Is carotid body denervation the silver bullet for heart failure?

The carotid body chemoreceptors are traditionally viewed as the body's primary oxygen sensors. Activation of the carotid body chemoreceptors in response to a fall in arterial oxygen levels results in reflex increases in both ventilation and sympathetic nervous system activity. Additionally, a growing body of experimental evidence in both animals and humans supports a role for the carotid body chemoreceptors in the pathophysiology of several sympathoexcitatory conditions such as hypertension, sleep apnoea and congestive heart failure (CHF).

Consistent with this idea, in a recent issue of The Journal Physiology, Marcus and colleagues (Marcus et al. 2013) confirmed that the carotid body chemoreceptors play a central role in CHF pathophysiology. Expanding on their previous experiments in rats (Del Rio et al. 2013), Marcus et al. induced CHF in a group of rabbits through ventricular pacing and examined the effect of carotid body denervation on ventilation, autonomic nervous system activity and markers of cardiac function. Remarkably, only 9 days after denervation, a number of ventilatory, autonomic and cardiac function variables commonly impaired in CHF were improved. These results raise several important questions regarding the contribution of the carotid body chemoreceptors to CHF pathophysiology: how does carotid body denervation initiate improvements in CHF; what is the link between the carotid body chemoreceptors and cardiac function in CHF; could carotid body denervation replace traditional therapeutic strategies for CHF?

Temporal changes in CHF following carotid body denervation

Given the widespread benefits of carotid body denervation on CHF pathophysiology, it may be difficult to determine the driving mechanism behind the observed adaptations. Importantly, Marcus and colleagues (Marcus et al. 2013) examined the temporal sequence of changes in ventilatory parameters, autonomic activity and markers of cardiac function. Initially, carotid body denervation rapidly (3 days post) abolished the elevation in peripheral chemosensitivity, improved measures of ventilation, decreased oscillatory breathing, lowered the frequency of apnoeic events, and reduced the incidence of ventricular arrhythmias. Following these improvements (6–9 days post), left ventricular diastolic and systolic volumes progressed toward pre-CHF values. Although arterial blood gases were not reported, we speculate that the initial reduction in the frequency of apnoeic events and oscillatory breathing in carotid body-denervated rabbits resulted in improvements in arterial oxygen levels. Along with the restoration in autonomic balance, corrections in circulating oxygen can positively influence cardiac function. Consequently, by reducing drastic fluctuations in blood gasses, carotid body denervation in CHF may decrease the frequency of arrhythmias and improve cardiac function. In this context, cardiomyocytes exposed to hypoxia have abnormal L-type calcium channel function. Reduced calcium flux into cardiomyocytes probably reduces intracellular release of calcium stored in the sarcoplasmic reticulum. In support of this, CHF rats have abnormal calcium release from the sarcoplasmic reticulum (Hu et al. 2011). Collectively, impaired calcium handling in cardiomyocytes might lead to an increase in arrhythmia frequency and compromised excitation–contraction coupling in CHF – both of which are linked to impairments in cardiac function.

Targeting ventilation

Given the temporal findings from Marcus and colleagues, carotid body denervation probably contributes to improved CHF pathophysiology through initial changes in ventilation. Breathing disorders, primarily during sleep and/or exercise, are present in a majority of CHF patients and are thought to accelerate the progression of CHF by augmenting carotid body chemoreceptor-mediated sympathetic activity. Along these lines, treatment with positive airway pressure (PAP) and/or oxygen therapies can decrease carotid body chemosensitivity, reverse oscillatory breathing, and reduce the apnoea/hypopnoea index in patients with CHF. Although some effects of PAP on measures of cardiac function in CHF patients are probably attributed to changes in intrathoracic pressures, PAP therapies have been shown to have similar systemic effects to those presented by Marcus and colleagues (Marcus et al. 2013), such as improved blood oxygenation, reduced sympathetic nervous system activity, increased heart rate variability, increased baroreflex sensitivity, alleviation of hypertension, increased cardiac output, and increased left ventricular ejection fraction. Furthermore, even acute hyperoxic exposures can improve heart rate variability and baroreflex sensitivity in patients with CHF. In this context, antioxidant therapy directed at reducing oxidative stress within the carotid body may also blunt chemosensitivity. Although each have their own limitations, these collective data suggest that interventions targeted at reducing elevated carotid body chemosensitivity in patients with CHF may result in, not only improvements in ventilatory parameters, but also measures of autonomic and cardiac function. Because these clinical interventions in humans elicit similar benefits to those of early carotid body denervation in rabbits (Marcus et al. 2013) and rats (Del Rio et al. 2013), they clearly indicate an important role of the carotid body in the pathophysiology and progression of cardiac dysfunction in CHF.

A directed approach in humans

Carotid body resection in humans has been used to treat carotid body tumours, asthma and chronic obstructive pulmonary disease. However, the first attempt at carotid body removal for the treatment of human CHF was only recently reported by Niewinski and colleagues (2013). Similar to the results from both rabbit (Marcus et al. 2013) and rat (Del Rio et al. 2013) models of CHF, unilateral removal of the right carotid body chemoreceptor from a patient with CHF resulted in a prompt (1 month post-surgery) decrease in peripheral chemosensitivity. This observation was followed (2 months post-surgery) by a reduction in the apnoea/hypopnoea index, improved autonomic function, and increased ejection fraction (Niewinski et al. 2013). More recent work by the same group using bilateral carotid body resection shows similar reductions in peripheral chemosensitivity in a larger cohort of CHF patients. Although this is still a very new area of exploration in humans, it appears that unilateral or bilateral removal of the carotid body chemoreceptors may be a viable treatment option for patients with CHF. However, long-term outcomes in patients with overt cardiovascular disease have yet to be systematically examined. Furthermore, in line with recent results obtained from rats which show large interindividual variations in carotid body signalling (Peng et al. 2014), not all CHF patients have elevated carotid body chemosensitivity; therefore, would denervation or alternative approaches which lower carotid body chemosensitivity be beneficial in these patients?

Widespread effects

Carotid body denervation presents a unique opportunity to potentially eliminate a host of CHF-mediated maladaptations with a single ‘treatment’. Because of its beneficial and widespread effects, carotid body denervation raises the question: are traditional therapies no longer necessary in CHF patients? Similar to the changes following carotid body denervation (Del Rio et al. 2013; Marcus et al. 2013), β–blocker therapy reduces cardiac arrhythmias, limits unfavourable cardiac remodelling, reduces sympathetic activity and lowers the risk of all-cause mortality in CHF patients. Furthermore, any reduction in renal sympathetic nerve activity due to carotid body denervation may improve the regulation of blood volume and eliminate the need for angiotensin-converting enzyme inhibitors, aldosterone antagonists, or loop diuretics. Interesting follow-up studies could examine these comparisons or perhaps how the widespread physiological responses to carotid body denervation interact with these traditional therapies. Additionally, a direct comparison between carotid body denervation and exercise training in CHF, which shares many of the same benefits as carotid body denervation, would also be intriguing.

Conclusion

A growing body of evidence from both animals and humans suggests that the carotid body chemoreceptors are chronically activated in CHF. Importantly, the work by Marcus and colleagues (Del Rio et al. 2013; Marcus et al. 2013) confirms the idea that the activated carotid body chemoreceptors contribute to disordered breathing patterns and elevated sympathetic nerve activity in CHF. Interestingly, the activated carotid body chemoreceptors also appear to contribute to cardiac dysfunction and denervation of the carotid bodies can initiate improvements in cardiac function. In this context, could therapies directed at reducing carotid body activation be a silver bullet to treat CHF? Regardless of whether carotid body denervation becomes a reality for the treatment of CHF in humans, the recent work by Marcus and colleagues (Marcus et al. 2013) clearly highlights the importance of the carotid body chemoreceptors in the pathophysiology and progression of cardiac dysfunction in CHF.

Additional information

Competing interests

None declared.