Ho Carolyn Y, Carlsen Christian, Thune Jens Jakob, Havndrup Ole, Bundgaard Henning, Farrohi Faranak, Rivero Jose, Cirino Allison L, Andersen Paal Skytt, Christiansen Michael, Maron Barry J, Orav E John, Køber Lars
Cardiovascular Division, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Circ Cardiovasc Genet. 2009 Aug;2(4):314-21. doi: 10.1161/CIRCGENETICS.109.862128. Epub 2009 Jun 19.
Genetic testing identifies sarcomere mutation carriers (G+) before clinical diagnosis of hypertrophic cardiomyopathy (HCM), allowing characterization of initial disease manifestations. Previous studies demonstrated that impaired relaxation develops before left ventricular hypertrophy (LVH). The precise impact of sarcomere mutations on systolic function in early and late disease is unclear.
Comprehensive echocardiography with strain imaging was performed on 146 genotyped individuals with mutations in 5 sarcomere genes. Contractile parameters were compared in 68 preclinical (G+/LVH-), 40 overt (G+/LVH+) subjects with HCM, and 38 mutation (-) normal control relatives. All subjects had normal left ventricular ejection fraction. In preclinical HCM, global and regional peak systolic strain (epsilon(sys)) and longitudinal systolic strain rate were not significantly different from controls, but early diastolic mitral annular velocity (Ea) was reduced by 13%. In overt HCM, there was a significant 27% and 14% decrease in global longitudinal epsilon(sys) and systolic strain rate, respectively, compared with both preclinical HCM and controls (P<0.013 for all comparisons), and a 33% reduction in Ea.
Sarcomere mutations have disparate initial effects on diastolic and systolic functions. Preclinical HCM is characterized by impaired relaxation but preserved systolic strain. In contrast, both diastolic and longitudinal systolic abnormalities are present in overt disease despite normal ejection fraction. We propose that diastolic dysfunction is an early consequence of sarcomere mutations, whereas systolic dysfunction results from mutations combined with subsequent pathological remodeling. Identifying mechanistic pathways triggered by these mutations may begin to reshape the clinical paradigm for treatment, based on early diagnosis and disease prevention.
基因检测可在肥厚型心肌病（HCM）临床诊断之前识别出肌节突变携带者（G+），从而对疾病的初始表现进行特征描述。既往研究表明，舒张功能受损在左心室肥厚（LVH）之前就已出现。肌节突变对疾病早期和晚期收缩功能的确切影响尚不清楚。
对146名5种肌节基因突变的基因分型个体进行了综合超声心动图及应变成像检查。比较了68名临床前期（G+/LVH-）、40名显性（G+/LVH+）HCM患者以及38名突变（-）正常对照亲属的收缩参数。所有受试者左心室射血分数均正常。在临床前期HCM中，整体和局部收缩期峰值应变（ε(sys)）以及纵向收缩期应变率与对照组无显著差异，但舒张早期二尖瓣环速度（Ea）降低了13%。在显性HCM中，与临床前期HCM和对照组相比，整体纵向ε(sys)和收缩期应变率分别显著降低了27%和14%（所有比较P<0.013），Ea降低了33%。
肌节突变对舒张和收缩功能有不同的初始影响。临床前期HCM的特征是舒张功能受损但收缩期应变保留。相比之下，尽管射血分数正常，但显性疾病中同时存在舒张期和纵向收缩期异常。我们认为，舒张功能障碍是肌节突变的早期后果，而收缩功能障碍是由突变与随后的病理重塑共同导致的。识别由这些突变触发的机制途径可能会基于早期诊断和疾病预防开始重塑临床治疗模式。
