Anne-Marie Koop

3 67 MATERIAL AND METHODS Literature search We performed a systematic literature search in Medline and EMBASE on 29 November 2017. The search strategy and global methodological approach using Systematic Review Protocol for Animal Studies, version 2.0 formatted by SYRCLE 24,25 was published on the online platform of the working group Collaborative Approach to Meta-Analysis and Review of Animal Data form Experimental Studies (CAMARADES) at 13 December 2016. The search strategywas composed to capture overlapping parts of the following domains: (i) right ventricle, (ii) pressure load, and (iii) metabolism (see supplemental methods). Study selection Two researchers (A.M.C.K. and G.P.L.B.) independently screened the identified abstracts according to the following inclusion criteria: (i) English, (ii) original article, (iii) right ventricular pressure load, (iv) no reversible pressure load, (v) no mixed loading, and (vi) right ventricular metabolism. Full texts were screened for control group and sufficiency of the model by confirming increased pressure load by at least (a) increased right ventricular pressure load (i.e. right ventricular systolic pressure (RSVP) or mean pulmonary artery pressure (mPAP)), or (b) hypertrophy (i.e. RV weight, Fulton index (RV divided by LV + interventricular septum (IVS)) or RV to body weight ratio (RV/BW)). For inclusion of human studies, a control group for pressure load measurements was not required, since inclusion of individuals at study-level did meet the criteria of international guidelines for pulmonary hypertension. 26 Data extraction For the meta-analysis inclusion, the study had to report on metabolic variables, that were investigated in at least two or more other studies. Variable of metabolism was defined as: a) mRNAexpression of genes involved in substrate uptake of metabolism, b) protein expression and/or activity of genes involved in substrate uptake of metabolism, or c) metabolism measured in vivo or in vitro using either oxygraphy in isolated mitochondria (e.g. Oroboros, Clark-type electrode), oxygraphy in whole cells (e.g. Seahorse) or in isolated hearts (e.g. Langendorf). General upstream regulators also involved in metabolism (e.g. mitogen-activated protein kinase and protein kinase B (AKT)) were not included. In addition, study characteristics as species, model/type of pressure load, degree and duration of pressure load of selected studies were extracted. We extracted the mean, standard deviation (SD) (if not presented, standard error (SE)) and number of subjects (n) of the selected variables