# The Intrinsic Cardiac Nervous System and Atrial Pacemakers - Implications for Sinus Node Dysfunction

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $58,122

## Abstract

Abstract
 The sinus node initiates pacemaking activity in mammalian hearts with robust regularity. Sinus node
dysfunction is a common, heterogenous disorder resulting in syncope, fatigue, and chronotropic incompetence.
No pharmacologic therapy current exists for sinus node dysfunction, and the only available therapeutic
modality is implantation of a permanent pacemaker. Although the canonical hierarchy of pacemaking activity
states that atrioventricular foci lead pacemaking activity when the sinus node fails, experimental data suggests
that subsidiary right atrial pacemakers (SAPs) emerge, mature, and lead pacemaking function in the absence
of the sinus node. The intrinsic cardiac nervous system (ICNS), a network of discrete ganglia distributed on the
epicardial surface of the heart, modulates regional cardiac electrical and mechanical activity on a beat-by-beat
basis. Dysfunction of the ICNS has been implicated in various rhythm disorders including sinus node
dysfunction, though clinical interventions targeting the ICNS have reported mixed results. The right atrial
ganglionated plexus (RAGP) and inferior vena cava-inferior atrial ganglionated plexus (IVC-IA GP) robustly
innervate the rostral and caudal right atrium, where SAPs typically emerge. These SAPs are influenced by the
autonomic nervous system, and disruption of autonomic innervation may impact the maturation and function of
these SAPs.
 In this proposal, we aim to evaluate the role of the ICNS in the maturation of SAPs in a porcine model
following excision of the sinus node. In Aim 1, we will evaluate the emergence of SAPs using continuous ECG-
telemetry, in vivo electrophysiologic mapping, and autonomic challenges before and after excision of the sinus
node. We will then characterize atrial and pacemaker protein and gene expression profiles using
immunohistochemistry and RNA-sequencing in the SAP compared to sinus node and remote atrium. In Aim 2,
we will selectively remove the RAGP or IVC-IA GP and excise the sinus node, and evaluate the emergence of
SAPs using similar techniques. This study will determine the role of the ICNS in establishing pacemaker
function, and elucidate whether subsidiary pacemaking function is dependent on neuronal input. In addition,
structural and transcriptomic characteristics of SAPs will be defined, providing insight into pathways that
mediate pacemaking independent of the sinus node complex.

## Key facts

- **NIH application ID:** 10315954
- **Project number:** 1F32HL160163-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Joseph Elias Hadaya
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $58,122
- **Award type:** 1
- **Project period:** 2021-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10315954

## Citation

> US National Institutes of Health, RePORTER application 10315954, The Intrinsic Cardiac Nervous System and Atrial Pacemakers - Implications for Sinus Node Dysfunction (1F32HL160163-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10315954. Licensed CC0.

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