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1 Declaration of conflict of interest Nothing to disclose

2 Strategies for prevention and regression of vascular calcification: new treatment options? Leon J Schurgers, PhD Department of Biochemistry Maastricht University The Netherlands European Society of Cardiology Munich, 29 th of August 2012

3 Vascular calcification as a marker of increased cardiovascular risk: a meta-analysis CV death Rennenberg et al. Vascular health and risk management ( ) Coronary artery calcium is a better predictor of cardiovascular events than the Framingham risk score and can help to reclassify asymptomatic individuals into high risk or low risk categories Alexopoulos et al. Nature Reviews Cardiology 2009

4 Balance between inhibitors and Initiators of calcification BMP-2 Matrix vesicles Apoptotic bodies OxLDL Ca 2+ and PO4 3- oxidative stress cytokines high glucose Warfarin MGP OP OPG Fetuin-A pyrophosphate acid ph Initiators of calcification Inhibition of calcification

5 Matrix Gla-protein (MGP) Von Kossa Alizerin o vitamin K-dependent protein o 84 amino acids (Mw ~11 kd) o Gla-residues (required for activity) o Serine-phosphorylation (function unknown) Luo et al. Nature 1997

6 VKA: from rat poison to drug 1948, dicoumarols launched as rat poison 1951, unsuccessful suicide attempt by US army soldier with warfarin 1954, warfarin approved as medicine 1955, Eisenhower one of the first famous recipient because of an heart attack Wisconsin Alumni Research Foundation

7 Interference with vitamin K-metabolism O O KH 2 KO K Glu COO - COO --

8 Schurgers et al. TMM 2012

9 Influence of VKA on medial calcification: time dependency

10 Low-risk AF patients on VKA treatment Weijs et al. Eur Heart J 2011

11 D ucmgp; Control E ucmgp; Warfarin

12 ouse models What about vascular calcification in the intima in a mouse model for atherosclerosis?

13 a m i l l i m a

14 Microcalcification is often accompanied by macrocalcification Type-II collagen stain

15 l i m A C m l o i B D

16 g-carboxylation affects VSMCs in vitro + vitamin K + warfarin What about in vivo effect of vitamin K? Schurgers et al. J Thromb Haem 2007

17 Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats n = 18 Control diet Control diet Control n = 6 3 mg Warfarin / 1,5 mg K1 3 mg Warfarin / 1,5 mg K1 Calcification n = 6 3 mg Warfarin / 1,5 mg K1 5 µg Vitamin K1 Low vitamin K n = 12 3 mg Warfarin / 1,5 mg K1 100 µg Vitamin K1 or K2 High vitamin K 0 6 Schurgers et al. Blood 2007 weeks 12

18 Aortic calcification (µg/mg tissue) Can we stop or even regress pre-formed medial artery calcification? 3,5 3 2,5 2 control warfarin low vit K * * * high vit K * 1,5 1 * = P < , Weeks 37% reduction Schurgers et al. Blood 2007

19 Von Kossa ucmgp cmgp Control diet Warfarin / 1,5 mg K1 low Vitamin K high Vitamin K Schurgers et al. Blood 2007

20 Strong upregulation of ucmgp in calcified vascular tissue Von Kossa staining. In black calcification ucmgp staining. In red immuno localization of inactive MGP Schurgers et al, ATVB 2005

Intimal vascular calcification is triggering by increased ucmgp correlation coefficient: 0.933; P < 0.

21 Intimal vascular calcification is triggering by increased ucmgp correlation coefficient: 0.933; P < Ca yield analysis of the thickened intima of type I to IV lesions with the proton microprobe. Microcalcification signal intensity increases from blue to red to yellow. Scale bars = 100 μm Roijers et al. Am J Path 2011

22 CAC Score Progression Vitamin K supplementation reduces progression of VC Design: Results: n= 388, mean age 68 years, 500µg K1 supplementation daily Endpoint: Coronary artery calcification (CAC) progression over 3 y. Significant differences were only apparent after secondary analysis, restricted to patients >85% adherent to supplementation (n = 367). Baseline CAC > All 60 (38-80) 40 (24-50) (4-29) 20 (3-47) 0 K1 Control 0 K1 Control K1 supplementation slows the progression of CAC in healthy older adults with preexisting CAC, independent of its effect on total MGP concentrations. No difference in CV morbidity / mortality between the groups. Shea et al. AJCN 2009

23 VitaK-CAC Study - Design - Population CAC-patients (n = 200) Not on VKA CAC score >100; < 400 Standard therapy + placebo (n = 100) randomised (1:1) follow-up = 2.0 years Standard therapy + Vitamin K2 (360) (n =100) Week 0 Week 52 Week 104 End points: primary = progress of coronary calcification secondary = vascular stiffness and biomarkers

0 years Standard therapy + Vitamin K1 (2mg) (n =100) Week 0 Week 52 End points:

24 Aortic stenosis - Study - Design - Population AS-patients (n = 200) Not on VKA AVC score > 50 Standard therapy + placebo (n = 100) randomised (1:1) follow-up = 1.0 years Standard therapy + Vitamin K1 (2mg) (n =100) Week 0 Week 52 End points: primary = progress of aortic valve calcification and CAC secondary = Echocardiography and biomarkers

25 Acknowledgements Chris Reutelingsperger Roger Rennenberg Cees Vermeer Catherine Shanahan Alexander Kapustin Rukshana Shroff Juergen Floege Willi Jahnen-Dechent Vincent Brandenburg Thilo Krueger Georg Schlieper Ralf Koos Martin Shearer Ralf Westenfeld

Declaration of conflict of interest

Declaration of conflict of interest Inhibitors of vascular calcification what have we learned from animal models Ralf Westenfeld Department of Cardiology Heinrich-Heine-University Düsseldorf Do you know