Grant: Project Grant

The continuous beating of our hearts requires a large amount of energy. Heart muscle metabolism is essential to maintain this function. It is well known that in many forms of heart disease, heart metabolism is abnormal. But, we don't know whether these differences caused the disease, or are a result of it. Many have proposed that altering metabolism in the heart may be a way to improve the function of failing hearts. New treatments for this debilitating condition, which affects 2-3% of Canadians and results in fatality in half the cases are urgently needed. Through genetic studies, we have found a protein, called PDK1, and have shown that when this protein is inactive, fat levels in our blood are lower (good) but fat builds up in the heart (potentially bad). PDK1 is found at high levels in the heart and regulates the metabolism of fat and sugar. Manipulation of PDK1 may be useful to improve metabolism in failing hearts but first we need to know how exactly blocking PDK1 affects heart metabolism and the resulting effects on heart function. In these studies we will: 1) test how reduced PDK1 affects metabolism in the heart and the resulting effects on heart function, and how drugs that are currently being made that block PDK1 affect metabolism and heart function; 2) test what effects are specifically due to the action of PDK1 in the heart, as opposed to changes in metabolism occurring elsewhere in the body; 3) test how the amount of fat and sugar in the diet influences the effects of changing PDK1. Together, these studies will determine how PDK1 affects metabolism and heart function and provide key information about the potential role(s) of PDK1 in heart health. Ultimately it is expected the knowledge created will inform the development of new treatment strategies to improve the health of Canadians with heart disease.