Energy metabolism in heart failure and remodelling

Abstract

Myocytes of the failing heart undergo impressive metabolic remodelling. The time line for changes in the pathways for ATP synthesis in compensated hypertrophy is: flux through the creatine kinase (CK) reaction falls as both creatine concentration ([Cr]) and CK activity fall; increases in [ADP] and [AMP] lead to increases in glucose uptake and utilization; fatty acid oxidation either remains the same or decreases. In uncompensated hypertrophy and in other forms of heart failure, CK flux and fatty acid oxidation are both lower; any increases in glucose uptake and utilization are not sufficient to compensate for overall decreases in the capacity for ATP supply and [ATP] falls. Metabolic remodelling is under transcriptional and post-transcriptional control. The lower metabolic reserve of the failing heart contributes to impaired contractile reserve.

Figure 1

Loss of ATP in the failing heart. (A) ³¹P NMR spectra from failing human heart showing the loss of PCr and ATP (reprinted from Neubauer et al.). (B) Data from the pacing dog heart model of heart failure showing the progressive fall in ATP, the progressive loss of the total adenine nucleotide pool (TAN) and the close relationship between ATP and TAN (reprinted from Shen et al.). (C) Data for ATP (insert) and rate-pressure product (RPP) for wild-type (WT, solid bars) and PGC-1α null mouse hearts (TG, grey bars) at baseline and during inotropic challenge with dobutamine with two different substrate mixes (reprinted with permission from Elsevier from Arany et al.).

Figure 2

Loss of Cr in the failing heart. (A) [Creatine, Cr] (top) and CK activity (bottom) obtained from biopsy specimens of human myocardium are lower for both accident victims maintained on inotropic support and ventilation and for heart failure patients (reprinted from Nascimben et al.). (B) Data from the pacing dog heart model of heart failure showing the progressive and rapid fall in Cr (reprinted from Shen et al.). (C) Product of CK activity and [Cr], an index of energy reserve via the CK reaction, plotted against the increases in left ventricular developed pressure (LVDP, top), change in heart rate (HR, middle), and increases in rate-pressure product (RPP) as an index in contractile reserve (bottom) for TO2 and non-failing Syrian hamster hearts (reprinted with permission from Elsevier from Tian et al.).

Figure 3

Coordinate control of glycolysis by AMP-activated protein kinase (AMPK). In chronic pressure-overload cardiac hypertrophy in the rat, increased ATP demand signalled as decreased [PCr] leads to an increase in glycolytic flux by two coordinate mechanisms: increasing glucose transport (increasing substrate supply) and activating phosphofructokinase in the glycolytic pathway (increasing utilization), both mediated by AMPK. Redrawn with permission.