Each heartbeat is initiated by cyclic spontaneous depolarization of cardiomyocytes in the sinus node forming the primary natural pacemaker. In patients with end-stage renal disease undergoing hemodialysis, it was recently shown that the heart rate drops to very low values before they suffer from sudden cardiac death with an unexplained high incidence. We hypothesize that the electrolyte changes commonly occurring in these patients affect sinus node beating rate and could be responsible for severe bradycardia. To test this hypothesis, we extended the Fabbri et al. computational model of human sinus node cells to account for the dynamic intracellular balance of ion concentrations. Using this model, we systematically tested the effect of altered extracellular potassium, calcium, and sodium concentrations. Although sodium changes had negligible (0.15 bpm/mM) and potassium changes mild effects (8 bpm/mM), calcium changes markedly affected the beating rate (46 bpm/mM ionized calcium without autonomic control). This pronounced bradycardic effect of hypocalcemia was mediated primarily by ICaL attenuation due to reduced driving force, particularly during late depolarization. This, in turn, caused secondary reduction of calcium concentration in the intracellular compartments and subsequent attenuation of inward INaCa and reduction of intracellular sodium. Our in silico findings are complemented and substantiated by an empirical database study comprising 22,501 pairs of blood samples and in vivo heart rate measurements in hemodialysis patients and healthy individuals. A reduction of extracellular calcium was correlated with a decrease of heartrate by 9.9 bpm/mM total serum calcium (p < 0.001) with intact autonomic control in the cross-sectional population. In conclusion, we present mechanistic in silico and empirical in vivo data supporting the so far neglected but experimentally testable and potentially important mechanism of hypocalcemia-induced bradycardia and asystole, potentially responsible for the highly increased and so far unexplained risk of sudden cardiac death in the hemodialysis patient population.

中文翻译：

---

低钙血症引起的人类窦房结起搏速度减慢

每次心跳都由窦房结中心肌细胞的循环自发去极化引发，形成主要的自然起搏器。在接受血液透析的终末期肾病患者中，最近的研究表明，在他们遭受无法解释的高发病率的心源性猝死之前，心率下降到非常低的值。我们假设这些患者中常见的电解质变化会影响窦房结搏动率，并可能导致严重的心动过缓。为了检验这个假设，我们扩展了 Fabbri 等人。人类窦房结细胞的计算模型，以解释离子浓度的动态细胞内平衡。使用该模型，我们系统地测试了细胞外钾、钙和钠浓度改变的影响。尽管钠的变化可以忽略不计（0. 15 bpm/mM) 和钾变化轻度影响 (8 bpm/mM)，钙变化显着影响跳动率（46 bpm/mM 离子钙，无自主控制）。低钙血症的这种明显的心动过缓效应主要是由驱动力降低引起的 ICaL 衰减介导的，尤其是在晚期去极化期间。这反过来又导致细胞内隔室中钙浓度的继发性降低以及随后内向 INaCa 的衰减和细胞内钠的减少。我们的计算机研究结果得到了一项经验数据库研究的补充和证实，该研究包括 22,501 对血液样本和血液透析患者和健康个体的体内心率测量值。细胞外钙的减少与心率减少 9.9 bpm/mM 总血清钙相关（p < 0. 001）在横断面人群中具有完整的自主控制。总之，我们提出了计算机模拟和体内经验数据支持低钙血症引起的心动过缓和心搏停止的迄今为止被忽视但在实验上可测试且潜在的重要机制，这可能是导致心源性猝死风险高度增加且迄今为止无法解释的原因。血液透析患者群体。