| Background and Objective:Cyanotic congenital heart disease, due to the right to left shunt of blood flow in heart,can cause chronic hypoxia and cyanosis of patients, with a very high mortality andmorbidity of the newborns. The various compensatory mechanisms, including elevatinglevels of hemoglobin, myoglobin, intracellular mitochondrial, and enhancing glycolysis, arein the sake of maximizing the tolerance of cardiomyocytes in hypoxia, by increasingoxygen release and decreasing energy consumption, so to maintain the survival and basicfunctions of cells.Iron, an essential element of myogolobin, cytochrome, and electron transport chain,mainly involves in the transportation and utilization of oxygen in cardiomyocytes. Genesrelated with iron homostasis express differently in hypoxia, many of which are directtargets of hypoxia-inducible factors (HIFs). HIFs can enhance the expression of target geneby directly acting on the hypoxia-responsive elements (HRE). Transferrin receptor-1(TfR-1)is the major protein involving in iron uptaking of cardiomyocytes, and an HRE wasreported on the promoter of TfR-1.In this project, four closely related factors of cyanotic congenital heart disease werestudied, including serum iron, total iron-binding capacity, noheme iron and the expressionof TfR-1in myocardium, to determine the changes of iron metabolism in peripheral bloodand myocardium of cyanotic patients and to explore the correlative mechanisms andsignificance.Methods:This project was approved by the Ethics Committee of Xinqiao Hospital, and divided into three parts:Part1: Venous blood was collected from twenty two patients with cyanotic (n=23) andacyanotic (n=24) congenital heart disease, to determine the concentration of hemoglobin,hematocrit, and serum iron and total iron-binding capacity were detected by ferrozinemethod.Part2: Myocardium of right ventricular outflow tract was collected in operation fromthirty five infants with cyanotic (n=20) and acyanotic (n=15) congenital heart disease, todetect the concentration of nonheme iron by ferrozine method and the distribution of iron inmyocardium by Perls-DAB.Part3: The expression and distribution of TfR-1were determined by Western blot andimmunohistochemistry respectively in the same myocardium tissue of the35cases.Results:1.The hemoglobin and hematocrit of children from both groups were in the normalrange, yet with significant difference (p<0.05)). Compared with the patients withoutcyanotic congenital heart disease, the cyanotic ones demonstrated higher hemoglobin(166.7g/L±22.1g/L vs125.6g/L±11.9g/L, p<0.05), and mean corpuscular volume (52.4%±8.8%vs37.7%±3.1%,p<0.05).2.Compared with the children without cyanotic congenital heart disease, the cyanoticones were with lower level of serum iron (23.25μmol/L±4.4μmol/L vs31.34μmol/L±4.2μmol/L, p<0.05), and higher total iron-binding capacity in serum (69.59μmol/L±5.8μmol/Lvs52.67μmol/L±9.2μmol/L, p<0.05).3.Compared with the control group, nonheme-iron in myocardium of cyanotic childrenwas increased (6.12μmol/g±0.67μmol/g比4.02μmol/g±0.68μmol/g, p<0.05),. Thedistribution of iron also showed difference in two groups: more positive particles wereobserved in the myocardium of the cyanotic group, while only a few of the control group.4.Compared with the control group, TfR-1expression was enhanced in myocardium ofcyanotic children, with OD0.62±0.02vs0.39±0.02,p<0.001. By immunohistochemistry,TfR-1of the cyanotic children was identified both on the membrane and in the cytoplasm ofcardiomyocytes, and with a more extensive expression compared with the control group. Conclusion:1.The changes observed in peripheral blood of cyanotic children, including theincrease of hemoglobin and hematocrit, the decrease of serum iron and elevated totaliron-binding capacity, indicate that in chronic hypoxia, a potential iron deficiency mightexist, for large amount of iron being uptaken by cells to adapt to hypoxia. For example, tosynthesize more hemoglobin and to produce more erythrocytes to improve the oxygencarrying capacity, leading to a decrease of iron storage.2.The significant increase of iron particles and nonheme iron in myocardiumdemonstrates that besides the iron consumption in hemoglobin synthesization, large amountof iron is also absorbed by myocardium in cyanotic children, to faciliate the enhancedsynthesization of related iron binding proteins, which may be the key change of chronichypoxia adaption of myocardium.3.The significantly higher expression of TfR-1in cyanotic children indicates thatenhanced expression of TfR-1, the major iron intake molecule in myocardium, facilitatesthe iron intake and assists the cardiomyocytes in hypoxia adaption.
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