The vitamin D-cardiovascular nexus unraveling mechanistic promise and trial reality

Epidemiological data consistently associate low vitamin D status with elevated cardiovascular risk, yet causal mechanisms remain contested. This review synthesized evidence through a protocol-guided approach, with database searches (PubMed/Embase/Web of Science; 2010–2024) focused on RCTs, mechanistic studies of cardiovascular pathways, and high-quality meta-analyses (AMSTAR-2 score ≥ 8). Mechanistic investigations consistently demonstrate vitamin D’s pleiotropic cardiovascular actions, including suppression of the renin-angiotensin-aldosterone system, enhancement of endothelial nitric oxide bioavailability, and attenuation of vascular inflammation and fibrosis—effects validated in human models. In contrast, large-scale randomized trials and their meta-analyses have uniformly failed to demonstrate significant cardiovascular benefit from vitamin D supplementation in the general population. This discordance appears largely attributable to methodological limitations in trial design, particularly the inclusion of predominantly vitamin D-sufficient participants and the absence of stratification for baseline deficiency status or genetic determinants of vitamin D metabolism. Notably, post-hoc analyses suggest potential signal enrichment in cohorts with severe baseline deficiency, though these observations require prospective validation. Current evidence does not support population-wide vitamin D supplementation for cardiovascular risk reduction. The persistent mechanistic-clinical disconnect underscores fundamental gaps in trial methodology rather than invalidating biological plausibility. Future research must prioritize precision nutrition frameworks that integrate baseline vitamin D status, dynamic response biomarkers, and genomic profiling to identify subgroups where supplementation may confer meaningful benefit. Until such evidence emerges from rigorously designed trials, clinical efforts should focus on correcting documented deficiencies in high-risk metabolic phenotypes, with cardiovascular outcomes regarded as potential secondary benefits rather than primary therapeutic targets.