Evidence for a novel mechanism independent of myocardial iron in β-thalassemia cardiac pathogenesis.
Evidence for a novel mechanism independent of myocardial iron in β-thalassemia cardiac pathogenesis.
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DOI：
10.1371/journal.pone.0052128
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Trudel M
中科院分区：
文献类型：
--
作者：
Stoyanova E;Cloutier G;Felfly H;Lemsaddek W;Ah-Son N;Trudel M
人重型β-地中海贫血是最常见的遗传性疾病之一，其特征是β-珠蛋白链产生减少/缺失，红细胞数量减少。接受长期输血治疗的重型β地中海贫血患者的主要死亡原因是早期心脏并发症，尽管进行了最佳螯合治疗，但这些并发症仍归因于继发性铁过载。在此，我们研究了在不存在与输血相关的混杂效应的情况下，6至15个月龄的严重β-地中海贫血小鼠模型中心血管功能障碍的病理生理学机制。我们的纵向超声心动图分析显示，β-地中海贫血小鼠首先表现出心输出量显著增加，以响应有限的携氧红细胞，其迅速进展为左心室肥大和结构重塑。在这种代偿性肥大之后，β-地中海贫血小鼠发生了左心室收缩力和功能障碍的年龄依赖性恶化，导致失代偿性心力衰竭。一致地，小鼠β-地中海贫血心脏组织病理学显示心脏重塑，间质纤维化增加，但实际上没有心肌铁沉积。重要的是，地中海贫血性心脏肥大和功能障碍的发展独立于铁超载已经解除了这些心脏病理过程。总之，我们对β-地中海贫血主要血红蛋白病的研究指出了两个连续的阶段，这两个阶段是由严重的慢性贫血和作为地中海贫血心脏病病理生理贡献者的继发性诱导机制引起的。
Human β-thalassemia major is one of the most prevalent genetic diseases characterized by decrease/absence of β-globin chain production with reduction of erythrocyte number. The main cause of death of treated β-thalassemia major patients with chronic blood transfusion is early cardiac complications that have been attributed to secondary iron overload despite optimal chelation. Herein, we investigated pathophysiological mechanisms of cardiovascular dysfunction in a severe murine model of β-thalassemia from 6 to 15-months of age in the absence of confounding effects related to transfusion. Our longitudinal echocardiography analysis showed that β-thalassemic mice first display a significant increase of cardiac output in response to limited oxygen-carrying erythrocytes that progressed rapidly to left ventricular hypertrophy and structural remodeling. Following this compensated hypertrophy, β-thalassemic mice developed age-dependent deterioration of left ventricular contractility and dysfunction that led toward decompensated heart failure. Consistently, murine β-thalassemic hearts histopathology revealed cardiac remodeling with increased interstitial fibrosis but virtual absence of myocardial iron deposits. Importantly, development of thalassemic cardiac hypertrophy and dysfunction independently of iron overload has uncoupled these cardiopathogenic processes. Altogether our study on β-thalassemia major hemoglobinopathy points to two successive phases resulting from severe chronic anemia and from secondarily induced mechanisms as pathophysiologic contributors to thalassemic cardiopathy.
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影响因子：
20.1
作者：
IIMOTO, DS;COVELL, JW;HARPER, E
通讯作者：
HARPER, E
DOI：
10.1152/ajpheart.00463.2008
发表时间：
2009-03-01
影响因子：
4.8
作者：
Naito, Yoshiro;Tsujino, Takeshi;Masuyama, Tohru
通讯作者：
Masuyama, Tohru
影响因子：
4.8
作者：
BAHL, VK;MALHOTRA, OP;SHRIVASTAVA, S
通讯作者：
SHRIVASTAVA, S
影响因子：
3.5
作者：
LOMBARDO, T;MORRONE, ML;CALVI, V
通讯作者：
CALVI, V
影响因子：
4.6
作者：
Anand, Inder S.
通讯作者：
Anand, Inder S.