Bucek, Adriana

Abstract 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.

Background Myocarditis is an important cause of acute and chronic heart failure. Men with myocarditis have worse recovery and an increased need for transplantation compared with women, but the reason for the sex difference remains unclear. Elevated sera soluble (s) ST 2 predicts mortality from acute and chronic heart failure, but has not been studied in myocarditis patients. Methods and Results Adults with a diagnosis of clinically suspected myocarditis (n=303, 78% male) were identified according to the 2013 European Society of Cardiology position statement. Sera sST 2 levels were examined by ELISA in humans and mice and correlated with heart function according to sex and age. Sera sST 2 levels were higher in healthy men ( P =8×10 −6 ) and men with myocarditis ( P =0.004) compared with women. sST 2 levels were elevated in patients with myocarditis and New York Heart Association class III ‐ IV heart failure ( P =0.002), predominantly in men ( P =0.0003). Sera sST 2 levels were associated with New York Heart Association class in men with myocarditis who were ≤50 years old ( r =0.231, P =0.0006), but not in women ( r =0.172, P =0.57). Sera sST 2 levels were also significantly higher in male mice with myocarditis ( P =0.005) where levels were associated with cardiac inflammation. Gonadectomy with hormone replacement showed that testosterone ( P <0.001), but not estradiol ( P =0.32), increased sera sST 2 levels in male mice with myocarditis. Conclusions We show in a well‐characterized subset of heart failure patients with clinically suspected and biopsy‐confirmed myocarditis that elevated sera sST 2 is associated with an increased risk of heart failure based on New York Heart Association class in men ≤50 years old.