Department of Biochemistry, Stanford University School of Medicine, Stanford, California, USA.
Biophys J. 2012 Jun 20;102(12):2782-90. doi: 10.1016/j.bpj.2012.04.049. Epub 2012 Jun 19.
Human familial hypertrophic cardiomyopathy is the most common Mendelian cardiovascular disease worldwide. Among the most severe presentations of the disease are those in families heterozygous for the mutation R403Q in β-cardiac myosin. Mice heterozygous for this mutation in the α-cardiac myosin isoform display typical familial hypertrophic cardiomyopathy pathology. Here, we study cardiomyocytes from heterozygous 403/+ mice. The effects of the R403Q mutation on force-generating capabilities and dynamics of cardiomyocytes were investigated using a dual carbon nanofiber technique to measure single-cell parameters. We demonstrate the Frank-Starling effect at the single cardiomyocyte level by showing that cell stretch causes an increase in amplitude of contraction. Mutant 403/+ cardiomyocytes exhibit higher end-diastolic and end-systolic stiffness than +/+ cardiomyocytes, whereas active force generation capabilities remain unchanged. Additionally, 403/+ cardiomyocytes show slowed relaxation dynamics. These phenotypes are consistent with increased end-diastolic and end-systolic chamber elastance, as well as diastolic dysfunction seen at the level of the whole heart. Our results show that these functional effects of the R403Q mutation are cell-intrinsic, a property that may be a general phenomenon in familial hypertrophic cardiomyopathy.
人类家族性肥厚型心肌病是全球最常见的孟德尔心血管疾病。在该病最严重的表现中，有一种是β-心肌球蛋白突变 R403Q 的杂合子家族。在α-心肌球蛋白同工型中携带这种突变的杂合子小鼠表现出典型的家族性肥厚型心肌病病理。在这里，我们研究了杂合子 403/+ 小鼠的心肌细胞。使用双碳纤维技术测量单细胞参数，研究了 R403Q 突变对心肌细胞产生力的能力和动力学的影响。我们通过证明细胞拉伸会导致收缩幅度增加，在单个心肌细胞水平上展示了 Frank-Starling 效应。与 +/+ 心肌细胞相比，突变型 403/+ 心肌细胞的舒张末期和收缩末期硬度更高，而主动力生成能力保持不变。此外，403/+ 心肌细胞表现出松弛动力学减慢。这些表型与整个心脏水平上观察到的舒张末期和收缩末期腔室弹性增加以及舒张功能障碍一致。我们的结果表明，这种 R403Q 突变的这些功能效应是细胞内在的，这一特性可能是家族性肥厚型心肌病的普遍现象。
