Turnaround in the history of carotid chemoreflex contribution to cardiorespiratory control in COPD: what are the upcoming chapters?

Corneille Heymans and colleagues conducted key studies in animal models in the 1930s investigating the neural control of breathing and circulation. One of their main findings was that the carotid bodies play a crucial role in ventilatory and circulatory responses to changes in the level of O₂, CO₂ and H⁺ in the arterial blood. Corneille Heymans's scientific achievements were promptly recognized by the scientific community, leading him to the award of a Nobel Prize in 1938. Soon after that, surgeons started to translate basic scientific findings into clinical practice. As an example of that, between the 1940s and the 1960s many patients with asthma were submitted to unilateral or bilateral removal of the carotid bodies in an attempt to correct the autonomic control of airways and reduce the drive to breathe and dyspnoea. Reports from that time suggested carotid chemoreceptor removal was successful for some phenotypes of patients with asthma. However, the successful advance of pharmacotherapy for asthma left behind the surgical removal of the carotid bodies.

Later, in the 1990s, it was supposed that patients with advanced chronic obstructive pulmonary disease (COPD), who presented chronic hypoxaemia, hypercapnia and alveolar hypoventilation, had low drive to breathe. And the drive reduction was supposedly attributable to low carotid chemoreflex activity and sensitivity. Based on that, doxapram, a carotid chemoreceptor stimulator, was used in an attempt to correct the hypothesized low carotid chemoreflex drive. However, the use of doxapram did not yield the expected results. Later, in the 2000s, the use of more robust approaches to assess the drive to breathe in humans revealed that patients with advanced COPD do not have low drive to breathe. Instead, they usually have high drive to breathe along with no ‘room’ to breathe due to hyperinflation.

Science moved on, and during the past 15 years or so, the focus of many studies on the role of the carotid chemoreflex in cardiorespiratory control has shifted direction toward the pathophysiology of cardiovascular diseases. Nowadays, compelling evidence indicates that carotid chemoreceptor tonic activity is increased in prevalent cardiovascular diseases, like systemic hypertension and chronic heart failure, even though classic stimuli of the carotid chemoreceptors are not present (i.e. hypoxia and hypercapnia). As a result, in one study carotid body denervation in young spontaneously hypertensive rats attenuated the resting arterial pressure increase throughout 13 weeks of follow‐up (Abdala et al. 2012). In addition, carotid body denervation in rats with coronary ligation‐induced chronic heart failure improved cardiorespiratory control and increased survival (Del Rio et al. 2013). Therefore, such novel findings have again brought the proposal of carotid body removal, but now for patients with resistant hypertension and advanced chronic heart failure.

Most of the beneficial effects of carotid body denervation in animal models of systemic hypertension and chronic heart failure seem to be attributed to reduced sympathetic outflow to the cardiovascular system. In this sense, patients with COPD have increased arterial stiffness and muscle sympathetic nerve activity, both of which contribute to worse cardiovascular function. In addition, even patients with mild COPD may have enough signals to enhance carotid chemoreceptor activity despite being normoxaemic (e.g. inflammation and oxidative stress). The burning question then is: does increased carotid chemoreflex activity contribute to dysfunctional cardiovascular control in patients with COPD?

This question was addressed by Phillips et al. (2018) in a recent publication in The Journal of Physiology. The authors assessed patients with mild to moderate COPD (GOLD stages I and II), who were normoxaemic at rest and peak exercise. In addition, patients had mean peak oxygen uptake within the normal range (i.e. >80% predicted), and had no established cardiovascular diseases or severe sleep apnoea. These patients were contrasted with age‐ and risk‐matched controls. Two different methods were used to acutely inhibit the activity of carotid chemoreceptors: inhalation of 100% O₂ and low‐dose intravenous dopamine infusion (2 μg kg⁻¹ min⁻¹). Furthermore, hyperoxia and dopamine were concomitantly administered to assure the inhibition of the carotid chemoreceptors. Inhalation of 21% O₂ under intravenous infusion of saline served as the control condition. All procedures were conducted in random order and patients were blinded as to experimental interventions. Endpoints included muscle sympathetic nerve activity (MSNA), which was measured only during normoxia and hyperoxia trials in a subset of the subjects, central and peripheral cardiovascular parameters, and pulmonary ventilation.

The main results were that hyperoxia reduced MSNA, peripheral pulse‐wave velocity and ventilation in patients with COPD, but not in controls. Dopamine and hyperoxia plus dopamine also reduced peripheral pulse‐wave velocity and ventilation only in patients with COPD, and furthermore, reduced central pulse‐wave velocity and mean arterial pressure, as well as raising brachial artery conductance and total vascular conductance. Collectively, these results suggest that the carotid chemoreflex tonically contributes to resting sympathetic outflow in patients with mild to moderate COPD, which may lead to increased mean arterial pressure, decreased vascular conductance and increased arterial stiffness. In addition, the carotid chemoreflex activity contributes to raise resting ventilation in mild to moderate COPD. Therefore, the results from Phillips et al. (2018) are in line with those mentioned in experimental models of systemic hypertension and chronic heart failure, suggesting a possible protagonism of the carotid chemoreflex for cardiovascular morbidity and mortality in patients with COPD.

The merit of the authors’ conducting well‐designed experiments in humans should be emphasized. Two different methods were used in isolation and combination to inhibit carotid chemoreceptors, which circumvented intrinsic limitations of systemic hyperoxia and dopamine administration, and, consequently, strengthened data interpretation. Measurement of sympathetic activity by a direct method (i.e. microneurography) was also a positive point. Moreover, investigation of carotid chemoreflex activity may have important implications, given that the carotid body tonus may be relevant 24 h a day, and not only during acute episodes of increased excitatory signals (e.g. hypoxia and hypercapnia).

As an interesting study, Phillips et al. (2018) raises new questions. An important one is: what mechanisms underlie the increase in the carotid chemoreflex activity in patients with COPD? The answer to this is crucial to advance therapeutic strategies. Multiple mechanisms have been shown to increase carotid chemoreceptor activity, including, for example, catecholamines, nitric oxide, angiotensin II, inflammation and oxidative stress (Kumar & Prabhakar, 2012). In this sense, some results from Phillips et al. (2018) give clues about possible mediators. For example, patients had normal oxygen saturation at rest and exercise. Therefore, chronic hypoxaemia did not seem to play a role. On the other hand, it is not possible to rule out that chronic intermittent hypoxia was not involved, because patients may have had some degree of sleep apnoea. Patients and controls presented similar MSNA, and so increased sympathetic activity to the carotid body may not be a key factor. Nitric oxide, angiotensin II, inflammation and oxidative stress were not measured, but are commonly altered in patients with COPD and may be involved. Of note, patients were assessed at rest, and other mechanisms may jump in during physiological challenges like physical exercise. For instance, our group recently showed that the ventilatory response to hypoxia (i.e. carotid chemoreflex stimulation) during passive limb movement (i.e. muscle mechanoreflex stimulation) was higher than the sum of ventilatory responses to isolated hypoxia and passive limb movement in healthy young humans. These results therefore support a hyperadditive interaction between the muscle mechanoreflex and the carotid chemoreflex for the regulation of ventilation, which, perhaps, may contribute to the cardiorespiratory control during exercise in subjects with both enhanced carotid chemoreflex and muscle reflexes, such as those with COPD (Silva et al. 2018).

Finally, testing the aforementioned mechanisms will certainly shed light on the increased carotid chemoreflex activity phenomenon. However, it is also important to take into account the possible translation of pathophysiological findings to patient care. For instance, if nitric oxide is involved in the increased carotid chemoreceptor activity, a specific pharmacological method to target the nitric oxide pathway may work for patients with mild COPD, but not for those with more advanced disease. The reason is that patients with advanced COPD commonly present chronic hypoxaemia, which leads to compensatory pulmonary vasoconstriction. Such hypoxic vasoconstriction ends up optimizing ventilation–perfusion matching. As a result, administration of sildenafil, a phosphodiesterase type 5 inhibitor, in patients with advanced COPD worsens pulmonary gas exchange provoking greater hypoxaemia and hypercapnia. Therefore, COPD severity and integrative physiology should be considered in the investigation of mechanisms responsible for the raised carotid chemoreflex activity in COPD to allow a proper translation of basic to clinical science.

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