Energy metabolism in heart failure

Abstract

Heart failure (HF) is a syndrome resulting from the inability of the cardiac pump to meet the energy requirements of the body. Despite intensive work, the pathogenesis of the cardiac intracellular abnormalities that result from HF remains incompletely understood. Factors that lead to abnormal contraction and relaxation in the failing heart include metabolic pathway abnormalities that result in decreased energy production, energy transfer and energy utilization. Heart failure also affects the periphery. Patients suffering from heart failure always complain of early muscular fatigue and exercise intolerance. This is linked in part to intrinsic alterations of skeletal muscle, among which decreases in the mitochondrial ATP production and in the transfer of energy through the phosphotransfer kinases play an important role. Alterations in energy metabolism that affect both cardiac and skeletal muscles argue for a generalized metabolic myopathy in heart failure. Recent evidence shows that decreased expression of mitochondrial transcription factors and mitochondrial proteins are involved in mechanisms causing the energy starvation in heart failure. This review will focus on energy metabolism alterations in long-term chronic heart failure with only a few references to compensated hypertrophy when necessary. It will briefly describe the energy metabolism of normal heart and skeletal muscles and their alterations in chronic heart failure. It is beyond the scope of this review to address the metabolic switches occurring in compensated hypertrophy; readers could refer to well-documented reviews on this subject.

Figure 1. Heart failure progression

A mismatch between the load applied to the heart and the energy needed to meet the load may arise from mechanical and/or metabolic factors. The deleterious way into failure activates numerous pathways that increase peripheral resistance and induce compensatory as well as harmful skeletal muscle and cardiac remodelling. Increased peripheral resistances and adverse remodelling aggravate heart failure.

Figure 2. Metabolic alterations in heart failure

Defects in energy production, transfer and utilization have been described in both cardiac and skeletal muscle in HF. These defects lead to altered high-energy phosphate content and decreased phosphorylation potential that precipitate alterations in calcium homeostasis and contractility.

Figure 3. Mitochondrial biogenesis

Mitochondrial biogenesis depends on the coordinated function of mitochondrial and nuclear genomes. The mitochondrial transcription factor (mtTFA) is encoded by the nuclear genome and activates transcription and replication of the mitochondrial DNA. mtTFA expression is controlled by nuclear respiratory factors (NRFs) that additionally stimulate the expression of numerous nuclear-encoded mitochondrial proteins. NRF expression and transcriptional activity are under the control of the transcriptional coactivator PGC-1α (transcriptional coactivator of peroxisome proliferator-activated receptor gamma). ADNmt, mitochondrial DNA.

Figure 4. Mitochondrial biogenesis in heart failure

The mRNA expression level of PGC-1α correlates with the enzymatic activity of citrate synthase (CS) or maximal respiration rate (V_max) of fibres from left ventricle (LV), soleus (SOL) and gastrocnemius (GAS) of sham-operated and HF rats. r is the correlation coefficient and p is the statistical significance. This suggests that PGC-1α may set the oxidative capacity in different muscle types and in healthy and diseased muscles. (Adapted from Garnier et al. 2003.)