Abstract：
Genetic hypertrophic cardiomyopathy (HCM) is classically caused by pathogenic/likely pathogenic variants in sarcomere genes (G+). Currently, HCM is diagnosed if there is unexplained left ventricular (LV) hypertrophy with LV wall thickness ≥15 mm in probands or ≥13 mm in at-risk relatives. Although LV hypertrophy is a key feature, this binary metric does not encompass the full constellation of phenotypic features, particularly in the subclinical stage of the disease. Subtle phenotypic manifestations can be identified in sarcomere variant carriers with normal LV wall thickness, before diagnosis with HCM (G+/LV hypertrophy-; subclinical HCM). We conducted a systematic review to summarize current knowledge about the phenotypic spectrum of subclinical HCM and factors influencing penetrance and expressivity. Although the mechanisms driving the development of LV hypertrophy are yet to be elucidated, activation of profibrotic pathways, impaired relaxation, abnormal Ca2+ signaling, altered myocardial energetics, and microvascular dysfunction have all been identified in subclinical HCM. Progression from subclinical to clinically overt HCM may be more likely if early phenotypic manifestations are present, including abnormal ECG, longer mitral valve leaflets, lower global E\' velocities on Doppler echocardiography, and higher serum N-terminal propeptide of B-type natriuretic peptide. Longitudinal studies of variant carriers are critically needed to improve our understanding of penetrance, characterize the transition to disease, identify risk predictors of phenotypic evolution, and guide the development of novel treatment strategies aimed at influencing disease trajectory.
摘要：
遗传性肥厚型心肌病（HCM）是由肌节基因（G）中的致病性/可能的致病性变异引起的。目前,如果存在无法解释的左心室（LV）肥大，先证者的LV壁厚≥15mm或高危亲属的LV壁厚≥13mm，则诊断为HCM。尽管左心室肥大是一个关键特征，这个二元度量不包括表型特征的完整星座，特别是在疾病的亚临床阶段。在左心室壁厚正常的肌节变异携带者中可以识别出细微的表型表现，在诊断前使用HCM（G+/LV增生；亚临床HCM）。我们进行了系统综述，以总结有关亚临床HCM的表型谱以及影响外显率和表达率的因素的最新知识。尽管驱动LV肥大发展的机制尚未阐明，促纤维化通路的激活，放松受损，异常的Ca2+信号，改变心肌能量学，和微血管功能障碍均已在亚临床型HCM中发现。如果存在早期表型表现，从亚临床进展到临床上明显的HCM可能更有可能，包括异常的心电图,较长的二尖瓣小叶，在多普勒超声心动图上降低全球E'速度，和较高的血清N端前肽B型利钠肽。变异携带者的纵向研究对于提高我们对外显率的理解是至关重要的，表征向疾病的过渡，确定表型进化的风险预测因子，并指导旨在影响疾病轨迹的新型治疗策略的开发。
