| Part one:Experimental study on the mechanism of high altitude exposure to congenital heart disease associated with pulmonary arterial hypertension Objective:The incidence and prevalence of Congenital heart disease(CHD)are significantly higher in high-altitude areas than in plain areas,and the prevalence of CHD among infants living in high-altitude areas is about 10 times that of those living in low-altitude areas.About 8 to 10% of these patients will further develop into congenital heart disease with pulmonary arterial hypertension(CHD-PAH).It is characterized by the progressive increase of pulmonary vascular pressure or resistance,which eventually leads to right heart failure,seriously threatening the life of children.Currently,surgical treatment,targeted drug therapy and combined therapy can significantly improve the quality of life,prolong the survival time,and even cure CHD-PAH children in low altitude areas.However,no consensus has been reached on the treatment strategies for children with CHD-PAH at high altitude,and there are even few studies on the formation mechanism of CHD-PAH at high altitude.This study aims to explore the influence of plateau environment on CHD-PAH formation by establishing an animal model of CHD-PAH at high altitude,and to provide theoretical basis for the treatment of patients with CHD-PAH at high altitude.Methods:A total of 180 male Sprague-Dawley(SD)rats,weighing243.67±8.27 g,were selected to establish CHD animal models by repeated puncture and stomatography through abdominal aorta and inferior vena cava,and then randomly divided into plain CHD group(n=60,then they were randomly divided into 1 to 6 weeks groups with 10 rats in each group),3000 m group(n=60,then they were randomly divided into 1 to 6 weeks groups with 10 rats in each group)and 5000 m group(n=60,then they were randomly divided into 1 to 6 weeks groups with 10 rats in each group).The plain CHD group rats were kept in the individual ventilated cages(IVC).The rats in the 3000 m CHD group and the 5000 m CHD group were reared in low-pressure and low-oxygen chambers respectively,and the simulated altitude was set at 3000 m and 5000 m.Small animal ultrasound was used to detect the patency of fistulas every weekend,and the diameter of fistulas was measured and recorded.The rats with large difference in fistula closure and diameter were removed.If the number of rats in each group meeting the standard was less than 8,the model was constructed again to make up 8 rats;if the number was more than 8,8 rats were randomly selected for thoracotomy to measure the value of pulmonary artery pressure(PAP)and record the growth and development of the rats.Modeling results showed that PAH related indexes in CHD animal models of the Plateau group tended to be stable at the end of the 5th to 6th week.SD rats were selected at the end of the6 th week to collect PAP values,blood samples,heart and lung tissues.Blood samples were collected from the Clinical laboratory of The General Hospital of the Western Theater Command to detect inflammation indicators.HE staining and Masson staining were used to evaluate the pathological changes of peripheral pulmonary arterioles.The expression levels of proliferation-related protein Notch3 and its downstream protein Hes5,apoptosis related protein PD-L1 and its downstream protein caspase-1 in rat lung tissues were detected by Western-blot method.The mRNA expressions of proliferation-related protein Notch3 and its downstream protein Hes5,apoptosis related protein PD-L1 and its downstream caspase-1 in rat lung tissue were detected by RT-qPCR.Results:1.The situation of CHD-PAH animal model in plateau:(1)Abdominal color ultrasound indicated that anastomosis continued to exist.Considering the success of arteriovenous anastomotic fistula formed by shunting operation,the patency rate of fistula in the three groups were 98.4%,100% and 96%,respectively.What’s more,there was no statistical difference in fistula diameter among the three groups(P>0.05);(2)Cyanosis,lethargy and shortness of breath were observed in all the rats with unblocked fistulas.With the increase of altitude and time,the above symptoms gradually became worse,and the weight gain slowed down significantly(P<0.05).The survival rate of plain CHD group,3000 m CHD group and 5000 m CHD group was 93.3%,83.3% and 61%,respectively.(3)HE staining results showed that:with the extension of time,the alveolar septum widened gradually,and the lumen became narrow gradually,and the higher the height,the more obvious the degree of stenosis.There was no significant difference between the pulmonary vessel measurement results at the fifth week and the sixth week.(4)Pulmonary artery pressure measured by thoracotomy and precision electronic balance showed that PAP and RVI/(L+S)values gradually increased with the extension of time,and the higher the height,the greater the value, and tended to be stable at the sixth week.2.Effects of high altitude on PAH formation in CHD rats:(1)Influence of plateau on PAP indicators:After 6 weeks,PAP and RVI/(L+S)values of SD rats increased significantly with the increase of height,HE staining of lung tissue showed obvious proliferation of pulmonary arterial blood wall,Masson staining showed obvious increase of pulmonary arterial blood wall fibrosis,and the differences among the three groups were statistically significant(P<0.05).(2)Influence of plateau on inflammatory indicators:The number of white blood cells(WBC),C-reactive protein(CRP)content and NLR were significantly different in plain CHD group,3000 m CHD group and 5000 m CHD group(P<0.05),and all increased with the elevation.(3)The effects of altitude on proteins related to the proliferation pathway:with the increase of altitude,the protein content and mRNA expression levels of Notch3 and Hes5 increased,with statistical significance(P<0.05);(4)The effect of altitude on proteins related to apoptosis pathway:with the increase of altitude,the protein content and mRNA expression levels of PD-L1 and Caspase-1 decreased,with statistical significance(P<0.05).Conclusion:1.The plateau CHD-PAH rat model was successfully constructed by simulating the plateau environment at 3000 m and 5000 m for six consecutive weeks.The growth and development of CHD-PAH rats in the plateau environment were significantly restricted,and the PAP values of CHD-PAH rats in the 5000 m plateau environment were higher,and the growth and development limitation were more obvious.2.High altitude environment can significantly accelerate the progression of CHD-PAH disease by enhancing inflammatory mediators infiltration,promoting pulmonary smooth muscle proliferation and inhibiting cell apoptosis,and "inflammation" and "proliferation" are the main factors.Part two:Factor analysis of influence on postoperative acute kidney injury in clinical children Objective:Acute kidney injury(AKI)is one of the most common and serious complications after congenital heart disease associated with pulmonary arterial hypertension(CHD-PAH)in children cardiac surgery under cardiopulmonary bypass(CPB),with an incidence of about 3% to 52%.At the same time,it often leads to adverse clinical outcomes and even death of children.At present,there is no unified treatment strategy for the treatment of postoperative AKI in CHD-PAH.Although the medical level has made great progress in recent years,and the treatment level for critically ill patients has been continuously improved,the mortality rate of postoperative AKI remains high.According to statistics,the fatality rate can reach 14%-51%,and the management strategy for postoperative AKI in CHD-PAH patients is "prevention" rather than "treatment".Therefore,this study aims to explore the influencing factors of early postoperative AKI in CHD-PAH children,so as to take effective preventive measures to reduce its occurrence and improve the prognosis of the children.Methods:During June 2016 to December 2020,the children under 3years old underwent cardiac surgery under CPB in the Cardiac Surgery Department of the General Hospital of the Western Theater Command.All the children were diagnosed as CHD-PAH,and a total of 299 children were included.According to the occurrence of postoperative AKI,the children were divided into AKI(n=62)and non-AKI(n=237)groups.Perioperative data were collected,including general data:age,sex,height,weight and congenital heart disease type.Preoperative data:pulmonary infection,PASP value,left ventricular ejection fraction(LVEF),serum creatinine value and CHD risk adjustment-1 score.Intraoperative data:duration of operation,CPB transit time,duration of aortic occlusion,and rate of cardiac automatic repulse.Postoperative data:serum creatinine,blood urea nitrogen(BNU).Outcome data:proportion of secondary intubation,bloodstream infection,hypoproteinemia,renal replacement therapy,mechanical assisted ventilation time,ICU stay,total length of hospital stay,mortality.Preoperative and intraoperative data were used to predict the risk factors for postoperative AKI.Results:Singlefactor analysis showed that age,height,body weight,pulmonary infection,preoperative serum creatinine serum creatinine value,intraoperative CPB time,aortic occlusion time,and CHD risk adjustment-1score were closely correlated with the incidence of AKI after surgery(P<0.05).Multivariate Logistic regression analysis showed that age,preoperative pulmonary infection,preoperative serum creatinine value and aortic occlusion time were independent risk factors for AKI(P<0.05).Postoperative complications in the AKI group were significantly higher than those in the non-AKI group,including secondary intubation,renal replacement therapy and blood infection(P<0.05),and postoperative mechanical ventilation time,ICU stay time,total hospital stay time and mortality were significantly increased(P<0.05).Conclusions:Young age,preoperative low serum creatinine value,preoperative pulmonary infection and long aortic occlusion time are independent risk factors for postoperative AKI.Making active preventive measures for high-risk population may be an effective way to reduce postoperative AKI and improve clinical prognosis. |
PDF Full Text Request