Carotid body function in heart failure

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Abstract

In this review, we summarize the present state of knowledge of the functional characteristics of the carotid body (CB) chemoreflex with respect to control of sympathetic nerve activity (SNA) in chronic heart failure (CHF). Evidence from both CHF patients and animal models of CHF has clearly established that the CB chemoreflex is enhanced in CHF and contributes to the tonic elevation in SNA. This adaptive change derives from altered function at the level of both the afferent and central nervous system (CNS) pathways of the reflex arc. At the level of the CB, an elevation in basal afferent discharge occurs under normoxic conditions in CHF rabbits, and the discharge responsiveness to hypoxia is enhanced. Outward voltage-gated K+ currents (IK) are suppressed in CB glomus cells from CHF rabbits, and their sensitivity to hypoxic inhibition is enhanced. These changes in IK derive partly from downregulation of nitric oxide synthase (NOS)/NO signaling and upregulation of angiotensin II (Ang II)/Ang II receptor (AT1R) signaling in glomus cells. At the level of the CNS, interactions of the enhanced input from CB chemoreceptors with altered input from baroreceptor and cardiac afferent pathways and from central Ang II further enhance sympathetic drive. In addition, impaired function of NO in the paraventricular nucleus of the hypothalamus participates in the increased SNA response to CB chemoreceptor activation. These results underscore the principle that multiple mechanisms involving Ang II and NO at the level of both the CB and CNS represent complementary and perhaps redundant adaptive mechanisms to enhance CB chemoreflex function in CHF.

Introduction

The chemoreflexes (central and peripheral) play a pivotal role in the control of alveolar ventilation to ensure that gas exchange rate in the lungs continually matches metabolic demand for O2 uptake and CO2 removal. Often overlooked, however, is the fact that these reflexes also exert important influences on cardiac and vascular control to regulate blood flow and thus gas exchange at the level of the tissues. An important component to chemoreflex activation is an increase in sympathetic outflow to the vascular beds. This response aids in the maintenance of arterial pressure in the face of the direct vasodilatory effects of hypoxemia or hypercapnia, and thus assists in the maintenance of a driving pressure for adequate blood flow and gas exchange in tissues. It should come as no surprise, therefore, that there are circumstances in which alterations in arterial chemoreflex function may contribute to the progression and severity of certain cardiovascular diseases that are influenced by sympathetic neural function, such as hypertension and heart failure.

An impediment to a better understanding of the significance of chemoreflexes in cardiovascular control has been the assumption that chemoreflexes normally are not activated at rest (normoxia/isocapnia) and thus should have little influence on the tonic control of sympathetic tone. This assumption however, has been shown to be incorrect. In normal humans at rest, hyperoxia, which inhibits peripheral chemoreceptor activity, decreases sympathetic nerve activity (Seals et al., 1991). In addition, animal models (Sun et al., 1999a, Sun et al., 1999b) and patients (Chua et al., 1996) with chronic heart failure (CHF) exhibit increased chemoreflex drive under normoxic conditions. Thus, it is not unreasonable to suggest that chemoreflexes contribute to sympathetic tone, even in the absence of hypoxia.

CHF is a major public health care problem. Acute coronary syndromes are the progenitor of CHF in many patients. The dramatic increase in survival rates after coronary infarcts due to more effective interventions and treatments, and the general aging of the global population are causing the incidence, prevalence, and economic burden of CHF to increase at a faster rate than any other cardiovascular disease. After age 60, more than one in 10 of all men and women develop CHF in the United States (Rosamond et al., 2007) and Europe (Tendera, 2005). Current prognosis is poor: 50% of all patients with CHF die within 5 years of diagnosis and less than 15% survive more than 10 years (Rosamond et al., 2007, Tendera, 2005). The need for a better understanding of the pathophysiological processes responsible for the progression of CHF is clear.

This review will focus specifically on a discussion of the alterations that occur in peripheral chemoreflex function in chronic heart failure (CHF), particularly that of the carotid body (CB) chemoreflex and its effects on sympathetic activity, the possible mechanisms that contribute to these alterations, and the role that these alterations may play in the pathophysiology of the disease.

Section snippets

Chemoreflex control of sympathetic function in heart failure

Sympathohumoral activation is characteristic of all forms of chronic left ventricular failure and is a major influence on the rate of progression and ultimate mortality of CHF (Esler et al., 1997). To a limited extent, activation of the sympathetic nervous system is beneficial to the maintenance of arterial pressure as cardiac output declines with dysfunction of the left ventricle. However, the continually increasing sympathetic activation to the heart appears to engage a positive feedback

Carotid body function in heart failure

There is an enhanced afferent input from CB chemoreceptors in the CHF rabbits (Sun et al., 1999b), which provides a primary contribution to the augmentation of reflex function. The baseline discharge in the normoxic state and the magnitude of the afferent response to corresponding levels of isocapnic hypoxia are greater in CHF rabbits than in sham rabbits (Fig. 3). These alterations were observed both in the intact (blood perfused) and isolated CB preparations (Sun et al., 1999b). This

Central interaction with other reflexes and brainstem mechanisms

Considerable interaction is known to occur between baroreceptor and CB chemoreceptor control of sympathetic nerve activity (Trzebski et al., 1975, Somers et al., 1991). The two afferent inputs have a mutual inhibitory interaction on sympathetic outflow: baroreceptor input suppresses chemoreflex activation of sympathetic outflow and chemoreceptor input suppresses baroreflex inhibition of sympathetic outflow (Wennergren et al., 1976).

The impaired baroreflex sensitivity (Zucker et al., 2004) and

Summary

In this review, we have summarized the present state of knowledge on the functional characteristics of the carotid body chemoreflex with respect to control of sympathetic function in heart failure. Evidence in both CHF patients and animal models of CHF has clearly established that the CB chemoreflex is enhanced in CHF and contributes to the tonic elevation in sympathetic function. This derangement derives from altered function at the level of both the afferent and central pathways of the reflex

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