Warfarin, but not rivaroxaban, promotes the calcification of the aortic valve in ApoE-/- mice.

SummaryIntroductionVitamin 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.AimsTo compare the effect of warfarin and rivaroxaban on the progression of aortic valve calcification in atherosclerotic mice.Results42 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.ConclusionWe 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

Innate immunity and atherogenesis

Impact factor 2007: 2.24

Osteoprotegerin in Cardiovascular Disease:Ally or Enemy?

The OPG/RANK/RANKL axis is now recognized as a master regulator of bone remodeling, controlling osteoclast's maturation and extracellular matrix calcification. Nevertheless, a number of clinical and basic science studies conducted in the last few years demonstrated that the triad could be also involved in several physiological and pathological processes outside the bone tissue. In particular, evidences have been collected showing an active participation of OPG and RANKL in vascular pathology, including atherogenesis and arterial calcification. A series of epidemiological studies also showed that increased circulating levels of OPG are associated with significant, independent predictive value for future cardiovascular mortality/morbidity. However, the human studies did not unravel whether OPG should be considered as a promoter, a protective mechanism or is instead neutral with regard of vascular disease progression. Main objective of the present review is to summarize findings from both in vivo and in vitro investigations on the role played by OPG in vascular disease progression and to delineate a plausible scenario on the actual involvement of the OPG/RANK/RANKL triad and TRAIL in cardiovascular pathology

Hypertension and vascular calcification: a vicious cycle?

It is now well established that hypertension is accompanied by remodeling of the arterial wall with significant modifications in extracellular matrix composition and in vascular cell phenotype. Some of these changes, particularly elastin fragments generation, increased proteases activity and activation of transforming growth factor-\u3b2 signaling together with deposition of collagen and proteoglycans might generate a permissive soil for vascular calcification. On the other hand, calcium deposits within large arterial conduits can reduce vessel's elasticity and contribute to the generation of blood pressure pattern associated with vascular stiffness, namely isolated systolic hypertension. Hence, a hypothetical vicious cycle exists between hypertensive arterial damage and vascular calcification. Herein, we revised clinical and basic science findings supporting this possibilit

Fibroblast growth factor 23 and the bone-vascular axis: lessons learned from animal studies.

Calcification of arteries and cardiac valves is observed commonly in dialysis patients and represents a major determinant of the heightened cardiovascular risk observed during chronic kidney disease (CKD) progression. Recent advances from clinical and basic science studies suggest that vascular calcification should be considered a systemic disease in which pathologic processes occurring in the bone and kidney contribute to calcium deposition in the vasculature. Among the factors potentially involved in the vascular-bone axis dysregulation associated with CKD, there now is increasing interest in the role of the phosphaturic hormone fibroblast growth factor 23 (FGF-23). Increased FGF-23 plasma levels are observed with a decrease in kidney function and predict the risk of future cardiovascular mortality. However, clinical data are still unclear about whether a direct pathogenetic effect of FGF-23 on vascular/kidney/bone health exists. In the last few years, a series of basic science studies, performed using engineered mice, have contributed important pathophysiologic information about FGF-23 activities. This review summarizes findings from these studies and discusses the potential role of FGF-23 during the pathologic interplay between kidney, vessels, and bone in CKD

Lipoprotein remnants and dense LDL are associated with features of unstable carotid plaque: A flag for non-HDL-C

OBJECTIVE: We investigated the association between cholesterol across the LDL density range and in the VLDL and IDL particles with the prevalence of inflammatory cells in plaques of patients with severe carotid artery stenosis. METHODS: Forty-five patients undergoing carotid endarterectomy were studied. Plaque specimens were analyzed for cellular composition by immunocytochemistry using monoclonal antibodies. Lipoprotein subclasses were separated by gradient ultracentrifugation. RESULTS: We found no correlations between LDL-C, HDL-C and plasma triglyceride levels with plaque cellular composition. On the other hand, macrophage content was significantly related to cholesterol in the dense LDL subclasses (r = 0.30, p < 0.01) and in the triglyceride-rich lipoprotein remnants, namely dense VLDL and IDL particles (r = 0.46, p < 0.01). HDL subclasses were not correlated with plaque cellular composition. In a mirror manner, smooth muscle cells were inversely associated with cholesterol levels of the dense LDL subclasses (r = -0.32, p < 0.01 fraction 10; r = -0.26, p < 0.05 fraction 11) while only a non-significant trend was observed with the cholesterol in the VLDL-IDL fractions. These results provide the pathophysiological background to account for the relevance of non-HDL-C as the only lipid parameter, aside LDL density, significantly associated (\u3b2 = 0.351, p = 0.021) with carotid plaque macrophage content. CONCLUSIONS: We provide evidence that lipoprotein subclasses, specifically cholesterol in the dense LDL fractions and in the triglyceride-rich lipoprotein remnants, significantly affect carotid plaque cellular composition, in particular macrophages content