Using Genetics for Early Phenotyping & Prevention of Hypertrophic Cardiomyopathy

利用遗传学进行早期表型分析

基本信息

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
项目类别：
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

项目摘要

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）：发现人心脏病的遗传基础所带来的最终机会是对疾病的准确预测和预防。通过在临床诊断之前识别高危人群并开发新的疗法以延迟或预防表型表达，遗传发现可以改变医学。肥厚的心肌病（HOM）为实现这一机会提供了一个范式。 HOM是由肌节基因突变引起的，是最常见的遗传心血管疾病。它的特征是左心室肥大（LVH），舒张功能障碍以及心律不齐，猝死和心力衰竭的风险增加，以及在组织病理学上通过心肌肥大，混乱和纤维化在组织病理学上。疾病通常在青春期后期出现，症状是进行性的。当代对HOM的临床诊断在于在心脏成像上发现无法解释的LVH。但是，该二进制指标仅定义已建立的疾病，并且无法捕获突变引起的早期表型。相比之下，使用基因检测，我们可以鉴定患有致病性肌膜突变（基因型（G）+）的个体在出现明显的临床表现（LVH-）之前患疾病的高风险。我们对G+/LVH-受试者的研究已经定义了早期疾病的新标志物在这一重要的新子集中，表示为临床前H（3M。研究临床前HCM可以进一步鉴定早期表型，以及治疗反应的替代终点，以及治疗的替代终点，以及治疗的启动，以防止疾病的启动。我们已经确定了新的治疗方法。使用Diltiazem，通过TGF-Beta使用Losartan，在LVH上进行的治疗方法是无效的。临床前疾病的综合研究，受试者的鉴定以及治疗反应的替代终点的定义。这些努力将在第二阶段的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（请参阅说明）：肥厚性心肌病（HCM）是最常见的心血管遗传疾病，与猝死和心力衰竭的风险增加有关。基本研究定义了遗传病因，阐明疾病机制，并确定了预防疾病的策略。现在可以使用临床翻译，通过使用遗传学来识别高危患者并开始早期治疗，从而重塑医学。