Background: We described chronic heart failure with preserved ejection fraction (HFpEF) as a long-term sequel in survivors of severe pediatric burn injury (BI) (Hundeshagen et al., Lancet Child & Adolescent Health, 2017). Applying a widely used standardized scald injury rat model in burn research, we sought to uncover systemic and molecular pathomechanisms that may cause post-BI HFpEF development.

Methods and Results: Male adolescent SD-rats were subjected to a 60% total body surface area full-thickness BI (B; 100% survival) or sham (S) procedure (each n=10) and characterized them up to 90 days (3, 7, 30 and 90d) by serial echocardiography (E), bulk myocardial NGS and -proteomics, RT-PCR, IB, histology (H) and plasma proteomics for cardiac performance and molecular alterations, respectively. B rats mirrored typical post-burn clinical traits as significant loss in body (-27%*) or skeletal muscle weight (-30%*) e.g., with elevated atrophy markers as Murf1 (5-fold*) throughout the observation period vs S (30d, *P<0.05) Our focus on the heart revealed in vivo heart weight loss (-22%*), cardiomyocyte hypotrophy (-8%*) and diminished mTOR activity in B hearts (p/t-mTORC2 -43%*) vs S as well as significantly diminished left ventricular (LV) GLS with unchanged LV-EF. RT-PCR and H showed significant cardiac accumulation of cardiodepressive factors (i.e., S100A8 and A9) and e.g., granulocyte (MPO, >3-fold*) infiltration as well LV fibrosis (2.2-fold*). Cardiac proteomics yielded e.g., neutrophil degranulation as lead GO-term. Serial blood and plasma proteomic and ELISA analysis indicated elevated WBC (+26%*) and levels e.g., of IL6, S100A8/A9, CH3L1 and other HF markers alike changes in human post-BI plasma samples. WGCNA for bulk myocardial NGS and clinical traits related activated immunological and pro-fibrotic pathways in post-BI hearts to cardiac dysfunction in B.

Conclusion: The first ever report of the development of HFpEF as a novel systemic consequence of severe burn injury in a rodent model prepares the ground for further mechanistic and translational studies. Cardiac inflammation and fibrosis that negatively impact cardiac performance may be mechanistic key findings guiding further therapeutic studies and validation of post-BI HF biomarkers.