Female Apoe mice (age 12 weeks) were fed western type diet (WTD) as control or supplemented with dabigatran etexilate or warfarin for 6 or 18 weeks. Vascular calcification was measured in whole aortic arches using µCT and [ F]-NaF. Atherosclerotic burden was assessed by (immuno)histochemistry. Additionally, in vitro effects of warfarin, thrombin and dabigatran on primary vascular smooth muscle cells (VSMC) were assessed.
Short-term treatment with warfarin promoted formation of atherosclerotic lesions with a pro-inflammatory phenotype, and more rapid plaque progression compared to control and dabigatran. In contrast, dabigatran significantly reduced plaque progression compared to control. Long-term warfarin treatment significantly increased both presence and activity of plaque calcification compared to control and dabigatran. Calcification induced by warfarin treatment was accompanied by increased presence of uncarboxylated matrix Gla protein. In vitro, both warfarin and thrombin significantly increased VSMC oxidative stress and extracellular vesicle release, which was prevented by dabigatran.
Warfarin aggravates atherosclerotic disease activity, increasing plaque inflammation, active calcification and plaque progression. Dabigatran lacks undesired vascular side effects and reveals beneficial effects on atherosclerosis progression and calcification. The choice of anticoagulation impacts atherosclerotic disease by differential off target effect. Future clinical studies should test whether this beneficial effect also applies to patients.
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