**6.1. Metabolic therapeutic interventions**

Enhancing glucose oxidation at the expense of FAO as emerged as a therapeutic strategy in RV dysfunction, based on the reciprocal relationship between these two energy sources. In large part, enhancing glucose oxidation has gained attention as a strategy because of the higher ATP production per oxygen molecule provided by carbohydrate compared to lipid sources. Partial inhibitors of FAO are approved for a few human cardiovascular indications including refractory ischemia [103]. These drugs (trimetazidine) have also been experimentally tested in RV dysfunction [86]. Rats with PAB-induced RV dysfunction treated with partial FAO inhibitors had elevated RV glucose oxidation alongside increased exercise capacity and cardiac output. The beneficial effect of this drug has also been demonstrated in MCT-induced RV dysfunction, where trimetazidine enhanced cardiac mitochondrial function and increased oxygen consumption while reducing ROS formation [104].

The metabolic switch that occurs in the hypertrophied RV is suggested to be mediated in part through PDK4 [81]. Dichloroacetate (DCA), a small molecule inhibitor of pyruvate dehydrogenase, improves glucose oxidation and has reported improvements in RV stroke volume, cardiac output, and exercise capacity [81, 105]. It is also associated with restoration of RV mitochondrial function and mitochondrial-dependent apoptosis [106]. Though a Phase I clinical trial has been completed in subjects with advanced PH (Clinical Trial Identifier NCT01083524), study results have not been published, and the therapeutic potential of DCA in human RV failure remains unknown. As discussed above, the therapeutic strategy of FAO and improved glucose oxidation lacks consensus [89], and in part is predicated on the balance between ATP production and oxygen availability. While continued efforts to test metabolic mediators in RHF are warranted, a mechanistic understanding of energy production, relative RV ischemia, and the molecular regulators of these processes are necessary for development of targeted metabolic therapy.
