Metabolism—the lost child of cardiology

Energy transfer in the heart

Because the whole is greater than the sum of its parts, an understanding of the control and regulation of energy substrate metabolism remains an important field of research. Energy is the capacity to do work. The release of energy from fuels is achieved by the step-by-step processes of enzymatically controlled fuel metabolism and mitochondrial oxidative phosphorylation, in which the energy content of fuels is transferred to the high energy phosphate bonds of adenosine triphosphate (ATP). Metabolism and contraction of the heart are therefore inseparably linked, which means that ATP must be continuously remade by the dynamo of metabolism. The high turnover rate of ATP means that energy passes through it for all but a fleeting moment. As a result, there is also no correlation between ATP content and ATP turnover in the normal or reperfused heart (5,7).

The first law of thermodynamics is that energy cannot be created or destroyed by any process. It can only be converted from one form into another form. In the heart, like in all cells of the body, efficient energy transfer arises from the interaction of a series of moiety conserved cycles (3). The cell’s key task is to match rates of ATP production to rates of ATP consumption; this is made difficult because the primary site of ATP production (mitochondria) is separate from the primary site of ATP utilization (sarcomeres). The mechanism by which the precise matching between ATP production and utilization occurs is presently unknown. We can say with certainty, however, that “all is in flux.”

Which fuel?

The heart is a metabolic omnivore and is able to meet its need for energy from the oxidation of fatty acids, glucose, lactate and other oxidizable substrates. Studies in the isolated working rat heart, where substrate concentrations can be precisely controlled, have shown that fatty acids inhibit glucose oxidation to a greater extent than glucose inhibits fatty acid oxidation, and that the heart functions best when it oxidizes the two substrates simultaneously (8). This principle is appropriately illustrated by the development of hypertrophy and failure in tissue-specific knock-out models of enzymes of glucose (9) or fatty acid metabolism (10) and by the recently described lipotoxic heart disease in obese rats (11).

Metabolism of glucose to lactate is the main source of energy for the ischemic heart. When lack of oxygen induces a shift from aerobic to anaerobic metabolism, there is rapid stimulation of glucose uptake, glycogenolysis, glycolytic flux and ATP hydrolysis (12). Such an increase in glycolysis is also observed in hypertrophied hearts perfused with low concentrations of fatty acids (13) and is consistent with an increase in glycolytic enzyme activities (14). Despite this increase in glycolysis, rates of glucose oxidation are decreased in hypertrophied as compared with normal hearts, resulting in a greater amount of pyruvate converted to lactate and in an uncoupling of glycolysis from glucose oxidation (13). Hydrolysis of two ATPs for each molecule of glucose metabolized to lactate (and not oxidized) produces two hydrogen ions (H⁺) (15). Acidosis is implicated in contractile dysfunction of the heart (16,17). The excess production of H⁺ may contribute to impaired function of the failing heart.

In the isolated working rat heart, brief periods of ischemia (up to 20 min) result in a dissociation between the early return of oxidative metabolism and a delayed return of contractile function (18). Although it has long been appreciated that fatty acids decrease cardiac efficiency (19,20), the main reason for contractile dysfunction is thought to be the delayed clearance of protons from the cell. One hypothesis is that increased glucose oxidation during reperfusion reduces the proton load and improves functional recovery (21,22).

Metabolic adaptations

Ischemia followed by reperfusion, on the one hand, and hypertrophy on the other, represent two separate but interrelated processes. The former stimulates reactions realized instantly, which are immediately available, whereas the latter produces more gradually evolving reactions, which are of long-term adaptive benefit. Immediate adaptation involves reactions for which the organ has ready-made mechanisms in place. They include the sudden increase in glycogenolysis and glucose oxidation in response to a sudden increase in the work load of the heart (23) and the switching from aerobic to anaerobic metabolism in response to a lack of oxygen, with a resulting accumulation of metabolic products. Long-term adaptation involves reactions for which the heart possesses the genomic prerequisites that allow the gradual evolution of adaptive mechanisms in the face of repeated or persistent environmental stimuli (24). For example, the adaptive responses to training enable the organism to perform levels of physical work not possible in the inherited untrained state. Likewise, the heart’s adaptation to pressure overload prevents the adaptive capacity of the organism from being exhausted when environmental requirements are excessive or sustained (25). Part of this adaptive process is a switch from fatty acids to glucose as the main fuel for respiration, which would be a beneficial adaptive response (26,27). This adaptive metabolic response can precede any trophic changes (14) and may, in its early phase, result in improved efficiency of the heart.

Within this conceptual framework, it is easy to propose that metabolic activity links gene expression with heart function. Although the exact mechanisms of this link are not yet completely understood, a growing body of evidence indicates that the overall metabolic adaptations are brought about, at least in part, by adjustments in the rate of transcription of genes encoding proteins involved in energy substrate metabolism (28).

Targeting metabolism to improve efficiency

As the study by Wambolt et al. (1) shows, adaptation turns into maladaptation when an acute stress (ischemia and reperfusion) is superimposed on an adaptive response. The excess production of protons from enhanced glycolytic metabolism results in contractile dysfunction by mechanisms that are not completely understood. The deleterious effects on contraction that accompany enhanced glycolytic flux are prevented by the addition of a drug that promotes pyruvate oxidation, thereby reducing its conversion to lactate. Dichloroacetate, like ranolazine, and probably also l-carnitine, activate the pyruvate dehydrogenase (PDH) complex by inhibiting pyruvate dehydrogenase kinase (PDK) (29–32). Restoring carbon flux through PDH may be all that is necessary to improve postischemic contractile function (30). Dichloroacetate, although not a specific inhibitor of PDK (33), is one member of the growing group of drugs that target metabolism and metabolic efficiency in the normal, stressed, ischemic or postischemic heart (34,35). These drugs include propionyl l-carnitine (36), etomoxir (34), trimetazidine (37) and troglitazone (38). Although acting at different sites, all of them cause a pharmacologic switch from fatty acid to glucose oxidation. Although it may have been possible to predict the results of the present study, the work exposes an important principle: Metabolic adaptation and maladaptation of the heart are potential targets for pharmacotherapy. Glucose is good for the heart as long as the heart can oxidize glucose. In the future, this concept of intervening in altered cellular metabolism may become as important as intervening in altered blood supply through revascularization of the ischemic heart.

However, this is not yet the time to rush to the pharmacy. First, the observations were made in isolated perfused hearts, and the systemic and toxic effects of the drugs may be considerable. Second, dichloroacetate has been advocated as a drug for the treatment of lactic acidosis (39) and congestive heart failure (40). Yet, the effect of the drug is only temporary and not sustained. Third, we still know far too little about the inner workings of the heart. For example, in the study by Wambolt et al. (1), proton production was only calculated, and neither pH nor the redox state nor lactate production was directly measured (refer to my earlier comment on “lactate levels pending”). Because the control of glycolytic flux is most likely distributed over several enzymes in the pathway (41), and because enzymes may be regulated by several allosteric and covalent regulators, we still do not precisely know the mechanism by which glycolysis and glucose oxidation are “out of step” in the hypertrophied and reperfused heart. As Wambolt et al. discuss, direct measurement of changes in intracellular pH, Na⁺ and Ca²⁺ concentration would be necessary to support the conclusions. Many more small steps are needed to master metabolism and to understand the interplay between gene regulation and metabolic regulation of the heart. One example is the mitochondrial involvement in apoptosis (42,43), and the metabolic regulation of this process (24). The message is clear: Heart muscle has its own fuel economy that responds to a wide spectrum of changes in its environment. More importantly, drugs that improve ischemia tolerance, or drugs that slow down programmed cell death, offer the promise of targeted metabolic interventions, either in the short term (by changing enzyme activities) or in the long term (by alternating gene expression), in the heart. We may be on our way to reclaim cardiology’s lost child.