Abstract
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 magnitude 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 direction 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.
Highlights
The heart’s intrinsic pacemaker, the sinoatrial node (SAN), generates spontaneous action potentials (AP) through a system of coupled oscillators whose common output initiates each normal heartbeat
Stretch of rabbit SAN caused an increase in beating rate (BR) at strain levels of 20% or greater (p < 0.05 by mixed-effects analysis) with BR returning to baseline between each stretch application and with the magnitude of the change in BR correlating with the amount of strain (Figure 2A and Supplementary Figure S2A)
Stretch of mouse SAN resulted in a more variable chronotropic response: BR increased in three mice, decreased in one mouse, and varied between increase and decrease in four mice (Supplementary Figure S2B)
Summary
The heart’s intrinsic pacemaker, the sinoatrial node (SAN), generates spontaneous action potentials (AP) through a system of coupled oscillators whose common output initiates each normal heartbeat. The SAN responds to altered hemodynamic load through the Bainbridge response: an increase in BR upon right atrial distention, which may help in matching cardiac output to venous return (Bainbridge, 1915). This response was initially thought to be neurally mediated; mechanically induced changes in BR have since been demonstrated in isolated heart, atria, SAN, and single SAN cells, indicating the involvement of mechano-sensitive mechanisms (Quinn and Kohl, 2020) intrinsic to pacemaker cells (Quinn and Kohl, 2012). We investigate how structural and mechanical properties of the SAN relate to amplitude and directionality of stretch-induced changes in BR, including a comparison between rabbit and mouse as important species-specific differences may exist (Cooper and Kohl, 2005)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
