Mechanical Determinants of the Chronotropic Response to Sinoatrial Stretch

MacDonald, E. and Quinn, T. A. (2018) Mechanical Determinants of the Chronotropic Response to Sinoatrial Stretch. Journal of Molecular and Cellular Cardiology 124:91. Meeting Abstract: 2018 ISHR-NAS annual meeting, Halifax, NS, Canada, 29 May - 1 Jun 2018. (doi: 10.1016/j.yjmcc.2018.07.030)

Abstract

The sinoatrial node (SAN) adapts its firing to changes in mechanical load, with stretch increasing heart rate (HR). This response is important for matching cardiac output to venous return and may contribute to SAN dysfunction in disease. Surprisingly, in mouse stretch decreases HR, reducing its utility for exploring underlying mechanisms. The zebrafish represents an attractive alternative model, as its cardiac electrophysiology is similar to human and it is easily genetically modified. We have demonstrated that stretch of zebrafish SAN increases HR in a magnitude-dependent manner similar to mammals, such as rabbit. Yet molecular mechanisms and mechanical determinants of this chronotropic response remain unknown. Our aim is to determine factors underlying the SAN response to stretch using zebrafish and rabbit. The SAN was isolated from hearts of adult zebrafish (n=10) and rabbits (n=8). The zebrafish SAN (an oval-shaped ring) had a pair of custom micro-sized glass hooks (coupled to a piezo-translator and force transducer) inserted into its opening and 10-50% strain was applied from the pre-stretched state. The rabbit SAN was attached at either end to clips (coupled to a linear servomotor and force transducer) and 10-50% strain was applied from a baseline force of 0.5g. HR was measured by local electrocardiogram. For the zebrafish SAN it was found that the increase in HR was correlated with pre-stretch force, rather than applied force, suggesting the need for a consistent baseline force. For the rabbit SAN, the stretch-induced increase in HR (from a similar baseline force) was instead correlated with applied force but interestingly, inversely correlated with tissue stiffness. Similar experiments are now being performed in zebrafish. Results confirm that in both zebrafish and rabbits the chronotropic response to SAN stretch is magnitude-dependent but is also influenced by tissue mechanics. Molecular mechanisms are now being explored using pharmacologic, genetic, and optogenetic interventions.

• Item Type: Conference or Workshop Item
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: MacDonald, Dr Eilidh
• Authors: MacDonald, E., and Quinn, T. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• ISSN: 0022-2828
• Published Online: 25 November 2018