Diastolic dysfunction and altered energetics in the αMHC403/+ mouse model of familial hypertrophic cardiomyopathy
Diastolic dysfunction and altered energetics in the αMHC403/+ mouse model of familial hypertrophic cardiomyopathy
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DOI：
10.1172/jci1940
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发表时间：
1998-04-15
影响因子：
15.9
通讯作者：
Ingwall, JS
中科院分区：
文献类型：
--
作者：
Spindler, M;Saupe, KW;Ingwall, JS
β-心肌肌球蛋白重链403位精氨酸-谷氨酰胺错义突变引起家族性肥厚型心肌病在这里，我们研究了小鼠有这种相同的错义突变（α MHC 403/+）使用一个孤立的，等容心脏准备，心脏性能与心脏能量使用P-31核磁共振光谱同时测量。我们观察到α MHC 403/+小鼠心脏的生理学和生物能量学的三个主要改变。首先，虽然没有收缩功能障碍的证据，但在变力性刺激期间舒张功能受损。舒张功能障碍表现为左心室舒张速率降低和舒张末期压升高。其次，在基线条件下，α MHC 403/+心脏具有较低的磷酸肌酸和增加的无机磷酸盐含量，导致ATP水解释放的自由能的计算值降低。第三，来自非起搏研究的α MHC 403/+心脏的心脏通过降低心率约为野生型的两倍来响应增加的灌注液钙。我们的结论是，从α MHC 403/+小鼠心脏表现出类似于人类形式的家族性肥厚型心肌病的工作负荷依赖性舒张功能障碍，高能磷酸盐含量的变化表明，一个能量需求的过程可能有助于观察到的舒张功能障碍。
An arginine to glutamine missense mutation at position 403 of the beta-cardiac myosin heavy chain causes familial hypertrophic cardiomyopathy. Here we study mice which have this same missense mutation (alpha MHC403/+) using an isolated, isovolumic heart preparation where cardiac performance is measured simultaneously with cardiac energetics using P-31 nuclear magnetic resonance spectroscopy. We observed three major alterations in the physiology and bioenergetics of the alpha MHC403/+ mouse hearts, First, while there was no evidence of systolic dysfunction, diastolic function was impaired during inotropic stimulation. Diastolic dysfunction was manifest as both a decreased rate of left ventricular relaxation and an increase in end-diastolic pressure. Second, under baseline conditions alpha MHC403/+ hearts had lower phosphocreatine and increased inorganic phosphate contents resulting in a decrease in the calculated value for the free energy released from ATP hydrolysis. Third, hearts from alpha MHC403/+ hearts that were studied unpaced responded to increased perfusate calcium by decreasing heart rate approximately twice as much as wild types. We conclude that hearts from alpha MHC403/+ mice demonstrate work load-dependent diastolic dysfunction resembling the human form of familial hypertrophic cardiomyopathy, Changes in high-energy phosphate content suggest that an energy-requiring process may contribute to the observed diastolic dysfunction.