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：
8010880
负责人：
Carolyn Y Ho
金额：
$ 73.34万
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 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8010880
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）：发现人类心脏病的遗传基础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高危个体并开发新疗法来延迟或预防表型表达，基因发现可以改变医学。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厚（LVH）、舒张功能障碍以及心律失常、猝死和心力衰竭风险增加，组织病理学特征为肌细胞肥大、紊乱和纤维化。疾病通常出现在青春期晚期，并且症状是进行性的。 HOM 的当代临床诊断依赖于通过心脏影像发现无法解释的 LVH。然而，这种二元度量仅定义已确定的疾病，无法捕获由突变引起的早期表型。相比之下，通过基因检测，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）+）的高风险个体。我们对 G+/LVH- 受试者的研究在这个重要的新子集中定义了早期疾病的新标志物，称为临床前 H(3M)。研究临床前 HCM 可以进一步识别早期表型、治疗反应的替代终点以及治疗的启动我们已经确定了有希望的新治疗方式，通过使用地尔硫卓和 TGF-β 改变细胞内钙处理来减轻动物模型中 HCM 的发展。重要的是，LVH 建立后进行的治疗对于逆转组织病理学是无效的。这些数据共同表明，我们有一个独特的机会来识别 HCM 的遗传风险并进行早期干预。我们将建立一个 HCM 临床网络，用于临床前疾病的综合研究、受试者的识别和治疗反应替代终点的定义。这些努力将在第二阶段临床试验中达到顶峰，以测试 HCM 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）：肥厚性心肌病 (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相关。基础研究明确了遗传病因，阐明了疾病机制，并确定了预防疾病的策略。现在可以进行临床转化，通过利用遗传学来识别高危患者并启动早期治疗来重塑医学。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Integrating Genetics and Medicine: Disease-Modifying Treatment Strategies for Hypertrophic Cardiomyopathy.

整合遗传学和医学：肥厚型心肌病的疾病缓解治疗策略。

DOI：
10.1016/j.ppedcard.2016.01.007
发表时间：
2016
期刊：
Progress in pediatric cardiology
影响因子：
0.9
作者：
Ho,CarolynY
通讯作者：
Ho,CarolynY

Genetic considerations in hypertrophic cardiomyopathy.

DOI：
10.1016/j.pcad.2012.03.004
发表时间：
2012-05
期刊：
PROGRESS IN CARDIOVASCULAR DISEASES
影响因子：
9.1
作者：
Ho, Carolyn Y.
通讯作者：
Ho, Carolyn Y.

Genetics and clinical destiny: improving care in hypertrophic cardiomyopathy.

DOI：
10.1161/circulationaha.110.978924
发表时间：
2010-12-07
期刊：
Circulation
影响因子：
37.8
作者：
Ho CY
通讯作者：
Ho CY

Ω-Net (Omega-Net): Fully automatic, multi-view cardiac MR detection, orientation, and segmentation with deep neural networks.

DOI：
10.1016/j.media.2018.05.008
发表时间：
2018-08
期刊：
Medical image analysis
影响因子：
10.9
作者：
Vigneault DM;Xie W;Ho CY;Bluemke DA;Noble JA
通讯作者：
Noble JA

Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial.

DOI：
10.1038/s41591-021-01505-4
发表时间：
2021-10
期刊：
Nature medicine
影响因子：
82.9
作者：
Ho CY;Day SM;Axelsson A;Russell MW;Zahka K;Lever HM;Pereira AC;Colan SD;Margossian R;Murphy AM;Canter C;Bach RG;Wheeler MT;Rossano JW;Owens AT;Bundgaard H;Benson L;Mestroni L;Taylor MRG;Patel AR;Wilmot I;Thrush P;Vargas JD;Soslow JH;Becker JR;Seidman CE;Lakdawala NK;Cirino AL;VANISH Investigators;Burns KM;McMurray JJV;MacRae CA;Solomon SD;Orav EJ;Braunwald E
通讯作者：
Braunwald E