Hypertrophic Cardiomyopathy: Understanding the Heterogeneity of Disease Expression and Outcomes

项目总结 肥厚性心肌病(HCM)是一种主要的心肌疾病，其特征是 不明原因的左心室肥厚(LVH)、心肌细胞紊乱和纤维化。它是最普遍的遗传基因 心脏病，每500人中就有1人受到影响。肥厚型心肌病一直是临床和基础科学研究的焦点。 几十年来。这些工作提供了对霍奇金淋巴瘤的分子基础和临床过程的非凡洞察力。 疾病-将肌节突变定义为最常见的遗传病因，并表征了 表型谱。此外，先前的研究已经强调了HCM的巨大异质性。虽然 许多患者有严重的后果，包括心律失常、晚期心力衰竭和心脏骤停。 除了死亡，许多其他人经历了轻微的疾病，症状负担较低，正常寿命。此外，还有 心脏形态和功能有惊人的多样性，即使在基础相同的患者中也是如此 肌节突变。导致这种显著异质性的因素人们知之甚少，这突显了 迫切需要更好地描述疾病表现和临床结果的决定因素。 这项建议旨在确定导致高度多样性的基因和表型特征 肥厚型心肌病的临床表现。这些目标将通过利用最近成立的萨科姆来实现 人类心肌病登记表(SHARE)，包含9000多名肥厚型心肌病患者的数据，并应用 最先进的遗传、成像和统计分析。我们的目标是：(1)识别常见的遗传变异 肌节突变对肥厚型心肌梗死患者疾病表达的影响 和非肉瘤性HCM)。这些分析将询问背景遗传变异，以检查 个体的基因构成影响他们对疾病的易感性或抵抗力。我们还将发展 评估常见基因变异对疾病表达的累积影响的多基因风险评分。(2) 利用机器学习技术来表征影响疾病表现的表型因素 从常规的心脏磁学检查中识别新的、定量的高维成像特征 共振(CMR)研究。然后，我们将把这些功能整合到严格的预测模型中，以改进 临床风险分层。这种方法将使我们能够更深入地研究 通过使用从CMR成像获得的数字数据的全阵列，从而得出新的相关性 表型、疾病表现和临床结果之间的关系。这些目标的成功实现将 加深我们对为什么不同患者的疾病体验会如此不同的理解，提供新的 深入了解机制和治疗目标，并确定疾病严重程度的新生物标记物。这些 结果将通过提高精密度和准确性来影响肥厚性心肌病患者的临床管理 诊断和风险分层。最后，所获得的洞察力可能会为更常见的心脏病形式提供信息， 例如射血分数保留的心力衰竭，具有类似的高度不均匀的表现。

PROJECT SUMMARY Hypertrophic cardiomyopathy (HCM) is a primary disorder of the myocardium that is characterized by unexplained left ventricular hypertrophy (LVH), myocyte disarray, and fibrosis. It is the most prevalent genetic heart disorder, affecting ~1 in 500 people. HCM has been the focus of intense clinical and basic science study for decades. These efforts have provided remarkable insights into the molecular basis and clinical course of disease-- defining sarcomere mutations as the most common genetic etiology and characterizing the phenotypic spectrum. Additionally, prior studies have underscored the great heterogeneity of HCM. Although many patients have serious outcomes, including arrhythmias, advanced heart failure, and sudden cardiac death, many others experience mild disease with low symptom burden and normal longevity. Moreover, there is striking diversity in cardiac morphology and function, even amongst patients with identical underlying sarcomere mutations. The factors that drive such marked heterogeneity are poorly understood, highlighting the critical need to better characterize determinants of disease expression and clinical outcomes. This proposal seeks to identify genotypic and phenotypic features that account for the highly diverse manifestations of HCM. These goals will be addressed by leveraging the recently established Sarcomeric Human Cardiomyopathy Registry (SHaRe), containing data on over 9000 HCM patients, and applying state-of- the-art genetic, imaging, and statistical analyses. Our aims are: (1) To identify common genetic variation that impacts disease expression in HCM patients both with and without a driving sarcomere mutation (sarcomeric and non-sarcomeric HCM). These analyses will interrogate background genetic variation to examine how an individual’s genetic make-up influences their susceptibility or resistance to disease. We will also develop polygenic risk scores to assess the cumulative effect of common genetic variants on disease expression. (2) To characterize phenotypic factors that influence disease expression by utilizing machine-learning techniques to identify novel, quantitative high-dimensional imaging features from routinely-performed cardiac magnetic resonance (CMR) studies. We will then incorporate these features into rigorous prediction models to improve clinical risk stratification. This approach will allow us to look more deeply into the structure and function of the heart by using the full array of digital data available from CMR imaging, thereby drawing new correlations between phenotype, disease manifestations, and clinical outcomes. Successful completion of these aims will advance our understanding of why disease experience can be so different from patient to patient, provide new insights into mechanism and therapeutic targets, and identify novel biomarkers of disease severity. These results will impact clinical management of patients with HCM by improving the precision and accuracy of diagnosis and risk stratification. Finally, insights gained will likely inform more common forms of heart disease, such as heart failure with preserved ejection fraction, with similarly highly heterogeneous manifestations.