Grant: Project Grant

Heart failure (HF) remains a leading cause of death and a significant economic burden in Canada. In ~50% of HF patients, the heart muscle becomes stiff and unable to properly relax following contraction, leading to fluid accumulation in body organs and tissues. This type of HF is called HF with preserved ejection fraction (HFpEF). While the exact causes of HFpEF are still unknown, macrophages, a type of immune cell, play a major role in the development of HFpEF by causing cardiac inflammation and triggering the growth of stiff tissue fibres (i.e. fibrosis) in the failing heart. Macrophage activity is influenced by the type of fuel (i.e. sugar, fat, ketone) they metabolize (burn) to generate energy. Past research has heavily focused on understanding the regulation of macrophage fat and sugar metabolism in health and how they malfunction in various diseases such as obesity and diabetes. However, the regulation of macrophage ketone metabolism in health and disease has received much less attention and remains a knowledge gap. Exciting data in our lab have shown that changes in the ability of heart macrophages to burn ketone for energy are linked to impaired cardiac function in HFpEF. The major goal of our research project is to understand how altering heart macrophages' ability to burn ketone worsens cardiac function. We hypothesize that altered ketone use in heart macrophages contributes to cardiac inflammation and abnormal heart function in HFpEF. To test our hypothesis, our lab generated an HFpEF mouse model to examine how modulating macrophage ketone use (using genetics, drugs and dietary interventions) influences cardiac inflammation and function in HFpEF. We speculate that manipulating macrophage ketone use can be a therapeutic strategy to lessen cardiac inflammation and improve heart function in HFpEF. Our research may lead to the discovery of a new approach to improve cardiac function in HFpEF while defining how this improvement occurs at the cellular level.