Figures
- FIGURE 1
a) 6-min walking distance (6MWD) and b) pulmonary vascular resistance (PVR) index at baseline and 3-month follow-up in each group using fitted lines. The estimated difference between the groups from ANCOVA is the vertical distance between the two lines.
- FIGURE 2
Pulmonary mRNA expression of a) endothelial nitric oxide synthase (NOS3), b) inducible NO synthase (NOS2), c) neuronal NO synthase (NOS1), d) endothelin 1 (EDN1), e) endothelin 2 (EDN2), f) endothelin receptor type A (EDNRA) and g) endothelin receptor type B (EDNRB) after bosentan monotherapy (Mono) and bosentan/metformin combination therapy (Combi) for 3 months. Groups were compared using Student's t-test. Expression was normalised to the geometric mean of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and β-actin (ACTB). Data are presented as mean±sd. *: p<0.05.
Tables
- TABLE 1
Baseline characteristics in bosentan monotherapy and bosentan/metformin combination therapy groups
Bosentan Bosentan/metformin p-value# Patients n 48 45 Age years 32.5±13.2 28.6±10.4 0.119 Females n (%) 32 (66.7%) 26 (57.8%) 0.399 BMI kg·m−2 22.4±5.4 23.6±6.4 0.331 Heart defects n (%) 0.663 ASD 7 (14.6%) 5 (11.1%) VSD 39 (81.2%) 38 (84.4%) PDA 0 (0%) 1 (2.2%) TAPVR 2 (4.2%) 1 (2.2%) WHO functional class n (%) 0.761 II 4 (8.3%) 3 (6.7%) III 44 (91.7%) 42 (93.3%) 6MWD m 315±125 329±122 0.586 NT-proBNP ng·L−1 626±253 746±319 0.046 Peak TRV m·s−1 3.5±0.7 3.9±1.2 0.051 RA area cm2 30±8 33±9 0.092 Mean PAP mmHg 55±12 61±18 0.060 RAP mmHg 18±8 16±7 0.204 PAWP mmHg 8.9±3.3 8.8±3.6 0.889 PVR index WU·m−2 6.8±0.9 6.6±0.9 0.287 PVR/SVR ratio 0.38±0.13 0.41±0.16 0.322 Cardiac index L·min−1·m−2 2.2±0.3 2.3±0.2 0.635 SvO2 68±9% 70±9% 0.287 Data are presented as mean±sd unless otherwise stated. BMI: body mass index; ASD: atrial septal defect; VSD: ventricular septal defect; PDA: patent ductus arteriosus; TAPVR: total anomalous pulmonary venous return; WHO: World Health Organization; 6MWD: 6-min walking distance; NT-proBNP: N-terminal pro-brain natriuretic peptide; TRV: tricuspid regurgitation velocity; RA: right atrial; PAP: pulmonary arterial pressure; RAP: right atrial pressure; PAWP: pulmonary arterial wedge pressure; PVR: pulmonary vascular resistance; WU: Wood unit; SVR: systemic vascular resistance; SvO2: mixed venous oxygen saturation.#: Chi-squared test or t-test as appropriate.
- TABLE 2
Baseline characteristics and haemodynamic changes from baseline to 3 months evaluation in the bosentan monotherapy group versus the bosentan/metformin combination therapy group
Variables Bosentan# Bosentan/metformin¶ Baseline 3 months p-value+ Baseline 3 months p value+ BMI kg·m−2 22.4±5.4 23.1±6.2 0.557 23.5±6.1 22.5±5.4 0.397 WHO functional class n (%) <0.001 <0.001 II 4 (8.3%) 22 (45.8%) 3 (6.8%) 28 (63.6%) III 44 (91.7%) 26 (54.2%) 41 (93.2%) 16 (36.4%) 6MWD m 315±125 368±103 0.026 324±121 426±111 <0.001 NT-proBNP ng·L−1 626±253 438±189 <0.001 743±316 568±269 0.006 Peak TRV m·s−1 3.5±0.7 3.1±0.6 0.003 3.9±1.2 3.2±0.9 0.003 RA area cm2 30±8 28±9 0.253 32±9 31±8 0.583 Mean PAP mmHg 55±12 43±9 <0.001 60 ±18 40±10 <0.001 RAP mmHg 18±8 11±7 <0.001 16±6 10±6 <0.001 PAWP mmHg 8.9±3.3 9.2±3.8 0.681 8.7±3.5 8.9±3.4 0.786 PVR index WU·m−2 6.8±0.9 5.6±1.1
5.3±1.3§<0.001 6.6±0.9 4.8±0.8
4.4±1.5§<0.001 PVR/SVR ratio 0.38±0.13 0.28±0.16
0.26±0.18§<0.001 0.41±0.17 0.31±0.11
0.25±0.15§<0.001 Cardiac index L·min−1·m−2 2.2±0.3 2.5±0.4 <0.001 2.3±0.2 2.6±0.4 <0.001 SvO2 68±9% 70±8% 0.253 71±9% 72±9% 0.604 Data are presented as mean±sd unless otherwise stated. BMI: body mass index; WHO: World Health Organization; 6MWD: 6-min walking distance; NT-proBNP: N-terminal pro-brain natriuretic peptide; TRV: tricuspid regurgitation velocity; RA: right atrial; PAP: pulmonary arterial pressure; RAP: right atrial pressure; PAWP: pulmonary arterial wedge pressure; PVR: pulmonary vascular resistance; WU: Wood unit; SVR: systemic vascular resistance; SvO2: mixed venous oxygen saturation. #: n=48; ¶: n=44; +: Chi-squared test or t-test as appropriate; §: results of acute vasoreactivity testing with nitric oxide.
- TABLE 3
Differences in treatment effects between the bosentan monotherapy and bosentan/metformin combination therapy groups
Variables Change from baseline mean±sd Treatment effect
mean change (95% CI)p-value# Bosentan Bosentan/metformin 6MWD m 48±119 95±136 52 (10–95) 0.017 NT-proBNP ng·L−1 −176±325 −183±415 −141 (−236– −47) 0.094 Mean PAP mmHg −12±15 −20±19 −3 (−7–1) 0.145 PVR index WU·m−2 −1.2±1.3 −1.8±1.2 −0.8 (−1.2– −0.4) <0.001 PVR/SVR ratio −0.07±0.19 −0.11±0.19 −0.10 (−0.63–0.43) 0.148 Cardiac index L·min−1·m−2 0.3±0.5 0.3±0.4 0.11 (−0.61–0.28) 0.27 6MWD: 6-min walking distance; NT-proBNP: N-terminal pro-brain natriuretic peptide; PAP: pulmonary arterial pressure; PVR: pulmonary vascular resistance; WU: Wood unit; SVR: systemic vascular resistance.#: ANCOVA adjusted for a baseline covariate.
- TABLE 4
Peri- and postoperative characteristics in the bosentan monotherapy and bosentan/metformin combination therapy groups
Bosentan Bosentan/metformin Patients undergoing operation n (%) 40 (83.3%) 38 (86.4%) CPB time min 48±13 56±13 Cross-clamping time min 26±9 24±8 Hospital mortality 0 (0%) 0 (0%) Mechanical ventilation time h 18±8 16±6 Length of ICU stay h 36±9 28±6 Length of hospital stay days 12±6 10±4 Infection 4 (10%) 6 (15.8%) Reintubation 3 (7.5%) 2 (5.3%) Tracheotomy 1 (2.5%) 0 (0%) Arrhythmia 12 (30%) 9 (23.7%) Neurologic complication 2 (5%) 3 (7.9%) Data are presented as mean±sd or n (%). CPB: cardiopulmonary bypass; ICU: intensive care unit.
