Aims: We aimed to investigate the association of clinically overt and silent brain lesions with cognitive function in atrial fibrillation (AF) patients. Methods and results: We enrolled 1227 AF patients in a prospective, multicentre cohort study (Swiss-AF). Patients underwent standardized brain magnetic resonance imaging (MRI) at baseline and after 2 years. We quantified new small non-cortical infarcts (SNCIs) and large non-cortical or cortical infarcts (LNCCIs), white matter lesions (WML), and microbleeds (Mb). Clinically, silent infarcts were defined as new SNCI/LNCCI on follow-up MRI in patients without a clinical stroke or transient ischaemic attack (TIA) during follow-up. Cognition was assessed using validated tests. The mean age was 71 years, 26.1% were females, and 89.9% were anticoagulated. Twenty-eight patients (2.3%) experienced a stroke/TIA during 2 years of follow-up. Of the 68 (5.5%) patients with ≥1 SNCI/LNCCI, 60 (88.2%) were anticoagulated at baseline and 58 (85.3%) had a silent infarct. Patients with brain infarcts had a larger decline in cognition [median (interquartile range)] changes in Cognitive Construct score [−0.12 (−0.22; −0.07)] than patients without new brain infarcts [0.07 (−0.09; 0.25)]. New WML or Mb were not associated with cognitive decline. Conclusion: In a contemporary cohort of AF patients, 5.5% had a new brain infarct on MRI after 2 years. The majority of these infarcts was clinically silent and occurred in anticoagulated patients. Clinically, overt and silent brain infarcts had a similar impact on cognitive decline. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02105844, https://clinicaltrials.gov/ct2/show/NCT02105844

Background: Diabetes is a major risk factor for atrial fibrillation (AF). However, it remains unclear whether individual AF phenotype and related comorbidities differ between patients who have AF with and without diabetes. This study investigated the association of diabetes with AF phenotype and cardiac and neurological comorbidities in patients with documented AF. Methods and Results: Participants in the multicenter Swiss‐AF (Swiss Atrial Fibrillation) study with data on diabetes and AF phenotype were eligible. Primary outcomes were parameters of AF phenotype, including AF type, AF symptoms, and quality of life (assessed by the European Quality of Life‐5 Dimensions Questionnaire [EQ‐5D]). Secondary outcomes were cardiac (ie, history of hypertension, myocardial infarction, and heart failure) and neurological (ie, history of stroke and cognitive impairment) comorbidities. The cross‐sectional association of diabetes with these outcomes was assessed using logistic and linear regression, adjusted for age, sex, and cardiovascular risk factors. We included 2411 patients with AF (27.4% women; median age, 73.6 years). Diabetes was not associated with nonparoxysmal AF (odds ratio [OR], 1.01; 95% CI, 0.81–1.27). Patients with diabetes less often perceived AF symptoms (OR, 0.74; 95% CI, 0.59–0.92) but had worse quality of life (β=−4.54; 95% CI, −6.40 to −2.68) than those without diabetes. Patients with diabetes were more likely to have cardiac (hypertension [OR, 3.04; 95% CI, 2.19–4.22], myocardial infarction [OR, 1.55; 95% CI, 1.18–2.03], heart failure [OR, 1.99; 95% CI, 1.57–2.51]) and neurological (stroke [OR, 1.39, 95% CI, 1.03–1.87], cognitive impairment [OR, 1.75, 95% CI, 1.39–2.21]) comorbidities. Conclusions: Patients who have AF with diabetes less often perceive AF symptoms but have worse quality of life and more cardiac and neurological comorbidities than those without diabetes. This raises the question of whether patients with diabetes should be systematically screened for silent AF. Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT02105844.

Objective: Trimethylamine-N-oxide (TMAO) is a metabolite derived from the microbial processing of dietary phosphatidylcholine and carnitine and the subsequent hepatic oxidation. Due to its prothrombotic and inflammatory mechanisms, we aimed to assess its role in the prediction of adverse events in a susceptible population, namely patients with atrial fibrillation.Methods: Baseline TMAO plasma levels were measured by liquid chromatography-tandem mass spectrometry in 2379 subjects from the ongoing Swiss Atrial Fibrillation cohort. 1722 underwent brain MRI at baseline. Participants were prospectively followed for 4 years (Q1–Q3: 3.0–5.0) and stratified into baseline TMAO tertiles. Cox proportional hazards and linear and logistic mixed effect models were employed adjusting for risk factors.Results: Subjects in the highest TMAO tertile were older (75.4±8.1 vs 70.6±8.5 years, p<0.01), had poorer renal function (median glomerular filtration rate: 49.0 mL/min/1.73 m²(35.6–62.5) vs 67.3 mL/min/1.73 m²(57.8–78.9), p<0.01), were more likely to have diabetes (26.9% vs 9.1%, p<0.01) and had a higher prevalence of heart failure (37.9% vs 15.8%, p<0.01) compared with patients in the lowest tertile. Oral anticoagulants were taken by 89.1%, 94.0% and 88.2% of participants, respectively (from high to low tertiles). Cox models, adjusting for baseline covariates, showed increased total mortality (HR 1.65, 95% CI 1.17 to 2.32, p<0.01) as well as cardiovascular mortality (HR 1.86, 95% CI 1.21 to 2.88, p<0.01) in the highest compared with the lowest tertile. When present, subjects in the highest tertile had more voluminous, large, non-cortical and cortical infarcts on MRI (log-transformed volumes; exponentiated estimate 1.89, 95% CI 1.11 to 3.21, p=0.02) and a higher chance of small non-cortical infarcts (OR 1.61, 95% CI 1.16 to 2.22, p<0.01).Conclusions: High levels of TMAO are associated with increased risk of cardiovascular mortality and cerebral infarction in patients with atrial fibrillation.Trial registration number: NCT02105844.

To determine the risk of subsequent adverse clinical outcomes in anticoagulated patients with atrial fibrillation (AF) who experienced a new bleeding event. Anticoagulated AF patients were followed in two prospective cohort studies. Information on incident bleeding was systematically collected during yearly follow-up visits and events were adjudicated as major bleeding or clinically relevant non-major bleeding (CRNMB) according to the International Society on Thrombosis and Haemostasis guidelines. The primary outcome was a composite of stroke, myocardial infarction (MI), or all-cause death. Time-updated multivariable Cox proportional-hazards models were used to compare outcomes in patients with and without incident bleeding. Median follow-up was 4.08 years [interquartile range (IQR): 2.93–5.98]. Of the 3277 patients included (mean age 72 years, 28.5% women), 646 (19.7%) developed a new bleeding, 297 (9.1%) a major bleeding and 418 (12.8%) a CRNMB. The incidence of the primary outcome was 7.08 and 4.04 per 100 patient-years in patients with and without any bleeding [adjusted hazard ratio (aHR): 1.36, 95% confidence interval (CI): 1.16–1.61; P < 0.001; median time between a new bleeding and a primary outcome 306 days (IQR: 23–832)]. Recurrent bleeding occurred in 126 patients [incidence, 8.65 per 100 patient-years (95% CI: 7.26–10.30)]. In patients with and without a major bleeding, the incidence of the primary outcome was 11.00 and 4.06 per 100 patient-years [aHR: 2.04, 95% CI: 1.69–2.46; P < 0.001; median time to a primary outcome 142 days (IQR: 9–518)], and 59 had recurrent bleeding [11.61 per 100 patient-years (95% CI: 8.99–14.98)]. The incidence of the primary outcome was 5.29 and 4.55 in patients with and without CRNMB [aHR: 0.94, 95% CI: 0.76–1.15; P = 0.53; median time to a composite outcome 505 days (IQR: 153–1079)], and 87 had recurrent bleeding [8.43 per 100 patient-years (95% CI: 6.83–10.40)]. Patients who had their oral anticoagulation (OAC) discontinued after their first bleeding episode had a higher incidence of the primary composite than those who continued OAC (63/89 vs. 159/557 patients; aHR: 4.46, 95% CI: 3.16–6.31; P < 0.001). In anticoagulated AF patients, major bleeding but not CRNMB was associated with a high risk of adverse outcomes, part of which may be explained by OAC discontinuation. Most events occurred late after the bleeding episode, emphasizing the importance of long-term follow-up in these patients. Relationships between bleeding events and the risk of subsequent adverse outcomes in anticoagulated patients with atrial fibrillation. Composite consisted of stroke, MI or death; AF = atrial fibrillation, OAC = oral anticoagulation, F-up = follow-up, CRNMB = clinically relevant non-major bleeding, MI = myocardial infarction.

Background: Hospitalization for heart failure (HF) is very common in patients with atrial fibrillation (AF). We hypothesized that biomarkers of inflammation can identify patients with AF at increased risk of this important complication. Methods and Results: Patients with established AF were prospectively enrolled. Levels of hs‐CRP (high‐sensitivity C‐reactive protein) and interleukin‐6 were measured from plasma samples obtained at baseline. We calculated an inflammation score ranging from 0 to 4 (1 point for each biomarker between the 50th and 75th percentile, 2 points for each biomarker above the 75th percentile). Individual associations of biomarkers and the inflammation score with HF hospitalization were obtained from multivariable Cox proportional hazards models. A total of 3784 patients with AF (median age 72 years, 24% prior HF) were followed for a median of 4.0 years. The median (interquartile range) plasma levels of hs‐CRP and interleukin‐6 were 1.64 (0.81–3.69) mg/L and 3.42 (2.14–5.60) pg/mL, respectively. The overall incidence of HF hospitalization was 3.04 per 100 person‐years and increased from 1.34 to 7.31 per 100 person‐years across inflammation score categories. After multivariable adjustment, both biomarkers were significantly associated with the risk of HF hospitalization (per increase in 1 SD, adjusted hazard ratio [HR], 1.22; 95% CI, 1.11–1.34 for log‐transformed hs‐CRP; adjusted HR, 1.48; 95% CI, 1.35–1.62 for log‐transformed interleukin‐6). Similar results were obtained for the inflammation score (highest versus lowest score, adjusted HR, 2.43; 95% CI, 1.80–3.30; P value for trend <0.001). Conclusions: Biomarkers of inflammation strongly predicted HF hospitalization in a large, contemporary sample of patients with AF. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02105844.

The omega-3 fatty acid (n-3 FA) eicosapentaenoic acid (EPA) reduces stroke in patients with atherosclerotic cardiovascular disease. Whether EPA affects stroke or cerebral small vessel dis-ease in patients with atrial fibrillation (AF) remains uncertain. EPA, docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and alpha-linolenic acid (ALA) were determined by gas chromatography in 1657 AF patients from the Swiss Atrial Fibrillation study. All patients underwent brain MRI to detect ischemic brain infarcts, classified as large noncortical or cortical infarcts (LNCCIs); markers of small vessel disease, classified as small noncortical infarcts (SNCIs), number of microbleeds, and white matter lesion (WML) volumes. Individual and total n-3 FAs (EPA + DHA + DPA + ALA) were correlated with LNCCIs and SNCIs using logistic regression, with numbers of microbleeds using a hurdle model, and WML volumes using linear regression. LNCCIs were detected in 372 patients (22.5%). EPA correlated inversely with the prevalence of LNCCIs (odds ratio [OR] 0.51 per increase of 1 percentage point EPA, 95% confidence interval [CI] 0.29–0.90). DPA correlated with a higher LNCCI prevalence (OR 2.48, 95%CI 1.49–4.13). No associations with LNCCIs were found for DHA, ALA, and total n-3 FAs. Neither individual nor total n-3 FAs correlated with markers of small vessel disease. In conclusion, EPA correlates inversely with the prevalence of ischemic brain infarcts, but not with markers of small vessel disease in patients with AF.