Uncarboxylated Matrix Gla Protein Research Articles

Correlation between circulating dephosphorylated uncarboxylated matrix Gla protein and vascular calcification in peritoneal dialysis patients.

To explore the association between serum Dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP) and abdominal aortic calcification (AAC) in peritoneal dialysis (PD) patients. A total 128 PD patients and 120 healthy controls were enrolled into the study. Serum dp-ucMGP was measured by enzyme-linked immunosorbent assay. Abdominal lateral plain radiography was used to evaluate the abdominal aortic calcification score (AACS). PD patients were divided into two groups according to the presence or absence of AAC. The relationships between dp-ucMGP levels and AACS were assessed by Spearman analysis and the value of dp-ucMGP in predicting AAC was evaluated by receiver operating characteristic (ROC). Serum dp-ucMGP in PD patients were significantly higher than controls (p < 0.05). And PD patients with AAC had higher serum dp-ucMGP than that of PD patients without AAC (p < 0.05). The serum dp-ucMGP levels was positively associated with AACS (r = 0.794, p < 0.0001) in PD patients. The multivariate logistic regression analyses showed that serum dp-ucMGP was independent factors of AAC in PD patients (OR = 2.555, 95% CI = 1.415-4.609). The area under ROC curve of dp-ucMGP was 0.9227, the corresponding sensitivity was 0.86, and the specificity was 0.92. Serum dp-ucMGP levels were positively associated with the AACS in PD patients. Higher serum dp-ucMGP level is independently associated with AAC in PD patients.

Rivaroxaban versus vitamin K antagonist treatment on the progression of coronary calcification: the IRIVASC-trial

Vitamin K antagonists (VKA) remain the only option of anticoagulation for people with mechanical valve replacement and due to their wider availability and lower acquisition costs, VKA’s remain widely used in low- and middle-income countries. It has been suggested that prolonged use of VKAs can increase the development of vascular and valvular calcification, though this effect has not been examined in larger randomized prospective trials. This investigator-initiated multicenter, prospective, randomized, open-label interventional trial randomized patients with baseline coronary or valvular calcification and an indication for prolonged oral anticoagulation therapy to Marcumar or Rivaroxaban. Patients were followed-up through repeat coronary computed tomographies to measure the progression of coronary and valvular calcification for up to 24 months. 192 patients were randomized between 2013 and 2018 to receive either Rivaroxaban or Marcumar and followed for up to 24 months. Coronary calcification significantly increased over time although there was no significant difference in progression between the groups after 12 and 24 months as measured by the Agatston score [360.7 (90.2; 1075.3) vs 380.4 (136.4; 1546.9) p = 0.69], the volume score [295.8 (93.0; 995.3) vs 335.5 (128.7; 1316.9) p = 0.95] and the mass score [58.5 (15.9; 172.0) vs 71.1 (24.8; 257.3) p = 0.5]. Dephosphorylated, uncarboxylated matrix Gla Protein (Dp-ucMGP) significantly decreased in the VKA group [Δ dp-uc MGP – 95.2 (− 554.1; 156.0) vs 231.3 (− 59.7; 388.1) p < 0.001]. There does not appear to be a relevant effect of vitamin K inhibition by the vitamin K antagonist marcumar upon coronary calcification.

Higher levels of circulating desphospho-uncarboxylated matrix Gla protein over time are associated with worse survival: the prospective Maastricht Intensive Care COVID cohort

BackgroundExtra-hepatic vitamin K-status, measured by dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP), maintains vascular health, with high levels reflecting poor vitamin K status. The occurrence of extra-hepatic vitamin K deficiency throughout the disease of COVID-19 and possible associations with pulmonary embolism (PE), and mortality in intensive care unit (ICU) patients has not been studied. The aim of this study was to investigated the association between dp-ucMGP, at endotracheal intubation (ETI) and both ICU and six months mortality. Furthermore, we studied the associations between serially measured dp-ucMGP and both PE and mortality.MethodsWe included 112 ICU patients with confirmed COVID-19. Over the course of 4 weeks after ETI, dp-ucMGP was measured serially. All patients underwent computed tomography pulmonary angiography (CTPA) to rule out PE. Results were adjusted for patient characteristics, disease severity scores, inflammation, renal function, history of coumarin use, and coronary artery calcification (CAC) scores.ResultsPer 100 pmol/L dp-ucMGP, at ETI, the odds ratio (OR) was 1.056 (95% CI: 0.977 to 1.141, p = 0.172) for ICU mortality and 1.059 (95% CI: 0.976 to 1.059, p = 0.170) for six months mortality. After adjustments for age, gender, and APACHE II score, the mean difference in plasma dp-ucMGP over time of ICU admission was 167 pmol/L (95% CI: 4 to 332, p = 0.047). After additional adjustments for c-reactive protein, creatinine, and history of coumarin use, the difference was 199 pmol/L (95% CI: 50 to 346, p = 0.010). After additional adjustment for CAC score the difference was 213 pmol/L (95% CI: 3 to 422, p = 0.051) higher in ICU non-survivors compared to the ICU survivors. The regression slope, indicating changes over time, did not differ. Moreover, dp-ucMGP was not associated with PE.ConclusionICU mortality in COVID-19 patients was associated with higher dp-ucMGP levels over 4 weeks, independent of age, gender, and APACHE II score, and not explained by inflammation, renal function, history of coumarin use, and CAC score. No association with PE was observed. At ETI, higher levels of dp-ucMGP were associated with higher OR for both ICU and six month mortality in crude and adjusted modes, although not statistically significantly.

New Cardiovascular Biomarkers in Breast Cancer Patients Undergoing Doxorubicin-Based Chemotherapy.

Central Illustration : New Cardiovascular Biomarkers in Breast Cancer Patients Undergoing Doxorubicin-Based Chemotherapy. Cardiovascular diseases (CVDs) are relevant to the management of breast cancer treatment since a substantial number of patients develop these complications after chemotherapy. This study aims to evaluate new cardiovascular biomarkers, namely CXCL-16 (C-X-C motif ligand 16), FABP3 (fatty acid binding protein 3), FABP4 (fatty acid binding protein 4), LIGHT (tumor necrosis factor superfamily member 14/TNFS14), GDF-15 (Growth/differentiation factor 15), sCD4 (soluble form of CD14), and ucMGP (uncarboxylated Matrix Gla-Protein) in breast cancer patients treated with doxorubicin (DOXO). This case-control study was conducted in an oncology clinic that included 34 women diagnosed with breast cancer and chemotherapy with DOXO and 34 control women without cancer and CVD. The markers were determined immediately after the last cycle of chemotherapy. The statistical significance level adopted was 5%. The breast cancer group presented higher levels of GDF-15 (p<0.001), while control subjects had higher levels of FABP3 (p=0.038), FABP4 (p=0003), sCD14, and ucMGP (p<0.001 for both). Positive correlations were observed between FABPs and BMI in the cancer group. GDF15 is an emerging biomarker with potential clinical applicability in this scenario. FABPs are proteins related to adiposity, which are potentially involved in breast cancer biology. sCD14 and ucMGP engage in inflammatory and vascular calcification. The evaluation of these novel cardiovascular biomarkers could be useful in the management of breast cancer chemotherapy with DOXO.

Vitamin K2 (MK-7) attenuates LPS-induced acute lung injury via inhibiting inflammation, apoptosis, and ferroptosis.

Acute lung injury (ALI) is a life-threatening disease that has received considerable critical attention in the field of intensive care. This study aimed to explore the role and mechanism of vitamin K2 (VK2) in ALI. Intraperitoneal injection of 7 mg/kg LPS was used to induce ALI in mice, and VK2 injection was intragastrically administered with the dose of 0.2 and 15 mg/kg. We found that VK2 improved the pulmonary pathology, reduced myeloperoxidase (MPO) activity and levels of TNF-α and IL-6, and boosted the level of IL-10 of mice with ALI. Moreover, VK2 played a significant part in apoptosis by downregulating and upregulating Caspase-3 and Bcl-2 expressions, respectively. As for further mechanism exploration, we found that VK2 inhibited P38 MAPK signaling. Our results also showed that VK2 inhibited ferroptosis, which manifested by reducing malondialdehyde (MDA) and iron levels, increasing glutathione (GSH) level, and upregulated and downregulated glutathione peroxidase 4 (GPX4) and heme oxygenase-1 (HO-1) expressions, respectively. In addition, VK2 also inhibited elastin degradation by reducing levels of uncarboxylated matrix Gla protein (uc-MGP) and desmosine (DES). Overall, VK2 robustly alleviated ALI by inhibiting LPS-induced inflammation, apoptosis, ferroptosis, and elastin degradation, making it a potential novel therapeutic candidate for ALI.

#5745 CORRELATION BETWEEN MATRIX GLA PROTEIN LEVEL AND EFFECT OF VITAMIN K2 THERAPY ON VASCULAR CALCIFICATION IN HEMODIALYSIS PATIENTS

Abstract Background and Aims In hemodialysis patients, vascular calcifications are precocious, frequent, and excessive. The association between the level of vascular calcifications and mortality has been described in dialysis patients. The dephosphorylated and uncarboxylated matrix Gla protein (dp-ucMGP) is an indicator of vitamin K2 status and correlates with markers of vascular calcification. It is activated by γ glutamyl carboxylase that converts inactive matrix Gla protein into an active form, and vitamin K2 is a cofactor of this reaction. The active form of matrix Gla protein is a known inhibitor of arterial wall calcification and plays an essential role in bone turnover. The biological activity of the calcification-inhibitory matrix Gla protein can be achieved by simple administration of oral vitamin K2. Aim To assess the effect of vitamin k2 supplementation on vascular calcification and matrix Gla protein in hemodialysis patients. In addition, we wanted to clarify the role of vitamin k2 as prophylaxis against vascular calcification in hemodialysis patients not suffering from vascular calcifications. Method The study included 112 hemodialysis adult patients not receiving vitamin k antagonists. The study was conducted at the Urology and Nephrology Center, Mansoura University. Patients who suffered from vascular calcification (68 patients) received oral 180 μgr of vitamin K2 every day for one year. Uncarboxylated matrix Gla protein concentrations were quantified using ELISA before administering vitamin k2 and after 12 months of treatment. In addition, we used an abdominal CT scan to assess aortic calcification with Agatston score. The scan was performed at the beginning of the study and after 12 months of follow-up. Patients who did not suffer from vascular calcification (44 patients) were randomly assigned to either receive oral vitamin K2 or no treatment. Uncarboxylated matrix Gla protein concentrations were quantified using ELISA at randomization and 12 months. Aortic calcification was evaluated using Agatston score after an abdominal CT scan that was performed at the beginning and at 12 months of follow-up. Results There was a positive and statistically significant correlation between un-carboxylated matrix Gla protein level and vascular calcification (rs = 0.64, P-value &amp;lt; 0.001). Among patients with vascular calcification, the baseline plasma (dp-ucMGP) significantly decreased by 21.3% after treatment of vitamin k2 for one year. Besides, the median baseline calcium score significantly decreased by 15.1% after 1year of vitamin k2 treatment. On the other hand, patients without vascular calcification had their 1-year matrix GLA protein comparable between the two groups. Despite the reduction of matrix GLA protein in the vitamin k2 naïve group, there was no statistically significant difference. In addition, the calcium score after one year was comparable between both groups. Conclusion Hemodialysis patients are at risk of vascular calcification. There is a positive correlation between (dp-ucMGP) protein and vascular calcification. Supplementation of vitamin K2 is safe and improves the serum markers of its deficiency. Also, vitamin K2 supplementation slows the progression of calcification. On the other hand, there is a lack of strong evidence that vitamin K2 supplementation slows down the calcification progression in dialysis patients. Therefore, we recommend further studies to delineate the efficacy and cost-effectiveness of the drug.

Association of Red Blood Cell Distribution Width and Neutrophil-to-Lymphocyte Ratio with Calcification and Cardiovascular Markers in Chronic Kidney Disease.

We aimed to investigate the association between Red Blood Cell Distribution Width (RDW) and Neutrophil-to-Lymphocyte Ratio (NLR), simple, rapidly assessed markers from the complete blood count with vascular calcification (VC)/stiffness and cardiovascular disease (CVD) in chronic kidney disease (CKD). Dephosphorylated, uncarboxylated matrix Gla-protein (dp-ucMGP), and central/peripheral hemodynamics' parameters were measured in 158 CKD patients, including Hemodialysis and Peritoneal Dialysis. Spearman's rho analysis showed that RDW correlated with C-reactive protein (CRP) (r = 0.29, p < 0.001), dp-ucMGP (r = 0.43, p = < 0.0001), central diastolic blood pressure (DBP) (r = -0.19, p = 0.02), and albuminuria (r = -0.17, p = 0.03). NLR correlated with the duration of CVD (r = 0.32, p < 0.001), CRP (r = 0.27, p = 0.01), dp-ucMGP (r = 0.43, p < 0.0001), central DBP (r = -0.32, p < 0.0001) and eGFR (r = -0.25, p = 0.04). In multiple regression models, circulating dp-ucMGP was an independent predictor of RDW (β = 0.001, p = 0.001) and NLR (β = 0.002, p = 0.002). In CKD patients, RDW and NLR are associated with traditional and novel markers of VC and CVD.

Effect of vitamin K supplementation on serum calcification propensity and arterial stiffness in vitamin K-deficient kidney transplant recipients: A double-blind, randomized, placebo-controlled clinical trial

Vitamin K deficiency is common among kidney transplant recipients (KTRs) and likely contributes to progressive vascular calcification and stiffness. In this single-center, randomized, double-blind, placebo-controlled trial, we aimed to investigate the effects of vitamin K supplementation on the primary end point, serum calcification propensity (calciprotein particle maturation time, T50), and secondary end points arterial stiffness (pulse wave velocity [PWV]) and vitamin K status in 40 vitamin K-deficient KTRs (plasma dephosphorylated uncarboxylated matrix Gla protein [dp-ucMGP] ≥500 pmol/L). Participants (35% female; age, 57 ± 13 years) were randomized 1:1 to vitamin K2 (menaquinone-7, 360 μg/day) or placebo for 12 weeks. Vitamin K supplementation had no effect on calcification propensity (change in T50 vs baseline +2.3 ± 27.4 minutes) compared with placebo (+0.8 ± 34.4 minutes; Pbetween group = .88) but prevented progression of PWV (change vs baseline −0.06 ± 0.26 m/s) compared with placebo (+0.27 ± 0.43 m/s; Pbetween group = .010). Vitamin K supplementation strongly improved vitamin K status (change in dp-ucMGP vs baseline −385 [−631 to −269] pmol/L) compared with placebo (+39 [−188 to +183] pmol/L; Pbetween group < .001), although most patients remained vitamin K-deficient. In conclusion, vitamin K supplementation did not alter serum calcification propensity but prevented progression of arterial stiffness, suggesting that vitamin K has vascular effects independent of calciprotein particles. These results set the stage for longer-term intervention studies with vitamin K supplementation in KTRs. Trial registryEU Clinical Trials Register (EudraCT Number: 2019-004906-88) and the Dutch Trial Register (NTR number: NL7687).

Vitamin K1 and progression of cardiovascular calcifications in hemodialysis patients: the VitaVasK randomized controlled trial.

Cardiovascular calcifications are prevented by matrix Gla protein (MGP), a vitamin K-dependent protein. Haemodialysis patients exhibit marked vitamin K deficiency. The randomized, prospective, open-label, multicentre VitaVasK trial analysed whether vitamin K1 supplementation reduces progression of coronary artery calcifications (CACs) and thoracic aortic calcifications (TACs). Patients with pre-existing CACs were randomized to continue on standard care or to additionally receive 5mg of vitamin K1 orally thrice weekly. Hierarchically ordered primary endpoints were progression of TAC and CAC in computed tomography scans at 18months. Linear mixed effects models with repeated measures at baseline and 12 and 18months assessed treatment effects after adjusting for study site. Of 60 randomized patients, 20 dropped out for reasons unrelated to vitamin K1, resulting in 23 control and 17 vitamin K1 patients. The trial was stopped early due to slow recruitment. At 18months, the average TAC progression was 56% lower in the vitamin K1 compared with the control group (p=.039). CAC significantly progressed within the control group, but not within the vitamin K1 group. Average progression at 18 months was 68% lower in the vitamin K1 compared to the control group (P=.072). Vitamin K1 reduced plasma levels of pro-calcific uncarboxylated MGP by 69% at 18months. No treatment-related adverse events were noted. Vitamin K1 intervention is a potent, safe and cost-effective approach to correct vitamin K deficiency and to potentially reduce cardiovascular calcification in this high-risk population.

The effect of menaquinone-7 supplementation on dp-ucMGP, PIVKAII, inflammatory markers, and body composition in type 2 diabetes patients: a randomized clinical trial

BackgroundType 2 diabetes mellitus (T2DM) is a common disorder that is characterized by chronic hyperglycemia and chronic inflammation, which also have a reinforcing effect on each other. The present research studied the effects of menaquinone (MK-7) supplementation on serum dp-ucMGP (dephospho uncarboxylated Matrix Gla Protein), PIVKAII (Prothrombin Induced by Vitamin K Absence), inflammatory markers and body composition indices in type 2 diabetes mellitus (T2DM) patients.MethodsThis 12-week double-blind placebo-controlled randomized clinical trial allocated 60 T2DM patients equally into a MK-7 (200 mcg/day) group or a placebo group. All patients also received dietary advice at the beginning of study and their dietary intakes were checked using a 3-day food record. The body composition of each patient was also measured and their vitamin K status was assessed using the ELISA method to measure serum dp-ucMGP and PIVKAII. In addition, inflammatory status indices were also measured, including hsCRP (high-sensitivity C-reactive protein), IL-6 (interleukin-6) and TNF-α (tumor necrosis factor alpha). All measurements were made both before and after the intervention period.ResultsIn total 45 patients completed the trial (MK-7 group = 23 and placebo group = 22). The calorie and macronutrient intake of the two groups were similar pre and post intervention. There were statistically significant increases in dietary vitamin K intake for both groups over the course of the study (p < 0.05), but the intergroup differences were not significant. The body composition indices (i.e., body fat percentage, fat mass, fat free mass, muscle mass, bone mass and total body water) were not significantly different between groups or across the trial. The serum levels of the vitamin K markers, PIVKAII and dp-ucMGP, decreased significantly in the MK-7 group over the course of the study (p < 0.05), but there was no decrease in the placebo group. However, after adjusting for the baseline levels and changes in vitamin K intake, the between group differences were only significant for PIVKAII (p < 0.05). Following the intervention, the serum levels of the inflammatory markers (hsCRP, IL-6, and TNF-α) were significantly lower in the MK-7 group (p < 0.05), but not in the placebo group. However, the between group differences in the inflammatory markers were not statistically significant.ConclusionsAlthough further studies are needed, it appears that MK-7 supplementation can be effective in improving PIVKAII levels, but not for improving dp-ucMGP, inflammatory status or the body composition indices of T2DM patients.Trial registration numberThis study was prospectively registered at the Iranian Registry of Clinical Trials on the 20th of May 2019 (ID: IRCT20100123003140N22).

Biological Role of Vitamin K-With Particular Emphasis on Cardiovascular and Renal Aspects.

Vitamin K (VK) plays many important functions in the body. The most important of them include the contribution in calcium homeostasis and anticoagulation. Vascular calcification (VC) is one of the most important mechanisms of renal pathology. The most potent inhibitor of this process—matrix Gla protein (MGP) is VK-dependent. Chronic kidney disease (CKD) patients, both non-dialysed and hemodialysed, often have VK deficiency. Elevated uncarboxylated matrix Gla protein (ucMGP) levels indirectly reflected VK deficiency and are associated with a higher risk of cardiovascular events in these patients. It has been suggested that VK intake may reduce the VC and related cardiovascular risk. Vitamin K intake has been suggested to reduce VC and the associated cardiovascular risk. The role and possibility of VK supplementation as well as the impact of anticoagulation therapy on VK deficiency in CKD patients is discussed.

The Active Isoforms of MGP Are Expressed in Healthy and Varicose Veins without Calcification.

Matrix Gla protein (MGP), a local inhibitor of tissue mineralization, is associated with vascular calcification. Depending on the carboxylation and phosphorylation status, MGP has active conformations, e.g., carboxylated MGP (cMGP) and phosphorylated MGP (pMGP), but also inactive conformations, e.g., uncarboxylated MGP (ucMGP) and dephosphorylated MGP (dpMGP). Our purpose was to assess the presence of all MGP conformations in healthy veins (HV) and varicose veins (VV), concurrently with the analysis of circulating total MGP (tMGP) before and after the surgical stripping of VV. We collected samples from the great saphenous vein, considered as control group, and tissue from VV, designated as VV group. Plasma levels of tMGP were significantly decreased after the surgical removal of the VV (before 59.5 ± 17.2 vs. after 38.1 ± 11.3, p < 0.001). By using immunohistochemistry staining, we identified local cMGP and pMGP in the control and VV groups, both without calcification, while ucMGP and dpMGP were absent. cMGP was observed in the nucleus and cytoplasm and pMGP in the nucleus of cells belonging to the tunica media, tunica intima and vasa vasorum. Therefore, the active conformations of MGP (cMGP and pMGP) are prevalent in HV and VV without calcification, affirming their anti-calcifying role in veins.

Combining phosphate binder therapy with vitamin K2 inhibits vascular calcification in an experimental animal model of kidney failure.

Hyperphosphataemia is strongly associated with cardiovascular disease and mortality. Recently, phosphate binders (PBs), which are used to bind intestinal phosphate, have been shown to bind vitamin K, thereby potentially aggravating vitamin K deficiency. This vitamin K binding by PBs may offset the beneficial effects of phosphate reduction in reducing vascular calcification (VC). Here we assessed whether combining PBs with vitamin K2 supplementation inhibits VC. We performed 3/4 nephrectomy in rats, after which warfarin was given for 3 weeks to induce vitamin K deficiency. Next, animals were fed a high phosphate diet in the presence of low or high vitamin K2 and were randomized to either control or one of four different PBs for 8 weeks. The primary outcome was the amount of thoracic and abdominal aorta VC measured by high-resolution micro-computed tomography (µCT). Vitamin K status was measured by plasma MK7 levels and immunohistochemically analysed in vasculature using uncarboxylated matrix Gla protein (ucMGP) specific antibodies. The combination of a high vitamin K2 diet and PB treatment significantly reduced VC as measured by µCT for both the thoracic (P = 0.026) and abdominal aorta (P = 0.023), compared with MK7 or PB treatment alone. UcMGP stain was significantly more present in the low vitamin K2-treated groups in both the thoracic (P < 0.01) and abdominal aorta (P < 0.01) as compared with high vitamin K2-treated groups. Moreover, a high vitamin K diet and PBs led to reduced vascular oxidative stress. In an animal model of kidney failure with vitamin K deficiency, neither PB therapy nor vitamin K2 supplementation alone prevented VC. However, the combination of high vitamin K2 with PB treatment significantly attenuated VC.

Kidney Function-Dependence of Vitamin K-Status Parameters: Results from the TransplantLines Biobank and Cohort Studies.

High circulating dephosphorylated (dp) uncarboxylated (uc) matrix Gla protein (MGP) and uc osteocalcin (OC) concentrations are regarded as markers of vitamin K-deficiency. However, because MGP and OC are small molecules, they may potentially pass the glomerulus, and their blood concentrations may strongly depend on kidney function. However, many studies with vitamin K-status parameters do not structurally adjust for baseline kidney function, and detailed studies on kidney function-dependence of vitamin K-status markers are lacking. We therefore measured plasma dp-ucMGP using a chemiluminescent assay in 578 kidney transplant recipients (41% females, age 56 ± 13y, 7.5 (3.2 to 13.7)y after transplantation, eGFR 49 ± 17 mL/min/1.73 m2) participating in the prospective TransplantLines Cohort Studies. Additionally, dp-carboxylated MGP, ucOC and carboxylated OC were measured using ELISA in plasma of a subgroup of 60 participants. Finally, dp-ucMGP was measured in a separate cohort of 124 kidney transplant recipients before and three months after kidney transplantation. Dp-ucMGP positively correlated with creatinine, cystatin C, and negatively with eGFR (Spearman’s ρ 0.54, 0.60, and −0.54, respectively, p < 0.001 for all), and each 10 mL/min/1.73 m2 increase in eGFR was associated with a 14.0% lower dp-ucMGP. Additionally, dp-ucMGP strongly declined after kidney transplantation (pretransplantation: 1252 (868 to 1744) pmol/L to posttransplantation: 609 (451 to 914) pmol/L, p < 0.001). Proportions of dp-ucMGP over total MGP and ucOC over total OC were not associated with eGFR. This study highlights that dp-ucMGP is strongly associated with kidney function, and that levels strongly decrease after kidney transplantation. We therefore propose adequate adjustment for kidney function, or the use of kidney function-independent parameters such as proportion of uncarboxylated MGP or OC in the assessment of vitamin K-status in clinical practice and research.

Vitamin K &amp; D Deficiencies Are Independently Associated With COVID-19 Disease Severity

BackgroundWe investigated the association of vitamin K and vitamin D with coronavirus disease 2019 (COVID-19) outcomes.MethodsLevels of inactive vitamin K–dependent dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP; marker of vitamin K status) and 25-hydroxyvitamin D (25(OH)D; vitamin D status) were measured in plasma samples from participants with confirmed acute COVID-19 and were age- and sex-matched to healthy controls. Unadjusted odds ratios and adjusted odds ratios (AORs) with 95% CIs were computed using cumulative logistic regression.ResultsOne hundred fifty subjects were included, 100 COVID-19+ and 50 controls. The median age (interquartile range) was 55 (48–63) years, and 50% were females. Thirty-four percent had mild COVID-19 disease, 51% moderate disease, and 15% severe. Dp-ucMGP levels were higher (ie, worse K status) in COVID-19+ vs controls (776.5 ng/mL vs 549.8 ng/mL; P < .0001) with similar 25(OH)D between groups (25.8 vs 21.9 ng/mL; P = .09). Participants who were vitamin D deficient (<20 ng/mL) had the worse vitamin K status (dp-ucMGP >780 ng/mL) and experienced the most severe COVID-19 outcomes. In adjusted models, every 1-unit increase in the log2 dp-ucMGP nearly doubled the odds of acute critical disease or death (AOR, 1.84; 95% CI, 1.01–3.45), and every 1-unit decrease in the natural log 25(OH)D was associated with >3 times the likelihood of severe COVID-19 disease (AOR, 0.29; 95% CI, 0.11–0.67).ConclusionsEarly in acute COVID-19, both vitamin K and vitamin D deficiency were independently associated with worse COVID-19 disease severity, suggesting a potential synergistic interplay between these 2 vitamins in COVID-19.

Is circulating Gla-rich protein linked with coronary calcium and cardiovascular pathology in patients with atrial fibrillation or heart failure? A pilot study

Introduction: Nowadays Gla-rich protein (GRP) is recognized as a novel biomarker playing a pivotal role in the crosstalk between chronic inflammation and vascular calcification. Aim: The aim of this article is to study the link between circulating GRP, cardiovascular pathology, and the degree of arterial calcification evaluated by the coronary arterial calcium score (CACS) in a Bulgarian population sample. Materials and Methods: Adult participants (n = 81) of both genders were divided into: controls (n = 41)—subjects with estimated moderate-to-high risk without known cardiovascular diseases (CVDs) and a combined CVD group (n = 40)—patients with paroxysmal or persistent atrial fibrillation in sinus rhythm, and heart failure subjects with preserved ejection fraction. A structured interview was carried out for evaluation of the classical CVD risk factors. CACS was determined by multislice computed tomography. Routine laboratory parameters were extracted from medical records. Serum levels of total GRP, matrix Gla protein, and osteocalcin were estimated by commercial ELISA kits. Standard statistical methods (descriptive statistics, Student’s t-test and Spearman’s correlation) were applied. Statistical significance was considered at p&lt;0.05. Results: Significantly lower GRP levels were established in patients with coronary calcium compared to those without calcium deposits. Clear tendency for decreased levels of GRP was observed in the combined CVD group vs controls. Circulating GRP significantly correlates with uncarboxylated matrix Gla protein. An association between serum GRP, CRP, and low-density lipoproteins (LDLs) was demonstrated. Conclusion: This study adds new information regarding the role of circulating GRP as a new player in calcification inhibition. Our findings illuminate the link between total circulating GRP, CVD pathology, and the degree of coronary calcification.

Off‐target effects of oral anticoagulants – vascular effects of vitamin K antagonist and non‐vitamin K antagonist oral anticoagulant dabigatran etexilate

IntroductionVitamin K antagonists (VKA) and non‐vitamin K oral antagonist anticoagulants (NOAC) are used in the clinic to reduce risk of thrombosis. However, they also exhibit vascular off‐target effects. The aim of this study is to compare VKA and NOAC on atherosclerosis progression and calcification in an experimental setup. Material and methodsFemale Apoe−/− mice (age 12 weeks) were fed Western‐type diet as control or supplemented with dabigatran etexilate or warfarin for 6 or 18 weeks. Vascular calcification was measured in whole aortic arches using µCT and [18F]‐NaF. Atherosclerotic burden was assessed by (immuno)histochemistry. Additionally, in vitro effects of warfarin, thrombin, and dabigatran on primary vascular smooth muscle cells (VSMC) were assessed. ResultsShort‐term treatment with warfarin promoted formation of atherosclerotic lesions with a pro‐inflammatory phenotype, and more rapid plaque progression compared with control and dabigatran. In contrast, dabigatran significantly reduced plaque progression compared with control. Long‐term warfarin treatment significantly increased both presence and activity of plaque calcification compared with control and dabigatran. Calcification induced by warfarin treatment was accompanied by increased presence of uncarboxylated matrix Gla protein. In vitro, both warfarin and thrombin significantly increased VSMC oxidative stress and extracellular vesicle release, which was prevented by dabigatran. ConclusionWarfarin aggravates atherosclerotic disease activity, increasing plaque inflammation, active calcification, and plaque progression. Dabigatran lacks undesired vascular side effects and reveals beneficial effects on atherosclerosis progression and calcification. The choice of anticoagulation impacts atherosclerotic disease by differential off target effect. Future clinical studies should test whether this beneficial effect also applies to patients.

Statins, vascular calcification, and vitamin K-dependent proteins: Is there a relation?

The present cross-sectional clinical study aimed to examine the connection between statin exposure, coronary artery calcification (CAC), and vitamin K-dependent proteins (VKDPs) in patients with cardiovascular (CV) conditions. Two groups of patients were studied: patients with established CV disease (CVD) and healthy patients at moderate risk for CVD (a control group). The groups were also split into statin users and non-users. The following VKDPs were measured in plasma: uncarboxylated Matrix Gla-protein (ucMGP), undercarboxylated (ucOC), and carboxylated osteocalcin (cOC), Gla-rich protein (GRP). CAC score (CACS) was determined by multislice computed tomography. Among all the participants in the study, CACS was more pronounced in statin users compared to non-users; the same was found also among the CVD patients and among the controls. While the levels of ucMGP and GRP did not differ between statin users and non-users, ucOC and ucOC/cOC were significantly elevated in statin users, indicating vitamin K deficiency. There was a positive correlation between the levels of ucOC and CACS in the entire population and in the group of statin users, but not in statin non-users. No association was found between ucMGP or GRP and CACS. Statins had also an impact on the international normalized ratio and interacted with vitamin K antagonists (VKAs). Our results are in agreement with the existing evidence about positive association between statins and vascular calcification. They enlighten to a certain extent the possible mechanisms through which statins may enhance calcium accumulation in arterial wall, namely, by inhibition of vitamin K dependent proteins and functions involved in vascular protection.

Inactive matrix Gla protein is elevated in patients with inflammatory bowel disease.

BACKGROUNDMatrix Gla protein (MGP) is a vitamin K dependent peptide which has an established role in suppression of vascular calcification. Recent studies have pointed to a possible link between immunomodulatory effect of MGP and inflammatory bowel disease (IBD).AIMTo compare plasma levels of dephosphorylated and uncarboxylated MGP (dp-ucMGP) between IBD patients and controls.METHODSThis cross-sectional study was conducted on 70 patients with IBD (30 patients with ulcerative colitis and 40 patients with Crohn’s disease) and 60 age and gender matching healthy controls. Plasma dp-ucMGP levels were analyzed from blood samples by CLIA method using IDS-iSYS InaKtif MGP (Immunodiagnostic Systems, Frankfurt, Germany) according to the manufacturer's instructions. fecal calprotectin (FC) levels were determined from stool samples by turbidimetric immunoassay method using Bühlmann fecal calprotectin turbo assay (Bühlmann Laboratories Aktiengesellschaft, Schonenbuch, Switzerland). Other parameters were analyzed according to the standard laboratory procedures.RESULTSPlasma levels of dp-ucMGP were significantly higher in patients with IBD compared to the healthy control group (629.83 ± 124.20 pmol/mL vs 546.7 ± 122.09 pmol/mL, P < 0.001), and there was no significant difference between patients with Crohn’s disease and patients with ulcerative colitis (640.02 ± 131.88 pmol/mL vs 616.23 ± 113.92 pmol/mL, P = 0.432). Furthermore, a significant positive correlation of plasma dp-ucMGP levels was found with both FC levels (r = 0.396, P < 0.001) and high sensitivity C-reactive protein (hsCRP) levels (r = 0.477, P < 0.001). Moreover, in the total study population a significant positive correlation was found between dp-ucMGP with age (r = 0.210, P = 0.016) and waist circumference (r = 0.264, P = 0.002). Multiple linear regression analysis showed that dp-ucMGP levels retained significant association with FC (β ± SE, 0.06 ± 0.02, P = 0.003).CONCLUSIONStudy results support experimental data of MGP immunomodulatory IBD effect and indicate potential involvement in the pathophysiology of the disease, and possibly extraintestinal manifestations.

The Association of dp-ucMGP with Cardiovascular Morbidity and Decreased Renal Function in Diabetic Chronic Kidney Disease.

We aimed to investigate the possible association of the inactive, dephosphorylated, uncarboxylated matrix Gla protein (dp-ucMGP) with oxidized low-density lipoprotein (ox-LDL) and all-cause/cardiovascular (CV) mortality and renal function in diabetic chronic kidney disease (CKD). Ox-LDL and dp-ucMGP were determined in 66 diabetic CKD patients. All patients were prospectively followed for seven years, or until the occurrence of death, or a composite renal outcome of 30% estimated glomerular filtration rate (eGFR) reduction or progression to end-stage renal disease (ESRD) requiring dialysis occurred. Secondary outcomes were the occurrence of CV events. Kaplan–Meier curves showed that patients with plasma dp-ucMGP levels above the median (≥656 pM) had a significantly higher risk for all study endpoints. After adjustment for several well-known cofounders, multivariate Cox analysis showed that high plasma dp-ucMGP levels were associated with all-cause mortality (Hazard ratio-HR = 2.63, 95% Confidence Interval-CI = 1.17–5.94, p = 0.02), CV mortality (HR = 2.82, 95% CI = 1.07–7.49, p = 0.037) and progression of CKD (HR = 4.02, 95% CI = 1.20–13.46, p = 0.024). Circulating dp-ucMGP is associated with mortality and decreased renal function in diabetic CKD.