The Mechanism And Genetic Predisposition Of Dilated Ischemic Cardiomyopathy And Dilated Cardiomyopathy

Background With advance in revascularization of coronary heart disease(CHD),more and more patients survived acute myocardial infarction(AMI)but suffered from impaired cardiac function and were at risk of events,who were diagnosed as ischemic cardiomyopathy(ICM).Despite that the prognosis of patients with ICM is rapidly improving,it is still one of the leading cause for development of heart failure.The term ICM was first introduced by Burch and colleagues to guide the management of therapy,for example,Coronary Artery Bypass Graft(CABG).In the last decades,it has been established that CABG plus guideline-based medical therapy produced great improvement in clinical outcome of ICM patients.As is accepted,it is the improvement in systolic function,which reflects the myocardial viability,that leads to better prognosis of ICM patients.As such,studies focusing on relationship between myocardial viability and the long-term outcome aimed to select patients for CABG but no significant interaction was found.The results made us wandering that was the cardiac dysfunction attributed to more complicated causes rather than merely coronary artery disease(CAD)? In addition,we have noticed that among the ICM patients,there is a considerable proportion of individuals present as dilated ICM(DICM).The condition of dilation is presumed to be secondary to CAD,and clinically diagnosed as ICM which was therefore excluded from dilated cardiomyopathy(DCM),the most common cardiomyopathy deemed to be of inheritance.Nevertheless,only few patients with CAD develop into DICM in clinical practice.On the second thought,is it possible that the complex condition of DICM resulted from DCM accompanied by CHD? DICM Patients shared much similar clinical characteristics with DCM,for example,progressive systolic dysfunction and enlargement of cardiac dimensions,as well as nonspecific histologic findings on biopsy.Mutations in a large number of genes have been identified to cause DCM.Given the genetics of DCM,we presumed whether DICM shares a similar genetic background.Therefore,we performed whole exome sequencing on 413 DICM patients and 588 DCM patients as well as 414 healthy controls to explore the contribution of variants in DCM associated genes.Methods 588 patients with DCM and 413 DICM cases were enrolled in Tongji Hospital,Wuhan,China between July,2007 and Dec,2018.The DCM was defined by Left ventricular or biventricular systolic dysfunction and dilatation without abnormal loading conditions or coronary artery disease according to the ESC guidelines relative to the DICM,which was characterized as Left ventricular or biventricular systolic dysfunction after revascularization and dilatation with significant CHD.The severe CHD was defined as at least 75% stenosis in one of the three major coronary arteries confirmed by coronary artery angiography or with a history of myocardial infarction or revascularization.Particularly,in the present study,we filtered for DCM and DICM patients with significant dilation of Left Ventricular enddiastolic diameters(LVEDD)> 55 mm.Patients with abnormal loading conditions like valvular heart disease or ventricular aneurysm resulted from myocardial infarction were excluded from the current study.Genomic DNA was extracted from peripheral blood leukocytes of all subjects.The filtered variant call set was annotated using ANNOVAR.Principle analysis for population stratification and genetic relatedness analysis of GCTA(Genome-wide Complex Trait Analysis)was conducted with eigenstrata using the linkage disequilibrium-prune variants with an MAF of >0.05.To compare the distribution of variants in the selected gene set,we used maftools from R to graph the waterfall plot and lollipop plot.Fasta sequences of the RBM20 protein were first queried against PDB sequence database(http://www.rcsb.org/)using BLAST which gives an approximate estimate of the difficulty for modeling.Then the sequences were split into chunks corresponding to prediction of domains and treated individually in tertiary structure prediction by I-TASSER.We used either Fisher's exact test or Pearson's chi-square test of association to ascertain thedifferences in frequencies across the groups.All P values are two-tailed,and below the threshold of P value of 0.05 was considered as statistical significance.Results The mean age of the DCM group is 55.72 years,the DICM group 61.56 years and the control group 66.09 years.There is a similar proportion of male patients between DCM and DICM groups,with 437(74.3%)males in DCM group,358(84.8%)in DICM group while only 187(45.2%)in control group(p < 0.001).In addition,the two cardiomyopathy group shared a wide spectrum of characteristics corresponding to echocardiogram,such as left atrial enddiastolic inner diameter(LAEDD),interventricular septum(IVS),left ventricular posterior wall(LVPW)and left ventricular ejection function(LVEF).(p=0.0.470,p=0.310,p=0.58 and p=0.315).A total of 12 variants were classified into likely pathogenic from 37 carriers according to Clin Var database while 83 likely pathogenic variants were identified in 23(5.6%)DICM patients,49(8.3%)DCM subjects and only 8(1.9%)control individuals(P = 0.017)according to ACMG standards.There are 13(3.1%)carriers of variants from MYH7,followed by 6(1.5%)carriers from TTN in DICM group.Furthermore,we identified a known pathogenic variant of DCM in a DICM case.Conclusions From the preliminary data,we conclude that DICM shares an overall prevalence of genetic predisposition with DCM but slightly distinct from it.And the double hit of variants from DCM causal genes plus CHD increased the risk of DICM.