Grant: Operating Grant

Despite the known association between cardiac hypertrophy and heart failure the mechanisms involved in the transition from compensated hypertrophy to failure remain poorly understood. Several evidences indicate that in the failing stage mitochondria (the cellular powerhouses) display overt defects, which can contribute to energy starvation. In addition, mitochondria contribute to cell death observed in the failing heart by their capacity to trigger cell death. This phenomenon is important as loss of cardiac cells is viewed as a critical contributor to the failure process. However, the factors that set the stage for these events in the failing heart remain poorly understood. Identification of contributing factors early during the disease is critical in order to develop treatments to prevent or attenuate the relentless progression of this pathology. We have recently shown that mitochondrial vulnerability to stress develops early in compensated hypertrophy at a time when overt mitochondrial defects are not yet apparent. This observation is highly relevant as hypertrophied hearts are often exposed to prolong periods of stress well before the occurrence of cardiac failure. The general objective of this proposal is to further define whether mitochondrial vulnerability to stress represents an early factor contributing to cardiac decompensation. This will be done by determining 1) when and how mitochondrial vulnerability develops in the hypertrophied heart following myocardial infarction, 2) how it impacts of heart function and cell death mechanisms in response to acute stresses and 3) if genetic and pharmacological inhibition of mitochondrial vulnerability affects the tolerance of the heart to acute stress and disease progression. This program will increase our understanding of the role of mitochondria in myocardial patho-physiology and contribute to the identification of therapeutic means to prevent of reduce the progression towards heart failure.