Atrial Fibrillation, Cerebral Small Vessel Disease and Gender Medicine: Focus on Biomarkers and Neuroimaging

Background/Objectives: Atrial fibrillation (AF) is the most common supraventricular arrhythmia and one of the most commonly encountered heart conditions in clinical practice. Emerging evidence suggests a significant role of inflammation, endothelial disfunction and extracellular matrix (ECM) remodeling in the pathogenesis of AF. Population studies have also suggested an association between AF and cerebral small vessel disease (CSVD), with growing evidence indicating that the burden of certain markers of CSVD is greater in women. However, the association between female sex and CSVD remains poorly understood. The aim of this study was thus to investigate the role of female sex in the association between circulating biomarkers and the presence of CSVD in AF patients undergoing oral anticoagulant therapy. Methods: The Strat-AF study is an observational, prospective, single-center, hospital-based study enrolling elderly patients with AF. Results refer to 170 patients (59 women and 111 men). Recruited patients are evaluated by means of a comprehensive protocol, with clinical, cerebral magnetic resonance imaging (MRI) and circulating biomarker assessments. Results: From a multivariate logistic regression analysis adjusted for multiple confounders, independent predictors were: in women, elevated vWF levels for the presence of lacunar infarcts [OR 3.24 (1.23-8.55), p = 0.018], elevated MMP-12, TIMP-1, TIMP-2, and TIMP-4 levels for the presence of CMBs [OR 7.76 (1.60-37.69), p = 0.021; OR 1.90 (1.02-3.52), p = 0.042; OR 2.46 (1.27-4.80), p = 0.008; and OR 2.36 (1.12-4.95), p = 0.023, respectively], elevated IL-6 and MMP-2 levels for the presence of WMH [OR 10.65 (1.31-86.67), p = 0.027; OR 3.36 (1.23-9.15), p = 0.018, respectively] and elevated MMP-12 and TIMP-2 levels for the presence of bgEPVS [OR 2.57 (1.22-5.93), p = 0.027; OR 2.15 (1.03-4.53), p = 0.043, respectively]; and in men: elevated TIMP-1 levels for the presence of WMH [OR 2.10 (1.08-4.08), p = 0.030], elevated TIMP-1 levels for the presence of bgEPVS [OR 2.20 (1.11-4.38), p = 0.025] and elevated TIMP-1 levels for SVDs positivity [OR 7.25 (2.18-24.15), p = 0.001]. Conclusions: These results from the Strat-AF study demonstrated that a complete biohumoral and instrumental assessment can jointly identify female patients with AF at higher risk of CSVD. These findings pave the way for the implementation of clinical protocols incorporating brain MRI and circulating biomarkers as potential innovative tools for an increasingly refined-and sex-specific-stratification of cardiovascular risk in AF patients undergoing oral anticoagulant therapy.