Enhanced CaMKII-Dependent Late INa Induces Atrial Proarrhythmic Activity in Patients With Sleep-Disordered Breathing
Enhanced CaMKII-Dependent Late INa Induces Atrial Proarrhythmic Activity in Patients With Sleep-Disordered Breathing
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DOI：
10.1161/circresaha.119.315755
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发表时间：
2020-02-28
影响因子：
20.1
通讯作者：
Wagner, Stefan
中科院分区：
文献类型：
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作者：
Lebek, Simon;Pichler, Konstantin;Wagner, Stefan
理论基础：睡眠呼吸紊乱(SDB)经常与房性心律失常有关。CaMKII(钙/钙调蛋白依赖的蛋白激酶II)活性升高与房性心律失常的发生有关。目的：我们假设依赖于CaMKII的钠电流调节失调(I-Na)可能与SDB患者的房性心律失常活动有关。方法和结果：我们前瞻性地招募了113名接受择期冠状动脉旁路移植术的患者进行横断面研究，并收集了右心耳活检标本。手术前一晚使用便携式SDB监护仪评估SDB的存在(定义为呼吸暂停低通气指数=15/h)。与56例无SDB的患者相比，SDB患者(57例)的CaMKII活性水平显著升高。采用膜片钳技术测定细胞内钠离子浓度。SDB患者心房肌细胞I-Na晚期显著升高，但峰值I-Na因稳态失活增强而降低，与CaMKII依赖的心肌Na通道磷酸化(Na(V)1.5，丝氨酸571，Western blotting)显著增加一致。这些门控改变可被急性CaMKII抑制(AIP)完全逆转。因此，我们观察到明显更多的细胞后去极化和更严重的房性早搏患者的房小梁，这可以被aip或kn93(N-[2-[[[(E)-3-(4-chlorophenyl)prop-2-enyl]-methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide).阻断。在包括年龄、性别、体重指数、既有心房颤动、既有心力衰竭、糖尿病和肌酐水平在内的多变量线性回归模型中，呼吸暂停低通气指数与CaMKII活性增加、晚期I-Na增加独立相关，并与房早收缩程度相关。结论：在SDB患者的心房心肌中，CaMKII依赖的Na(V)1.5磷酸化增加导致I-Na调节失调，并伴随心律失常活动，这种异常与既往存在的并发症无关。抑制CaMKII可能有助于预防或治疗SDB的心律失常。
Rationale: Sleep-disordered breathing (SDB) is frequently associated with atrial arrhythmias. Increased CaMKII (Ca/calmodulin-dependent protein kinase II) activity has been previously implicated in atrial arrhythmogenesis.Objective:We hypothesized that CaMKII-dependent dysregulation of Na current (I-Na) may contribute to atrial proarrhythmic activity in patients with SDB.Methods and Results: We prospectively enrolled 113 patients undergoing elective coronary artery bypass grafting for cross-sectional study and collected right atrial appendage biopsies. The presence of SDB (defined as apnea-hypopnea index >= 15/h) was assessed with a portable SDB monitor the night before surgery. Compared with 56 patients without SDB, patients with SDB (57) showed a significantly increased level of activated CaMKII. Patch clamp was used to measure I-Na. There was a significantly enhanced late I-Na, but reduced peak I-Na due to enhanced steady-state inactivation in atrial myocytes of patients with SDB consistent with significantly increased CaMKII-dependent cardiac Na channel phosphorylation (Na(V)1.5, at serine 571, Western blotting). These gating changes could be fully reversed by acute CaMKII inhibition (AIP [autocamtide-2 related inhibitory peptide]). As a consequence, we observed significantly more cellular afterdepolarizations and more severe premature atrial contractions in atrial trabeculae of patients with SDB, which could be blocked by either AIP or KN93 (N-[2-[[[(E)-3-(4-chlorophenyl)prop-2-enyl]-methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide). In multivariable linear regression models incorporating age, sex, body mass index, existing atrial fibrillation, existing heart failure, diabetes mellitus, and creatinine levels, apnea-hypopnea index was independently associated with increased CaMKII activity, enhanced late I-Na and correlated with premature atrial contraction severity.Conclusions: In atrial myocardium of patients with SDB, increased CaMKII-dependent phosphorylation of Na(V)1.5 results in dysregulation of I-Na with proarrhythmic activity that was independent from preexisting comorbidities. Inhibition of CaMKII may be useful for prevention or treatment of arrhythmias in SDB.