A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy.
A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy.
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DOI：
10.1016/j.cell.2016.04.002
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发表时间：
2016-05-19
期刊：
影响因子：
64.5
通讯作者：
Molkentin JD
中科院分区：
文献类型：
--
作者：
Davis J;Davis LC;Correll RN;Makarewich CA;Schwanekamp JA;Moussavi-Harami F;Wang D;York AJ;Wu H;Houser SR;Seidman CE;Seidman JG;Regnier M;Metzger JM;Wu JC;Molkentin JD
负责收缩和泵送的肌合成蛋白编码基因的家族突变导致心脏肥大或扩张。这些突变通常会改变肌节内钙依赖性张力的产生，但这如何转化为肥厚型与扩张型心肌病的谱尚不清楚。通过建立一系列心脏特异性小鼠模型，允许系统调节肌肉张力产生和钙通量，我们确定了随时间发展的张力大小与心脏生长之间的显著关系。当形成计算模型时，肌丝张力发育的积分可以预测与任何肉瘤基因突变相关的小鼠肥厚性和扩张性心肌病，但也可以从家族性心肌病患者诱导多能干细胞衍生的肌细胞中准确预测人类心脏表型。这种基于张力的模型也有可能为心肌病患者的药物治疗选择提供信息。
The heart either hypertrophies or dilates in response to familial mutations in genes encoding sarcomeric proteins, which are responsible for contraction and pumping. These mutations typically alter calcium-dependent tension generation within the sarcomeres, but how this translates into the spectrum of hypertrophic versus dilated cardiomyopathy is unknown. By generating a series of cardiac-specific mouse models that permit the systematic tuning of sarcomeric tension generation and calcium fluxing, we identify a significant relationship between the magnitude of tension developed over time and heart growth. When formulated into a computational model the integral of myofilament tension development predicts hypertrophic and dilated cardiomyopathies in mice associated with essentially any sarcomeric gene mutations, but also accurately predicts human cardiac phenotypes from data generated in induced-pluripotent stem cell-derived myocytes from familial cardiomyopathy patients. This tension-based model also has the potential to inform pharmacologic treatment options in cardiomyopathy patients.