Hemodynamic and metabolomic responses to infusion of GLP-1 agonist exenatide in pulmonary arterial hypertension

Figures

• 

  Figure 1. Change in pulmonary hemodynamics before and after exenatide in patients with IPAH (n = 9) and CTEPH (n = 8). (A–C) Shown are the change in mean pulmonary artery pressure (A), cardiac index (B), pulmonary vascular resistance (C), heart rate (D), pulmonary artery saturation (E), stroke volume index (F), right ventricular contractility (n = 4) (G), right ventricular afterload (n = 4) (H), and ventricular vascular coupling (I). *P < 0.05. The P value was determined using the paired sample Wilcoxon signed-rank test (A–I).

• 

  Figure 2. Heatmap demonstrating the change in levels of 47 metabolites before and after exenatide sampled at the radial artery. All the metabolites had a significant change (FDR q < 0.05) least significant change. Metabolite levels were normalized by Box-Cox transformations and processed as previously described (16).

• 

  Figure 3. Change in metabolites with known prognostic importance in IPAH. (A–C) Exenatide administration associated with significant changes in 6 metabolites known be prognostically important in IPAH. Shown are the metabolite levels (z score) before and after exenatide infusion at each sampling site. SVC, superior vena cava; PA, pulmonary artery; RA, radial artery. *P < 0.05. **FDR-corrected P < 0.05. P values were determined by paired t test.

• 

  Figure 4. Change in metabolite gradients across sample sites before and after exenatide. (A–C) Shown are metabolite gradients between SVC-PA (A), PA-RA (B), RA-SVC (C) for 47 metabolites with significant change in level following exenatide infusion (FDR q < 0.05). (D and E) The metabolite levels at each sampling site for 2 free fatty acids — palmitate and oleate, respectively — known to be increased in PAH. Exenatide significantly reversed the direction of metabolite gradients across sampling sites. (F) The overlap in metabolite number demonstrating reversal of the direction of gradients with exenatide. Absolute difference in measurements reported (A–C). Data are shown as mean ± SEM (D and E).

• 

  Figure 5. Effects of exenatide in the monocrotaline PAH model. (A and B) The changes in RV (A) and LV (B) ejection fraction from baseline following administration of exenatide in the MCT and control groups. (C) Representative original short-axis CMR images acquired at end diastole and end systole. Midventricular slices were obtained from cine images from MCT rats before and after exenatide infusion for 30 minutes. Arrows point to the interventricular septum displacement demonstrating reversal in septal flattening post exenatide. *P < 0.05. P values were determined by the independent sample Kruskal-Wallis test.

• 

  Figure 6. Study flowchart demonstrating sequence of measurements made at right heart catheterization before and after exenatide infusion. RHC, right heart catheterization; SVC, superior vena cava; PA, pulmonary artery; PV, pressure-volume; IV, intravenous.