Research Director; Professor University of Liège - GIGA - Cardiovascular Sciences Liège, Liege, Belgium
Background: Hypercholesterolemia promotes calcification of arteries and of the aortic valve. The extent of calcification predicts poor cardiovascular outcome. Several studies indicate that platelets could play an active role in the calcification process. However, the link between hypercholesterolemia, platelets and vascular or valvular calcification remains unclear.
Aims: Our study aimed at assessing the role of platelets in arterial and aortic valve calcification under conditions of hypercholesterolemia.
Methods: We used a well-established rabbit model of aorta and aortic valve calcification induced by 16 weeks of a cholesterol-rich diet (0.3% cholesterol) supplemented with vitaminD2 (25.000U/day) for 15 days. Rabbits were treated with the antiplatelet drug ticagrelor administered in food. Vascular and valvular calcification were detected by computed tomography (CT) and alizarin red staining of heart sections. The presence of platelets on aortic valve surface was analyzed by scanning electron microscopy. We then conducted an unbiased proteomic analysis of releasates of platelets isolated from rabbit blood to assess cholesterol-induced changes in platelet function and identify potential soluble mediators of calcification.
Results: Aortic wall and valvular calcification developed in all rabbits fed a cholesterol rich-diet (n=13). Platelets were detected near calcification nodules on aortic valves. Ticagrelor treatment (n=6) inhibited ex vivo platelet reactivity to ADP, and it reduced by half the number of rabbits with detectable aortic macrocalcification on CT scans, while fully preventing aortic valve calcification. Among 543 detected proteins, the 16-week cholesterol-rich diet modified the levels of 79 proteins from platelet releasates as compared to baseline. Remarkably, 40 of these proteins are known regulators of vascular or valvular calcification, including paraoxonase-1, heparanase, periostin, fetuins, serpin proteases, thrombospondins, fibulins, CTGF, HGF, CD44, VCAM-1, vitronectin, fibronectin, and the complement system.
Conclusion(s): Platelet inhibition with ticagrelor limits vascular and valvular calcification induced under hypercholesterolemia. Platelets may represent sources of soluble mediators driving the calcification process.
