A Novel Clinical Risk Prediction Model For Cardiovascular Complications Among Pregnant Women With Structure Heart Disease And The Study On The Mechanism Of Ventricular Remodeling

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A novel clinical risk prediction model for cardiovascular complications among pregnant women with structural heart diseaseAim To analyze data collected from women with structural heart disease who attended Renji Hospital between Jan 1^st,2003 and Dec 31^st,2015 and evaluate the performance of CARPREG score,ZAHARA score,and modified World Health Organization(mWHO)risk classification in these patients,so that risk factors for adverse cardiac events could be identified in an effort to develop a new cardiovascular risk prediction model for pregnant women with structural heart disease in East China.Method The patients were divided into two groups:566 patients(Jan 1^st,2003 to Dec31^st,2012)in the development cohort and 314 patients(Jan 1^st,2013 to Dec 31^st,2015)in the validation cohort.With a retrospective analysis of the development cohort,independent predictors of adverse cardiac events were determined using logistic regression model.The exponent value was used to weigh the risk factors and attribute points to each risk factor,which added up to be the predictive cardiac events rate:Renji score for the patients in the East China.The CARPREG score,ZAHARA score,modified World Health Organization(mWHO)risk classification and Renji score were applied in the development cohort and the validation cohort.Discrimination and calibration of these four risk prediction models were compared using c-statistics and Hosmer–Lemeshow test.Results In the Renji score,independent predictors for cardiac events included left ventricular systolic dysfunction(EF<40%)(3.1 points),prior cardiac events or arrhythmia(2.5 points),moderate to severe pulmonary arterial hypertension(?50mmHg)(1.7 points),mechanical valve replacement(0.9 points),moderate to severe mitral stenosis(<1.5cm²)(1.0 points),surgical intervention before pregnancy(-1.5 points).The incidence of cardiac events in patients with a score of<0points,0-0.9 points,1-2.4 points,2.5-3.4 points and?3.5 points were 1.9%,8.0%,35.4%,59.0%and 84.6%respectively.In the development cohort,the c-statistics for mWHO risk classification,CARPREG score,ZAHARA score and Renji risk score were 0.683?0.693?0.729?0.844 respectively.The P-values of Hosmer–Lemeshow test in this cohort for the four prediction models were 0.008,0.626,0.110,0.640.In the validation cohort,the c-statistics were 0.659,0.741,0.614,0.768 and the P-values of Hosmer–Lemeshow test were 0.072,0.056,0.999,0.750.For Renji score,the slope of the calibration curve were 1.0 in the development cohort and 0.84 in the validation cohort.The Renji score show good calibration and discrimination in the study.Conclusion Novel predictors for cardiac complications was identified in the study.Compared to the three risk assessment systems developed outside China,Renji score was a better risk prediction model for pregnant women with structural heart disease in East China with broad application spectrum.There were two limitations in the present study:its single-centered profile and a relatively small sample size for external validation.Part ? The role of Notch1 signaling pathway in ventricular remodeling due to pressure overload induced by transverse aortic constriction in pregnant Sprague-Dawley ratsAim To identify the expression of Notch1 and Notch1 associated proteins in ventricular remodeling due to pressure overload induced by transverse aortic constriction(TAC)in pregnant Sprague-Dawley(SD)rats.Method TAC was used to induce left ventricular hypertrophy models in SD rats.Models were confirmed successful by myocardial pathological analysis and echocardiography.The expression of Notch1 and Notch1 associated proteins in myocardium was investigated by immunohistochemistry,Western blot,and real-time reverse transcription-polymerase chain reaction(RT-PCR)in the control group(pregnant rats after sham operation),model group(pregnant rats after TAC surgery)and treatment group(model group with?-secretase inhibitor DAPT).Results The myocardial morphology with HE staining for rats at four weeks after TAC were as followed: hypertrophied cells,thickened cell diameter,larger cell volume,bigger and darker-stained cell nuclei,disordered and widened space between myocardial fibers,with inflammatory cell infiltration.Also,increasing myocardial fibers were found with picric Sirius red staining.Compared to cardiac function by echocardiography before TAC surgery,there were statistically significant((P<0.05)increases in HR,LVESD and decrease in EF,FS respectively after TAC.And results from immunohistochemistry showed the increased expression of Notch1,Jagged1,Hey1,Hes1,bcl-2 in myocardial tissues in the model group and the decreased expression of them in the treatment group.The expression of Bax proteins in myocardial tissues was highest in the treatment group.Moreover,Notch associated proteins were detected in myocardial cells.Results from Western blot showed increased expression of Notch1,Jagged1,Bcl-2 in the myocardial cells of the model group relative to those of the control group(P<0.05).No significant difference was found between the model group and the treatment group.Compared to the control group,results from Real-time RT-PCR showed a significant increase in the m RNA expression levels of Notch1,Jagged1,Hes1(P<0.01)and an increase in the m RNA expression levels of Hey1,Bcl-2 in the model group(P<0.05).Compared to the model group,decreased m RNA expression of Notch1 during the first trimester(P<0.01),Notch1(P<0.01),Hey1(P<0.01)and Bcl-2(P<0.05)during the second trimester and increased m RNA expression of Bax(P<0.01)during the second trimester were observed in the treatment group.Conclusion The model of ventricular hypertrophy induced by TAC was proved to be successful using the pathological analysis of myocardium and ultrasonography.These results suggested that Notch1 activation,along with its ligand could inhibit ventricular remodeling due to pressure overload by increasing myocardial resistance to injury,promoting myocardial cell survival,inhibiting myocardial fibrosis,which provided the theoretical foundation for the treatment of myocardial dysfunction during pregnancy.The limitation of the study was the lack of echocardiographic follow-ups of cardiac function after the transverse aortic constriction surgery in the SD rats during the pregnancy.