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Exp Physiol. Author manuscript; available in PMC 2016 Feb 1.
Published in final edited form as:
PMCID: PMC4638138
NIHMSID: NIHMS734608
PMID: 25398713

Mechanisms of carotid body chemoreflex dysfunction during heart failure

Abstract

Recent advances have drawn interest in the potential for carotid body (CB) ablation or desensitization as an effective strategy for clinical treatment and management of cardio-respiratory diseases including hypertension, heart failure, diabetes mellitus, metabolic syndrome, and renal failure. These disease states have in common sympathetic overactivity, which plays an important role in the development and progression of the disease and is often associated with breathing dysregulation, which in turn likely mediates or aggravates the autonomic imbalance. Evidence from both chronic heart failure (CHF) patients and animal models indicates that the CB chemoreflex is enhanced in CHF and contributes to the tonic elevation in sympathetic activity and the development of periodic breathing associated with the disease. Although this maladaptive change likely derives from altered function at all levels of the reflex arc, a tonic increase in afferent activity from CB glomus cells is likely to be a main driving force. This report will focus on our understanding of mechanisms that alter CB function in CHF and their potential translational impact on treatment of CHF.

Keywords: heart failure, carotid body, sympathetic nerve activity, breathing, oxidative stress, nitric oxide, blood flow, KLF2

Introduction

The carotid body (CB) chemoreflex plays a primary role in oxygen homeostasis for the body. Glomus (type I) cells in the CB are stimulated by a reduction in arterial PO2, and this neural input to the brainstem reflexively increases ventilation to avert the developing hypoxemia. Another important component to the CB chemoreflex is activation of sympathetic outflow to resistance vessels to avert the direct vasodilatory effects of hypoxemia, and thus maintain arterial pressure for adequate blood flow and gas exchange to essential organs, particularly the heart and brain. However, the CB can become maladaptive in disease states. In particular, CHF is characterized by tonic over-activation of sympathetic neural outflow, particularly to the heart and kidneys, that exacerbates the progression of the cardiac failure (Esler, 2010). CHF is also characterized by the development of breathing instability with Cheyne-Stokes breathing and central apneas that further negatively impact autonomic and metabolic homeostasis (Brack et al., 2012). Animal models (Schultz et al., 2013) and patients (Ponikowski et al., 2001) with CHF exhibit increased CB chemoreflex drive that contributes to sympathetic outflow and ventilation under both normoxic and hypoxic conditions. Moreover, the high CB chemoreflex sensitivity is correlated with poor prognosis in patients with CHF (Ponikowski et al., 2001) and has been shown to contribute to mortality and the pathophysiology of CHF in animal models of CHF (Del Rio et al., 2013a; Marcus et al., 2014).

Factors Contributing to Tonic Activation of the Carotid Body in CHF

Fundamentally, there is an enhanced discharge of CB chemoreceptors in CHF that provides a primary contribution to the augmentation of reflex function. This finding has been documented in tachycardia pacing-induced CHF in rabbits (Sun et al., 1999), myocardial infarct-induced CHF in rats (Del Rio et al., 2013b), and genetic cardiomyopathic CHF in mice (Wang et al., 2012). Thus, the factors reponsible for enhanced CB function do not appear to be related specifically to the etologies of the cardiac failure. Integral to understanding the maladaptive role of CB in CHF is the observation that basal CB afferent discharge is markedly elevated at rest under normoxia conditions in CHF animals to levels that would otherwise represent significant hypoxemia in normal animals (Sun et al., 1999; Del Rio et al., 2013b). This results in a tonic reflex drive that contributes to sympathetic hyperactivity, hyperventilation and the associated breathing instability that are characteristic of CHF. This concept is borne out by studies showing that inhibition of CB chemoreceptor activity by hyperoxia in CHF sheep (Xing et al., 2014) decreases cardiac sympathetic drive and that CB ablation in CHF rabbits and rats reduces tonic sympathetic outflow and oscillatory breathing which is followed by improvement in cardiac function and prolonged survival. (Del Rio et al., 2013a; Marcus et al., 2014). Hemodynamic, ventilatory, humoral, and local tissue changes occur in the development of CHF that collectively play important roles in the sensitization of CB chemoreceptors to drive increased CB reflex function in CHF.

Local tissue and humoral factors

Oxidative stress has been shown to play an important role in activating the CB in CHF. Both circulating and local tissue levels of the pro-oxidant angiotensin II (Ang II) peptide are elevated in CHF (Li et al., 2006). Ang II activates NADPH oxidase (NOX) to enhance superoxide (O2•−) production, which in turn enhances the excitability of the CB glomus cells and central autonomic neurons via the AT1 receptor (AT1R) (Li et al., 2007). This pathway is upregulated in the CB in CHF (Li et al., 2007). Ang II-O2•− enhances the sensitivity of the CB chemoreceptors, at least in part, by inhibiting oxygen sensitive potassium channels (IKv) in CB glomus cells (Fig. 1) (Li & Schultz, 2006). It is also very likely that the Ang II-O2•− pathway alters the sensitivity of other ion channels in CB glomus cells to enhance excitability in CHF, but to date, this inference has not been confirmed. These changes in channel function are likely to include sensitization of voltage gated Ca2+ channels, which mediate depolarization and release of neurotransmitters from the glomus cells, and suppression of background K+ channels responsible for maintenance of the resting membrane potential in glomus cells. Other pro-oxidant pathways may play a contributory role in the sensitization of the CB in CHF but have not been closely analyzed. For example, endothelin and inflammatory cytokines are elevated in CHF and can stimulate ROS production.

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Illustrative model of known and proposed cellular pathways contributing to the enhanced CB chemoafferent sensitivity in CHF, and potential beneficial mechanism of exercise and statin therapy. Statins and exercise (green) act to prevent suppression of KLF2 in CHF. Details and abbreviations as discussed in the text. Ex: regular exercise; Statin: simvastatin. Modified from Schultz and Marcus (2012), Figure 3, with kind permission from Springer Science and Business Media.

The relative contribution of humoral vs. local tissue origin of pro-oxidant mediators in the sensitization of the CB in CHF is not clear. The circulating renin-angiotensin system (RAS) is activated in CHF due to renal hypoperfusion, and thus could serve as an important source for Ang II effects on the CB. However, local production of Ang II and other Ang metabolites in the CB can serve as a direct link to modulation of CB function in disease states (Leung et al., 2003). The fact that CB neural activity remains elevated after isolation from the circulation in CHF animals and remains responsive to angiotensin blockers supports an important role of the local Ang system in the CB in CHF (Li & Schultz, 2006). Nevertheless, an important additional influence from circulating Ang II and other pro-oxidant mediators should not be discounted.

Contributing to local oxidative stress in the CB, expression of both copper/zinc superoxide dismutase (CuZnSOD) and manganese SOD (MnSOD), endogenous intracellular scavengers of O2•−, is suppressed in glomus cells of the CB in CHF (Ding et al., 2009; Ding et al., 2010). These changes serve to amplify the Ang II-O2•− activation of CB chemoreceptor activity (Fig. 1). Gene transfer to restore expression of either of the SOD isoforms in the CB reverses the enhanced CB chemoreceptor and chemoreflex activation (Ding et al., 2009; Ding et al., 2010) implicating a dual role of both cytosolic and mitochondrial O2•− in the Ang II-NOX signaling cascade within CB glomus cells.

Other angiotensin metabolites also may play a role in modulating CB function in CHF. Ang-(1–7) counteracts the neural actions of Ang II. Ang-(1–7) enhances IKv in catecholaminergic neurons, including glomus cells, via MasR activation of neural nitric oxide synthase (nNOS) and NO production: an effect that opposes the inhibitory effect of Ang II-O2•− on these channels (Yang et al., 2011). However, basal NO production and nNOS/eNOS expression within the CB are depressed in CHF (Ding et al., 2008). Thus, the tonic inhibitory effect of NO on the activity of CB chemoreceptors is virtually absent in CHF animals. Downregulation of the inhibitory effects of Ang (1–7) and NO within the CB thus work synergistically with pro-oxidant effects to create tonic activation of CB chemoreceptor discharge even under normoxic conditions in CHF (Fig 1).

In addition to NO, gasotransmitters CO and H2S also influence CB chemoreceptor sensitivity (Fig. 1) (Prabhakar, 2012). CO is constiuitively regulated by heme-oxygenase-2 (HO-2) in the CB, and HO-2 protein expression is markedly decreased in the CB in CHF animals (Ding et al., 2008). CO, similar to NO, restrains hypoxic sensitivity of the CB (Ding et al., 2008), and downregulation of the CO and NO pathways in the CB have cumulative effects to enhance peripheral chemoreflex function in pacing-induced CHF (Ding et al., 2008).

H2S derived from cystathionine γ-lyase (CSE) also contributes to the CB chemosensory response to hypoxia (Prabhakar, 2012). CSE expression is maintained in the CB during CHF and CSE inhibition reduces CB activity, suggesting that H2S contributes to the maintenance of exaggerated CB afferent responsiveness in CHF (Del Rio et al., 2013b). Furthermore, due to an inhibitory influence of CO on CSE activity, H2S production in the CB is linked to HO-2 (Prabhakar, 2012). Since HO-2 is downregulated in the CB in CHF (Ding et al., 2008), CSE activity would be promoted to enhance H2S-mediated activation of CB chemoreceptor afferent activity as observed in the CHF rats (Fig. 1) (Del Rio et al., 2013b).

Hemodynamic factors

The hallmark of chronic systolic CHF is a marked reduction in cardiac output due to loss of cardiac function. Although acute changes in systemic hemodynamics are known to have little effect on chemoreceptor activity, chronic changes in blood flow could impact CB function possibly by chronic changes in oxygen delivery, or as we hypothesize, via alterations in endothelial function and signaling pathways.

A chronic reduction in blood flow to the CB, sustained over 3 weeks with adjustable cuff occluders on the carotid arteries in rabbits, increased AT1R expression and decreased nNOS expression in the CB and induced an increase in CB afferent activity that were similar to changes observed in CHF rabbits over a similar time course (Ding et al., 2011). However, the link between reduced CB flow and the altered signaling pathways in the CB was not identified. The transcriptional regulation of angiotensin converting enzyme (ACE) and eNOS expression in vascular endothelial cells is influenced by changes in blood flow via altered shear stress (Miyakawa et al., 2004; Dekker et al., 2005). Thus, an endothelial response to changes in blood flow in the CB may play an important role in regulating Ang metabolism and NO effects on CB chemoreceptor function in CHF. However, it is uncertain whether the changes in CB protein expression may be driven by a reduction in brainstem perfusion, which could increase circulating hormones such as Ang II.

Kruppel-like factor 2 (KLF2) is a mechano-activated transcription factor that is important in the transduction of shear-stress effects on endothelial function (Dekker et al., 2005). KLF2 represses transcription of ACE and induces transcription of eNOS in endothelial cells (Dekker et al., 2005) as well as activating expression of transcription factors that regulate expression of anti-oxidant and oxidant enzymes (Nrf2 and NFkB respectively).

Preliminary results from our lab suggest that KLF2 expression is decreased in the CB in CHF, and that adenoviral gene transfer of KLF2 to the CB normalizes the hypoxic ventilatory response and decreases the incidence of periodic breathing in CHF (Schultz & Marcus, 2012). These findings suggest that KLF2 plays a fundamental role in the alteration in CB function that occurs with a reduction in CB blood flow in CHF. Further studies will be needed to confirm whether these functional effects of KLF2 are linked to normalization of oxidative and nitrosative redox pathways in the CB as discussed above.

In addition to effects of reduced cardiac output, reflex activation of sympathetic nerve activity to the CB in CHF may affect glomus cell excitability or contribute to reduced CB blood flow via local vasoconstriction. This idea has not been rigorously tested, but in preliminary experiments, we have found little effect of acute adrenergic blockade on CB function in CHF animals (unpublished). Additionally, the isolated CB from CHF animals (with sympathetic innervation interrupted) exhibits elevated basal discharge and hypersensitivity to hypoxia (Sun et al., 1999; Wang et al., 2012; Del Rio et al., 2013b). Nevertheless, the contribution of sympathetic innervation of the CB in CHF needs to be better illuminated.

Ventilatory factors

The hyperventilatory state induced by CB overactivity in CHF contributes to breathing instability, characterized as Cheyne-Stokes breathing and increased incidence of central apneas (Del Rio et al., 2013a; Marcus et al., 2014). Oscillatory breathing and central apneas may produce intermittent hypoxia and contribute to sensitization of the CB in CHF in a manner similar to that observed in animals exposed to chronic intermittent hypoxia as a model of sleep apnea (Fung et al., 2014). Indeed, the beneficial effects of CB ablation on cardiac and autonomic function in CHF may be due in part to its effect to rapidly restore normal breathing patterns in CHF animals (Del Rio et al., 2013a; Marcus et al., 2014). However, it is difficult to envision destabilized breathing as a primary contributing factor to CB hyperactivity in CHF since CB hyperactivity itself is required to drive the oscillatory ventilation and apneas (Del Rio et al., 2013a; Marcus et al., 2014).

Alterations in the relationship between central control of respiratory and sympathetic neural drive may underlie the association of altered respiratory patterns and increased sympathetic outflow in CHF. Similar to the phenomenon seen in animals exposed to chronic intermittent hypoxia (Zoccal & Machado, 2011), sympathetic activity is more tightly entrained to the respiratory pattern in CHF animals (Marcus et al., 2014), which is abrogated after CB ablation. Thus, oscillatory breathing patterns in CHF have the potential to drive increased tonic sympathetic outflow as a result of the increased sympathetic-respiratory coupling (SRC) driven by the CB. Nevertheless, SRC, like oscillatory breathing, should be viewed as a consequence rather than a cause of CB hyperactivity in CHF. However, these ventilatory consequences may serve a feed-forward influence to aggravate hemodynamic, humoral and local mechanisms discussed above.

Temporal Sequence of Events

The temporal sequence of events that transforms CB excitability from normal to tonically activated state in CHF suggests a progressive process over days to weeks. CB chemoreflex sensitivity progressively increases over the course of 3–4 weeks of pacing in CHF rabbits(Schultz et al., 2007). This change correlates with the progressive decrease in left ventricular function over the pacing interval, and was mimicked by a progressive reduction in carotid body blood flow over the same time frame using carotid occluders (Ding et al., 2011). A similar correlation was seen after myocardial infarct in rats (unpublished) where CB afferent and chemoreflex function increased in concert with progressive loss of ventricular function over the course of days to weeks. These correlations would suggest that changes in carotid blood flow to impact KLF2 expression in the CB is a major event (Figure 1) in initiating changes in downstream cascade of signaling pathways described above and as shown (Figure 1).

Similarly, The functional consequences of CB hyperactivity during the progression of CHF are tonically driven by the changes in afferent function. Ablation of the CBs at later stages of CHF results in a rapid reduction in renal sympathetic nerve activity and cardiac arrhythmias, and increased breathing stability and autonomic balance within the time frame of recovery from the surgery in CHF animals (Marcus et al., 2014). These autonomic changes preceded the improvement in cardiac function that subsequently occurred over the course of several days. When the CB ablation was performed early after myocardial infarct, deterioration of cardiac function was obtunded over subsequent weeks and survival increased (Del Rio et al., 2013a).

Translational Impact of CB Hyperactivity in CHF

Of major clinical relevance, CB ablation has been shown to improve cardiac function, reduce cardiac remodeling, and increase survival rate in the CHF animals (Del Rio et al., 2013a; Marcus et al., 2014) and to improve autonomic balance in recent human case study (Niewinski et al., 2013). The mechanisms by which removal of the CB improves cardiac performance and survival remain to be elucidated but it is likely to involve improved autonomic control of hemodynamics, cardiac and renal function, and improved control of breathing. Although CB ablation has proven to be efficacious in animal models, the potential adverse implications of CB removal in patients with marked hypoxemia or tenuous cardio-respiratory status must be realized. Finding approaches that can reduce excessive tonic CB activity without eliminating its normal protective responses to hypoxia are likely to be a preferred clinical treatment strategy in humans.

A number of pharmacological and genetic approaches have been shown to reduce CB afferent activity in CHF animals and reduce sympathetic nerve activity or improve breathing stability. These methods include AT1R antagonist (Li et al., 2006), NO and CO donors (Ding et al., 2008), anti-oxidants (Li et al., 2007), overexpression of nNOS, Mn-SOD or Cu/Zn-SOD in the CB (Li et al., 2005; Ding et al., 2009; Ding et al., 2010), and CSE antagonist (Del Rio et al., 2013b). However, the long-term efficacy of most of these approaches, singly or in combination, to improve functional status and survival in CHF animals has not been assessed. Potential adverse effects and applicability in humans also has to be considered. ACE inhibitors and AT1R blockers (ARBs) are routinely used to treat CHF with variable success, but there has been no effort to relate the clinical efficacy of these drugs to effects on chemoreflex function. In fact, the standard clinical use of Ang inhibitors in humans with CHF may be a contributing factor to the variable degrees of CB chemoreflex sensitivity observed in CHF patients (Chua et al., 1997).

In searching for efficacious treatments for CHF patients without undesirable side effects, it should be noted that moderate regular exercise has been shown to improve the functional status of CHF patients (Downing & Balady, 2011) that includes normalization of sympatho-vagal balance. The beneficial effects of exercise may be due, at least in part, to improved CB function (Fig. 1). Regular exercise is effective in normalizing CB chemoreflex function in CHF rabbits via enhancing NO bioavailability and reducing Ang II- O2•− influences on the CB (Li et al., 2008). These changes may be due to the effects of exercise to increase blood flow and improve endothelial function and KLF2 expression in the CB.

Clinically, statin treatment has been shown to lower resting sympathetic nerve activity in CHF patients (Deo et al., 2012). Furthermore, simvastatin has been shown to reduce the incidence of arrhythmias and oscillatory breathing and reduce CB chemoreflex sensitivity in CHF rats (Haack et al., 2014). These improvements corresponded with an increase in KLF2 and eNOS expression and a decrease in AT1R expression in the CB. These data suggest that oral simvastatin treatment may be another therapeutic strategy in patients with high chemoreflex sensitivity (Fig. 1).

Ultimately, the goal is to normalize CB function in humans to allow improvement in functional status to the same degree and success as seen by CB ablation in animal models of CHF. However, the cure may be as complex as the cause in the search for effective methods that work in all patients. Nevertheless, a better understanding of the physiological and molecular mechanisms responsible for CB hyperactivity in CHF will contribute to the development of effective therapeutic approaches.

New Findings

  • What is the topic of this review?

    Carotid body chemoreceptor activity is tonically elevated in heart failure and contributes to morbidity due to the reflex activation of sympathetic nerve activity and destabilization of breathing. The potential causes for the enhanced chemoreceptor activation in heart failure are discussed.

  • What advances does it highlight?

    The role of a chronic reduction in blood flow to the carotid body due to cardiac failure and its impact on signaling pathways in the carotid body is discussed.

Acknowledgments

Funding

HDS is supported by a Program Project Grant from the Heart, Lung and Blood Institute of NIH (PO1-HL62222).

NJM is supported by a Ruth L. Kirschstein National Research Service Award (NRSA) from NIH (5F32HL108592)

RDR is supported by Fondo de Desarrollo Cientifico y Tecnologico (Fondecyt #1140275)

Footnotes

Conflicting Interests:

The authors have no conflicts of interest to disclose.

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