Metabolic agents: a new approach in treating ischemic heart disease

Professor Gary D. Lopaschuk
Cardiovascular Research Group, University of Alberta, Edmonton, Canada

Myocardial ischemia results in a decrease in oxygen supply to the heart, thereby decreasing energy production in the heart. Therapeutic strategies for treating myocardial ischemia have concentrated on either increasing oxygen supply to the heart muscle or decreasing the oxygen demand of the muscle. While these approaches have dramatically improved the prognosis of patients with angina pectoris or those suffering an acute myocardial infarction, complications of myocardial ischemia remain a major cause of mortality and morbidity worldwide.
As the 20th century comes to an end, a new approach to treating myocardial ischemia is emerging, which involves improving the efficiency of oxygen utilization by cardiac tissue. It is now becoming clear that it possible to increase cardiac efficiency by pharmacologically optimizing fuel use in the heart.[1,2,3,4]

Fuel use by the heart
The production of energy (in the form of adenosine triphosphate [ATP]) is primarily derived in the heart from the catabolism of both fatty acids and carbohydrates (principally glucose). Normally a balance between these two pathways exists, with fatty acid oxidation providing 60–70% of overall cardiac ATP supply, and glucose and lactate providing the remainder. Glucose metabolism consists of two important components, glycolysis and glucose oxidation. Glycolysis is the initial sequence of reactions involved in the breakdown of glucose to pyruvate, while glucose oxidation involves the subsequent mitochondrial oxidation of pyruvate. Glycolysis is important in that it produces ATP without the need for oxygen. While glycolysis only contributes small yields of ATP (normally about 5% of total ATP produced by the aerobic heart), it is widely believed that this glycolytic supply of ATP is essential to maintain ionic stability and cell integrity.[2,4] During ischemia, glycolysis is accelerated, producing a greater proportion of the heart’s ATP supply. However, if glycolysis in not coupled to glucose oxidation, protons and lactate are also a byproduct of this pathway. As a result, acceleration of glycolysis during ischemia can have detrimental consequences if glucose oxidation does not increase in parallel.
Unlike glucose metabolism, all ATP production from the metabolism of fatty acids is oxygen-dependent and occurs in the mitochondria. As a result, fatty acid oxidation is not as efficient as glucose as a source of energy and requires more oxygen to produce an equivalent amount of ATP. However, another major problem with fatty acids is that, as oxidation of fatty acids increases, there is a concomitant decrease in glucose oxidation. This can lead to an uncoupling of glycolysis from glucose oxidation and an increase in proton and lactate production.[4]

Energy metabolism during and following ischemia
Increasing glycolysis and the contribution of glucose oxidation to residual oxidative metabolism during ischemia is one approach to benefiting the ischemic heart. However, fatty acid oxidation effectively competes with glucose oxidation for this ‘residual oxygen’, resulting in acidosis due to the accumulation of lactate and protons within the heart. During a severe ischemic insult this can lead to a substantial intracellular acidosis, which can lead to sodium and calcium accumulation within the myocyte. The requirement for energy to reestablish ionic homeostasis then leads to a decrease in cardiac efficiency.
Upon reperfusion of reversibly injured ischemic myocardium, contractile function recovers once energy production has been restored, and cytosolic calcium levels normalize. However, due to both increases in circulating levels of fatty acids and changes in the cellular control of fatty acid metabolism, fatty acid oxidation dominates as a source of energy, which again leads to proton production, an uncoupling of glycolysis to glucose oxidation, and a decrease in cardiac function and efficiency.[4,5]

Optimizing energy metabolism during and following ischemia
Two significant events have recently occurred that have resulted in a resurgence of interest in energy metabolism as a target for pharmacological therapy. The first is the observation that a number of existing pharmacological agents beneficial in treating angina exert their effects by optimizing energy metabolism. The second is the recent confirmation that glucose-insulin-potassium (GIK) infusions are beneficial in patients following acute myocardial infarction.
Pharmacological inhibition of fatty acid oxidation and stimulation of glucose oxidation have recently been shown to significantly improve cardiac efficiency in the heart (cardiac work/oxygen consumed). One agent used clinically to treat ischemic heart disease is trimetazidine, which acts by directly inhibiting fatty acid oxidation.[6] This inhibition of fatty acid oxidation is accompanied by a significant increase in glucose oxidation and a decrease in myocardial acidosis.[7] Several clinical trials have demonstrated the anti-anginal efficacy of trimetazidine, which is equivalent to that of propranolol and calcium channel blockers but without any hemodynamic or vasodilatory effects.[8] Trimetazidine also has beneficial effects in the setting of acute myocardial infarction, coronary angioplasty and cardiac surgery.
Other inhibitors of fatty acid oxidation that may soon see clinical use are ranolazine,[9] which is efficacious in chronic stable angina, or carnitine palmitoyl transferase-1 inhibitors. Direct stimulation of glucose oxidation both during and following ischemia may also benefit the ischemic heart. An example of this is dichloroacetate, which, while clinically beneficial,[10] will probably not see widespread clinical use due to its poor pharmacokinetics. Two other agents that also stimulate glucose oxidation and that may see clinical use are L-carnitine and propionyl L-carnitine. Both of these are natural compounds that stimulate glucose oxidation in the heart and are efficacious in angina pectoris. In a recent multicentre trial, L-carnitine was shown to reduce ventricular end-diastolic pressure and attenuate the progression of left ventricular dilatation in patients following a myocardial infarction.[11]
Another approach to optimizing energy metabolism is to alter glucose and fatty acid availability to the heart. The concept that increasing glucose supply to the ischemic myocardium may protect the ischemic heart dates back to the 1960s, and was the rationale for the development of GIK therapy.[12] This therapeutic approach increases myocardial glucose uptake and promotes myocardial glycogen storage (depending on the degree of ischemia), which can serve as a source of glucose for glycolysis, thereby increasing ATP supply. However, this intervention also has the potential to increase hydrogen and lactate accumulation within the ischemic myocardium. The complex ramifications of this seemingly simple intervention require further study. New data from the ECLA (Estudios Cardiologicos Latinoamerica) Collaborative Group report a dramatic reduction in relative risk of in-hospital mortality from acute myocardial infarction with GIK.[13] One possible benefit of GIK may actually be related to a decrease in circulating fatty acid levels, since insulin inhibits the mobilization of free fatty acids from adipocytes.
In conclusion, I believe the 21st century will see the start of an era in which optimizing energy metabolism in the heart will become an important clinical approach to treating ischemic syndromes. Inhibiting fatty acid oxidation or directly stimulating myocardial glucose oxidation may be one such approach to optimizing metabolism in the heart.•

REFERENCES
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