Enhanced Depolarization Drive in Failing Rabbit Ventricular Myocytes Calcium-Dependent and ß-Adrenergic Effects on Late Sodium, L-Type Calcium, and Sodium-Calcium Exchange Currents
Enhanced Depolarization Drive in Failing Rabbit Ventricular Myocytes Calcium-Dependent and ß-Adrenergic Effects on Late Sodium, L-Type Calcium, and Sodium-Calcium Exchange Currents
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衰竭兔心室肌细胞去极化驱动增强钙依赖性和β-肾上腺素能对晚期钠、L型钙和钠-钙交换电流的影响
DOI：
10.1161/circep.118.007061
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发表时间：
2019-03-01
影响因子：
8.4
通讯作者：
Bers, Donald M.
中科院分区：
文献类型：
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作者：
Hegyi, Bence;Morotti, Stefano;Bers, Donald M.
背景：心力衰竭(HF)的特征是电生理重构，导致心律失常的风险增加。以前的报道表明，HF内向离子电流的增加促进了动作电位(AP)的延长，增加了AP复极的短期变异性，并延迟了后除极。然而，晚期钠电流(I-NAL)、L型钙电流和钠/钙交换器电流的潜在变化通常是在非生理性条件下(方波电压钳、慢起搏率、外源性钙缓冲液)测量的。方法：我们测定了慢性压力/容量超负荷心衰(与年龄匹配的对照组)兔心室肌细胞生理AP钳下的主要内向电流及其钙和肾上腺素能依赖性。结果：心衰时AP持续时间延长，AP复极的短时变异性增加，更重要的是，抑制INAL使这两个参数降低到对照水平。即使细胞内钙离子被强烈缓冲，HF组的INAL仍略高于对照组。但在钙循环正常的生理性AP钳下，与对照组相比，HF组ICal显著上调(主要依赖于CaMKII[Ca~(2+)/钙调蛋白依赖性蛋白激酶II]活性)。SS-肾上腺素能刺激(通常在HF时升高)进一步增强I-NAL。缓冲Ca~(2+)后，HF的L型钙电流降低，但CaMKⅡ介导的钙依赖易化作用使生理性L型钙电流上调至对照水平。此外，肾上腺素能刺激对L型钙电流的反应在HF时明显减弱。结合实验数据和计算模型评估，心衰患者AP的内向Ncx电流在3相上调。结论：我们的结果表明，依赖CaMKII的IAL上调显著地导致AP延长和AP复极的短期变异性增加，这可能导致心律失常倾向的增加，肾上腺素能应激进一步加重。
BACKGROUND: Heart failure (HF) is characterized by electrophysiological remodeling resulting in increased risk of cardiac arrhythmias. Previous reports suggest that elevated inward ionic currents in HF promote action potential (AP) prolongation, increased short-term variability of AP repolarization, and delayed afterdepolarizations. However, the underlying changes in late Na+ current (I-NaL), L-type Ca2+ current, and NCX (Na+/Ca2+ exchanger) current are often measured in nonphysiological conditions (square-pulse voltage clamp, slow pacing rates, exogenous Ca2+ buffers).METHODS: We measured the major inward currents and their Ca2+ and ss-adrenergic dependence under physiological AP clamp in rabbit ventricular myocytes in chronic pressure/volume overload-induced HF (versus age-matched control).RESULTS: AP duration and short-term variability of AP repolarization were increased in HF, and importantly, inhibition of I NaL decreased both parameters to the control level. I NaL was slightly increased in HF versus control even when intracellular Ca2+ was strongly buffered. But under physiological AP clamp with normal Ca2+ cycling, I NaL was markedly upregulated in HF versus control (dependent largely on CaMKII [Ca2+/calmodulin-dependent protein kinase II] activity). ss-Adrenergic stimulation (often elevated in HF) further enhanced I NaL. L-type Ca2+ current was decreased in HF when Ca2+ was buffered, but CaMKII-mediated Ca2+ dependent facilitation upregulated physiological L-type Ca2+ current to the control level. Furthermore, L-type Ca2+ current response to ss-adrenergic stimulation was significantly attenuated in HF. Inward NCX current was upregulated at phase 3 of AP in HF when assessed by combining experimental data and computational modeling.CONCLUSIONS: Our results suggest that CaMKII-dependent upregulation of I NaL in HF significantly contributes to AP prolongation and increased short-term variability of AP repolarization, which may lead to increased arrhythmia propensity, and is further exacerbated by adrenergic stress.