Pharmacological optimization of cardiac metabolism in ischemic heart disease

Dr Steven Quentzel
Internist, Paris, France

Diabetes will be one of the most challenging health problems of the 21st century,[1] and the cardiologist is certain to have a central role in caring for these patients. Heart disease in diabetics is a modern epidemic which requires a coordinated approach and the close attention of the cardiologist. In a recent health survey, 22% of diabetic patients reported they had seen a cardiologist in the preceding 12 months.[2] It is now well established that diabetics are at increased risk of coronary heart disease (CHD) and congestive heart failure,[2] and that they have a 1.5–3 times greater risk of death or reinfarction.[3] Furthermore, the existence of a separate diabetic cardiomyopathy, independent of ischemic heart disease or hypertension, is now recognized.[2]
In diabetics, a strategy of strict glycemic control, as shown in the UKPDS which involved over 5000 patients with a median follow-up of 10 years, is associated with a 16% reduction in the incidence of acute myocardial infarction,[4] which nearly attains statistical significance (P = 0.052). Further, and perhaps stronger, evidence in favor of strict glycemic control has come from the DIGAMI study in the setting of acute ischemia.[5] In this study, all patients admitted with acute myocardial infarction and a blood glucose 11 mmol/l were randomized to an intensive regimen of glucose-insulin-potassium (GIK) or to control. The result was an astonishing overall 1-year 27% reduction in relative mortality in the GIK group compared with the control group.
How can these results with GIK be explained? In non-diabetics under non-ischemic conditions, fatty acid metabolism provides 60–80% of the ATP production, while glucose metabolism provides 40–60%. Diabetics are even more dependent on fatty acid metabolism than are non-diabetics, deriving at times more than 90% of their ATP from fatty acid metabolism.[6] Furthermore, diabetes is characterized by an increase in circulating free fatty acids. It has been known for over 20 years that fatty acids are deleterious in ischemia.[6] GIK has a number of beneficial effects on myocardial metabolism in diabetics in ischemia, including, as shown by Rackley et al. nearly 20 years ago,[7] a decrease in fatty acid metabolism compared with glucose metabolism.

Applying metabolic concepts to ischemic heart disease in diabetics
The results with GIK provide strong corroboration of what has now become recognized as the importance of metabolic interventions in cardiac disease. Metabolic agents, which include trimetazidine, ranolazine, dichloroacetate and etomoxir, act on specific metabolic processes, and are now attracting great interest for their potential value in treating ischemic heart disease. Trimetazidine, which directly inhibits fatty acid beta-oxidation and secondarily stimulates glucose oxidation, has anti-ischemic and anti-anginal properties.[8, 9]
This metabolic mechanism of action explains the rationale for trimetazidine in diabetes. 
The hallmarks of the metabolic abnormalities in the diabetic heart are impaired glucose oxidation and an increase in dependence on fatty acid oxidation for energy production.10 The increased use of fatty acids causes an increased use of myocardial oxygen and enhanced intracellular accumulation of metabolic intermediates, leading to intracardiac conduction disturbances, arrhythmias, ion pump dysfunction, calcium overload, and contractile dysfunction. Furthermore, lactic acid accumulation further promotes the degradation of fatty acids.[2] These meta-bolic abnormalities are now thought to be an important contributing factor in the increased morbidity and mortality of ischemic heart disease (IHD) in diabetes.
By shifting the energy substrate away from fatty acids and towards glucose metabolism, trimetazidine optimizes cardiac metabolism in ischemia. In a clinical trial in 50 diabetic patients with stable angina pectoris, the addition of trimetazidine 20 mg t.i.d. to baseline monotherapy with a beta-blocker, calcium channel antagonist or long-acting nitrate led to a statistically significant improvement in terms of both clinical and ergometric parameters after 4 weeks of study treatment.[11] Average time to 1 mm ST-segment depression was increased by 52 s in these patients (P < 0.01), and time to onset of angina by 162 s. Total exercise duration increased by 57 s (P < 0.01) (Figure 1) and total work, on average, increased from 8.67 to 9.39 METs (P < 0.01). 

Figure 1. Exercise duration in diabetic patients after 4 weeks of trimetazidine. [11]

In terms of clinical parameters, mean weekly anginal frequency decreased by 36% from 4.79 to 3.06 (P < 0.01) and short-acting nitrate consumption decreased by 45% from 4.2 to 2.29 per week (P < 0.01).
These results demonstrate the usefulness of a metabolic approach to treating ischemic heart disease in diabetics. Interestingly, 98% of patients assessed the tolerability of trimetazidine as good or excellent.

Importance of metabolic management in all patients with CHD
The anti-anginal properties of the metabolic agent trimetazidine have been previously confirmed in numerous clinical studies in both monotherapy[8,12,13] and in combination therapy with conventional hemodynamic drugs.[14–16]
A double-blind, randomized, placebo-controlled trial in 227 patients with stable angina pectoris taking metoprolol was presented at the last ESC congress in Barcelona.[17] Patients were randomized to receive trimetazidine or placebo. After 12 weeks, trimetazidine significantly improved all ergometric and clinical parameters compared with placebo. Time to 1 mm ST-segment depression was increased by 68 s (P < 0.01 compared with placebo) (Figure 2). 

Figure 2. Increase in time to 1 mm ST-segment depression with trimetazidine.[17]

This study adds a further example of the benefits of a metabolic intervention in all coronary patients.
There is also an increasing understanding of the role played by metabolic changes in ischemic cardiomyopathy,[18] and there are some very good data about the effect of trimetazidine on both stress-induced left ventricular dysfunction and on hibernating myocardium. In a study by Lu et al.,[19] 15 patients with stress-induced ventricular dysfunction were randomized to receive either trimetazidine or placebo for 15 days and then crossed over to the alternative treatment for another 15 days. Dobutamine stress echocardiography was performed at baseline and at the end of both treatment periods. Trimetazidine significantly reduced the wall motion score index (WMSI) from 1.40 to 1.34 at rest (P < 0.013) and from 1.71 to 1.61 at peak stress (P < 0.018). It is important to recognize that trimetazidine also delayed the onset of the ischemic threshold, as shown by significant increases in dobutamine infusion dose and time. Thus the WMSI was actually improved, even at a greater myocardial stress.
Equally interestingly, another study has shown that trimetazidine significantly improves the WMSI at rest and peak stress in patients with chronic ischemic left ventricular dysfunction.[20] Twenty-two patients with documented viable or hibernating myocardium, as determined by dobutamine stress echocardiography, were randomized to receive either trimetazidine 20 mg t.i.d. or placebo. In this population, all patients had a history of myocardial infarction, and mean baseline left ventricular ejection fraction was 33%. At rest, compared with placebo, trimetazidine caused a reduction in WMSI from 2.05 to 1.61 (P = 0.038 compared with placebo). At peak dobutamine infusion, trimetazidine decreased the WMSI from 1.66 to 1.32 (P = 0.030 compared with placebo) (Figure 3). 

Figure 3. Trimetazidine decreases the wall motion score index (WMSI) at rest and at peak stress in patients with chronic left ventricular dysfunction and hibernating myocardium.[20]

Trimetazidine also increased mean ejection fraction from 41 to 51% at peak dobutamine infusion (P = 0.008 compared with placebo).
The improvement in the WMSI with trimetazidine seems to be at least comparable to that observed after percutaneous transluminal coronary angioplasty in patients with viable myocardium.[21]

Conclusion
The importance of metabolic abnormalities in the pathophysiology of heart disease — including CHD, heart failure and diabetic cardiomyopathy — is now being recognized, in part because of the successes of metabolic therapy. The metabolic agent, trimetazidine, by shifting energy metabolism away from fatty acids towards the glucose pathway, has been demonstrated to be an effective anti-anginal and anti-ischemic agent in patients with stable angina pectoris and in those with other ischemic syndromes.

REFERENCES
1. Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabetic Med 1997; 14 (Suppl.5): S7–S85.
2. Soläng L, Malmberg K, Rydén L. Diabetes mellitus and congestive heart failure: further knowledge needed. Eur Heart J 1999; 20: 789–795.
3. Zonszein J, Sonnenblick EH. Endocrine diseases and the cardiovascular system. In: Alexander W, Schlant R, Fuster V, eds. Hurst’s the heart. 9th ed. New York: McGraw-Hill, 1998; 2117–2142.
4. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–853.
5. Malmberg K, Rydén L, Hamsten A et al., on behalf of the DIGAMI Study Group. Effects of insulin treatment on cause-specific one-year mortality and morbidity in diabetic patients with acute myocardial infarction. Eur Heart J 1996; 17: 1337–1344.
6. Stanley WC, Lopaschuk GD, Hall JL, McCormack JG. Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions: potential for pharmacological interventions. Cardiovasc Res 1997; 33: 243–257.
7. Rackley CE, Russell RO Jr, Rogers WJ et al. Clinical experience with glucose-insulin-potassium therapy in acute myocardial infarction. Am Heart J 1981; 102: 1038–1049.
8. McClellan KJ, Plosker GL. Trimetazidine: a review of its use in stable angina pectoris and other coronary conditions. Drugs 1999; 58: 143–157.
9. Lopaschuk GD, Kozak R. Trimetazidine inhibits fatty acid oxidation in the heart. J Mol Cell Cardiol 1998; 30: A112.
10. Stanley WC. Metabolic dysfunction in the diabetic heart. In: The diabetic coronary patient. London: Science Press, 1999; 13–28.
11. Szwed H, Pachocki R. Domzal-Bochenska M et al. The antiischemic effects and tolerability of trimetazidine in coronaray diabetic patients: a substudy from TRIMPOL-I. Cardiovasc Drugs Ther 1999; 13: 217–222.
12. Detry JM, Sellier P, Pennaforte D et al., on behalf of the Trimetazidine European Multicenter Study Group. Trimetazidine: a new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Br J Clin Pharmacol 1994; 37: 279–288.
13. Dalla-Volta S, Maraglino G, Della-Valentina P et al. Comparison of trimetazidine with nifedipine in effort angina: a double-blind crossover study. Cardiovasc Drugs Ther 1990; 824–825.
14. Michaelides AP, Spiropoulos K, Dimopoulos K et al. Antianginal efficacy of the combination of trimetazidine-propranolol compared with isosorbide dinitrate-propranolol in patients with stable angina. Clin Drugs Invest 1997; 13: 8–14.
15. Manchanda SC, Krishnaswami S. Combination treatment with trimetazidine and diltiazem in stable angina pectoris. Heart 1997; 78: 353–357.
16. Levy S and the Group of South of France Investigators. Combination therapy of trimetazidine with diltiazem in patients with coronary artery disease. Am J Cardiol 1995; 76: 12B–16B.
17. Szwed H, Sadowski Z, Pachocki R et al. Efficacy and safety of trimetazidine in patients with stable angina pectoris under beta-blocker therapy. TRIMPOL-II – multicentre study (abstract). Eur Heart J 1999; 20: 478.
18. Katz AM. Is the failing heart energy depleted? Cardiol Clin 1998; 16: 633–644.
19. Lu C, Dabrowski P, Fragasso G, Chierchia SL. Effects of trimetazidine on ischemic left ventricular dysfunction in patients with coronary artery disease. Am J Cardiol 1998; 82: 898–901.
20. Belardinelli R, Purcaro A. Trimetazidine improves the contractile response of hibernating myocardium to low-dose dobutamine in ischemic cardiomyopathy. Circulation 1998; 98 (suppl I): I–709.
21. Kao HL, Wu CC, Ho YL et al. Dobutamine stress echocardiography predicts early wall motion improvement after elective percutaneous transluminal coronary angioplasty. Am J Cardiol 1995; 76: 652–656.