High-risk carotid plaques and incident ischemic stroke in patients with atrial fibrillation in the Cardiovascular Health Study.

BACKGROUND AND PURPOSE: Whether carotid artery disease could improve stroke risk stratification tools in patients with atrial fibrillation (AF) remains uncertain. This study was undertaken to investigate the risk of ischemic stroke associated with occlusive and nonocclusive carotid atherosclerotic disease in patients with AF in the prospective population-based Cardiovascular Health Study. METHODS: We included participants aged ≥65 years with AF. We used multivariable Cox regression analysis to explore the risk of ischemic stroke associated with the percentage of carotid stenosis, plaque irregularity, echogenicity, and vulnerability (markedly irregular, ulcerated, or hypoechoic plaques). RESULTS: A total of 1398 participants were included (55.2% female, 61.7% aged 65-74 years). The maximum carotid stenosis was <50%, 50%-99%, and 100% in 94.5%, 5%, and 0.5% of participants, respectively. High-risk plaques based on echogenicity and plaque irregularity were found in 25.6% and 8.9% of participants, respectively. After a median follow-up of 10.9 years (interquartile range = 7.5-15.6), 298 ischemic strokes were recorded. There was no difference in the incidence of ischemic stroke according to the degree of carotid artery stenosis (p = 0.44), plaque echogenicity (low vs. high risk, p = 0.68), plaque irregularity (low vs. high risk, p = 0.55), and plaque vulnerability (p = 0.86). The CHA2DS2-VASc score was associated with an increased risk of ischemic stroke (adjusted hazard ratio = 1.28, 95% confidence interval = 1.18-1.40, p < 0.001). Both maximum grade of stenosis and plaque vulnerability were not associated with incident ischemic stroke (all p > 0.05). CONCLUSIONS: Neither the degree of carotid stenosis nor the presence of vulnerable plaques was associated with incident ischemic stroke in this cohort of individuals with AF. This suggests that carotid disease was probably not a significant contributor to ischemic stroke in this population.

Bridging the language gap - A call for the wider use of Human phenotype ontology by non-geneticist clinicians when requesting genomic tests.

Advances in genomic technology including the development of next-generation sequencing (NGS) have enabled the identification of thousands of variations at a time, allowing the discovery of novel genetic diseases. Given the volume of data generated by these investigations, attention is drawn towards reporting relevant clinical features by clinicians to guide the diagnosis and management of their patients. The Human Phenotype Ontology (HPO) developed in 2008, revolutionized the semantic vocabulary of phenotypic descriptions in genomic medicine allowing researchers, laboratories and clinical geneticists to better understand each other. In this era of personalized medicine where genetic tests are becoming more accessible, non-geneticist clinicians are expected to be more involved than ever in the process of ordering genetic tests and interpreting genetic reports. It is therefore essential that they understand and adequately apply HPO nomenclature to integrate the patient care chain and seize the opportunity offered by this tailored language. The current article highlights the importance of using HPO vocabularies in clinical practice and advocates for its wider use by non-geneticist clinicians. Correct use of HPO will reduce misunderstandings between healthcare professionals and ultimately improve the healthcare system.

Association of Thrombin Generation With Leukocyte Inflammatory Profile in Patients With Acute Ischemic Stroke.

BACKGROUND AND OBJECTIVES: Thrombosis is central to the pathogenesis of acute ischemic stroke, with higher thrombin generation being associated with increased stroke risk. The immune system may contribute to thrombin generation in stroke and thus may offer novel strategies for stroke prevention. This study addresses the research question regarding the relationship of thrombin generation to leukocyte gene expression in patients with acute ischemic stroke. METHODS: We isolated RNA from whole blood and examined the relationship to thrombin generation capacity in patients with acute ischemic stroke. Due to its effects on thrombin generation, patients on anticoagulants were excluded from the study. The relationship of gene expression with peak thrombin was evaluated by analysis of covariance across peak thrombin quartiles adjusted for sex and age. RESULTS: In 97 patients with acute ischemic stroke, peak thrombin was variable, ranging from 252.0 to 752.4 nM. Increased peak thrombin was associated with differences in thromboinflammatory leukocyte gene expression, including a decrease in ADAM metallopeptidase with thrombospondin type 1 motif 13 and an increase in nuclear factor κB (NF-κB)-activating protein, protein disulfide isomerase family A member 5, and tissue factor pathway inhibitor 2. Pathways associated with peak thrombin included interleukin 6 signaling, thrombin signaling, and NF-κB signaling. A linear discriminant analysis model summarizing the immune activation associated with peak thrombin in a first cohort of stroke could distinguish patients with low peak thrombin from high peak thrombin in a second cohort of 112 patients with acute ischemic stroke. DISCUSSION: The identified genes and pathways support a role of the immune system contributing to thrombus formation in patients with stroke. These may have relevance to antithrombotic strategies for stroke prevention.

Interleukin-6 Predicts Carotid Plaque Severity, Vulnerability, and Progression.

BACKGROUND: IL-6 (interleukin-6) has important roles in atherosclerosis pathophysiology. To determine if anti-IL-6 therapy warrants evaluation as an adjuvant stroke prevention strategy in patients with carotid atherosclerosis, we tested whether circulating IL-6 levels predict carotid plaque severity, vulnerability, and progression in the prospective population-based CHS (Cardiovascular Health Study). METHODS: Duplex carotid ultrasound was performed at baseline and 5 years. Baseline plaque severity was scored 0 to 5 based on North American Symptomatic Carotid Endarterectomy Trial grade of stenosis. Plaque vulnerability at baseline was the presence of markedly irregular, ulcerated, or echolucent plaques. Plaque progression at 5 years was a ≥1 point increase in stenosis severity. The relationship of baseline plasma IL-6 levels with plaque characteristics was modeled using multivariable linear (severity) or logistic (vulnerability and progression) regression. Risk factors of atherosclerosis were included as independent variables. Stepwise backward elimination was used with P>0.05 for variable removal. To assess model stability, we computed the E-value or minimum strength of association (odds ratio scale) that unmeasured confounders must have with log IL-6 and the outcome to suppress the association. We performed internal validation with 100 bootstrap samples. RESULTS: There were 4334 participants with complete data (58.9% women, mean age: 72.7±5.1 years), including 1267 (29.2%) with vulnerable plaque and 1474 (34.0%) with plaque progression. Log IL-6 predicted plaque severity (ß=0.09, P=1.3×10-3), vulnerability (OR, 1.21 [95% CI, 1.05-1.40]; P=7.4×10-3, E-value=1.71), and progression (OR, 1.44 [95% CI, 1.23-1.69], P=9.1×10-6, E-value 2.24). In participants with >50% predicted probability of progression, mean log IL-6 was 0.54 corresponding to 2.0 pg/mL. Dichotomizing IL-6 levels did not affect the performance of prediction models. CONCLUSIONS: Circulating IL-6 predicts carotid plaque severity, vulnerability, and progression. The 2.0 pg/mL cutoff could facilitate the selection of individuals that would benefit from anti-IL-6 drugs for stroke prevention.

Trends in Stroke Presentations before and during the COVID-19 Pandemic: A Meta-Analysis.

BACKGROUND AND PURPOSE: There are reports of decline in the rates of acute emergency presentations during coronavirus disease 2019 (COVID-19) pandemic including stroke. We performed a meta-analysis of the impact of COVID-19 pandemic on rates of stroke presentations and on rates of reperfusion therapy. METHODS: Following the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines, we systematically searched the literature for studies reporting changes in stroke presentations and treatment rates before and during the COVID-19 pandemic. Aggregated data were pooled using meta-analysis with random-effect models. RESULTS: We identified 37 observational studies (n=375,657). Pooled analysis showed decline in rates of all strokes (26.0%; 95% confidence interval [CI], 22.4 to 29.7) and its subtypes; ischemic (25.3%; 95% CI, 21.0 to 30.0), hemorrhagic (27.6%; 95% CI, 20.4 to 35.5), transient ischemic attacks (41.9%; 95% CI, 34.8 to 49.3), and stroke mimics (45.6%; 95% CI, 33.5 to 58.0) during months of pandemic compared with the pre-pandemic period. The decline was most evident for mild symptoms (40% mild vs. 25%-29% moderate/severe). Although rates of intravenous thrombolytic (IVT) and endovascular thrombectomy (EVT) decreased during pandemic, the likelihood of being treated with IVT and EVT did not differ between the two periods, both in primary and in comprehensive stroke centers (odds ratio [OR], 1.08; 95% CI, 0.94 to 1.24 and OR, 0.95; 95% CI, 0.83 to 1.09, respectively). CONCLUSIONS: Rates of all strokes types decreased significantly during pandemic. It is of paramount importance that general population should be educated to seek medical care immediately for stroke-like symptoms during COVID-19 pandemic. Whether delay in initiation of secondary prevention would affect eventual stroke outcomes in the long run needs further study.

Addition of direct oral anticoagulants to the World Health Organization model list of essential medicines for the treatment of atrial fibrillation: An African perspective.

Atrial fibrillation (AF) is a major cause of adverse cardiovascular outcomes, and its prevalence is fast rising in Africa. The advent of direct oral anticoagulants (DOACs) has been a major revolution for the prevention of AF-related stroke and systemic embolism given the significant advantage over vitamin K antagonists in terms of both efficacy, safety, and adherence. However, due to their high cost, equitable access to DOACs has been a challenge, especially in low- and middle-income countries. Therefore, the recent addition of DOACs to the 21st WHO list of essential medicines comes as good news. African governments should take this opportunity to scale up the accessibility to DOACs for African patients with AF. This could be achieved through advocacy, appropriate training of health professionals, task shifting, patient education, strategic partnership to increase availability and quality of low-cost generic drugs, and appropriate medico-economic studies.

Association of CT-Based Hypoperfusion Index With Ischemic Core Enlargement in Patients With Medium and Large Vessel Stroke.

BACKGROUND AND OBJECTIVES: The rate of infarct core progression in patients with acute ischemic stroke is variable and affects outcome of reperfusion therapy. We evaluated the hypoperfusion index (HI) to estimate the initial rate of core progression in patients with medium vessel occlusion (MeVO) compared to large vessel occlusion (LVO) stroke and within a larger time frame since stroke onset. METHODS: Core progression was assessed in 106 patients with acute stroke and CT perfusion. Using reperfusion trial core time criteria, fast progressors had core >70 mL within 6 hours of stroke onset and slow progressors had core ≤70 mL, mismatch ≥15 mL, and mismatch to core ratio ≥1.8 within 6 to 24 hours. The relationship between HI and infarct core progression (core/time) was examined using receiver operating characteristics to determine optimal HI cutoff. The HI cutoff was then tested in the overall cohort, compared between MeVO and LVO, and evaluated in patients up to 24 hours from stroke onset to differentiate fast from slow rate of core progression. HI threshold was assessed in a second independent cohort of 110 patients with acute ischemic stroke. RESULTS: In 106 patients with acute stroke, 6.6% were fast progressors, 27.4% were slow progressors, and 66% were not classified as fast or slow progressor by reperfusion trial core time criteria. HI >0.5 was associated with fast progression and able to distinguish fast from slow progressors (area under the curve [AUC] 0.94; 95% confidence interval [CI] 0.80-0.99). In MeVO (n = 26) HI >0.5 had a core progression of 0.30 mL/min compared to 0.03 mL/min for HI ≤0.5 (p < 0.001). In LVO (n = 80), HI >0.5 had a core progression of 0.26 mL/min compared to 0.02 mL/min for HI ≤0.5 (p < 0.001). In patients not classified as fast or slow progressor by reperfusion trial criteria, those with HI >0.5 had progression rate of 0.21 mL/min compared to 0.03 mL/min for those with HI ≤0.5 (p < 0.001). Validation in a second cohort of patients with acute ischemic stroke (n = 110; MeVO = 42, LVO = 68) yielded similar results for HI >0.5 to distinguish fast and slow core progression with an AUC of 0.84 (95% CI 0.72-0.97). DISCUSSION: HI can differentiate fast from slow core progression in MeVO and LVO within the first 24 hours of acute ischemic stroke. Consideration of core progression rate at time of stroke evaluation may have implications in the selection of patients with MeVO and LVO stroke for reperfusion therapy that warrant further study.

Non-stenotic Carotid Plaques in Embolic Stroke of Unknown Source.

Embolic stroke of unknown source (ESUS) represents one in five ischemic strokes. Ipsilateral non-stenotic carotid plaques are identified in 40% of all ESUS. In this narrative review, we summarize the evidence supporting the potential causal relationship between ESUS and non-stenotic carotid plaques; discuss the remaining challenges in establishing the causal link between non-stenotic plaques and ESUS and describe biomarkers of potential interest for future research. In support of the causal relationship between ESUS and non-stenotic carotid plaques, studies have shown that plaques with high-risk features are five times more prevalent in the ipsilateral vs. the contralateral carotid and there is a lower incidence of atrial fibrillation during follow-up in patients with ipsilateral non-stenotic carotid plaques. However, non-stenotic carotid plaques with or without high-risk features often coexist with other potential etiologies of stroke, notably atrial fibrillation (8.5%), intracranial atherosclerosis (8.4%), patent foramen ovale (5-9%), and atrial cardiopathy (2.4%). Such puzzling clinical associations make it challenging to confirm the causal link between non-stenotic plaques and ESUS. There are several ongoing studies exploring whether select protein and RNA biomarkers of plaque progression or vulnerability could facilitate the reclassification of some ESUS as large vessel strokes or help to optimize secondary prevention strategies.

Neurological manifestations in patients with symptomatic COVID-19 admitted to the Bafoussam Regional Hospital, Cameroon.

INTRODUCTION: although the main manifestations of COVID-19 are respiratory, several neurological symptoms and complications have also been reported. The pandemic seems to have some epidemiological specificities in sub-Saharan Africa, and this may be reflected in the type and frequency of neurological symptoms. This study aimed to report neurological manifestations associated with symptomatic COVID-19 in a sub-Saharan African setting. METHODS: we conducted a retrospective review of symptomatic PCR-confirmed COVID-19 cases admitted to the Bafoussam Regional Hospital between March and September 2020. Patients' files were reviewed at discharge by a consultant neurologist. Socio-demographic characteristics, co-morbidities, symptoms on admission, neurological symptoms during hospitalization, management, and in-hospital outcome were recorded. Comparisons between patients with and without neurological symptoms were performed using Fisher's exact and Mann-Whitney U test. RESULTS: we enrolled 177 symptomatic patients (68% men). Mean age was 54.6 ± 17.8 years (range 2-99 years). Co-morbidities were present in 57.6% of patients, including hypertension (27.1%) and diabetes mellitus (25.4%). Neurological symptoms were found in 113 (63.8%) patients. The most frequent were headache (39.0%), myalgia (35.6%), anosmia (11.9%), impaired consciousness (10.7%) and delirium (5.6%). Regarding the presenting symptoms, fever was more frequent in patients with neurological symptoms than in those without (81.4% versus 50.0%, p< 0.001), while digestive symptoms were less frequent in patients with neurological symptoms (0.9% versus 9.4%, p= 0.004). CONCLUSION: neurological manifestations are frequent and heterogeneous in patients with symptomatic COVID-19. Further studies are needed to clarify the pathophysiology of neurological symptoms in COVID-19 and their impact on patients' long-term outcome.

Hemorrhagic Transformation in Ischemic Stroke and the Role of Inflammation.

Hemorrhagic transformation (HT) is a common complication in patients with acute ischemic stroke. It occurs when peripheral blood extravasates across a disrupted blood brain barrier (BBB) into the brain following ischemic stroke. Preventing HT is important as it worsens stroke outcome and increases mortality. Factors associated with increased risk of HT include stroke severity, reperfusion therapy (thrombolysis and thrombectomy), hypertension, hyperglycemia, and age. Inflammation and the immune system are important contributors to BBB disruption and HT and are associated with many of the risk factors for HT. In this review, we present the relationship of inflammation and immune activation to HT in the context of reperfusion therapy, hypertension, hyperglycemia, and age. Differences in inflammatory pathways relating to HT are discussed. The role of inflammation to stratify the risk of HT and therapies targeting the immune system to reduce the risk of HT are presented.

Rhythm monitoring strategies for atrial fibrillation detection in patients with cryptogenic stroke: A systematic review and meta-analysis.

OBJECTIVE: To summarize data on atrial fibrillation (AF) detection rates and predictors across different rhythm monitoring strategies in patients with cryptogenic stroke (CS) or embolic stroke of undetermined source (ESUS). METHODS: MEDLINE, Embase, and Web of Science were searched to identify all published studies providing relevant data through July 6, 2020. Random-effects meta-analysis method was used to pool estimates. RESULTS: We included 47 studies reporting on a pooled population of 8,215 patients with CS or ESUS. Using implantable cardiac monitor (ICM), the pooled rate of AF was 12.2% (95% CI 9.4-15.0) at 3 months, 16.0% (95% CI 13.2-18.8) at 6 months, 18.7% (95% CI 15.7-21.7) at 12 months, 22.8% (95% CI 19.1-26.5) at 24 months, and 28.5% (95% CI 17.6-39.3) at 36 months. AF rates were significantly higher in patients with ESUS vs CS (22.0% vs 14.2%; p < 0.001) at 6 months, and in studies using Reveal LINQ vs Reveal XT ICM (19.1% vs 13.0%; p = 0.001) at 12 months. Using mobile cardiac outpatient telemetry (MCOT), the pooled rate of AF was 13.7% (95% CI 10.2-17.2) at 1 month. Predictors of AF detection with ICM included older age, CHA2DS2-VASc score, left atrial enlargement, P wave maximal duration and prolonged PR interval. CONCLUSION: The yield of ICM increases with the duration of monitoring. More than a quarter of patients with CS or ESUS will be diagnosed with AF during follow-up. About one in seven patients had AF detected within a month of MCOT, suggesting that a non-invasive rhythm monitoring strategy should be considered before invasive monitoring.

White matter hyperintensities in patients with Parkinson's disease: A systematic review and meta-analysis.

INTRODUCTION: Mechanisms driving neurodegeneration in Parkinson's disease (PD) are unclear and neurovascular dysfunction may be a contributing factor. White matter hyperintensities (WMH) are commonly found on brain MRI in patients with PD. It is controversial if they are more prevalent or more severe in PD compared with controls. This systematic review aims to answer this question. METHODS: A systematic search of electronic databases was conducted for studies of WMH in patients with PD. A qualitative synthesis was done for studies reporting WMH prevalence or WMH scores on a visual rating scale (VRS). In studies reporting total WMH volume, the difference between patients with PD and controls was pooled using random effects meta-analysis. RESULTS: Among 3860 subjects from 24 studies, 2360 were cases and 1500 controls. Fifteen studies reported WMH scores and four studies reported the prevalence of WMH. On VRS, five studies reported no difference in WMH scores, three found higher WMH scores in PD compared to controls, three reported increased WMH scores either in periventricular or deep white matter, and four reported higher scores only in PD with dementia. In studies reporting WMH volume, there was no difference between patients with PD and controls (pooled standardized mean difference = 0.1, 95%CI: -0.1-0.4, I2 = 81%). CONCLUSION: WMH are not more prevalent or severe in patients with PD than in age-matched controls. PD dementia may have more severe WMH compared to controls and PD with normal cognition. Prospective studies using standardized methods of WMH assessment are needed.

Stroke risk associated with carotid and aortic atherosclerosis in patients with atrial fibrillation: A systematic review.

OBJECTIVE: This review aimed to summarize the evidence on the risk of thromboembolism associated with carotid and aortic atherosclerosis in patients with AF, and the potential impact of their inclusion in current stroke risk stratification scores. METHODS: MEDLINE, Web of Science and EMBASE were systematically searched to identify all published studies providing relevant data through 28 February 2021. RESULTS: We identified 10 eligible studies. There was high heterogeneity across studies, precluding a meta-analysis. Carotid stenosis was not associated with incident ischemic stroke in three prospective studies, including the SPAF II trial and the ROCKET-AF trial. An association between carotid stenosis and thromboembolism was found in two studies, with a potential reporting bias due to their retrospective design. The evidence suggesting that carotid plaque predicts stroke or transient ischemic attack in AF patients were more consistent in the four studies evaluating this association. The inclusion of carotid plaque and carotid intima-media thickness (cIMT) into stroke risk stratification tools for AF patients improved their performance. Data on the association of aortic plaque with thromboembolism is scarce in patients with AF. The two studies reporting on this association suggest that aortic plaque alone does not predict incident ischemic stroke. CONCLUSION: Available data suggest an association of carotid atherosclerosis with the risk of stroke and transient ischemic attack in patients with AF. Future studies should evaluate whether incorporating cIMT and characteristics of carotid and aortic plaques into scoring systems would improve stroke prediction and prevention in patients with AF.

Aging Immune System in Acute Ischemic Stroke: A Transcriptomic Analysis.

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