Abstract Body: Myocardial infarction is the leading cause of death worldwide. Strategies to promote heart regeneration and treat cardiomyopathies are urgently needed. Neonatal hearts respond to injury by forming new cardiomyocytes, however this response fades within the first postnatal week. In the heart, sympathetic neurons (SNs) control the heart rate and contractility, and disruption of SNs often leads to cardiac disease in adults. SNs innervate the heart at mid gestation and remain anatomically, molecularly, and functionally heterogeneous. Moreover, the role of SNs during heart development and regeneration is unclear, while most prior studies focused almost exclusively on adrenergic signaling with conflicting results. We have previously demonstrated that genetic inhibition of cardiac SNs in mice increased postnatal cardiomyocyte proliferation, thus we hypothesized that hearts lacking SNs would exhibit improved myocardial repair after injury. To test our hypothesis, we generated a novel mouse model of disrupted cardiac SNs. Mice had unchanged circulating norepinephrine levels and were subjected to injury at postnatal day 8. Surprisingly, decreased proliferation markers were observed in denervated mice and that was consistent with transcriptomic analyses. Interestingly, increased inflammatory cytokines were also observed in denervated hearts post injury, suggesting potential neuroinflammatory effects. Myocardial function and scar formation were unchanged at 4 months. Furthermore, utilizing viral tracing and single cell transcriptomics we characterized the transcriptomic changes of cardiac neuronal subpopulations within the adrenergic ganglia after injury. We specifically analyzed gender and anatomical differences as well as changes in secreted neurotransmitters and neuropeptides. To our knowledge this the first comprehensive analysis regarding the effects of cardiac SNs during postnatal myocardial repair. Considering the remarkable diversity and pleotropic effects of SNs that extend beyond adrenergic signaling, our work can contribute to the development of more specialized neuromodulatory therapies for cardiac disease.