AF-related Stroke Research Articles

TARGET: A Major European Project Aiming to Advance the Personalised Management of Atrial Fibrillation-Related Stroke via the Development of Health Virtual Twins Technology and Artificial Intelligence.

TARGET: A Major European Project Aiming to Advance the Personalised Management of Atrial Fibrillation-Related Stroke via the Development of Health Virtual Twins Technology and Artificial Intelligence.

How can the detection of AF be improved? Insights from patient journeys and primary care clinicians

Abstract Background Atrial fibrillation (AF) is underdiagnosed and it is estimated that a third of people with AF remain undiagnosed. AF is complex to detect because it can be intermittent and some patients are asymptomatic. When symptoms are present they can be non-specific. In the absence of a screening programme to detect AF it is important to identify ways to improve its detection of AF in order to reduce the risk of AF-related stroke. Purpose We conducted a qualitative study in primary care to explore the patient path to diagnosis of AF and identify ways to improve detection Methods We recruited patients with a recent diagnosis of AF (< 6 months) and interviewed them to understand their path to diagnosis. We interviewed GPs and practice nurses to explore their experience of detecting AF in primary care. The interviews were audio-recorded and transcribed, and the data were analysed using framework analysis. Results Thirty patients and ten primary care clinicians were interviewed. The presence and nature of symptoms experienced by patients and how they interpreted these were significant in the pathways to diagnosis. Patients with acute symptoms presented to A &E and had a quick diagnosis while asymptomatic patients were diagnosed incidentally. Patients with non-specific symptoms generally did not perceive the symptoms as serious, and many delayed seeing a healthcare professional. Their experiences in primary care aligned with findings from interviews with primary care clinicians, who acknowledged AF may not necessarily be the initial suspicion when a patient presents with certain non-specific symptoms. Primary care clinicians described narratives of good practice in the form of opportunistic pulse palpation, as well as challenges of detecting AF in primary care. These included lack of access to 24-hour ambulatory ECG in primary care and limited opportunities to detect AF due to healthcare assistants taking on more responsibilities. Conclusions A number of opportunities to improve the detection of AF can be drawn from these findings. Public education about AF, its signs and symptoms would increase patient knowledge and presentation to healthcare professionals. Standardizing good practice of opportunistic pulse palpation in primary care and training healthcare assistants to perform this is also indicated. Access to 24-hour ambulatory ECG in primary care will reduce delays in diagnosis. Further research on which patients are likely to have undiagnosed AF will facilitate detection in primary care.

Could the Early Detection of Atrial Fibrillation Reduce the Risk of Developing Dementia?

Atrial fibrillation (AF) and dementia are major global public health issues and share common risk factors, especially after the age of 65 and regardless of the presence of stroke. Despite accounting for potential confounders, AF appears to be an independent risk factor for cognitive decline and dementia. The mechanisms are likely to be multifactorial and may include AF-related ischemic stroke, cerebral hypoperfusion, microbleeds, systemic inflammation, genetic factors, and small vessel disease, leading to brain atrophy and white matter damage. The early aggressive management of AF and comorbidities may reduce the risk of dementia. Indeed, the early detection of AF-related cognitive impairment should allow for the early implementation of measures to prevent the development of dementia, mainly through integrative approaches involving the correction of risk factors and maintenance of rhythm control. Well-designed prospective studies are needed to determine whether early detection and AF treatment can prevent dementia and identify whether optimal integrative measures are effective in preventing cognitive impairment and dementia.

Risk of stroke in male and female patients with atrial fibrillation in a nationwide cohort

Female sex has been suggested as a risk modifier for stroke in patients with atrial fibrillation (AF) with comorbid prevalent stroke risk factors. Management has evolved over time towards a holistic approach that may have diminished any sex difference in AF-related stroke. In a nationwide cohort of AF patients free from oral anticoagulant treatment, we examine the time trends in stroke risk overall and in relation to risk differences between male and female patients. Here we show that among 158,982 patients with AF (median age 78 years (IQR: 71 to 85); 52% female) the 1-year thromboembolic risk was highest between 1997–2000 with a risk of 5.6% and lowest between 2013–2016 with a risk of 3.8%, declining over the last two decades. The excess stroke risk for female vs male patients has also been declining, with risk-score adjusted relative risk estimates suggesting limited sex-difference in recent years.

Comparative Rates of Stroke and Rehospitalization of Atrial Fibrillation in Patients with Perioperative Atrial Fibrillation Following Major Emergency Abdominal Surgery and Patients with Non-perioperative Atrial Fibrillation.

Major emergency abdominal surgery is associated with postoperative complications and high mortality. Long-term outcomes in patients with perioperative atrial fibrillation (POAF) have recently received increased attention, especially POAF in non-thoracic surgery. This study aimed to compare long-term AF related hospitalization and stroke in patients with POAF in relation to major emergency abdominal surgery and in patients with non-perioperative AF. We crosslinked data from Danish nationwide registries and identified all patients who underwent major emergency abdominal surgery (2000-2018) and were diagnosed with POAF, and patients who developed AF in a non-perioperative setting. Patients with POAF were matched in a 1:5 ratio on age, sex, year of AF diagnosis and oral anticoagulation (OAC) status at the beginning of follow-up with patients with non-perioperative AF. From discharge, we examined adjusted hazard ratios (HR) of stroke using multivariable Cox regression analysis. The study population comprised 1,041 (out of 42,021 who underwent major emergency abdominal surgery) patients with POAF and 5,205 patients with non-perioperative AF. The median age was 78 years [interquartile range: 71-84] for those initiated on OAC therapy and 78 years [interquartile range: 71-85] for those not initiated on OAC therapy. During the first year of follow up, POAF was associated with similar rates of stroke as non-perioperative AF (patients initiated on OAC: HR 0.96 (95% confidence interval (CI) 0.52-1.77) and patients not initiated on OAC: HR 0.69 (95% CI 0.41-1.15). POAF in relation to major emergency abdominal surgery was associated with similar rates of stroke as non-perioperative AF. These results suggest that POAF not only carry an acute burden but also a long-term burden in patients undergoing major emergency abdominal surgery.

Laboratory Findings in Atrial Fibrillation-related Stroke Patients Underwent Reperfusion Treatment

Laboratory Findings in Atrial Fibrillation-related Stroke Patients Underwent Reperfusion Treatment

Machine Learning in Hypertrophic Cardiomyopathy: Nonlinear Model From Clinical and CMR Features Predicting Cardiovascular Events

BackgroundThe cumulative burden of hypertrophic cardiomyopathy (HCM) is significant, with a noteworthy percentage (10%-15%) of patients with HCM per year experiencing major adverse cardiovascular events (MACEs). A current risk stratification scheme for HCM had only limited accuracy in predicting sudden cardiac death (SCD) and failed to account for a broader spectrum of adverse cardiovascular events and cardiac magnetic resonance (CMR) parameters. ObjectivesThis study sought to develop and evaluate a machine learning (ML) framework that integrates CMR imaging and clinical characteristics to predict MACEs in patients with HCM. MethodsA total of 758 patients with HCM (67% male; age 49 ± 14 years) who were admitted between 2010 and 2017 from 4 medical centers were included. The ML model was built on the internal discovery cohort (533 patients with HCM, admitted to Fuwai Hospital, Beijing, China) by using the light gradient-boosting machine and internally evaluated using cross-validation. The external test cohort consisted of 225 patients with HCM from 3 medical centers. A total of 14 CMR imaging features (strain and late gadolinium enhancement [LGE]) and 23 clinical variables were evaluated and used to inform the ML model. MACEs included a composite of arrhythmic events, SCD, heart failure, and atrial fibrillation–related stroke. ResultsMACEs occurred in 191 (25%) patients over a median follow-up period of 109.0 months (Q1-Q3: 73.0-118.8 months). Our ML model achieved areas under the curve (AUCs) of 0.830 and 0.812 (internally and externally, respectively). The model outperformed the classic HCM Risk-SCD model, with significant improvement (P < 0.001) of 22.7% in the AUC. Using the cubic spline analysis, the study showed that the extent of LGE and the impairment of global radial strain (GRS) and global circumferential strain (GCS) were nonlinearly correlated with MACEs: an elevated risk of adverse cardiovascular events was observed when these parameters reached the high enough second tertiles (11.6% for LGE, 25.8% for GRS, −17.3% for GCS). ConclusionsML-empowered risk stratification using CMR and clinical features enabled accurate MACE prediction beyond the classic HCM Risk-SCD model. In addition, the nonlinear correlation between CMR features (LGE and left ventricular pressure gradient) and MACEs uncovered in this study provides valuable insights for the clinical assessment and management of HCM.

Oral Anticoagulation in Patients with Acute Stroke and Atrial Fibrillation

Introduction. Patients who have experienced acute ischemic stroke (AIS) and have atrial fibrillation (AF) are often prescribed oral anticoagulants (OACs) to lower their risk of recurrent stroke or vascular embolism. This therapy is rarely advised as a preventive measure for reducing the risk of recurrent ischemic stroke associated with non-valvular atrial AF. The ideal timing for initiating oral anticoagulation in these patients remains uncertain. Methods. Research was conducted in the major medical databases containing articles. The following terms were used: atrial fibrillation, acute ischemic stroke, oral anticoagulants, stroke recurrence, and prevention. We excluded studies performed earlier than 10 years since the medical information was no longer valid in practice. Results. Information gathered from observational studies and control groups in randomized trials indicates that the early recurrence rate following an atrial fibrillation-related ischemic stroke falls within the range of approximately 0.5% to 1.3% per day during the initial two weeks. The research targeted adults (aged ≥18 years) with AF and a recent ischemic stroke (IS) (occurring within 72 hours of symptom onset) who satisfied the criteria for and were amenable to starting treatment with NOACs. Atrial fibrillation encompassed paroxysmal, persistent, and permanent forms, whether they were pre-existing conditions or diagnosed during the initial hospitalization. Observational studies indicate that the risk of recurrent stroke is seven times higher than the risk of hemorrhagic transformation during the early phase after a recent stroke. Conclusions. Early prevention treatments are critical because the acute phase after an ischemic stroke increases the risk of stroke recurrence. It is critical to balance the possible benefits of early oral anticoagulation against the dangers of developing intracerebral hemorrhage or hemorrhagic transformation of the ischemic injury at this critical time.

Laboratory Findings in Atrial Fibrillation-related Stroke Patients Underwent Reperfusion Treatment

Laboratory Findings in Atrial Fibrillation-related Stroke Patients Underwent Reperfusion Treatment

Atrial fibrillation is associated with higher first pass effect following thrombectomy for large vessel occlusion

BackgroundFirst pass effect (FPE), defined as single-pass complete or near complete reperfusion during endovascular thrombectomy (EVT) for large vessel occlusion (LVO) strokes, is a critical performance metric. Atrial fibrillation (AF)-related...

Serum protein profiling reveals mechanism of activated thrombus formation in patients with stroke and atrial fibrillation

Stroke is an acute cerebrovascular disease in which blood flow to the brain is suddenly disrupted, causing damage to nerve cells. It involves complex and diverse pathophysiological processes and the treatment strategies are also diverse. The treatment for patients with stroke and atrial fibrillation (AF) is aimed at suppressing thrombus formation and migration. However, information regarding the protein networking involved in different thrombus formation pathways in patients with AF and stroke is insufficient. We performed protein profiling of patients with ischemic stroke with and without AF to investigate the mechanisms of thrombus formation and its pathophysiological association while providing helpful information for treating and managing patients with AF. These two groups were compared to identify the protein networks related to thrombus formation in AF. We observed that patients with ischemic stroke and AF had activated inflammatory responses induced by C-reactive protein, lipopolysaccharide-binding protein, and alpha-1-acid glycoprotein 1. In contrast, thyroid hormones were increased due to a decrease in transthyretin and retinol-binding protein 4 levels. The mechanism underlying enhanced cardiac activity, vasodilation, and the resulting thrombosis pathway were confirmed in AF. These findings will play an essential role in improving the prevention and treatment of AF-related stroke.

Bioinformatics Analysis Reveals HIST1H2BH as a Novel Diagnostic Biomarker for Atrial Fibrillation-Related Cardiogenic Thromboembolic Stroke.

Atrial fibrillation (AF) is a significant precursor to cerebral embolism. Our study sought to unearth new diagnostic biomarkers for atrial fibrillation-related cerebral embolism (AF-CE) by meticulously examining multiple GEO datasets and meta-analysis. The gene expression omnibus (GEO) database provided RNA sequencing data associated with AF and stroke. We began by pinpointing genes with varied expressions in AF-CE patient blood samples. A meta-analysis was subsequently undertaken using several RNA sequencing datasets to verify these genes. LASSO regression discerned key genes for AF-CE, with their diagnostic prowess verified through ROC curve examination. Active signaling pathways within stroke patients were discerned via GO and KEGG enrichment, with PPI interactions detailing gene interplay. Differential gene analysis revealed an upregulation of sixteen genes and a downregulation of four in stroke patient blood samples. Eight genes showcased varied expression in the meta-analysis. LASSO regression zeroed in on five of these, culminating in HIST1H2BH's identification as a characteristic gene. HIST1H2BH's prowess in predicting AF-CE was confirmed through ROC. Integrin signaling, platelet activation, ECM interactions, and the PI3K-Akt pathway were found active in stroke victims. HIST1H2BH's interaction with the notably upregulated ITGA2B was spotlighted by PPI. Additionally, HIST1H2BH exhibited links with NK cells and eosinophils. HIST1H2BH emerges as an insightful diagnostic beacon for AF-CE. Its presence, post AF, potentially modulates pathways, accentuating platelet activation and consequent thrombus generation, leading to cerebral embolism.

Time-trends of sex differences in stroke risk in atrial fibrillation: Are female patients still at higher risk today? A nationwide cohort study

Abstract Background Female sex is associated with higher risk of stroke in patients with atrial fibrillation (AF), particularly in the presence of other stroke risk factors. This has implications for oral anticoagulant treatment (OAC) decision-making, based on points of the CHA2DS2-VASc score. However, stroke rates have declined over recent years, and management has evolved over time towards a holistic approach that may have diminished the sex differences in AF-related stroke. Purpose To examine the changes in stroke risk over time in relation to risk differences between males and females not treated with oral anticoagulants in a nationwide cohort study. Methods This was an observational cohort study including patients with a hospital diagnosis of AF between 2007 and 2021. Data were obtained from the Danish nationwide registries. We identified a cohort of adult patients who were not receiving OAC treatment for up to 30 days after their AF diagnosis. Patients were followed up for thromboembolic events within one year after the AF diagnosis. Survival analysis was applied to describe the yearly rate of events and to estimate the risk ratio for females vs males of thromboembolism according to baseline risk levels, i.e., the CHA2DS2-VA score level (leaving out the ‘Sc’ sex criterion). Results A total of 188,704 AF patients (median age 75 years (IQR: 64 to 84); 49.7% female) who did not receive OAC treatment were included. The risk of thromboembolism during the entire study period was overall higher in females (3.5% in males vs. 4.7% among females). The overall one-year thromboembolic risk declined over time from 4.9% between 1997-2000 to 3.3% between 2017-2020, with male-female risk differences less evident in recent years (Figure 1a). The relative risk of stroke diminished from 1.22 (95%CI 1.10-1.34) in years 1997-2000 to 1.02 (95%CI 0.85-1.19) in years 2017-2020 for patients with a CHA2DS2-VA score of ≥2 (Figure 1b). For patients with a score of &amp;lt;2, the relative risk was lowest between 2005-2008 (1.02 (95%CI 0.63-1.42)) and was 1.18 (95%CI 0.54-1.83) in the latest time period. Formal statistical test for time trends according to score level revealed non-significant results (p-value=0.10 for score 0-1; p-value=0.17 for score levels of ≥2). Conclusion The risk of stroke among patients with AF has been declining over the last two decades. The excess stroke risk observed among females relative to males has also diminished, most evident among AF patients with ≥2 prevalent stroke risk factors.

Prediction of atrial fibrillation in patients with stroke: a systematic review with meta-analysis

Abstract Background Atrial fibrillation-related strokes have a high rate of recurrence,1 and are associated with substantial morbidity, long-term disability, and mortality.2,3 Detection of AF at the time of stroke may require extended cardiac rhythm monitoring,4-6 which is costly.7 Identifying patients with stroke at high risk for AF can be challenging but important for preventing recurrent strokes. Purpose To provide an overview of prediction tools for AF in patients with an acute stroke, and to determine suitability for clinical use by synthesising discriminatory abilities. Methods We performed a systematic review of prediction tools (including multivariable scores and individual parameters) derived, validated and/or augmented for AF prediction in patients with strokes using Medline and Embase through 25 October 2023. Discrimination measures for tools with c-statistic data from ≥3 cohorts were pooled by Bayesian meta-analysis, with heterogeneity assessed through a 95% prediction interval (PI). Summary discrimination values of &amp;lt;0.60, 0.60-0.70, 0.70-0.80, and &amp;gt;0.80 were defined a priori as inadequate, adequate, good and excellent.1 Results From 8125 unique records we included 71 studies from 135 cohorts with a mean age and percentage of women ranging from 43.0 years to 77.5 years, and 25.2% to 55.3%, respectively. We identified 99 prediction tools for incident AF after a stroke. 33 predictive tools used clinical variables, 13 only used Echocardiographic data, 14 only used electrocardiogram (ECG) data, and 39 used combinations of the above modalities. 87 tools were developed with Cox or logistic regression and 12 tools through machine learning approaches. 36 had undergone external validation, with 27 demonstrating a c-statistic &amp;gt;0.75 on external validation. Nine multivariable prediction models and two predictive factors (B-type natriuretic peptide and age) were eligible for meta-analysis. Of multivariable prediction models, 4 showed good summary discrimination with wide heterogeneity (Figure 1): LADS (n = 1286, summary c-statistic 0.713, 95% CI 0.534-0.882 95% PI 0.379 -0.979), CHASE-LESS (n = 22747 summary c-statistic 0.726, 95% CI 0.667-0.785 95% PI 0.608-0.836), AS5F (n = 31517, summary c-statistic 0.726, 95% CI 0.693-0.754 95% PI 0.645-0.808), STAF (n = 3759, summary c-statistic 0.771, 95% CI 0.679-0.859 95% PI 0.456-0.973). BNP showed excellent summary discrimination with acceptable heterogeneity (Figure 2), (n = 1343 summary c-statistic 0.832, 95% CI 0.776-0.886 95% PI 0.718-0.927). Conclusions Five prediction tools externally validated for prediction of risk of AF in those who have had an acute stroke demonstrate good predictive ability. In meta-analysis, BNP performed the best out of all the models and variables tested.

Epidemiology and comprehensive economic impact of atrial fibrillation and associated stroke in Slovakia.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. It is also a major risk factor for ischemic stroke. The main objective of our study was to identify direct and indirect costs of AF and AF-related stroke in Slovakia. We conducted a retrospective population-based study of AF and stroke related costs both from the third-party healthcare payers and societal perspective. The prevalence and incidence of AF and stroke were determined from central government run healthcare database. Further we estimated both indirect and direct costs of AF and stroke. All costs and healthcare resources were assessed from 2015 through 2019 and were expressed in the respective year. Over the 5-year study period, the prevalence of AF increased by 26% to a total of 149,198 AF cases in 2019, with an estimated total annual economic burden of €66,242,359. Direct medical costs accounted for 94% of the total cost of AF. The total cost of treating patients with stroke in 2019 was estimated at €89,505,669. As a result, the medical costs of stroke that develops as a complication of AF have been estimated to be €25,734,080 in 2019. Our study shows a substantial economic burden of AF and AF-related stroke in Slovakia. In view of the above, both screening for asymptomatic AF in high-risk populations and effective early management of AF with a focused on thromboprophylaxis rhythm control should be implemented.

Racial Differences in Ischemic and Hemorrhagic Stroke: An Ecological Epidemiological Study.

This study aimed to evaluate racial differences in the incidence of stroke by conducting an ecological epidemiological study using UK Biobank and Korean nationwide data. This study used individual data from the Korean National Health Insurance Service-Health Screening and UK Biobank, which included participants who underwent health examinations between 2006 and 2010. We included 112,750 East Asians (50.7% men, mean age: 52.6 years) and 210,995 Caucasians (44.7% men, mean age: 55.0 years) who were not diagnosed with atrial fibrillation, cardiovascular diseases, chronic kidney disease, chronic obstructive pulmonary disease, or cancer. The primary outcome was defined as a composite of ischemic and hemorrhagic stroke. East Asians tended to have a lower body mass index (23.7 vs. 26.4 kg/m2, p < 0.001) and a higher proportion of participants who did not engage in moderate-to-vigorous physical activity (49.6% vs. 10.7%, p < 0.001) than Caucasians. During the follow-up, East Asians had higher 5-year incidence rates (presented as per 1,000 person-years) for primary outcome (1.73 vs. 0.50; IR ratio [IRR]: 3.48, 95% confidence interval [CI]: 3.13-3.88), ischemic stroke (1.23 vs. 0.33; IRR: 3.70, 95% CI: 3.25-4.21), hemorrhagic stroke (0.56 vs. 0.18; IRR: 3.20, 95% CI: 2.67-3.84), and atrial fibrillation-related stroke (0.19 vs. 0.09; IRR: 2.04, 95% CI: 1.55-2.68). Based on this ecological epidemiological study, racial differences in stroke incidence were robust to a variety of statistical analyses, regardless of the subtype. This suggests the need for region-specific approaches to stroke prevention.

Use of Adult Gerontology Acute Care Nurse Practitioners on a Neurocardiology Team

The neurocardiology team provides innovative, evidence-based care for patients with cryptogenic stroke, stroke associated with a patent foramen ovale, and atrial fibrillation-related stroke in patients unsuitable for long-term anticoagulation. Considerable evidence supports the value of advanced practice registered nurses on process improvement metrics and clinical outcomes; however, current literature in stroke management almost exclusively emphasizes interdisciplinary collaboration between physicians. This clinical feature discusses ways in which the adult gerontology acute care nurse practitioner can aid in the delivery of evidence-based stroke care and contribute to educational, administrative, and research missions as a collaborative member of a multidisciplinary neurocardiology team.

Using machine learning to identify proteomic and metabolomic signatures of stroke in atrial fibrillation

Atrial fibrillation (AF) is a common cardiac arrhythmia, with stroke being its most detrimental comorbidity. The exact mechanism of AF related stroke (AFS) still needs to be explored. In this study, we integrated proteomics and metabolomics platform to explore disordered plasma proteins and metabolites between AF patients and AFS patients. There were 22 up-regulated and 31 down-regulated differentially expressed proteins (DEPs) in AFS plasma samples. Moreover, 63 up-regulated and 51 down-regulated differentially expressed metabolites (DEMs) were discovered in AFS plasma samples. We integrated proteomics and metabolomics based on the topological interactions of DEPs and DEMs, which yielded revealed several related pathways such as arachidonic acid metabolism, serotonergic synapse, purine metabolism, tyrosine metabolism and steroid hormone biosynthesis. We then performed a machine learning model to identify potential biomarkers of stroke in AF. Finally, we selected 6 proteins and 6 metabolites as candidate biomarkers for predicting stroke in AF by random forest, the area under the curve being 0.976. In conclusion, this study provides new perspectives for understanding the progressive mechanisms of AF related stroke and discovering innovative biomarkers for determining the prognosis of stroke in AF.

Both HFpEF and HFmrEF should be included in calculating CHA2DS2-VASc score: A Taiwanese longitudinal cohort

BackgroundCongestive heart failure (CHF) as a risk of stroke in patients with atrial fibrillation (AF) mainly referred to patients with left ventricular systolic dysfunction. Whether this should include patients with preserved ejection fraction is debatable. ObjectiveThe study aimed to investigate the variation in stroke risk of AF patients with heart failure with preserved ejection fraction (HFpEF), heart failure with mid-range ejection fraction (HFmrEF), and heart failure with reduced ejection fraction (HFrEF) for enhancing risk assessment and subsequent management strategies. MethodsIn a longitudinal study using the National Taiwan University Hospital integrated Medical Database, 8358 patients with AF were observed for 10 years (mean follow-up, 3.76 years). The study evaluated the risk of ischemic stroke in patients with differing ejection fractions and CHA2DS2-VASc score, further using Cox models adjusted for risk factors of AF-related stroke. ResultsPatients with HFpEF and HFmrEF had a higher mean CHA2DS2-VASc score compared with patients with HFrEF (4.30 ± 1.729 vs 4.15 ± 1.736 vs 3.73 ± 1.712; P < .001) and higher risk of stroke during follow-up (hazard ratio [HR], 1.40 [1.161–1.688; P < .001] for HFmrEF; HR, 1.184 [1.075–1.303; P = .001] for HFpEF vs no CHF) after multivariate adjustment). In patients with lower CHA2DS2-VASc score (0–4), presence of any type of CHF increased ischemic stroke risk (HFrEF HR, 1.568 [1.189–2.068; P = .001]; HFmrEF HR, 1.890 [1.372–2.603; P < .001]; HFpEF HR, 1.800 [1.526–2.123; P < .001] vs no CHF). ConclusionAfter multivariate adjustment, HFpEF and HFmrEF showed a similar risk of stroke in AF patients. Therefore, it is important to extend the criteria for C in the CHA2DS2-VASc score to include patients with HFpEF and HFmrEF. In patients with fewer concomitant stroke risk factors, the presence of any subtype of CHF increases risk for ischemic stroke.

LNK/SH2B3 loss of function increases susceptibility to murine and human atrial fibrillation.

The lymphocyte adaptor protein (LNK) is a negative regulator of cytokine and growth factor signalling. The rs3184504 variant in SH2B3 reduces LNK function and is linked to cardiovascular, inflammatory, and haematologic disorders, including stroke. In mice, deletion of Lnk causes inflammation and oxidative stress. We hypothesized that Lnk-/- mice are susceptible to atrial fibrillation (AF) and that rs3184504 is associated with AF and AF-related stroke in humans. During inflammation, reactive lipid dicarbonyls are the major components of oxidative injury, and we further hypothesized that these mediators are critical drivers of the AF substrate in Lnk-/- mice. Lnk-/- or wild-type (WT) mice were treated with vehicle or 2-hydroxybenzylamine (2-HOBA), a dicarbonyl scavenger, for 3 months. Compared with WT, Lnk-/- mice displayed increased AF duration that was prevented by 2-HOBA. In the Lnk-/- atria, action potentials were prolonged with reduced transient outward K+ current, increased late Na+ current, and reduced peak Na+ current, pro-arrhythmic effects that were inhibited by 2-HOBA. Mitochondrial dysfunction, especially for Complex I, was evident in Lnk-/- atria, while scavenging lipid dicarbonyls prevented this abnormality. Tumour necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1β) were elevated in Lnk-/- plasma and atrial tissue, respectively, both of which caused electrical and bioenergetic remodelling in vitro. Inhibition of soluble TNF-α prevented electrical remodelling and AF susceptibility, while IL-1β inhibition improved mitochondrial respiration but had no effect on AF susceptibility. In a large database of genotyped patients, rs3184504 was associated with AF, as well as AF-related stroke. These findings identify a novel role for LNK in the pathophysiology of AF in both experimental mice and humans. Moreover, reactive lipid dicarbonyls are critical to the inflammatory AF substrate in Lnk-/- mice and mediate the pro-arrhythmic effects of pro-inflammatory cytokines, primarily through electrical remodelling.