Clinical Characteristics Of The Screening And NVM Of Sarcomere Mutations

Background:Non-compaction of ventricular myocardium (NVM) is an uncommon genetic cardiomyopathy, which is characterized by a two-layered myocardium with a thin compacted epicardial layer and a thick loosened endocardial layer composed of numerous prominent trabeculations and deep intertrabecular recesses. Because left ventricle is commonly involved, it is also called left ventricular non-compaction (LVNC). LVNC shows a remarkable genetic heterogeneity. Defects in several genes have been proved to be related to this disorder, including TAZ, DTNA, LDB3, MIB1and PRDM16. However, these genes were only responsible for a small number of LVNC cases. Sarcomeric gene mutations are generally considered to be the primary etiology of hypertrophic cardiomyopathy (HCM), and to be associated with inherited dilated cardiomyopathy (DCM) and restrictive cardiomyopathy. Recently, LVNC is also demonstrated to be caused by sarcomeric mutations. Some studies even reported that approximately30%of cases resulted from these mutations. However, these researches were conducted based on Caucasian cohorts with a small number of individuals. Thus, it remains unclear whether these gene mutations are the main cause of LVNC in Chinese populations.Aims:This study was aimed to investigate the prevalence of sarcomeric gene mutations in a Chinese population with LVNC, and to preliminarily explore the relationship between the genotype and phenotype of this disorder.Methods:Between2003to2010, patients diagnosed with LVNC were prospectively included at Fuwai Hospital, Beijing, China. Comprehensive clinical evaluation was provided to the probands and the available family members. DNA samples were isolated from the peripheral blood of the index cases. Ten sarcomeric genes were screened by next-generation sequencing technology, including MYH7, MYBPC3, MYL2, MYL3, MYH6, TNNC1, TNNT2, TNNI3, TPM1and ACTC1.Results:Of the57patients included, only7(12%) carried sarcomeric gene mutations. These heterozygous mutations were distributed among4genes,4mutations in MYH7(△Phe155, Arg249Gly, Arg369Gln and Glu929Lys),1each in ACTC1(Ile329Thr), TNNT2(Arg102Gln) and TPM1(Ala242Val). Of these mutations, one (Arg369Gln in MYH7) was previously reported in LVNC. HCM or DCM could be detected in family members of the3probands with sarcomeric gene mutations. A family history of cardiomyopathy occurred more frequently in mutation-positive patients than that in mutation-negative patients (71%vs.8%, P=0.001). No significant difference was observed in other clinical characteristics at baseline between the two group patients. Duding a follow-up of3.5±1.7years, the Kaplan-Meier analysis showed that survival free from death was comparable between mutation-positive and mutation-negative groups (P=0.90).Conclusions:Sarcomeric gene mutations are not the primary etiology of LVNC in Chinese Han populations. Phenotypic variation may occur in the family members of the probands with sarcomeric mutations. The mutation-positive index cases more likely have a family history of cardiomyopathy. The phenotypic severity of LVNC seems to be independent of presence or absence of sarcomeric mutations. Background:Non-compaction of ventricular myocardium (NVM), which is also called left ventricular non-compaction (LVNC), is an inherited cardiomyopathy characteristic of a two-layered myocardium with a thin compacted epicardial layer and a thick non-compacted endocardial layer composed of numerous prominent trabeculations and deep intertrabecular recesses. Initial studies showed that heart failure, arrhythmia and systemic embolism were common findings in LVNC, and that the patients had a poor prognosis with an annual mortality and heart transplantation rate of13-24%. However, previous studies only included small numbers of subjects and the great majority of them were conducted in Caucasian populations. So, its clinical profile and prognosis in Asians need to be further evaluated, and the predictors for poor prognosis also need to be identified.Aims:This study was undertaken to evaluate the clinical course of isolated LVNC, and to identify the predictors for adverse outcome in a Chinese population.Methods:Between2003and2012, adult patients diagnosed with isolated LVNC at Fuwai Hospital were consecutively included in this study. The medical history, electrocardiograms, and echocardiograms of these patients were analyzed by chart review. Follow-up data were collected by regular outpatient and/or telephone interviews with the patients or their family members.Results:A total of106subjects were included in this studies. Mean age of the patients was46±17(range:16±78years). Among these patients,64(60%) showed New York Heart Association (NYHA) functional class Ⅲ/Ⅳ,84(79%) had left ventricular systolic dysfunction (left ventricular ejection fraction (LVEF),<50%) and71(67%) had dilated left ventricle (left ventricular end-diastolic diameter (LVEDD),≥60mm). Decreased LVEF was correlated to NYHA functional class Ⅲ/Ⅳ (r=-0.72, P<0.001), dilated LVEED (r=-0.65, P<0.001), enlarged left atrial diameter (r=-0.44, P<0.001), presence of pulmonary hypertension (r=-0.38, P<0.001) and low systolic blood pressure (r=0.20, P=0.04). Of the58patients receiving Holter monitoring, nonsustained ventricular tachycardia and frequent ventricular premature beats were detected in29(50%) and26(47%) of the patients, respectively. During a follow-up of2.9±2.1years,28(26%) patients died or underwent heart transplantation, and systemic embolism occurred in4(4%) patients. The annual incidence of mortality and transplantation was9.1%. Multivariate Cox analysis revealed that decreased LVEF (HR:0.96;95%CI:0.92-1.00; P=0.03), right bundle branch block (HR:7.94;95%CI;2.36-26.72; P=0.001) and low systolic blood pressure (HR:0.97;95%CI:0.94-1.00; P=0.02) were independent risk factors for death and heart transplantation.Conclusions:Heart failure and arrhythmia are common findings in Chinese isolated LVNC population, but systemic embolism is not. The prognosis of this disorder is better than that initially reported, although it is related to a relatively high incidence of death and heart transplantation. Left ventricular dysfunction predicts adverse outcome of isolated LVNC. Right ventricular dysfunction may also worsen the prognosis.