Altered Repolarization Reserve in Failing Rabbit Ventricular Myocytes: Calcium and β-Adrenergic Effects on Delayed- and Inward-Rectifier Potassium Currents.
Altered Repolarization Reserve in Failing Rabbit Ventricular Myocytes: Calcium and β-Adrenergic Effects on Delayed- and Inward-Rectifier Potassium Currents.
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DOI：
10.1161/circep.117.005852
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发表时间：
2018-03
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影响因子：
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通讯作者：
Bers DM
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作者：
Hegyi B;Bossuyt J;Ginsburg KS;Mendoza LM;Talken L;Ferrier WT;Pogwizd SM;Izu LT;Chen-Izu Y;Bers DM
电生理重塑和心律失常易感性增加是心力衰竭 (HF) 的标志。心力衰竭时心室动作电位 (AP) 持续时间 (APD) 通常延长，复极储备减少。然而，潜在的 K+ 电流变化通常是在非生理条件下测量的（电压钳、低起搏速率、胞质 Ca2+ 缓冲液）。我们测量了慢性压力/容量超负荷引起的心力衰竭（与年龄匹配的对照）中兔心室肌细胞的主要 K+ 电流（IKr、IKs、IK1）及其 Ca2+ 和 β 肾上腺素能依赖性。在生理离子条件和温度下，只有在心力衰竭中较低起搏频率（0.2-1 Hz）时，APD 才会显着延长。然而，当细胞质 Ca2+ 被缓冲时，心力衰竭中的 APD 延长在较高起搏速率下也很显着。心力衰竭时 APD 的逐搏变异性也显着增加。在 AP 钳夹下的 HF 中，IKr 和 IK 均显着上调，但仅当胞质 Ca2+ 未缓冲时才发生。 CaMKII 抑制消除了 HF 中 IK 的上调，但不影响 IKr。心力衰竭时 IK 对 β 肾上腺素能刺激的反应也显着减弱。无论 Ca2+ 缓冲、CaMKII 抑制或 β-肾上腺素能刺激如何，心力衰竭中 IK1 也会降低。与强胞质 Ca2+ 缓冲的条件不同，在基线时，HF 中 IKr 和 IK 的 Ca2+ 依赖性上调抵消了 IK1 的降低，从而在生理条件下维持复极储备（尤其是在较高心率时）。然而，在 β 肾上腺素能刺激下，IK 反应性降低严重限制了 HF 中的综合复极 K+ 电流和复极储备。这会增加心力衰竭时发生心律失常的倾向，尤其是在肾上腺素能应激期间。
Electrophysiological remodeling and increased susceptibility for cardiac arrhythmias are hallmarks of heart failure (HF). Ventricular action potential (AP) duration (APD) is typically prolonged in HF, with reduced repolarization reserve. However, underlying K+ current changes are often measured in non-physiological conditions (voltage-clamp, low pacing rates, cytosolic Ca2+ buffers). We measured the major K+ currents (IKr, IKs, IK1) and their Ca2+- and beta-adrenergic dependence in rabbit ventricular myocytes in chronic pressure/volume overload-induced HF (vs. age-matched controls). APD was significantly prolonged only at lower pacing rates (0.2–1 Hz) in HF under physiological ionic conditions and temperature. However, when cytosolic Ca2+ was buffered, APD prolongation in HF was also significant at higher pacing rates. Beat-to-beat variability of APD was also significantly increased in HF. Both IKr and IKs were significantly upregulated in HF under AP-clamp, but only when cytosolic Ca2+ was not buffered. CaMKII inhibition abolished IKs upregulation in HF, but it did not affect IKr. IKs response to beta-adrenergic stimulation was also significantly diminished in HF. IK1 was also decreased in HF regardless of Ca2+ buffering, CaMKII inhibition or beta-adrenergic stimulation. At baseline Ca2+-dependent upregulation of IKr and IKs in HF counterbalances the reduced IK1, maintaining repolarization reserve (especially at higher heart rates) in physiological conditions, unlike conditions of strong cytosolic Ca2+ buffering. However, under beta-adrenergic stimulation, reduced IKs responsiveness severely limits integrated repolarizing K+ current and repolarization reserve in HF. This would increase arrhythmia propensity in HF, especially during adrenergic stress.