Macrophage migration inhibitory factor and chemokine RANTES in young pediatric patients with congenital cardiac communications: Relation to hemodynamic parameters and the presence of Down syndrome.

Inflammation and immunity are central in the pathobiology of pulmonary vascular disorders. Preliminary headway has been made in understanding the relationships between inflammatory proteins and clinical parameters in pediatric congenital heart disease. In this study, we analyzed serum levels of macrophage migration inhibitory factor (MIF) and regulated on activation normal T cell expressed and secreted chemokine (RANTES) in 87 patients with unrestrictive congenital cardiac communications and signs of pulmonary hypertension (age 2-36 months) and 50 pediatric controls. They were investigated in relation to clinical and hemodynamic parameters and the presence of Down syndrome. Hemodynamics was assessed by transthoracic Doppler echocardiography and cardiac catheterization. Chemokines were analyzed in serum using a chemiluminescence assay. The highest MIF levels were observed in very young subjects with heightened pulmonary vascular resistance but who presented a positive response to vasodilator challenge with inhaled nitric oxide. In contrast, RANTES levels were higher in patients with pulmonary overcirculation and congestion, correlating nonlinearly with pulmonary blood flow. Levels of both chemokines were higher in subjects with Down syndrome than in nonsyndromic individuals, but the difference was observed only in patients, not in the control group. In patients with Down syndrome, there was a direct relationship between preoperative serum MIF and the level of pulmonary artery pressure observed 6 months after surgical repair of cardiac anomalies. Thus, it was interesting to observe that MIF, which is key in the innate immune response and chemokine RANTES, which is highly expressed in respiratory viral infections were related to clinical and hemodynamic abnormalities associated with pediatric congenital heart disease.

Immune Abnormalities in Fontan Protein-Losing Enteropathy: A Case-Control Study.

OBJECTIVE: To comprehensively characterize the immunologic characteristics of patients with protein-losing enteropathy (PLE) post-Fontan and compare them with patients without PLE post-Fontan. STUDY DESIGN: Patients with PLE post-Fontan and age-matched controls post-Fontan were prospectively studied with laboratory markers of immune function. Infectious history was obtained by interview and chart review. The groups' demographics, cardiac history, immune characteristics, and infection history were compared using appropriate 2-group statistics. RESULTS: A total of 16 patients enrolled (8 patients with PLE and 8 controls). All patients with PLE had lymphopenia compared with 25% of controls (P = .01). All patients with PLE had markedly depressed CD4 T cell counts (median 58 cells/µL) compared with controls (median 450 cells/µL, P = .0002); CD4% was also low in the PLE group (12.3%) and normal in control (36.9%, P = .004). Both groups had mildly depressed CD8 T cells and normal to slightly elevated natural killer and B-cell subsets. A majority of patients with PLE (62.5%) had negative titers to measles, mumps, and rubella vaccination, compared with no control Fontan with a negative titer (P = .03). Despite profoundly low CD4 counts, the frequency of infection was not different between groups with no reported opportunistic infections. CONCLUSIONS: Patients with Fontan-associated PLE have extensive quantitative immune abnormalities, particularly CD4 deficiency. These immune abnormalities are similar to those found in non-Fontan patients with PLE caused by intestinal lymphangiectasia.

Lipid profiles and inflammatory markers after periodontal treatment in children with congenital heart disease and at risk for atherosclerosis.

Due to the biological associations between periodontal and cardiovascular diseases, as well as the fact that atherosclerosis begins in childhood, behavior based on oral health care and metabolic control from an early age is essential for patients with cardiovascular disease. The aim of this research was to examine the effect of full-mouth scaling and root planing on the reduction of periodontal disease in children with congenital heart disease. In this study, treatments were related to clinical periodontal parameters and also to blood ones, such as lipid profile and inflammatory markers. The patients were divided into two groups: group 1 (n=17), scaling and root planing; and group 2 (n=16), full-mouth scaling and root planing. The results showed a significant improvement in clinical periodontal parameters (P<0.05) in both groups. Considering lipid parameters, total cholesterol, triglycerides, and very-low-density lipoprotein parameters showed significant improvement (P<0.05). There was also an improvement in C-reactive protein (ultrasensitive) in the group treated with scaling and root planing (P<0.05). Fibrinogen and interleukin-6 parameters improved (P<0.05) in both groups. We suggest that both periodontal treatments were effective in children with congenital heart disease, though neither demonstrated superiority.

Late-gestation ventricular myocardial reduction in fetuses of hyperglycemic CD1 mice is associated with increased apoptosis.

BACKGROUND: Previous work in our laboratory showed reduced myocardium and dilated ventricular chambers in gestation day (GD) 17 hearts that were collected from hyperglycemic CD1 mouse dams. Pre-breeding maternal immune stimulation, using Freund's complete adjuvant (FCA), diminished the severity of these fetal heart lesions. The following experiments were performed to detect possible changes in fetal heart apoptotic cell death, under hyperglycemic conditions and with or without maternal immune stimulation. METHODS: Female CD1 mice were injected with 200 mg/kg of streptozocin (STZ) to induce insulin-dependent diabetes mellitus. Half of these mice received prior FCA injection. Fetal hearts were collected on GD 17 and myocardial apoptotic cells were quantified using flow cytometry. A panel of apoptosis regulatory genes (Bcl2, p53, Casp3, Casp9, PkCe) was then examined in the fetal myocardium using RT-PCR. RESULTS: Early apoptotic cells and late apoptotic/necrotic cells were significantly increased in fetal hearts from STZ or STZ+FCA dams. Pre-treatment with FCA reduced late apoptotic/necrotic cells to control level, suggesting some cell death protection was rendered by FCA. Paradoxically in the face of such increased cell death, the expression of pro-apoptotic genes Casp3 and Casp9 was decreased by diabetes, while the anti-apoptotic gene Bcl2 was increased. CONCLUSIONS: Maternal hyperglycemia causes dys-regulated apoptosis of fetal myocardial cells. Such effect may be prevented by maternal immune stimulation.

Decreased numbers of T-lymphocytes and predominance of recently recruited macrophages in the walls of peripheral pulmonary arteries from 26 patients with pulmonary hypertension secondary to congenital cardiac shunts.

INTRODUCTION: In the primary form of pulmonary hypertension (PH), the involvement of inflammation in the physiopathology of the vascular lesions is well established. Its role in secondary PH is yet to be investigated. We quantified the inflammatory cells on the walls of peripheral pulmonary arteries from patients with congenital heart shunts. METHODS: Twenty-six lung biopsies from patients with increased pulmonary flow and 10 lung fragments from control participants were examined. B-lymphocytes (CD20), T-lymphocytes (CD3), recently recruited macrophages (MAC387) and granulocytes (CD15) were quantified by area of the adventitia in arteries >50 microm. An index of inflammatory cells infiltrating the medial and intimal layers was also determined. RESULTS: There was no difference in the sum of densities of adventitial inflammatory cells between the groups. A prevalence of MAC387-labeled cells was detected in the PH group and of CD3-labeled cells in the controls. There was a lower density of T-lymphocytes in the PH group (P<.004). Patients with intimal proliferative lesions showed prevalence of MAC387-labeled cells (P=.004). PH participants showed a higher index of MAC387-labeled cells infiltrating the arterial medial and intimal layers (P<.001). CONCLUSION: The predominance of recently recruited macrophages in the PH group is compatible with ongoing inflammatory reaction in the arterial walls. This could be related to the pathogenesis of the vascular lesions, as a consequence of cytokines produced by the inflammatory cells. The smaller number of adventitial T-lymphocytes in patients with congenital shunts can reflect an impairment of their immune response.

Characterization of cellular phenotypes and cytokine expression in balt from children with congenital heart diseases.

UNLABELLED: The present study was performed to target and call attention to the bronchial associated lymphoid tissue (BALT), part of our immune system, from which, we believe, several forms of prophylactic and therapeutic approaches can be developed. The characterization of its immune components, cells, and cytokines, in absence of antigenic stimuli, is pioneer in literature. Eighteen cases of necropsies were chosen and selected the paraffin-embedded lungs. The ages of 11 females and 7 males varied from 5 to 31 months. Cause of death: congenital heart diseases. EXCLUSION CRITERIA: lung infection at necropsy and/or arterial hypertrophy greater than Heath-Edwards' 1st degree. Immunohistochemical technique was applied to identify the cell phenotypes and the cytokines in situ. BALT was identified in all cases in this study. The main cellular phenotypes in BALT were T helper (TH) and B lymphocytes surrounded by T cytotoxic lymphocytes, natural killer cells, and dendritic cells in less quantities. Interleukin 10 and Tumor Necrosis Factor alpha were the predominant cytokines in BALT without antigenic stimuli. BALT is an important structure of the lung immune system in infants, with a tendency to maintain an environment favorable to the Th2 arm of immune response. It needs more exploration to define its behavior in front of infections, especially those with pulmonary tropism.

Autoantibodies against neonatal heart M1 muscarinic acetylcholine receptor in children with congenital heart block.

Isolated congenital heart block may be associated with autoimmune disorder such as Sjögren Syndrome and systemic lupus erythematosus. In this work we demonstrate circulating autoantibodies against neonatal heart M1 muscarinic acetylcholine receptor (mAChR) in the sera of children with congenital heart block. This antibody were able to react with the second extracellular loop of the human M1 mAChR as demonstrated using a synthetic peptide in enzyme immune assay and binding assay. Affinity purified anti-peptide IgG as well as total IgG from children with congenital heart block, interfered with the specific radioligand occupancy from neonatal heart M1 mAChR, interacting irreversibly. The antipeptide antibodies also displayed an 'agonist-like' activity, i.e. decreased contractility, activated nitric oxide synthase activity and increased production of cyclic GMP. All of these effects were selectively blunted by pirenzepine and neutralized by the synthetic M1 peptide. Both binding and biological effects were obtained using neonatal rat heart instead adult heart and were independent of Ro/SS-A and La/SS-B antibodies and were also absent in the sera of normal children. A clinical relevance of these findings is demonstrated by a strong association between the existence of circulating M1 mAChR antipeptide antibodies and the presence of isolated congenital heart block, making these antibodies a proper marker of this disease.

Cytokines and pediatric open heart surgery with cardiopulmonary bypass.

It is well known that, subsequent to cardiopulmonary bypass, and particularly in children, an inflammatory response within the body can often result in a characteristic syndrome. Recently, it has been suggested that this phenomenon is due to a systemic inflammatory response, with significant involvement of cytokines. With this in mind, we investigated the behavior of tumour necrosis factor-alpha and interleukin-6 during the operative and in the immediate postoperative period in a group of children submitted to open heart surgery. We investigated any possible relation between the levels of these cytokines in the serum and the length of cardiopulmonary bypass, with the serum levels of lactate, and with the extent of use of inotropic drugs in postoperative period. The cytokines were measured in samples withdrawn after induction of anesthesia, after 10 minutes of cardiopulmonary bypass, after re-establishment of circulation, and then 2 and 24 hours after the end of cardiopulmonary bypass. The levels of tumour necrosis factor-alpha and interleukin-6 increased between the beginning and at two hours of the end of cardiopulmonary bypass. There was no correlation between the levels of these cytokines in the serum and the length of cardiopulmonary bypass, although there was a positive relation between levels of interleukin-6 and lactate in samples withdrawn at two hours of the end of bypass, and the measured levels of the cytokines correlated with the extent of inotropic drugs employed in the postoperative period.

[Anti-rubella IgM and IgG antibodies in congenital cardiopathy]. / Anticuerpos IgM e IgG antirubéola en cardiopatía congénita.

In utero infection by rubella virus is a well known cause of congenital heart disease. We look for prevalence of anti-rubella antibodies of IgM (primary response) or IgG (anamnestic response) classes in sera of 32 children with congenital heart disease and in 12 normal children of the same socioeconomic background. Only in a patient with a full congenital rubella syndrome we found high titers of IgG anti-rubella antibodies, there was no difference in prevalence of IgM nor IgG anti-rubella antibodies between normals and cardiac patients. There is no reason to look for anti-rubella antibodies in the isolated congenital heart disease.