Brainstem pre‐sympathetic neuron controls oscillatory breathing in heart failure
Authors: Del Rio Rodrigo , Andrade David C. , Toledo Camilo , Diaz Hugo S. , Lucero Claudia , Arce‐Alvarez Alexis 
Published: June 2021

Heart failure with preserved ejection fraction (HFpEF) is characterized by sympathoexcitation and breathing disturbances. We recently showed that rostral ventrolateral medulla (RVLM) pre‐sympathetic neurons are hyperactive in HFpEF and this was closely related to autonomic control impairment and disordered breathing. In addition, acute activation of the central chemoreflex (CC) worsens autonomic control and cardiac dysfunction. However, there are no direct evidence between the relationship of RVLM chronic hyperactivation, sympathoexcitation and breathing disturbances in HFpEF. We hypothesized that selective elimination of cathecolaminergic neurons from RVLM (C1 cells) delay cardiac deterioration in HFpEF rats. CHF was induced by volume overload in male Sprague‐Dawley rats (250±20g). The selective ablation of C1 RVLM neurons was performed by anti‐dopamine‐beta hydroxylase (DβH)–saporin toxin (DβH+SAP) injected stereotaxically into the RVLM (7.5 ng/150nl, bilateral). The degree of HF was estimated by echocardiography. Cardiac function was assessed by intraventricular pressure‐volume loops. Arrhythmia incidence and breathing disturbances were scored. Central and peripheral chemoreflex drives were study measuring hypercapnic and hypoxic ventilatory responses (HCVR and HVR, respectively). Autonomic control was assessed by propranolol (1 mg/kg i.p.) and atropine (1 mg/kg i.p.) tests, heart rate variability and time‐varying Kalman smoother method analysis. Also, lentiviral vector containing the light‐sensitive cation channel, Channelrhodopsin2, was stereotaxical injected into the RVLM to assess the effects of the solely activation of C1 cells on autonomic function and breathing regularity. Ablation of C1 RVLM neurons (80%) delay the decrease of fractional shortening in CHF rats (CHF+Veh: 59.3±5.1 vs. 45.1±1.3 %, p<0.05, pre vs. post vehicle, respectively; CHF+ DβH‐SAP: 57.2±4.7 vs. 51.1±4.8 %, p>0.05, pre vs. post toxin, respectively). In addition, CHF rats that underwent C1 neurons ablation showed improve sympathetic drive (−98.0±12.1 vs. −52.2±7.9 ΔHR, p<0.05, CHF+Veh vs. CHF+DβH‐SAP, respectively), diastolic (0.009±0.001 vs. 0.004±0.001 mmHg/μl, p<0.05, CHF+Veh vs. CHF+DβH‐SAP, respectively) and systolic function (0.2±0.01 vs. 0.5±0.1 mmHg/μl, p<0.05, CHF+Veh vs. CHF+DβH‐SAP, respectively) and cardiac arrhythmogenesis (91.0±20.5 vs. 48.3±14.6 events/hour, p<0.05, CHF+Veh vs. CHF+DβH‐SAP, respectively). Optogenetic stimulation of C1 neurons in vivo in healthy animals triggers irregular breathing, an effect that was abolished by C1 neurons ablation. Indeed, breath‐to‐breath interval variability and tidal volume oscillations following optogenetic stimulation were increased by 2‐ and 1.5‐ fold, respectively. Accordingly, CHF‐rats that underwent C1 neuron ablation showed normal resting breathing patterns. Indeed, breathing disorders were significantly lower in CHF+DβH‐SAP (9.0±1.3 vs. 6.0±1.7 events/hour, p<0.05, CHF+Veh vs. CHF+DβH‐SAP, respectively). Also, sympathetic activation and cardiac diastolic function deterioration, induced by CC activation in CHF rats, were prevented by DβH‐SAP treatment. In summary, we showed for the first time that RVLM C1 neurons have a critical role on the progression of cardiac deterioration and breathing disorders in HFpEF. In addition, sympathoexcitation and cardiac function deterioration induced by CC activation are critically dependent on C1 neurons.Support or Funding InformationSupported by Fondecyt 1140275.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.