Anne-Marie Koop

88 and independent 59,50,75 cellular uptake. Support of load dependent uptake was given by the reversibility of increased uptake after abolishing increased pressure load in patients with chronic thromboembolic pulmonary hypertension 74 . In addition, positive correlations between fatty acid uptake and markers of RV hypertrophy were observed 60,75 and, as shown for glucose uptake measured by PET-CT, uptake of free fatty acids has been inversely correlated with RV ejection fraction 59,75 as well. Although, no correlation was found with cardiac index 74 , fatty acid uptake has been positively correlatedwith clinical outcome, expressed by sixminutewalking distance, NYHA class and mortality 74,75 . Mitochondrial uptake of long-chain fatty acids in the healthy heart is predominately facilitated by CPT1B. CPT1B at mRNA level negatively correlated with the duration of pressure load ( figure 4b ). However, CPT1B expression in human forms of PAH tended to increase 37 . Few studies described CPT1A, describing inconsistent results. 14,16,27,76 Although CPT1A was originally considered as an insignificant player inmuscle (including heart) tissue, recent publications identified increased CPT1A as a key step in early metabolic remodelling which is linked to reduced fatty acid oxidation. 77 Besides the contradictive results regarding fatty acid uptake between the different animal models and between different patients cohorts, no structural consistency was found between a specific animal models with a specific human disease. Nevertheless, a disease specific pattern seems to apply for intramyocardial lipid deposition. Published results indicate lipid accumulation based on decreased fatty acid oxidation and increased fatty acid uptake by increased translation of CD36 to plasma membrane in heritable PAH specifically, 78,79 whereas RV ceramide content in chronic hypoxia decreased. 80 Unfortunately, only three studies reported intracardiac lipid deposition studying varied lipids which made meta-analysis impossible. Further research should aim better understanding of the translational possibilities from experimental studies to human disease. PGC1 α acts on transcriptions factors as the PPARs and is an important transcription factor of mitochondrial content. Co-activation of PGC1 α with PPAR isoforms is known to induce activation of downstream genes regarding fatty acid handling including uptake and β -oxidation, especially fat transporter genes CD36 and CPT1B, and β -oxidation gene MCAD. 81-84 PPAR α is the most studied PPAR in the heart and this also applies for the pressure loaded RV specifically. 27,34,85 Nevertheless, data of PPAR α expression in the pressure loaded RV is still limited and mostly showing statistically insignificant results ( suppl. figure 4d ). This is in contrast to PGC1 α , which is significantly negative affected in the pressure loaded RV and seems to be related to mitochondrial content in models of RV pressure load. It need to be said that the different studies identified mitochondrial content with different methods since standardized methods are lacking. Future studies should clarify if decreased mitochondrial content indeed is predominately established in models of SuHx and to what extend this mechanism is relevant for human PH disease. Remarkably, both