vessel disease). However, none of these trials or subsequent meta-analyses of all available RCTs have shown a reduction in stroke recurrence associated with the use of prolonged cardiac monitoring. In this article, we review the clinical and research implications of recent RCTs of antithrombotic therapy in patients with ESUS and in high-risk populations with and without stroke, with device-detected asymptomatic atrial fibrillation.

Prognosis of ischemic stroke patients with both aortic atheroma and cardioembolic sources.

This study aimed to investigate the relationship between complex aortic plaque (CAP) and short-term as well as long-term outcomes following cardioembolic stroke. CAP is a known risk factor for occurrence and recurrence of ischemic stroke. However, the association of CAP on cardioembolic stroke remains unclear. This was retrospective study using prospective cohort of consecutive patients with cardioembolic stroke who underwent transesophageal echocardiography. The functional outcome was evaluated using the modified Rankin Scale score at 3 months, and long-term outcomes were assessed by recurrence of ischemic stroke and occurrence of major adverse cardiovascular events (MACE). Among 759 patients with cardioembolic stroke, 91 (12.0%) had CAP. Early ischemic stroke recurrence within 3 months was associated with CAP (p = 0.025), whereas CAP was not associated with functional outcome at 3 months (odd ratio 1.01, 95% confidence interval [CI] 0.57-1.84, p = 0.973). During a median follow-up of 3.02 years, CAP was significantly associated with ischemic stroke recurrence (hazard ratio = 2.68, 95% CI 1.48-4.88, p = 0.001) and MACE occurrence (hazard ratio = 1.61, 95% CI 1.03-2.51, p = 0.039). In conclusion, CAP was associated with early ischemic stroke recurrence and poor long-term outcomes in patients with cardioembolic stroke. It might be helpful to consider transesophageal echocardiography for patients with cardioembolic stroke to identify CAP.

Increased plasma levels of N-terminal pro-B-type natriuretic peptide as biomarker for the diagnosis of cardioembolic ischaemic stroke.

BACKGROUND: Despite comprehensive study, the aetiology of stroke is not identified in 35% of cases. AIMS: We conducted a study to assess the diagnostic capacity of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the identification of ischaemic stroke of cardioembolic origin. The secondary purpose of the study was to evaluate the prognostic value of NT-proBNP for predicting 90-day all-cause mortality. METHODS: We designed a prospective observational study including patients hospitalised due to stroke between March 2019 and March 2020. Blood samples were collected on admission to the emergency department and serum NT-proBNP levels were determined. Statistical analysis was performed using a bivariate logistic regression model and receiver operating characteristic (ROC) and Kaplan-Meier curves. Statistical significance was established at p<.05. RESULTS: The study included 207 patients with first ischaemic stroke. Plasma NT-proBNP levels were significantly higher (p<.001) in the cardioembolic stroke group (2069pg/mL±488.5). ROC curves showed that NT-proBNP>499pg/mL was the optimum value for diagnosing cardioembolic ischaemic stroke (sensitivity, 82%; specificity, 80%). Moreover, plasma NT-proBNP levels>499pg/mL were independently associated with cardioembolic stroke (OR: 9.881; p=.001). Finally, NT-proBNP>1500pg/mL was useful for predicting 90-day mortality (sensitivity, 70%; specificity, 93%). CONCLUSIONS: NT-proBNP was independently associated with cardioembolic stroke and should be quantified in blood tests within 24h of stroke onset. High plasma levels (>499pg/mL) may indicate an underlying cardioembolic cause, which should be further studied, while NT-proBNP >1500pg/mL was associated with increased 90-day mortality.

Dual Antiplatelet Therapy After Embolic Stroke of Undetermined Source: A Subgroup Analysis of the CHANCE-2 Trial.

BACKGROUND: The atherosclerotic sources of embolism are a significant contributor to embolic stroke of undetermined source (ESUS). However, there is limited evidence for the efficacy of intensive dual antiplatelet therapy for ESUS. We conducted an investigation to determine whether gene-directed dual antiplatelet therapy could reduce the risk of recurrent stroke in patients with ESUS. METHODS: CHANCE-2 (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events-II) was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial that objectively compared ticagrelor plus aspirin and clopidogrel plus aspirin in patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles in China. All study participants were classified into ESUS and non-ESUS groups for the prespecified exploratory analysis. Cox proportional hazards models were used to assess the interaction of the state of ESUS with the effects of dual antiplatelet therapy with ticagrelor-aspirin versus clopidogrel-aspirin, adjusting for sociodemographic and clinical factors. RESULTS: The subgroup analysis comprised 5796 participants (90.4% of the total 6412 participants) in the CHANCE-2 trial, with a median age of 64.9 years (range, 57.0-71.4 years), of whom 1964 (33.9%) were female. These participants underwent diffusion-weighted imaging as part of the study protocol. After systematic evaluation, 15.2% of patients (881/5796) were deemed to have ESUS. The incidence of stroke recurrence in patients with ESUS was found to be 5.6% in the ticagrelor-aspirin group and 9.2% in the clopidogrel-aspirin group (hazard ratio, 0.57 [95% CI, 0.33-0.99]; P=0.04). In patients without ESUS, the respective incidence rates were 5.6% and 7.5% (hazard ratio, 0.72 [95% CI, 0.58-0.90]; P<0.01). The P value was 0.56 for the treatment × ESUS status interaction effect. CONCLUSIONS: In this prespecified exploratory analysis, ticagrelor with aspirin was superior to clopidogrel with aspirin for preventing stroke at 90 days in patients with acute ischemic stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles and were classified as ESUS. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04078737.

Cardioembolic Stroke: Past Advancements, Current Challenges, and Future Directions.

Cardioembolic stroke accounts for over 20% of ischemic strokes and is associated with worse outcomes than other types of strokes. Atrial fibrillation (AF) is the most common risk factor for cardioembolic stroke. In this narrative review, we present an update about cardioembolic stroke mainly related to AF and atrial cardiopathy. Direct oral anticoagulants (DOACs) have revolutionized stroke prevention in patients with AF; however, their efficacy in preventing recurrent embolic stroke of unknown source remains uncertain. Various cardiac monitoring methods are used to detect AF, which is crucial for preventing stroke recurrence. DOACs are preferred over warfarin for AF-related stroke prevention; however, the timing of initiation after acute ischemic stroke is debated. Resuming anticoagulation after intracerebral hemorrhage in AF patients requires careful assessment of the risks. While catheter ablation may reduce the incidence of cardiovascular events, its effect on stroke prevention is unclear, especially in heart failure patients. Atrial cardiopathy is the emerging cause of embolic stroke of unknown source, which indicates atrial structural and functional disorders that can precede AF. Future research should focus on refining stroke risk prediction models, optimizing AF detection, understanding the roles of ablation and anticoagulation in stroke prevention, and establishing atrial cardiopathy as a therapeutic target, which could significantly reduce the burden of stroke.

Cardioembolic Stroke.

Cardioembolism accounts globally for around 25% of ischemic strokes and is more often associated with higher rates of morbidity and mortality. Potential sources of cardioembolism into the intracranial circulation include paradoxic embolism, dysrhythmias, structural heart disease, and valvular heart disease. To identify the etiology of a patient's ischemic stroke, thorough investigation of the intracardiac structures, assessment of dysrhythmias, and consideration of high-risk events such as cardiac surgery are crucial. Treatment after cardioembolic stroke can be personalized based on the underlying cardioembolic source to minimize the risk of recurrent cerebral ischemic events.

Research progress on genetics in cardioembolic stroke.

Cardioembolic stroke, characterized by severe illness, poor prognosis, and high recurrence rate, is one of the important causes of ischemic stroke. In the field of genetic research, numerous genes associated with cardioembolic stroke have been identified, and their potential in predicting disease risk and evaluating risk factors has been progressively explored. Here, we provide an overview of the latest advancements in genetics for cardioembolic stroke, including genome-wide association studies, copy number variation studies, whole-genome sequencing studies. Furthermore, we also summarize the application of genetic datasets in polygenic risk score and Mendelian randomization. The aim of this overview is to provide insights and references from multiple perspectives for future investigations on the genetic information for cardioembolic stroke.

The role of the D-dimer to fibrinogen ratio in the classification of cardioembolism and atherosclerotic stroke.

BACKGROUND: The D-dimer-to-fibrinogen ratio (DFR) is a good indicator of thrombus activity in thrombotic diseases, but its clinical role in acute ischaemic stroke (AIS) patients with different etiologies has not been studied. We evaluated the diagnostic value of the DFR for different subtypes of AIS. METHODS: We conducted a single-center retrospective study of 269 patients with AIS who were referred to our stroke center within 4.5 h from Jan 2017 to Oct 2019. Coagulation data including DFRs were compared among the different stroke subtypes, and a separate retrospective validation sample was utilized to evaluate the prediction efficiency of the DFR for subtype diagnosis. RESULTS: A higher DFR was observed in patients with cardioembolism than in those with large artery atherosclerosis (LAA) (odds ratio (OR) per 0.1 increase of the DFR: 1.49 [1.01-2.18]) after we adjusted for vascular risk factors. The diagnostic value of the DFR for detecting cardioembolism (AUC = 0.722, 95 % CI = 0.623-0.820) exceeded that of isolated D-dimer or fibrinogen. The validation sample (n = 117) further supported the notion that a diagnosis of cardioembolism was more common in patients with a DFR > 0.11 (multivariable risk ratio = 3.11[1.33-7.31], P = 0.009). CONCLUSION: High DFRs were associated with cardioembolism in patients with AIS. The utilization of DFR can be beneficial for distinguishing a cardiac embolic source from atherosclerotic stroke.

Silent brain infarctions in patients with acute cardioembolic stroke.

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.

Hypothyroidism's effect on stroke limited to specific subtypes: A Mendelian randomization study.

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.

MRI in the Evaluation of Cryptogenic Stroke and Embolic Stroke of Undetermined Source.

Cryptogenic stroke refers to a stroke of undetermined etiology. It accounts for approximately one-fifth of ischemic strokes and has a higher prevalence in younger patients. Embolic stroke of undetermined source (ESUS) refers to a subgroup of patients with nonlacunar cryptogenic strokes in whom embolism is the suspected stroke mechanism. Under the classifications of cryptogenic stroke or ESUS, there is wide heterogeneity in possible stroke mechanisms. In the absence of a confirmed stroke etiology, there is no established treatment for secondary prevention of stroke in patients experiencing cryptogenic stroke or ESUS, despite several clinical trials, leaving physicians with a clinical dilemma. Both conventional and advanced MRI techniques are available in clinical practice to identify differentiating features and stroke patterns and to determine or infer the underlying etiologic cause, such as atherosclerotic plaques and cardiogenic or paradoxical embolism due to occult pelvic venous thrombi. The aim of this review is to highlight the diagnostic utility of various MRI techniques in patients with cryptogenic stroke or ESUS. Future trends in technological advancement for promoting the adoption of MRI in such a special clinical application are also discussed.

Long-term outcomes of patients with embolic stroke of undetermined source according to subtype.

The prognosis of patients with embolic stroke of undetermined source (ESUS) may vary according to the underlying cause. Therefore, we aimed to divide ESUS into subtypes and assess the long-term outcomes. Consecutive patients with acute ischemic stroke who underwent a comprehensive workup, including transesophageal echocardiography and prolonged electrocardiography monitoring, were enrolled. We classified ESUS into minor cardioembolic (CE) ESUS, arteriogenic ESUS, two or more causes ESUS, and no cause ESUS. Arteriogenic ESUS was sub-classified into complex aortic plaque (CAP) ESUS and non-stenotic (< 50%) relevant artery plaque (NAP) ESUS. A total of 775 patients were enrolled. During 1286 ± 748 days follow-up, 116 major adverse cardiovascular events (MACE) occurred (4.2 events/100 patient-years). Among the ESUS subtypes, CAP ESUS was associated with the highest MACE frequency (9.7/100 patient-years, p = 0.021). Cox regression analyses showed that CAP ESUS was associated with MACE (hazard ratio 2.466, 95% confidence interval 1.305-4.660) and any stroke recurrence (hazard ratio 2.470, 95% confidence interval, 1.108-5.508). The prognosis of ESUS varies according to the subtype, with CAP ESUS having the worst prognosis. Categorizing ESUS into subtypes could improve patient care and refine clinical trials.

A novel NODAL variant in a young embolic stroke patient with visceral heterotaxy.

BACKGROUND: Ischemic stroke in young adults can be caused by a variety of etiologies including the monogenic disorders. Visceral heterotaxy is a condition caused by abnormal left-right determinations during embryonic development. We aimed to determine the cause of a young ischemic stroke patient with visceral heterotaxy. CASE PRESENTATION: We performed neurological, radiological, and genetic evaluations in a 17-year-old male patient presenting ischemic stroke and visceral heterotaxy to determine the underlying cause of this rare disease combination. Brain magnetic resonance imaging (MRI) showed evidence of embolic stroke, abdominal computed tomography (CT) showed visceral heterotaxy, and echocardiogram showed cardiac anomaly with right-to-left-shunt (RLS). Whole genome sequencing (WGS) revealed a heterozygous missense variant (NM_018055.5: c.1016 T > C, p.(Met339Val)) in the NODAL gene, which is essential to the determination of the left-right body axis. CONCLUSIONS: Our study highlights the importance of evaluating genetic etiology in young ischemic stroke and the need for stroke risk management in visceral heterotaxy patients with RLS. To the best of our knowledge, we report the first genetically-confirmed case of visceral heterotaxy with young embolic stroke reported to date.

Clinical practice of continuous rhythm monitoring after embolic stroke of undetermined source.

AIMS: Embolic stroke of undetermined source (ESUS) accounts for up to 20% of ischemic strokes annually. Undetected atrial fibrillation (AF) is one important potential underlying cause. For AF, oral anticoagulation has evolved as the most preferable means of secondary stroke prevention. To detect unrecognized paroxysmal AF, long-term ECG monitoring is required, and implantable cardiac monitors (ICM) appear most suitable. Yet, ICMs are particularly costly, implantation is invasive, and remote monitoring places a personnel burden on health care providers. Here, we use data from a large cohort of ESUS patients to systematically analyze the effort of ICM remote monitoring for AF diagnosis and the strain on health care providers. METHODS AND RESULTS: From a prospective, single-center, observational ESUS registry, we analyzed all ICM-equipped patients post-ESUS (n = 172) between January 1st, 2018, and December 31st, 2019. Through January 2nd, 2023, 48 patients (27.9%) were diagnosed with AF by ICM remote monitoring. During follow-up, a total of 29,180 remote monitoring episodes were transmitted, of which 17,742 were alarms for AF. A systematic estimation of workload revealed that on average, 20.3 trained physician workhours are required to diagnose one patient with AF. CONCLUSION: ICM remote monitoring is useful to diagnose AF in cohort of post-ESUS patients. However, the number of ICM alarms is high, even in a cohort at known high risk of AF and in whom AF detection is therapeutically consequential. Improved automated event classification, clear recommendations for ICM interrogation after AF diagnosis, and a careful patient selection for ICM monitoring are warranted.

Embolic strokes of undetermined source: a clinical consensus statement of the ESC Council on Stroke, the European Association of Cardiovascular Imaging and the European Heart Rhythm Association of the ESC.

One in six ischaemic stroke patients has an embolic stroke of undetermined source (ESUS), defined as a stroke with unclear aetiology despite recommended diagnostic evaluation. The overall cardiovascular risk of ESUS is high and it is important to optimize strategies to prevent recurrent stroke and other cardiovascular events. The aim of clinicians when confronted with a patient not only with ESUS but also with any other medical condition of unclear aetiology is to identify the actual cause amongst a list of potential differential diagnoses, in order to optimize secondary prevention. However, specifically in ESUS, this may be challenging as multiple potential thromboembolic sources frequently coexist. Also, it can be delusively reassuring because despite the implementation of specific treatments for the individual pathology presumed to be the actual thromboembolic source, patients can still be vulnerable to stroke and other cardiovascular events caused by other pathologies already identified during the index diagnostic evaluation but whose thromboembolic potential was underestimated. Therefore, rather than trying to presume which particular mechanism is the actual embolic source in an ESUS patient, it is important to assess the overall thromboembolic risk of the patient through synthesis of the individual risks linked to all pathologies present, regardless if presumed causally associated or not. In this paper, a multi-disciplinary panel of clinicians/researchers from various backgrounds of expertise and specialties (cardiology, internal medicine, neurology, radiology and vascular surgery) proposes a comprehensive multi-dimensional assessment of the overall thromboembolic risk in ESUS patients through the composition of individual risks associated with all prevalent pathologies.