Diagnosis Of Arrhythmogenic Cardiomyopathy And Prognosis After Transplantatio

Part Ⅰ.Desmosomal Protein Remodeling in Arrhythmogenic CardiomyopathyAimsArrhythmogenic Cardiomyopathy(ACM)is a hereditary cardiomyopathy with cardiac tissue loss and replacement of fibrous adipose tissue.The destruction of intercellular adhesion structure is considered to be the main pathogenesis of arrhythmogenic cardiomyopathy.Previous reports mainly focused on the expression of intracellular components of desmosome(plakophilin 2,plakoglobin,desmocollin 2,desmoglein 2,desmoplakin)and their structural abnormalities.The purpose of this study was to comprehensively investigate the remodeling of desmosomal proteins in ACM.MethodsA total of 137 transplanted hearts were included in the Fuwai cohort,and the pathologic types of hearts were determined on the basis of double-blind examination by two pathologists.Among them,49 had ACM,along with 29 transplants of hearts with dilated cardiomyopathy(DCM),17 hypertrophic cardiomyopathy(HCM)and 42 normal donors.These specimens served as the discovery cohort,while 11 ACM samples and 5 normal samples from Zurich served as the validation cohort.The expressions of plakophilin 2,plakoglobin,desmocollin 2 and desmoglein 2 were quantitatively transplanted by Western Blot.The intracellular localization distribution and expression of desmosomes were semi-quantified by immunofluorescence and immunohistochemical staining.At the same time,CX43 and N-Cadherin protein expression levels were used as baseline quantitation of protein expression in different cardiomyopathy.Image software analyzed gray value statistics by Western Blot.ResultsBy comparing the baseline data of the included population,we found that the preoperative clinical phenotypes of all patients were consistent with the corresponding characteristics of cardiomyopathy:right ventricular enlargement in ACM patients,significant left ventricular dilatation and decreased ejection fraction in DCM patients,ventricular septal thickening and left atrium enlargement in HCM patients.In the discovery cohort,expression of desmocollin 2 was significantly reduced in the right ventricle myocardium of ACM hearts compared with other cardiomyopathy and normal donors(p<0.001),while there was no significant change in expression in DCM and HCM,which was also confirmed by immunofluorescence staining.The expressions of plakophilin 2(p<0.05)and plakoglobin(p<0.05)were also decreased in ACM.ACM was divided into 4 clusters according to preoperative clinical characteristics and postoperative pathological characteristics,and the expression of desmosomal proteins in the left and right ventricles of the 4 clusters of ACM was further analyzed.We found that desmocollin 2 expression was significantly decreased in the right ventricle(p<0.001,a 3-4 fold decrease),as well as in cluster 2(p=0.008)and cluster 3(p=0.0021).The expression of plakoglobin was significantly decreased in cluster 1 and cluster 3,and decreased in only a few cases in cluster 2.Desmoglein 2 expression did not change significantly in right ventricles of all ACM clusters.The expression of plakophilin 2 decreased slightly in cluster 2 and cluster 3 but did not change significantly in cluster 1.Quantitative results of left ventricular protein showed that desmocollin 2 was significantly down-regulated in cluster 1 ACM(p<0.001).Compared with the results of protein expression in left and right ventricles,only desmocollin 2 showed different expression.On the basis of protein quantitation,the diagnostic efficiency of desmosomal proteins for different ACM clusters was analyzed by ROC curve.The results showed that desmocollin 2 could well diagnose different ACM subtypes(AUC of cluster 1=0.94,p<0.001;The AUC of cluster 2 was 0.85,p<0.001;The AUC of cluster 3 was 0.89,p=0.0002).Plakoglobin,as a traditional diagnostic marker,was phenotypically significant only in cluster 1(AUC=0.72,p=0.0051)and cluster 3(AUC=0.82,p=0.0017).These results indicated that the expression of desmocollin 2 as a diagnostic marker was significantly decreased in all ACM subtypes and all ACM patients.Compared with plakoglobin,desmocollin 2 is a better diagnostic marker.The 11 ACM cases in the validation cohort included 4 transplanted hearts and 7 biopsy samples,all of which were pathologically embedded wax blocks.Immunohistochemical staining showed that desmocollin 2 expression was significantly decreased in 10(90.9%)of 11 heart samples.These results indicated that desmocollin 2 decreased significantly in different disease periods and ACM cohorts.ConclusionDesmocollin 2 was down-regulated in right ventricular tissues of different ACM subtypes and different pathological stages.Compared with plakoglobin,desmocollin 2 could be a better diagnostic marker for ACM diseases.Part Ⅱ.Prognosis After Heart Transplantation in PatientsWith Arrhythmogenic Right Ventricular Cardiomyopathy and Dilated CardiomyopathyAimsThe lesion of Arrhythmogenic Cardiomyopathy(ACM)mainly affects the right ventricle,but can progress to the left ventricle in the late stage.In a few patients,the lesion is mainly the left ventricle.The main clinical manifestations were arrhythmia,right ventricular dilatation and heart failure.Different from ACM,Dilated Cardiomyopathy(DCM)is a primary or secondary cause of cardiomyopathy characterized by left ventricular dilation combined with decreased systolic function.The patients are older in onset and have a long course of disease.In the course of ACM patients,malignant arrhythmias such as ventricular tachycardia,ventricular fibrillation and even sudden cardiac death may occur,and ventricular defibrillation treatment can be managed clinically.When patients develop end-stage heart failure,heart transplantation is the best treatment for ACM patients.Previous studies on the prognosis of ACM transplantation are few,and most of them are small sample size studies.However,the prognosis of transplantation in Chinese ACM population has not been reported.Based on the cardiomyopathy transplant cohort of Fuwai Hospital.this study explored the clinical features of ACM and DCM patients before transplantation,as well as the transplant prognosis of patients with two types of cardiomyopathies.MethodsA total of 60 ACM transplant patients and ninety-two pathologically diagnosed dilated cardiomyopathy(DCM)patients 1:1.5 matched by transplant year,transplant age and gender were included.Patients with coronary heart disease,valvular disease,myocardial densification insufficiency and other diseases were excluded.The patients’disease history and perioperative clinical data of heart transplantation were recorded and counted.Long-term follow-up(1,3,6,12 months and annually thereafter)was performed for all transplant patients through telephone inquiry and outpatient visits:echocardiography,immunosuppressive use,and clinical symptoms after transplantation.Malignant arrhythmia events include ventricular tachycardia(VT),ventricular fibrillation(VF),syncope,and ICD discharge in patients treated with ICDs.The primary end point was defined as all-cause death and repeated cardiac transplantation.Kaplan-Meier curve was used to evaluate the survival prognosis of the patients after transplantation based on long term follow-up.ResultsPreoperative clinical information showed that the onset and transplantation age of ACM patients was early,with the onset of heart failure or arrhythmia at the average 30 years old,and the average transplantation age of ACM patients at 37.Compared with DCM,ACM patients had lower pulmonary artery systolic blood pressure(32.22 vs.51.67mmHg),pulmonary artery diastolic blood pressure(16.48 vs.25.17mmHg)and pulmonary capillary wedge pressure(14.55 vs.23.73mmHg)(all p<0.001).Pulmonary artery pressure at ACM was slightly elevated compared to the normal range(pulmonary artery systolic pressure:10-30 mmHg,pulmonary artery diastolic pressure:5-10 mmHg,pulmonary capillary wedge pressure:6-12 mmHg).Pulmonary systolic blood pressure,pulmonary diastolic blood pressure,and pulmonary capillary wedge pressure were all lower in patients with dilated cardiomyopathy.ACM patients are more prone to malignant arrhythmia events.Therefore,30%of ACM transplant patients received implantable resynchronization therapy such as ICD/CRT/CRTD before surgery,significantly higher than 9.78%of DCM patients.Long-term follow-up was conducted for all patients after surgery,and the median follow-up time for ACM and DCM patients was 6.00 years(1.48-15.36)and 5.48 years(0.23-14.38),respectively.Including hospitalization endpoint events(all-cause death or repeat heart transplantation),a total of 11 patients died in DCM patients:Two patients had graft failure,three had sudden death,one had infection,three had sudden death,one had malignant tumor,and one had died of multiple organ failure.The 1-year,5-year and 10-year survival rates of patients with dilated cardiomyopathy were 98.9%,91.7%and 82.3%,respectively.Only 1 patient with arrhythmogenic cardiomyopathy underwent in-hospital secondary transplantation,and no endpoint event occurred during out-of-hospital follow-up.The biventricular structure and function were in the normal range up to 5 years after the postoperative follow-up,and the 10-year survival rate of the patient was 100%.The left and right ventricular functions of both ACM and DCM returned to normal after transplantation,and the cardiac functions of the patients were within the normal range without significant changes during the follow-up period of six months,one year and 3-5 years after the surgery.ConclusionACM transplantation has a better prognosis and a higher long-term survival rate compared with DCM,which may be related to the lower preoperative pulmonary arterial pressure in ACM patients.Part III.Global Insights into Chronic Obstructive Pulmonary Disease and Coronary Artery DiseaseAimsChronic obstructive pulmonary disease(COPD)is the fourth most common specific cause of death although there is an underestimated prevalence.Comorbid COPD in coronary artery disease(CAD)patients presents a series of additional complications and has a detrimental impact on outcomes.Previous systematic reviews have reported the prevalence of COPD in adults and in those with atrial fibrillation although,none have considered the impact of COPD on the CAD patient population.Evidence related to revascularization methods for COPD-CAD patients is lacking and therefore there is a need to review and synthesize the current evidence-base to guide further research and for database development.MethodsPubMed,Web of Science,Embase,and the grey literature were searched until 26th November,2021.Prevalences were calculated and data were grouped according to COPD diagnostic methods,interventions,region,and economic status etc.Outcomes including all-cause death,cardiac death,myocardial infarction,revascularization,stroke,heart failure,and respiratory failure were analyzed.ResultsOverall,the prevalence of COPD in CAD patients was 14.2%(95%CI:13.315.1%).North America has the highest prevalence,followed by Asia,Europe and South America.Prevalence was significantly higher in the PFT group than in the ICD-coded or self-reported group(21.3%vs.14.6%vs.8.8%)(p<0.0001).There is no significant difference between high-income and upper-middle-income countries.Patients with COPD-CAD complications were more likely to develop cardiovascular and respiratory complications,including hypertension,diabetes,atrial fibrillation,stroke,smoking,dyspnea,wheezing,and chronic bronchitis,and were significantly higher in the COPD-CAD group than in the non-COPD-CAD group(all OR>1,95%CI>1).The incidence of atrial fibrillation and stroke was also higher in the group with COPD,with an OR of 1.64(95%CI:1.14-2.36)for atrial fibrillation and 1.72(95%CI:1.35-2.18)for history of stroke.COPD-CAD had a higher mortality rate(HR 2.81,95%CI 2.40-3.29),and the total all-cause mortality in COPD was three times higher than in non-COPD(hazard ratio[RR]=2.81,95%CI:2.40-3.29).And myocardial infarction,stroke,and respiratory failure(all with OR values greater than 1).Subgroup analysis showed a slightly higher mortality rate in the PFT group compared with the ICD-codes/self-report methods group,but no significant difference(3.08 vs.2.94,p=0.833 for subgroup difference).We also found no significant reduction in mortality in the CABG group compared to the PCI group(2.97 vs.3.43,subgroup difference p=0.427).In CAD patients with COPD,revascularization was significantly reduced(OR:0.43,95%CI:0.20-0.94)and myocardial infarction was reduced(OR:0.62,95%CI:0.18-2.11)after CABG treatment compared with PCI,without increased mortality.However,there was an increased risk of stroke after revascularization in the CABG group(OR:2.00,95%CI:0.50-7.94).ConclusionThe global prevalence of COPD is particularly high in CAD patients.COPD-CAD patients are more likely to encounter cardiovascular and respiratory complications,and have poorer outcomes.Limited evidence suggests CABG may reduce the need for revascularization without increasing mortality although further research is required.