Translating physiology of the arterial chemoreflex into novel therapeutic interventions targeting carotid bodies in cardiometabolic disorders

Abstract

This review resulted from a conference on the pathological role of arterial chemoreflex and carotid bodies in cardiometabolic diseases held at the 27th Congress of the Polish Cardiac Society in September 2023 in Poznan, Poland. It reflects the contribution of Polish researchers and their international collaborations, which have been fundamental in the development of the field. Aberrant activity of the carotid bodies leads to both high tonicity and increased sensitivity of the arterial chemoreflex with resultant sympathoexcitation in chronic heart failure, resistant hypertension and obstructive sleep apnoea. This observation has led to several successful attempts of removing or denervating the carotid bodies as a therapeutic option in humans. Regrettably, such interventions are accompanied by serious respiratory and acid-base balance side-effects. Rather than a single stereotyped reaction, arterial chemoreflex comprises an integrative multi-system response to a variety of stimulants and its specific reflex components may be individually conveyed at varying intensities. Recent research has revealed that carotid bodies express diverse receptors, synthesize a cocktail of mediators, and respond to a plethora of metabolic, hormonal and autonomic nervous stimuli. This state-of-the-art summary discusses exciting new discoveries regarding GLP-1 receptors, purinergic receptors, the glutamate-GABA system, efferent innervation and regulation of blood flow in the carotid body and how they open new avenues for novel pharmacological treatments selectively targeting specific receptors, mediators and neural pathways to correct distinct responses of the carotid body-evoked arterial chemoreflex in cardiometabolic diseases. The carotid body offers novel and advantageous therapeutic opportunities for future consideration by trialists.

Keywords: carotid body; diabetes mellitus; heart failure; hyperglycaemia; hypertension; hypoxia; sleep apnoea; sympathetic nervous system.

Figure 1. The ribbon cable hypothesis of carotid body connectivity

The CB contains clusters of chemosensitive glomus cells (type I) that show varied sensitivities to distinct and specific stimuli (e.g. oxygen partial pressures, acidity) and have unique neurochemical phenotypes (expressed enzymes, receptors, transmembrane transporters and transmitters). Histological and functional evidence indicates that different glomus cells and their clusters may be connected to defined physiological outputs and reflex arcs. Distinct/separate/individual pathways connecting the CB with the NTS and other centres of the brainstem would allow for selective or preferential engagement of various effectors of the arterial chemoreflex (Zera et al., 2019). Glomus cells and the CB vasculature receive efferent postganglionic sympathetic fibres from the superior cervical ganglion (SCG) via the ganglioglomerular nerve (GGN) that may modulate CB activity directly by acting on the glomus cells or by affecting CB blood flow (Brognara et al., ; Gold et al., 2022). Created with Biorender.com. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2. Hyperactivity of the CB and arterial chemoreflex comprises hypertonicity and hyperreflexia

Carotid sinus nerve (CSN) activity in the normotensive rat (NTR) and spontaneously hypertensive rat (SHR) in response to decreased levels of oxygen in respiratory gas mixture [$F_{{\mathrm{O}}_2}$ (%)] shows a greater response in SHR (hyperactivity) – note that CO₂ [$F_{\mathrm{C}{\mathrm{O}}_2}$ (%)] and blood pressure (BP) are kept constant (A); response of the CSN activity to varied levels of oxygen [$F_{\mathrm{ET}{\mathrm{O}}_2}$ (%)] shows a steeper slope (hyperreflexia) and right‐shift of the relationship to higher concentrations of O₂ (hypertonicity) (B) (Fukuda et al., 1987). Recordings of CSN activity in SHR and normotensive Wistar rats at rest and in response to pharmacological CB‐evoked chemoreflex with cyanide show increased tonicity and hyperreflexia (increased reflex sensitivity) in hypertensive rats (C); quantitative evaluation of hypertonicity (D) and hyperreflexia (E) in SHR rats (red bars) (Pijacka et al., 2016). Reproduced with permission from Fukuda et al. (1987) and Pijacka et al. (2016). [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 3. Hyperactivity of the arterial chemoreflex in obstructive sleep apnoea, hypertension and heart failure

Electrocardiogram (ECG) and sympathetic nerve activity (SNA) in a patient with obstructive sleep apnoea (OSA; top) and a normal subject (bottom) recorded in resting conditions and in the third minute of hypoxia. During hypoxia, increase in minute ventilation and heart rate were higher in patients with obstructive sleep apnoea compared to the control group; increased sympathetic activity was particularly evident during the apnoea, indicative of hyperreflexia (A) (Narkiewicz et al., 1999). ECG and muscle SNA (MSNA) in a hypertensive patient (top) and normotensive subject (bottom) exposed to room oxygen and during hyperoxia to silence arterial chemoreceptors; hyperoxia‐induced reduction of MSNA was greater in the hypertensive patient, indicative of hypertonicity (B) (Sinski et al., 2012). Bilateral CB ablation (CBX) in a heart failure patient reduced SNA (C) (Niewinski et al., 2017). Unilateral CBX in resistant hypertensive patients decreased SNA at 6 months (6M) from baseline in responders (blue), and had no effect on non‐responders (red) (D) (Narkiewicz et al., 2016). These CBX trials show tonic CB‐evoked sympathoexcitation in heart failure and hypertension in humans. Reproduced with permission from Narkiewicz et al. (1999), Sinski et al. (2012), Niewinski et al. (2017) and under CC‐BY licence from Narkiewicz et al. (2016). [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 4. Evaluation of arterial chemoreflex in humans

Activation of the chemoreflex includes (counterclockwise): (1) acute exposure to pure nitrogen (N₂) leading to a decrease in arterial O₂ and hypocapnia; (2) single breath CO₂ producing hypercapnia and transient hypoxia; (3) exposure to hyperoxia leading to an increase in arterial O₂ and decrease in CO₂; (4) steady‐state hypoxia with clamped CO₂ levels allowing for precise control over stimulus; (5) classic rebreathing; and (6) Duffin's modified rebreathing method. The advantages and disadvantages of each method are in black and red font, respectively. Created with Biorender.com. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 5. Preferential involvement of purinergic P2X receptors in CB‐evoked sympathoexciation in hypertension and heart failure

The P2X3 and P2X2/3 antagonist (AF‐353) applied bilaterally to both carotid bodies normalizes the ongoing basal thoracic chain sympathetic activity (arrow) in spontaneously hypertensive rats (SHR) to the levels of normotensive Wistar rats and attenuates the sympathetic nerve reflex response (arrowhead) to pharmacologically evoked arterial chemoreflex with sodium cyanide (NaCN) without affecting phrenic nerve activity (PN) (A) (Pijacka et al., 2016). Administration of the P2X3 and P2X2/3 antagonist (AF‐353) to the CBs attenuated sympathetic hyperactivity and abolished spontaneous CB discharge causing sympathetic activity surges and CB‐induced apnoea (B) (Lataro et al., 2023). Abbreviations: thoracic chain sympathetic activity (raw – tSN; integrated – ∫tSN) and phrenic activity (raw – PN; integrated – ∫PN) and heart rate (HR). Reproduced with permission from Pijacka et al. (2016) and under CC‐BY licence from Lataro et al. (2023).

Figure 6. Incretins and CB‐evoked sympathoexcitation

Administration of exendin‐4, a GLP1R agonist, locally into the CB in the in situ working heart–brainstem preparation (A) or systemically in vivo in conscious rats (B) decreased CB‐evoked sympathoexcitation and blood pressure rises, respectively, in response to pharmacological activation of the CB with sodium cyanide (NaCN) in both normotensive Wistar‐Kyoto (WKY) and spontaneously hypertensive (SHR) rats (Pauza et al., 2022). Abbreviations: sympathetic nerve activity (raw – tSNA; integrated – ∫tSNA); heart rate (HR); arterial pressure (AP). Reproduced under CC‐BY licence from Pauza et al. (2022).

Figure 7. Local down‐regulation of P2X3 receptors in the CB decreases arterial blood pressure

The CB‐targeted local delivery of cationic microbubbles (CMBs) made of octafluoropropane (C3F8) with CRISPR/Cas9 plasmid engineered for disruption of the P2X3 gene with low‐intensity focused ultrasound (LIFU) (A) effectively down‐regulated mRNA expression of the P2X3 receptor in the CBs (B) and resulted in decreased arterial blood pressure evaluated at day 14 from baseline in a canine hypertension model as shown in pulsatile arterial pressure recordings (C) (Xue et al., 2021). Red dashed lines indicate 120 mmHg. Reproduced and modified with permission from Xue et al. (2021). [Colour figure can be viewed at wileyonlinelibrary.com]