Effects of vitamin k2 and d3 supplementation on cardiac and systemic inflammation: a randomized controlled trial

Abstract Background Emerging evidence suggests that vitamins K2 and D3 may influence cardiovascular health by modulating inflammation. These vitamins have been shown to inhibit pro-inflammatory cytokines, such as IL-6 and TNF-α, and may reduce vascular calcification through matrix Gla protein (MGP) activation. Inflammation within epicardial adipose tissue (EAT) and pericoronary adipose tissue (PCAT) plays a key role in coronary artery disease (CAD) progression, making them valuable markers of cardiac inflammation measured by cardiac computed tomography (CT). Purpose We investigated whether high-dose vitamin K2 and D3 supplementation reduces cardiac and systemic inflammation in high-risk elderly men. Methods In the AVADEC randomized, double-blinded, placebo-controlled trial, 388 men (aged 65–74) received daily vitamin K2 (720 μg) and D3 (25 μg) or placebo for 24 months. Cardiac inflammation was measured via epicardial adipose tissue (EAT) volume and attenuation on non-contrast CT, and pericoronary adipose tissue (PCAT) attenuation on contrast enhanced CT at baseline and 24 months follow-up. Systemic inflammation was evaluated at baseline and follow-up using blood tests of hs-CRP, IL-6, TNF-α, Fetuin-A, and Osteopontin (OPN). Moreover, dephosporylated uncarboxylated MGP (dp-ucMGP) analysis was used as a proxy of vitamin K2 levels and effect. Results At 24 months, the placebo group had a significant increase in EAT volume (∆5.66 cm³, p=0.010) versus a non-significant change in the vitamin group (∆3.44 cm³, p=0.082), yielding a between-group difference of –2.22 cm³ (p=0.453). Mean EAT attenuation declined similarly (placebo: ∆–1.16 HU vs vitamin: ∆–0.84 HU; p=0.249) and PCAT attenuation was unchanged (placebo: ∆–0.50 HU vs vitamin: ∆ –0.00 HU; p=0.619). Systemic markers (hs-CRP, IL-6, TNF-α, Fetuin-A) were unaltered from baseline to follow-up, while OPN increased in the vitamin group (∆25.72 pg/mL, p=0.031) but without significant between-group difference (18.32 pg/mL, p=0.299). Dp-ucMGP was reduced significantly in the intervention group compared to the placebo group (∆–212 pmol/L vs ∆45 pmol/L, p0.001). In subgroup analysis of participants with coronary artery calcification (CAC) score / ≥ 400, no statin use and statin use, dp-ucMGP / ≥ median, the results remained consistent with no significant difference between groups. Conclusions Despite significant changes in dp-ucMGP, indicating effective vitamin K2 supplementation, high-dose vitamin K2 and D3 did not significantly modify cardiac or systemic inflammation in this high-risk elderly cohort across CAC burden, statin use and dp-ucMGP levels. These results suggest alternative strategies may be required to target inflammation in cardiovascular disease prevention.