Abstract Myocardial infarction (MI) due to underlying atherosclerosis is the leading disease sequela that precipitates heart failure in the Western world. Our ability to treat these patients and their heart failure has not progressed beyond a mild 20-30% extension in life span realized some 3 decades ago with neuroendocrine-based management [1]. New therapeutic avenues are needed, the most dramatic of which would be directly generating new cardiomyocyte to regenerate the damaged area of heart tissue. Previous attempts to regenerate the heart through new myocyte production have not been successful despite more than 18 years of research using adult progenitor cells. However, studies with cardiac progenitor cells in rodent models did show a functional benefit to the MI-injured heart, although we now understand that this is not due to significant new myocyte production. Instead we and others have identified a novel mechanism of benefit whereby injected progenitor cells have a rejuvenating effect on the MI-injured heart through refinement of the immune response. Indeed, we have shown that cell therapy injections that flank the recently injured area of the heart from ischemia- reperfusion (7 days later) can optimize healing, reduce infarct area expansion and augment scar borderzone physical properties (Vagnozzi et al., 2020, Nature). These beneficial effects were mediated through selective macrophage subtype activity in the heart, underscoring the importance of the immune response in cardiovascular health and infarct healing and compensation. Here we propose the hypothesis that selective innate immune response signaling pathways, and macrophage subtype polarization can be exploited to help heal the heart. Our more specific hypothesis is that therapy has an underlying protective component through Toll-like receptor (TLR) signaling in both cardiomyocytes and macrophages, and this can be therapeutically exploited to polarize the immune response for better healing. The specific aims are: AIM #1, To examine the mechanism of innate immune signaling in the heart through TLR signaling. AIM #2, To inducibly alter macrophage subtypes in the heart to reprogram the innate immune response and healing dynamics by cell therapy. AIM #3, To determine how fibroblasts communicate with macrophage subtypes in the post-MI injured heart to affect healing dynamics by cell therapy. Such studies will be critical for examining how innate immune signaling at the level of macrophages and cardiomyocytes impacts the heart during an inflammatory injury response with the goal of modifying this response to benefit cardiac healing in patients.

Relevance The relevance of this application is rooted in the fundamental translational biology of how the immune system impacts cardiac disease presentation and resolution. It is very important to understand and define the basic science mechanisms underlying how the adult human heart heals after ischemic injury and how the immune system intimately regulates this process. Here we will attempt to define therapeutic applications for directly altering the immune response in the heart during and after injury.