Abstract Thu042: Defining Predictive Signatures for Diagnostic, Prognostic, and Therapeutic Indices for Tissue Repair in Chronic Ischemic Heart Failure

Introduction: Our team has developed a unique biologically active platform to treat chronic ischemic heart failure that increases the prevalence of alternatively activated M2 macrophage phenotypes in immune competent animal models (mice, rat, swine). This repair mechanism is mediated through endogenous immune modulation in the stromal cell population (PMID: 31075250 , PMID: 38007534).This biologic platform is composed of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes and neonatal fibroblasts on a bioresorbable matrix that is implanted at the site of injury. The biologic restores left ventricular contractile function, increases blood flow, and repairs damaged cardiomyocytes. Hypothesis: Our biologic treatment induced modulation of the immune response, marked by a transition of immune cell transcriptomes from an inflammatory to a reparative state, facilitates the identification of distinct immune markers in peripheral blood, which can serve as a predictive signature for cardiac repair. Methods: We use multivariate analysis to identify biomarker changes in peripheral blood associated with cardiac repair following treatment with our therapeutic. We correlate improvements in cardiac function with detection of a predictive signature using transcriptomics, proteomics, and Multiplex ELISAs. We use peripheral blood samples from heart failure patients to perform coculture experiments to identify cell phenotypes via flow cytometry and analyze associated biomarkers. We will identify differences in predictive signatures based on patient demographics such as age, gender, race, etc. All data will be analyzed for statistical significance between groups (P<0.05). Results: The experiments to date have demonstrated the ability to delineate classically activated from alternatively activated macrophage markers with statistical significance in vitro , giving a platform to test blood-derived tissues exposed to other therapies. Furthermore, the data suggest CD45+ cells exposed to the biologic platform reduce inflammatory markers and elevate alternatively activated macrophage markers in vivo . Conclusions: This work has the potential to be expanded to understand the systemic effects of biologic treatments targeting the immune system in other diseases. Thus, developing this signature can facilitate the development of diagnostics, prognostics, and therapeutics aiming to leverage the immune system that are not specific to our therapeutic or heart failure alone.