Clinical Characteristics, Long-term Prognosis And Gene Mutation Characteristics Of Special Types Of Hypertrophic Cardiomyopathy

Part 1.The prevalence,clinical characteristics and long-term outcomes of extreme right versus extreme left ventricular hypertrophic cardiomyopathy characterized by progressive deterioration to increased cardiovascular mortality and morbidity.Right ventricle should be emphasized in HCM.Objectives:Extreme left ventricular hypertrophy(LVH)was a risk factor for sudden cardiac death(SCD)in hypertrophic cardiomyopathy(HCM).Extreme right ventricular hypertrophy(RVH)is rare and whether it is also linked to a poor outcome is unknown.This study compared the prevalence,clinical features and outcomes between HCM patients with extreme RVH and with extreme LVH.Methods:31 HCM patients with extreme RVH(maximum right ventricular wall thickness>10 mm)and 194 HCM patients with extreme LVH(maximum left ventricular wall thickness>30 mm)from Fuwai hospital were performed.The prevalence,clinical characteristics and natural history of two groups were compared.The Kaplan-Meier method and log-rank test was used for survival estimates.Risk factors for cardiovascular death and events and 95%confidence interval(CI)were determined by univariate and multivariate Cox proportional hazards regression models.Results:1.Extreme RVH was identified in 31 of 2413 HCM patients(1.3%)and 194 patients were classified as extreme LVH group(8.0%).HCM patients with extreme RVH were much younger,more women involved and more symptomatic(P<0.01).2.The cardiovascular mortality and morbidity within 10 years were significantly greater in extreme RVH group(p<0.05).The multivariate Cox regression analysis indicated a few independent clinical predictors for cardiovascular death including age ≤18 with a hazard ratio of 4.3(95%CI:1.72-10.85,P = 0.0018),LV end diastolic dimension ≥50 mm with a hazard ratio of 2.9(95%Cl:1.61-7.45,P = 0.0230).Pre-syncope syndrome was an independent predictor for cardiovascular morbidity with a hazard ratio of 1.6(95%Cl:1.07-2.5,P = 0.0240).There was a 4.2-fold(95%CI:1.48 to 11.84,P ＝0.0069)and a 1.9-fold(95%CI:1.14 to 3.03,P = 0.0135)increased risk of cardiovascular death and events within 10 years for patients with extreme RVH compared with extreme LVH.3.The microscopic findings of patients with extreme RVH showed myocardial cells hypertrophy,disarray and massive fibrosis.Conclusions:Compared with extreme LVH extreme RVH showed a quite poor prognosisPart 2.The clinical features,outcomes and genetic characteristics of hypertrophic cardiomyopathy patients with severe right ventricular hypertrophyIntroductions:Extreme right ventricular hypertrophy(RVH)is a rare phenotype in hypertrophic cardiomyopathy(HCM)for which limited information is available.This study was undertaken to investigate the clinical,prognostic and genetic characteristics of HCM patients with extreme RVH.Methods:extreme RVH was defined as HCM with a maximum right ventricular wall thickness ≥10 mm.Whole-genome sequencing(WGS)was performed in HCM patients with severe RVH using Illumina HiSeq X.Multivariate Cox proportional hazards regression models were used to identify risk factors for cardiac death and events in patients with extreme RVH Patients with apical hypertrophic cardiomyopathy(ApHCM)were selected as a comparison group.The diagnosis of ApHCM was based on the presence of asymmetric hypertrophy that was confined predominantly to the left ventricular apex and was characterized by a maximal apical wall thickness ≥15 mm and a maximal apical-to-posterior wall thickness ratio>1.5.Subjects were selected from among 2650 HCM patients treated at 7 centers or hospitals from 1996 to 2013.A total of 34 HCM patients with extreme RVH and 273 ApHCM patients were enrolled in the study and the clinical features and outcomes of the two groups were compared.The Kaplan-Meier method and log-rank test was used for survival estimates.Risk factors for cardiovascular death and events and 95%confidence interval(CI)were determined by univariate and multivariate Cox proportional hazards regression models.Results:1.Compared with the ApHCM group,the HCM with extreme RVH group included younger patients and a higher proportion of female patients and also displayed higher cardiovascular morbidity and mortality.2.The multivariate Cox proportional hazards regression models identified 2 independent predictors of cardiovascular death in HCM patients with extreme RVH,a New York Heart Association class ≥ Ⅲ(hazard ratio[HR]=8.7,95%confidence interval(CI):1.43-52.87,P = 0.019)and an age at the time of HCM diagnosis ≤18(HR=5.5,95%Cl:1.24-28.36,P = 0.026).3.Among the 11 HCM patients with extreme RVH who underwent WGS,10(90.9%)were identified as carriers of at least one specific sarcomere gene mutation.MYH7 and TTN mutations were the most common sarcomere mutations noted in this study.Two or more HCM-related genes were observed in 9(82%)patients,and mutations in either other cardiomyopathy-related genes or ion-channel disease-related genes were found in 8(73%)patients.Conclusions:Patients with extreme RVH is an uncommon phenotype in HCM and is characterized by progressive clinical deterioration and a relatively poor prognosis.Multiple gene mutations are associated with this phenotype and may be related to the mechanisms underlying the prognosis and heterogeneity associated with HCM.Anticipation and Genetic Basis of a Special Form of Hypertrophic Cardiomyopathy with Sudden Cardiac Death in a FamilyBackgroundHypertrophic cardiomyopathy(HCM)is the most common heritable heart disease,affects one in every 500 people in the general population and represents a major cause of sudden cardiac death(SCD)in adolescent athletes.Genetic anticipation is a phenomenon in which the age of onset of an inherited disorder decreases and/or the severity of the phenotype increases in successive generations.It is a phenomenon that has been well established in a number of inherited neurodegenerative disorders and other autosomal dominant genetic diseases,and it has long been suspected in HCM.Patients with a family history of HCM tend to exhibit symptoms earlier and to demonstrate more severe symptoms,such as greater hypertrophic myocardial or premature SCD,in the clinic.Czechs et al described the anticipation phenomenon in HCM patients,but the genetic mechanisms underlying it remain unclear.Objectivewe report clinical and genetic findings in a multi-generation Chinese family in which genetic anticipation coexists with premature SCD.This is the first study to reveal a genetic basis for the anticipation phenomenon in HCM.MethodsA HCM family comprising 5 generations and 74 members was studied.Two-dimensional echocardiography was used to diagnose HCM.The onset age of HCM was obtained by the first diagnosis of HCM from hospital records.The age of SCD was conformed by at least 2 members in the family.The Whole genome sequencing was performed in 4 HCM subjects and 1 control in the family.Illumina HiSeq X(Illumina,San Diego,CA)was used for WGS.Potential pathogenic mutations were required to be absent in publicly available databases,including the dbSNP,the 1000 Genomes Project,and the Blood Institute(NHLBI)Grand Opportunity Exome Sequencing Project(ESP 6500)Identified mutations were tested by Sanger sequencing in all available family members and 216 unrelated healthy controls.Parent-child generations with HCM were compared using the Wilcoxon rank-sum test.The age at onset of HCM was compared across generations using the Kruskal-Wallis test.Results1.The median age of onset was 63.5 years old in the 2nd generation,38.5 years old in the 3rd generation,and 18.0 years old in the 4th generation.There was a statistically significant difference in the age of onset of HCM between each pair of generations and among all five generations.In particular,SCD in the 3rd generation occurred at 30-40 years old and at approximately 8 am,whereas in the 4th generation,all 5 SCD males were 16 years old and death occurred at 8 am.In summary,the age of onset in individuals with HCM became earlier with each successive generation,and the severity of the clinical phenotype increased with each generation,with more heart failure,syncope and SCD being observed in younger generations.2.The sarcomere gene mutations,a known MYH7-A719H and a novel MYOZ2-L169G were found in all HCM individuals of the family.HCM patients with MYOZ2-L169G showed a worse prognosis than without this mutation.An additional sarcomere gene mutation TTN-130136T was also found in the SCD case(son of the proband).Moreover,heterozygous mutation in DNAJC19-A20H,CTNNA3 Leu814*,NEBL-S429 L associated with arrhythmogenic right ventricular cardiomyopathy or ion channel disease were detected.The number of mutations increased were detected more frequently in younger generations.3.In addition to single nucleotide mutations,a large deletion(～400 bp)was found in the intragenic region between the MYH7 and NGDN genes in four of the subjects who had the HCM phenotype in WGS.However,this SV was not detected in the phenotype-negative individualConclusions HCM may exhibit genetic anticipation with increased severity in successive generations with characteristic SCD.Multiple gene mutation may contribute to the genetic anticipation of HCM and might have prognostic value.Mutation related to other cardiomyopathy of ion channel disease may contribute to the heterogeneity of HCM.The MYOZ2-L169G mutation alone was not found to be pathogenic,but it did appear to play a modifying role in HCM.