Anne-Marie Koop

3 89 PGC1α and PPARα are not identified in studies with unbiased approach by performing microarray 5,55,86-88 or proteomics 87 . This could imply changes of PGC1 α or PPAR α are not causal for altered processes due to RV pressure load. As shown in this review, metabolic modulation has been primarily focused on the reduction of glycolysis by activation of glucose oxidation. The most studied compound is DCA which inhibits PDK and hereby indirectly stimulates activation of PDH. Interestingly, in the pressure loaded RV, the different isoforms of PDK and PDH encompasses varied results ( suppl. figure 2 and figure 5 ). However, studies specifically focusing on interfering on the activity of these enzymes in the pressure loaded RV by DCA, showpositive effects on cell homeostasis, mitochondrial function and cardiac function, 15-17 with no effect on these functions in controls. 15 In MCT and FHR, at respectively six weeks and more than 10-20 months of treatment, DCA leads to normalized levels of the upregulated PDK2 and PDK4, with restoration of PDH activity. 16-17 This was accompanied by normalization of FOXO1 levels, which were upregulated in disease in FHR animals and patients with PAH. 16 This suits the concept of activation of the fetal gene program and insulin-independent mechanisms in the pressure loaded RV, since sustained FOXO1 activation in neonatal cardiomyocytes is known to diminish insulin signaling and impaired glucose metabolism. 89 Limitations This study comes with some limitations that should be discussed. To guarantee actual pressure load on the RV, meta-analysis includes both studies with proven increased pressure load by RSVP and mPAP, and by RVH. RVH was expressed as increased RV weight, Fulton index or RV to bodyweight ratio. Although hypertrophy is a plausible effect of pressure load, the degree of hypertrophy within studies from current literature search is independent of the actual degree of pressure load (data not shown) . This might be explained by a predominant use of models of severe pressure load. This together with the fact that RVH based on weight is a widely supported confirmation of RV pressure overload, resulted in RVH as inclusion criterion in addition to increased pressure load. In line with the statement of the Systematic Review Center for Laboratory animal Experimentation (SYRCLE), 24 the aim of this meta-analysis was to assess the general direction and magnitude of RV pressure load of the specific variable (rather than to obtain a precise point estimate explicitly) with additional exploration of the sources of heterogeneity by using meta-regression analyses. We used effect size defined as Hedge’s g. Hedge’s g is the golden standard in small samples (<10 samples per group), which includes a correction factor for small sample size bias, 90,91 and therefore is considered as golden standard in meta-analysis of