https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Bonn Medizinische Klinik und Poliklinik II Bonn, Deutschland; 2Universitätsklinikum Bonn Institut für Experimentelle Hämatologie und Transfusionsmedizin Bonn, Deutschland; 3Universitätsklinikum Bonn Klinik für Anästhesiologie Bonn, Deutschland
Background:
With mortality rates ranging from 15 to 40% under optimal medical treatment, infectious endocarditis (IE) remains one of the deadliest infectious diseases worldwide. Staphylococcus aureus (S. aureus) is the most common pathogen and the aortic valve the most often affected valve. While data suggests a close link between inflammation and activation of primary and secondary coagulation, there is limited data on its involvement in an endocarditis model.
Hypothesis:
We hypothesize that inactivation of fibrin through oral Dabigatran treatment reduces susceptibility to endocarditis in a murine model of S. aureus induced IE.
Methods:
Dabigatran was administered orally as supplement in the normal chow (10 mg/g). To assess coagulation, partial thromboplastin (pTT) time was measured from whole blood samples. Standardized IE was induced via intravenous injection of 105 CFU S. aureus 72h after ultrasound guided endothelial injury of the aortic valve with a coronary guide wire. Pro-inflammatory cytokines (IL6, TNF-a, IL-1b) were measured in plasma samples obtained immediately before sacrifice, at either 1d or 3d after bacterial challenge. Bacterial cultivation was performed from peripheral blood and valve tissue. Systemic cellular immune response and platelet function was analyzed using flow cytometry.
Results:
Oral Dabigatran raised pTT in whole blood samples from 11.4s to 232.8s. Cultivation of infected IE valves revealed reduced bacterial burden in Dabigatran treated mice (Dabi-: 3.48 CFU Dabi+: 2.6 CFU), correspondingly we found decreased bacteremia in Dabigatran treated mice (Dabi-: 11.6 CFU Dabi+: 6.8 CFU) and reduced pro-inflammatory cytokine (IL6 Dabi-: 1524pg/ml; Dabi+:975.0 pg/ml). Both treatment groups showed neutrophilia after bacterial injection. We found a reduction in indirect signs of endocarditis in the echocardiography, such as the occurrence of aortic valve regurgitation or a decrease in aortic valve thickness (Dabi-: 0.32mm; Dabi+:0.15mm). Flow cytometry revealed reduced platelet activity and immune-platelet complex formations (Dabi-:4897; Dabi+1734).
Conclusion:
Oral Dabigatran treatment impairs IE development in a murine model. Dabigatran treatment reduced direct endocarditis signs including blood and valvular cultures and immunofluorescence S. aureus staining and indirect signs in echocardiography such as aortic valve cusp diameter and aortic regurgitation frequency. Overall Dabigatran represents a promising agent for the prevention of aortic valve endocarditis. Future studies should examine human registry data to confirm this finding.