Autonomic Control of Mammalian Heart Rhythm

The normal heartbeat originates as an action potential in a small group of pacemaker cells known as the sinoatrial (SA) node, located in the upper right chamber of the heart. Since its initial discovery in the early 20th century, the SA node has fascinated electrophysiologists and cardiologists in understanding its method of electrical initiation. Though the “textbook” location of the SA node is identified to be near the superior vena cava (SVC), the anatomical site of origin of the SA node’s pacemaker activity has been shown to dynamically change in response to various physiological inputs. These mechanisms of dominant pacemaker site shift are not well understood. A great deal of progress has been made in researching and modeling individual SA nodal cells, but the scientific literature still lacks cohesive and consistent knowledge about the mammalian SA node’s spatial and temporal heterogeneity at the tissue level. A deeper understanding of how intrinsic pacemaking activity is generated has implications for both basic science and translatable medicine, from understanding SA nodal dysfunction to developing anti-arrhythmia therapies. This dissertation investigates the autonomic control of the mammalian heart rhythm, specifically the response of the SA node to autonomic nerve stimuli and pharmacological stimulation of adrenergic and cholinergic receptors on a beat-to-beat basis. Using optical mapping and RNA sequencing techniques, this dissertation presents functional and molecular evidence of two competing right atrial pacemakers located near the orifices of two great veins, the SVC and the inferior vena cava (IVC). Named the superior SA node (sSAN) and the inferior SA node (iSAN), these regions are demonstrated to preferentially control the fast and slow heart rates during sympathetic or parasympathetic stimulation, respectively. RNAseq confirms unique transcriptional profiles of sSAN and iSAN which differ from neighboring myocardial tissues. These findings clarify previously observed migrations of dominant pacemaker activity and corresponding changes in P-wave morphology in many species. Furthermore, these findings shed light onto the possible pathogenesis of aberrant pacemakers responsible for life-threatening arrhythmias near the orifices of other major vessels such as the coronary sinus, pulmonary veins, aorta, and the right ventricular outflow tract.

Author

• Brennan, Jaclyn Ann

Language

• en

Keyword

• cardiac electrophysiology
• arrhythmias
• optical mapping
• pacemaker shift
• sinoatrial node
• autonomic nervous system

Date created

• 2020

Type of Work

• Dissertation

License

• All rights reserved

Rights statement

• In Copyright

GW Unit

• Biomedical Engineering

Degree

• Ph.D.

Advisor

• Zara, Jason M
• Efimov, Igor R

Committee Member(s)

• Kay, Matthew W
• Mendelowitz, David
• Kuzmiak-Glancy, Sarah

Persistent URL

•  https://scholarspace.library.gwu.edu/etd/v692t6944