Vitamin D Responsiveness in Cardiovascular Health: A Narrative Review of Endocrine and Vascular Interactions

The role of vitamin D (VD) in cardiovascular health remains controversial. Observational studies have associated low serum 25(OH)D₃ levels with increased risk of cardiovascular events, while interventional trials and Mendelian randomization studies have largely failed to confirm causality. This inconsistency may arise from unrecognized interindividual differences in VD responsiveness, as well as from the poor correlation between circulating VD metabolites and tissue-specific biological activity. This review highlights the emerging paradigm of variable VD sensitivity, which spans from VD resistance (VDRES) to hypersensitivity (VDHY). Individuals with VDRES exhibit impaired responses to standard supplementation due to genetic or acquired factors affecting VD metabolism, transport, or receptor signaling. In contrast, those with VDHY may develop adverse effects—such as hypercalcemia or vascular calcification—even under normal VD exposure, particularly if mutations impair VD catabolism (e.g., CYP24A1 variants). These opposing phenotypes may account for the heterogeneous outcomes observed in clinical studies. Further, recent findings suggest that VD signaling intersects with cholesterol metabolism and vascular pathology. Locally dysregulated VD activation within vascular smooth muscle cells may promote calcification and plaque instability independent of systemic levels. By integrating insights from endocrinology, vascular biology, and genetics, this review argues for a shift away from one-size-fits-all supplementation strategies. A better understanding of the molecular determinants of VD responsiveness may improve cardiovascular risk assessment and allow for personalized therapeutic approaches. Until tools become available to assess tissue-level VD activity or predict individual responsiveness, clinicians should remain cautious—particularly in populations at risk of either insufficient effect or toxicity.