Introduction: Atherosclerosis is a chronic inflammatory condition characterized by the accumulation of lipids, inflammatory cells, and fibrous elements in the arterial walls, leading to plaque formation and vascular narrowing. It is a leading cause of cardiovascular diseases, including myocardial infarction and stroke, which are the primary causes of morbidity and mortality worldwide. Traditional risk factors for atherosclerosis include hyperlipidemia, hypertension, diabetes mellitus, smoking, and a sedentary lifestyle. Recent research, however, has also highlighted the potential role of vitamin D deficiency as an independent risk factor for the development and progression of atherosclerosis. Vitamin D, a fat-soluble vitamin primarily synthesized in the skin upon exposure to sunlight, is well-known for its role in calcium homeostasis and bone metabolism. Nonetheless, emerging evidence suggests that vitamin D also possesses cardiovascular protective properties, including anti-inflammatory, anti-proliferative, and immunomodulatory effects.
Methods: A comprehensive literature search was conducted using PubMed, Cochrane Library, and Scopus, focusing on studies published in the last 15 years. Search terms included "vitamin D," "atherosclerosis," "cardiovascular disease," "supplementation," and "endothelial dysfunction." Observational studies, randomized controlled trials (RCTs), and meta-analyses were included to evaluate the effects of vitamin D on atherosclerosis and related markers.
Results: Several observational studies have reported an inverse relationship between serum 25-hydroxyvitamin D [25(OH)D] levels and the risk of atherosclerotic cardiovascular disease (ASCVD). Low levels of vitamin D have been associated with increased prevalence of hypertension, diabetes, and dyslipidemia, which are known contributors to atherosclerosis. Vitamin D is hypothesized to exert its protective effects against atherosclerosis through multiple mechanisms. These include the modulation of the renin-angiotensin-aldosterone system, reduction of pro-inflammatory cytokines such as interleukin-6 and TNF-α, and improvement of endothelial function by enhancing nitric oxide (NO) availability.
Evidence from RCTs, however, remains inconclusive. Some studies have demonstrated that vitamin D supplementation significantly reduces surrogate markers of atherosclerosis, such as carotid intima-media thickness and coronary artery calcium scores. These findings are particularly evident in individuals with severe vitamin D deficiency or those with coexisting cardiovascular risk factors. For example, trials involving patients with chronic kidney disease, a population prone to both vitamin D deficiency and accelerated atherosclerosis, have shown that vitamin D analogs can improve vascular health markers. However, other RCTs, especially those involving general populations or those without significant baseline deficiency, have reported minimal to no impact on these markers, leading to mixed conclusions.
These discrepancies may arise from variations in study design, including differences in baseline vitamin D status, dosage and formulation of supplementation, study duration, and the presence of other risk factors. Some studies suggest a threshold effect, where only those with critically low vitamin D levels derive significant benefit from supplementation, while others propose that very high doses may not confer additional protective effects and could even be harmful.
Conclusion: While there is a biological plausibility and some clinical evidence supporting the role of vitamin D in reducing atherosclerotic risk, the data from RCTs remain inconsistent. These mixed results underscore the need for larger, well-designed trials that stratify participants by baseline vitamin D levels, comorbid conditions, and other relevant factors. Future research should focus on determining optimal dosing regimens, identifying populations that would benefit most from supplementation, and clarifying the molecular mechanisms through which vitamin D affects the atherosclerotic process. Until such data are available, it may be prudent to consider vitamin D supplementation on an individual basis, particularly in those with documented deficiency and elevated cardiovascular risk. Given the global burden of atherosclerosis and its complications, integrating vitamin D status into cardiovascular risk assessment could represent an additional strategy in preventive cardiology.