Abstract Body: Introduction: Outcomes after myocardial infarction (MI) vary between patients, ranging from functional recovery to heart failure. Despite this observation, few genetic mechanisms have been defined. To this end, we used a rodent panel to examine heritable changes in the cardiac transcriptome that precede heritable divergence in MI outcomes.

Methods: Across 12 strains from the Hybrid Rat Diversity Panel (HRDP), we performed surgical induction of MI via permanent ligation, alongside echocardiography at three timepoints, scar assessment, and BrdU injections. Four strains with comparable subacute function but divergent long-term outcomes were selected for single-nucleus RNA-sequencing (snRNA-seq, N=2-3 per strain/condition). Left ventricular tissue was taken at baseline and 4 days post-injury (4 DPI), a transition point between the inflammatory and reparative phases of the canonical MI response. We confirmed MI by echocardiography and retained ejection fraction (EF) as a covariate to isolate differences in genetics from injury severity. We then tested for inter-strain variation in cell-specific pseudobulk gene expression and higher-order transcriptomic features (slingshot pseudotime, CellChat signaling, PROGENy pathway activity).

Results: From 12 strains in the HRDP, we observed significant differences in EF recovery (p=0.018, One-way ANOVA), scar area (p=3.6x10^-4), and cardiomyocyte DNA synthesis (% BrdU⁺, p=1.1x10^-5). snRNA-seq in all four sequenced strains captured the expected cell dynamics, such as cardiomyocyte loss, immune cell expansion, and fibroblast activation. Even so, we found 1,304 baseline cell-specific differentially expressed genes (DEGs) between strains, which increased to 5,632 DEGs post-MI. Further, 21 higher order features differed between strains, including epicardial-to-mesenchymal transition (p=5.1x10^-4), macrophage IL1β signaling (p=9.6 x10^-5), and fibroblast JAK-STAT activity (p=9.7 x 10^-4). Pairing correlation analysis to gene set enrichment revealed that 4 DPI induction of macrophage “wound healing” genes negatively correlated with predicted EF recovery, while fibroblast pseudotime positively correlated with hypertrophy.

Conclusions: Our results identify key features of the early MI response that differ between genetically distinct individuals prior to divergent outcomes. Sequencing additional strains and integration with human multi-omics data will identify genetic mechanisms and therapeutic targets in the subacute phase post-MI.