Episodic stimulation of central chemoreceptor neurons elicits disordered breathing and autonomic dysfunction in volume overload heart failure

Abstract

Enhanced central chemoreflex (CC) gain is observed in volume overload heart failure (HF) and is correlated with autonomic dysfunction and breathing disorders. The aim of this study was to determine the role of the CC in the development of respiratory and autonomic dysfunction in HF. Volume overload was surgically created to induce HF in male Sprague-Dawley rats. Radiotelemetry transmitters were implanted for continuous monitoring of blood pressure and heart rate. After recovering from surgery, conscious unrestrained rats were exposed to episodic hypercapnic stimulation [EHS; 10 cycles/5 min, inspiratory fraction of carbon dioxide ([Formula: see text]) 7%] in a whole body plethysmograph for recording of cardiorespiratory function. To determine the contribution of CC to cardiorespiratory variables, selective ablation of chemoreceptor neurons within the retrotrapezoid nucleus (RTN) was performed via injection of saporin toxin conjugated to substance P (SSP-SAP). Vehicle-treated rats (HF+Veh and Sham+Veh) were used as controls for SSP-SAP experiments. Sixty minutes post-EHS, minute ventilation was depressed in sham animals relative to HF animals (ΔV̇e: −5.55 ± 2.10 vs. 1.24 ± 1.35 mL/min 100 g, P < 0.05; Sham+Veh vs. HF+Veh). Furthermore, EHS resulted in autonomic imbalance, cardiorespiratory entrainment, and ventilatory disturbances in HF+Veh but not Sham+Veh rats, and these effects were significantly attenuated by SSP-SAP treatment. Also, the apnea-hypopnea index (AHI) was significantly lower in HF+SSP-SAP rats compared with HF+Veh rats (AHI: 5.5 ± 0.8 vs. 14.4 ± 1.3 events/h, HF+SSP-SAP vs. HF+Veh, respectively, P < 0.05). Finally, EHS-induced respiratory-cardiovascular coupling in HF rats depends on RTN chemoreceptor neurons because it was reduced by SSP-SAP treatment. Overall, EHS triggers ventilatory plasticity and elicits cardiorespiratory abnormalities in HF that are largely dependent on RTN chemoreceptor neurons.

Effects of enriched-potassium diet on cardiorespiratory outcomes in experimental non-ischemic chronic heart failure

“…Non-ischemic chronic heart failure (CHF) was produced by the surgical creation of an arteriovenous shunt between the abdominal aorta and the cava vein to induced chronic volume overload [ 16 , 17 , 31 – 34 ]. Under anesthesia (induction with 5% of isoflurane and 2% for maintenance, balance with O 2 ) laparotomy was performed.…”

“…Recordings were made from the left parasternal short-axis view. An increase of 1.5-fold in the end diastolic volume (EDV) and stroke volume (SV) relative to sham condition were the criteria for CHF [ 16 , 17 , 31 , 33 , 34 ]. Left ventricle (LV) end diastolic and systolic diameter (LVEDD and LVESD, respectively) were measured from 3 consecutive cycles.…”

ERS International Congress, Madrid, 2019: highlights from the Sleep and Clinical Physiology Assembly

“…However, disordered breathing and autonomic dysfunction are pathophysiological hallmarks of heart failure. Using a heart failure rat model where chemoreceptors of the retrotrapezoid nucleus (RTN) were destroyed, DÍAZ et al [35] showed that episodic hypercapnia stimulation triggers ventilator plasticity and elicits cardiorespiratory abnormalities that depend on RTN neurons. Using the same model but eliminating the brainstem pre-sympathetic neurons (RVLM-C1) instead, DEL RIO et al [36] showed that they play a major role in development/maintenance of irregular breathing pattern.…”

“…Using a heart failure rat model where chemoreceptors of the retrotrapezoid nucleus (RTN) were destroyed, D íaz et al . [ 35 ] showed that episodic hypercapnia stimulation triggers ventilator plasticity and elicits cardiorespiratory abnormalities that depend on RTN neurons. Using the same model but eliminating the brainstem pre-sympathetic neurons (RVLM-C1) instead, D el R io et al .…”

Taking it to heart: dissecting cardiopulmonary interactions in diseases of the lung and the cardiovascular system

“…These articles center on a variety of topics such as sex differences and estrogen signaling in RV function in PH (9,18); effects of perinatal hyperoxia or hypoxia on RV function later in life (10,15); effects of HIV, opioids, or vaping on endothelial function and cardiorespiratory parameters (1, 3); bone morphogenetic protein receptor 2 (BMPR2) regulation of insulin and glucose signaling in cardiomyocytes ( 13); interdependence of RV glucose uptake, hypoxia and ␤-adrenergic receptor signaling in PH (28); effects of pulmonary vascular thrombospondin 1/CD47 signaling on RV afterload in sickle cell disease (22); differences in mesothelial mobilization between the developing lung and heart (19); and effects of episodic hypercapnic stimulation on respiratory-cardiovascular coupling in volume-overload heart failure (6). Two studies assessed the effects of established treatments for pulmonary arterial hypertension (PAH; used in combination with other established or emerging PAH treatments) on RV adaptation, using novel end points or novel delivery methods (16,23).…”