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SUMMARY:Clinically observed phenomena on cardiac energetics in heart failu
 re emerge from simulations of cardiac metabolism - Beard\, D (Medical Coll
 ege of Wisconsin)
DTSTART:20090720T111500Z
DTEND:20090720T113000Z
UID:TALK19181@talks.cam.ac.uk
CONTACT:Mustapha Amrani
DESCRIPTION: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 ene
 rgy state evolves due to changes in key metabolic pools. Our findingsXconf
 irmed by in vivo 31P-magnetic resonance spectroscopy (31P-MRS)Xindicate th
 at the transition between the clinically observed early compensatory phase
  and heart failure and the critical point at which the transition occurs a
 re emergent properties of cardiac energy metabolism. Specifically\, analys
 is reveals a phenomenon in which low and moderate reductions in metabolite
  pools have no major negative impact on oxidative capacity while reduction
 s beyond a critical tipping point lead to a severely compromised energy st
 ate. Furthermore\, our analysis reveals: (1.) the predicted metabolic tipp
 ing 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 i
 s approximately 1.6 mM and equal to the apparent AMP concentration at half
 -maximal activation of cardiac AMP-activated protein kinase\; (4.) oxidati
 ve stress in the myocardium is predicted to progressively increase as the 
 metabolic pools are diminished\; and (5.) at given values of TAN and TEP d
 uring hypertrophic remodeling\, CRtot attains a value that is associated w
 ith optimal GATPase. Thus\, both increases and decreases to the creatine p
 ool are predicted to result in diminished energetic state unless accompani
 ed by appropriate simultaneous changes in the other pools.
LOCATION:Seminar Room 1\, Newton Institute
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