Relation of Macrophage Migration Inhibitory Factor to Pulmonary Hemodynamics and Vascular Structure and Carbamyl-Phosphate Synthetase I Genetic Variations in Pediatric Patients with Congenital Cardiac Shunts

Figures

• 

  Figure 1. Serum MIF levels in patients compared to controls. (a) MIF levels tended to decrease with increasing age. Using analysis of covariance, p = 0.029 and p = 0.045, respectively, for the age effect and between-groups difference. For the whole study population, the equation was y = 8294.0 – 79.3∗x (r = −0.34), p = 0.005. On the bottom, MIF levels are shown as original values (b, unadjusted geometric means with 95% CI) and after adjustment for age (c, estimated marginal means with SE).

• 

  Figure 2. Serum MIF levels in patient groups according to the clinical/hemodynamic presentation (a) and carbamyl-phosphate synthetase I (CPSI) T1405N polymorphism (b, c, d). Despite a relatively small number of subjects for the subgroup analysis, specific data for the subgroups with (d) and without Down syndrome (c) are presented. In all graphs, the bars represent the estimated marginal means with SE after adjustment for age. Means not sharing the same letter were significantly different by post hoc multiple comparison tests. PBF and PVR, pulmonary blood flow and pulmonary vascular resistance, respectively. CC and AC, CPSI T1405N genotypes present in the study population.

• 

  Figure 3. Serum MIF levels in patient subgroups according to the clinical/hemodynamic profile and CPSI T1405N genotypes analyzed in combination. All results are presented as estimated marginal means with SE after adjustment for age. PBF and PVR, pulmonary blood flow and pulmonary vascular resistance, respectively. CC and AC, CPSI T1405N genotypes present in the study population.

• 

  Figure 4. Photomicrographs of arteries accompanying terminal bronchioles showing severe hypertrophy of the medial layer and absence of intimal lesions. Miller's elastic stain, objective magnification 20x for both panels. (a) 9-month-old patient with Down syndrome, with atrioventricular septal defect. Peripheral oxygen saturation was 88%, and pulmonary vascular resistance was 5.3 Wood units × m2 decreasing to 1.8 units × m2 during nitric oxide inhalation. Z-score transformed pulmonary artery wall thickness was 8.1, and serum MIF level was 12305 upi by chemiluminescence. (b) 4-month-old patient, with ventricular septal defect. Peripheral oxygen saturation was 95%, and pulmonary vascular resistance was 4.0 Wood units × m2 decreasing to 1.3 units × m2 while on nitric oxide. Pulmonary artery wall thickness was 21.2 (Z-score), and serum MIF level corresponded to 11014 upi. Both patients had AC CPSI T1405N genotype.

• 

  Figure 5. (a) Relation of medial hypertrophy of intra-acinar pulmonary arteries to the circulating (serum) levels of MIF chemokine. The data correspond to patients with high-PVR clinical profile and AC CPSI T1405N genotype for whom lung biopsy specimens could be collected intraoperatively (no significant association was seen in subjects with the CC genotype). These patients were characterized by high levels of serum MIF (i.e., above 7000 upi). The magnitude of wall thickness was similar between intra-acinar arteries (p = 0.470) but varied across MIF levels (p = 0.033). The regression equations for arteries accompanying the respiratory bronchioles and alveolar ducts were y = −12.99 + 1.81E-3∗x (r = 0.64), and y = −11.24 + 1.48E-3∗x (r = 0.66), respectively. (b) Pulmonary vascular response to inhaled nitric oxide (NO) in the same patients. The level of pulmonary vascular resistance at 10 minutes of NO inhalation is shown as pulmonary-to-systemic vascular resistance ratio (PVR/SVR). Subjects with higher levels of MIF (the ones with higher degree of arteriolar hypertrophy) had a more pronounced response (y = 0.92 – 6.98E-5∗x (r = −0.90), p = 0.014). No significant correlation was seen in…