Cui Chang, Geng Le, Shi Jiaojiao, Zhu Yue, Yang Gang, Wang Zidun, Wang Jiaxian, Chen Minglong
Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Stem Cell Res Ther. 2017 May 11;8(1):109. doi: 10.1186/s13287-017-0566-6.
Long-term ventricular pacing has deleterious effects and becomes more significant when cumulative percent ventricular pacing (Cum%VP) exceeds 40% of time. However, cellular disturbances and pathways by which pacing leads to myocardial disorders are not well understood. Attempts to resolve these questions have been hampered by difficulties in obtaining human cardiac tissue and the inability to build a longer-lasting (lasting longer than weeks) pacing model in vitro.
Human induced pluripotent stem cell-derived ventricular cardiomyocytes (VCMs) were cultured in the presence of electrical stimulation for 2 weeks. Quantitative structural and electrophysiological analyses were used to define the functional disturbances of pacing.
Compared to controls, paced VCMs exhibited a remarkable reduction in the contractile protein expression, an increased apoptosis ratio and electrophysiological remodelling in a Cum%VP-dependent manner. Investigation of the protein expression levels revealed that long-term pacing universally activated both ER stress and downstream calpain. Moreover, the inhibition of calpain attenuated the adverse effects on the structural remodelling and increased the I in paced VCMs.
The results demonstrated that pacing VCMs for 2 weeks in vitro led to a series of structural and electrophysiological dysfunctions. The increased ER stress and downstream calpain could be a central mechanism underlying the disease pathogenesis. This finding could represent a new therapeutic target in the management of long-term pacing patients.
长期心室起搏具有有害影响，当累积心室起搏百分比（Cum%VP）超过总时间的40%时，这种影响会更加显著。然而，起搏导致心肌疾病的细胞紊乱和途径尚未完全明确。获取人类心脏组织存在困难，且无法在体外构建持续时间更长（超过数周）的起搏模型，这阻碍了人们对这些问题的研究。
在电刺激条件下培养人诱导多能干细胞衍生的心室心肌细胞（VCMs）2周。采用定量结构和电生理分析来确定起搏的功能紊乱。
与对照组相比，起搏的VCMs表现出收缩蛋白表达显著降低、凋亡率增加以及电生理重塑，且呈Cum%VP依赖性。对蛋白质表达水平的研究表明，长期起搏普遍激活了内质网应激和下游的钙蛋白酶。此外，抑制钙蛋白酶可减轻对结构重塑的不利影响，并增加起搏VCMs中的I电流。
结果表明，体外起搏VCMs 2周会导致一系列结构和电生理功能障碍。内质网应激增加和下游钙蛋白酶可能是疾病发病机制的核心机制。这一发现可能为长期起搏患者的治疗提供新的靶点。
