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性疾病，以组织病理改变、心肌细胞紊乱和纤维化为特征，临床表现为原因不明的左心室肥厚(LVH)、舒张期功能障碍和猝死风险增加。这是一种常见的遗传性心血管疾病，在普通人群中大约每1000人中就有1人受到影响。肌节基因突变是肥厚性心肌病的分子基础，这种疾病与其他类型的遗传性或继发性左心室肥厚的病因不同。尽管对致因遗传缺陷的了解日益复杂，但确切的表型表现仍然相对较少。在分子发现能够有效地转化为疾病的实际治疗之前，需要合作的基础科学和人类临床研究来确定HCM表型的全谱。基于基因的诊断可以在典型的临床表现(如左心室肥厚)表现之前，及早识别出患有肥厚性心肌病的风险个体。对这种疾病的临床前阶段的更多了解可能最终会启发理性的治疗策略，这些治疗策略将从当代症状缓解转向改变疾病的自然历史。准确识别遗传病的早期临床标记也将为监测治疗效果提供基准。这项由两部分组成的纵向研究建议对肥厚型心肌病的早期阶段进行检查和操作。首先，将对基因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变化，结合系列超声心动图与多普勒组织和应变分析，增强的心脏磁共振成像，以及血液动力学应激的血清生物标记物的评估。其次，将进行一项先导性干预试验，以评估地尔硫卓治疗在改善舒张期功能参数方面对这一临床前人群的耐受性和有效性，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.