Clinically observed phenomena on cardiac energetics in heart failure emerge from simulations of cardiac metabolism
Seminar Room 1, Newton Institute
The failing heart is hypothesized to suffer from energy supply inadequate for supporting normal cardiac function. We analyzed data from a canine left ventricular hypertrophy (LVH) model to determine how the energy state evolves due to changes in key metabolic pools. Our findings¡Xconfirmed by in vivo 31P-magnetic resonance spectroscopy (31P-MRS)¡Xindicate that the transition between the clinically observed early compensatory phase and heart failure and the critical point at which the transition occurs are emergent properties of cardiac energy metabolism. Specifically, analysis reveals a phenomenon in which low and moderate reductions in metabolite pools have no major negative impact on oxidative capacity while reductions beyond a critical tipping point lead to a severely compromised energy state.
Furthermore, our analysis reveals: (1.) the predicted metabolic tipping point coincides with the transition to severe cardiac dysfunction; (2.) the tipping point is associated with a ~30% reduction of TAN reduction corresponds to the reduction observed in humans in heart failure [Circ Res 95:135-145]; (3.), the predicted cytoplasmic AMP at the tipping point is approximately 1.6 mM and equal to the apparent AMP concentration at half-maximal activation of cardiac AMP-activated protein kinase; (4.) oxidative stress in the myocardium is predicted to progressively increase as the metabolic pools are diminished; and (5.) at given values of TAN and TEP during hypertrophic remodeling, CRtot attains a value that is associated with optimal ƒ´GATPase. Thus, both increases and decreases to the creatine pool are predicted to result in diminished energetic state unless accompanied by appropriate simultaneous changes in the other pools.