Anne-Marie Koop

86 DISCUSSION In this systematic review on metabolism in the pressure loaded RV, we identified 26 animal and four human studies eligible for meta-analysis. The systematic review combined with multiple separate meta-analyses yielded a uniform increase in glucose uptake and glycolysis, whereas fatty acid uptake and changes in oxidative metabolismwere less consistent. The effect of therapeutic interventions could not be analyzed due to the large variety of used outcome variables and used compounds. In the current study, there are strong indications that glycolysis is increased in the pressure overloaded RV. Both gene expression of HK1, an important enzyme controlling the first step of glycolysis, and the capacity for glycolysis measured by Seahorse and Langendorf were significantly increased. In contrast, HK2 was unchanged. Previous studies in the LV have identified HK2 as modulator of reactive oxygen species an described attenuating effects on cardiac hypertrophy. 48,49 HK2, involved in anabolic pathways by providing glucose-6-phosphate for glycogen synthesis, also fulfills a role in providing glucose-6-phosphate to the pentose phosphate pathway. Contrary to the many roles of HK2, HK1 primarily facilities glycolysis. 50,51 HK1 is primarilyexpressed inneonatalcardiomyocytes and is associated with the fetal gene program, 50,52,53 characterized by better resistance against an oxygen poor environment such as in the RVpressure load. 5,39,54-56 The activation of the fetal gene program is also reflected in an increased expression of GLUT1, supporting increased glucose uptake which increases the ability of increased glycolysis. 16,27,32 Remarkably, HK1 and GLUT1 both concern insulin-independent isoforms whereas HK2 and GLUT4 concern insulin-dependent isoforms. 57 The current meta-analysis reveals a clear pattern in the pressure-overloaded RV differentiating between the insulin-independent versus insulin-dependent profiles, directing to glycolysis by activation of insulin-insensitive mechanisms. The increase of glycolysis in the pressure loaded RV is also supported by the increased glucose uptake measured by FDG by PET-CT. PET-CT has the ability to assess the actual uptake in vivo, whereas gene or protein expression of involved genes and respiratory capacity of isolated mitochondria, are an approximation of the actual situation in vivo. However, FDG-uptake represents glucose uptake rather than metabolic capacity itself. Studies describing FDG-uptake which were excluded from meta-analysis, endorse our findings. 58-62 In addition, increased RV FDG-uptake has been associated with increased pressure load 58,60,63,64 and altered dimensions, 60,62,64,65 and inverse correlations with RV-function, 62,63,65 cardiac function 60 and clinical outcome. 66,67 Meta-analysis of substrate specific oxidative metabolism in the pressure loaded RV reflects an ambivalent character. Glucose oxidation is regulated via PDK which