Anne-Marie Koop

44 Downregulation of energy metabolism in RVF Relativehypoxia andaltered states of oxidative stress of thehypertrophicmyocardium have been suggested to cause metabolic changes in the RV. 35 RV pressure load leads to changes in fatty acid oxidation (FAO) and uncoupling of glycolysis from glucose-oxidation (GO), but so far it is unclear whether these changes are adaptive or, in contrast, contribute to failure. 31,36,37 In compensated PAB models FAO has been described to be enhanced and pharmacological inhibition of FAO improved cardiac output. 36,37 However, in our failing PAB model there was marked down regulation of the FAO related gene program which suggests that this therapeutic approach might be detrimental in advanced clinical RVF. Although downregulation of genes expressing FAO enzymes not necessarily implies reduced protein, Faber et al previously showed reduced levels of proteins involved in FAO in a model of PAB. 38 The concomitant down regulation of gene sets involved in carbohydratemetabolism, tricarboxylic acid cycle and oxidative phosphorylation in PAB+CF may reflect energy deprivation of themyocardiumwhich is thought tobe a final commonpathway in heart failure. 39 Indeed, in models of compensated RV pressure load, transcriptome and protemic studies show upregulation of carbohydrate and oxidative phosphorylation pathways, 29,38 which may be a prelude to the transition to failure. Taken together, these findings substantiate hypotheses originating from studies in left ventricular failure and gene profiling studies in different models of RV overload, and suggest that multi-level disruption of the myocardial energy metabolism may be pivotal in the pathobiology of RV failure. Yet, despite the similarities with findings in LV failure, application of medical therapies successful in targeting LV failure did not show any benefit in patients or animal models of RVF. 18,34,40 Thus, the similarities in response do not explain the different phenotypes and further studies to the differences in response are warranted to explain the development of RV failure. Predictability of clinical RVF facilitates future mechanistic and intervention studies The here presented approach to the PAB model yields exciting opportunities for mechanistic and intervention studies to further explore the role of myocardial energy metabolism in RVF. As shown in figure 5 , echocardiographic measurements at 5 weeks (when all rats are still asymptomatic) can be used to predict which rats will develop symptoms of RVF in a limited timeframe. This feature allows for detailed metabolic studies (answering the question whether the metabolic derangement is cause or effect in RVF). Moreover, it allows targeted interventions in either phenotype; at the 5 week time point rats could be randomized to receive pharmacological treatment targeted at either prevention or delay of symptoms (in the PAB+CF group) or improvement of function in the more compensated phenotype (PAB- group).