Carotid body function in heart failure

Schultz, Harold D.; Li, Yu Long

doi:10.1016/j.resp.2007.02.011

Cited by 95 publications

(78 citation statements)

References 75 publications

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“…24 Moreover, resting RSNA and plasma norepinephrine levels are attenuated in CHF rabbits with CB denervation. 19,28 These studies confirm clinical evidence suggesting that arterial chemoreflex function is enhanced in CHF and further demonstrate that enhanced CB function is an important contributory mechanism for sympathetic activation in CHF. …”

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confidence: 71%

Arterial Chemoreceptors and Sympathetic Nerve Activity

2007

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C hronic elevation in sympathetic nerve activity (SNA) is associated with the development and maintenance of certain types of hypertension 1 and contributes to the progression of chronic heart failure (CHF). 2 The mechanisms involved in sympathetic dysfunction in these disorders appear to be complex and multifactorial. A unified hypothesis is likely to encompass alterations in multiple autonomic reflex pathways, central integratory sites, and chemical mediators that control sympathetic outflow. For example, tonic restraint of sympathetic outflow by arterial and cardiopulmonary baroreflexes is depressed in CHF 2 and depressed or reset in hypertension. 3 Moreover, maladaptive changes also occur in the central nervous system at integrative sites for autonomic control in both disease processes. 4,5 It is also clear that sympathoexcitatory cardiac, 6 somatic, 7 and central/peripheral chemoreceptor reflexes 8 are enhanced in CHF and hypertension.Arterial chemoreceptors serve an important regulatory role in the control of alveolar ventilation, but they also exert a powerful influence on cardiovascular function. 9 Activation of arterial chemoreceptors by hypoxemia increases sympathetic outflow to systemic vascular beds to compensate for the direct vasodilating effects of hypoxia on these vessels and to redistribute blood flow to essential organs. In this review, we highlight relevant information that implicates the arterial chemoreflex as a contributory mechanism for the sympathetic hyperactivity in CHF and hypertension and illustrate proposed mechanisms for this altered function. The Sympathetic Response to Arterial Chemoreceptor ActivationArterial chemoreceptors located in the aortic and carotid bodies (CBs) respond to hypoxemia and hypercapnia. Because central chemoreceptors also respond to hypercapnia, hypoxia is typically used as a specific stimulus to arterial chemoreceptors. In some mammals, such as rats and rabbits, reflex responses to hypoxemia arise solely from the CB, whereas in other species, the aortic chemoreceptor contribution can be significant. However, it is not possible to experimentally separate the relative contribution of the aortic and CBs to reflex responses in conscious animals or humans. For these reasons, discussions on the arterial chemoreflex generally relate functionality to that of the CB, which has been more extensively studied. Glomus cells in the CB depolarize in response to hypoxia and release multiple putative neurotransmitters (including acetylcholine, serotonin, ATP, and substance P) that activate impulses in afferent fibers traveling to the medulla via the carotid sinus nerve. 10 Arterial chemoreceptor stimulation in freely breathing humans and conscious animals increases sympathetic vasoconstrictor outflow to muscle, splanchnic, and renal beds to elevate arterial pressure, and, in humans, increases cardiac sympathetic activity to increase heart rate and contractility. 9 There is preferential activation of sympathetic fibers going to the adrenal gland to increase norepinephrine but...

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confidence: 71%

Arterial Chemoreceptors and Sympathetic Nerve Activity

2007

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“…42,43 The downregulation of angiotensin I receptors in the carotid bodies can reduce tonic chemoreflex activity. 44 Moreover, both angiotensin II and endothelin are known to stimulate sympathetic nerve traffic in the central nervous system, sympathetic ganglia and sympathetic nerve endings. In this study, some patients were taking drugs that might potentially influence sympathetic outflow, for example, angiotensinconverting enzyme inhibitors and b-blockers.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin reduces sympathetic activity in men with hypertension and hypercholesterolemia

et al. 2010

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Beyond their hypolipidemic effect, statins reduce cardiovascular risk in hypertensive subjects via various mechanisms; one suggested mechanism is that they reduce sympathetic activity. We investigated the hypothesis that simvastatin decreased muscle sympathetic nerve activity (MSNA) in 31 hypertensive subjects with hypercholesterolemia (aged 38.7±10 years). In this randomized, placebocontrolled, double-blinded study, patients were treated with simvastatin (40 mg day À1 ; n¼15) or placebo (n¼16) for 8 weeks. Before and after treatment, we measured MSNA, blood pressure and heart rate. Baroreceptor control of the heart rate, or baroreceptor sensitivity (BRS), was computed by the sequence method, a cross-analysis of systolic blood pressure and the electrocardiogram R-R interval. Blood samples were tested for plasma levels of catecholamines, neuropeptide Y, aldosterone, endothelin and renin activity. Simvastatin significantly reduced MSNA (from 36.5 ± 5 to 27.8 ± 6 bursts per min, P¼0.001), heart rate (from 77 ± 6.7 to 71 ± 6.1 beats per min, P¼0.01) and both total and low-density lipoprotein cholesterol (from 249±30.6 to 184±28.3 mg dl À1 , P¼0.001 and from 169±30.6 to 117±31.2 mg dl À1 , P¼0.01, respectively). Simvastatin also improved BRS (from 10.3 ± 4.1 to 17.1 ± 4.3 ms per mm Hg, P¼0.04). No changes were observed in systolic or diastolic blood pressures, or in plasma levels of catecholamines, neuropeptide Y, endothelin, aldosterone and renin activity. After simvastatin therapy, MSNA and BRS were inversely related (r¼À0.94, Po0.05). In conclusion, we found that, in patients with hypertension and hypercholesterolemia, simvastatin reduced MSNA, and this was related to increased baroreceptor sensitivity.

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“…In addition, carotid bodies from PM-challenged CREB A133 mice exhibited marked gene up-regulation of Na 1 channels (scnn1b and scn8a) and Na 1 -Ca 1 exchangers (slc8a1) with concomitant down-regulation of K 1 channels (kcnd3, kcnmb2, kcnc1, kcnd1, and kcnd2), responses which potentially contribute to hyperexcitability of carotid body sensory activity (16,38). Furthermore, significant down-regulation of glial-derived neurotrophic factor (GDNF), which is critical for maintenance of the dopaminergic phenotype of hypoxic-sensing type I carotid body cells (39), was observed in PM-challenged CREB A133 mice (Table E1).…”

Section: Genomic Analyses To Evaluate Gene Deregulation In Chf Micementioning

confidence: 99%

“…Sympathetic nervous system hyperreactivity is a hallmark of CHF in humans and experimental models and may involve heightened carotid body reflexes (16,17). We used a murine model of dilated cardiomyopathy to address potential mechanistic links between PM exposure and the development of life-threatening cardiac dysrhythmias in people with CHF.…”

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confidence: 99%

Particulate Matter Induces Cardiac Arrhythmias via Dysregulation of Carotid Body Sensitivity and Cardiac Sodium Channels

Wang¹,

Lang²,

Moreno‐Vinasco³

et al. 2012

Am J Respir Cell Mol Biol

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The mechanistic links between exposure to airborne particulate matter (PM) pollution and the associated increases in cardiovascular morbidity and mortality, particularly in people with congestive heart failure (CHF), have not been identified. To advance understanding of this issue, genetically engineered mice (CREB A133 ) exhibiting severe dilated cardiomyopathic changes were exposed to ambient PM collected in Baltimore. CREB A133 mice, which display aberrant cardiac physiology and anatomy reminiscent of human CHF, displayed evidence of basal autonomic aberrancies (compared with wild-type mice) with PM exposure via aspiration, producing significantly reduced heart rate variability, respiratory dysynchrony, and increased ventricular arrhythmias. Carotid body afferent nerve responses to hypoxia and hyperoxia-induced respiratory depression were pronounced in PM-challenged CREB A133 mice, and denervation of the carotid bodies significantly reduced PM-mediated cardiac arrhythmias. Genome-wide expression analyses of CREB A133 left ventricular tissues demonstrated prominent Na 1 and K 1 channel pathway gene dysregulation. Subsequent PM challenge increased tyrosine phosphorylation and nitration of the voltage-gated type V cardiac muscle a-subunit of the Na 1 channel encoded by SCN5A. Ranolazine, a Na 1 channel modulator that reduces late cardiac Na 1 channel currents, attenuated PM-mediated cardiac arrhythmias and shortened PMelongated QT intervals in vivo. These observations provide mechanistic insights into the epidemiologic findings in susceptibility of human CHF populations to PM exposure. Our results suggest a multiorgan pathobiology inherent to the CHF phenotype that is exaggerated by PM exposure via heightened carotid body sensitivity and cardiac Na 1 channel dysfunction.

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Carotid body function in heart failure

Cited by 95 publications

References 75 publications

Arterial Chemoreceptors and Sympathetic Nerve Activity

Arterial Chemoreceptors and Sympathetic Nerve Activity

Simvastatin reduces sympathetic activity in men with hypertension and hypercholesterolemia

Particulate Matter Induces Cardiac Arrhythmias via Dysregulation of Carotid Body Sensitivity and Cardiac Sodium Channels

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