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 () 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.
Highlights
Heart failure (HF) affects more than 20% of the population over 75 yr of age, and its prevalence is expected to double by 2030 (34)
The main aim of this study was to assess whether acute episodic stimulation of chemoreceptors with hypercapnia in the setting of volume overload HF could elicit ventilatory plasticity, leading to the onset of irregular breathing patterns and autonomic imbalance (3, 7, 11, 18)
We show that episodic stimulation of the central chemoreflex elicits ventilatory long-term depression in normal rats, which was not observed in HFϩVeh animals
Summary
Heart failure (HF) affects more than 20% of the population over 75 yr of age, and its prevalence is expected to double by 2030 (34). Disordered breathing (3, 11) and autonomic dysfunction (19) are pathophysiological hallmarks of HF, which are associated with deterioration of cardiac function and increased mortality risk (16, 19, 42). Chemoreflexes, is thought to play a crucial role in the development of these autonomic and respiratory disturbances (8, 11, 40). In support of this notion, HF patients display enhanced ventilatory responses to hypoxia and/or hypercapnia (11). We have shown that volume overload HF rats display enhanced central chemoreflex (CC) gain concomitant with autonomic dysfunction (7, 39). Of note, enhanced central chemoreflex gain was correlated with disordered breathing and augmented sympathetic tone in these animals (39). No comprehensive studies addressing a link between central chemoreceptors and cardiorespiratory alterations in volume overload HF have been conducted
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