Abstract Body: Atrial fibrillation and heart failure have a strong epidemiologic link, however the mechanisms underlying their mutual risk remain unresolved. We revealed a remarkable correlation of both gene expression and genomic features in the atria of atrial fibrillation (AF, Tbx5 deletion) and heart failure (HF, TAC banding) mouse models. Tbx5- and TAC-dependent gene expression in the left atria demonstrated a correlation coefficient of 0.8. Remarkably, 118 transcription factors were dysregulated in both models and 109 shared directionality in both cases, suggesting a shared transcriptional response. Differential non-coding transcriptional profiling to identify altered cis-regulatory regions demonstrated a correlation coefficient of 0.81 between the models, including ~1,800 shared differentially expressed ncRNAs, of which ~400 emanated from accessible candidate regulatory elements. Integration with chromatin architecture allowed identification of lineage-specific shared AF and HF gene regulatory networks. A TBX5-driven ncRNA-defined regulatory element drives expression of Klf15, an inhibitor of cardiac hypertrophy, in the wild-type cardiomyocytes that is downregulated in both mouse and human heart failure. Whereas in mouse HF and AF a disease-specific ncRNA-defined regulatory element is upregulated with Sox9, an important transcriptional regulator of fibroblast activation. This work indicates that AF and HF initiate a shared atrial pathological genomic response, including downregulation of a wild-type GRN that normally prevents injury-based disease signaling and upregulation of a disease GRN that promotes atrial remodeling, uncovering a common genomic underpinning of atrial disease.