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Results from the discovery study. Proteins selected to be verified in the whole Phase 1 are highlighted in grey. Proteins in bold but not highlighted were already tested in the whole phase 1 as part of a previous published work.

Growing evidence suggests a consistent association between atrial fibrillation (AF) and cognitive impairment and dementia that is independent of clinical stroke. This report from the AF-SCREEN International Collaboration summarizes the evidence linking AF to cognitive impairment and dementia. It provides guidance on the investigation and management of dementia in patients with AF on the basis of best available evidence. The document also addresses suspected pathophysiologic mechanisms and identifies knowledge gaps for future research. Whereas AF and dementia share numerous risk factors, the association appears to be independent of these variables. Nevertheless, the evidence remains inconclusive regarding a direct causal effect. Several pathophysiologic mechanisms have been proposed, some of which are potentially amenable to early intervention, including cerebral microinfarction, AF-related cerebral hypoperfusion, inflammation, microhemorrhage, brain atrophy, and systemic atherosclerotic vascular disease. The mitigating role of oral anticoagulation in specific subgroups (eg, low stroke risk, short duration or silent AF, after successful AF ablation, or atrial cardiopathy) and the effect of rhythm versus rate control strategies remain unknown. Likewise, screening for AF (in cognitively normal or cognitively impaired patients) and screening for cognitive impairment in patients with AF are debated. The pathophysiology of dementia and therapeutic strategies to reduce cognitive impairment warrant further investigation in individuals with AF. Cognition should be evaluated in future AF studies and integrated with patient-specific outcome priorities and patient preferences. Further large-scale prospective studies and randomized trials are needed to establish whether AF is a risk factor for cognitive impairment, to investigate strategies to prevent dementia, and to determine whether screening for unknown AF followed by targeted therapy might prevent or reduce cognitive impair

[Background and objective] AFRICAT is a prospective cohort study intending to develop an atrial fibrillation (AF) screening program through the combination of blood markers, rhythm detection devices, and long-term monitoring in our community. In particular, we aimed to validate the use of NT-proBNP, and identify new blood biomarkers associated with AF. Also, we aimed to compare AF detection using various wearables and long-term Holter monitoring., [Methods] 359 subjects aged 65–75 years with hypertension and diabetes were included in two phases: Phase I (n = 100) and Phase II (n = 259). AF diagnosis was performed by baseline 12-lead ECG, 4 weeks of Holter monitoring (NuuboTM), and/or medical history. An aptamer array including 1310 proteins was measured in the blood of 26 patients. Candidates were selected according to p-value, logFC and biological function to be tested in verification and validation phases. Several screening devices were tested and compared: AliveCor, Watch BP, MyDiagnostick and Fibricheck., [Results] AF was present in 34 subjects (9.47%). The aptamer array revealed 41 proteins with differential expression in AF individuals. TIMP-2 and ST-2 were the most promising candidates in the verification analysis, but none of them was further validated. NT-proBNP (log-transformed) (OR = 1.934; p<0.001) was the only independent biomarker to detect AF in the whole cohort. Compared to an ECG, WatchBP had the highest sensitivity (84.6%) and AUC (0.895 [0.780–1]), while MyDiagnostick showed the highest specificity (97.10%)., [Conclusion] The inclusion and monitoring of a cohort of primary care patients for AF detection, together with the testing of biomarkers and screening devices provided useful lessons about AF screening in our community. An AF screening strategy using rhythm detection devices and short monitoring periods among high-risk patients with high NT-proBNP levels could be feasible.

An accurate etiological classification is key to optimize secondary prevention after ischemic stroke, but the cause remains undetermined in one third of patients. Several studies pointed out the usefulness of circulating gene expression markers to discriminate cardioembolic (CE) strokes, mainly due to atrial fibrillation (AF), while only exploring them in small cohorts. A systematic review of studies analyzing high-throughput gene expression in blood samples to discriminate CE strokes was performed. Significantly dysregulated genes were considered as candidates, and a selection of them was validated by RT-qPCR in 100 patients with defined CE or atherothrombotic (LAA) stroke etiology. Longitudinal performance was evaluated in 12 patients at three time points. Their usefulness as biomarkers for AF was tested in 120 cryptogenic strokes and 100 individuals at high-risk for stroke. Three published studies plus three unpublished datasets were considered for candidate selection. Sixty-seven genes were found dysregulated in CE strokes. CREM, PELI1, and ZAK were verified to be up-regulated in CE vs LAA (p = 0.010, p = 0.003, p < 0.001, respectively), without changes in their expression within the first 24 h after stroke onset. The combined up-regulation of these three biomarkers increased the probability of suffering from CE stroke by 23-fold. In cryptogenic strokes with subsequent AF detection, PELI1 and CREM showed overexpression (p = 0.017, p = 0.059, respectively), whereas in high-risk asymptomatic populations, all three genes showed potential to detect AF (p = 0.007, p = 0.007, p = 0.015). The proved discriminatory capacity of these gene expression markers to detect cardioembolism even in cryptogenic strokes and asymptomatic high-risk populations might bring up their use as biomarkers.

[Background]: Atrial fibrillation (AF) systematic screening studies have not shown a clear usefulness in stroke prevention, as AF might present as paroxysmal and asymptomatic. This study aims to determine the usefulness of some blood-biomarkers to identify paroxysmal atrial fibrillation in the context of a screening programme., [Methods]: A total of 100 subjects aged 65–75 years with hypertension and diabetes were randomly selected. AF was assessed by conventional electrocardiogram (ECG) and 4 weeks monitoring with a wearable Holter device (Nuubo™). N-terminal pro B-type natriuretic peptide (NT-proBNP), apolipoprotein CIII (ApoC-III), von Willebrand factor (vWF), ADAMTS13, urokinase plasminogen activator surface receptor (uPAR), and urokinase plasminogen activator (uPA) were determined in serum/plasma samples and the levels were compared depending on AF presence and mode of detection., [Results]: The AF prevalence in the studied population was found to be 20%. In seven subjects, AF was only detected after 1 month of Holter monitoring (hAF group). NT-proBNP levels were higher in subjects with AF compared with subjects with no AF (p < 0.0001), even when only taking into account the hAF group (p = 0.031). No significant differences were found in the other biomarkers. The NT-proBNP >95 pg/ml cut-off showed high sensitivity and specificity to detect AF (95%, 66.2%) or hAF (85.72%, 66.2%) and was found to be an independent predictor of AF and hAF in a logistic regression analysis. NT-proBNP correlated with AF burden (r = 0.597, p = 0.024)., [Conclusion]: NT-proBNP was elevated in AF cases not identified by ECG; thus, it may be used as a screening biomarker in asymptomatic high-risk populations, with a promising cut-off point of 95 pg/ml that requires further validation.