Arrhythmogenesis and contractile dysfunction in heart failure -: Roles of sodium-calcium exchange, inward rectifier potassium current, and residual β-adrenergic responsiveness
Arrhythmogenesis and contractile dysfunction in heart failure -: Roles of sodium-calcium exchange, inward rectifier potassium current, and residual β-adrenergic responsiveness
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DOI：
10.1161/hh1101.091193
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发表时间：
2001-06-08
影响因子：
20.1
通讯作者：
Bers, DM
中科院分区：
文献类型：
--
作者：
Pogwizd, SM;Schlotthauer, K;Bers, DM
室性心律失常和心肌收缩功能障碍是导致心力衰竭（HF）患者死亡的主要原因。在复制人HF的这些相同方面的兔HF模型中，我们证明了Na+-Ca 2+交换（NaCaX）的2倍功能上调卸载肌浆网（SR）Ca 2+储存，减少Ca 2+瞬变和收缩功能，而β-肾上腺素能受体（β-AR）在I-IF中逐渐下调，在这个关键的HF阶段残留的β-AR反应性允许SR Ca 2+负荷增加，引起自发SR Ca 2+释放和由NaCaX携带的瞬时内向电流。给定的Ca 2+释放在HF中产生更大的促心律失常向内电流（由于NaCaX上调），并且在HF中触发动作电位所需的Ca 2+释放减少约50%。内向整流钾电流（I-K1）在HF中减少了49%，这使得给定的NaCaX电流具有更大的去极化。用钡部分阻断对照细胞中的I-K1模拟HF中所见的给定电流注入的更大去极化。因此，我们提出的数据来支持一个新的。在一个范例中，NaCaX和I-K1以及残余β-AR反应性的变化共同大大增加了HF中触发心律失常的倾向。此外，NaCaX上调似乎是收缩功能障碍和血管生成之间的关键联系。
Ventricular arrhythmias and contractile dysfunction are the main causes of death in human heart failure (HF). In a rabbit HF model reproducing these same aspects of human HF, we demonstrate that a 2-fold functional upregulation of Na+-Ca2+ exchange (NaCaX) unloads sarcoplasmic reticulum (SR) Ca2+ stores, reducing Ca2+ transients and contractile function, Whereas beta -adrenergic receptors (beta -ARs) are progressively downregulated in I-IF, residual beta -AR responsiveness at this critical HF stage allows SR Ca2+ load to increase, causing spontaneous SR Ca2+ release and transient inward current carried by NaCaX. A given Ca2+ release produces greater arrhythmogenic inward current in HF las a result of NaCaX upregulation), and approximate to 50% less Ca2+ release is required to trigger an action potential in HF. The inward rectifier potassium current (I-K1) is reduced by 49% in HF, and this allows greater depolarization for a given NaCaX current. partially blocking I-K1 in control cells with barium mimics the greater depolarization for a given current injection seen in HF. Thus, we present data to support a novel. paradigm in which changes in NaCaX and I-K1 and residual beta -AR responsiveness, conspire to greatly increase the propensity for triggered arrhythmias in HF. In addition, NaCaX upregulation appears to be a critical link between contractile dysfunction and arrhythmogenesis.