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Molecular Insights Into Cardioembolism: NT-proBNP and D-Dimer Augment Risk Stratification and Drive
1Department of Neurology, The Affiliated Wenling Hospital of Wenzhou Medical University (The First People's Hospital of Wenling), Wenling, China.
Insights
This study enhances cardioembolic stroke (CE) prediction by integrating NT-proBNP and D-dimer into the STAF score. These biomarkers synergistically promote inflammation and injury via the NF-κB-NLRP3 pathway.
Area of Science:
- Biomedical research
- Cardiovascular science
- Neurology
Background:
- The STAF score aids in predicting cardioembolic stroke (CE).
- Optimizing CE prediction requires incorporating novel biomarkers.
- Understanding the molecular mechanisms of CE is crucial.
Purpose of the Study:
- To enhance the STAF score for predicting CE by including NT-proBNP and D-dimer.
- To investigate the synergistic molecular mechanisms of NT-proBNP and D-dimer in CE.
Main Methods:
- A retrospective study of 371 acute ischemic stroke (AIS) patients.
- Development and validation of a modified STAF score using clinical, imaging, and biochemical data.
- In vitro and in vivo experiments using H9c2 cardiomyocytes and an AF rat model to assess molecular mechanisms.
Main Results:
- The modified STAF score, incorporating NT-proBNP and D-dimer, showed significantly higher predictive accuracy (AUC 0.942) than the original STAF (AUC 0.846).
- NT-proBNP and D-dimer synergistically increased cardiomyocyte apoptosis and inflammation by activating the NF-κB pathway.
- In vivo, biomarker overexpression exacerbated cerebral injury, while knockdown mitigated it, involving the NLRP3 pathway.
Conclusions:
- Incorporating NT-proBNP and D-dimer significantly improves the STAF score's accuracy for CE prediction.
- NT-proBNP and D-dimer synergistically induce cardioembolic inflammation and injury through NF-κB-NLRP3 pathway activation.
- These biomarkers represent potential therapeutic targets for CE.
Abstract:
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.
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