**5.1. Metabolic remodeling in right heart failure**

Although the data are less extensive than in the LV, the metabolic switch that occurs during LV hypertrophy and dysfunction also occurs in models of RV dysfunction [81, 82]. Several groups have reported upregulated glycolysis with suppression of FAO, and associated global changes in gene expression favoring glucose oxidation and downregulation of PPARα target genes [62]. Mechanistically, pyruvate dehydrogenase kinase (PDK) has been linked to the metabolic switch. PDK, an inhibitor of pyruvate dehydrogenase, is upregulated in RV hypertrophy. This PDK-mediated metabolic switch is associated with decreased RV myocyte contractility and cardiac output [81]. The shift to aerobic glycolysis has several consequences for the heart. First, greater amounts of lactate are produced, shifting redox status and other homeostatic outcomes, and second, fewer ATP molecules/glucose molecule are produced (32 during glucose oxidation, and 2 during glycolysis). To compensate for increased glycolysis, glucose uptake is accelerated, and can be assessed by positron emission tomography, both in experimental PH and RV dysfunction [83, 84], and in patients with pulmonary arterial hypertension [85].

As in left heart failure, researchers have attempted to explain the metabolic switch based on energy production relative to oxygen availability. The pressure overloaded RV is oxygen deprived. In the setting of an oxygen limited hypertrophic RV, energy production which favors a high ATP/O<sup>2</sup> ratio would benefit the working heart, and FAO uses 12% more oxygen than glucose oxidation to generate the same amount of ATP [86]. Some experimental data support this hypothesis, with reports of systolic perfusion gradients limiting coronary artery flow [87], coupled with increased metabolic demands in the hypertrophied heart, which result in a localized RV ischemia. However, the question of oxygen supply in RV hypertrophy is insufficiently answered. While it may be true that angiogenic potential in the failing RV is attenuated, resulting in ischemia [88], methodological difficulties have precluded accurate assessment of RV oxygen supply. Further, other groups have argued that reliance on carbohydrate metabolism predisposes the hypertrophied myocardium to contractile dysfunction, and maintaining the inherent metabolic profile of fatty acid fuel preference may be a more beneficial approach [89].
