Prevention of myocarditis using regenerative medicine therapy

Abstract

Abstract Myocarditis is an important cause of acute and chronic heart failure. We wanted to determine whether purified exosome product (PEP) can improve and/or prevent myocarditis using a preclinical mouse model of myocarditis. Because estrogen protects women from myocarditis and heart failure we also tested premenopausal PEP (pmPEP). To determine the appropriate dose of PEP/pmPEP, we administered PEP and pmPEP vs. PBS controls ip to male BALB/c mice at day −1, 0 and +1 after viral infection to induce myocarditis and harvested mice at day 10 post infection (pi) during the peak of acute myocarditis. We found that the dose and exposure route was successful. We found that pmPEP, but not PEP, significantly decreased acute myocarditis based on histology (ANOVA p=0.0009). and decreased total immune cells (CD45 p=0.008), macrophages, neutrophils and mast cells (CD11b p=0.04), macrophages (F4/80 p=0.009), and T cells (CD3 p=0.02, CD4 p=0.01) but no other immune cell populations in the heart. Markers for both M1 and M2 macrophages were also significantly decreased with pmPEP treatment, indicating a “global” decrease in inflammation. Importantly, CR1, the central inhibitor of the complement cascade, was significantly increased by pmPEP but not PEP (p=0.004). Next we treated male BALB/c mice with PEP, pmPEP or PBS ip on day 8, 9 and 10 pi (a clinically relevant timepoint) and harvested on day 11 pi during acute myocarditis. Here we found that both PEP and pmPEP significantly reduced acute myocarditis compared to controls (ANOVA PEP p=0.006, pmPEP p= 0.005). These findings suggest that PEP/pmPEP could be given to patients who come in with acute onset myocarditis to decrease the severity of disease and potentially prevent sudden death.