Purpose: We wanted to determine whether purified exosome product (PEP) or premenopausal PEP (pmPEP) could improve and/or prevent myocarditis and prevent dilated cardiomyopathy (DCM) using a preclinical mouse model of myocarditis/DCM. We looked at pmPEP because estrogen protects women from myocarditis and heart failure. We also investigated if Adipose Derived Extracellular Vesicles (AEV) was a more effective and efficient treatment product.
Methods: We administered PEP, pmPEP or AEV vs. control ip to male BALB/c mice at day -1, 0 and +1 with virus inoculation on day 0 to induce myocarditis, and harvested mice at day 10 post infection (pi) during the peak of acute myocarditis. Next we treated male BALB/c mice with PEP, pmPEP, AEV or control ip on day 7, 8 and 9 pi (a clinically relevant timepoint) and harvested on day 10 pi during acute myocarditis or day 35 pi during DCM.
Results: We found that the dose and exposure route were successful. pmPEP and AEV, but not PEP, significantly decreased acute myocarditis based on histology (ANOVA p=0.0009) and decreased total immune cells (CD45 p=0.008). Importantly, CR1, the central inhibitor of the complement cascade, was significantly increased by pmPEP (p=0.004). Visual qualitative observations in AEV treated mice indicated improved health in mice receiving regenerative treatment. Body weight was also significantly increased in mice treated with AEV indicating improved health. When assessing clinically relevant dosing timepoint we that found that both PEP and pmPEP treatment given during myocarditis significantly reduced inflammation compared to PBS (ANOVA PEP p=0.006, pmPEP p= 0.005) and decreased fibrosis when assessed at day 35pi
Conclusion: These findings suggest that regenerative medicine treatments; PEP, pmPEP and AEV, could be administered to patients who present with acute onset myocarditis to decrease the severity of disease and potentially prevent heart failure and sudden death.