Diagnostic and Treatment Strategies for Preclinical HCM

临床前 HCM 的诊断和治疗策略

• 批准号: 7126356
• 负责人: Carolyn Y Ho
• 金额: $ 16.09万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-26 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7126356
• 关键词: asymmetric septal hypertrophy; biomarker; blood tests; calcium channel blockers; cardiovascular disorder chemotherapy; cardiovascular disorder diagnosis; cardiovascular disorder prevention; cardiovascular disorder risk; clinical research; clinical trials; diltiazem; drug screening /evaluation; early diagnosis; echocardiography; gadolinium; genetic disorder diagnosis; heart contraction; heart imaging /visualization /scanning; human subject; human therapy evaluation; hypertrophic myocardiopathy; longitudinal human study; magnetic resonance imaging; patient oriented research; sarcomeres

DESCRIPTION (provided by applicant): Hypertrophic cardiomyopathy (HCM), an autosomal dominant disorder characterized by histopathologic findings myocyte disarray and fibrosis, has clinical manifestations of unexplained left ventricular hypertrophy (LVH), diastolic dysfunction, and an increased risk for sudden death. It is a common genetic cardiovascular disorder, affecting approximately 1 in 1000 individuals in the general population. The identification of sarcomere gene mutations as the molecular basis of HCM differentiates this disorder from other types of inherited or secondary causes of LVH. Despite increasingly sophisticated understanding of the causal genetic defects, the precise phenotypic manifestations remain relatively poorly understood. Collaborative basic science and human clinical studies to define the full spectrum of the HCM phenotype are required before molecular discoveries can be effectively translated into the practical management of disease. Genetic-based diagnosis allows for early identification of individuals at risk for developing HCM, prior to the expression of typical clinical manifestations (e.g. LVH). Greater understanding of the preclinical phase of this condition may ultimately inspire rational treatment strategies that will move from contemporary symptom palliation to altering the natural history of disease. Precise identification of early clinical markers of genetic disease will also provide benchmarks for monitoring treatment efficacy. This 2-part longitudinal study proposes to examine and manipulate the early stages of HCM. First, a genotype-positive preclinical population will be examined to detect early alterations in contractile function and myocardial architecture incorporating serial echocardiography with Doppler tissue and strain analysis, gadolinium-enhanced cardiac magnetic resonance imaging, and assessment of serum biomarkers of hemodynamic stress. Second, a pilot interventional trial will be performed to assess the tolerability and efficacy of diltiazem treatment of this preclinical population in improving parameters of diastolic function and to serve as the basis for future larger-scale trials of efficacy.

描述（由申请人提供）： 肥厚性心肌病（HCM）是一种以组织病理学发现为特征的常染色体显性疾病，其肌细胞混乱和纤维化，具有无法解释的左心室肥大（LVH），舒张功能障碍的临床表现，舒张功能障碍和突然死亡的风险增加。它是一种常见的遗传性心血管疾病，在普通人群中影响约1000人。肌膜基因突变为HCM的分子基础的鉴定将这种疾病与其他类型的LVH遗传原因或继发原因区分开。尽管对因果遗传缺陷的理解越来越复杂，但精确的表型表现仍然相对较少了解。在有效地转化为疾病的实际管理之前，需要进行协作基础科学和人类临床研究来定义HCM表型的全部谱。基于遗传的诊断可以在表达典型的临床表现（例如LVH）之前早期鉴定出患有HCM风险的个体。对这种状况的临床前阶段的更多了解最终可能会激发从当代症状抑制转变为改变疾病的自然史的理性治疗策略。对遗传疾病的早期临床标记的精确鉴定还将为监测治疗功效提供基准。这项2部分纵向研究建议检查和操纵HCM的早期阶段。首先，将检查一个基因型阳性临床前种群，以检测收缩功能和心肌结构的早期改变，并结合了具有多普勒组织的连续超声心动图和菌株分析，增强心脏磁共振成像以及血液动力学血清生物标志物的评估。其次，将进行一项试点介入试验，以评估该临床前人群对改善舒张功能参数的diltiazem治疗的耐受性和功效，并作为未来大规模效力试验的基础。