The pathogenesis of familial hypertrophic cardiomyopathy:: Early and evolving effects from an α-cardiac myosin heavy chain missense mutation
The pathogenesis of familial hypertrophic cardiomyopathy:: Early and evolving effects from an α-cardiac myosin heavy chain missense mutation
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DOI：
10.1038/6549
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发表时间：
1999-03-01
期刊：
影响因子：
82.9
通讯作者：
Kass, DA
中科院分区：
文献类型：
--
作者：
Georgakopoulos, D;Christe, ME;Kass, DA
家族性肥厚性心肌病(FHC)是一种由编码肌节蛋白(1，2)基因突变引起的遗传性疾病。这通常会导致高动力射血(3)，松弛功能受损，早期充盈延迟(4)，心肌细胞紊乱和纤维化，以及心腔收缩末期僵硬增加(5，6)。为了更好地了解疾病的发病机制，必须将早期(原发)异常与对遗传缺陷的进化反应区分开来。我们使用带有Arg403Glnα-心肌肌球蛋白重链错义突变的FHC小鼠模型进行体内分析(7)，并使用新开发的方法评估原位压力-体积关系(8)。幼龄突变小鼠(6周龄)的心脏收缩动力学发生改变，压力松弛和腔充盈明显延迟，但收缩压加速上升。年龄较大的突变小鼠(20周大)出现纤维紊乱和纤维化，其舒张期和收缩期动力学变化类似于年轻小鼠，如果不是略低于年轻小鼠的话。然而，老年突变小鼠的心脏也表现出高度动力收缩，收缩末期心腔僵硬增加，流出道压差增加，心脏指数降低，因为心腔充盈减少；这些都是人类疾病的特征。这些数据为FHC的时间演变提供了新的见解。这些数据可能有助于指导新的治疗策略，以减缓疾病的进展。
Familial hypertrophic cardiomyopathy (FHC) is a genetic disorder resulting from mutations in genes encoding sarcomeric proteins(1,2). This typically induces hyperdynamic ejection(3), impaired relaxation, delayed early filling(4), myocyte disarray and fibrosis, and increased chamber end-systolic stiffness(5,6). To better understand the disease pathogenesis, early (primary) abnormalities must be distinguished from evolving responses to the genetic defect. We did in vivo analysis using a mouse model of FHC with an Arg403Gln alpha-cardiac myosin heavy chain missense mutation(7) and used newly developed methods for assessing in situ pressure-volume relations(8). Hearts of young mutant mice (6 weeks old), which show no chamber morphologic or gross histologic abnormalities, had altered contraction kinetics, with considerably delayed pressure relaxation and chamber filling, yet accelerated systolic pressure rise. Older mutant mice (20 weeks old), which develop fiber disarray and fibrosis, had diastolic and systolic kinetic changes similar to if not slightly less than those of younger mice. However, the hearts of older mutant mice also showed hyperdynamic contraction, with increased end-systolic chamber stiffness, outflow tract pressure gradients and a lower cardiac index due to reduced chamber filling; all 'hallmarks' of human disease. These data provide new insights into the temporal evolution of FHC. Such data may help direct new therapeutic strategies to diminish disease progression.