Brainstem pre‐sympathetic neurons contribute to irregular breathing patterns in volume overload heart failure
Authors: Toledo Camilo , Andrade David Cristobal , Del Rio Rodrigo 
Published: June 2021

Chronic heart failure (CHF) is characterized by sympathoexcitation and a high prevalence of breathing disorders. It has been shown that rostral ventrolateral medulla catecholaminergic neurons (RVLM‐C1) contributes to sympathetic outflow regulation in CHF and that RVLM‐C1 neurons are hyperactivated in experimental CHF. Recently, it has been shown that acute activation of RVLM‐C1 neurons also stimulates breathing in healthy rodents. However, there is no evidence showing the contribution of RVLM‐C1 neurons, if any, on breathing disorders in CHF. Therefore, we aimed to determine the role of RVLM‐C1 neurons on disordered breathing in CHF. Sprague‐Dawley rats underwent volume overload to induce CHF. Stereotaxic bilateral injections of anti‐dopamine β‐hydroxylase‐saporin toxin (DβH–SAP: 5ng/150nl) were used to selectively eliminate RVLM‐C1 neurons. Whole‐body plethysmography, blood pressure radiotelemetry and pression‐volume conductance catheter were used to study breathing stability, chemoreflex function, cardiac autonomic control, respiratory‐cardiovascular coupling (RCC) and cardiac function. Depletion of RVLM‐C1 neurons (~70%) in CHF rats (CHF+Veh vs. CHF+DβH+SAP, respectively) restored regular breathing pattern (Breathing irregularity score: 25.5 ± 3.0 vs. 11.9 ± 1.2 %; p<0.05), decreased apnea/hypopnea incidence (11.0 ± 0.9 vs. 6.5 ± 0.8 events/hr; p<0.05) and improves cardiac autonomic control as evidenced by a decrease in the low/high frequency component of spectral analysis of heart rate variability (HRV) (LF/HFHRV 2.7 ± 0.3 vs. 1.5 ± 0.1; p<0.05). In addition, CHF rats displayed active expiration compared to Sham rats, evidenced by the increase in the early/late expiration ratio (E2/E1: 0.51 ± 0.02 vs. 1.07 ± 0.07 Sham+Veh vs. CHF+Veh, p<0.05) and DβH–SAP toxin treatment decrease active expiration in CHF rats (E2/E1: 1.07 ± 0.07 vs. 0.81 ± 0.01 ml, CHF+Veh vs. CHF+DβH‐SAP; p<0.05). Accordingly, DβH–SAP toxin treatment eliminate RCC in CHF rats (Coherencepeak: 0.74 ± 0.04 vs. 0.59 ± 0.05, CHF+Veh vs. HF+DβH–SAP; p<0.05). In addition, the deleterious effects of central chemoreflex activation on diastolic cardiac function and cardiac autonomic control were blunted after RVLM‐C1 neuron ablation (EDPVR: 0.023 ± 0.008 vs. 0.005 ± 0.001 mmHg/μl; LF/HFHRV 2.19 ± 0.15 vs. 1.09 ± 0.23; CHF+Veh+Hypercapnia vs. CHF+DβH‐SAP+ Hypercapnia; p<0.05). No changes in central chemoreflex drive and/or in the number of central chemoreceptor neurons (from the retrotrapezoid nucleus) were found in CHF+DβH‐SAP rats compared to CHF+Veh treated rats. Our results showed that RVLM‐C1 neurons play a critical role in the maintenance of altered breathing patterns in CHF rats and highlighted their contribution to the worsening of cardiac function during central chemoreflex activation.Support or Funding InformationFondecyt 1180172; The basal Center of Excellence in Aging and Regeneration (AFB 170005)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.