Optimization of cardiac metabolism:
a clinical reality

Dr S. Quentzel
Internist, Paris, France

The renaissance of clinical cardiac metabolism
There is a resurgence of interest in cardiac metabolism among practising cardiologists. This is largely due to the increasing evidence that metabolic manipulation can be efficaciously applied to numerous clinical situations, as was made clear at a symposium held during the last congress of the European Society of Cardiology (ESC) in Barcelona. One of the messages of this symposium was that cardiologists should have a solid understanding of cardiac metabolism in order to apply the lessons of recent studies to their therapeutic armamentarium. Based on a wholly rational approach, metabolic intervention is being used successfully in several settings of ischaemic heart disease, and its place in management is expanding.

Glucose-insulin-potassium (GIK) validates an experimental concept
The major energy-producing substrates in the heart are glucose and free fatty acids (FFA). For over 20 years, there has been increasing evidence that raising glucose metabolism and decreasing fatty acid oxidation can be beneficial in ischaemia. The major reason for this is that the adenosine triphosphate (ATP) yield (in moles per mole of oxygen) is greater with glucose metabolism than with fatty acid metabolism.[1] Although experimental arguments have been made for some time, it is only in recent years that hard clinical evidence has come to validate a metabolic approach to ischaemic heart disease.

The comeback of GIK
Professor C. Apstein, Director of the Cardiac Muscle Research Laboratory at Boston University, USA, participated at the ESC congress, offering convincing evidence that the provision of a high level of glucose and insulin is beneficial during acute myocardial infarction and postoperative cardiogenic shock. Beginning with the classic study by SodiPallares et al.[2] in 1962 which first described benefit from a regimen of glucose, insulin and potassium (GIK), Professor Apstein retraced the subsequent disappointing trials with GIK, pointing out many of the limitations of these studies, including GIK being initiated as late as 48 h after the onset of chest pain and inadequate glucose and insulin administration. One of the best early randomized trials was done by Rackley et al.,[3] showing that GIK improved cardiac function, decreased ventricular arrhythmias, and was associated with a trend towards decreased mortality.

The mechanism of action of GIK
GIK works by stimulating glucose uptake and glycogen synthesis while inhibiting fatty acid release from adipocytes. In the study by Rackley et al.,[3] GIK induced an increase in the respiratory quotient, demonstrating a shift in energy substrate metabolism from lipids to carbohydrate. Related factors may also come into play, such as improved sodium and calcium homeostasis.

GIK today
The benefit of GIK persists even in the age of thrombolysis, as strongly shown by the DIGAMI (Diabetes Insulin-Glucose in Acute Myocardial Infarction) study[4] in patients with diabetes or hyperglycaemia at admission. In that study, there was a 29% relative mortality reduction at 1 year in patients receiving GIK. The recent ECLA (Estudios Cardiologicos Latinoamerica) study,[5] however, adds the most persuasive evidence of the value and applicability of GIK in myocardial infarction with a 66% relative risk reduction in in-hospital mortality in both diabetic and non-diabetic patients receiving thrombolytic therapy.
These studies with GIK have clearly validated the metabolic approach to myocardial ischaemia and have raised awareness about the value of a metabolic approach to treating ischaemic cardiac disease. However, as Professor Apstein noted, GIK can only be given intravenously and is only adapted to the acute coronary setting. Specific pharmacological agents that can shift energy metabolism from FFA to carbohydrate utilization can expand the role and clinical setting of the metabolic approach in cardiac disease.

Current and potential applications of metabolic intervention in ischaemic heart disease
Professor Apstein defined several different clinical situations in which a metabolic approach is now appropriate or may potentially be appropriate:

• situations with strong evidence for metabolic intervention:

• acute myocardial infarction treated with thrombolysis,
• before and after cardiac surgery, especially for postoperative hypotension and heart failure,
• angina pectoris;

• situations with some evidence of benefit or with unproven but theoretical potential for benefit from metabolic intervention:

• cardiogenic shock,
• during percutaneous transluminal coronary angioplasty (PTCA),
• in unstable angina with diffuse ischaemia due to severe coronary artery disease,
• left ventricular hypertrophy with diffuse subendocardial ischaemia,
• ischaemic cardiomyopathy with congestive heart failure.

Pharmacologic agents that can modify cardiac metabolism in ischaemia have been studied in several different clinical settings. The current evidence, however, is stronger for certain agents than for others.

Pharmacological agents can improve cardiac metabolism in ischaemia
Several metabolic agents, including etomoxir, dichloroacetate, carnitine, ranolazine and trimetazidine, modify energy substrate utilization. Of these, trimetazidine is the best known and the most widely studied. Professor G. Lopaschuk has definitively shown that trimetazidine stimulates glucose oxidation through an inhibition of fatty acid metabolism in ischaemic hearts. In this way, trimetazidine improves ATP yield during ischaemia. Additionally, this shift in energy substrate preference has the effect of recoupling glycolysis to glucose oxidation, an effect which reduces intracellular acidosis. As a result, Professor Lopaschuk has shown that trimetazidine increases the recovery of cardiac work by 33% and improves cardiac efficiency by 24% in ischaemia and reperfusion.6 Trimetazidine also increases the turnover of membrane fatty acids, which avoids the accumulation of fatty acids in the cytoplasm.[7] This activity gives trimetazidine a pronounced anti-ischaemic effect which has been shown to reduce infarct size in rabbits and to cause an increased recovery of ATP stores in dogs during ischaemia and reperfusion. This anti-ischaemic activity has been equally demonstrated in several well-controlled clinical studies in angina pectoris.

Metabolic intervention in clinical practice: experience in angina pectoris
As Dr G. Jackson (London, UK) observed, myocardial ischaemia is characterized by metabolic abnormalities; it therefore makes sense to tackle a metabolic problem using a metabolic agent. The absence of haemodynamic effects makes these agents even more attractive.

Efficacy and safety of a metabolic agent in monotherapy and combination therapy
Clinical studies with the fatty acid beta-oxidation inhibitor trimetazidine have shown it to be as effective as propranolol[8,9] or nifedipine[10] in treating angina in terms of clinical and ergometric parameters. Since trimetazidine has no haemodynamic effect, no serious side effects, and requires no dose adjustment in association with other drugs, its use in combination with haemodynamic agents has been tested. As expected because of the totally different modes of action, trimetazidine provides additive benefit — in terms of clinical and ergometric parameters — in combination with a beta-blocker,[11–13] a calcium channel blocker[12–15] or a long-acting nitrate.[12,16] The combination of trimetazidine and propranolol was superior to propranolol and isosorbide dinitrate.[11]

Role of a metabolic agent in diabetics and the elderly
Efficacious and safe due to its metabolic mode of action, trimetazidine can be prescribed in the elderly and in diabetic patients, populations which may be particularly sensitive to the side effects of haemodynamic drugs in ischaemic heart disease. Adverse drug reactions, including symptomatic bradycardia, heart failure and syncopal episodes, are more common in the elderly. In diabetic patients, beta-blockers can mask the awareness signs of hypoglycaemia while peripheral vasodilatation induced by calcium antagonists can be potentially hazardous due to diabetic autonomic neuropathy. Furthermore, diabetic patients derive most of their cardiac energy from the metabolism of fatty acids, and this is probably a contributing factor to the greater cardiac mortality found in diabetics.[17] Indeed, as Dr Jackson pointed out, given the fact that impaired glucose oxidation may be a cardinal reason for the poor outcome of diabetic patients with coronary artery disease, there is reason to believe that metabolic agents which decrease fatty acid metabolism and increase glucose oxidation may be ideal for use in these patients.
In the TRIMPOL-I diabetic substudy,[18] trimetazidine was shown to be effective and well tolerated in 50 diabetic patients, with no adverse effect on glycaemic control. Trimetazidine significantly improved both clinical and exercise test results. Ninety-eight percent of patients rated the tolerability of trimetazidine 20 mg as excellent. Self-assessed quality of life never worsened but actually improved in over 75% of patients taking trimetazidine.
Metabolic agents are thus establishing themselves as an extremely valuable strategy in the treatment of angina pectoris. Two recent studies may lend weight to the expanding role of metabolic agents in different settings in the care of patients with coronary artery disease.

Recent studies with metabolic agents in different settings of ischaemic heart disease
Two recent studies demonstrate in extremely varied clinical settings the activity of trimetazidine.

Effects of metabolic manipulation on ischaemic left ventricular dysfunction
Improvement of ischaemia in patients with coronary artery disease is usually measured by the exercise test using chiefly the parameters of time to 1-mm ST-segment depression and total work and exercise duration. Unfortunately, total work and exercise duration can be influenced by factors that are not purely ischaemic, such as patient motivation and muscular conditioning. It is obviously interesting to have an idea of the improvement in cardiac function itself, especially since ventricular dysfunction is known to precede ischaemic ECG changes. Stress echocardiography is particularly useful in this regard because it can provide an objective correlation between ischaemia and ventricular function. Improvement in wall motion and contractility can be directly visualized to define the true onset of ischaemia, and wall motion is not affected by patient motivation. Dobutamine stress echocardiography (DSE) can further improve the usefulness of this technique by eliminating the artefactual problems posed by echocardiography during active exercise. Dobutamine is infused at a progressive rate, mimicking the progressive stress of an exercise protocol.
To objectively quantify ventricular function, the wall motion score index (WMSI) can be calculated by grading wall motion on a four-point scale in each of 16 ventricular segments. A grade of 1 is given if the wall motion is normal, 2 if there is hypokinesia, 3 if there is akinesia, and 4 if there is dyskinesia. The average of all segments is taken: a low score signifies a better ventricular function than a high score. During exercise or stress with dobutamine, the WMSI increases as ventricular function deteriorates in patients with ischaemia. The onset of ischaemia corresponds to the worsening of wall motion in a segment by at least one grade; for example, a segment that goes from hypokinetic to akinetic.
Using this technique, Professor S. Chierchia and colleagues studied the effects of the metabolic agent trimetazidine in a randomized, placebo-controlled, crossover study in 15 patients with documented coronary artery disease over two 15-day treatment periods (Figure 1).[19] 

Figure 1. Study design for trimetazidine in coronary artery disease patients with ventricular dysfunction. DSE, dobutamine stress echocardiography.

Ventricular function was assessed both at rest and during stress by DSE before and after the treatment periods with trimetazidine 20 mg and placebo. Compared with placebo, trimetazidine significantly decreased WMSI both at rest and at peak infusion. This is all the more impressive because peak dobutamine infusion dose and time were also significantly higher after the trimetazidine treatment period (Figure 2). 

Figure 2. Effect of trimetazidine 20 mg on dobutamine infusion dose and time in coronary artery disease patients with ventricular dysfunction.

Thus, trimetazidine improves resting ventricular function, prolongs time to ischaemic threshold, and preserves wall motion even at a higher cardiac stress.
This study further validates the benefit of a shift in energy substrate metabolism from fatty acids toward glucose and demonstrates the activity of a metabolic agent, trimetazidine, in improving not only the exercise test parameters but also cardiac function itself.
Value of metabolic manipulation during primary PTCA for acute myocardial infarction
Despite the great progress that has been made in recent years in reopening occluded coronary arteries by pharmacological thrombolysis or PTCA, there is clearly an excess early mortality in some patients, the so-called ‘early hazard’.[20] Since catecholamines, induced by stress, increase circulating FFA levels, FFAs rapidly become the dominant energy substrate during reperfusion. Heparin, which is given in the setting of both PTCA and thrombolysis, also raises FFA levels. As a result, during reperfusion, fatty acid oxidation predominates in the cardiomyocyte while glucose oxidation is almost shut down. Although the cardiomyocyte is trying to rapidly re-establish its ATP stores, the excessive fatty acid oxidation leads to an uncoupling between glycolysis and glucose oxidation.
Thus, a likely role for metabolic intervention during primary PTCA for acute myocardial infarction would be to lessen the metabolic consequences of ischaemia and reperfusion by shifting energy substrate metabolism from fatty acids to glucose.
Although the exact nature and aetiology of reperfusion injury remain difficult to define, it is apparent that among patients with complete angiographic recanalization (TIMI grade 3 flow) of the coronary arteries, there is a wide spectrum of clinical outcomes. As shown by the group from Zwolle[21] who evaluated a population having undergone successful primary PTCA, patients with a complete return of the ST-segment to baseline on the standard 12-lead ECG had the best outcome, while patients with incomplete resolution of ST-segment elevation had an increased relative risk of death, and those with no ST resolution had the worst outcome of all.
During the ESC symposium, Professor P.G. Steg (Paris, France) presented results from a multicentre, double-blind, randomized, placebo-controlled study to evaluate the effect of a shift in energy substrate metabolism from fatty acid to glucose on signs of reperfusion injury in 94 patients undergoing PTCA for acute myocardial infarction. Patients received either a placebo IV bolus or an IV bolus of trimetazidine 40 mg followed by a continuous infusion of 60 mg over 48 h. Using a continuous vectorcardiographic system (MIDA), it was shown that trimetazidine significantly increased the rate of return to baseline of the ST-segment after primary PTCA (Figure 3). 

Figure 3. Earlier and more marked return to baseline of ST-segment elevation with trimetazidine (P < 0.014). H, hour.

Furthermore, there was a lower frequency of ST exacerbation, although this did not attain statistical significance (23 vs 42%, P=0.11).
It is probable that the improved electrocardiographic recovery seen with trimetazidine after primary PTCA is due to a more rapid reconstitution of ATP stores during reperfusion.

Conclusion
After decades of laboratory research and many false starts, metabolic therapies are enjoying a resurgence of interest. While GIK has paved the way and has shown its utility in acute myocardial infarction, pharmacological agents have a number of advantages, including oral administration and an excellent safety profile, both of which allow for broader clinical utilization. Trimetazidine, the most extensively studied metabolic agent in the clinical setting, is now available in most countries for the treatment of angina pectoris. Based on a wholly rational approach to treating heart disease, metabolic intervention is reshaping therapeutic strategies in ischaemic heart disease.

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