Molecular Insights Into Cardioembolism: <scp>NT</scp> ‐ <scp>proBNP</scp> and D‐Dimer Augment Risk Stratification and Drive <scp>NF</scp> ‐ <scp>κB</scp> / <scp>NLRP3</scp> ‐Mediated Injury

To optimize the STAF score by incorporating NT-proBNP and D-dimer for improved prediction of cardioembolic stroke (CE) and to investigate their synergistic molecular mechanisms. A retrospective study enrolled 371 AIS patients classified by TOAST criteria (CE vs. non-CE). Clinical, imaging, and biochemical data were used to construct/evaluate a modified STAF. Diagnostic performance was assessed via ROC curves, DeLong's test, IDI, and NRI. In vitro, H9c2 cardiomyocytes under hypoxia were treated with NT-proBNP/D-dimer to assess viability, apoptosis, inflammation, and signaling. In vivo, an AF rat model with cerebral embolism received AAV-mediated interventions (overexpression/knockdown). The modified STAF incorporated NT-proBNP ≥ 321.5 ng/L and D-dimer ≥ 0.67 μg/mL, achieving a significantly higher AUC (0.942) than the original STAF (0.846, p < 0.001). In vitro, NT-proBNP and D-dimer synergistically increased apoptosis and inflammation in cardiomyocytes by activating NF-κB. In vivo, overexpression exacerbated cerebral infarct size and upregulated NLRP3 pathway proteins, while knockdown mitigated these injuries. Incorporating NT-proBNP and D-dimer significantly enhances STAF accuracy for CE prediction. These biomarkers synergistically promote cardioembolic inflammation and injury via NF-κB-NLRP3 pathway activation, suggesting potential therapeutic targets.