Anne-Marie Koop

310 capacity of glucose oxidation compared to fatty acid oxidation after mild depression of both in very early stages of RV pressure load. Albeit not all significant, negative trends of mitochondrial respiratory capacity for fatty acids ( chapter 4 ), and medium- chain acyl-CoA dehydrogenase (MCAD) ( chapter 3 and 4 ) were found. However, our meta-analyzes ( chapter 2 ) revealed ambiguous results for mitochondrial respiratory capacity of fatty acids in various animal models. To conclude, based our findings on metabolic alternations, further research should test the hypotheses whether 1) disappearance of increased glucose utilization and/or glycolysis will eventually lead to the development of RV failure and 2) increased RV pressure load itself negatively affects the mitochondrial activity for fatty acid oxidation. The role of intracardiac lipids in the pressure loaded right ventricle As shown in models of pulmonary arterial hypertension, we hypothesized that a decrease in fatty acid metabolism would result in the accumulation of toxic lipids in the pressure loaded RV. Surprisingly, in chapter 4 we found no clear evidence of decreased fatty acid metabolism and neither we found accumulation of toxic lipids in response to increased pressure load. However, a firm decrease of poly-unsatured intracardiac lipids was measured, especially tetralinoleoylcardiolipin which forms an essential component of inner mitochondrial membrane. Interestingly, this occurs before significant deterioration of mitochondrial respiratory function and before the progression of RV dysfunction towards clinical RV failure. These findings may suggest cardiac lipid alternations due to early presence of low amounts of oxidative stress. Poly-unsaturated lipids are vulnerable to oxidative stress because their hydrogen atoms are easily taken by hydroxyl radicals due to their presence close to multiple double bounds. There may be also other players affecting cardiac lipid content, like insufficient uptake or defects in the formation of lipids. However, we found no abnormalities at gene level of the enzymes of the cardiolipin synthesis pathway. We hypothesize that poly-unsaturated fatty acids serve as a defencemechanism against oxidative stress via their capacity to quench oxygen radicals. The decrease of poly- unsaturated fatty acids, especially the decrease of cardiolipins, may be one of the first signs of functional metabolic deterioration in the stressed RV. Pilot experiments in our laboratory showed that therapywith the synthetic analogue of resveratrol, also knownas aBET-bromodomain inhibitor, in rats subjected topulmonaryarterybanding (PAB) was accompanied with preservation of intracardiac lipids and cardiac function, with the absence of a fetal switch and changes in metabolism. The preservation of intracardiac lipids, especially poly-unsaturated lipids, may result in longer beneficial adaptation before pathologic remodelling occurs. Upcoming research should focus Our findings may indicate that cardiac lipid alternations are the result of early presence of low levels of oxidative stress.