Inhibition of coagulation factor Xa attenuates myocardial ischemia reperfusion injury in mice

J. J. Posma, J. J. Posthuma, R. Van Oerle, H. Ten Cate, H. H. Spronk (Maastricht, Netherlands)

Arterial thrombosis
Date: 17.02.2017,
Time: 17:15 - 18:15

Objective: Myocardial infarction (MI) accounts for over 10% of all mortalities and is thereby one of the leading causes of death worldwide. Ischemic/reperfusion injury (IRI) has substantial effects on MI outcome. Several processes are involved in IRI, including the complex interaction between coagulation and inflammation. Although there is great progression in reperfusion treatment, long term morbidity in patients with coronary syndrome is still substantial. A limitation of the current treatment options for MI is the lack of prevention regarding IR events. Coagulation proteases such as thrombin or factor Xa (FXa) play central roles in the crosstalk between coagulation and inflammation. In vivo studies demonstrate that inhibition of coagulation proteases can attenuate IRI, mediated by protease activated receptors (PARs). Although in vivo thrombin inhibition (indirect) decreased IRI, FXa’s involvement in IRI is less evident. To elucidate FXa’s role in IRI after a MI, we studied the effect of FXa inhibition on myocardial IRI in an IR mouse model.

Methods: Male WT c57BL/6 mice (age 8-9 weeks) surgically received a ligature around the left anterior descending coronary artery. After seven days of recovery, myocardial ischemia was induced by tightening the ligature for 1h followed by loosening the ligature for 4h or 24h to induce reperfusion. The intervention consisted of one IV-injection of 100μl rivaroxaban (400 ng/ml) or placebo (0.9%NaCl) after 15min ischemia and 5min after reperfusion. Mice were then injected with Evans blue to visualize the area at risk (AAR). AAR is the area exposed to ischemia. Heart tissue was collected and stained with triphenyl tetrazolium chloride to differentiate between the AAR and area of infarction (AOI). AOI is the area with irreversible damage.

Results: Rivaroxaban treated mice showed significant reduced AOI/AAR compared to controls after 4 and 24h reperfusion. A reduction in AOI/AAR of 19.34% ±4.381 (mean+SEM) (n=8, p=0.0007) and 17.06% ±5.262 (mean±SEM) (n=8, p=0.0055) was observed after respectively 4 and 24 hours’ reperfusion.

Conclusion: Direct FXa inhibition by Rivaroxaban significantly reduces IRI in mice. This observation suggests that it might be beneficial to treat myocardial IRI with anti-coagulants. Although it has great clinical potential, future research is needed to elucidate the mechanisms of action.