# 5HT-a common unifying mechanism responsible for central sleep apnea, sympathoexcitation and heart failure in spinal cord injury.

> **NIH VA I01** · JOHN D DINGELL VA MEDICAL CENTER · 2024 · —

## Abstract

Sleep disordered breathing (SDB) affects 4-9% of the general population and up to 60 % of the Veteran
population. There is also a high prevalence of sleep disordered breathing in patients with subacute and chronic
spinal cord injury (SCI), and the frequency of SCI is approximately 3 times greater in the Veteran population.
Close to 90 % of individuals with cervical SCI demonstrate central sleep apnea (CSA). The presence of CSA is
often accompanied by cardiovascular disease and hypertension. A common underlying mechanism could be
responsible for this coupling. An intriguing possibility is that reductions in central nervous system serotonin,
and/or modifications in serotonin receptor sub-types, that might underlie mental health disorders (e.g. post-
traumatic stress disorder), or be altered in response to SCI, could be responsible for the coupling of central sleep
apnea and heart failure. Thus, our general hypothesis is that depletion of serotonin, induced either genetically
or because of SCI, causes increases in the severity of CSA (i.e. frequency and duration of events). This increase
is coupled to increased sympathetic outflow and ultimately heart failure that manifests with age. To test this
general hypothesis, we will explore in Aim 1a if SCI in young and elderly tryptophan hydroxylase 2 wild type
(TPH2+/+) and knock-out (TPH2-/-) mice leads to more frequent and prolonged apneic events coupled to reduced
arousal and chemoreflex responses to hypoxia and hypercapnia. Aim 1b will explore if modifications in central
nervous system serotonin or its receptor sub-types induced genetically or via spinal cord injury also leads to
increased sympathetic outflow and left ventricular hypertrophy with conserved ejection fraction in young male
mice. We propose that with age these modifications will ultimately lead to heart failure characterized by a reduced
ejection fraction. Lastly, we will determine if treatment with a selective serotonin re-uptake inhibitor (i.e.
paroxetine) will lead to reductions in the number and duration of apneic events along with reductions in lumbar
sympathetic nerve activity and left ventricular hypertrophy coupled to an increase in ejection fraction.The findings
from this proposal will be a significant step toward determining if modulation of serotonin in the central nervous
system is an important mechanistic link between CSA and heart failure in SCI Veterans. The findings will also
provide the rationale to therapeutically modulate serotonin levels to mitigate centrally modulated apneic events
and cardiac dysfunction in intact or SCI Veterans.

## Key facts

- **NIH application ID:** 10702078
- **Project number:** 1I01BX006288-01
- **Recipient organization:** JOHN D DINGELL VA MEDICAL CENTER
- **Principal Investigator:** Jason H. Mateika
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10702078

## Citation

> US National Institutes of Health, RePORTER application 10702078, 5HT-a common unifying mechanism responsible for central sleep apnea, sympathoexcitation and heart failure in spinal cord injury. (1I01BX006288-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10702078. Licensed CC0.

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