Contribution of peripheral and central chemoreceptors to sympatho‐excitation in heart failure

Abstract

Chronic heart failure (CHF) is a major public health problem. Tonic hyper-activation of sympathetic neural outflow is commonly observed in patients with CHF. Importantly, sympatho-excitation in CHF exacerbates its progression and is strongly related to poor prognosis and high mortality risk. Increases in both peripheral and central chemoreflex drive are considered markers of the severity of CHF. The principal peripheral chemoreceptors are the carotid bodies (CBs) and alteration in their function has been described in CHF. Mainly, during CHF the CB chemosensitivity is enhanced leading to increases in ventilation and sympathetic outflow. In addition to peripheral control of breathing, central chemoreceptors (CCs) are considered a dominant mechanism in ventilatory regulation. Potentiation of the ventilatory and sympathetic drive in response to CC activation has been shown in patients with CHF as well as in animal models. Therefore, improving understanding of the contribution of the peripheral and central chemoreflexes to augmented sympathetic discharge in CHF could help in developing new therapeutic approaches intended to attenuate the progression of CHF. Accordingly, the main focus of this review is to discuss recent evidence that peripheral and central chemoreflex function are altered in CHF and that they contribute to autonomic imbalance and progression of CHF. Abstract figure legend Chronic heart failure is characterized by exacerbation of the peripheral and central chemoreflexes, which contributes to the establishment and progression of sympathoexcitation and breathing disorders. Importantly, chemoreflex activation is strongly associated with cardiac arrhythmogenesis, cardiac adverse remodelling, periodic breathing and central apnoeas and hypopnoeas.

Role of A5 noradrenergic neurons in the chemoreflex control of respiratory and sympathetic activities in unanesthetized conditions

“…Moreover, previous studies have evidenced that severe loss of A5 neurons in the A5 area contributes to the manifestation of autonomic disorder associated with the neurodegenerative disease of multiple system atrophy (Benarroch et al, 2008). These observations open the possibility that changes in the functioning of A5 neurons may underpin the development of augmented sympathetic levels, especially in pathological conditions associated with hyperactivity of peripheral chemoreceptors, such as obstructive sleep apnea (Narkiewicz et al, 1998), heart failure (Toledo et al, 2017) and neurogenic hypertension (Pijacka et al, 2016). …”

Sleep-Disordered Breathing in Heart Failure ― A Therapeutic Dilemma ―

“…25 Progressive reduction, during apnea, in the partial pressure of oxygen and parallel increases in carbon dioxide tension will stimulate peripheral and central chemoreceptor-mediated reflex sympathetic excitation, 26 itself augmented in HF. 27 Any induction, by hypoxia, of pul-…”

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

“…Toledo et al . () 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.…”

“…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.…”

“…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.…”