Hypertrophic Cardiomyopathy: An Analysis Of Clinical Features, Prognostic Factors And Candidate Genes Mutations Screening

PartⅠ:Clinical and Prognostic Analysis of Patients with Hypertrophic CardiomyopathyObjectives:To investigate the clinical characteristics,long-term prognosis and death hazards in patients with hypertrophic cardiomyopathy(HCM).Methods:The medical record of the 234 patients with HCM recruited from June,1999 to March,2006 were retrospectively analyzed,199 patients were followed up and the outcome data was statistically analyzed by SPSS ver13.0.Results:Two hundreds and thirty-four patients(158 males,76 females;symptomatic age[51.0±15.6]years) diagnosed with HCM were studied.Among the 234 patients, females symptomatic age was older than males and more females compared with atrial fibrillation than males(P＜0.05 ).Symptoms in most of patients were nonspecific and 6.4%patients did not have symptoms.Changes of electrocardiogram in HCM were nonspecific and 6.4%did not have changes,but inverted T waves were sawed in patients with thicker wall in apex of heart.M-mode,2D,and echocardiogram showed the average maximal thickness of ventricular wall were(19.5±4.6)mm; 57(24.9%) patients were diagnosed with apical hypertrophic cardiomyopathy (AHCM),and the ratio between male and female was 3.4.The 15.5%patients who underwent coronary angiography had stenosis of coronary artery.Most of the patients received treatment and sudden death occurred to 5 patients.Among the 234 patients with HCM,199 patients(85%) were followed up with the mean time of 31.7±22.6 months,and the time interval from the first diagnosis till the end of the research was 52.2±66.6 months.Twenty-one patients died in the follow-up duration,HCM-related death occurred in 19 patients including 11(57.9%) patients of cardiac arrest, 7(36.8%)patients of heart failure,1 patient of stroke;1 patient of misadventure and 1 patient of acute pancreatitis..The free survival rates of all the followed patients at 1,2, 3,4 and 5 years were 96.7%,94.7%,94.7%,93.6%and 89.0%in respective. One-way ANOVA analysis indicated that sex,cardiac function,atrial fibrillation, sustained or non-sustained ventricular tachycardia(SVT or NSVT),enlargement of left atrium,obstructive outflow of left ventricular(LVOT),family history were associated with prognosis of patients.In the Cox model,the multivariate analysis showed HCM related death risk ratios were 2.234 for SVT or NSVT(p＜0.001), 1.964 for cardiac function of NYHA classⅢ-Ⅳ(P=0.003).Among the death patients,Maron typeⅢwere more common(73.7%)and only one patient merely involving apical myocardial hypertrophy(5.2%).Cardiac arrest was most common in patients＜60 years old(P=0.12),whereas heart failure occurred more frequently in patients≥60 years old(p=0.22).As for the death patients with cardiac arrest and heart failure,(1) 7 patients with cardiac arrest occurred under the age of 60(P=0.12,only one patient with onset age before 35),the onset age of 5 patients with heart failure were above 60(P=0.22);(2) LVOT occurred in only two patients with cardiac arrest and one patient with heart failure;(3)seven patients with cardiac arrest and 2 patients with heart failure combined SVT or NSVT;(4) maximum wall thicknesses of the patients with cardiac arrest and heart failure were 20.4±4.7mm versus 22.7±6.3mm.Conclusions:The clinical manifestations of HCM in china is nonspecific,but the symptomatic age is older than that in other countries.Symptomatic age was older in females than that in males,and the female patients were prone to atrial fibrillation. Non-obstructive hypertrophic cardiomyopathy was much more common(204/234). The incidence of apical hypertrophic cardiomyopathy was 1/4 and more common in males.The outcomes of most of patients were good.A relatively benign long-term prognosis was shown in this group of HCM patients,especially in patients merely involving apical myocardial hypertrophy;Sustained or non-sustained ventricular tachycardia,cardiac function of NYHA classⅢ-Ⅳare the independent risk factors for main adverse cardio-cerebral events;cardiac arrest may occur in all ages of patients.PartⅡ:Screening of cardiac myosin-binding protein C gene mutations of Chinese HCM and study of the correlation between genotype and phenotypeObjective:To study the cardiac myosin-binding protein C(MYBPC3) gene mutations in Chinese patients with hypertrophic cardiomyopathy(HCM),and to analyze the correlation between genotype and phenotype.Methods:One hundred and five patients with HCM and 120 control individuals were chosen for the study.Thirty-four exons in the functional regions of the MYBPC3 were amplified with polymerase chain reactions(PCR) respectively and the products were sequenced.The patients with positive results underwent family screen.Results:Among the 105 patients,20 patients were identified familial hypertrophic cardiomyopathy(FHCM) and 85 patients identified sporatic hypertrophic cardiomyopathy(SHCM).Seven mutations were identified in 10 patients which respectively located in exon 5,12,16,17,25,31and 32.And no mutations were not detected in A group of 120 anonymous healthy individuals.Among the 10 patients with mutations,3 patient were identified FHCM,accounted for 15%of the total 20 patients with FHCM.Although the same mutation was identified in 2 patients' children,their ultrasonic cardiogram examination was normal.The other 5 patients were identified SHCM, accounted for 5.9%of the total 85 patients with SHCM.The seven mutations included 1 missense mutation and 6 frame shift mutation.Mutation pro459fs was identified in 4 patients and the mutation was identified in 2 patients' children,but their ultrasonic cardiogram examination was normal.The other 6 mutations were respectively identified in 6 patients.Mutation Pro 186fs,Lys 814fs,Pro1208fs were identified in patients with FHCM.Mutation Arg346fs and Gly507Arg were identified in patients with SHCM.Mutation Pro186fs,Pro459fs and Tyr1119fs were firstly identified in patients with HCM.Mutation Gly507Arg and Pro1208fs were identical to foreign reports.Mutation Arg346fs was identified in Chinese patients with HCM. Mutation Lys814fs was identified in Chinese patients and foreign patients with HCM. Among the 10 families with mutations,mutations were identified in 15 person. Eleven of the total 15 person with mutation were diagnosed patients with HCM, accounted for 73.3%.Five patients' symptomatic age was less than 35 years old, accounted for 45%of the total 11 patients.Seven patients were associated with ventricular tachycardia or ventricular fibrillation or left ventricular outflow tract obstru-cttion or congestive cardiac failure.Conclusions:Cardiac myosin-binding protein C(cMYBPC3) was one of the main disease-causing genes,accounted for 15%of the total 20 patients with FHCM.The penetrance was high of the cMYBPC3 gene mutations,and the symptomatic age of 45%patients with the mutations was less than 35 years old.The outcomes of most of the patients with the MYBPC3 gene mutation were not good.This indicated that the MYBPC3 gene mutation was not a good factor for the outcomes of the patients with HCM unlike what ever reported.Mutation Pro186fs,Pro459fs and Tyr1119fs were firstly identified in patients with HCM.Arg346fs and Pro459fs were hot spot mutation in Chinese patients with HCM.PartⅢ:Screening of cardiac Troponin T gene mutations of Chinese HCM and study of the correlation between genotype and phenotypeObjective:To study the cardiac Troponin T(TNNT2) gene mutations in Chinese patients with hypertrophic cardiomyopathy(HCM),and to analyze the correlation between genotype and phenotype.Methods:Ninety-five patients with HCM which had been scanned in MYBPC3 gene and had nomutaions found and 120 control individuals were chosen for the study. Seven exons(exon 8,9,10,11,14,15,16) in the functional regions of the TNNT2 were amplified with polymerase chain reactions(PCR) respectively and the products were sequenced.The patients with positive results underwent family screen.Results:The study could not find any mutation in TNNT2 gene.Conclusion:This study did not find any HCM-caused mutation in TNNT2 gene, which was much lower than 10%-20%that foreign reported.This research displayed that different race had different distribution of HCM-caused genes.PartⅣ:Screening of cardiac Troponin I gene mutations of Chinese HCM and study of the correlation between genotype and phenotypeObjective:To study the cardiac Troponin I(TNNI3) gene mutations in Chinese patients with hypertrophic cardiomyopathy(HCM),and to analyze the correlation between genotype and phenotype.Methods:Ninety-five patients with HCM and 120 control individuals were chosen for the study.The patients with HCM had been scanned in MYBPC3 gene and TNNT2 gene,and no mutaions had been found.Three exons in the functional regions of the TNNI3 were amplified with polymerase chain reactions(PCR) respectively and the products were sequenced.The patients with positive results underwent family screen.Results:The study could not find any mutation in TNNI3 gene.Conclusion:This study did not find any HCM-caused mutation in TNNI3 gene, which was much lower than 5%that foreign reported.This research displayed that different race had different distribution of HCM-caused genes.