Clinical And Prognostic Analysis Of Patients With Dilated Cardiomyopathy And Screen Of Candidate Genes Mutations In Patients With Dilated Or Hypertrophic Cardiomyopathy

Dilated cardiomyopathy(DCM) and hypertrophic cardiomyopathy(HCM) are the two most common types of cardiomyopathies. In recent years, increasing evidence showed that the prognosis of DCM had been improved significantly. Familial dilated cardiomyopathy(FDCM) have been paid much more attention to and considered to be related with 20-48 percent of DCM. Lots of disease-causing genes and mutations were identified in DCM and HCM respectively through molecular genetics studies which brought new hope to the early diagnosis and genetic intervention. However, there were still lack of data updates about Chinese patients with DCM or FDCM. Investigations on disease-causing genes in DCM and HCM were relatively insufficient at home. Thus, our study focus on exploring the clinical and prognostic characteristics of patients with DCM or FDCM through data reviews and analysis. Beta-myosin heavy chain gene(MYH-7) and cardiac actin gene(ACTC) were also screened as candidate genes in order to identify if there were mutations in patients with DCM or HCM.Part I : Clinical and Prognostic Analysis of Patients with Dilated CardiomyopathyObjective: To explore the clinical characteristics and prognosis of patients with dilated cardiomyopathy (DCM) and to investigate the proportion of familial DCM(FDCM) in DCM and its features.Methods: Clinical data of 280 patients with DCM and follow-up outcomes of 187 patients (66.8%) were analyzed.Results: All the patients, 221 cases (78.9%) of male and 59 (21.1%) of female, were aged 48.0±14.2 years on diagnosis. NYHA class I—II was found in 60 patients (21.4%) and III in 155 (55.4%), IV in 65 (23.2%) respectively. Eight patientswere FDCM with younger age of onset than that of sporadic ones (35.4±11.4 vs. 48.4±14.1, P<0.01). Arrhythmias were observed in 253 patients(90.4%), including 71 cases (25.4%) with atrial fibrillation, 90 (32.1%) with polymorphic ventricular premature beats, 130 (46.4%) with paroxysmal ventricular tachycardia, 64 (22.9%) with left bundle branch block. Most patients showed enlargement of left or all cardiac chambers in echocardiography. Larger left ventricular end-diastolic diameters (68.9±8.4mm vs. 63.8 ±7.8mm) and lower left ventricular ejection fractions (31.8±10.1% vs. 41.8±12.0%) were found in patients with NYHA class III-IV than in those with class I — II (P<0.01) . Medical treatments included angiotensin converting enzyme inhibitors or angiotensin II receptor blockers in 237 patients (84.7%) and beta-blockers in 168 (60.0%). One hundred and eighty-seven patients (66.8%) were followed up for 29.8±23.2 months. Fifty patients died during follow-up, including 27 patients (54.0%) died of heart failure and 20 (40.0%) of sudden death. In addition, 7 patients underwent heart transplantation. The transplant free survial rates at 2 and 5 years after diagnosis were 86.0% and 65.3% respectively . The 5 year survial rate of the 8 index patients with FDCM was lower than that of sporadic ones (40.0% vs. 65.5%, P<0.05 ) .Conclusion: Most patients with DCM manifested heart failure of NYHA class III—IV with complex arrhythmias and enlargement of cardiac chambers when diagnosed. The 2 and 5 years survival rates were higher than those had been reported before, which indicated the clinical improvements in DCM. However, heart failure and sudden death were still the main causes of mortality. Patients with FDCM were often with relatively younger onset age and worse prognosis than sporadic ones.Part II: Screen of Candidate Genes Mutations in Patients with Dilated or Hypertrophic CardiomyopathyObjective:To study the beta-myosin heavy chain gene(MYH-7) and cardiacactin gene(ACTC) mutations in Chinese patients with dilated cardiomyopathy(DCM) or hypertrophic cardiomyopathy(HCM), and to analyze the correlation between genotype and phenotype.Methods: Eighty-one patients with DCM, 25 patients with HCM and 110 control individuals were chosen for the study. Fifteen exons in the functional regions of the MYH-7 and 2 in ACTC were amplified with polymerase chain reactions(PCR) respectively and the products were sequenced. The patients with positive results underwent family screen.Results: In a pedigree with Familial HCM(FHCM), a C→G transversion was identified in the exon 20 of MYH-7 gene, resulting in the arginine in condon 723 substituted by glycine. This Arg723Gly missense mutation was not found in 110 control individuals. All the 13 adult members carrying the mutation in this family were clinically diagnosed as HCM patients including 4 with dilated left ventricles. There were 6 members who had died of heart failure and 1 of sudden death in this pedigree. It's the first time that the Arg723Gly mutation was identified in Chinese patients with HCM. No disease-causing mutation in MYH-7 gene was found in patients with DCM. No ACTC gene mutation was identified in patients with DCM or HCM.Conclusion: MYH-7 gene may be one of the main disease-causing genes in Chinese patients with HCM. Arg723Gly mutation in MYH-7 was of high penetrance and patients with this mutation had early-onset symptoms and were susceptible to developing to heart failure, all of which indicated the malignant property of this mutaion. MYH-7 gene may not be one of the main disease-causing genes in Chinese patients with DCM. ACTC mutation may be of very low frequency both in Chinese patients with DCM and HCM.