Symmetric Dimethylarginine for Risk Stratification of Cardioembolic Stroke

A significant proportion of ischemic strokes are classified as embolic stroke of undetermined source (ESUS), complicating secondary prevention. Nitric oxide metabolism is regulated by L-arginine (Arg), asymmetric (ADMA) and symmetric dimethylarginine (SDMA), contributing to increased cardiovascular risk. Previous studies suggest that SDMA and the ratio of Arg/SDMA help to detect atrial fibrillation (AF). We hypothesized that SDMA and Arg/SDMA improve diagnosis of cardioembolic stroke (CES), which may enable more accurate secondary prevention. This prospective nested case-control study included ischemic stroke patients (CES or ESUS) at Hannover Medical School between January 2022 and July 2023. Blood samples were collected after 24 h of stroke onset. ADMA, SDMA and Arg concentrations were measured and relevant biomarker ratios were calculated. Logistic regression and receiver operating curve analyses examined discriminatory biomarker performances for CES versus ESUS, alongside established clinical risk scores. 235 patients (107 CES, 128 ESUS) were analyzed. Arg/SDMA ratio and SDMA values showed comparable or better discriminatory power between CES and ESUS than clinical AF scores (AUC SDMA = 0.71 (95%CI: 0.64-0.77, p < 0.001); AUC Arg/SDMA = 0.74 (95%CI: 0.67-0.80, p < 0.001)). The same was true for AF detected after stroke (AFDAS) vs. ESUS. When combining Arg/SDMA-ratio and AS5F, the diagnostic accuracy was modestly improved compared to AS5F alone (DeltaAUC = 0.03 (95%CI: -0.06-0.11)). In conclusion, SDMA and Arg/SDMA ratio can serve as biomarkers for AF and AFDAS. While the additional predictive value in combination with clinical scores may be limited, these findings support the pathogenic role of the Arg/SDMA pathway in stroke pathophysiology. Trial Registration: The study is retrospectively registered in the German Clinical Trial Register (StudyID DRKS00038459).