Energy starvation and the metabolic approach to ventricular dysfunction

Dr S. Quentzel
Internist, Paris, France

Heart failure afflicts 1–2% of the overall population, increasing to at least 7% in the over-75s, and has an annual mortality rate of up to 20%.[1] Heart failure is also an increasingly common cause of hospital admissions, almost doubling over the past 15 years.[2] The aging of the population, the increasing prevalence of diabetes mellitus and the improving survival of patients after myocardial infarction are several of the major epidemiological trends behind the increasing prevalence of heart failure.[3]
Conventional therapy for heart failure unloads the heart but does not directly improve the cardiac function itself. The positive inotropes, which increase myocardial energy expenditure, have proven to be disappointing or even dangerous in heart failure.[4] In fact, a decrease in the availability of adenosine triphosphate (ATP), or ‘energy starvation’ as it has been called,[5] is likely to be a major factor in the development and progression of heart failure.

Energy starvation in heart failure
The work of Starling during and after World War I led to the idea that the overloaded heart has increased energy demands. Over the past few decades, it has become clear that cardiomyocytes in the overloaded heart are characterized by reduced ATP availability. Multiple factors are responsible for this decrease in ATP availability in heart failure, including regional ischemia, reduced oxygen delivery (decreased capillary supply, reduced coronary flow reserve), impaired oxygen diffusion (increased cardiomyocyte size, fibrosis) and altered oxidative phosphorylation due to mitochondrial abnormalities.[5] Furthermore, it has recently been demonstrated that abnormalities in glucose metabolism play an important role in the energy starvation of heart failure.
The combination of an increased energy demand on the ventricle, as described by Starling, and the reduced ATP availability leads to decreases in both ATP concentrations and the ATP:adenosine diphosphate ratio. As a result, there is a reduction in energy-consuming reactions involved in contractility and ion exchange and an attenuation of certain allosteric effects which are attributable to high ATP concentrations. These allosteric effects of ATP, likened to those of a lubricant, allow ATP, without undergoing hydrolysis, to accelerate a number of ion pumps and ion exchangers as well as passive ion fluxes through membrane channels and movements of the thick and thin filaments of the sarcomere.[5] As a result, when ATP levels fall in the heart, both contractility and relaxation are inhibited.

Insulin resistance and metabolic disturbances in heart failure
Contributing to the energy starvation in heart failure are abnormalities in glucose metabolism, including changes in enzyme activity6 and abnormalities in insulin sensitivity. The main effect of insulin on insulin-sensitive tissues, such as the heart and skeletal muscle, is to increase glucose uptake and utilization while reducing free fatty acid metabolism. While glycolysis normally accounts for only about 5–10% of total ATP production in cardiomyocytes,[7] it is thought to have a particularly important role in supplying ATP to nearby energy-consuming reactions involving the contractile proteins and energy pumps.[8] This is because, unlike glucose and fatty acid oxidation, glycolysis takes place in the cytoplasm and not in the mitochondria. This role for glucose in providing local energy for contractile function may be particularly important under pathologic conditions of energy starvation found in heart failure.
Cellular insulin resistance can thus reduce the availability of glucose and the ability of cardiomyocytes to metabolize glucose. Heart failure, whether ischemic or idiopathic, is a state of insulin resistance.[9] It has been shown that patients with coronary artery disease who have no signs of heart failure have significant insulin resistance compared with healthy controls and have basal and stimulated (after a glucose load) elevations in insulin and C-peptide levels.[10] A similar degree of insulin resistance, along with similar elevations in insulin and C-peptide levels, has been observed in patients with idiopathic dilated cardiomyopathy.[10] In patients with congestive heart failure due to ischemic cardiomyopathy, insulin resistance is even further increased, as though the two conditions, coronary artery disease and congestive heart failure, exerted an additive effect on inhibiting glucose metabolism.[10] Thus, both coronary artery disease and heart failure are states of insulin resistance, and patients with ischemic cardiomyopathy are particularly affected.

Positron emission tomography (PET) studies on insulin resistance
The above findings, based on laboratory blood tests, have been supported by data from positron emission tomography (PET) scanning, which has been used to evaluate myocardial insulin resistance using a labeled deoxyglucose tracer fluorine-18 fluorodeoxyglucose (¹⁸FDG). Paternostro et al. showed that non-diabetic patients with previous myocardial infarction, left ventricular dysfunction and heart failure are insulin-resistant.[11] They also showed that myocardial uptake of glucose in myocardium remote from the site of infarction was approximately 50% of that found in control subjects, despite comparable blood flow. To standardize conditions, the authors used the hyperinsulinemic-euglycemic clamp technique whereby supraphysiologic levels of insulin can be given to optimize glucose uptake. In this way, glucose uptake can be considered to be limited only by the sensitivity of tissue to insulin. The authors proposed that the reduced glucose uptake by cardiomyocytes in the non-infarcted (remote) myocardium is a feature of adaptive hypertrophy and remodeling. In a separate study, also standardized using ¹⁸FDG PET and the euglycemic clamp, they showed that myocardial glucose uptake in the normally contracting segments in patients with coronary artery disease and associated chronic left ventricular dysfunction was 35% lower than in the myocardium of normal subjects.[12] Thus, in patients with ischemia-induced left ventricular dysfunction, myocardium in both ischemic and non-ischemic regions is insulin-resistant.
From a molecular viewpoint, reduced insulin sensitivity may be due to a reduction in GLUT-4 transporter protein.[9]
While therapy with vasodilators and diuretics is certainly effective in improving symptoms, new approaches which more directly respond to the problems posed by energy starvation and insulin resistance are needed to improve the management of patients with heart failure — of both ischemic and non-ischemic origin — and with ischemia-induced ventricular dysfunction.

Metabolic strategies to treat heart failure
Among the possible strategies to overcome energy starvation in heart failure, two recent papers by the group of Hasenfuss in Germany have assessed the effects of pyruvate on contractility.[13,14] Pyruvate is the product of glycolysis which goes on to be converted to acetyl coenzyme A, which can then go on to be oxidized in the Krebs cycle to produce nicotinamide adenine dinucleotide (NADH). NADH provides H+ ions necessary for the electron transport chain used in oxidative phosphorylation to generate ATP.
By adding pyruvate 20 mM to rabbit and failing human myocardium, the authors found significant increases in contractility. Despite this, with pyruvate, there was a non-significant trend toward improved utilization of oxygen, as shown by an improved economy of myocardial contraction relative to oxygen consumption.[5]
This experiment shows that a metabolic therapy, unlike other types of positive inotropic therapy, can improve contractility without a corresponding increase in energy and oxygen expenditure which, over time, is likely to be harmful.[5]

Strategies to switch energy substrate
Another approach to metabolic therapy is with agents which decrease fatty acid oxidation and increase glucose metabolism. Such agents can be of double value: they can reduce the toxic byproducts of fatty acid metabolism known to be harmful in terms of contractility and ion exchange,[3] while increasing glucose metabolism which is more efficient than fatty acid metabolism in terms of ATP production per mole of oxygen utilized. Furthermore, such an approach can stimulate glycolysis, which is suppressed by fatty acid metabolism. As seen above, this can be very important for local energy-demanding reactions, including contractility and ion exchange. Additionally, agents which stimulate glucose oxidation reduce the lactate accumulation and the acidosis that are produced by glycolysis when it is uncoupled from the second step of glucose metabolism, known as glucose oxidation, in which acetyl coenzyme A from pyruvate is metabolized in the Krebs cycle.[15]
Trimetazidine is a metabolic agent which works by inhibiting a key step in fatty acid beta-oxidation. This inhibition secondarily stimulates glucose oxidation.[16] In this way, trimetazidine causes a switch in energy substrate utilization from fatty acids toward glucose.
Several studies have now shown that trimetazidine, due to this metabolic mechanism of action, can have a significantly favorable effect on contractility in different clinical situations.[17,18]

Evidence for the benefit of trimetazidine in stress-induced ischemic left ventricular dysfunction
Supporting the importance of metabolic abnormalities in contractile dysfunction and the great potential offered by therapies that modulate cardiac metabolism, several clinical studies have shown that trimetazidine, through a metabolic switch from fatty acids to glucose metabolism, can produce marked clinical benefits.
Lu et al., using dobutamine stress echocardiography (DSE), evaluated trimetazidine in a double-blind, randomized, crossover trial in 15 patients with documented coronary artery disease and stress-induced wall motion abnormalities.[17] DSE was carried out at the end of two 15-day treatment periods, during which patients received trimetazidine (20 mg t.i.d.) or placebo. Although wall motion function was generally well preserved in these patients, patients had significant improvement in the wall motion score index (WMSI) both at rest and at peak dobutamine stress when they were receiving trimetazidine. Since dobutamine infusion dose and time were also increased by trimetazidine, the reduction in the WMSI actually occurred at a greater cardiac workload. Confirming the findings of previous studies, trimetazidine had no effect on heart rate or blood pressure.[19,20]

Metabolic approach with trimetazidine in ischemic cardiomyopathy
The results of the study discussed above address a particular population with predominantly stress-induced ventricular dysfunction. A separate study evaluated the effect of trimetazidine in a population with chronic dysfunctional but viable myocardium.[18] This was a randomized, double-blind, placebo-controlled trial in 22 patients (mean age 53 ± 7 years) with a history of myocardial infarction, reduced left ventricular ejection fraction (mean 33 ± 7%) and New York Heart Association class II–III heart failure. All patients were taking conventional therapy for heart failure and angina, including diuretics, angiotensin-converting enzyme inhibitors and nitrates. Patients were randomized to trimetazidine 20 mg t.i.d. or placebo in addition to their conventional therapy.
To evaluate the effect of trimetazidine on regional contractility, dobutamine stress echocardiography was performed at baseline and after 2 months of study treatment.
The trimetazidine-treated patients had significant reductions in WMSI both at rest (2.05 ± 0.5 to 1.61 ± 0.4; P < 0.05) and at peak infusion (1.66 ± 0.3 to 1.32 ± 0.4; P < 0.05) (Figure 1). 

Figure 1.Effect of trimetazidine on WMSI at rest and at stress in patients with hibernating myocardium.[18]

There was no change in WMSI in the placebo group and there was no difference in any of the hemodynamic variables between the two groups.
The results of these two studies, while not addressing the efficacy of the metabolic approach in heart failure of non-ischemic origin, do show that the metabolic approach, already proven effective (in the case of trimetazidine) in improving ergometric parameters in ischemic patients, can also improve cardiac contractile function in the setting of both chronic and stress-induced ischemia.
The benefit of trimetazidine in these patients is due to its effects on fatty acid and glucose metabolism. By inhibiting fatty acid oxidation, trimetazidine stimulates total glucose utilization, including both glycolysis and glucose oxidation.[21] Since glycolysis is coupled to glucose oxidation, lactate and proton accumulation, which could otherwise lead to intracellular acidosis and calcium overload, is prevented. Furthermore, it is known that administration of trimetazidine increases the incorporation of long-chain fatty acids into the cardiomyocyte membrane,[22] thus significantly reducing the availability of cytosolic free fatty acids and acylcarnitine, which can have deleterious effects on calcium handling.[23]

Conclusion
Heart failure and ischemic left ventricular dysfunction are increasingly common syndromes. It is becoming clear that metabolic abnormalities such as energy starvation and insulin resistance play an important role in the pathophysiology of contractile dysfunction and heart failure, particularly in the setting of ischemic cardiomyopathy. Treatment for heart failure has classically included positive inotropic agents (likened to ‘whipping a tired horse’) and vasodilators (likened to ‘unloading the wagon’). As pointed out by Katz, the short-term gain from whipping the horse is likely to be at the expense of an adverse long-term outcome, and drugs that improve symptoms in heart failure at the expense of an increase in cardiac energy expenditure can be expected to worsen prognosis.[5] Trimetazidine improves cardiac metabolism through a switch which reduces fatty acid metabolism and increases glucose metabolism. Studies with this agent demonstrate that it is possible to improve cardiac function without altering blood pressure or heart rate. As recently observed, the heart is more than a pump, it is also an organ that needs energy from metabolism.[24] By directly improving cardiac metabolism, trimetazidine, which is currently widely used for the treatment of angina pectoris, improves ventricular function without hemodynamic side effects or drug interactions, opening up a new strategy in the treatment of ischemic heart failure and ventricular dysfunction.

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