Number 27, 2005
Metabolic approach in heart failure

Metabolic approach in heart failure: the rationale for metabolic interventions

Back to the Summary

Gary D. Lopaschuk¹, William A. Stanley², Catharine C. Lopaschuk^1
1Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada ²Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
Correspondence: Professor Gary D. Lopaschuk, 4–23 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
Tel: +1 (780) 4922170, fax: +1 (780) 4929753, e-mail: gary.lopaschuk@ualberta.ca

Introduction
Modern health care has brought us to a point at which we are living much longer and with a better quality of life. However, cardiovascular disease remains the primary cause of death and disability in the industrialized world. Advancements in acute cardiac care have improved survival after acute myocardial infarctions, but alongside this there has been an increase in mortality as a result of heart failure [1].
The term ‘heart failure’ encompasses a number of clinical variations and differing etiologies. Heart failure is defined as ‘a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood’ [2]. Treatment of heart failure currently targets fluid overload and neurohormonal activation. Diuretics, digoxin, and inotropes treat fluid overload and improve hemodynamics; while angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, ß-receptor antagonists, and aldosterone antagonists suppress neurohormonal activation. In spite of these treatments, there is still progression of contractile dysfunction and continuing left ventricular enlargement [3–5]. Furthermore, recent evidence has shown that more aggressive treatment with aldosterone antagonists does not provide any better outcome [6–8]. Therefore, there is a need for new treatments for heart failure that work independently of mechanisms already targeted.
Emerging evidence suggests that the failure of the myocardium in heart failure is caused by alterations in substrate metabolism (reviewed in Stanley et al [9]). In particular, there is now evidence that in the failing heart, shifting metabolism away from a preference for fatty acids towards more carbohydrate oxidation can improve contractile function and slow the progression of pump failure [10–17].

Energy metabolism in the normal heart
In the normal, healthy heart, the large amounts of adenosine triphosphate (ATP) necessary to sustain contractile function and basal metabolism are generated primarily by mitochondrial oxidative metabolism, with a small proportion derived from glycolysis (Figure 1). The heart is an omnivore and can use many different energy substrates (fatty acids, glucose, lactate, ketones, amino acids), but mitochondrial ATP is primarily produced by the oxidation of fatty acids and of pyruvate (derived from either glycolysis or lactate) (Figure 1). The rate of metabolism along these different pathways is determined by arterial substrate concentration, hormones, coronary flow, inotropic state, and nutritional status [9]. These effects are mediated by various enzymes and substrate–product relationships. In the normal heart, approximately 10–40% of the ATP is produced via pyruvate oxidation, whereas the remaining 60–90% is derived from the oxidation of fatty acids. An important enzyme at the interface between carbohydrate oxidation and fatty acid metabolism is pyruvate dehydrogenase (PDH), which decarboxylates pyruvate to acetyl coenzyme A (CoA) (Figure 1). PDH activity is influenced not only by glycolysis, but also by an inhibitory effect exerted through fatty acid oxidation. In situations in which the circulating free fatty acid concentrations are high, the oxidation of glucose and pyruvate and the activity of PDH are decreased. As a result of this, pyruvate is redirected towards lactate production and released from the heart. This produces protons, which the heart must also clear – a process that often requires energy, and results in redirecting ATP away from contractile function, which can decrease cardiac efficiency [18]. Conversely, decreasing plasma free fatty acid concentrations, or directly inhibiting fatty acid oxidation, increases PDH activity and, hence, pyruvate oxidation and cardiac efficiency [18,19].

Energy metabolism in the failing heart
Because of the difficulty of obtaining myocardial tissue samples and assessing cardiac energy metabolism in humans, direct measurements of energy metabolism in the failing heart are few. However, studies both in patients with heart failure and in animal models of heart failure show that there is a decrease in tissue ATP content, an increase in ADP, and a decrease in the phosphorylation potential (reviewed in Stanley et al [9]), thus impairing the kinetics for the utilization of ATP for cell contraction. In addition, heart failure impairs the capacity for the creatine kinase system to transfer mitochondrial ATP to the myofibril, and decreases mitochondrial oxidative capacity, in part as a result of a decrease in electron transport chain activity [9]. The electron transport chain defects in heart failure are consistent with the concept that, in heart failure, there is a major lesion in oxidative metabolism at the level of the chain. It appears that impairment in the electron transport chain reduces the in-vivo capacity for myocardial generation of ATP and thus limits cardiac contractile function during high-level work, such as exercise or acute adrenergic stress. This is supported by the studies in dogs with pacing-induced heart failure, that reduced myocardial oxygen consumption in response to increased cardiac work was the result of a limitation of oxygen extraction, not of myocardial blood flow [20,21]. These findings are consistent with the concept of impaired mitochondrial respiratory capacity in heart failure, resulting in reduced ability to generate ATP in response to increased demand for cardiac power. In support, of this, recent studies have demonstrated that downregulation of the enzymes of fatty acid oxidation can be triggered by a defect in the electron transport chain in the mouse heart [22].
Numerous studies, in patients and in animal models, have shown that heart failure reduces the capacity to transduce the energy from foodstuffs into ATP, but less is known about the effects of heart failure on myocardial substrate metabolism and fuel selection. In the early stages of heart failure, there is a normal (or slightly increased) rate of fatty acid oxidation, and in advanced or endstage heart failure there is downregulation of fatty acid oxidation. Paolisso et al [23] found increased extraction and uptake of plasma free fatty acids and decreased glucose uptake in patients with congestive heart failure Classes II and III compared with age-matched healthy individuals. In these patients there was a corresponding 60% decrease in cardiac carbohydrate oxidation compared with the healthy controls. Using positron emission tomography (PET), Taylor et al [24] found greater myocardial uptake of a radiolabeled fatty acid analog and less uptake of a radiolabeled deoxyglucose in patients with Class III heart failure compared with those in healthy individuals. In contrast, patients with idiopathic dilated cardiomyopathy appear to exhibit the reverse: a greater myocardial glucose uptake and less fatty acid uptake compared with normal people. Yazaki et al [25] and Dávila-Román et al [26] found impaired utilization of fatty acids in patients with severe idiopathic dilated cardiomyopathy. It is important to note that, with PET, although one can estimate glucose uptake, it is not possible to make a direct measurement of the rate of glucose oxidation. It is therefore not clear from these studies whether flux through PDH is altered in these patients. To date, the limited availability of data on clinical investigations may be attributable to the severity of heart failure, supporting the idea that, in the early stages of heart failure, there is a normal (or slightly increased) rate of fatty acid oxidation, with a dramatic downregulation of fatty acid oxidation in advanced or endstage heart failure.
Studies in animal models of heart failure parallel human studies that suggest increased or normal fatty acid oxidation in early heart failure and impaired fatty acid oxidation in severe heart failure. Chandler et al [27] measured myocardial substrate oxidation in dogs with well compensated microembolization-induced heart failure using isotopic tracers, and found no differences in myocardial glucose, lactate, or fatty acid metabolism compared with those in normal dogs. In a canine rapid-pacing model of heart failure, Recchi et al [28] showed a relatively normal myocardial substrate metabolism in the early and middle stages of heart failure, and a decrease in fatty acid oxidation in severe heart failure. In general, measurements of the level of expression of key enzymes in fatty acid oxidation support these direct measurements of energy metabolism (reviewed in Stanley et al [9]).

Therapeutic options in the metabolic treatment of heart failure
Because heart failure can decrease cardiac energy reserve, and utilization of fatty acid oxidation is less efficient than glucose oxidation, it may be possible to improve myocardial contractile function by reducing fatty acid oxidation and increasing the flux through PDH. There are already limited clinical data to support this concept. For instance, patients with Classes II and III heart failure were infused with dichloroacetate [29,30], a compound that inhibits PDH kinase and thereby activates PDH and increases glucose oxidation. This resulted in an increase in stroke volume and ejection fraction, in addition to an improvement in cardiac efficiency. Increasing the plasma insulin concentration will also increase glucose oxidation and inhibit fatty acid oxidation. Patients with ischemic heart disease and left ventricular dysfunction were treated with an infusion of insulin and showed an improvement in their wall motion scores and left ventricular ejection fraction [31]. Thus, in the short term, left ventricular function and mechanical efficiency are improved by the acute stimulation of myocardial carbohydrate metabolism and inhibition of fatty acid oxidation. This can be achieved by increasing activity at the level of PDH.
In long-term studies, patients with New York Heart Association (NYHA) Classes II and III heart failure have been followed while receiving trimetazidine [15,32,33], a fatty acid oxidation inhibitor. Two months of treatment resulted in significant improvement in left ventricular ejection fraction at rest and in left ventricular wall motion during a dobutamine stress test as compared with placebo. Six months of treatment with trimetazidine improved diastolic function, whereas no change was seen in patients receiving placebo. A recent study by Di Napoli et al [34] also showed that, in patients with NYHA Classes II and III heart failure with ischemic dilated cardiomyopathy, chronic treatment (up to 18 months) with trimetazidine can increase ejection fraction in the patients by 26–38%. Large-scale clinical trials are still needed.
Another way of suppressing fatty acid oxidation is to inhibit CPT-1 (Figure 2). It has now been shown that inhibiting CPT-1 with oxfenicine can prevent ventricular remodeling and slow the progression of heart failure in dogs [35,36]. Other pharmacological agents available for long-term treatment include ß blockers, ACE inhibitors, and angiotensin receptor antagonists. The clinical improvement in heart failure seen with these agents is associated with a switch in myocardial metabolism away from fatty acid oxidation towards more glucose uptake and carbohydrate oxidation [37–39]. The mechanism for this is unknown.

Conclusions
Newly emerging evidence suggests that the mechanism of myocardial injury that leads to failing heart function is based on a switch in metabolic substrate preference by the heart. Improvements in heart function, in both the short and the long term, have been achieved by enhancing carbohydrate metabolism and inhibiting fatty acid metabolism. To date, the most promising results have come from increasing activity at the level of PDH in the mitochondria.
Current medical treatments for heart failure will improve heart function for a time, but act only to slow, not prevent, the progression of disease or reverse the damage to the myocardium. New treatments, through a metabolic approach, can be used to achieve further enhancement of performance in the failing heart. Much more research needs to be done in this exciting and potentially highly therapeutic area. ?

Back to the Summary

REFERENCES

Back to the Summary