RESUMO
INTRODUCTION: Vitamin K antagonists, such as warfarin, are known to promote arterial calcification through blockade of gamma-carboxylation of Matrix-Gla-Protein. It is currently unknown whether other oral anticoagulants such as direct inhibitors of Factor Xa can have protective effects on the progression of aortic valve calcification. AIMS: To compare the effect of warfarin and rivaroxaban on the progression of aortic valve calcification in atherosclerotic mice. RESULTS: 42 ApoE-/- mice fed with Western-type Diet (WTD) were randomized to treatment with warfarin (n = 14), rivaroxaban (n = 14) or control (n = 14) for 8 weeks. Histological analyses were performed to quantify the calcification of aortic valve leaflets and the development of atherosclerosis. The analyses showed a significant increase in valve calcification in mice treated with warfarin as compared to WTD alone (P = .025) or rivaroxaban (P = .005), whereas no significant differences were found between rivaroxaban and WTD (P = .35). Quantification of atherosclerosis and intimal calcification was performed on the innominate artery of the mice and no differences were found between the 3 treatments as far as atherogenesis and calcium deposition is concerned. In vitro experiments performed using bovine interstitial valve cells (VIC) showed that treatment with rivaroxaban did not prevent the osteogenic conversion of the cells but reduce the over-expression of COX-2 induced by inflammatory mediators. CONCLUSION: We showed that warfarin, but not rivaroxaban, could induce calcific valve degeneration in a mouse model of atherosclerosis. Both the treatments did not significantly affect the progression of atherosclerosis. Overall, these data suggest a safer profile of rivaroxaban on the risk of cardiovascular disease progression.
Assuntos
Anticoagulantes/uso terapêutico , Estenose da Valva Aórtica/induzido quimicamente , Valva Aórtica/efeitos dos fármacos , Valva Aórtica/patologia , Calcinose/induzido quimicamente , Inibidores do Fator Xa/farmacologia , Rivaroxabana/farmacologia , Varfarina/toxicidade , Animais , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Calcinose/genética , Calcinose/metabolismo , Calcinose/patologia , Bovinos , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Inibidores do Fator Xa/toxicidade , Feminino , Masculino , Camundongos Knockout para ApoE , Medição de Risco , Rivaroxabana/toxicidade , Fatores de Tempo , Calcificação Vascular/genética , Calcificação Vascular/metabolismo , Calcificação Vascular/patologiaRESUMO
We aimed to investigate whether the expression of the OPG/RANK/RANKL triad in peripheral blood mononuclear cells (PBMC) and circulating levels of markers of ectopic mineralization (OPG, FGF-23, PPi) are modified in patients with calcific aortic valve disease (CAVD). We found that patients affected by CAVD (n = 50) had significantly higher circulating levels of OPG as compared to control individuals (p = 0.003). No differences between the two groups were found in FGF-23 and PPi levels. RANKL expression was higher in the PBMC from CAVD patients (p = 0.018) and was directly correlated with the amount of valve calcification (p = 0.032). In vitro studies showed that treatment of valve interstitial cells (VIC) with RANKL plus phosphate was followed by increase in matrix mineralization (p = 0.001). In conclusion, RANKL expression is increased in PBMC of patients with CAVD, is directly correlated with the degree of valve calcification, and promotes pro-calcific differentiation of VIC.