Anne-Marie Koop

3 87 inhibits breakdown of pyruvate. The expression of PDK in response to pressure load in the RV varied widely with different models used ( suppl. figure 4a-d ). In addition, the respiratory capacity for carbohydrates was also affected by the model used. Although in both MCT and PAB model cardiac performance was decreased to the same extent respiratory capacity increased in MCT models, but decreased in pressure load only via PAB. Similarly, with respect to respiratory capacity for fatty acids, PAB models behaved differently from FHR, while there are no data from MCT models. Taken together, these data suggest that the RV oxidative capacity changes in response to pressure load are dependent upon methodological differences, and may be subsequently dependent onmodel or disease, cardiac function and possibly on clinical severity. More cooperations between research groups and comparative studies between fixed RV-PA uncoupling (in PAB) vs. dynamic RV-PA uncoupling (e.g. in MCT) are needed to identify the systemic changes that may interfere with the cardiac response. Intriguingly, whereas there was variation in the respiratory capacity for fatty acids, the changes in one of genes oxidizing fatty acids (MCAD) were uniform. Downregulation of the β -oxidation was supported in literature by decrease of other genes from the acyl-coenzyme A (CoA) dehydrogenases family at both mRNA 16,27 and protein level 27,46,68 . Downregulation of the oxidation phase has been suggested based on decreased expression of genes as HADH 5,69 , HADHA, HADHB and EHHADH 5,68,70 . In addition, malonyl-coA decarboxylase (MCD) is described to be decreased in a model of hypoxia 34 . Oxidative metabolism in general in the pressure loaded RV was studied in two studies and therefore not included in meta-analysis. The clearance of 11 C-acetate was used as representative of tricarboxylic cycle. RV clearance rates correlated to the rate pressure product and oxygen consumption in idiopathic PAH (iPAH) 71 , and appeared to higher PH (chronic thromboembolic PH (CTEPH), pulmonary arterial hypertension (PAH) and PH with unclear multifactorial mechanisms) compared to controls 72 . The current study stresses the need for further research in order to clarify changes due to pressure load itself and changes as results of the specific inducement of RV pressure load or a potential systemic disease. The systematic literature search showed that processes involved in the transport of long-chain fatty acids varied in different models and different cohorts of patients with PH. Gene expression of CD36, the transporter of long-chain fatty acids across the cellular membrane, was decreased in SuHx rats, unaffected in PAB rats and increased at protein level in patients with a BMPR2 mutation 27,41 . Studies measuring gene expression of fatty acid binding proteins (FABP1-7) and fatty acids transporters (SLC7A1-6) in the pressure loaded RV are scarce and were ambivalent 16,31 . We excluded studies describing actual fatty acid uptake measured with PET-tracers in patient cohort without a control group. These studies also yielded various changes. Different cohorts representing different types of diseases, including precapillary PH and chronic obstructive lung disease, showed both pressure load dependent 73,74