Iron overload decreases CaV1.3-dependent L-type Ca2+ currents leading to bradycardia, altered electrical conduction, and atrial fibrillation.
Iron overload decreases CaV1.3-dependent L-type Ca2+ currents leading to bradycardia, altered electrical conduction, and atrial fibrillation.
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DOI：
10.1161/circep.110.960401
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发表时间：
2011-10
期刊：
影响因子：
--
通讯作者：
Backx PH
中科院分区：
文献类型：
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作者：
Rose RA;Sellan M;Simpson JA;Izaddoustdar F;Cifelli C;Panama BK;Davis M;Zhao D;Markhani M;Murphy GG;Striessnig J;Liu PP;Heximer SP;Backx PH
慢性铁超负荷（CIO）与血液疾病如地中海贫血和血色病有关。CIO患者生存的主要预后指标是铁介导的心肌病，其特征在于收缩功能障碍和电干扰，包括心率减慢（HR;心动过缓）和心脏传导阻滞。我们使用CIO小鼠模型来研究铁对窦房结（SAN）功能的影响。与人类一样，CIO降低了清醒小鼠以及自主神经系统阻滞麻醉小鼠和离体Langendorff灌注小鼠心脏的HR（~20%），表明心动过缓源于固有SAN起搏器功能的改变。事实上，CIO患者SAN肌细胞的自发动作电位频率降低，与L型钙电流（伊卡，L）密度降低和伊卡，L激活中的正电压偏移相关。起搏器电流（If）不受CIO的影响。由于SAN肌细胞（以及心房和传导系统肌细胞）中的伊卡，L由于CaV1.3通道（除了CaV1.2通道）的存在而在相对负的电位下激活，我们的数据表明，铁的升高优先抑制CaV1.3通道功能。与这一建议一致，CIO使心房组织（含有SAN）中CaV1.3 mRNA水平降低约40%，并且不会降低CaV1.3敲除小鼠的HR。CIO还诱导PR间期延长、心脏传导阻滞和心房纤颤，这些病症也见于CaV1.3敲除小鼠。我们的研究结果表明，CIO选择性地降低CaV1.3介导的伊卡，L，导致心动过缓，电传导减慢和心房颤动，如在铁超负荷患者中所见。
Chronic iron-overload (CIO) is associated with blood disorders such as thalassemias and hemochromatosis. A major prognostic indicator of survival in patients with CIO is iron-mediated cardiomyopathy, characterized by contractile dysfunction and electrical disturbances including slow heart rate (HR; bradycardia) and heart block. We have used a mouse model of CIO to investigate the effects of iron on sinoatrial node (SAN) function. As in humans, CIO reduced HR (~20%) in conscious mice as well as in anesthetized mice with autonomic nervous system blockade and in isolated Langendorff-perfused mouse hearts, suggesting bradycardia originates from altered intrinsic SAN pacemaker function. Indeed, spontaneous action potential frequencies in SAN myocytes with CIO were reduced in association with decreased L-type Ca2+ current (ICa,L) densities and positive (rightward) voltage shifts in ICa,L activation. Pacemaker current (If) current was not affected by CIO. Since ICa,L in SAN myocytes (as well as in atrial and conducting system myocytes) activates at relatively negative potentials due to the presence of CaV1.3 channels (in addition to CaV1.2 channels), our data suggest that elevated iron preferentially suppresses CaV1.3 channel function. Consistent with this suggestion, CIO reduced CaV1.3 mRNA levels by ~40% in atrial tissue (containing SAN) and did not lower HR in CaV1.3 knockout mice. CIO also induced PR interval prolongation, heart block, and atrial fibrillation, conditions also seen in CaV1.3 knockout mice. Our results demonstrate that CIO selectively reduces CaV1.3-mediated ICa,L leading to bradycardia, slowing of electrical conduction and atrial fibrillation as seen in iron-overload patients.