Targeting autonomic imbalance in pathophysiology: is the carotid body the new nirvana? (2016)

Historically, and based on acute studies, much has been described about the powerful reflex control that the carotid body chemoreceptors have on ventilation, heart rate, blood pressure and the sympathoadrenal axis. Discussion on whether these are protective reflex responses or simply a homeostatic mechanism would make insightful reading. Chronically, the carotid body has been studied in conjunction with the reflex responses and adjustments made at high altitude, and it is well established that much of the pathology associated with sleep apnoea is a product of intermittent activation of the carotid body. Currently, attention is firmly on the carotid body and its causative role in numerous syndromes and disease states that involve autonomic imbalance. This issue of The Journal of Physiology contains a set of papers based on platform presentations that explored the breadth and depth of the carotid body's role in the initiation and progression of cardiometabolic and respiratory diseases. They were presented at the recent International Society of Autonomic Neuroscience (ISAN) meeting in Stresa, Italy (26–29 September 2015), which was the first joint ISAN meeting with the American Autonomic Society, the European Federation of Autonomic Societies and the Japan Society of Neurovegetative Research. The papers focus on disease states of insulin resistance, heart failure, hypertension and breathing disturbances. Peripheral chemosensitivity is a feature of numerous afferents on different organs throughout the body. One that is most intensively studied is the carotid body chemoreceptor. Represented bilaterally, the carotid bodies reside at the bifurcation of the common carotid artery, a major conduit of brain blood flow, and respond to hypoxia, hypercapnia, ischaemia, a drop in pH and low blood flow. Given their strategic location it is not surprising that carotid bodies mediate powerful and long lasting reflex responses as well as being capable of inducing synaptic plasticity within neural circuits regulating the autonomic and respiratory systems. Conde et al. (2017) consider whether the carotid body is responsible for the metabolic disturbances of insulin resistance, dyslipidaemia and raised sympathetic activity. They show that by disconnecting the carotid body's inputs to the brain they are able to reverse the pathophysiology of insulin resistance, hyperglycaemia, dyslipidaemia and hypertension in rats fed a hypercaloric diet. They argue that the signals driving the carotid body could be insulin itself (but not glucose) as insulin receptors are present within the carotid body. They also consider leptin, pro-inflammatory cytokines and reactive oxygen species as possible mechanisms driving a carotid body–sympathoadrenal reflex pathway causing insulin resistance. It will become clear that alterations in inflammatory mediated process and the redox state within the carotid body appear common to a number of disease states. Toledo et al. (2017) review the compelling evidence of the therapeutic action of removing both carotid bodies in animals with heart failure. They describe both hyperreflexia and pathological tonicity generation by the carotid bodies in heart failure. Removing carotid bodies bilaterally regained autonomic balance with profound reductions in sympathetic activity, reduced cardiac arrhythmias and alleviation of breathing irregularities and apnoeas. Important clinically, they show that bilateral carotid body ablation also improved survival post-myocardial infarct in these animals. Discussion of possible mediators of carotid body sensitivity and tonicity included angiotensin II, oxidative stress and NADPH generation, and reduced blood flow resulting from lowered cardiac output. Toledo et al. (2017) also discuss the potential role of the central chemoreceptors and in particular carbon dioxide-sensitive neurones of the retrotrapezoid body and how these may contribute to the sympathetic excess and breathing disturbances in heart failure. Given that the carbon dioxide sensitivity is elevated in patients with heart failure, and is correlated with the severity of the condition, a contribution of central chemoreceptors to sympathetic excess in heart failure cannot be ruled out. The peripheral and central chemoreceptors may work in a complimentary and integral fashion as the carotid body also detects carbon dioxide and provides a significant excitatory drive to the retrotrapezoid neurones. The question would be whether reducing peripheral chemosensitivity in an animal with heart failure affects central chemoreceptor reflex sensitivity to carbon dioxide and how this relates to survival in heart failure. The coupling between these mechanisms is without question important to our comprehensive understanding of autonomic imbalance and one wonders whether other diseases in which the carotid body has been proposed as a culprit, such as insulin resistance, may also involve alterations in central chemoreception that precipitates sympathetic excess and breathing disturbances. The aforementioned papers were based on animal models that have led the authors to make clinical predictions about removing carotid bodies to alleviate disease symptoms; these have included insulin resistance, hypertension and sympathetic excess. The paper presented by Niewinski (2017) considers possible surgical complications and outcomes if carotid bodies are removed from patients with systolic heart failure. A phenotype of heart failure includes an exaggerated respiratory response to transient breathing of nitrogen. This has been termed the hypoxic ventilatory response and is used as a gauge of peripheral chemoreflex sensitivity, at least for the reflex ventilatory adjustment, as it is correlated with the severity of the condition. Niewinski (2017) describes how a loss of hypoxic sensing may be deleterious in terms of sleep apnoeas, often present in heart failure patients, and could augment apnoea duration thereby lowering oxygen desaturations. The offer of unilateral carotid body resection is voiced as a plausible and safer alternative strategy. Niewinski (2017) also emphasises the need to adequately screen patients: proof that they have high carotid body sensitivity by assessing the hypoxic ventilatory response is imperative as is the presence of high sympathetic tone. The point is well made that reducing sympathetic activity too much could be equally deleterious. Lowering blood pressure in heart failure is also likely to be counterproductive causing poor end organ blood flow and triggering baroreceptor reflex increases in sympathetic activity, compounding sympathetically mediated cardiac arrhythmias. Thus, careful consideration and patient phenotyping will be needed if carotid body ablation is to be used to treat a sympathetically mediated disease. Many cardiometabolic diseases are associated with sleep disturbances in breathing as seen in heart failure mentioned above. This causes frequent periods of apnoea and hypopnoea and resultant reductions in blood oxygen saturation and rises in carbon dioxide during sleep. To mimic these frequent hypoxic periods, animals have been subjected to intermittent hypoxia which causes apnoeas and hypertension. Nanduri et al. (2017) report on the mechanisms involved within the carotid body that underlie its sensitisation caused by intermittent hypoxia exposure. Such exposure caused hypertension, irregular breathing and raised plasma catecholamines as well as elevations in reactive oxygen species within the carotid body. Nanduri et al. (2017) review how anti-oxidant enzymes are depressed in the carotid body following long term exposure to intermittent hypoxia. This was found to be due to increased DNA methylation of genes encoding the anti-oxidant enzymes. Indeed by blocking DNA methylation, the hypertension and breathing irregularity were eliminated in rats. This review shows how an environmental stimulus (intermittent hypoxia) can affect gene expression that causes a cascade of events centred on altering the redox state within the carotid body resulting in its sensitisation, which through reflex responses agonise pathology. Indeed, the authors conclude that blocking DNA methylation may assist patients with sleep apnoea. Whether such a mechanism is present in insulin resistance and heart failure remains to be established. In conclusion, this series of papers highlights a paradigm shift in our thinking about novel ways to combat cardiometabolic and respiratory diseases by targeting sources of peripheral afferent activity that drive sympathoexcitation. Given its powerful reflex responses and the remedial actions when its activity is removed or diminished, the carotid body appears to be a most viable target for many diseases in which autonomic imbalance exists, at least in rodent models. Although the importance to human disease has been speculated upon, the bold step of actually translating from rat-ology to human diseases will be critical in determining the real potential of the carotid body as an efficacious therapeutic target.