New paradigms in hypertrophic cardiomyopathy: Insights from genetics
New paradigms in hypertrophic cardiomyopathy: Insights from genetics
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DOI：
10.1016/j.ppedcard.2011.02.005
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发表时间：
2011-05-01
影响因子：
0.9
通讯作者：
Ho, Carolyn Y.
中科院分区：
文献类型：
--
作者：
Ho, Carolyn Y.
了解肥厚型心肌病（HCM）的遗传基础为预测和预防疾病提供了极好的机会。HCM是由肌节基因突变引起的，是最常见的单基因心血管疾病。虽然不明原因的左心室肥大（LVH）被认为是诊断，LVH并不总是存在。左室壁厚度通常正常，直到青春期或更晚，即使在已知携带致病性肌节突变的个体中。相比之下，基因检测可以识别携带致病性肌节突变并具有HCM临床诊断的个体，以及尚未表现出LVH但很可能发生疾病的突变携带者。研究这一重要的新患者亚群，指定为早期或临床前HCM，允许在明显的肥大性重塑发生之前表征肌节突变的初始后果。这种研究已经确定了新的早期表型，包括左心室舒张功能受损，心肌能量不足，改变胶原代谢，在突变携带者与明显正常的心脏形态。这些结果表明，肌节突变对心肌功能和生物化学发生之前，坦率的肥大有实质性的影响。此外，临床前HCM的动物模型已经确定了有希望的新治疗策略，可能会减少显性疾病的出现。我们现在可以开始重塑治疗遗传疾病的范例。随着对机制的深入了解和早期诊断能力的提高，遗传学的进步可以为疾病的改良和预防带来新的方法。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
Understanding the genetic basis of hypertrophic cardiomyopathy (HCM) provides a remarkable opportunity to predict and prevent disease. HCM is caused by mutations in sarcomere genes and is the most common monogenic cardiovascular disorder. Although unexplained left ventricular hypertrophy (LVH) is considered diagnostic, LVH is not always present. LV wall thickness is often normal until adolescence or later, even in individuals known to carry pathogenic sarcomere mutations. In contrast, genetic testing can identify both individuals who carry pathogenic sarcomere mutations and have a clinical diagnosis of HCM, as well as mutation carriers who have not yet manifested LVH but are very likely to develop disease. Studying this important new patient subset, designated early or preclinical HCM, allows characterization of the initial consequences of sarcomere mutations, prior to the onset of overt hypertrophic remodeling. Such study has defined novel early phenotypes, including impaired left ventricular relaxation, myocardial energetic deficiencies, and altered collagen metabolism, in mutation carriers with apparently normal cardiac morphology. These results indicate that sarcomere mutations have substantial impact on myocardial function and biochemistry before the onset of frank hypertrophy. Furthermore, animal models of preclinical HCM have identified promising new treatment strategies that may diminish the emergence of overt disease. We can now begin to reshape the paradigm for treating genetic disorders. With improved mechanistic insight and the capability for early diagnosis, genetic advances can lead to new approaches for disease modification and prevention. (C) 2011 Elsevier Ireland Ltd. All rights reserved.