MacDonald Eilidh A, Madl Josef, Greiner Joachim, Ramadan Ahmed F, Wells Sarah M, Torrente Angelo G, Kohl Peter, Rog-Zielinska Eva A, Quinn T Alexander
Department of Physiology and Biophysics, Dalhousie University, Halifax, NS, Canada.
Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg - Bad Krozingen, and Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Front Physiol. 2020 Jul 22;11:809. doi: 10.3389/fphys.2020.00809. eCollection 2020.
The rhythmic electrical activity of the heart's natural pacemaker, the sinoatrial node (SAN), determines cardiac beating rate (BR). SAN electrical activity is tightly controlled by multiple factors, including tissue stretch, which may contribute to adaptation of BR to changes in venous return. In most animals, including human, there is a robust increase in BR when the SAN is stretched. However, the chronotropic response to sustained stretch differs in mouse SAN, where it causes variable responses, including decreased BR. The reasons for this species difference are unclear. They are thought to relate to dissimilarities in SAN electrophysiology (particularly action potential morphology) between mouse and other species and to how these interact with subcellular stretch-activated mechanisms. Furthermore, species-related differences in structural and mechanical properties of the SAN may influence the chronotropic response to SAN stretch. Here we assess (i) how the BR response to sustained stretch of rabbit and mouse isolated SAN relates to tissue stiffness, (ii) whether structural differences could account for observed differences in BR responsiveness to stretch, and (iii) whether pharmacological modification of mouse SAN electrophysiology alters stretch-induced chronotropy. We found disparities in the relationship between SAN stiffness and the of the chronotropic response to stretch between rabbit and mouse along with differences in SAN collagen structure, alignment, and changes with stretch. We further observed that pharmacological modification to prolong mouse SAN action potential plateau duration rectified the of BR changes during sustained stretch, resulting in a positive chronotropic response akin to that of other species. Overall, our results suggest that structural, mechanical, and background electrophysiological properties of the SAN influence the chronotropic response to stretch. Improved insight into the biophysical determinants of stretch effects on SAN pacemaking is essential for a comprehensive understanding of SAN regulation with important implications for studies of SAN physiology and its dysfunction, such as in the aging and fibrotic heart.
心脏天然起搏器窦房结（SAN）的节律性电活动决定了心脏跳动速率（BR）。SAN的电活动受到多种因素的严格控制，包括组织拉伸，这可能有助于BR适应静脉回流的变化。在包括人类在内的大多数动物中，当SAN被拉伸时，BR会显著增加。然而，小鼠SAN对持续拉伸的变时反应有所不同，它会引起多种反应，包括BR降低。这种物种差异的原因尚不清楚。人们认为这与小鼠和其他物种之间SAN电生理学（特别是动作电位形态）的差异以及这些差异如何与亚细胞拉伸激活机制相互作用有关。此外，SAN结构和机械特性的物种相关差异可能会影响对SAN拉伸的变时反应。在这里，我们评估：（i）兔和小鼠离体SAN对持续拉伸的BR反应与组织硬度的关系；（ii）结构差异是否可以解释观察到的BR对拉伸反应性的差异；（iii）小鼠SAN电生理学的药理学改变是否会改变拉伸诱导的变时性。我们发现兔和小鼠之间SAN硬度与拉伸变时反应之间的关系存在差异，同时SAN胶原结构、排列以及拉伸时的变化也存在差异。我们进一步观察到，通过药理学改变延长小鼠SAN动作电位平台期持续时间，可以纠正持续拉伸期间BR变化的方向，从而产生类似于其他物种的正性变时反应。总体而言，我们的结果表明，SAN的结构、机械和背景电生理特性会影响对拉伸的变时反应。深入了解拉伸对SAN起搏作用的生物物理决定因素，对于全面理解SAN调节至关重要，这对SAN生理学及其功能障碍（如在衰老和纤维化心脏中）的研究具有重要意义。
