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• W3016929461 abstract "HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 40, No. 5Risks of Vitamin K Antagonism Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBRisks of Vitamin K AntagonismMammograms as a Powerful Tool to Assess Calcification Progression Mandy E. Turner and Rachel M. Holden Mandy E. TurnerMandy E. Turner From the Department of Biomedical and Molecular Science (M.E.T., R.M.H.), Queen’s University, Kingston, ON, Canada. Search for more papers by this author and Rachel M. HoldenRachel M. Holden Correspondence to: Rachel M. Holden, MD, Department of Medicine, Queen's University, 3048 C Etherington Hall, Kingston K7L 3V6, Canada. Email E-mail Address: [email protected] From the Department of Biomedical and Molecular Science (M.E.T., R.M.H.), Queen’s University, Kingston, ON, Canada. Department of Medicine (R.M.H.), Queen’s University, Kingston, ON, Canada. Search for more papers by this author Originally published22 Apr 2020https://doi.org/10.1161/ATVBAHA.120.314117Arteriosclerosis, Thrombosis, and Vascular Biology. 2020;40:1022–1024This article is a commentary on the followingWarfarin Accelerates Medial Arterial Calcification in HumansThere is a positive linear relationship between the burden of vascular calcification (VC) and all cause- and cardiovascular-mortality.1–3 VC is not a single entity but a cluster of calcifications occurring in different layers and anatomic locations across the vascular tree, with different risk factors and cardiovascular (CV) consequences.4 Medial calcification, which occurs with aging and is accelerated by kidney disease, results in circumferential thickening of the blood vessels and loss of compliance, while intimal calcification occurs within atherosclerotic plaques. The gold standard method for VC assessment, coronary artery calcification (CAC), does not distinguish these 2 types and coronary arteries are more prone to intimal calcification.5 Breast artery calcification (BAC) observed on mammograms is an emerging tool for the specific assessment of medial calcification in women.6See accompanying article on page 1413Medial VC is regulated, in part, by a balance of extracellular molecules that actively promote or inhibit pathological calcium and phosphate deposition into the extracellular matrix.7 A critical inhibitor of VC is vitamin K-dependent MGP (matrix Gla protein). MGP is a VMSC- and endothelium-derived protein that contains negatively charged Gla residues that bind calcium.8 Functional MGP requires vitamin K-dependent post-translational modification. By inhibiting vitamin K recycling, warfarin treatment depletes tissue vitamin K, thereby impairing the function of MGP (Figure).9Download figureDownload PowerPointFigure. Schematic of the impact of warfarin on vascular calcification. In vascular smooth muscle and endothelial cells, warfarin inhibits vitamin K recycling through the inhibition of VKORC1 (vitamin K epoxide reductase complex). Vitamin K is required as a substrate for the gamma carboxylation of important proteins in the coagulation cascade, as well as activation of MGP (matrix Gla protein). Both phosphorylation (indicated by the P) and gamma carboxylation (indicated by the C) is required for functional MGP. Active MGP binds to calcium crystals forming in the extracellular matrix and prevents growth.In this issue of Arteriosclerosis, Thrombosis and Vascular Biology, Alappan et al10 present a retrospective case-control study using serial mammograms to assess the effect of warfarin treatment on BAC in women with and without chronic kidney disease (CKD). Non-CKD women receiving warfarin (N=35) had a 5-fold increase in the median rate of calcification compared with those on direct oral anticoagulants (DOACs; N=35; 9.9 [3.8–16] versus 1.9 [0.2–5.4] mm/breast per year). This finding suggests a vitamin K-specific effect that likely cannot be attributed to its anticoagulant activity or co-occurrence of cardiovascular disease (CVD) with anticoagulation therapy. In this way, this study improves on past observational studies reporting an impact of warfarin on VC.As expected, the progression of BAC increased with severity of kidney disease; those requiring dialysis progressed the most quickly at a rate of 20 (7.4–51) mm/breast per year (N=36), and this rate more than doubled with warfarin use 56 (29–233) mm/breast per year (N=14). An interesting paired analysis compared BAC progression rate during and after the cessation of warfarin treatment, whereby the majority of patients markedly reduced their rate of BAC progression (9/13). This finding is in the opposite direction of age, which is a confounding factor, and to the best of our knowledge, is the first indication that warfarin does not permanently alter the calcification of vascular tissue and suggests that conversion from established warfarin use to DOACs in eligible patients would likely mitigate BAC.This article addresses progression of BAC, as opposed to the net burden of calcification. While not necessarily a limitation, it would have been interesting to have included the baseline burden of calcification and the duration of time between mammograms, as they have done previously.11 Investigation of the potential role of warfarin on VC initiation and the impact of the burden of VC at the start of warfarin treatment on progression are interesting future directions. It is recognized that propagation and initiation of VC may occur through different mechanisms.12,13 Treatment with vitamin K for over 3 years modestly slowed the progression of CAC in healthy older adults but only in people with preexisting CAC at baseline.14In addition, this study reports VC regression (a negative rate of BAC progression) in some patients after the cessation of warfarin. This phenomenon is not commonly reported with other VC assessment methods,15 suggesting that either BAC is unique in this capacity, or there is a degree of measurement error that accounts for these participants. This group has previously published that BAC has a unique presentation, without apoptosis or osteogenic transdifferentiation of vascular smooth muscle cells.16 Alternatively, the intrareader and inter-reader variability for this method of quantifying BAC was reported as 13% and 14%, respectively, which may have generated negative rates.11The role of vitamin K antagonism on VC is an exciting area of research. While patients with CKD are often reported to be vitamin K deficient,17–19 in this study the relative increase in progression with warfarin was actually higher in women without kidney disease. This suggests that MGP-depletion and alterations associated with CKD are not synergistically accelerating VC. It is interesting to note that vitamin K supplementation is actively being investigated as a mechanism to slow VC in dialysis patients.20,21BAC consistently associates with CVD independent of known CVD risk factors and CAC scores.6 Studies investigating how BAC relates to medial calcification in other tissue beds, and whether the risk factors identified also relate to men are sparse. In a previous study by this group, peripheral arterial calcification in the ankle and foot in men and women, indicative of medial calcification, were each associated with duration of warfarin use.22 Thus, the results found in breast arteries may be generalizable to other vascular beds and to males as well.The American Heart Association recommends that, in patients with nonvalvular atrial fibrillation where anticoagulation is advised, DOACs should be favored for use over warfarin in eligible patients.23 This evidence base extends to patients with CKD stage 3 but in later stages of CKD, where VC is severe, the optimal treatment is uncertain as these patients have not been included in the relevant trials.24 However, on the horizon are a number of randomized trials in dialysis patients to address this question.25 The primary end point of all trials comparing warfarin to DOACs is bleeding risk and, although cardiovascular events are being assessed, unfortunately none of these trials propose to include a measure of VC or stiffness.Traditional risk assessment tools underestimate the risk of cardiovascular disease in females and, as demonstrated in the MESA study (Multi-Ethnic Study of Atherosclerosis), the addition of a CAC score improved risk stratification in females.26 Mammography represents an inexpensive and widely available potential alternative to computed tomography for the detection of calcification in females without additional radiation exposure. Screening mammography within an age range applicable to CVD has been routine for many years and thus a large body of retrospective data exists to determine risk factors and treatments that are unique for medial calcification. In this exciting contribution, Alappan et al10 demonstrated that vitamin K antagonism with warfarin is a risk factor for the progression of breast arterial calcification in females. The novel findings of this work include reversibility of calcification progression rates after warfarin cessation and the comparison to DOACs.DisclosuresNone.FootnotesFor Disclosures, see page 1024.Correspondence to: Rachel M. Holden, MD, Department of Medicine, Queen's University, 3048 C Etherington Hall, Kingston K7L 3V6, Canada. Email rachel.[email protected]caReferences1. Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, Liu K, Shea S, Szklo M, Bluemke DA, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups.N Engl J Med. 2008; 358:1336–1345. doi: 10.1056/NEJMoa072100CrossrefMedlineGoogle Scholar2. Peeters MJ, van den Brand JA, van Zuilen AD, Koster Y, Bots ML, Vervloet MG, Blankestijn PJ, Wetzels JF; MASTERPLAN Study Group. Abdominal aortic calcification in patients with CKD.J Nephrol. 2017; 30:109–118. doi: 10.1007/s40620-015-0260-7CrossrefMedlineGoogle Scholar3. London GM. Cardiovascular calcifications in uremic patients: clinical impact on cardiovascular function.J Am Soc Nephrol. 2003; 14(9suppl 4):S305–S309. doi: 10.1097/01.asn.0000081664.65772.ebCrossrefMedlineGoogle Scholar4. Vervloet M, Cozzolino M. Vascular calcification in chronic kidney disease: different bricks in the wall?Kidney Int. 2017; 91:808–817. doi: 10.1016/j.kint.2016.09.024CrossrefMedlineGoogle Scholar5. Nakamura Y, Naito M, Hayashi K, Fotovati A, Abu-Ali S. Effect of combined treatment with alendronate and calcitriol on femoral neck strength in osteopenic rats.J Orthop Surg Res. 2008; 3:51. doi: 10.1186/1749-799X-3-51CrossrefMedlineGoogle Scholar6. Bui QM, Daniels LB. A review of the role of breast arterial calcification for cardiovascular risk stratification in women.Circulation. 2019; 139:1094–1101. doi: 10.1161/CIRCULATIONAHA.118.038092LinkGoogle Scholar7. Paloian NJ, Giachelli CM. A current understanding of vascular calcification in CKD.Am J Physiol Renal Physiol. 2014; 307:F891–F900. doi: 10.1152/ajprenal.00163.2014CrossrefMedlineGoogle Scholar8. Wei FF, Trenson S, Verhamme P, Vermeer C, Staessen JA. Vitamin K–dependent matrix Gla protein as multifaceted protector of vascular and tissue integrity.Hypertension. 2019; 73:1160–1169. doi: 10.1161/HYPERTENSIONAHA.119.12412LinkGoogle Scholar9. McCabe KM, Booth SL, Fu X, Shobeiri N, Pang JJ, Adams MA, Holden RM. Dietary vitamin K and therapeutic warfarin alter the susceptibility to vascular calcification in experimental chronic kidney disease.Kidney Int. 2013; 83:835–844. doi: 10.1038/ki.2012.477CrossrefMedlineGoogle Scholar10. Alappan HR, Kaur G, Manzoor S, Navarrete J, O’Neill WC. Warfarin accelerates medial arterial calcification in humans.Arterioscler Thromb Vasc Biol. 2020; 40:1413–1419. doi: 10.1161/ATVBAHA.119.313879LinkGoogle Scholar11. Manzoor S, Ahmed S, Ali A, Han KH, Sechopoulos I, O’Neill A, Fei B, O’Neill WC. Progression of medial arterial calcification in CKD.Kidney Int Rep. 2018; 3:1328–1335. doi: 10.1016/j.ekir.2018.07.011CrossrefMedlineGoogle Scholar12. Chen NX, O’Neill KD, Moe SM. Matrix vesicles induce calcification of recipient vascular smooth muscle cells through multiple signaling pathways.Kidney Int. 2018; 93:343–354. doi: 10.1016/j.kint.2017.07.019CrossrefMedlineGoogle Scholar13. Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.Kidney Int. 2007; 71:438–441. doi: 10.1038/sj.ki.5002059CrossrefMedlineGoogle Scholar14. Shea MK, O’Donnell CJ, Hoffmann U, Dallal GE, Dawson-Hughes B, Ordovas JM, Price PA, Williamson MK, Booth SL. Vitamin K supplementation and progression of coronary artery calcium in older men and women.Am J Clin Nutr. 2009; 89:1799–1807. doi: 10.3945/ajcn.2008.27338CrossrefMedlineGoogle Scholar15. Wyatt CM, Drueke TB. Vascular calcification in chronic kidney disease: here to stay?Kidney Int. 2017; 92:276–278. doi: 10.1016/j.kint.2017.05.019CrossrefMedlineGoogle Scholar16. O’Neill WC, Adams AL. Breast arterial calcification in chronic kidney disease: absence of smooth muscle apoptosis and osteogenic transdifferentiation.Kidney Int. 2014; 85:668–676. doi: 10.1038/ki.2013.351CrossrefMedlineGoogle Scholar17. Turner ME, Adams MA, Holden RM. The Vitamin K metabolome in chronic kidney disease.Nutrients. 2018; 10:1076. doi: 10.3390/nu10081076CrossrefGoogle Scholar18. Holden RM, Morton AR, Garland JS, Pavlov A, Day AG, Booth SL. Vitamins K and D status in stages 3–5 chronic kidney disease.Clin J Am Soc Nephrol. 2010; 5:590–597. doi: 10.2215/CJN.06420909CrossrefMedlineGoogle Scholar19. Pilkey RM, Morton AR, Boffa MB, Noordhof C, Day AG, Su Y, Miller LM, Koschinsky ML, Booth SL. Subclinical vitamin K deficiency in hemodialysis patients.Am J Kidney Dis. 2007; 49:432–439. doi: 10.1053/j.ajkd.2006.11.041CrossrefMedlineGoogle Scholar20. Holden RM, Booth SL, Day AG, Clase CM, Zimmerman D, Moist L, Shea MK, McCabe KM, Jamal SA, Tobe S, et al. Inhibiting the progression of arterial calcification with vitamin K in HemoDialysis patients (iPACK-HD) trial: rationale and study design for a randomized trial of vitamin K in patients with end stage kidney disease.Can J Kidney Health Dis. 2015; 2:17. doi: 10.1186/s40697-015-0053-xCrossrefMedlineGoogle Scholar21. Krueger T, Schlieper G, Schurgers L, Cornelis T, Cozzolino M, Jacobi J, Jadoul M, Ketteler M, Rump LC, Stenvinkel P, et al. Vitamin K1 to slow vascular calcification in haemodialysis patients (VitaVasK trial): a rationale and study protocol.Nephrol Dial Transplant. 2014; 29:1633–1638. doi: 10.1093/ndt/gft459CrossrefMedlineGoogle Scholar22. Han KH, O’Neill WC. Increased peripheral arterial calcification in patients receiving warfarin.J Am Heart Assoc. 2016; 5:e002665. doi: 10.1161/JAHA.115.002665LinkGoogle Scholar23. January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC, Ellinor PT, Ezekowitz MD, Field ME, Furie KL, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the heart rhythm society in collaboration with the society of thoracic surgeons.Circulation. 2019; 140:e125–e151. doi: 10.1161/CIR.0000000000000665LinkGoogle Scholar24. Kimachi M, Furukawa TA, Kimachi K, Goto Y, Fukuma S, Fukuhara S. Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease.Cochrane Database Syst Rev. 2017; 11:CD011373. doi: 10.1002/14651858.CD011373.pub2MedlineGoogle Scholar25. Nigwekar SU, Thadhani R. Long-term anticoagulation for patients receiving dialysis.Circulation. 2018; 138:1530–1533. doi: 10.1161/CIRCULATIONAHA.118.037091LinkGoogle Scholar26. Lakoski SG, Greenland P, Wong ND, Schreiner PJ, Herrington DM, Kronmal RA, Liu K, Blumenthal RS. Coronary artery calcium scores and risk for cardiovascular events in women classified as “low risk” based on Framingham risk score: the multi-ethnic study of atherosclerosis (MESA).Arch Intern Med. 2007; 167:2437–2442. doi: 10.1001/archinte.167.22.2437CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Elango K, Javaid A, Khetarpal B, Ramalingam S, Kolandaivel K, Gunasekaran K and Ahsan C (2021) The Effects of Warfarin and Direct Oral Anticoagulants on Systemic Vascular Calcification: A Review, Cells, 10.3390/cells10040773, 10:4, (773) Related articlesWarfarin Accelerates Medial Arterial Calcification in HumansHarish R. Alappan, et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2020;40:1413-1419 May 2020Vol 40, Issue 5 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.120.314117PMID: 32320292 Originally publishedApril 22, 2020 Keywordscardiovascular diseasewarfarinvascular diseasevitamin KanticoagulantsEditorialsPDF download Advertisement" @default.
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