Vitamin D Binding Protein as a Potential Biomarker for Heart Failure in Myocarditis: Translational Animal Model Reveals Mechanism

Introduction An estimated 3.1 million cases of myocarditis/cardiomyopathy were diagnosed in 2017. Myocarditis, inflammation of the myocardium, is a leading cause of sudden death from heart failure in children and young adults worldwide. Patients can progress to dilated cardiomyopathy, heart and heart transplant. Studies have found that Vitamin D binding protein (DBP) could be instrumental in response to tissue injury and activation of the immune response. This chemotaxis activation has been shown to be due to activation of the complement cascade via C5a. The involvement of DBP in disease has never been assessed for myocarditis or other cardiovascular diseases. Hypothesis We hypothesized that DBP activates the immune response by altering the complement cascade in a sex-specific manner leading to increased myocarditis. The overall goal of this study was to examine the role of DBP and complement in patients with myocarditis and determine the mechanism in which DBP alters cardiac inflammation in a translational animal model of viral myocarditis. Methods We utilized a translational animal model of viral myocarditis to assess the mechanism in which DBP could be altering disease pathway activation and increasing acute myocarditis. We also utilized stored serum samples from myocarditis patients and patient data to assess the relationship between DBP levels in patient sera to ejection fraction (EF) by sex and age. Results We found that DBP was upregulated 45-fold in men with myocarditis compared to women and correlated to %EF in women (p = 0.0004). Additionally we found that men with myocarditis had significantly higher levels of complement C3, C4b, C8 (p  Conclusion Our translational animal model of viral myocarditis has revealed that DBP can increase inflammation, myocarditis, by upregulating the complement cascade. We found that having a mechanistic understanding of circulating DBP in patients and mice could be used to predict disease severity in patients with myocarditis and potentially other forms of heart failure.