Grant: Project Grant

Heart failure is a debilitating disease that is a major cause of death and disability in Canada. Heart failure occurs as a result of damage to the heart muscle and/or the heart having to work against high workloads (i.e. such as in patients with high blood pressure). Being overweight and obese can also increase the risk of developing heart failure. In heart failure patients there are dramatic changes in cardiac energy metabolism, which includes a decrease in the ability of the heart to produce the energy necessary to sustain muscle contraction. In addition, the heart muscle can become insensitive to insulin stimulation of glucose use, a condition called "cardiac insulin resistance". This cardiac insulin resistance is exacerbated in obese patients, and contributes to the decreased ability of the heart to produce the energy necessary for normal contractile function. Branch chain amino acids (BCAA) accumulation in the heart contributes to the development of insulin resistance. BCAA metabolism is impaired in hearts from obese mice, causing a build-up of BCAA in the heart. We hypothesize that the accumulation of BCAA in the heart turns on a pathway, called the mTOR pathway, contributing both to the severity of insulin resistance and contractile dysfunction. Using a mouse model of heart failure we will determine how high BCAA levels contribute to the development of insulin resistance and heart failure. In addition, we will also attempt to improve insulin signaling and heart function in the failing heart by increasing heart BCAA metabolism and by decreasing BCAA levels. Combined, these studies will elucidate what role BCAA has in insulin resistance in the heart, and whether stimulating BCAA metabolism in the heart can decrease the progression of heart failure in the obesity and heart failure.