Vitamin D in atherosclerosis and cardiovascular events

Both experimental and clinical findings linking vitamin D to cardiovascular (CV) risk have prompted consideration of its supplementation to improve overall health. Yet several meta-analyses do not provide support for the clinical effectiveness of this strategy. Meanwhile, the understanding of the roles of vitamin D in the pathophysiology of CV diseases has evolved. Specifically, recent work has revealed some non-classical pleiotropic effects of vitamin D, increasing the complexity of vitamin D signalling. Within particular microenvironments (e.g. dysfunctional adipose tissue and atherosclerotic plaque), vitamin D can act locally at cellular level through intracrine/autocrine/paracrine feedforward and feedback circuits. Within atherosclerotic tissues, 'local' vitamin D levels may influence relevant systemic consequences independently of its circulating pool. Moreover, vitamin D links closely to other signalling pathways of CV relevance including those driving cellular senescence, ageing, and age-related diseases-among them CV conditions. This review updates knowledge on vitamin D biology aiming to clarify the widening gap between experimental and clinical evidence. It highlights the potential reverse causation confounding correlation between vitamin D status and CV health, and the need to consider novel pathophysiological concepts in the design of future clinical trials that explore the effects of vitamin D on atherosclerosis and risk of CV events.