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Benefit of buspirone on chemoreflex and central apnoeas in heart failure: a randomized controlled crossover trial
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Benefit of buspirone on chemoreflex and central apnoeas in heart failure: a randomized controlled crossover trial

Alberto Giannoni, Chiara Borrelli, Gianluca Mirizzi, George B Richerson, Michele Emdin and Claudio Passino
European journal of heart failure, Vol.23(2), pp.312-320
02/2021
DOI: 10.1002/ejhf.1854
PMID: 32441857

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Abstract

Aims Increased chemosensitivity to carbon dioxide (CO2) is an important trigger of central apnoeas (CA) in heart failure (HF), with negative impact on outcome. We hypothesized that buspirone, a 5HT1A receptor agonist that inhibits serotonergic chemoreceptor neuron firing in animals, can decrease CO2 chemosensitivity and CA in HF. Methods and results The BREATH study was a randomized, double‐blind, placebo‐controlled, crossover study (EudraCT‐code 2015‐005383‐42). Outpatients with systolic HF (left ventricular ejection fraction <50%) and moderate‐severe CA [nocturnal apnoea‐hypopnoea index (AHI) ≥15 events/h] were randomly assigned to either oral buspirone (15 mg thrice daily) or placebo for 1 week, with a crossover design (1 week of wash‐out). The primary effectiveness endpoint was a decrease in CO2 chemosensitivity >0.5 L/min/mmHg. The primary safety endpoint was freedom from serious adverse events. Sixteen patients (age 71.3 ± 5.8 years, all males, left ventricular ejection fraction 29.8 ± 7.8%) were enrolled. In the intention‐to‐treat analysis, more patients treated with buspirone (8/16, 50%) had a CO2 chemosensitivity reduction >0.5 L/min/mmHg from baseline than those treated with placebo (1/16, 6.7%) (difference between groups 43%, 95% confidence interval 14–73%, P = 0.016). Buspirone compared to baseline led to a 41% reduction in CO2 chemosensitivity (P = 0.001) and to a reduction in the AHI, central apnoea index and oxygen desaturation index of 42%, 79%, 77% at nighttime and 50%, 78%, 86% at daytime (all P < 0.01); no difference was observed after placebo administration (all P > 0.05). No patient reported buspirone‐related serious adverse events. Conclusions Buspirone reduces CO2 chemosensitivity and improves CA and oxygen saturation across the 24 h in patients with HF. The increased chemoreflex gain (CG), which causes central apnoeas in heart failure (A), is blunted by buspirone, which increases the difference between CO2 at the equilibrium setpoint (ES) and at apnoeic threshold (AT) and stabilizes breathing (B). Buspirone acts on the serotonergic system (C), linking to pre‐synaptic 5‐HT1A autoreceptors and decreasing the release of serotonin in the synaptic cleft (D). ETCO2, end‐tidal pressure of carbon dioxide; ETO2, end‐tidal pressure of oxygen; VENT, ventilation.
 Heart failure Chemosensitivity Chemoreflex Central apnoeas Buspirone Cheyne–Stokes respiration

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