Abstract 9832: Liver-Heart Crosstalk Mediated by Coagulation Factor XI Protects Against Heart Failure

Abstract

Introduction: Tissue-tissue crosstalk by endocrine factors is a vital mechanism to maintain proper physiologic homeostasis. The heart and the liver display multifaceted interactions and it is common to observe heart diseases affecting the liver and vice versa. Hypothesis: We hypothesized that the liver-heart interactions may be mediated by novel endocrine factors. Methods: Global transcriptomic data from the heart and the liver were generated across all 100 diverse inbred strains of mice, the Hybrid Mouse Diversity Panel (HMDP), and used to detect the correlation structure between secreted proteins from the liver and their downstream effects on the heart. Candidates were validated in a “two-hit” model of heart failure with preserved ejection fraction (HFpEF) and plasma samples from HFpEF patients and controls were used to examine the clinical relevance. Results: Using the bioinformatics framework, we predicted that coagulation factor XI (FXI) is a liver-derived protein that influences heart gene expression and diastolic dysfunction, a key trait of HFpEF. In a mouse model of HFpEF, mice overexpressing FXI in the liver showed improved diastolic function and reduced inflammation and fibrosis, whereas FXI knockout mice were sensitized for diastolic dysfunction. FXI overexpression activated the bone morphogenetic protein (BMP)-Smad1/5 pathway in the heart, thus inhibiting genes involved in inflammation and fibrosis. The action of FXI on heart requires proteolytic activity, as point mutations in its catalytic domain eliminated effects on BMP signaling and heart function. BMP7 is secreted as an inactive precursor and our results indicate that it is cleaved by FXI, releasing the active dimer and monomer growth factor from the prodomain that binds to the extracellular matrix. Further, plasma FXI was inversely correlated with E/e’ ratio in all human participants and HFpEF patients. Conclusions: Our studies indicate that liver-derived FXI specifically regulates cardiomyocytes through the BMP-Smad1/5 pathway, resulting in attenuation of fibrosis, inflammation, and diastolic dysfunction in the context of a HFpEF model. Our study reveals a protective role of FXI on heart injury, distinct from its role in coagulation.