Anne-Marie Koop

172 therapeutics inhibiting oxidative stress and stimulating antioxidants are likely to be more relevant in established heart failure than in early adaptation. In the current study we did not test the effect of metabolic modulation, used in previous studies in RV-failure. This study aimed at identification of changes in metabolic regulation over time, early in the process of RV adaptation towards RV dysfunction, preceding clinically overt RV failure. The results of this comprehensive study do challenge the widely assumed concept that altered metabolism in RV failure represents “an engine out of fuel”. Rather we speculate that early activation of oxidative stress affects intracardiac lipid content and thereby might contribute to acceleration of oxidative stress in the progression towards RV failure. Indeed, now we have identified early lipid alteration, including cardiolipins, in the development towards RV failure, the mechanism by which increased pressure load leads to this metabolic changes warrants further exploration. The results of this study reveal that both functional ( figure 1 ) and histopathological ( figure 2 ) changes of the pressure loaded RV precede significant changes in oxidative capacity ( figure 3 ). Furthermore, there are no indications that the decrease of specific lipids was preceded by increased fatty acidmetabolism. In addition, the initial increase inmarkers of oxidative stress preceded progressive functional deterioration. Based upon these findings we suggest to design intervention strategies based upon restoration of intracardiac fatty acid pool. To derive insights in metabolic changes, we studied several components of metabolism. By adding functional measurements of mitochondrial respiratory capacity using Oroboros, we attempted to create a better picture of the metabolic capacity in the pressure loaded RV. These data showed that the immediate increase in cardiac power ( figure 1g ), was associated with a slow increase in metabolic capacity of carbohydrates only. Combing these results with the altered lipid profile, indicates a role for preserving intracardiac lipid status in the initial response to pressure overload, rather than a change in fatty acid metabolic capacity itself. CONCLUSION In this study we showed that RV dysfunction, preceding RV failure due to chronic pressure load, is associatedwith decreased intracardiac unsaturated lipids, especially in the most abundant form of cardiolipin. These changes were accompanied by preserved mitochondrial capacity for fatty acid oxidation, with an increased mitochondrial capacity for glucose oxidation, and early expression of oxidative stress markers. We suggest that early interventions to prevent RV failure may be directed towards preservation of intracardiac lipid composition.