Anne-Marie Koop

9 309 Metabolic shifts in the pressure loaded right ventricle It is known for decades that cardiac metabolism plays a central role in the development of heart failure, due to reduced substrate uptake or oxidation. This has resulted in energy sparing treatment as beta-blockers, ACE-inhibitors and angiotensin II blockers in left sided heart failure. 17,18 From the LV we know that fatty acid oxidation gradually decreases in conditions of increased afterload, 19-21 whereas glucose and lactate utilization initially increases. 22,23 This metabolic switch is part of reactivation of the fetal gene program, possibly due to the fact that the stressed heart is exposed to lower oxygen conditions similar to fetal conditions. 24 In these conditions, glucose utilization is preferred because less oxygen is needed to generate one molecule of ATP compared to fatty acid utilization. Moreover, the use of glucose for ATP production by glycolysis concerns anaerobic metabolism. In more progressive stages of cardiac dysfunction glucose utilization decreases, 24,25 suggesting that the increased glucose utilization serves as an adaptive mechanism. Although these insights are known for many decades, up till now no therapy directly targeting cardiac metabolism has not been implemented to the clinic yet. As chapter 3 describes, studies in animal models and patients have shown that RV glucose uptake increases in conditions of increased RV afterload. This was illustrated by increased FDG-uptake and increased levels of expression of glucose transporter 1. 26-36 Also increased glycolysis was observed by increased expression of hexokinase 1 and glycolytic flux measured with Seahorse or Langendorf. 28,33,35,37,38 Because of the diversity of models used, encompassing various stages of RV disease and different ways of characterization, it was impossible to relate these metabolic alternations to clinical function. Based on these resultswewere unable to speculate about the role of the eventual decreases of glucose utilization and its potential role in the development towards clinical RV failure. Nevertheless, in chapter 2 , we found at genetic level that fatty acid metabolism was downregulated in both compensated RV dysfunction and clinical RV failure, whereas downregulation of glycolysis and gluconeogenesis was specifically decreased in animals with clinical RV failure. On one hand, this raises the question whether the metabolic shift towards glycolysis serves as a(n) (temporary) adaptation mechanism. On the other hand, various therapeutic agents aiming to reduce glycolysis by activation of glucose oxidation through indirect activation of pyruvate dehydrogenase, show positive effects on both mitochondrial and cardiac function. 34,39,40 To evaluate the early stages of RV disease, chapter 4 assessed mitochondrial respiratory capacity, as representative of RV oxidative metabolism, in conditions of RV pressure overload at three time points before any clinical signs of RV failure occurred. Here, we found a relative increase in the mitochondrial respiratory Increasedglucoseutilization in the pressure loaded right ventricle may serve as a adaptive mechanism.