Protein quality control systems in hypertrophic cardiomyopathy:pathogenesis and treatment potential

<正>Hypertrophic cardiomyopathy(HCM) is genetic cardiomyopathy with the risk of sudden death characterized by abnormal sarcomere protein.^[1] Although some pathogenic genes related to HCM have been reported,^[2] the disease phenotype and pathogenesis cannot be fully elucidated, which brings great difficulties to the diagnosis and treatment of HCM, especially the exploration of HCM treatment strategies.     

MicroRNAs as potential biomarkers for gastric cancer

Gastric cancer is the fourth most common cancer in the world and the second leading cause of cancerrelated death.More than 80%of diagnoses occur at the middle to late stage of the disease,highlighting an urgent need for novel biomarkers detectable at earlier stages.Recently,aberrantly expressed microRNAs(miRNAs)have received a great deal of attention as potential sensitive and accurate biomarkers for cancer diagnosis and prognosis.This review summarizes the current knowledge about potential miRNA biomarkers for gastric cancer that have been reported in the publicly available literature between 2008 and 2013.Available evidence indicates that aberrantly expressed miRNAs in gastric cancer correlate with tumorigenesis,tumor proliferation,distant metastasis and invasion.Furthermore,tissue and cancer types can be classified using miRNA expression profiles and next-generation sequencing.As miRNAs in plasma/serum are well protected from RNases,they remain stable under harsh conditions.Thus,potential functions of these circulating miRNAs can be deduced and may implicate their diagnostic value in cancer detection.Circulating miRNAs,as well as tissue miRNAs,may allow for the detection of gastric cancer at an early stage,prediction of prognosis,and monitoring of recurrence and/or lymph node metastasis.Taken together,the data suggest that the participation of miRNAs in biomarker development will enhance the sensitivity and specificity of diagnostic and prognostic tests for gastric cancer.     

Epigenetic DNA hypermethylation in cholangiocarcinoma: potential roles in pathogenesis,diagnosis and identification of treatment targets

Cholangiocarcinomas (CCs) are highly lethal malignant tumours arising from the biliary tract epithelium. The disease is notoriously difficult to diagnose and is usually fatal because of its typically late clinical presentation and the lack of effective non‐surgical therapeutic modalities. The overall survival rate, including resected patients is poor, with less than 5% of patients surviving 5 years, a rate which has not changed significantly over the past 30 years. Although CC is a relatively uncommon tumor, interest in this disease is rising as incidence and mortality rates for intrahepatic cholangiocarcinoma are increasing markedly worldwide. A variety of risk factors, including primary sclerosing cholangitis, liver fluke infestation, and hepatolithiasis have been described. However, for most CCs the cause is unknown, and affected individuals have no history of exposure to, or association with, known risk factors. Recent advances in molecular pathogenesis have highlighted the importance of epigenetic alterations in the form of promoter region hypermethylation and histone deacetylation in addition to genetic changes in the process of cholangiocarcinogenesis. This review provides a comprehensive overview of the genes reported to be methylated in CC to date and their putative roles in cholangiocarcinogenesis. Future directions in the study of methylated genes and their potential roles as diagnostic and prognostic markers are also discussed.     

肥厚型心肌病的诊断与治疗进展

许多西方国家及中国、日本等均报道,肥厚型心肌病患病率约为1／500,是一种全球性疾病。中国8080例人群超声心动图调查结果显示,全国约有肥厚型心肌病患100万人。以往献报道,多数患来自大的教学医院,不能代表社区肥厚型心肌病患的实际。调查显示,多数肥厚型心肌病患能够过正常或接近正常人的生活,有与常人相近的寿命。即使高危患,绝大多数经过手术及安装体内除颤起搏装置（ICD）,亦能解除危及他们生命的左室流出道梗阻及恶性心律失常,获得与正常人相近的生活质量与寿命。     

Determinants for clinical diagnosis of hypertrophic cardiomyopathy

Although hypertrophic cardiomyopathy (HC) occurs in 1 of 500 adults, most cardiology practices treat relatively few patients with HC, suggesting that many affected patients evade clinical recognition. Determining the clinical circumstances under which HC is identified will provide clues to its under-recognition. Clinical triggers leading to diagnostic echocardiograms were analyzed in 711 consecutive patients with HC. In most (384 [54%]), HC was initially suspected only after the onset of cardiac symptoms or acute cardiac events. In a substantial minority (327 [46%]), HC was recognized while patients were asymptomatic, including 225 (32%) by routine medical evaluations, in 27 of whom (4%) HC was recognized during preparticipation examinations for competitive sports or other activities. Women, older patients (age > or =50 years), and those with outflow obstruction at rest (gradient > or =30 mm Hg) were more likely suspected to have HC by virtue of cardiac symptoms or events (p <0.0001). Conversely, patients with extreme hypertrophy (wall thickness > or =30 mm) and those at high risk for sudden death were more often asymptomatic and identified by routine or family screenings (p <0.0001 and p = 0.004, respectively). Patients who subsequently died of heart failure or experienced embolic stroke were more often identified by virtue of symptoms or acute events (p = 0.03). In conclusion, although most patients with HC were recognized clinically only after overt disease manifestations, a substantial minority were diagnosed by routine examinations while asymptomatic, including an important subset of patients with HC recognized solely because of findings on sports preparticipation screening. These data underscore the need for heightened awareness and clinical suspicion of HC to increase the number of diagnosed patients, including many who may be at high risk for sudden death.     

肥厚型心肌病的诊断和防治进展

肥厚型心肌病(HCM)是由编码心肌肌节蛋白的基因突变所导致的最常见的遗传性心脏病,是青年人及运动员心原性猝死的主要原因。临床表现复杂多样,可表现为无症状、心绞痛、晕厥和猝死等。影像学诊断是目前HCM的主要诊断方法。治疗以缓解症状和防治并发症为主,包括药物治疗和非药物治疗。近年来,基因检测也逐渐应用于该病的早期诊断、危险分层、个体化治疗及优生优育。本文主要对HCM的诊断、治疗和早期预防等方面的研究进展进行综述。     

肥厚型心肌病研究、诊断和治疗的机遇与挑战

一、肥厚型心肌病的研究现状 1.肥厚型心肌病的病因:肥厚型心肌病是一种传统意义上的单基因疾病,至少已经找到20个致病基因,约1000个突变位点.其中编码肌小节蛋白的基因13个,8个常见的致病基因导致50%的病例,β-肌球蛋白重链(MYH7)与肌球蛋白结合蛋白-C(MYBPC3)2个基因约占已知致病基因的比率为80%～85%,肌钙蛋白T(TNNT2)、肌钙蛋白Ⅰ(TNNI3)与原肌球蛋白(TPM1)3个基因约占已知致病基因的10%～15%,其他肌小节蛋白,包括肌球蛋白轻链(MYL2、MYI3)、α-心脏肌动蛋白(ACTC)所占比例极少.     

肥厚型心肌病临床诊疗新进展

肥厚型心肌病(hypertrophic cardiomyopathy,HCM)是一种常见的典型常染色体显性遗传的心肌病,临床外显率可变,成人多数由1/12的心脏肌节蛋白基因突变引起。其病理改变以心室肌肥厚为主,主要累及左心室和室间隔,大多是非对称性的左心室肥厚,以室间隔肥厚最为显著且伴有左心室流出道狭窄,属梗阻性肥厚型心肌病     

Genetic basis for hypertrophic cardiomyopathy: implications for diagnosis and treatment

Familial hypertrophic cardiomyopathy is a genetic disease defined by cardiac hypertrophy in the absence of an increased external load. It is the most common inherited cardiac disorder occurring in 1 in 500 individuals. Ten genes exhibiting over 200 mutations have been identified. However, about 75% are due to mutations in just three genes: e-myosin heavy chain, cardiac troponin T, and myosin binding protein-C. Certain phenotypes are more common with certain genes, such as the myosin binding protein-C gene, which induces the disease predominantly in the fifth or sixth decade of life. Genetic animal models in the mouse and rabbit have helped to elucidate the pathophysiology. The primary defect imparted by the specific mutation alters contractile function, which stimulates release of various growth factors that induce secondary cardiac hypertrophy and fibrosis. Placebo single-blinded studies in the mouse indicate that losartan reverses the phenotype; in the rabbit, simvastatin essentially reversed the phenotype after 12 weeks of therapy. Clinical trials are ongoing in human familial hypertrophic cardiomyopathy.     

肥厚梗阻型心肌病的起搏治疗

对药物治疗抵抗的肥厚梗阻型心肌病患者,起搏治疗日益受到重视。本文就肥厚梗阻型心肌病的病理基础,起搏治疗的机 制及对预后的影响作一简要综述。     

Clinical diagnosis and pathogenesis of myocardial infarction complicated by hypertrophic cardiomyopathy: review of eight cases

Among 144 patients with hypertrophic cardiomyopathy, eight (58.3 +/- 7.0 years, M:F = 7:1) had complicating myocardial infarction, which was diagnosed clinically and by elevated cardiac enzymes or new Q-waves on electrocardiography. Coronary occlusion or stenosis evidenced by coronary angiography and nuclear cardiological findings were investigated. In six of the eight patients, coronary atherosclerosis caused infarction. These patients had many coronary risk factors compared to the other two patients. Sixteen of the 144 patients (11%) with hypertrophic cardiomyopathy had coronary atherosclerosis, the rate of which is reportedly 10 to 20%. Two of the eight patients had no coronary atherosclerosis. One patient had a diffusely spastic diathesis provoked by the intravenous administration of ergonovine maleate during coronary angiography, suggesting that coronary spasm caused myocardial infarction. The other patient had recurrent episodes of supraventricular tachyarrhythmia and no evidence of spasm during coronary angiography, suggesting coronary embolism as a cause of myocardial infarction. Myocardial infarction in patients with hypertrophic cardiomyopathy and normal coronary arteries as advocated by Maron et al. may have such pathogenesis. We conclude that coronary angiography may be mandatory in patients with hypertrophic cardiomyopathy, especially those who have many coronary risk factors and anginal symptoms. In these patients, ST-T changes and abnormal Q-waves on electrocardiography sometimes may be misleading when diagnosing the occurrence of acute myocardial infarction by electrocardiography alone. In such cases, infarct-avid scintigraphy with 99 m-Tc pyrophosphate is preferable.     

心电图对心尖肥厚型心肌病的诊断价值

心尖肥厚型心肌病（apical hypertrophic cardiomyopathy, AHCM）是1976年由日本学者首先报道的一种特殊类型的心肌病。我国自1984年刘王明心。报道首例AHCM以来的20多年来不断有这方面报道,本文对经超声心动图证实的12例心尖肥厚型心肌病患者的心电图特点进行分析,以便更好的了解和认识AHCM的心电图特点及变化。     

Current perspectives in hypertrophic cardiomyopathy: diagnosis, clinical management, and prevention of disability and sudden cardiac death

Hypertrophic cardiomyopathy is a rare primary myocardial disease known for its dramatic morphologic and clinical manifestations. Sudden cardiac death and functional cardiac symptoms are common. However, differing pathologic mechanisms may be responsible for similar clinical symptoms and make a unified approach to therapy impossible. This review will discuss the genetics, criteria for diagnosis, relationship among pathophysiologic abnormalities and clinical symptoms, and management of hypertrophic cardiomyopathy.     

肥厚型心肌病心房颤动:决定因素、临床进程与处理

Atrial fibrillation(AF)is the most common sustained arrhythmia in patients with hypertrophic cardiomyopathy(HCM),and represents an important complication in the clinical COUlee of the disease,with adverse consequences on functional status and outcome.Studies on community-based HCM patient populations have shown that AF is associated with long-term clinical deterioration,cardioembolic stroke and increaeed cardiovascular mortality due to heart failure and stroke.Moreover.acute onset of AF may cause severe hemodynamic impairment and represent a trigger of potentially lethal ventricular arrhythmias.However,the consequences of AF on the long-term prognosis of HCM patients are not uniformly unfavorable,and may be compatible with an uneventful course,when properly managed.Management of AF in HCM is challenging,particularly when onset occurs at a young age.Both paroxysmal and permanent AF represent clear indications for oral anticoagulation.In moat patients,maintenance of sinus rhythm is highly desirable but made difficult by the limited long-term efficacy and potentially hazardous side effects of available pharmacological options.In selected patients with HCM and severely symptomatic AF,radiofrequency catheter ablation may represent an effective therapeutic ahemative,improving functional status,and reducing or postponing the need for antiarrhythmic drugs. In patients with persistent AF,in whom maintenance of sinus rhythm is not feasible.adequate ventricular rate control should be pursued aggressively by atrio-ventricular node blocking agents.