Circadian Disruptions in Respiratory Control in Heart Failure Rats Are Associated with Reduced Nmb Levels in the Retrotrapezoid Nucleus

Non-ischemic heart failure (HF) with preserved ejection fraction is increasingly associated with disordered breathing. Clinically, many HF patients decompensate during inactive-active phase transitions, suggesting circadian vulnerability; however, changes in circadian rhythms and how they might impact breathing control in non-ischemic HF remain unknown. Interestingly, chemoreflex ventilatory control is enhanced in HF and retrotrapezoid nucleus (RTN) chemoreceptor neurons (Neuromedin B, Nmb+) play a pivotal role in the maintenance of breathing disorders in HF. Accordingly, we aimed to determine ventilatory circadian alterations in rats with HF. Also, we explored the role of Nmb on circadian ventilatory rhythm in HF rats. Adult male Sprague-Dawley underwent volume overload to induced non-ischemic HF. Circadian ventilatory dynamics were assessed using whole-body plethysmography. Nmb release at the level of the preBötzinger complex was measures using in-vivo microdialysis. Finally, Nmb expression in RTN neurons was measured using RNAscope. We found that HF animals showed a loss of normal circadian oscillation in breathing patterns with predominant increases in ventilatory irregularity/instability during the night-to-day transition compared to Sham animals. Indeed, ventilatory irregularity score was higher in HF (7.8 ± 0.5 vs. 9.2 ± 2.0%, Sham vs. HF, respectively). In addition, HF rats displayed a higher incidence of post-sigh apnea compated to Sham rats (9.3 ± 4.5 vs. 14.5 ± 3.3 events/h, Sham vs. HF, respectively). Oscillations in the amplitude of tidal volume were also higher in HF (10.2 ± 2.0 vs. 17.28 ± 1.93%, Sham vs. HF, respectively). Notably, we found that ventilatory instability in HF was closely linked to decreased release of Nmb at the preBötzinger complex. Indeed, we found a ~20% reduction in Nmb release in HF rats. Interestingly, reductions in Nmb release in HF was associated with a significant downregulation of Nmb in RTN neurons. Indeed, we found that HF rats showed a 70% reduction in Nmb mRNA expression in RTN neurons compared to the levels observed in RTN neurons from Sham rats. Remarkably, RTN-targeted Nmb knockdown in healthy rats reproduced the HF-like respiratory phenotype (i.e. increased VT variability, irregularity, and post-sigh apnea events). These findings identify the inactive-active phase transition as a vulnerable window in non-ischemic HF and show that impaired circadian Nmb signaling contributes to breathing instability. Funding: ANID Fondecyt 1220950 and NIH R01HL176779. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.