Vitamin K-Antagonists Accelerate Atherosclerotic Calcification and Induce a Vulnerable Plaque Phenotype

Abstract

BackgroundVitamin K-antagonists (VKA) are treatment of choice and standard care for patients with venous thrombosis and thromboembolic risk. In experimental animal models as well as humans, VKA have been shown to promote medial elastocalcinosis. As vascular calcification is considered an independent risk factor for plaque instability, we here investigated the effect of VKA on coronary calcification in patients and on calcification of atherosclerotic plaques in the ApoE−/− model of atherosclerosis.Methodology/Principal FindingsA total of 266 patients (133 VKA users and 133 gender and Framingham Risk Score matched non-VKA users) underwent 64-slice MDCT to assess the degree of coronary artery disease (CAD). VKA-users developed significantly more calcified coronary plaques as compared to non-VKA users. ApoE−/− mice (10 weeks) received a Western type diet (WTD) for 12 weeks, after which mice were fed a WTD supplemented with vitamin K1 (VK1, 1.5 mg/g) or vitamin K1 and warfarin (VK1&W; 1.5 mg/g & 3.0 mg/g) for 1 or 4 weeks, after which mice were sacrificed. Warfarin significantly increased frequency and extent of vascular calcification. Also, plaque calcification comprised microcalcification of the intimal layer. Furthermore, warfarin treatment decreased plaque expression of calcification regulatory protein carboxylated matrix Gla-protein, increased apoptosis and, surprisingly outward plaque remodeling, without affecting overall plaque burden.Conclusions/SignificanceVKA use is associated with coronary artery plaque calcification in patients with suspected CAD and causes changes in plaque morphology with features of plaque vulnerability in ApoE−/− mice. Our findings underscore the need for alternative anticoagulants that do not interfere with the vitamin K cycle.

VKORC1L1, an Enzyme Rescuing the Vitamin K 2,3-Epoxide Reductase Activity in Some Extrahepatic Tissues during Anticoagulation Therapy

“…The number of dispensed outpatient prescriptions for warfarin increased by 45%, from 21 million in 1998 to nearly 31 million in 2004 (19). Nevertheless, arterial calcifications were observed in human only after many years of VKA treatment (20,21). In laboratory animals, ectopic calcifications were observed in mice ApoE Ϫ/Ϫ treated by warfarin (20).…”

“…Nevertheless, arterial calcifications were observed in human only after many years of VKA treatment (20,21). In laboratory animals, ectopic calcifications were observed in mice ApoE Ϫ/Ϫ treated by warfarin (20). Similarly, OC depletion in bone was observed consecutively to the use of warfarin (22,23).…”

“…Warfarin Resistance of Extrahepatic Tissues May Be Explained by VKORC1L1-During long term anticoagulation therapy, effects on VKDPs involved in coagulation process are observed whereas effects on VKDPs produced in extrahepatic tissues are not apparent or quite difficult to observe. Indeed, to induce arterial calcification by warfarin in rats, excessive doses of anticoagulants widely superior to the therapeutic doses were used in the various studies previously published (20,32,33). Price et al (33) had to treat rats twice a day with 150 mg/kg warfarin (ϳ4000-fold higher than the therapeutic dose used in human medicine) to induce rapid calcification of the elastic lamellae in the media of major arteries and in aortic heart valves.…”

New Perspectives for the Nutritional Value of Vitamin K in Human Health

“…Furthermore, vitamin K was shown to induce a regression of preformed warfarin-induced vascular calcifications, with restoration of arterial distensibility [31]. The ApoE knockout mice model of atherosclerosis treated with warfarin displayed increased atherosclerotic plaque calcification and plaque vulnerability [32]. In humans, VKA use was associated with coronary artery plaque calcification in patients with suspected coronary artery disease (CAD), where calcification of coronary plaques significantly increased with prolonged VKA use [32,33].…”

“…The ApoE knockout mice model of atherosclerosis treated with warfarin displayed increased atherosclerotic plaque calcification and plaque vulnerability [32]. In humans, VKA use was associated with coronary artery plaque calcification in patients with suspected coronary artery disease (CAD), where calcification of coronary plaques significantly increased with prolonged VKA use [32,33]. Also, increased calcification of aortic valves was observed in patients receiving preoperative VKAs relative to non-treated patients [34,35].…”