Exercise training-induced bradycardia is caused by changes in intrinsic sinus node function
Exercise training-induced bradycardia is caused by changes in intrinsic sinus node function
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运动训练引起的心动过缓是由窦房结功能改变引起的
DOI：
10.1152/japplphysiol.00268.2017
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发表时间：
2017
影响因子：
3.3
通讯作者：
Billman George E.
中科院分区：
文献类型：
--
作者：
Boyett Mark R.;Wang Yanwen;Nakao Shu;Ariyaratnam Jonathan;Hart George;Monfredi Oliver;D'Souza Alicia;Billman George E.
众所周知，运动员有静息窦性心动过缓——他们的静息心率可能是正常值的一半 (7)——这通常归因于高迷走神经张力 (3)。这是一个合乎逻辑的假设，因为自 1921 年以来，我们从生理学家 Otto Loewi 的工作中得知，刺激迷走神经会降低心率 (8a)。然而，我们在这里认为心动过缓不是迷走神经张力的结果，而是窦房结电重塑的结果。在经过运动训练的大鼠和小鼠中，我们发现离子通道、细胞内 Ca2 处理分子、Na-K 泵亚基以及心脏起搏器窦房结的间隙连接通道出现下调 (5)。特别是，我们发现 HCN4 起搏器通道和相应的离子电流（有趣电流，If）的下调，并且 If 的阻断消除了经过训练和未经训练的动物之间的心率差异 (5)。最近，我们发现 microRNA (miR-423–5p) 的上调可防止 HCN4 和 If 的下调以及随之而来的心动过缓 (6)。高迷走神经张力假说的大部分证据都与心率变异性有关 (1)。例如，Billman 等人 (3) 认为，运动训练引起的狗心动过缓是迷走神经张力较高的结果，部分原因是运动训练后心率变异性较低。一般来说，众所周知，运动员的心率变异性较低，这被视为迷走神经张力较高的证据 (1)。然而，基于基本的生物物理学，Zaza 的小组 (12, 16) 和我们 (11) 已经表明，心率变异性主要是心率本身的非线性替代物，不能以任何简单的方式用作心脏自主神经活动的测量。 Billman 等人(3) 报告了心率变异性的两种测量方法：正常至正常心跳的标准差 (SDNN) 和高频功率。图 1 中的灰点显示了 SDNN 与心率之间的关系，这些研究来自我们收集和之前发表的大量已发表的研究（来自不同的物种、制剂和条件）(11)。灰点表明，无论数据来源如何，SDNN 和心率之间都存在独特的指数式关系，而与实验数据非常吻合的实线是通过简单的生物物理模型预测的 SDNN 和心率之间的关系 (11)。十字线显示了 Billman 等人 (3) 的所有可用数据。它们与显示的其他数据以及 SDNN 和心率之间的预测关系一致。根据 Billman 等人 (3) 论文中提供的所有数据，图 1 中的插图显示了高频功率与相应心率之间的关系 - 在他们研究的心率范围内，两者之间存在极好的线性关系（R2 0.73；P < 0.0001）。 Billman等[3]的研究得出结论，心率变异性的变化很大程度上是心率变化的结果，而不是自主神经张力变化的结果。自主神经张力的变化可能确实会导致心率变异性的变化，但任何此类变化几乎不可能与心率的压倒性影响区分开来。高迷走神经张力假说的第二个证据涉及完全自主神经阻断（通常通过阿托品和普萘洛尔）后在体内测量的“内在心率”。例如，Billman 等人 (3) 报告说，狗训练引起的心动过缓在完全自主神经阻断后消失，并引用此作为高迷走神经张力假说的证据。然而，与此相反，Billman 等人 (3) 也……
IT IS WELL KNOWN that athletes have a resting sinus bradycardia—their resting heart rate can be half the normal value (7)—and this is normally attributed to high vagal tone (3). This is a logical assumption, because we have known since 1921 from the work of the physiologist Otto Loewi that stimulating the vagus nerve decreases the heart rate (8a). However, we argue here that the bradycardia is not the result of vagal tone and instead is the result of an electrical remodeling of the sinus node. In exercise-trained rats and mice, we have shown a downregulation of ion channels, intracellular Ca2-handling molecules, Na-K pump subunits, and gap junction channels of the pacemaker of the heart, the sinus node (5). In particular, we have shown a downregulation of the HCN4 pacemaker channel and the corresponding ionic current (funny current, If), and block of If abolishes the difference in heart rate between trained and untrained animals (5). More recently, we have shown that upregulation of a microRNA (miR-423–5p) prevents the downregulation of HCN4 and If and the consequent bradycardia (6). Much of the evidence for the high vagal tone hypothesis concerns heart rate variability (1). For example, Billman et al.(3) argued that exercise training-induced bradycardia in the dog is the result of high vagal tone based partly on low heart rate variability after exercise training. In general, it is well established that heart rate variability is low in the athlete and this is taken as evidence of high vagal tone (1). However, based on the underlying biophysics, Zaza’s group (12, 16) and we (11) have shown that heart rate variability is primarily a nonlinear surrogate of heart rate itself and cannot be used in any simple manner as a measure of autonomic nerve activity to the heart. Billman et al.(3) report two measures of heart rate variability, the standard deviation of normal-to-normal beats (SDNN) and high frequency power. The gray points in Fig. 1 show the relationship between SDNN and heart rate from a wide range of published studies (from different species, preparations, and conditions) collected and previously published by us (11). The gray points show that regardless of the source of the data there is a unique exponential-like relationship between SDNN and heart rate, and the solid line, which is a good fit to the experimental data, is the relationship between SDNN and heart rate as predicted by a simple biophysical model (11). The crosses show all available data from Billman et al.(3). They are consistent with the other data shown as well as the predicted relationship between SDNN and heart rate. Based on all the data available in the paper from Billman et al.(3), the inset in Fig. 1 shows the relationship between high frequency power and the corresponding heart rates—over the range of heart rates in their study, there is an excellent linear relationship between the two (R2 0.73; P 0.0001). It is concluded that the changes in heart rate variability in the study of Billman et al.(3) are largely the result of the changes in heart rate rather than changes in autonomic tone. It is possible changes in autonomic tone do result in changes in heart rate variability, but any such changes will be almost impossible to distinguish from the overriding effect of heart rate. A second line of evidence for the high vagal tone hypothesis concerns the “intrinsic heart rate” measured in vivo after complete autonomic blockade (usually by atropine and propranolol). For example, Billman et al.(3) report that the training-induced bradycardia in dogs is abolished after complete autonomic blockade and cite this as evidence for the high vagal tone hypothesis. However, contrary to this, Billman et al.(3) also …