Anne-Marie Koop

4 171 mechanism still needs to be unraveled. In this respect, it is of specific interest that the current study shows early upregulation of GLUT4, which might contribute to higher levels of glucose in cardiomyocytes. In diabetic disease, hyperglyceamia leads to fibrosis by inflammation. 59 These observations suggest that similar mechansims, including oxidative stress, inflammation and pro-fibrotic activity, may be involved in the early adaptation of the RV to increased pressure load and preceding RV failure. Further research should clarify the initial cause of NADPH oxidase activation in the pressure loaded RV. Levels of oxidative stress and inflammation, measured by AOPP assay and GDF-15 ELISA, appeared to be not increased in blood plasma. This is in line with the relatively low activation of oxidative stress and inflammation in RV tissue, but also with the fact plasma pools are rarely influenced by dynamic changes in cardiac expression only. 60 Furthermore, blood derived biomarkers, other than cardiac specific markers, predominantly reflect systemic offects of heart failure, 60 while the animals in the current study developed RV dysfunction, but no clinical overt heart failure. Our findings are opposed to those in experimental PH due to BMPR2-deficiency, where intracardiac accumulation of fatty acid intermediaries has been associated to progressive RV dysfunction. 12 The results of the present study suggest a difference between chronic pressure load in the presence or absence of PH, or more specificly involvement of the BMPR2-mutation. The ambivalent character of these findings are in line with different changes in metabolic capacity reported in the different models of RV pressure load, 13,61-64 and need to be considered in developing therapeutic strategies in RV dysfunction due to different types of disease. The present study suggests that therapies aiming at maintenance of mitochondrial integrity via restoration of cardiolipin content may be more appropriate than targeting fatty acid oxidation itself. Recent studies showed that preservation of cardiolipin by diet or therapeutics led to preservation of normal mitochondrial function and preservation of left venticular function. Dietarymeasures, such as high-linoleate safflower oil, were able to preserve tetralinoleoylcardiolipin content and mitochondrial function, and improved left ventricular function in spontaneously hypertensive heart failure rats. 65,66 Resveratrol is known to improve fatty acid oxidation, to reduce ROS production, to be cardiac protective and to improve survival in experimental models of diabetic cardiomyopathy, myocardial infarction induced tachycardia, exercise training and high-fat diet induced cardiac myopathy, 67-70 and has been described as therapeutic option for up regulation of cardiolipin content. 71 In Barth syndrome, a cardiomyopathy due to disruption of the TAZ gene leading to reduced mature cardiolipin levels, substitution of cardiolipin itself via nanoparticles is currently being tested as a new therapeutic strategy. Preservation of substrates availability is a potential candidate for prevention or early interception in the development of RV dysfunction, whereas