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1.  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.
doi:10.3389/fphys.2014.00438
PMCID: PMC4241833  PMID: 25505417
carotid body chemoreceptors; Cheyne–Stokes respiration; sympathetic nervous system; heart failure; cardiorenal syndrome
2.  Role of the Carotid Body in the Pathophysiology of Heart Failure 
Current hypertension reports  2013;15(4):356-362.
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).
doi:10.1007/s11906-013-0368-x
PMCID: PMC3801176  PMID: 23824499
Hypertension; Carotid body chemoreflex; CB; Heart failure; Animal models; Gasotransmitters; Blood flow; CB ablation; Angiotensin
3.  EFFECT OF AT1 RECEPTOR BLOCKADE ON INTERMITTENT HYPOXIA-INDUCED ENDOTHELIAL DYSFUNCTION 
Chronic intermittent hypoxia (CIH) raises arterial pressure, impairs vasodilator responsiveness, and increases circulating angiotensin II (Ang II); however, the role of Ang II in CIH-induced vascular dysfunction is unknown. Rats were exposed to CIH or room air (NORM), and a subset of these animals was treated with losartan (Los) during the exposure period. After 28 days, vasodilatory responses to acetylcholine or nitroprusside were measured in isolated gracilis arteries. Superoxide levels and Ang II receptor protein expression were measured in saphenous arteries. After 28 days, arterial pressure was increased and acetylcholine-induced vasodilation was blunted in CIH vs. NORM, and this was prevented by Los. Responses to nitroprusside and superoxide levels did not differ between CIH and NORM. Expression of AT2R was decreased and the AT1R:AT2R ratio was increased in CIH vs. NORM, but this was unaffected by Los. These results indicate that the blood pressure elevation and endothelial dysfunction associated with CIH is dependent, at least in part, on RAS signaling.
doi:10.1016/j.resp.2012.05.025
PMCID: PMC3409315  PMID: 22728949
Intermittent hypoxia; Endothelial function; Angiotensin II
4.  Mechanisms of carotid body chemoreflex dysfunction during heart failure 
Experimental physiology  2015;100(2):124-129.
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.
doi:10.1113/expphysiol.2014.079517
PMCID: PMC4638138  PMID: 25398713
heart failure; carotid body; sympathetic nerve activity; breathing; oxidative stress; nitric oxide; blood flow; KLF2
5.  Selective carotid body ablation in experimental heart failure: a new therapeutic tool to improve cardiorespiratory control 
Experimental physiology  2015;100(2):136-142.
Chronic heart failure (CHF) is a leading medical problem worldwide. Common hallmarks of CHF include autonomic imbalance and breathing disorders, both of which are closely related to the progression of the disease and strongly predict mortality in CHF patients. The role played by the carotid body (CB) chemoreceptors on the progression of CHF has received attention since enhanced carotid chemoreflex drive is thought to contribute to autonomic dysfunction, abnormal breathing patterns, and increased mortality in CHF. Therefore, therapeutic tools intended to normalize CB-mediated chemoreflex drive could have the potential to better improve life quality and decrease mortality of CHF patients. In experimental CHF it has been shown an enhancement of the CB chemoreflex drive, elevated sympathetic outflow, increased resting breathing variability and apnoea incidence, and desensitization of the baroreflex. Notably, selective elimination of the CB reduced central presympathetic neuronal activation, normalized sympathetic outflow and baroreflex sensitivity, and stabilized breathing function in CHF. More remarkably, CB ablation has been shown to be a valuable therapeutic tool that significantly reduced aberrant cardiac remodeling and improved left ventricle ejection fraction and reduced cardiac arrhythmogenesis. Most importantly, CHF animals that underwent CB ablation showed a marked improvement in survival rate. Interestingly, a case report from a heart failure patient in which unilateral CB ablation was performed showed promising results with significant improvement in autonomic balance and breathing variability. Together, CHF data from experimental animals as well as humans unveil a major role for the carotid body chemoreceptors in the progression of heart failure and support the notion that CB ablation could represent a novel therapeutic strategy to reduce cardiorespiratory dysfunction and improve survival during heart failure.
doi:10.1113/expphysiol.2014.079566
PMCID: PMC4668710  PMID: 25398714
heart failure; autonomic function; breathing disorders; mortality; carotid body ablation
6.  Relevance of the Carotid Body Chemoreflex in the Progression of Heart Failure 
BioMed Research International  2015;2015:467597.
Chronic heart failure (CHF) is a global health problem affecting millions of people. Autonomic dysfunction and disordered breathing patterns are commonly observed in patients with CHF, and both are strongly related to poor prognosis and high mortality risk. Tonic activation of carotid body (CB) chemoreceptors contributes to sympathoexcitation and disordered breathing patterns in experimental models of CHF. Recent studies show that ablation of the CB chemoreceptors improves autonomic function and breathing control in CHF and improves survival. These exciting findings indicate that alterations in CB function are critical to the progression of CHF. Therefore, better understanding of the physiology of the CB chemoreflex in CHF could lead to improvements in current treatments and clinical management of patients with CHF characterized by high chemosensitivity. Accordingly, the main focus of this brief review is to summarize current knowledge of CB chemoreflex function in different experimental models of CHF and to comment on their potential translation to treatment of human CHF.
doi:10.1155/2015/467597
PMCID: PMC4686619  PMID: 26779536
7.  Time-Dependent Adaptation in the Hemodynamic Response to Hypoxia 
In rats, acute exposure to hypoxia causes a decrease in mean arterial pressure (MAP) caused by a predominance of hypoxic vasodilation over chemoreflex-induced vasoconstriction. We previously demonstrated that exposure to chronic intermittent hypoxia (CIH) impairs hypoxic vasodilation in isolated resistance arteries; therefore, we hypothesized that the acute systemic hemodynamic responses to hypoxia would be altered by exposure to CIH. To test this hypothesis, rats were exposed to CIH for 14 days. Heart rate (HR) and MAP were monitored by telemetry. On the first day of CIH exposure, acute episodes of hypoxia caused a decrease in MAP (-9±5 mmHg) and an increase in HR (+45±4 beats/minute). On the 14th day of CIH exposure the depressor response was attenuated (-4±1 mmHg; 44% of the day 1 response) and the tachycardia enhanced (+68±2 beats/minute; 151% of the day 1 response). The observed time-dependent modulation of the acute hemodynamic responses to hypoxia may reflect important changes in neurocirculatory regulation that contribute to CIH-induced hypertension.
doi:10.1016/j.resp.2008.10.013
PMCID: PMC2662762  PMID: 19013546
blood pressure; heart rate; intermittent hypoxia
8.  SIMVASTATIN TREATMENT ATTENUATES INCREASED RESPIRATORY VARIABILITY AND APNEA/HYPOPNEA INDEX IN RATS WITH CHRONIC HEART FAILURE RR 
Hypertension  2014;63(5):1041-1049.
Cheyne-Stokes respiration (CSR) and cardiac arrhythmias are associated with increased morbidity and mortality in patients with congestive heart failure (CHF). Enhanced carotid body chemoreflex (CBC) sensitivity is associated with these abnormalities in CHF. Reduced carotid body 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 (eNOS) in part by increasing Kruppel like Factor 2 (KLF2) expression. We hypothesized that statin treatment would ameliorate enhanced CBC sensitivity as well as increased respiratory variability (RV), apnea/hypopnea index (AHI), and arrhythmia index (AI), in a rodent model of CHF. Resting breathing pattern, cardiac rhythm, and the ventilatory and carotid body (CB) chemoreceptor afferent responses to hypoxia (CBC) 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 RV, AHI, and AI. Statin treatment prevented the increases in CBC sensitivity and the concomitant increases in RV, AHI, and AI. KLF2 and eNOS protein were decreased in the CB and nucleus tractus solitarii (NTS) 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 CSR and arrhythmias in patient populations with high chemoreflex sensitivity.
doi:10.1161/HYPERTENSIONAHA.113.02535
PMCID: PMC3993007  PMID: 24516105
chronic heart failure; statin; carotid body chemoreflex
9.  CAROTID CHEMORECEPTOR ABLATION IMPROVES SURVIVAL IN HEART FAILURE: RESCUING AUTONOMIC CONTROL OF CARDIORESPIRATORY FUNCTION 
Journal of the American College of Cardiology  2013;62(25):10.1016/j.jacc.2013.07.079.
Objectives
We investigated 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
CHF was induced by coronary ligation in rats. Selective CB denervation (CBD) was performed to remove carotid chemoreflex drive in the CHF state (16 weeks post MI). Indices of autonomic and respiratory function were assessed in CB intact and CBD animals. CBD at 2 weeks post-MI 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
CHF rats developed increased CB chemoreflex drive and chronic central pre-sympathetic neuronal activation, increased indices 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 indices 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 to 45% survival in CHF rats without the intervention.
Conclusion
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.
doi:10.1016/j.jacc.2013.07.079
PMCID: PMC3870030  PMID: 24013056
heart failure; autonomic function; breathing disorders; mortality; carotid body denervation
10.  Role of Neurotransmitter Gases in the Control of the Carotid Body in Heart Failure 
The peripheral arterial chemoreflex, arising primarily from the carotid body in most species, plays an important role in the control of breathing and in autonomic control of cardiovascular function. The peripheral chemoreflex is enhanced in heart failure patients and animal models of heart failure and contributes to the sympathetic hyperactivity and breathing instability that exacerbates the progression of the disease. Studies in animal models have shown that carotid body chemoreceptor activity is enhanced under both normoxic and hypoxic conditions in heart failure due to disruption of local mediators that control carotid body function. This brief review highlights evidence that the alterations in the gasotransmitters, nitric oxide, carbon monoxide, and hydrogen sulfide in the carotid body contribute to the exaggerated carotid body function observed in heart failure.
doi:10.1016/j.resp.2012.07.010
PMCID: PMC3483421  PMID: 22842006
11.  Xanthine Oxidase Inhibition Attenuates Endothelial Dysfunction Caused by Chronic Intermittent Hypoxia in Rats 
Respiration  2011;82(5):458-467.
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.
doi:10.1159/000329341
PMCID: PMC3214835  PMID: 21846958
Hypoxia; Allopurinol; Endothelium; Oxidative stress
12.  CHRONIC INTERMITTENT HYPOXIA AUGMENTS CHEMOREFLEX CONTROL OF SYMPATHETIC ACTIVITY: ROLE OF THE ANGIOTENSIN II TYPE 1 RECEPTOR 
Chronic exposure to intermittent hypoxia (CIH) increases carotid sinus nerve activity in normoxia and in response to acute hypoxia. We hypothesized that CIH augments basal and chemoreflex-stimulated sympathetic outflow through an angiotensin receptor-dependent mechanism. Rats were exposed to CIH for 28 days: a subset was treated with losartan. Then, lumbar sympathetic activity was recorded under anesthesia during 20-second apneas, isocapnic hypoxia, and potassium cyanide. We measured carotid body superoxide production and expression of angiotensin II type-1 receptor, neuronal nitric oxide synthase, and NADPH oxidase. Sympathetic activity was higher in CIH vs. control rats at baseline, during apneas and isocapnic hypoxia, but not cyanide. Carotid body superoxide production and expression of angiotensin II type 1 receptor and gp91phox subunit of NADPH oxidase were elevated in CIH rats, whereas expression of neuronal nitric oxide synthase was reduced. None of these differences were evident in animals treated with losartan. CIH-induced augmentation of chemoreflex sensitivity occurs, at least in part, via the renin-angiotensin system.
doi:10.1016/j.resp.2010.02.003
PMCID: PMC2846996  PMID: 20153844
chemoreceptors; angiotensin II; superoxide; angiotensin antagonist; oxidative stress
13.  TIME COURSE OF INTERMITTENT HYPOXIA-INDUCED IMPAIRMENTS IN RESISTANCE ARTERY STRUCTURE AND FUNCTION 
We previously demonstrated that chronic exposure to intermittent hypoxia (CIH) impairs endothelium-dependent vasodilation in rats. To determine the time course of this response, rats were exposed to CIH for 3, 14, 28, or 56 days. Then, we measured acetylcholine- and nitroprusside-induced vasodilation in isolated gracilis arteries. Also, we measured endothelial and inducible nitric oxide synthase, nitrotyrosine, and collagen in the arterial wall and urinary isoprostanes. Endothelium-dependent vasodilation was impaired after 2 weeks of CIH. Three days of CIH was not sufficient to produce this impairment and longer exposures (i.e. 4 and 8 weeks) did not exacerbate it. Impaired vasodilation was accompanied by increased collagen deposition. CIH elevated urinary isoprostane excretion, whereas there was no consistent effect on either isoform of nitric oxide synthase or nitrotyrosine. Exposure to CIH produces functional and structural deficits in skeletal muscle resistance arteries. These impairments develop within 2 weeks after initiation of exposure and they are accompanied by systemic evidence of oxidant stress.
doi:10.1016/j.resp.2009.12.003
PMCID: PMC2821713  PMID: 19969108
vasodilation; vascular endothelium; fibrillar collagens; isoprostanes

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