In recent studies exploring the mechanisms by which CaMKII mediates this progression we determined that inflammation is a key contributor to the adverse remodeling associated with heart failure. We found that activation of CaMKII in cardiomyocytes initiates cardiac inflammation in response to non-ischemic interventions such as angiotensin II infusion and pressure overload and that this contributes to the development of heart failure. CaMKII activates NFkB-mediated transcriptional responses that occur rapidly within cardiomyocytes to initiate inflammatory gene expression and activation of the NLRP3 inflammasome, processes which lead in turn to macrophage recruitment and fibrosis and ultimately the transition from hypertrophy to failure.  Our current work uses cardiac specific CaMKII knockout mice (CKO) and cardiac specific KO of the p65 subunit of NFkB, of the chemokine MCP-1, of the inflammasome protein NLRP3, and of the interleukin product IL-18 to provide further evidence for the involvement of the cardiomyocyte in igniting inflammation and to demonstrate that initiation of these processes in cardiomyocytes is a critical sites in development of fibrosis and ventricular dysfunction following TAC. Additional studies focus on macrophages and T-cells and use immunohistochemistry and flow cytometry to identify immune cells that accumulate in the heart after TAC, including single cell RNA seq to define the specific populations of macrophages that depend on CaMKII signaling. This work is significant because 1) the cardiomyocyte has not previously been considered as a generator of inflammatory signals or a target for blocking inflammatory responses; 2) how inflammatory responses are activated in the absence of damage signals released by dying cells has not been determined; and 3) the times, cellular sites and targets for inflammatory blockade to prevent heart failure induced by TAC are unknown.