Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology
Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology
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DOI：
10.1073/pnas.1600311113
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发表时间：
2016-08-30
影响因子：
11.1
通讯作者：
Malik, Punam
中科院分区：
文献类型：
--
作者：
Bakeer, Nihal;James, Jeanne;Malik, Punam
心脏病并发症是镰状细胞性贫血（SCA）死亡的主要原因。三尖瓣反流速度升高、肺动脉高压、舒张期和自主神经功能障碍均已被描述，但解释预后不良和猝死倾向的统一病理生理学和机制尚不明确。在此，SCA小鼠进行了纵向综合心脏分析，结合最先进的心脏成像与心电图，组织病理学和分子分析，以确定心脏功能障碍的基础。我们发现，在SCA小鼠中，贫血诱导的高动力生理学逐渐叠加限制性生理学，其特征是进行性左心房扩大和舒张功能障碍，保留收缩功能。这种现象在具有相似程度和持续时间的实验诱导慢性贫血的WT小鼠中不存在。限制性生理学与显微镜下心肌细胞丢失和继发性纤维化相关，可通过心脏MRI检测到细胞外体积增加。线粒体超微结构的变化与严重的慢性缺氧/缺血和肌节的线粒体长度缩短一致。转录组分析显示上调的基因涉及血管生成，细胞外基质，昼夜节律，氧化应激和缺氧，而离子通道转运和心脏传导下调。事实上，在猝死前，SCA小鼠中观察到进行性校正QT间期延长、心律失常和缺血性变化。心脏性猝死在限制性心肌病和长QT综合征患者中很常见。因此，我们的研究结果可能提供一个统一的心脏病理生理学，解释报告的心脏异常和猝死的人与SCA。
Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA.