Pathogenesis of Hypertrophic Cardiomyopathy is Mutation Rather Than Disease Specific: A Comparison of the Cardiac Troponin T E163R and R92Q Mouse Models.
Pathogenesis of Hypertrophic Cardiomyopathy is Mutation Rather Than Disease Specific: A Comparison of the Cardiac Troponin T E163R and R92Q Mouse Models.
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DOI：
10.1161/jaha.116.005407
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发表时间：
2017-07-22
影响因子：
5.4
通讯作者：
Poggesi C
中科院分区：
文献类型：
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作者：
Ferrantini C;Coppini R;Pioner JM;Gentile F;Tosi B;Mazzoni L;Scellini B;Piroddi N;Laurino A;Santini L;Spinelli V;Sacconi L;De Tombe P;Moore R;Tardiff J;Mugelli A;Olivotto I;Cerbai E;Tesi C;Poggesi C
在肥厚型心肌病患者的心肌细胞中，机械功能障碍和致炎性是由突变驱动的肌丝功能变化以及与不良重构相关的兴奋-收缩（E-C）偶联异常引起的。肌丝或E-C偶联改变是否在疾病发展中更相关尚不清楚。在这里，我们的目的是调查是否在决定肥厚型心肌病表型的肌丝功能障碍和E-C偶联重构的相对作用是突变特异性的。研究了携带R92 Q和E163 R TNNT 2突变的两种肥厚型心肌病小鼠模型。超声心动图显示两种模型的左心室肥大、收缩力增强和舒张功能障碍;然而，这些表型在R92 Q小鼠中更为明显。E163 R和R92 Q小梁均表现出延长的抽搐松弛和过早搏动的发生率增加。与野生型小鼠相比，E163 R心室肌原纤维或去皮小梁中，Ca 2+去除后的松弛时间延长;静息张力和静息ATP酶较高;最大Ca 2+激活时的等长ATP酶、张力产生的能量消耗和肌丝Ca 2+敏感性增加。与野生型小鼠相比，在R92 Q中未观察到肌节变化，除了肌丝Ca 2+敏感性大幅增加。在R92 Q心肌中，我们发现对变力性干预的反应迟钝，Ca 2+瞬变衰减较慢，SERCA功能降低，Ca 2 +/钙调蛋白激酶II活性增加。相反，E163 R心肌中E-C偶联和信号传导的继发性改变极小。在E163 R模型中，突变驱动的肌丝异常直接导致心肌功能障碍。在R92 Q中，舒张功能障碍和促心律失常性由深刻的心肌细胞信号传导和E-C偶联变化介导。类似的肥厚型心肌病表型可以通过不同的途径产生，这意味着精确医学治疗方法的不同策略。
In cardiomyocytes from patients with hypertrophic cardiomyopathy, mechanical dysfunction and arrhythmogenicity are caused by mutation‐driven changes in myofilament function combined with excitation‐contraction (E‐C) coupling abnormalities related to adverse remodeling. Whether myofilament or E‐C coupling alterations are more relevant in disease development is unknown. Here, we aim to investigate whether the relative roles of myofilament dysfunction and E‐C coupling remodeling in determining the hypertrophic cardiomyopathy phenotype are mutation specific. Two hypertrophic cardiomyopathy mouse models carrying the R92Q and the E163R TNNT2 mutations were investigated. Echocardiography showed left ventricular hypertrophy, enhanced contractility, and diastolic dysfunction in both models; however, these phenotypes were more pronounced in the R92Q mice. Both E163R and R92Q trabeculae showed prolonged twitch relaxation and increased occurrence of premature beats. In E163R ventricular myofibrils or skinned trabeculae, relaxation following Ca2+ removal was prolonged; resting tension and resting ATPase were higher; and isometric ATPase at maximal Ca2+ activation, the energy cost of tension generation, and myofilament Ca2+ sensitivity were increased compared with that in wild‐type mice. No sarcomeric changes were observed in R92Q versus wild‐type mice, except for a large increase in myofilament Ca2+ sensitivity. In R92Q myocardium, we found a blunted response to inotropic interventions, slower decay of Ca2+ transients, reduced SERCA function, and increased Ca2+/calmodulin kinase II activity. Contrarily, secondary alterations of E‐C coupling and signaling were minimal in E163R myocardium. In E163R models, mutation‐driven myofilament abnormalities directly cause myocardial dysfunction. In R92Q, diastolic dysfunction and arrhythmogenicity are mediated by profound cardiomyocyte signaling and E‐C coupling changes. Similar hypertrophic cardiomyopathy phenotypes can be generated through different pathways, implying different strategies for a precision medicine approach to treatment.