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Experimentally observed phenomena on cardiac energetics in heart failure emerge from simulations of cardiac metabolism.

ABSTRACT: 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 model to determine how the energy state evolves because of changes in key metabolic pools. Our findings--confirmed by in vivo (31)P-magnetic resonance spectroscopy--indicate 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, whereas reductions beyond a critical tipping point lead to a severely compromised energy state. The transition point corresponds to reductions in the total adenine nucleotide pool (TAN) of approximately 30%, corresponding to the reduction observed in humans in heart failure [Ingwall JS, Weiss RG (2004) Is the failing heart energy starved? On using chemical energy to support cardiac function. Circ Res 95(2):135-145]. At given values of TAN and the total exchangeable phosphate pool during hypertrophic remodeling, the creatine pool attains a value that is associated with optimal ATP hydrolysis potential. 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.

SUBMITTER: Wu F

PROVIDER: S-EPMC2667147 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:The role of coronary microvascular disease and its impact on functional and energetic reserve in heart failure with preserved ejection fraction (HFpEF) remains unclear. We hypothesized that in response to submaximal pharmacologic stress (dobutamine), patients with HFpEF have impairment in left ventricular (LV) myocardial mechanical (external work [EW]), energetic (myocardial O2 consumption [MVO2]), and myocardial blood flow (MBF) reserve. We further assessed whether coupling of MBF to EW is impaired in HFpEF and associated with compensatory increases or pathological decreases in myocardial O2 extraction. Lastly, we assessed whether coupling of MVO2 to EW (mechanical efficiency) was impaired in HFpEF. METHODS AND RESULTS:In prospectively enrolled patients with HFpEF (n=19) and age/sex-matched healthy controls (n=19), we performed 11C-acetate positron emission tomography assessing MVO2 and MBF at rest and during dobutamine infusion. EW was calculated as stroke volume (echo)×end-systolic pressure×heart rate. At rest, compared with controls, patients with HFpEF had higher LV EW, MVO2, and MBF. With dobutamine, LV EW, MVO2, and MBF increased in both HFpEF and controls; however, the magnitude of increases was significantly smaller in HFpEF. In both groups, MBF increased in relation to EW, but in HFpEF, the slope of the relationship was significantly smaller than in controls. Myocardial O2 extraction was increased in HFpEF. Mechanical efficiency was similar in HFpEF and controls. In a post hoc analysis, HFpEF patients with LV hypertrophy (n=10) had significant reductions in LV mechanical efficiency relative to controls. CONCLUSIONS:In HFpEF during submaximal dobutamine stress, there is myocardial mechanical-, energetic- and flow-reserve dysfunction with impaired coupling of blood flow to demand and slight increases in myocardial O2 extraction. These findings provide evidence that coronary microvascular dysfunction is present in HFpEF, limits O2 supply relative to demand, and is associated with reserve dysfunction.

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Experimentally observed phenomena on cardiac energetics in heart failure emerge from simulations of cardiac metabolism.

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