Prevention of vasculopathy by vitamin K supplementation: Can we turn fiction into fact?

Highlights

• We comprehensively summarize potential cardiovascular health benefits of vitamin K.

• We present an overview upon past and future studies regarding vitamin K supplementation and arteriosclerosis.

• We discuss how oral anticoagulant treatment with VKA might disturb the balance between pro- and anti-calcification factors.

• We describe human trials about the impact of vitamin K and coumadin-free anticoagulation upon calcifying arteriosclerosis.

Abstract

With the discovery that vitamin K-dependent matrix Gla-protein (MGP) is a strong and modifiable factor in the prevention of arterial calcification, vitamin K was put forward as novel treatment option in cardiovascular disease. The vasculoprotective properties of vitamin K are in part based on the ability to improve gamma-glutamylcarboxylation of MGP, which is a prerequisite for MGP as a calcification inhibitor. Data from experimental animal models reveal that high intake of vitamin K can prevent and even reverse vascular calcifications. In addition, clinical data demonstrate that prescription of vitamin K antagonists for long-term oral anticoagulant therapy accelerates vascular calcification. However, controlled data from randomized prospective vitamin K interventional trials are lacking, thereby weakening a general recommendation for supplementation. The present article summarizes our current knowledge on the association between vitamin K and cardiovascular health. Additionally, we focus on an outlook on important ongoing prospective vitamin K intervention studies. These studies address the issues whether vitamin K substitution helps modifying relevant cardiovascular surrogates such as vascular calcification and whether non-vitamin K oral anticoagulants provide an alternative to support cardiovascular health benefits. So research about cardiovascular protection by vitamin K is an evolving field in which we expect a boost of novel and relevant evidence shortly.

Introduction

Although vitamin K has originally emerged from a pure hemostasiological cofactor required to activate clotting factors, it is also a key factor in the regulation of bone and soft tissue calcification based on the anti-calcific property of vitamin K due to its ability to activate matrix-Gla protein (MGP). The unequivocal role of vitamin K is to function as cofactor in the post-translational gamma-glutamylcarboxylation of specific protein bound glutamate residues. Hence, these proteins are called vitamin K-dependent proteins (Gla-proteins). Data from epidemiological studies have pointed out to an important role of Vitamin K as a potentially protective factor for cardiovascular health [1], [2]. Replenishment of vitamin K via increased dietary intake or oral substitution is relatively easy and cost effective and thus it is intriguing to speculate about a favorable risk-benefit ratio. Vitamin K supplementation appears to be safe and the WHO has set no upper tolerance level for vitamin K intake [3]. Moreover, long-term high dosage therapy with vitamin K is not associated with increased thromboembolic events and no elevated event rate was recorded even with 45 mg vitamin K-2 (menatetrenone) daily for three years in 2185 postmenopausal osteoporotic women [4]. Prior to advise on recommendations for vitamin K supplementation, however, several gaps in evidence need to be acknowledged. Fig. 1 depicts a step-by-step approach of vitamin K replenishment from biological plausibility to large-scale evidence-providing, interventional, randomized-controlled trials (RCTs). We will guide the reader on this road and focus on ongoing clinical research in the vitamin K arena.