The effects of vitamin K₂ and vitamin D on aortic valve calcification Original paper

Aortic stenosis is a condition in which the aortic valve, one of the four valves of the heart, becomes abnormally narrowed.^[1] The major function of the aortic valve is to open and close to allow blood to exit the heart, so aortic stenosis impairs blood flow to the body. Aortic stenosis can therefore result in impaired exercise tolerance, fatigue, shortness of breath, heart failure, and death. A common cause of aortic stenosis is calcification of the aortic valve, a process in which calcium salts accumulate in the tissue, making it too stiff to open and close sufficiently.

Aortic stenosis

One factor that may influence the calcification of the aortic valve is vitamin K, as several vitamin K-dependent enzymes and proteins in the body have been suggested to protect against such pathological calcification.^[2] In line with this, use of the anticoagulant drug warfarin, which antagonizes vitamin K, is associated with a higher risk of aortic valve calcification.^[3] These observations are why the researchers who designed this study tested the effect of vitamin K supplementation on aortic valve calcification.

This 24-month randomized controlled trial examined the effect of vitamin K and vitamin D supplementation on the progression of aortic valve calcification (AVC) among 365 men (mean age of 71) with existing aortic stenosis. The participants were randomly assigned to take both vitamin K2 MK7 (720 µg) and vitamin D (1,000 IU), or a placebo, daily. The baseline AVC score, assessed using a noncontrast computer tomography (CT) scan, was 675 AU in the intervention group and 726 in the placebo group.

The primary outcome was change in AVC, assessed using a CT scan. Other outcomes included incidence of progressive aortic valve disease (defined as a greater than a 50% increase in AVC), progression of calcification in the aorta and coronary artery, aortic valve area, quality of life, and bone mineral density.

Compared to placebo, supplementation with vitamin K2 and vitamin D had no effect on aortic valve calcification. Both groups experienced increased calcification compared to baseline.

Supplementation with vitamin K2 and vitamin D also had no effect on aortic valve area, aortic calcification, coronary artery calcification, quality of life, bone mineral density, or the risk of progressive aortic valve disease, compared to the placebo.

Rates of cardiovascular disease (CVD) events were not different between groups. However, rates of CVD events were very low (20 events total, 10 events per group), meaning the study was likely underpowered for this outcome.

Levels of dephosphorylated-uncarboyxlated MGP decreased in the vitamin K2 plus vitamin D group compared to the placebo, indicating an improvement in vitamin K status.

In general, clinical trials are fairly consistent in reporting that vitamin K supplementation does not prevent calcification of the arteries in people with a high degree of existing calcification.^{[4][5][6][7][8]} On the other hand, a few studies suggest that vitamin K supplementation may be able to slow arterial calcification when said calcification is mild or has not yet occurred.^[9][10] However these beneficial findings derive from post-hoc (not initially planned) analyses, meaning more confirmatory research is needed.

All studies assessed calcification using CT or X-ray unless otherwise indicated. * Calcification assessed using 18F-NaF PET. ** Calcification assessed using 18F-NaF PET and CT.

Only one other clinical trial has tested the effect of vitamin K specifically on aortic valve calcification, noting an apparently beneficial effect. That trial administered 3 mg of vitamin K1 or a placebo daily to 99 people (mean age of 69) with aortic valve calcification, most of whom had aortic stenosis.^[11] After 12 months, calcification progressed less in the vitamin K1 group, compared to the placebo group. However, this study had a smaller sample size, a somewhat high dropout rate (27%, compared to 9.1% in the present trial), and was open label (meaning participants and researchers knew if they were getting vitamin K or the placebo). Finally, the published study reported results at 12 months, even though the trial preregistration indicated the trial was intended to last for 18 months. No explanation for this discrepancy was provided. As a result, this study seems to be comparatively weaker than the present trial.

This trial is unique compared to previous trials in that participants supplemented vitamin D along with vitamin K. There is limited research on the effect of vitamin D alone on arterial calcification, although one trial found that a higher daily dose of vitamin D supplements (either 10,000 IU or 4,000 IU) did not affect calcification of the tibial artery compared to a lower dose of 400 IU.^[12]