Metabolic Therapy for Heart Disease: Impact of Trimetazidine

Abstract

Coronary artery disease remains the major contributor to the development of heart failure. Despite the massive efforts targeted toward preventative therapy and life style changes, the incidence of coronary artery disease continues to be high, shows little or no signs of abatement, and remains the leading health economic burden in developed countries and, for that matter, worldwide. There is no doubt that the aggressive use of thrombolytic therapy and primary coronary angioplasty has had a major impact on limiting the sequelae of acute myocardial infarction. There is also little doubt that routine coronary revascularization through coronary artery bypass surgery or coronary angioplasty with attendant coronary stent deployment has had a positive impact, albeit transient, on limiting symptoms of coronary artery disease. Despite all of these successes of the twentieth century, however, chronic stable angina pectoris remains a major clinical problem that must be dealt with by cardiologists, internists and primary care physicians alike as we move into the next millenium. Many of the patients that present with stable angina pectoris are not candidates for further revascularization, or, in this the age of rationed health care, even if eligible, must “stand in line” to have the procedure performed. Needless to say that most, if not all, of these patients are candidates for the development of congestive heart failure (CHF), truly the disease of the next millenium. The myocardium depends on oxygen to support high energy phosphate production by oxidative phosphorylation. The latter is the only metabolic process that can generate sufficient chemical energy to fuel the continuous needs of the contractile machinery of the heart. Accordingly, when the amount of oxygen delivered to the myocardium is insufficient to meet the requirements for mitochondrial respiration, the production of high energy phosphates falls and lactate, the end product of anaerobic glycolysis, starts to accumulate. The interruption of oxygen supply to the myocardium or ischemia, regardless of etiology, leads to the clinical symptom of angina pectoris. Ischemia can be defined as an imbalance between the supply of oxygenated blood to the myocardium and the oxygen requirements of the myocardium. When the supply of oxygen cannot meet the demands, as is the case when coronary artery disease is present, contractile function diminishes along with clinical manifestation of anginal pain. The latter the result of stimulation of cardiac sensory afferent nerve fibers by “noxious stimuli” produced in the myocardium. The cardiac sensory afferents nerves are stimulated by a rise in interstitial adenosine and K+, both of which increase when oxygen delivery and aerobic ATP synthesis are reduced [1]. Electrocardiographically, ischemia is reflected through ST-segment elevation or depression on the electrocardiogram with the latter believed to reflect delayed repolarization in the ischemic zone, and has recently been attributed to KATP channels [2], which presumably open in response to the fall in ATP. Taken together, both angina and ST-segment changes during ischemia are arguably the result of a failure to regenerate ATP, and as such, are of metabolic origin.