Diagnostic and Treatment Strategies for Preclinical HCM

描述（由申请人提供）： 肥厚型心肌病（HCM）是一种常染色体显性遗传疾病，其特征是组织病理学发现肌细胞紊乱和纤维化，临床表现为不明原因的左心室肥大（LVH）、舒张功能障碍和猝死风险增加。它是一种常见的遗传性心血管疾病，在一般人群中影响约1/1000的个体。肌节基因突变作为HCM的分子基础的鉴定将这种疾病与其他类型的LVH的遗传或继发性原因区分开来。尽管越来越复杂的理解因果遗传缺陷，精确的表型表现仍然相对知之甚少。在分子发现可以有效地转化为疾病的实际管理之前，需要基础科学和人类临床合作研究来确定HCM表型的全谱。基于遗传学的诊断允许在典型临床表现（例如LVH）表达之前早期识别处于发展HCM风险的个体。对这种情况的临床前阶段的更深入了解可能最终会激发合理的治疗策略，这些策略将从当代症状缓解转向改变疾病的自然史。精确鉴定遗传病的早期临床标志物也将为监测治疗效果提供基准。这2部分纵向研究提出检查和操纵HCM的早期阶段。首先，将对基因型阳性的临床前人群进行检查，以检测收缩功能和心肌结构的早期改变，包括连续超声心动图与多普勒组织和应变分析、钆增强心脏磁共振成像以及血液动力学应激的血清生物标志物评估。其次，将进行一项初步干预性试验，以评估地尔硫卓治疗该临床前人群在改善舒张功能参数方面的耐受性和疗效，并作为未来更大规模疗效试验的基础。

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.