Introduction: Ischemic heart disease is the leading cause of heart failure and mortality in the Western world. Furthermore, survival rates after ST-Elevation Myocardial Infarction have stagnated, partly due to that the myocardial ischemia-reperfusion (MIR) injury induced by percutaneous coronary intervention is left untreated. This injury, driven by macrophages, activates myofibroblasts and contributes to scar formation. 

Methods: Supernatant from bone-marrow derived Mesenchymal stromal cells (bMSC) cultured both on laminin (LN) and plastic (PL) were dialysed using a 300kDa TFF system. Apart from EVs, the preparations contained a lot of ECM and was given the name ECMsomes.

Both preparations of ECMsomes were tested on macrophage assays, MLRs, in vivo MIR models in mice with LVEF as readout and a MIR model in pig where Troponin T was used to measure the damage to the heart. 

Lastly the LN-ECMsomes were tested together with a radioactive tracer, 68Ga-ATH001, that binds to PDGFRß to assess the damage after the MIR-model in mice.

Results: Both the LN and PL-ECMsome managed to down regulate IL-6 in macrophages but had varying degrees of benefits in the MLR. 

The LN-ECMsomes managed to retain the functionality in the heart better in the mouse model according to the LVEF unlike the PL-ECMsome, a decrease in activated myofibroblasts could also be measured when using the 68Ga-ATH001 probe.

The MIR-model in pigs also showed a preservation of the heart after LN-ECMsome treatment compared to placebo.

Conclusion: We developed an immune-modulatory EV-rich product from bone marrow mesenchymal stromal cells. In blinded, placebo-controlled MIR models in mice and pigs, the EV-product preserved myocardial function and showed cardio-protection. 

We also developed a positron emission tomography-based system for in vivo detection of myofibroblast activation, demonstrating reduced activation and scar size after treatment with the EV-product, suggesting a promising adjunct to PCI and individualized treatment of IHD.