Abstract 4362976: Serotonin reduction decreases apneas and the hypercapnic ventilatory response in ischemic heart failure mice

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 23 o C (room temperature) and 30 o C (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 23 o C 7.3±2.1 vs. 30 o C 55.9±19.0 events/h, p=0.002; 5-weeks 23 o C 4.7±2.0 vs. 30 o C 43.2±17.6 events/h, p=0.004, n=10). The HCVR was lower in HF compared to sham at 23 o C, but not at 30 o C. The number of apneas positively correlated with a higher response to CO 2 at 30 o C (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.