Abstract Body: Recurrent myocardial infarction (MI) is a major driver of adverse cardiac remodeling which often leads to heart failure, yet the immune mechanisms that exacerbate remodeling after repeated injury remain poorly understood. Foundational studies from our group previously established that MI induces robust recruitment of CCR2 positive inflammatory monocytes into the heart, which differentiate into diverse macrophage subsets that drive post-infarction inflammation, repair, and ventricular remodeling. While this axis represents a key determinant of myocardial inflammation after an initial injury, it remains unknown how subsequent cardiac events modulate monocyte recruitment, fate specification, myocardial inflammation, and remodeling. In this study, we demonstrate that an initial MI induces a state of immune memory within 2 compartments: bone marrow hematopoietic progenitor cells (HSPCs) and the heart. We observed durable trained immunity encoded within HSPCs, reprogramming their progeny toward heightened inflammatory and pro-fibrotic responses. Using a bone marrow transplantation model, we show that hematopoietic stem cells (HSCs) obtained from MI-experienced mice are sufficient to transfer maladaptive remodeling. Recipients reconstituted with MI-trained HSCs develop significantly worsened cardiac function and remodeling after injury, evidenced by increased end-diastolic and end-systolic volumes, expanded akinetic regions, reduced ejection fraction, and augmented interstitial fibrosis. Single-cell RNA sequencing further reveals that repeated injury selectively expands CCR2 positive monocyte-derived macrophages with robust pro-inflammatory and pro-fibrotic transcriptional programs. Within the diseased heart, depletion of monocyte-derived macrophages that infiltrate after the initial injury, improves cardiac function and reduces remodeling after a second MI. Mechanistically, we observed shifts in monocyte specification favoring populations with greater plasticity. Together, these findings establish 2 sites of immune memory that may explain why prior inflammatory heart injury predisposes to worse outcomes. Within this context, changes in monocyte plasticity, fate specification, and phenotype represent dominant mechanisms identifying a new potential therapeutic target to mitigate adverse outcomes after recurrent myocardial injury.