Role of medullary cardiorespiratory neurons on the maintenance of altered sleep function in heart failure

Abstract

Sleep‐disordered breathing (SDB) and sleep fragmentation (SF) (i.e. repetitive short interruptions of sleep) are frequently reported in heart failure (HF) patients. Interestingly, SDB and SF has been both closely associated with the generation of breathing disorders. Importantly, our previous work showed that partial ablation of pre‐sympathetic catecholaminergic neurons (C1) located at the rostral ventrolateral medulla (RVLM) results in marked improvements in breathing disorders in rats with HF. However, the contribution of RVLM‐C1 neurons on sleep‐related disorders in the setting of cardiac failure has not been previously studied. Therefore, we aimed to determine the contribution of RVLM‐C1 neurons on sleep architecture in HF. Adult male Sprague‐Dawley rats (250 g) underwent volume overload to induce HF. After four weeks, anti‐dopamine β‐hydroxylase‐saporin (DβH–SAP: 2.5ng/150nl; or saline) was used to selectively destroy RVLM‐C1 neurons (‐12.36 mm AP from bregma; ± 2.2 mm ML; 8.5 mm DV). Breathing function was determined by unrestrained whole‐body plethysmograph and sleep function/sleep stages were assessed in electroencephalogram and electromyogram recordings obtained for chronic implanted leads. Compared to Sham rats, HF animals displayed no differences in the total time spent in rapid eye movement (REM) and non‐rapid eye movement (nREM) sleep stages. However, duration of each nREM epoch was significantly (p<0.05) lower in HF rats (3.4 ± 0.3 vs. 2.2 ± 0.2 min, Sham vs. HF, respectively). Accordingly, HF rats showed an increased number of nREM epochs compared to Sham animals (12.0 ± 2 vs. 17 ± 2 events/h, Sham vs. HF, respectively). Interestingly, HF rats displayed loss of ventilatory stability compared to Sham rats only at nREM sleep (Irregularity score, nREM: 12.1 ± 2.0 vs. 15.9 ± 1.8%; REM: 22.9 ± 2.0 vs 24.1 ± 3.2%; Sham vs. HF, respectively). Furthermore, the incidence of sigh‐triggered arousal events during nREM sleep was increased in HF rats. Conversely, sleep probability was decreased by ~35% in HF animals compared to Sham animals. Remarkably, ablation of RVLM‐C1 neurons with DβH–SAP in HF improved nREM breathing regularity and restores normal nREM sleep duration (3.4 ± 0.3 vs. 3.1 ± 0.3 min, Sham vs. HF+DβH–SAP, respectively). In addition, DβH–SAP treatment in HF decreased sigh‐triggered arousals by ~45% being the outcome a reduction in SF in HF rats that underwent C1 ablation. Our data shows that irregular breathing is closely linked to altered sleep in HF rats and support a role for RVLM‐C1 neurons on sleep regulation in the setting of HF.