Sex differences in the effect of vitamin D on inflammatory heart disease: protective in women but damaging in men (P3069)

An estimated 1 billion people worldwide have deficient or insufficient levels of vitamin D (VitD), while roughly 25% of individuals in the US are reported to have inadequate VitD levels. Considerable evidence indicates that VitD deficiency is associated with an increased risk of cardiovascular disease (CVD), yet it remains unclear whether low VitD is simply a biomarker of CVD or has a true pathologic role. The role of VitD deficiency in the pathogenesis of inflammatory myocarditis is unknown- a disease that is higher in men. We found that only 20% of myocarditis patients had low VitD levels. When we examined VitD receptor (VDR) deficient mice in a model of viral myocarditis, we found that VDR decreased myocarditis in females (p=0.007) but increased inflammation in males (p=0.006). Examination of cytokines in the heart found that VDR-/- male mice had significantly reduced IFN-γ and IL-1β and increased IL-17A, but no significant differences were found in females. Comparison of microarray data during myocarditis to published VitD response element genes revealed around 200 genes associated with proinflammatory (e.g. caspase-1) and profibrotic (e.g. TGF-β1, MMP) responses were increased in WT male mice, which was confirmed by qRT-PCR in VDR-/- mice. Our data confirms that VitD through the VDR promotes myocardial inflammation in males, providing a mechanism for how low VitD levels in men increase myocarditis. This work was funded by NIH R01 HL087033 and HL111938.