Cardiac Chemoreflex: Targeting Carotid Bodies in Disease

The Role of Carotid Bodies in Cardiometabolic Disorders

The carotid bodies, small clusters of chemoreceptive cells located at the bifurcation of the carotid arteries, play a critical role in sensing changes in blood chemistry, particularly oxygen levels. These structures are integral to the arterial chemoreflex, a physiological mechanism that regulates respiratory and cardiovascular responses to maintain homeostasis. Aberrant activity of the carotid bodies can lead to sympathoexcitation and has been implicated in various cardiometabolic disorders, including heart failure, resistant hypertension, and obstructive sleep apnea (OSA) (Żera et al., 2025).

In chronic heart failure, for instance, increased sensitivity of the arterial chemoreflex is associated with heightened sympathetic nervous system activity, which can exacerbate the clinical condition. Studies have shown that interventions targeting the carotid bodies, such as surgical denervation, can reduce sympathetic overactivity, thereby improving cardiac function (Niewinski et al., 2017). However, these interventions often come with significant risks, including the potential for respiratory compromise and disrupted acid-base balance (Bardsley et al., 2023).

Furthermore, recent research has highlighted the role of various receptors within the carotid bodies, including glucagon-like peptide-1 (GLP-1) receptors, which suggest that pharmacological modulation of these receptors may offer new therapeutic avenues for treating diseases associated with carotid body dysfunction (Żera et al., 2025). Understanding the complex interplay between the carotid bodies and systemic metabolism is crucial for developing targeted interventions to mitigate the effects of cardiometabolic disorders.

Mechanisms Behind Arterial Chemoreflex Activation

The arterial chemoreflex is activated primarily by changes in arterial oxygen and carbon dioxide levels, as well as pH. When oxygen levels drop (hypoxia), the carotid bodies send signals to the brain to increase ventilation and adjust cardiovascular parameters to enhance oxygen delivery to tissues (Iturriaga et al., 2021). This response is mediated by a complex network of neurotransmitters and receptors, where glomus cells within the carotid bodies play a pivotal role.

Recent findings have expanded our understanding of the mechanisms involved in this activation. For instance, it has been shown that the closing of K+ channels in glomus cells due to hypoxia leads to depolarization, resulting in increased intracellular calcium and subsequent neurotransmitter release (Prabhakar, 2016a). This cascade of events ultimately results in increased sympathetic nervous system output, which is crucial for compensating for low oxygen levels.

In addition to oxygen sensing, the carotid bodies also respond to other metabolic signals, including glucose and lactate levels, thereby integrating multiple physiological responses. The presence of diverse receptors in the carotid bodies allows them to modulate their activity based on the specific metabolic state of the body, leading to unique reflexive responses tailored to the current physiological context (Gold et al., 2022; Zera et al., 2019).

Impacts of Carotid Denervation on Disease Progression

The surgical denervation of the carotid bodies has been explored as a therapeutic option for patients with chronic heart failure and resistant hypertension. Evidence suggests that this procedure can significantly reduce sympathetic nerve activity, leading to improvements in clinical outcomes (Niewinski et al., 2017). However, the benefits must be weighed against the risks, including potential respiratory complications.

In a study involving heart failure patients, those who underwent bilateral carotid body resection demonstrated a marked reduction in muscle sympathetic nerve activity and improved heart function (Niewinski et al., 2017). Conversely, the loss of chemosensitivity can result in impaired respiratory drive, particularly during sleep, leading to nocturnal hypoxemia and other complications (Niewinski et al., 2021).

Additionally, the long-term effects of carotid body denervation are not yet fully understood. While short-term benefits are evident, the potential for compensatory mechanisms to emerge, resulting in maladaptive responses, warrants further investigation. The arterial chemoreflex is a complex system, and interventions must consider the multifaceted nature of its regulation (Felippe et al., 2023).

Novel Therapeutic Approaches for Modulating Carotid Function

Recent advancements in our understanding of the carotid body’s role in cardiometabolic disorders have opened new avenues for therapeutic intervention. Rather than resorting to surgical denervation, researchers are exploring pharmacological agents that can selectively target receptors within the carotid bodies to modulate their activity without the associated risks of surgery.

For instance, GLP-1 receptor agonists have been shown to have cardioprotective effects and may enhance the function of the carotid bodies (Żera et al., 2025). These agents could improve metabolic responses and reduce sympathetic overactivity, providing a dual benefit for patients with heart failure and hypertension.

Furthermore, the exploration of purinergic receptors and their role in carotid body activity presents another potential therapeutic target. The use of P2X3 receptor antagonists has demonstrated promise in preclinical models, suggesting that modulation of these receptors may allow for the correction of aberrant arterial chemoreflex activity without impairing overall chemosensitivity (Pijacka et al., 2016).

The development of such pharmacological interventions could lead to more refined treatment strategies for patients with cardiometabolic disorders, allowing for personalized medicine approaches that optimize both safety and efficacy.

Implications for Future Research on Carotid Body Interventions

The evolving landscape of research on the carotid bodies underscores the need for continued exploration into their role in cardiovascular and metabolic health. Future studies should focus on elucidating the precise mechanisms through which carotid body dysfunction contributes to disease progression and the identification of novel therapeutic targets that can be exploited for clinical benefit.

There is a pressing need for long-term studies that assess the outcomes of pharmacological interventions targeting the carotid bodies, particularly in diverse patient populations. Additionally, the integration of imaging techniques to evaluate changes in carotid body activity over time could provide valuable insights into their role in health and disease (Bardsley et al., 2023).

Moreover, understanding the interplay between the carotid bodies and other organ systems, particularly in the context of comorbidities such as diabetes and obesity, will be critical for developing comprehensive treatment plans that address the multifactorial nature of cardiometabolic diseases.

FAQ

What are carotid bodies?

Carotid bodies are small chemoreceptive structures located at the bifurcation of the carotid arteries that play a crucial role in sensing blood oxygen and carbon dioxide levels.

How do carotid bodies affect cardiovascular health?

Aberrant activity of carotid bodies can contribute to sympathetic overactivity, which is linked to conditions such as chronic heart failure, hypertension, and sleep apne

What are the potential treatments targeting carotid body dysfunction?

Current research is exploring pharmacological agents, such as GLP-1 receptor agonists and P2X3 receptor antagonists, to modulate carotid body activity without the risks associated with surgical interventions.

What are the risks of carotid body denervation?

Surgical denervation of the carotid bodies can lead to significant respiratory compromise and acid-base imbalances, along with potential impairments in the body’s ability to respond to hypoxi

Why is further research needed on carotid bodies?

Continued research is crucial to fully understand the mechanisms of carotid body dysfunction and to identify safe and effective therapeutic targets for patients with cardiometabolic disorders.

References

1. Żera, T., Paleczny, B., Siński, M., Conde, S. V., Narkiewicz, K., Ponikowski, P., & Paton, J. F. R. (2025). Translating physiology of the arterial chemoreflex into novel therapeutic interventions targeting carotid bodies in cardiometabolic disorders. The Journal of Physiology

2. Niewinski, P., Engelman, Z., Janczak, D., & Paton, J. F. R. (2017). Bilateral carotid body resection in heart failure patients: A clinical trial. The Journal of Physiology

3. Bardsley, R. S., Del Río, R., & Niewinski, P. (2023). Aberrant activity of the carotid bodies in heart failure: A clinical perspective. The Journal of Physiology

4. Pijacka, W., Felippe, I., & Zera, T. (2016). P2X3 receptor antagonists as potential modulators of arterial chemoreflex activity: Implications for hypertension therapy. The Journal of Physiology