Pos1295 plasma dephosphorylated-uncarboxylated matrix gla-protein in systemic sclerosis patients: biomarker potential for vascular calcification and disease

Background Matrix Gla-protein (MGP) is a vitamin K dependent protein involved in the inhibition of vascular calcification (VC). Plasma dephosphorylated-uncarboxylated MGP (dp-ucMGP) is the fully inactivated form which correlates with increased risk of cardiovascular disease (CVD) and VC in certain patient groups such as hemodialysis patients [1]. In the arterial wall, it is primarily secreted by vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) [2]. In systemic sclerosis (SSc), inflammation and dysregulation of EC function strongly links to the development of vasculopathy. Interestingly, the risk of developing CVD is increased in SSc, even after adjustment for traditional cardiovascular risk factors, suggesting a role for vasculopathy and inflammation [3]. Objectives In this study, dp-ucMGP levels were determined in a well-defined historical cohort of early diagnosed SSc patients and compared with an age-matched Dutch cohort healthy controls (HCs). We studied the incidence of first-ever CVD in SSc and investigated if dp-ucMGP as a biomarker predicts CVD and/or all-cause mortality during long term follow-up and after adjustment for classical cardiovascular risk factors. Methods We conducted a retrospective cohort study among SSc patients originating from the POEMAS cohort of the Maastricht University Medical Center (MUMC) in the Netherlands, which started in 2005. Patients dependent on dialysis were excluded. Circulating plasma dp-ucMGP levels were determined at baseline and CVD and cardiovascular risk factors were retrieved from medical records. Results Our cohort consisted of 87 SSc patients, of which 64 (73.6%) were women, with a mean age at disease onset of 54.5 years (SD±19) and a median disease duration of 4.0 years (IQR 8.3). The median dp-ucMGP level at baseline was 634 pmol/L (IQR 301), which is greatly increased compared with 400 HCs (mean dp-ucMGP<393 pmol/L). Only one patient had prevalent CVD before onset SSc. Nine patients were lost to follow-up, in the remaining 78 SSc patients, 26 (33.3%) patients suffered from first CVD event during the study period, with a median time of 10.5 (IQR 15.2) years from onset SSc disease, corresponding to an incidence rate of 29.9 per 1000 person-years. Cardiovascular risk factors were not significantly different between patients with and without CVD. Odds ratios for sex (OR 2.44; 95%CI 0.89-6.72) and hypertension (OR 2.53; 95%CI 0.86-7.46) tended to predict CVD, but the association did not reach statistical significance. However, Kaplan-Meier analysis showed that elevated dp-ucMGP levels (>634 pmol/L) were associated with an increased risk for CVD and/or death during the first 10 years follow-up (log-rank test: P=0.006). Conclusion This study shows increased dp-ucMGP levels in SSc patients compared to age-matched HCs, indicating dp-ucMGP as a biomarker of disease. We confirm the high risk of CVD in SSc patients but traditional cardiovascular risk factors did not predict development of CVD. In contrast, high dp-ucMGP levels revealed an increased risk for CVD and/or death in SSc. It is still unclear what caused the increased dp-ucMGP levels in SSc patients, but given the strong, inverse association between dp-ucMGP and vitamin K status, a vitamin K deficiency is proposed. Whether this is caused by malabsorption or inflammation requires further research. References [1]Delanaye P et al. Dephosphorylated-uncarboxylated Matrix Gla protein concentration is predictive of vitamin K status and is correlated with vascular calcification in a cohort of hemodialysis patients. BMC Nephrol. 2014;15:145. [2]Barrett H et al. Is Matrix Gla Protein Associated with Vascular Calcification? A Systematic Review. Nutrients. 2018;10[4]. [3]Kurmann RD et al. Cardiovascular Risk Factors and Atherosclerotic Cardiovascular Events Among Incident Cases of Systemic Sclerosis: Results From a Population-Based Cohort (1980-2016). Mayo Clin Proc. 2020;95(7):1369-78. Acknowledgements: NIL. Disclosure of Interests Judith Potjewijd Speakers bureau: GSK, Jan Damoiseaux: None declared, Leon Schurgers: None declared, Pieter van Paassen Speakers bureau: GSK, Takeda, Shire, Grant/research support from: GSK.