Noah J. Marcus

Carotid body denervation improves autonomic and cardiac function and attenuates disordered breathing in congestive heart failure

A strong correlation between disordered breathing patterns, elevated sympathetic nerve activity and enhanced chemoreflex sensitivity exists in patients with heart failure. Evidence indicates that disordered breathing patterns and increased sympathetic nerve activity increases arrhythmia incidence in patients with heart failure. Enhanced coupling between sympathetic and respiratory neural drive underlies elevated sympathetic nerve activity in an animal model of sleep apnoea. We investigated the impact of carotid body chemoreceptor denervation on sympathetic nerve activity, disordered breathing and sympatho‐respiratory coupling in an animal model of heart failure. Renal sympathetic nerve activity, apnoea/hypopnoea incidence, variability measures of tidal volume and respiratory rate and arrhythmia incidence were quantified during resting breathing in heart failure animals with and without carotid body ablation. Our results indicate that carotid body chemoreceptor denervation reduces sympathetic nerve activity, disordered breathing patterns, arrhythmia incidence and sympatho‐respiratory coupling in experimental heart failure. These findings suggest that device‐oriented ablation of carotid body chemoreceptors is a viable treatment option for reduction of sympathetic nerve activity, disordered breathing patterns and arrhythmia incidence in heart failure.

Carotid chemoreceptor ablation improves survival in heart failure: Rescuing autonomic control of cardiorespiratory function

OBJECTIVES This study sought to investigate whether selective ablation of the carotid body (CB) chemoreceptors improves cardiorespiratory control and survival during heart failure. BACKGROUND Chronic heart failure (CHF) is a recognized health problem worldwide, and novel treatments are needed to better improve life quality and decrease mortality. Enhanced carotid chemoreflex drive from the CB is thought to contribute significantly to autonomic dysfunction, abnormal breathing patterns, and increased mortality in heart failure. METHODS Chronic heart failure was induced by coronary ligation in rats. Selective CB denervation was performed to remove carotid chemoreflex drive in the CHF state (16 weeks post-myocardial infarction). Indexes of autonomic and respiratory function were assessed in CB intact and CB denervated animals. CB denervation at 2 weeks post-myocardial infarction was performed to evaluate whether early targeted CB ablation decreases the progression of left ventricular dysfunction, cardiac remodeling, and arrhythmic episodes and improves survival. RESULTS The CHF rats developed increased CB chemoreflex drive and chronic central pre-sympathetic neuronal activation, increased indexes of elevated sympathetic outflow, increased breathing variability and apnea incidence, and desensitization of the baroreflex. Selective CB ablation reduced the central pre-sympathetic neuronal activation by 40%, normalized indexes of sympathetic outflow and baroreflex sensitivity, and reduced the incidence of apneas in CHF animals from 16.8 ± 1.8 events/h to 8.0 ± 1.4 events/h. Remarkably, when CB ablation was performed early, cardiac remodeling, deterioration of left ventricle ejection fraction, and cardiac arrhythmias were reduced. Most importantly, the rats that underwent early CB ablation exhibited an 85% survival rate compared with 45% survival in CHF rats without the intervention. CONCLUSIONS Carotid chemoreceptors play a seminal role in the pathogenesis of heart failure, and their targeted ablation might be of therapeutic value to reduce cardiorespiratory dysfunction and improve survival during CHF.

Xanthine oxidase inhibition attenuates endothelial dysfunction caused by chronic intermittent hypoxia in rats.

Background: Xanthine oxidase is a major source of superoxide in the vascular endothelium. Previous work in humans demonstrated improved conduit artery function following xanthine oxidase inhibition in patients with obstructive sleep apnea. Objectives: To determine whether impairments in endothelium-dependent vasodilation produced by exposure to chronic intermittent hypoxia are prevented by in vivo treatment with allopurinol, a xanthine oxidase inhibitor. Methods: Sprague-Dawley rats received allopurinol (65 mg/kg/day) or vehicle via oral gavage. Half of each group was exposed to intermittent hypoxia (FIO2 = 0.10 for 1 min, 15×/h, 12 h/day) and the other half to normoxia. After 14 days, gracilis arteries were isolated, cannulated with micropipettes, and perfused and superfused with physiological salt solution. Diameters were measured before and after exposure to acetylcholine (10–6M) and nitroprusside (10–4M). Results: In vehicle-treated rats, intermittent hypoxia impaired acetylcholine-induced vasodilation compared to normoxia (+4 ± 4 vs. +21 ± 6 µm, p = 0.01). Allopurinol attenuated this impairment (+26 ± 6 vs. +34 ± 9 µm for intermittent hypoxia and normoxia groups treated with allopurinol, p = 0.55). In contrast, nitroprusside-induced vasodilation was similar in all rats (p = 0.43). Neither allopurinol nor intermittent hypoxia affected vessel morphometry or systemic markers of oxidative stress. Urinary uric acid concentrations were reduced in allopurinol- versus vehicle-treated rats (p = 0.02). Conclusions: These data confirm previous findings that exposure to intermittent hypoxia impairs endothelium-dependent vasodilation in skeletal muscle resistance arteries and extend them by demonstrating that this impairment can be prevented with allopurinol. Thus, xanthine oxidase appears to play a key role in mediating intermittent hypoxia-induced vascular dysfunction.

Role of the Carotid Body in the Pathophysiology of Heart Failure

Important recent advances implicate a role of the carotid body (CB) chemoreflex in sympathetic and breathing dysregulation in several cardio-respiratory diseases, drawing renewed interest in its potential implications for clinical treatment. 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 nerve activity (SNA) and periodic breathing associated with the disease. Although this maladaptive change likely derives from altered function at all levels of the reflex arc, a change in afferent function of the CB is likely to be a main driving force. This review will focus on recent advances in our understanding of the pathophysiological mechanisms that alter CB function in CHF and their potential translational impact on treatment of chronic heart failure (CHF).

Inhibition of hydrogen sulfide restores normal breathing stability and improves autonomic control during experimental heart failure.

Cardiovascular autonomic imbalance and breathing instability are major contributors to the progression of heart failure (CHF). Potentiation of the carotid body (CB) chemoreflex has been shown to contribute to these effects. Hydrogen sulfide (H2S) recently has been proposed to mediate CB hypoxic chemoreception. We hypothesized that H2S synthesis inhibition should decrease CB chemoreflex activation and improve breathing stability and autonomic function in CHF rats. Using the irreversible inhibitor of cystathione γ-lyase dl-propargylglycine (PAG), we tested the effects of H2S inhibition on resting breathing patterns, the hypoxic and hypercapnic ventilatory responses, and the hypoxic sensitivity of CB chemoreceptor afferents in rats with CHF. In addition, heart rate variability (HRV) and systolic blood pressure variability (SBPV) were calculated as an index of autonomic function. CHF rats, compared with sham rats, exhibited increased breath interval variability and number of apneas, enhanced CB afferent discharge and ventilatory responses to hypoxia, decreased HRV, and increased low-frequency SBPV. Remarkably, PAG treatment reduced the apnea index by 90%, reduced breath interval variability by 40-60%, and reversed the enhanced hypoxic CB afferent and chemoreflex responses observed in CHF rats. Furthermore, PAG treatment partially reversed the alterations in HRV and SBPV in CHF rats. Our results show that PAG treatment restores breathing stability and cardiac autonomic function and reduces the enhanced ventilatory and CB chemosensory responses to hypoxia in CHF rats. These results support the idea that PAG treatment could potentially represent a novel pathway to control sympathetic outflow and breathing instability in CHF.

Mechanisms of carotid body chemoreflex dysfunction during heart failure

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 signalling pathways in the carotid body is discussed.

Simvastatin Treatment Attenuates Increased Respiratory Variability and Apnea/Hypopnea Index in Rats With Chronic Heart Failure

Cheyne–Stokes respiration and cardiac arrhythmias are associated with increased morbidity and mortality in patients with chronic heart failure (CHF). Enhanced carotid body chemoreflex (CBC) sensitivity is associated with these abnormalities in CHF. Reduced carotid body (CB) nitric oxide and nitric oxide synthase (NOS) levels play an important role in the enhanced CBC. In other disease models, Simvastatin (statin) treatment increases endothelial NOS, in part, by increasing Krüppel-like Factor 2 expression. We hypothesized that statin treatment would ameliorate enhanced CBC sensitivity as well as increased respiratory variability, apnea/hypopnea index, and arrhythmia index, in a rodent model of CHF. Resting breathing pattern, cardiac rhythm, and the ventilatory and CB chemoreceptor afferent responses to hypoxia were assessed in rats with CHF induced by coronary ligation. CHF was associated with enhanced ventilatory and CB afferent responses to hypoxia as well as increased respiratory variability, apnea/hypopnea index, and arrhythmia index. Statin treatment prevented the increases in CBC sensitivity and the concomitant increases in respiratory variability, apnea/hypopnea index, and arrhythmia index. Krüppel-like Factor 2 and endothelial NOS protein were decreased in the CB and nucleus tractus solitarii of CHF animals, and statin treatment increased the expression of these proteins. Our findings demonstrate that the increased CBC sensitivity, respiratory instability, and cardiac arrhythmias observed in CHF are ameliorated by statin treatment and suggest that statins may be an effective treatment for Cheyne–Stokes respiration and arrhythmias in patient populations with high chemoreflex sensitivity.

Role of the Carotid Body Chemoreflex in the Pathophysiology of Heart Failure: A Perspective from Animal Studies.

The treatment and management of chronic heart failure (CHF) remains an important focus for new and more effective clinical strategies. This important goal, however, is dependent upon advancing our understanding of the underlying pathophysiology. In CHF, sympathetic overactivity plays an important role in the development and progression of the cardiac and renal dysfunction and is often associated with breathing dysregulation, which in turn likely mediates or aggravates the autonomic imbalance. In this review we will summarize evidence that in CHF, the elevation in sympathetic activity and breathing instability that ultimately lead to cardiac and renal failure are driven, at least in part, by maladaptive activation of the carotid body (CB) chemoreflex. This maladaptive change derives from a tonic increase in CB afferent activity. We will focus our discussion on an understanding of mechanisms that alter CB afferent activity in CHF and its consequence on reflex control of autonomic, respiratory, renal, and cardiac function in animal models of CHF. We will also discuss the potential translational impact of targeting the CB in the treatment of CHF in humans, with relevance to other cardio-respiratory diseases.

Selective carotid body ablation in experimental heart failure: a new therapeutic tool to improve cardiorespiratory control

What is the topic of this review? This review summarizes the physiological role played by the carotid body in the autonomic dysregulation and breathing disturbances during the progression of chronic heart failure and the therapeutic potential of carotid body ablation to control cardiorespiratory imbalance and improve survival in heart failure. What advances does it highlight? Carotid body ablation markedly improves breathing stability and normalizes autonomic function in chronic heart failure. More importantly, if carotid body ablation is performed early during the progression of the disease it significantly improves animal survival.

Central role of carotid body chemoreceptors in disordered breathing and cardiorenal dysfunction in chronic heart failure.

Oscillatory breathing (OB) patterns are observed in pre-term infants, patients with cardio-renal impairment, and in otherwise healthy humans exposed to high altitude. Enhanced carotid body (CB) chemoreflex sensitivity is common to all of these populations and is thought to contribute to these abnormal patterns by destabilizing the respiratory control system. OB patterns in chronic heart failure (CHF) patients are associated with greater levels of tonic and chemoreflex-evoked sympathetic nerve activity (SNA), which is associated with greater morbidity and poor prognosis. Enhanced chemoreflex drive may contribute to tonic elevations in SNA by strengthening the relationship between respiratory and sympathetic neural outflow. Elimination of CB afferents in experimental models of CHF has been shown to reduce OB, respiratory-sympathetic coupling, and renal SNA, and to improve autonomic balance in the heart. The CB chemoreceptors may play an important role in progression of CHF by contributing to respiratory instability and OB, which in turn further exacerbates tonic and chemoreflex-evoked increases in SNA to the heart and kidney.