Ablation of the carotid bodies in disease: meeting its adverse effects

It is now 26 years since the publication of a seminal study that showed that carotid body (CB) chemoreceptors are involved in the progression of chronic intermittent hypoxia-induced hypertension (Fletcher et al. 1992). In that pioneer animal study, the authors showed that bilateral CB resection prevented the development of hypertension in rats exposed for 35 days to chronic intermittent hypoxia, which mimics the chronic intermittent hypoxia aspect of sleep apnoea (OSA) in humans (Fletcher et al. 1992). Over the subsequent decades, several reports came out linking the increased CB activity with the development and maintenance of several pathologies such as essential hypertension, OSA, chronic heart failure and type 2 diabetes. The role of the CB in the development and maintenance of these pathologies has been unveiled and this was only achievable due to the ability to ablate or resect the CB or its sensitive nerve, the carotid sinus nerve (CSN). For example, Abdala et al. (2012) showed in spontaneously hypertensive rats that bilateral resection of the CSN reduced both the development of hypertension and its maintenance, and was also associated with a reduction in sympathetic vasomotor tone, demonstrating that the CB is responsible for elevated sympathetic tone and critical for the genesis of hypertension in spontaneously hypertensive rats. Following animal studies and consistent with the role of the CB in these pathologies, the ablation of the CB was identified as having therapeutic potential for the treatment of these diseases and used in several clinical studies performed for essential hypertension and chronic heart failure. Distinct ablation techniques have been employed in the clinical studies, from surgical CB ablation to CB transvenous ultrasound ablation, with other techniques being also patented (cryo-ablation). Yet, some fundamental issues remain to be fully resolved, not least of which are the side effects related to CB ablation and therefore to the safety of these therapeutics. Knowing that the CBs mediate the responses to acute stressors such as hypoxia, hypercapnia and exercise, and due to the close proximity with the carotid baroreceptors, it is expected that CB ablation, and in particular surgical CB removal, might produce adverse effects, especially in conditions where CB activity is increased as in hypertension, heart failure and type 2 diabetes. The article by Pijacka et al. (2018), published in this issue of The Journal of Physiology, describes a new surgical approach in rats for the selective ablation of the CBs that spares the functional integrity of the carotid sinus baroreceptors and investigates the potential impact of CB removal on the response to acute stressors, such as exercise, hypoxia and hypercapnia, in conditions of hypertension. These authors have been, for the first time, able to surgically remove the CB chemoreflex without affecting the baroreflex. They showed that surgical selective ablation of the CB chemoreflex abolished the increase in systolic blood pressure and bradycardia induced by intravenous sodium cyanide administration, while the baroreceptor reflex gain, evaluated by the responses to phenylephrine and sodium nitroprusside, was maintained. Whereas this might be very interesting from the perspective of translation to humans, as it could avoid adverse effects related to baroreceptor removal, the surgical selective removal of the CB chemoreflex is technically difficult even at a large scale, as in humans. Perhaps more importantly, this study demonstrates the importance of the CB in the haemodynamic responses to acute stressors such as hypoxia and hypercapnia in conditions of hypertension, since the rise in blood pressure during these stressors was abolished and augmented, respectively, after selective CB removal while the response to exercise was unaffected. Therefore, the article by Pijacka et al. (2018) provides the first demonstration of the potential cardiovascular risks of CB ablation during hypoxia and hypercapnia in hypertensive rats and clearly suggests that methods to decrease the overactivation of the CB that is seen in pathological states could provide therapeutic advantages in relation to CB ablation methods. For example, Pijacka et al. (2016) found that ATP acting via P2X3 receptors is responsible for the CB hyperactivity and hyperreflexia seen in essential hypertension, supporting the idea of the modulation of P2X3 receptors as a non-surgical strategy to control human hypertension. More recently, Sacramento et al. (2018) demonstrated that bilateral bioelectronic modulation of CSN activity restores insulin sensitivity and glucose tolerance in a rat model of type 2 diabetes suggesting that a bioelectronic medicine approach could bring significant advances to standard care for type 2 diabetes, providing long-term glucose control and avoiding systemic effects. In this context and for safety purposes, studies are needed to find and refine therapeutic approaches that target the CB to reduce its activity and not to destroy it so that chemoreflex function is preserved.