DeCiphering Systemic Diurnal MetabOlism and EnDocrinE Signaling in HEART Failure

Objetivo

Heart failure (HF), the ultimate outcome of many cardiovascular pathologies, imposes a significant global health and economic burden while remaining associated with high mortality rates. There is therefore an urgent need for innovative approaches to comprehensively understand and treat HF. Most HF research, has thus far focused on the pathophysiology of the heart, only partially covering the role of non-cardiac organs, despite HF being a complex multiorgan syndrome. The extent to which extra-cardiac organs, particularly those playing a key role in metabolism control, contribute to HF remains largely unknown. CODE-HEART aims to bridge this knowledge gap by focusing on metabolic interorgan mechanisms of disease. Our metabolism is temporally coordinated across tissues by the circadian clock system, which orchestrates myriad of physiological and metabolic processes. My recent work has highlighted the significance of peripheral tissue-tissue communication for daily metabolic homeostasis. Notably, my preliminary findings suggest that when the heart is under stress, systemic glucose and lipid diurnal metabolism is rewired. In this project, I will test the hypothesis that the failing heart can alter systemic diurnal metabolic rhythms via the release of specific cardiac-secreted factors. To do so, I will first determine the impact of HF on systemic metabolic rhythms and on the diurnal transcriptional landscape of liver, skeletal muscle and white adipose tissue. Using specific knockout animal models, I will investigate the consequences of systemic metabolic rewiring on cardiac function in HF. Finally, I will pinpoint the metabolic communication network between the heart, liver, and other metabolic tissues by labelling cardiomyocyte-specific secreted proteins and screening their functions in vitro and in vivo. In summary, CODE-HEART will significantly advance our understanding of the metabolic and molecular adaptation occurring in HF.