Research On Risk Prediction, Pathological Mechanism And Targeted Intervention Of Heart Failur

Part 1.Novel Risk Prediction Model to Determine Adverse Heart Failure Outcomes in Arrhythmogenic Right Ventricular CardiomyopathyAimsArrhythmogenic right ventricular cardiomyopathy(ARVC)is an inherited progressive disease.Ventricular arrhythmia is a major cause of death in ARVC patients.However,with the improvement of arrhythmias management strategy,the life expectancy of ARVC patients,and the risk of progressive heart failure(HF)are increased significantly.Up to now,the researches on HF in ARVC fields are lacked,and there is no HF risk model is available for physicians.The aim of this study is to develop a clinical prediction model for individualized evaluating the risk of adverse HF outcomes,such as cardiac death and heart transplantation in ARVC patients.MethodsThis study was conducted by Fuwai Hospital(Chinese cohort)and University of Zurich Heart Center(Swiss cohort)in Switzerland.In this study,the prospective longitudinal cohorts were designed.The primary endpoints were heart transplant or death due to HF in ARVC patients.This model was developed based on LASSO regression and Cox regression.The internal validation of the model was completed by Bootstrap method,and the clinical application value was evaluated by decision curve analysis.ResultsA total of 290 ARVC patients were enrolled in the Chinese cohort and 99 patients were registered in the Swiss cohort.With 4.92±3.03 years follow-up of,a total of 48 patients experienced HF related heart transplantation and death.The application of implantable cardioverter defibrillators did not reduce the risk of end-stage HF.The atrial fibrillation,left ventricular ejection fraction,moderate/severe tricuspid regurgitation,and serum creatinine concentration were selected as the final predictors in the ARVC HF risk prediction model.ConclusionsIn this study,we developed a novel ARVC HF prediction model based on the well-known Chinese and Swiss cohort.This model can be used to individualized identify high-risk ARVC patients with HF,guide the physicians to optimize clinical treatments and provide timely hospice care.It can also be used as a practical tool for ARVC patients to assess risk by themselves.Part 2.Single-cell RNA sequencing reveals over-expression of COX7B attenuates heart failure in cardiac hypertrophyAimsCardiac hypertrophy could develop into end-stage heart failure(HF)stage in the natural disease courses,and eventually inevitably lead to cardiac transplantation or cardiac death.Protecting the systolic and pumping function of hypertrophic cardiomyocytes(CMs)plays an important role in improving the prognosis of patients with cardiac hypertrophy.In this study,we aim to investigate the transcriptional heterogeneity of hypertrophic CMs through single-cell sequencing of cardiomyocytes,illustrate the potential mechanism of cardiac hypertrophy leading to HF,and identify the key intervention targets for delaying the HF progression.MethodsIn this study,CMs suspensions were prepared from hypertrophic myocardial tissues collected from modified extended Morrow surgery.We applied single-cell tagged reverse transcription(STRT-seq)technology to sequence 338 human hypertrophic CMs,and used single-cell analysis and weighted correlation network analysis(WGCNA)strategy to interpret the heterogeneity of transcription characteristics of hypertrophic cardiomyocytes.Human myocardial samples and the cardiac hypertrophy mouse models induced by pressure overloads were utilized to verify our single-cell findings.Subsequently,the adeno-associated virus was used to specifically intervene the target genes in CMs to validate the effect on the progression of HF.ResultsOur results revealed that CMs could be categorized into three subsets in nonfailing HCM heart:high energy synthesis cluster,high cellular metabolism cluster and intermediate cluster.The expression of electron transport chain(ETC)was up-regulated in larger-sized CMs from high energy synthesis cluster.Of note,we found the expression of Cytochrome c oxidase subunit 7B(COX7B),a subunit of Complex Ⅳ in ETC was positively correlated with CMs size.Further,by assessing COX7B expression in healthy people,patients with cardiac hypertrophy in different stages of HF,and the mouse models,we speculated that COX7B was compensatory up-regulated at early-stage but down-regulated in failing HCM heart.To test the hypothesis that COX7B might participate both in hypertrophy and HF progression,we used adeno associated virus 9(AAV9)to mediate the expression of Cox7B in pressure overload-induced mice.Mice in vivo data supported that Cox7B overexpression could attenuates HF progression,restore partial cardiac function in hypertrophy,and raising the survival rate.ConclusionsOur result highlight targeting COX7B and preserving energy synthesis in hypertrophic CMs could delay the HF progression from cardiac hypertrophy.It will be a promising translational direction for HF therapeutic strategy.