Under aerobic conditions, the predominant substrate used by the normal adult human heart are free fatty acids, accounting for 60-90% of the energy generated (66-71). Carbohydrate metabolism, on the other hand, contributes only about 10-40% of energy generated by the healthy adult human heart (66-71). Glucose taken up by the myocardial cell is either stored as glycogen or converted into pyruvate by glycolysis. Pyruvate is then oxidized within the mitochondria by pyruvate dehydrogenase into acetyl CoA.
In contrast to the adult heart, the fetal heart (which operates under hypoxic conditions) uses glucose as its predominant fuel. The energetic advantages of incremental glucose utilization arise from the fact that though fatty acid oxidation yields more ATP than glycolysis in aerobic conditions, this occurs at the expense of greater oxygen consumption. Fatty acids require approx 10-15% more oxygen to generate an equivalent amount of ATP when compared to glucose. Two drugs, trimetazidine (available in Europe) and ranolazine (studied in the United States and
Europe), are p-FOX inhibitors, which inhibit fatty acid metabolism and promote glycolysis, potentially making the heart more energy efficient. Several clinical trials have demonstrated the potential benefits of trimetazidine in ischemic heart disease (66-69). However, a large, randomized, placebo-controlled trial recruiting 19,725 patients with acute myocardial infarction did not demonstrate short- or long-term mortality benefit (72,73). More recently, a small, double-blind, randomized, placebo-controlled study demonstrated improved exercise capacity and ST-segment depression during post-myocardial infarction exercise testing (74).
Ranolazine (66,67,70,71) is a substituted piperazine compound similar to trimetazidine. On the basis of recently completed phase 3 clinical trials, it appears to offer considerable potential.
The Monotherapy Assessment of Ranolazine in Stable Angina (MARISA) study (75) is a randomized, double-blind, crossover study that evaluated 191 patients with chronic stable angina given ranolazine as monotherapy following withdrawal of all other antianginal drugs. During follow-up ETT, patients had a significantly longer time to angina and 1-mm ST-segment depression while on ranolazine than with placebo.
The Combination Assessment of Ranolazine in Stable Angina (CARISA) trial (70) studied 823 patients with chronic stable angina on background antianginal therapy of either a ^-blocker or calcium-channel blocker who were randomized to either ranolazine (750 or 1000 mg twice daily) or placebo. At follow-up ETT, patients randomized to ranolazine had a significantly increased duration of exercise, time to onset of ST-segment depression, and time to angina, while also reporting fewer weekly angina episodes when compared to the placebo group. There was a minor prolongation of QT interval in the ranolazine group. Both the MARISA and CARISA clinical trials offer encouraging data and indicate that ranolazine has a significant antianginal effect both as monotherapy and in combination with other antianginal agents. However, its long-term safety, particularly in relation to QT prolongation, remains to be established; in addition, enrollment in the pivotal CARISA study was predominantly in Eastern Europe, where the pattern of CAD treatment differs significantly from the US standard. Thus, metabolic antianginal therapies induce a shift from utilization by the myocardium of free fatty acid to predominantly glucose to increase ATP generation per unit oxygen consumption. These promising results have yet to be proven in large-scale clinical trials.
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