Partial fatty acid oxidation inhibitors for stable angina

Partial fatty acid oxidation inhibition is effective therapy for the treatment of chronic stable angina and is particularly useful in patients with persistent angina despite optimal traditional therapy. The heart derives most of its energy from the oxidation of fatty acids. Fatty acid oxidation strongly inhibits pyruvate oxidation in the mitochondria and the uptake and oxidation of glucose. The primary effect of demand-induced ischaemia is impaired aerobic formation of ATP in the mitochondria, resulting in activation of non-oxidative glycolysis and lactate production, despite a relatively high residual myocardial oxygen consumption and continued reliance on fatty acid oxidation. Traditional drugs for chronic stable angina act by reducing the use of ATP through suppression of heart rate and blood pressure or by increasing aerobic formation of ATP by increasing coronary blood flow. Partial inhibition of fatty acid oxidation increases glucose and pyruvate oxidation and decreases lactate production, resulting in higher pH and improved contractile function during ischaemia. These agents do not affect heart rate, coronary blood flow or arterial blood pressure. Clinical trials with ranolazine or trimetazidine, either alone or in combination with a Ca2+ channel antagonist or a R-adrenergic receptor antagonist, have demonstrated reduced symptoms of exercise-induced angina.