Low vitamin D levels are associated with an increased risk of cardiovascular disease but, given the inconsistent results seen in trials of vitamin D repletion in high-risk populations, it remains uncertain whether or not vitamin D status is a mediator of disease or a consequence of poor health (decreased exercise and sunlight exposure etc.). There are a number of known pathways associated with vitamin D that could potentially influence cardiovascular risk (these headings are summarized from the NRN paper):
1. RAAS system: As mentioned in a previous post, vitamin D is a negative regulator of RAAS. Renin and angiotensin II levels are elevated in mice lacking the vitamin D receptor (VDR). In humans with low vitamin D levels, increased angiotensin II has been noted although it should be pointed out that patients with hereditary vitamin D resistant rickets (due to a lack of the VDR) do not have elevations in RAAS hormones.
2. Inflammation: Vitamin D has anti-inflammatory effects mediated via the downregulation of IL-6 and TNF expression. Cardiac endothelial cells contain VDRs and vitamin D treatment inhibits TNF activation in these cells. Given the association between inflammation and atherosclerosis, this is a potential mechanism for the putative link between vitamin D deficiency and atherosclerotic disease.
3. Endothelial Function: In vitro treatment with vitamin D downregulates the production of pro-thrombotic proteins in endothelial cells. Vitamin D deficiency has been associated with endothelial dysfunction in human studies but again, the contribution of residual confounding in these observational studies is uncertain and may be substantial.
4. Cardiac Remodeling: Studies in rodents have suggested a role for vitamin D in the prevention of LVH and adverse cardiac remodeling in models of hypertension and cardiovascular disease.
There is growing interest in the association between FGF-23 and CV disease. Treatment with vitamin D stimulates the release of FGF-23 and may be an adverse consequence of the use of supplements in patients with advanced CKD.
Given the amount of vitamin D prescribed in the dialysis world, it is important that we understand the potential consequences and mechanisms of the risks and benefits of this treatment. For appropriate references please see the NRN review. A previous summary of the use of vitamin D in CKD can be found here.