Autonomic and respiratory consequences of altered chemoreflex function: clinical and therapeutic implications in cardiovascular diseases

Abstract

The importance of chemoreflex function for cardiovascular health is increasingly recognized in clinical practice. The physiological function of the chemoreflex is to constantly adjust ventilation and circulatory control to match respiratory gases to metabolism. This is achieved in a highly integrated fashion with the baroreflex and the ergoreflex. The functionality of chemoreceptors is altered in cardiovascular diseases, causing unstable ventilation and apnoeas and promoting sympathovagal imbalance, and it is associated with arrhythmias and fatal cardiorespiratory events. In the last few years, opportunities to desensitize hyperactive chemoreceptors have emerged as potential options for treatment of hypertension and heart failure. This review summarizes up to date evidence of chemoreflex physiology/pathophysiology, highlighting the clinical significance of chemoreflex dysfunction, and lists the latest proof of concept studies based on modulation of the chemoreflex as a novel target in cardiovascular diseases.

Keywords: Arrhythmias; Baroreflex; Chemoreflex; Ergoreflex; Heart failure; Hypertension; Sleep apnoea.

Figure 1.. The integrated system of neuroreflexes

The central chemoreflex (CR) network is a highly integrated system of neurons and glia. Afferents from peripheral CR, baroreceptors, and ergoreflex receptors reach the brainstem at the nucleus tracti solitari (NTS) and rostral ventrolateral medulla (RVLM), where they interact with central CR signals. Together, all those systems regulate ventilation via the central pattern generator (CPG), blood pressure and heart rate via RVLM, and arousal/alertness responses through ascending cortical pathways. 5-HT: 5-hydroxytryptamine neurons (serotonergic); CVLM: caudal ventrolateral medulla; LC: locus coeruleus; SNS: sympathetic nervous system; RTN: retrotrapezoid nucleus.

Figure 2.. Rebreathing test.

Hypoxic hypercapnic (filled circles) and hyperoxic hypercapnic (open circles) rebreathing tests displayed plotting end tidal carbon dioxide (P_ETCO₂) as a function of ventilation (A) or muscle sympathetic nervous activity (MSNA) in a healthy volunteer. Big circles refer to bin-averaged values (from different subjects) of ventilation (left panel) and MSNA (right panel) for 2 mmHg intervals of P_ETCO₂ variation. Whiskers refer to the standard deviation of P_ETCO₂ (horizontal whiskers), and either ventilation or MSNA (vertical whiskers). Fitted double linear models are superimposed over the data (hyperoxia, black and hypoxia, grey). Gently taken and adapted (with permission) from Keir et al.

Figure 3.. Abnormal baroreflex (BRS) and chemoreflex sensitivities (CRS) in patients with chronic heart failure (HF).

Abnormal BRS and CRS may be frequently observed in chronic HF patients on modern therapies and both contribute to autonomic dysfunction. Abormal BRS is also associated with functional impairment and a significantly higher risk of cardiac death, while abnormal CRS (particularly when both the hypoxic [HVR] and the hypercapnic ventilatory responses [HCVR] are heightened) is associated with ventilatory instability and higher risk of HF hospitalization. When both reflexes are abnormal, the risk of adverse events is very high, with less than 10% of patients being free of events over a 60-month follow-up. Taken and adapted with permission from Giannoni A et al.

Figure 4.. Potential treatments of chemoreflex hyperactivation in heart failure and hypertension

In hypertension, surgical denervation of carotid bodies or their silencing with oxygen (O₂) has also been proposed to treat hyperactive peripheral chemoreceptors (CR), together with pharmacological modulation of the purinergic signaling with the novel P2X receptor (P2XR) antagonists. Similarly, pharmacological treatment of hyperactive central CR has also been tested with orexinergic receptor (OR) antagonists (almorexant and suvorexant) in neurogenic hypertension and high loop-gain obstructive apnoeas. In heart failure, modulation of carotid bodies with O₂ and CO₂ (especially given dynamically during CO₂ drops following hyperventilation), with caffeine or theophylline acting on the adenosine pathway, or with surgical denervation have been attempted to target hyperactive peripheral CR. Central CR modulation has also been attempted, both with exercise training and yoga and with pharmacological agents as buspirone, by decreasing the serotonergic firing.