| Research Background:Pulmonary arterial hypertension is a common and serious complication in left to right shunt congenital heart disease. The danger of the operation and death rate will markedly increase for children with serious pulmonary hypertension. At present it lacks effective therapeutic method for the disease. Therefore, it is necessary to study the formation mechanism of the pulmonary hypertension which can offer theoretical foundation for the clinic treatment.Researches prove that Endothelin-1(a strong endothelin released by endothelial cells and a vascular smooth muscle cell mitogen, which is discovered in recent years. It is by far the most potent vaso-excitor material), as a strong endogenous vasoconstrictor and a mitogen, participates in the pathophysiology processes of various cardiovascular diseases. Maybe it is one of the important reasons for PAH happening to patients with congenital heart disease. Thus inhibiting Endothelin-1can control the effect of PAH.(Researches in recent years finds that the Endothelin-1level in lung tissue of patient with pulmonary hypertension caused by left to right shunt congenital heart disease rises. The ET-1Mrna level in lung tissue of patient with pulmonary hypertension rises obviously according to in situ hybridization. It is considered that ET-1causes pulmonary hypertension by contracting pulmonary arteries, stimulating the proliferation of the smooth muscle cells in pulmonary arteries and excreter more extracellular matrix such as collagen. These make tube walls of the pulmonary arteries thicker, the lumen narrower which cause pulmonary hypertentsion. The ET-1receptor antagonists can not only block the proliferation and hypertrophy of the smooth muscle cells in pulmonary artery, but also block ET-1’s function of contracting pulmonary arteries of the rat with hypoxic pulmonary hypertension and function of reproducing the smooth muscle cells.)Bosentan is a nonselective ET receptor antagonist. It combines with ETA in the blood vessels and ETB in epithelial and smooth muscle cells, which can competitively inhibit the combination between ET1and ETA, ETB. Thus it can prevent the strong endogenous vasoconstriction, fibration and inflammatory function of ET-1. It can effectively prevent endothelial cell damage, decrease the pulmonary hypertension and pulmonary vascular resistance. It can reverse pulmonary fibrosis if used in long term. By now there has been more reports on PAH caused by idiopathic pulmonary hypertension, oxygen deficit and pulmonary inflammation. Most of the experiences come from treatment for the adults and children with higher age. There has been less research on treating pulmonary hypertension children with congenital heart diseases. It deserves a deep study on pulmonary hypertension infants, especially those who are below one year old and with congenital heart diseases.Data and Method:Case selecting:Pulmonary hypertension patients with congenital heart diseases who have received treatment for less than3months in our hospital between2012and2013are selected and randomly divided into three groups according to random number table.Grouping:The control group:those who receive regular treatment belong to the control group. The regular treatment includes:digoxin taken orally and antisterone taken orally.The captopril group:patients who receive regular treatment and take captoril orally belong to this group.The Bosentan group:patients who receive regular treatment and take ET receptor antagonist Bosentan orally (take Bosentan two times a day,6.25mg per time for seven days or two times a day,12.5mg per time for one to four weeks.) belong to the treatment group.1. Pulmonary arterial systolic pressures of infants in three groups are no less than60mm Hg and the mean pulmonary arterial pressures are no less than45mm Hg. The heart function grades of these infants are over grade two according to NYHA.2. Infants from three groups have signed the consent form and each has been taken2ml venous blood to test their liver function, blood platelet and myocardial enzyme so as to find Bosentan’s influence on blood platelet and liver function.3. Before and after the treatment, infants in the three groups will be taken2ml venous blood respectively. The ELISA method will be taken to test the ET-1level in infants’plasma and to test Bosentan’s influence on ET-1level in pulmonary hypertension infants’plasma.4. Real time PCR will be taken to measure the change of infants’ preproendothelin-1(PPET-1), endothelin receptor antagonist ETA and ETB so as to discuss the possible mechanism for Bosentan’s decreasing pulmonary art5. Ultrasonic cardiogram will be used to measure pulmonary arterial systolic pressure changes before taking medicine,1week and4weeks after taking medicine. The infants’exercise tolerance will be evaluated according to the time used when they take30ml milk. The recorded data will be compared among three groups to evaluate Bosentan’s clinical effect.5. Ultrasonic cardiogram will be used to measure pulmonary arterial systolic pressure changes before taking medicine,1week and4weeks after taking medicine. The infants’exercise tolerance will be evaluated according to the time used when they take30ml milk. The recorded data will be compared among three groups to evaluate Bosentan’s clinical effect.Statistical Treatment:All the data are expressed in the form "mean number±standard deviation". SPSS13.0is used to analyze all results. P<0.05, so the results have statistical significance.Result:1. oral bosentan in children with PAH associated with congenital heart disease, and pulmonary artery systolic pressure after treatment was significantly reduced. Bosentan group of children with therapeutic doses of2mg/kg,2times a day, orally four weeks and eight weeks after undergoing cardiac echocardiography monitoring, pulmonary artery systolic pressure that is significantly improved, four weeks after treatment, medication after comparison with the previous eight weeks treatment differences were statistically significant (P<0.05), whereby said Mingbo bosentan significantly reduced mean pulmonary arterial pressure PH children; captopril in children can mean pulmonary arterial pressure decreased However, four weeks, eight weeks after treatment difference compared with the previous administration after administration no significant (P>0.05). 2. After bosentan therapy, exercise tolerance in children can significantly be improved. Less baby movement behavior, there is no good way to assess the effects more baby exercise tolerance, usually when feeding the baby can focus, so the measurement is completed30ml milk1children (infant formula milk and breast milk) feeding time, you can easily amount as the assessment of children with exercise tolerance, feasible, and the more accurate measure. Oral bosentan (an endothelin receptor antagonist) treatment, children can30ml milk feeding time was significantly shortened, after four weeks of treatment, feeding time from an average of20.55min reduced16.05min, there was a significant (P<0.01).3. pulmonary hypertension, elevated levels of plasma ET-1, indicating that elevated pulmonary artery pressure, vascular endothelial cells to synthesize and release increased, compared with the control group, a significant difference (P<0.01). Bosentan group after four weeks, eight weeks after treatment compared with before treatment differences were statistically significant (P<0.05), shows that bosentan significantly decreased plasma ET-1levels (P<0.05); captopril make children fall in plasma ET-1level, but four weeks and eight weeks after treatment difference compared with the previous administration had no significant (P>0.05). 4. In this study, short-term, low-dose oral bosentan in the process, no adverse reactions have occurred in children and well tolerated. After four weeks of oral treatment and eight weeks, review the children liver function were within normal range.Conclusion:1. pulmonary hypertension in children with congenital heart disease plasma ET-1levels were significantly increased compared with control group, indicating that when the pulmonary artery pressure increased endothelial cell synthesis and release of ET-1increases.2. This is the first study in infants less than three months of application of Bosentan and Bosentan comparison with captopril can be more significantly reduced PAH associated with congenital heart disease in children with pulmonary arterial pressure.3. Bosentan significantly improved in children with PAH associated with congenital heart disease, cardiac function, increase exercise tolerance.4. Short-term, low-dose oral Bosentan small infants with congenital heart disease with pulmonary hypertension, liver and kidney function in children with no obvious abnormalities. Confirmed bosentan pulmonary hypertension baby safe and effective. |
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