Abstract
Abstract 4362976: Serotonin reduction decreases apneas and the hypercapnic ventilatory response in ischemic heart failure mice
Circulation (New York, N.Y.), Vol.152(Suppl_3), pp.A4362976-A4362976
11/04/2025
DOI: 10.1161/circ.152.suppl_3.4362976
Abstract
Background: Central apneas are highly prevalent in heart failure (HF), contributing to morbidity and mortality. Increased hypercapnic ventilatory response (HCVR) is a primary pathophysiological trigger of apneas in HF. Since serotonin (5HT) is responsible for ~50% of the HCVR, modulating 5HT signaling may be a therapeutic target for breathing disorders in HF.
Hypothesis: 5HT reduction will decrease the HCVR and the apneic burden in a mouse model of HF.
Methods: HF was induced with coronary artery ligation and confirmed if the ejection fraction was≤45% 1 week after surgery. At 1- and 5-weeks post HF, mice underwent 24-h breathing recording and hyperoxic HCVR with whole body plethysmography at 23oC (room temperature) and 30oC (thermoneutrality). Apneas were defined as lack of breathing for>1s. 5HT was depleted with parachlorophenylalanine (PCPA, a tryptophan hydroxylase inhibitor, 400 mg/kg ip) for 4-5 days, then HCVR and 24-h breathing were repeated. In a separate experiment, HF was induced in mice carrying an inhibitory designer receptor exclusively activated by designer drugs (DREADD) specifically in 5HT neurons, driven by the SERT promoter (SERT:Cre::hM4Di mice). 5HT neurons were acutely inhibited with dechloroclozapine (DCZ 0.03 mg/kg ip), then HCVR and 24-h breathing were repeated. Two-way ANOVA or t-tests were used as appropriate.
Results: HF mice had more apneas at higher room temperature at 1- and 5-weeks post-surgery (1-week 23oC 7.3±2.1 vs. 30oC 55.9±19.0 events/h, p=0.002; 5-weeks 23oC 4.7±2.0 vs. 30oC 43.2±17.6 events/h, p=0.004, n=10). The HCVR was lower in HF compared to sham at 23oC, but not at 30oC. The number of apneas positively correlated with a higher response to CO2 at 30oC (r=0.83, p=0.02). Preliminary data in HF mice indicated that treatment with PCPA reduced the HCVR (pre-PCPA 316±6 vs. post-PCPA 231±3%, n=4) and the apneic burden (pre-PCPA 23.3±8.2 vs post-PCPA 12.3±4.2 events/h). Preliminary data in SERT:Cre::hM4Di HF mice also showed that acute inactivation of 5HT neurons reduced the HCVR (pre-DCZ 379 vs. post-DCZ 168%) and the apneic burden (pre-DCZ 27.0 vs. post-DCZ 6.0 events/h).
Conclusions: HF mice have more apneas at higher room temperature, and the number of apneas positively correlates with increased HCVR. Pharmacological or chemogenetic modulation of 5HT reduces the HCVR and the apneic burden in HF mice. These results indicate that 5HT plays a key role in breathing disorders in HF and may represent a new therapeutic target.
Details
- Title: Subtitle
- Abstract 4362976: Serotonin reduction decreases apneas and the hypercapnic ventilatory response in ischemic heart failure mice
- Creators
- Chiara Borrelli - University of IowaJon Resch - University of IowaGeorge Richerson - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.152(Suppl_3), pp.A4362976-A4362976
- DOI
- 10.1161/circ.152.suppl_3.4362976
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Publisher
- Lippincott Williams & Wilkins
- Language
- English
- Date published
- 11/04/2025
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Neurosurgery
- Record Identifier
- 9985024149302771
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