Maltsev Victor A, Stern Michael D
Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, United States.
Front Physiol. 2022 Dec 9;13:1090162. doi: 10.3389/fphys.2022.1090162. eCollection 2022.
The current dogma about the heartbeat origin is based on "the pacemaker cell," a specialized cell residing in the sinoatrial node (SAN) that exhibits spontaneous diastolic depolarization triggering rhythmic action potentials (APs). Recent high-resolution imaging, however, demonstrated that Ca signals and APs in the SAN are heterogeneous, with many cells generating APs of different rates and rhythms or even remaining non-firing (dormant cells), i.e., generating only subthreshold signals. Here we numerically tested a hypothesis that a community of dormant cells can generate normal automaticity, i.e., "the pacemaker cell" is not required to initiate rhythmic cardiac impulses. Our model includes 1) non-excitable cells generating oscillatory local Ca releases and 2) an excitable cell lacking automaticity. While each cell in isolation was not "the pacemaker cell", the cell system generated rhythmic APs: The subthreshold signals of non-excitable cells were transformed into respective membrane potential oscillations electrogenic Na/Ca exchange and further transferred and integrated (computed) by the excitable cells to reach its AP threshold, generating rhythmic pacemaking. Cardiac impulse is an emergent property of the SAN cellular network and can be initiated by cells lacking intrinsic automaticity. Cell heterogeneity, weak coupling, subthreshold signals, and their summation are critical properties of the new pacemaker mechanism, i.e., cardiac pacemaker can operate a signaling process basically similar to that of "temporal summation" happening in a neuron with input from multiple presynaptic cells. The new mechanism, however, does not refute the classical pacemaker cell-based mechanism: both mechanisms can co-exist and interact within SAN tissue.
目前关于心跳起源的教条基于“起搏细胞”，这是一种存在于窦房结（SAN）中的特殊细胞，表现出自发性舒张期去极化，触发有节律的动作电位（AP）。然而，最近的高分辨率成像表明，窦房结中的钙信号和动作电位是异质性的，许多细胞产生不同频率和节律的动作电位，甚至保持不放电状态（休眠细胞），即仅产生阈下信号。在这里，我们通过数值模拟测试了一个假设，即一群休眠细胞可以产生正常的自律性，也就是说，启动有节律的心脏冲动不需要“起搏细胞”。我们的模型包括：1）产生振荡性局部钙释放的非兴奋性细胞；2）缺乏自律性的可兴奋细胞。虽然单个细胞都不是“起搏细胞”，但细胞系统产生了有节律的动作电位：非兴奋性细胞的阈下信号通过电致钠/钙交换转化为各自的膜电位振荡，并进一步由可兴奋细胞传递和整合（计算），以达到其动作电位阈值，产生有节律的起搏。心脏冲动是窦房结细胞网络的一种涌现特性，可以由缺乏内在自律性的细胞启动。细胞异质性、弱耦合、阈下信号及其总和是新起搏机制的关键特性，即心脏起搏器可以运行一个与神经元中多个突触前细胞输入时发生的“时间总和”基本相似的信号过程。然而，新机制并不反驳基于经典起搏细胞的机制：两种机制可以在窦房结组织中共存并相互作用。
