Using Genetics for Early Phenotyping & Prevention of Hypertrophic Cardiomyopathy

利用遗传学进行早期表型分析

• 批准号: 7867043
• 负责人: Carolyn Y Ho
• 金额: $ 76.74万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7867043
• 关键词: Adolescence; Animal Model; Arrhythmia; Calcium; Cardiac; Cardiovascular Diseases; Cardiovascular system; Clinical; Clinical Trials; Data; Development; Diltiazem; Disease; Early identification; Early treatment; Fibrosis; Functional disorder; Gene Mutation; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic screening method; Genotype; Heart Diseases; Heart failure; Hereditary Disease; Histopathology; Human; Hypertrophic Cardiomyopathy; Hypertrophy; Image; Individual; Instruction; Investigation; Left Ventricular Hypertrophy; Losartan; Medicine; Metric; Modality; Modification; Muscle Cells; Mutation; Onset of illness; Patients; Phenotype; Prevention; Rest; Risk; Sarcomeres; Staging; Sudden Death; Surrogate Endpoint; Symptoms; Testing; Transforming Growth Factor beta; Translations; base; clinical Diagnosis; disorder prevention; high risk; novel; novel marker; novel strategies; pre-clinical; preclinical study; prevent; treatment response

DESCRIPTION (provided by applicant): The ultimate opportunity presented by discovering the genetic basis of human heart disease is accurate prediction and prevention of disease. By identifying at-risk individuals prior to clinical diagnosis and developing novel therapies to delay or prevent phenotypic expression, genetic discoveries can change medicine. Hypertrophic cardiomyopathy (HOM) provides a paradigm for realizing this opportunity. HOM is caused by sarcomere gene mutations and is the most common genetic cardiovascular disorder. It is characterized clinically by left ventricular hypertrophy (LVH), diastolic dysfunction, and increased risk for arrhythmias, sudden death, and heart failure, and histopathologically by myocyte hypertrophy, disarray and fibrosis. Disease typically presents late in adolescence and symptoms are progressive. The contemporary clinical diagnosis of HOM rests on finding unexplained LVH on cardiac imaging. However this binary metric only defines established disease and fails to capture earlier phenotypes caused by mutations. In contrast, using genetic testing, we can identify individuals with a pathogenic sarcomere mutation (genotype (G)+) at high risk for developing disease before the emergence of overt clinical manifestations (LVH-). Our investigations of G+/LVH- subjects have defined novel markers of early disease in this important new subset, denoted preclinical H(3M. Studying preclinical HCM allows further identification of early phenotype, and surrogate endpoints of treatment response, as well as initiation of therapy to prevent disease onset. We have identified promising new treatment modalities that mitigate the development of HCM in animal models through modification of intracellular calcium handling using diltiazem, and through TGF-beta inhibition using losartan. Importantly, treatment administered after LVH was established was ineffective in reversing histopathology. Together these data indicate that we have a unique opportunity to identify genetic risk and intervene early in HCM. The proposed studies in this Stage 1 planning application will fulfill the prerequisites for effective translation to human clinical trials. We will establish a HCM clinical network for comprehensive study of preclinical disease, identification of subjects, and definition of surrogate endpoints of treatment response. These efforts will culminate in a Stage 2 clinical trial to test a novel strategy of disease prediction and prevention in HCM to decrease symptoms, sudden death, and heart failure. RELEVANCE (See instructions): Hypertrophic cardiomyopathy (HCM) is the most common cardiovascular genetic disorder and associated with an increased risk of sudden death and heart failure. Basic investigation has defined the genetic etiology, elucidated disease mechanisms, and identified strategies to prevent disease. Clinical translation is now possible, reshaping medicine by using genetics to identify at-risk patients and initiate early therapy.

描述（由申请人提供）： 发现人类心脏病的遗传基础所带来的最终机会是准确预测和预防疾病。通过在临床诊断之前识别有风险的个体，并开发新的疗法来延迟或阻止表型表达，遗传发现可以改变医学。肥厚型心肌病（HOM）为实现这一机会提供了一个范例。HOM是由肌节基因突变引起的，是最常见的遗传性心血管疾病。其临床特征为左心室肥大（LVH）、舒张功能障碍和心律失常、猝死和心力衰竭的风险增加，组织病理学特征为肌细胞肥大、紊乱和纤维化。疾病通常在青春期后期出现，症状是渐进的。现代HOM的临床诊断依赖于在心脏成像中发现原因不明的LVH。然而，这种二元度量仅定义了已建立的疾病，并且未能捕获由突变引起的早期表型。相比之下，使用基因检测，我们可以在出现明显的临床表现（LVH-）之前识别出具有致病性肌节突变（基因型（G）+）的个体，这些个体具有发生疾病的高风险。我们对G+/LVH-受试者的研究已经在这一重要的新亚组中定义了早期疾病的新标志物，称为临床前H（3 M）。研究临床前HCM可以进一步鉴定早期表型，治疗反应的替代终点，以及开始治疗以预防疾病发作。我们已经确定了有前途的新的治疗方式，通过使用地尔硫卓修饰细胞内钙处理，并通过使用氯沙坦抑制TGF-β，从而减轻动物模型中HCM的发展。重要的是，LVH建立后给予的治疗在逆转组织病理学方面无效。这些数据共同表明，我们有一个独特的机会来识别遗传风险并早期干预HCM。第1阶段规划申请中的拟议研究将满足有效转化为人体临床试验的先决条件。我们将建立一个HCM临床网络，用于临床前疾病的综合研究，识别受试者，并定义治疗反应的替代终点。这些努力将在第2阶段临床试验中达到高潮，以测试HCM中疾病预测和预防的新策略，以减少症状，猝死和心力衰竭。相关性（参见说明）：肥厚型心肌病（HCM）是最常见的心血管遗传性疾病，与猝死和心力衰竭的风险增加有关。基础研究已经确定了遗传病因，阐明了疾病机制，并确定了预防疾病的策略。临床转化现在是可能的，通过使用遗传学来识别高危患者并启动早期治疗来重塑医学。