Figure 2.

The Randle Cycle in Right Ventricular Dysfunction. The Randle cycle depicts a reciprocal, mutually-inhibitory relationship between glucose oxidation and fatty acid oxidation (FAO). The accumulation of acetyl-CoA and citrate from fatty acid β-oxidation inhibits pyruvate dehydrogenase (PDH) and phosphofructokinase, respectively. Moreover, the accumulation of glucose-6-phosphate inhibits hexokinase, further attenuating glycolysis. Inhibition of PDH, phosphofructokinase and hexokinase results in the inhibition of glucose oxidation; thus, FAO inhibits glucose oxidation in cardiomyocytes. Intervention with dichloroacetate (DCA) inhibits pyruvate dehydrogenase kinase (PDK)-mediated inhibition of PDH. The FAO inhibitors trimetazidine and ranolazine prevent acetyl-CoA and citrate accumulation, thereby preventing FAO-mediated shutdown of glucose oxidation.