亚临床肉节相关肥厚型心肌病的表型谱及向显性疾病的转变

IF 6 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation: Genomic and Precision Medicine Pub Date : 2024-08-01 Epub Date: 2024-06-24 DOI:10.1161/CIRCGEN.124.004580
Constantin-Cristian Topriceanu, James C Moon, Anna Axelsson Raja, Gabriella Captur, Carolyn Y Ho
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引用次数: 0

摘要

遗传性肥厚型心肌病(HCM)通常是由肌纤维基因(G+)中的致病性/可能致病性变异引起的。目前,如果不明原因的左心室(LV)肥厚,且原发性者左心室壁厚度≥15 毫米或高危亲属左心室壁厚度≥13 毫米,则可诊断为遗传性肥厚性心肌病。虽然左心室肥厚是一个关键特征,但这一二元指标并不能涵盖所有的表型特征,尤其是在疾病的亚临床阶段。在确诊为 HCM(G+/左心室肥厚-;亚临床 HCM)之前,可在左心室壁厚度正常的肌节变异携带者中发现微妙的表型表现。我们进行了一项系统性综述,总结了目前有关亚临床 HCM 表型谱以及影响穿透性和表达性因素的知识。虽然驱动左心室肥厚发展的机制尚未阐明,但已确定亚临床 HCM 中存在促组织坏死通路激活、松弛功能受损、Ca2+ 信号传导异常、心肌能量学改变和微血管功能障碍。如果出现早期表型表现,包括心电图异常、二尖瓣瓣叶变长、多普勒超声心动图显示整体 E'速度降低以及血清 B 型钠尿肽 N 端前肽升高,则更有可能从亚临床型发展为临床显性型 HCM。我们亟需对变异型携带者进行纵向研究,以提高我们对渗透性的认识,描述疾病转变的特征,确定表型演变的风险预测因素,并指导开发旨在影响疾病轨迹的新型治疗策略。
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Phenotypic Spectrum of Subclinical Sarcomere-Related Hypertrophic Cardiomyopathy and Transition to Overt Disease.

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 ECG abnormalities, 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.

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来源期刊
Circulation: Genomic and Precision Medicine
Circulation: Genomic and Precision Medicine Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
9.20
自引率
5.40%
发文量
144
期刊介绍: Circulation: Genomic and Precision Medicine is a distinguished journal dedicated to advancing the frontiers of cardiovascular genomics and precision medicine. It publishes a diverse array of original research articles that delve into the genetic and molecular underpinnings of cardiovascular diseases. The journal's scope is broad, encompassing studies from human subjects to laboratory models, and from in vitro experiments to computational simulations. Circulation: Genomic and Precision Medicine is committed to publishing studies that have direct relevance to human cardiovascular biology and disease, with the ultimate goal of improving patient care and outcomes. The journal serves as a platform for researchers to share their groundbreaking work, fostering collaboration and innovation in the field of cardiovascular genomics and precision medicine.
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