Impaired neuroanatomic development in infants with congenital heart disease.

OBJECTIVES: We performed a regional volumetric study of the brain using 3-dimensional magnetic resonance imaging in infants with congenital heart disease to search for variables in anatomic development of the brain that may be associated with functional impairment. METHODS: Forty infants with congenital heart disease-17 infants with single ventricle physiology, 5 with transposition of great arteries, and 18 with ventricular septal defect-were studied prospectively by 3-dimensional magnetic resonance imaging of the brain several months after heart surgery. RESULTS: The global volume of gray matter was significantly reduced in the patients with congenital heart disease compared with normal controls (P < .001), whereas no significant difference in the volume of white matter was observed. Further, the decrease in gray matter volume was more apparent in the frontal lobe than in the temporal lobe, especially in infants with single ventricle physiology or transposition of the great arteries. Multivariate analysis revealed that preoperative hypoxia is strongly associated with decreased frontal gray matter volume (P < .01), as well as a diagnosis of hypoplastic left heart syndrome (P < .05). Of note, frontal gray matter volume, which includes the motor area, correlated weakly with psychomotor developmental index scores (P < .01). CONCLUSIONS: Brain developmental impairment occurs in many infants with congenital heart disease, especially in those who have preoperative hypoxia and critical congenital heart disease. This quantitative volumetric study encourages larger scale and longitudinal follow-up to elucidate the significance of impaired neuroanatomic development on functional outcome.

Expression of myeloid-related protein-8 and -14 in patients with acute Kawasaki disease.

OBJECTIVES: This study investigated patients with acute Kawasaki disease (KD) to validate myeloid-related protein (MRP)-8/MRP-14 as a marker of disease activity and severity of coronary artery lesion development. BACKGROUND: Both MRP-8 and -14, which are S100-proteins secreted by activated neutrophils and monocytes, bind specifically to endothelial cells and induce thrombogenic and inflammatory responses in a variety of disease conditions. METHODS: We investigated 61 patients with acute KD and examined sequential changes in serum levels of MRP-8/MRP-14, messenger ribonucleic acid (mRNA) expression of MRP-8 and -14 in circulating granulocytes and monocytes, and amounts of MRP-8/MRP-14 bound to circulating endothelial cells. RESULTS: The serum MRP-8/MRP-14 levels as well as mRNA expressions of MRP-8 and -14 in granulocytes were strongly upregulated during the early stage of acute KD, and decreased dramatically within 24 h of intravenous immune globulin therapy (p < 0.05) in 45 responders. In contrast, in 16 nonresponders both of these increased after the initial treatment. The number of MRP-8/MRP-14-positive circulating endothelial cells was higher in patients with acute KD than in control patients and increased significantly by 2 weeks after the onset of KD, especially in patients in whom coronary artery lesions developed. CONCLUSIONS: We show for the first time that MRP-8/MRP-14 are exclusively secreted by granulocytes in patients with acute KD, and intravenous immune globulin treatment suppresses their gene expression. Serum levels of MRP-8/MRP-14 may be useful markers of disease activity, and the levels of MRP-8/MRP-14-positive circulating endothelial cell may predict the severity of vasculitis, confirming an important role for distinct inflammatory reactions in endothelium.

Neutrophil-derived S100A12 is profoundly upregulated in the early stage of acute Kawasaki disease.

Neutrophil-derived S100A12 is strongly upregulated during the acute stage of Kawasaki disease and decreases significantly in response to intravenous immune globulin (IVIG) treatment, whereas in nonresponders, serum concentrations increases after initial treatment. Decreased S100A12 expression in neutrophils was detected initially in nonresponders but increased significantly after IVIG treatment, suggesting delayed inflammatory response of neutrophils in nonresponders. Furthermore, in vitro S100A12 secretion increased with tumor necrosis factor-alpha (TNF-alpha) stimulation, whereas intracellular levels were lower in neutrophils with the higher TNF-alpha dose, suggesting intracellular depletion. S100A12 expression in neutrophils appears to reflect responsiveness to IVIG treatment and is possibly involved in the pathophysiology of acute vasculitis.

Enhanced iNOS expression in leukocytes and circulating endothelial cells is associated with the progression of coronary artery lesions in acute Kawasaki disease.

Nitric oxide (NO) serves many vasoprotective roles, but the massive release of NO causes arterial wall degeneration. We investigated whether enhanced nitric oxide synthase (iNOS) expression in peripheral blood leukocytes and circulating endothelial cells mirrors the progression of coronary arterial lesions in 55 children with acute Kawasaki disease (KD), including 24 with and 31 without coronary artery lesions (CAL). Patients were treated with i.v. gamma-globulin at the time of diagnosis and blood samples were collected before and after treatment. The cellular origin of NO synthesis was determined by flow cytometric analysis of iNOS expression in peripheral blood, and by immunohistochemical analysis of circulating endothelial cells and coronary arteries. iNOS expression in neutrophils peaked at the time of diagnosis, but did not peak in monocytes until 2 wk post onset of disease. Levels were significantly higher in both cell types in patients with CAL (p = 0.001 and p = 0.035, respectively). In addition, the number of circulating endothelial cells and levels of iNOS expression were higher in patients with CAL (p = 0.011 and p = 0.012, respectively). Immunohistochemical analysis of the coronary arteries from three patients with acute KD revealed iNOS immunoreactivity in endothelial cells, as well as infiltrating monocytes/macrophages in the aneurysms. We conclude that the expression of iNOS in peripheral blood leukocytes, as well as circulating endothelial cells, correlates with the severity of coronary arterial wall injury and the progression of CAL in patients with acute KD.