Serum biomarkers insights into occult atrial fibrillation related to embolic strokes of undetermined source: a narrative review

Embolic strokes of undetermined source (ESUS) often mask undiagnosed atrial fibrillation (AF), summing up for around 20–30% of these cryptogenic cases, given the experience that covert AF usually eludes routine monitoring (Justo ASDS, Nóbrega SMA, Silva ALA, J Clin Neurol 20:256, 2024). Early detection of AF is of utmost importance when guiding secondary stroke prevention therapies, biomarkers of atrial cardiopathy potentially being able to identify at-risk patients. This review synthetises serum biomarkers across four mechanistic domains – cardiac stress, inflammation and fibrosis, thrombosis and endothelial dysfunction, and metabolic and oxidative stress. We performed a narrative review with systematic search elements, in accordance with PRISMA guidelines for studies evaluating serum biomarkers that could potentially link ESUS to new-onset AF. A systematic search (1995 - Jan 2025) was conducted across PubMed, Embase, Cochrane, Scopus and Web of Science. The search performed yielded over 35 relevant studies encompassing over 6000 patients. Despite investigations of other candidates, NT-proBNP was the only biomarker consistently validated across multiple cohorts, permitting a brief meta-analysis of its diagnostic performance, its high levels being strongly associated with subsequent AF detection. Other biomarkers also showed promising results, especially those regarding the cardiac stress. Multimarker models integrating atrial-specific peptides, fibrosis and endothelial markers alongside ECG and imaging outperform single biomarker sampling. Natriuretic peptides (NPs) emerge as primary serum biomarkers guiding evaluation for subclinical AF including extended cardiac monitoring. Additional inflammatory, endothelial and remodelling markers may also provide insights about the subsequent mechanisms involved and potential prognostic value, besides indicating at-risk patients. Incorporating multimarker strategies may ultimately improve aetiological classification and secondary prevention in cryptogenic stroke.