Neue Daten zu potentiell antikalzifikatorischen Effekten von Vitamin K im kardiovaskulären System

Zwei aktuelle Publikationen liefern Daten, dass ein Vitamin K-Mangel an der Entwicklung einer Kalziphylaxie beteiligt sein könnte und umgekehrt, die Supplementierung von Vitamin K das Fortschreiten der Verkalkung bei Aortenklappenstenose verlangsamen kann. Die Einnahme von Vitamin K Antagonisten (VKA) zur oralen Antikoagulation wird seit langem als ein Risikofaktor für das Auftraten der Kalziphylaxie diskutiert. Dieser mögliche Zusammenhang ist einer der Gründe, warum eine orale Antikoagulation mit VKA sehr kritisch bei Dialysepatienten in einer Einzelfallentscheidung diskutiert werden sollte. Mehr über den Zusammenhang zwischen Vitamin K-Mangel and kalzifizierender Arteriosklerose lesen Sie hier: 

"Prevention of vasculopathy by vitamin K supplementation:
Can we turn fiction into fact?"
 
(
Brandenburg, Vincent M.; Schurgers, Leon J.; Kaesler, Nadine; Püsche, Katrin; van Gorp, Rick H.; Leftheriotis, Georges; Reinartz, Sebastian; Koos, Ralf; Krüger, Thilo)

Die beiden genannten Publikationen sind:

(1) "Slower Progress of Aortic Valve Calcification With Vitamin K Supplementation: Results From a Prospective Interventional Proof-of-Concept Study."
(Brandenburg VM, Reinartz S, Kaesler N, Krüger T, Dirrichs T, Kramann R, Peeters F, Floege J, Keszei A, Marx N, Schurgers LJ, Koos R.)

Trial synopsis:

Background: Calcific aortic stenosis (CAS) is a degenerative disease characterized by aortic valve calcification (AVC). A resident anticalcification factor in cardiovascular structures, matrix Gla-protein (MGP), is activated by Vitamin K. Hence, vitamin K replenishment might decelerate progression of AVC.

Methods: We performed a prospective, open-label, randomized, interventional pilot trial over 12 months in patients with asymptomatic or mildly symptomatic CAS (mean age 71±9 years, 59 males). Patients received either 2 mg phytomenadione (vitamin K1, Ka-vit ®) orally once daily or placebo. Patients underwent two cardiac CT-scannings, at baseline and at study end for AVC quantification. 72 patients were treated per protocol (38 in vitamin K, 34 placebo group). End-stage renal disease and vitamin K antagonist treatment were exclusion criteria.

Results: Over 12 months the volume calcification score progressed in the vitamin K group from 793.2±742.0mL to 870.7±791.4mL compared to 836.1±856.3mL to 1017.2±939.2mL in the placebo group representing an increase of 77.5±165.1mL (+9.7 %) versus 181.1±234.1mL (+ 21.6 %). Linear regression with treatment group and baseline AVC measurement, as independent variables, revealed an estimated difference in the change in volume between vitamin K and placebo groups of -101.2mL (95 % confidence intervals: -194.1 to -8.3mL, p=0.0332). Adding the year of birth to the model did not improve the model or change the estimated difference. Dp-ucMGP as marker protein for vitamin K deficiency decreased significantly only in the vitamin K group by approximately 45% (from 439 to 243 pmol/L).

Discussion: The present study is the first-in-man trial regarding the potential influence of vitamin K supplementation upon calcification progression in CAS. This trial showed that a 12 months application of 2 mg phytomenadione daily slowed down significantly the progression of AVC compared to placebo. The effect is most likely via the vitamin K-dependent MGP as vitamin K-treatment significantly reduced dp-ucMGP plasma levels.

(2) "Vitamin K-Dependent Carboxylation of Matrix Gla Protein Influences the Risk of Calciphylaxis."

(Nigwekar SU, Bloch DB, Nazarian RM, Vermeer C, Booth SL, Xu D, Thadhani RI, Malhotra R.)

The ability of Matrix Gla protein (MGP) to inhibit calcification requires the activity of a vitamin K-dependent enzyme, which mediates MGP carboxylation. The authors investigated how MGP carboxylation influences the risk of calciphylaxis in adult patients receiving dialysis and examined the effects of vitamin K deficiency on MGP carboxylation. The present study included 20 patients receiving hemodialysis with calciphylaxis (cases) and 20 patients receiving hemodialysis without calciphylaxis (controls) matched for age, sex, race, and warfarin use. Cases had higher plasma levels of uncarboxylated MGP (ucMGP) and carboxylated MGP (cMGP) than controls. However, the fraction of total MGP that was carboxylated (relative cMGP concentration = cMGP/[cMGP + uncarboxylated MGP]) was lower in cases than in controls (0.58±0.02 versus 0.69±0.03, respectively; P=0.003). In patients not taking warfarin, cases had a similarly lower relative cMGP concentration. Each 0.1 unit reduction in relative cMGP concentration associated with a more than two-fold increase in calciphylaxis risk. Vitamin K deficiency associated with lower relative cMGP concentration in multivariable adjusted analyses (β=-8.99; P=0.04). In conclusion, vitamin K deficiency-mediated reduction in relative cMGP concentration may have a role in the pathogenesis of calciphylaxis. The authors are currently undertaking a prospectice study in which Vitamin K supplementation is investigated as potential treatment against calciphylaxis.