Abstract Thu150: Characterization of the Immune Landscape in LMNA-associated Dilated Cardiomyopathy

Lamin A/C is an intermediate filament protein that maintains the structural integrity of the nuclear lamina, and mutations in LMNA are involved in cardiac laminopathies. Cardiac laminopathies can manifest in patients acutely through sudden cardiac death or through chronic conditions such as dilated cardiomyopathy (DCM). Among familial DCM patients, 10% have been tied to LMNA mutations. The underlying mechanism behind LMNA’s role in the development of DCM and how mutations impact disease progression remains understudied. Inflammation has been well-characterized as a driver of pathogenesis in non-LMNA-related DCM. This includes a sustained immune response through resident and recruited immune cells such as monocytes, macrophages, and T lymphocytes that promote myocardial damage and fibrosis. However, the immune landscape in LMNA-associated DCM has not been investigated to the same degree, and recent studies suggest that its role in disease progression may be more significant than previously appreciated. Here, we characterize the immune landscape in an intronic splice-site mutation mediated LMNA Exon3 deletion mouse model that yields an accelerated, severe DCM phenotype. We observed profound inflammation and cardiac fibrosis. Flow cytometry of cardiac tissue demonstrated an infiltration of pro-inflammatory CCR2+ macrophages in the heart. Furthermore, RNA-sequencing and qPCR revealed upregulation of pro-inflammatory cytokines: IFNg, IL6, and IL1b. Immunofluorescent staining suggests a periostin-related fibrotic pathology that may be mediated by an immune response due to infiltration of CCR2+ macrophages. In summary, our findings reveal a disregulated immune landscape in LMNA-associated DCM that underscores the potential for a distinct inflammatory response driving disease progression.