Risk Prediction Model For Patients With Coronary Artery Dilatation, Genetic Factors, And The Impact Of Diabetes On Dilatation Lesion

Background:Coronary artery ectasia(CAE)is a rare finding in coronary angiography and associated with poor clinical outcomes.However,prognostic factors have not been well studied,and no prognostication tool is available.Objectives:The aim of this study was to develop and validate a generalized linear regression model for predicting outcomes and guiding risk stratification in patients with CAE,based on 5year survival data.Methods:In a derivation set comprising 729 consecutive CAE patients between January 2009 to June 2014,a nomogram was developed using Cox regression.399 patients during July 2014 to December 2015 formed the validation set.The primary outcome was 5-year major adverse cardiovascular events(MACE),which was a component of cardiovascular death and nonfatal myocardial infarction.Besides clinical factors,we used quantitative coronary angiography(QCA)and defined QCA classification of 4 types:type 1,max diameter<5mm with only focal dilations;type 2,max diameter<5mm with diffuse dilation;type 3,max diameter≥ 5mm with only focal dilations;type 4,max diameter≥5mm with diffuse dilation.Model performance was assessed by discrimination and calibration.Time-dependent area under the curve(AUC)and Kaplan Meier methods were used to evaluate the discrimination of the model.The calibration was assessed by HosmerLemeshow goodness of fit test and calibration plots.Results:A total of 27 cardiovascular deaths and 41 myocardial infarctions occurred at 5year follow-up.The nomogram included age,prior PCI,high sensitivity C-reactive protein,N-terminal pro-brain natriuretic peptide and QCA classification as predictors.The model effectively predicted 5-year MACE risk(AUC 0.75,95%CI 0.68-0.82 in derivation set;AUC 0.71,95%CI 0.56-0.86 in validation set).Patients were classified as high-risk if prognostic scores ≥ 155 and low risk if prognostic scores<155.The Kaplan-Meier curves were well separated according to this stratification(log-rank P<0.001 in both sets).Calibration curve and Hosmer-Lemeshow test indicated similarity between predicted and actual 5-year MACE survival(p=0.90 in derivation and p=0.47 in validation set).Conclusions:This study developed and validated a simple-to-use method for assessing 5year MACE and risk stratification in patients with CAE.BackgroundCoronary artery ectasia(CAE)is a rare finding in coronary angiography,which is defined as the abnormally dilated coronary artery exceeding 1.5 times of the diameter of the adjacent normal segment.In the past decades,this disease has been gradually recognized by physicians,but its pathogenesis has not been fully studied,especially the genetic mechanisms.In recent years,the rapid development of high-throughput sequencing technology has provided more information for the study of genetic factors of many diseases.Whole exon sequencing(WES)has the advantages of relatively low cost and high sequencing depth;thus,it plays an important role in the study of association between rare diseases and rare variants.ObjectivesThis study aims to use the whole exon sequencing data of Chinese patients with CAE to identify genes associated with CAE development,and to provide a new perspective for the study of the mechanism of this rare disease.MethodsThis case-control study included 117 patients with angiographically confirmed coronary artery ectasia in our hospital between January 2017 to December 2018.Genomic DNA of the subjects was extracted from peripheral blood and then underwent whole exome sequencing.The control group used 4523 East Asian population controls from the genome aggregation database(gnomAD).Principle component analysis(PCA)was used to evaluate the structure of the study population and confirmed that all individuals in the case group belong to typical East Asian population.A gene-based association analysis,burden test,was performed to find the deleterious variants associated with CAE and the variants were confirmed by Sanger sequencing.Subsequently,another 50 patients with coronary artery ectasia from 3 centers in China were used as a validation cohort to replicate the results of gene-based association tests.ResultsWe identified PIEZO1 gene as a novel risk gene with the most significant difference between coronary artery ectasia group and control group(P=1.70×10-29,false discovery rate=1.27×10-25,Bonferroni corrected P=1.27×10-25),and a total of 18 PIEZO1 rare deleterious variants alleles were found in 117 patients in the discovery set.After excluding patients with atherosclerosis,PIEZO 1 was still significantly associated with CAE(P=2.35×10-8,FDR=1.51×10-5,Bonferroni adjusted P=4.52×10-5).It encodes a poreforming subunit of a mechanosensitive non-specific cation channel.All PIEZO1 mutations found in the study were highly conserved among species and were predicted to be deleterious missense or led to premature termination of protein synthesis.In addition,the gene was significantly expressed in coronary artery tissues.In the validation cohort,5 PIEZO1 rare deleterious variants alleles were found in 4 of the 50 patients.ConclusionsThis study strongly implicated that PIEZO1 gene as a new risk gene contributing to coronary artery ectasia.In the validation cohort this association is further verified.These findings provided new information for the pathogenesis,diagnosis,and treatment of coronary artery ectasia.BackgroundCoronary artery ectasia(CAE)is a rare finding in coronary angiography and commonly associated with atherosclerosis.Many studies in recent years have shown that CAE is associated with poor clinical prognosis.Unlike atherosclerosis,diabetes mellitus is not commonly seen in patients with coronary artery ectasia.However,it is not clear whether the clinical characteristics and prognosis of patients with diabetes mellitus are different from those without diabetes.ObjectivesThe aim of this study was to investigate the clinical characteristics of patients with coronary artery ectasia combined with type 2 diabetes mellitus(DM),especially the differences between coronary angiography and clinical outcomes.MethodsPatients with angiographically confirmed CAE between January 2009 to December 2015 were included.Quantitative coronary angiography(QCA)was performed to measure the diameter and length of the dilated lesions.The primary endpoint of the study was the maximum diameter and maximum length of the dilated lesions in baseline coronary angiography at patient level.The secondary endpoint was 5-year major adverse cardiovascular events(MACE),which was a component of cardiovascular death and nonfatal myocardial infarction(MI).Two propensity score matching methods including nearest neighbor method and optimal paired matching were used to balance covariates.Kaplan-Meier method and Cox regression were performed to assess the clinical outcomes.ResultsA total of 1128 patients were included and 258 were combined with type 2 DM.In the DM group,the maximum diameter of dilated lesion was significantly lower(5.26 mm vs.5.47 mm,P=0.004)and the maximum length of the dilated lesion was significantly shorter(25.20 mm vs.31.30mm,P=0.003).This reduction in dilated lesion diameter(5.25mm vs.5.44mm,P=0.030 in nearest neighbor matching;5.26mm vs.5.44mm,P=0.014 in optimal paired matching,respectively)and length(25.23mm vs.30.86mm,P=0.026 in nearest neighbor matching;25.20mm vs.28.76mm,P=0.034 in optimal paired matching,respectively)was consistently observed in the propensity score analysis.A total of 27 cardiovascular deaths and 41 myocardial infarctions occurred at 5-year follow-up.Compared with non-DM group,there were similar risks of MACE(6.02%vs.6.27%;HR 0.96,95%CI 0.54-1.71,P=0.894),cardiovascular death(2.04%vs.2.61%;HR 0.78,95%CI 0.29-2.05,P=0.606)and nonfatal MI(4.07%vs.3.72%;HR 1.11,95%CI 0.54-2.26,P=0.782)in patients with type 2 DM.Consistent result was observed in multivariable Cox regression.ConclusionsCompared to non-DM patients,patients with CAE and type 2 diabetes were associated with a smaller diameter and a shorter length of dilated vessels,suggesting the important role of DM on the pathophysiological process of CAE.Similar risks of MACE were found during 5-year follow up among diabetic and non-DM patients.