SEX DIFFERENCES IN THE EFFECT OF VITAMIN D ON INFLAMMATORY HEART DISEASE: PROTECTIVE IN WOMEN BUT DAMAGING IN MEN
Katelyn A. Bruno, Ph.D., Mayo Clinic, Jacksonville, FL, USA
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. Myocarditis, an inflammatory heart disease, appears as lymphocytic myocarditis (LM) or giant cell myocarditis (GCM), yet the role of VitD deficiency in the pathogenesis of disease is unknown. We found that 75% of GCM patients had deficient or inadequate levels of VitD (<19ng/mL) whereas only 20% of LM patients had low levels. Following therapy, VitD levels in women but not men with GCM significantly improved (p=0.04). Myocarditis patients are at risk of heart failure, which is reflected by a low ejection fraction (EF). In GCM patients, low EF correlated with low VitD levels in both men and women (r2 = 0.42). In contrast, poor EF and low VitD was only correlated in women with LM (r2=0.54), but surprisingly men had an opposite correlation- high VitD correlated with low EF (r2=0.81). When we used examined the role of VitD using VitD receptor (VDR) deficient mice in a model of LM, we found that VDR decreased myocarditis in females (p=0.007) but increased inflammation in males (p=0.006). Comparison of microarray data during myocarditis in mice to known VitD response element genes revealed that genes associated with proinflammatory (e.g. caspase-1, p=7.0x10-5) and profibrotic (e.g. TGF-beta, p=8.6x10-6) immune responses were significantly upregulated in the heart of males, providing a mechanism to explain how VDR increases disease in males. These findings in the mouse model confirm that sex differences exist in the function of VitD/VDR in men and women with LM.