Anne-Marie Koop

3 73 Hedges' g (95% CI) 0.94 (-0.25- 2.14) 6.52 (3.45- 9.58) 0.00 (-1.12- 1.12) 1.94 (0.54- 3.35) -0.9 (-2.09- 0.29) -0.33 (-1.46- 0.8) 2.30 (0.79- 3.8) 2.16 (0.8- 3.51) 1.24 (0.13- 2.36) 1.79 (0.3- 3.28) 1.99 (0.68- 3.31) 2.22 (0.93- 3.51) 1.79 (0.6- 2.98) 1.99 (1.26- 2.72) 0.30 (-0.91- 1.52) 3.42 (1.53- 5.3) 2.06 (0.6- 3.51) 1.00 (0.81- 3.4) 1.86 (0.62- 3.09) 0.58 (-0.39- 1.54) 1.09 (-0.09- 2.27) 0.78 (0.04- 1.53) 1.42 (0.81- 2.03) Hedges' g (95% CI) 2.24 (0.86- 3.61) 12.18 (6.09- 18.27) 1.01 (-0.22- 2.23) 0.87 (-0.33- 2.08) 0.94 (0.08- 1.8) 1.32 (-0.16- 2.81) 017 (0.86- 3.174) 1.48 (0.84- 2.11) 93 (1.23- 2.62) Study Hypoxia models Adrogue 2005, rat, 4 weeks (n=10) 34 Adrogue 2005, rat, 10 weeks (n=10) 34 Adrogue 2005, rat, 12 weeks (n=10) 34 Sharma 2003, rat, 2 days (n=10) 35 Sharma 2003, rat, 7 days (n=10) 35 Sharma 2003, rat, 14 days (n=10) 35 Sivitz 1992, rat, 2 days (n=11) 36 Sivitz 1992, rat, 14 days (n=14) 36 COMBINED (n=85): p = 0.059, I²= 88.8% COMBINED (n=85): p = 0.059, I²= 88.8% Hedges' g (95% CI) 1.54 (0.23- 2.85) -5.44 (-8.07- -2.81) -68.87 (-99.07- -38.67) -0.86 (-2.04- 0.32) 0.36 (-0.77- 1.49) -2.09 (-3.54- -0.64) -4.98 (-7.44- -2.53) -0.2 (-1.25- 0.85) -1.66 (-3.27- 0.06) -1.66 (-3.27- 0.06) GLUT4 - mRNA C-1 Study Hypoxia models Sivitz 1992, rat, 2 days (n=11) 36 Sivitz 1992, rat, 14 days (n=14) 36 Bruns 2014, calve, unknown, CO = (n=20) 38 COMBINED (n=45): p = 0.299, I²= 86.1% SuHx models Drozd 2016, rat, 5 weeks (n=6) 19 Drozd 2016, rat, 8 weeks , RVEF ↓ (n=9) 19 COMBINED (n=15): p = 0.129, I²= 69% MCT models Paulin 2015, rat, 3-4 weeks, CO =, compensated (n=10) 39 Paulin 2015, rat, 5-6 weeks, CO ↓ , decompensated (n=10) 39 Paulin 2015, rat, 3-4 weeks , CO = , compensated early (n=6) 39 Paulin 2015, rat, 3-4 weeks, CO = , compensated late (n=6) 39 Paulin 2015, rat, 5-6 weeks, CO ↓ , decompensate (n=6) 39 Broderick 2008, rat, 46 days (n=10) 40 COMBINED (n=48): p = 0.309, I²= 60% COMBINED (n=108): p = 0.482, I²= 73.4% Hedges' g (95% CI) -3.47 (-5.2- -1.73) -0.05 (-1.09- 1) 0.2 (-0.65- 1.04) -0.09 (-2.72- 0.84) 3.02 (0.89- 5.16) 0.74 (-0.54- 2.02) 1.71 (-0.5- 3.92) 1.16 (-0.07- 2.39) -1.1 (-2.32- 0.12) 0.77 (-0.59- 2.12) 2.37 (0.51- 4.22) 0.06 (-1.22- 1.34) 0.05 (-1.07- 1.17) 0.44 (-4.08- 1.29) 0.27 (-0.48- 1.02) GLUT4 - protein C-2 0 -5 5 -6 5 -5 0 5 0 Figure 2. Right ventricular uptake of carbohydrates. Forrest plots of FDG-uptake (A), GLUT1 expression at mRNA (B-1) and protein (B-2) level, and GLUT4 expression at mRNA (C-1) and protein (C-2) level. Data are prese ted as Hedges’ g. Combined Hedges’ g are presented as squares: grey representing Hedges’ g of a specific model, black representing Hedges’ g of all included studies. Bars represent 95% confidence int rval. SuHx = Sugen hypoxia, PAB = pulmonary artery banding, MCT = monocrotaline, FHR = fawn hoo ed rats, PH = pulmonary hypertension, FDG-uptake = fluorodeoxyglucose uptake , GLUT = glucose transporter. CO = cardiac output, CI = cardiac index, TAPSE = tricuspid annular plane systolic movement, RVEF = RV ejection fraction, ↓ = decreased, “=” = not statistically significant affected. 95% CI = 95% confidence interval, n = number of included animals, i² = level of heterogeneity, X = not included in meta-analysis, * = significantly (p < 0.05) increased compared to hypoxia, PAB- and FHR-models. were higher in the monocrotaline (MCT)-model 15 as compared to the hypoxia, PAB andFHRmodels 15,16,21 (p < 0.05 for all groups). In contrast toGLUT1, the gene expression of GLUT 34-36 and the GLUT4 proteins levels 19,36,38-40 were not altered ( figure 2c ). Meta- regression analyses for FDG-uptake, GLUT1 and GLUT4, revealed no statistical significant correlations with duration or degree of RV pressure load ( suppl. table 2 ). Meta-regression of GLUT1 at protein level and GLUT4 at gene level with degree of RV pressure load is not performed due to missing pressure measurements in the concerning studies. Glucose transport is coupled with glucose –phosphorylation by hexokinases, driving glucose into glycolysis. The mRNA expression of HK1 ( figure 3a ) was significantly increased in all models 18,21,27,29,30 . In addition, meta-regression analysis showed a negative trend with the duration of RV pressure load (p=0.08) ( figure 3b ). HK2 expression was not altered 15,16,21,27,29,30,37 ( figure 3c ) and meta-regression analysis revealed no correlations with duration of degree of pressure load ( suppl. table 2 and