Effect of Carotid Body Denervation on Systemic Endothelial Function in a Diabetic Animal Model.

Endothelial dysfunction is an essential intermediary for development of cardiovascular diseases associated with diabetes and hypertension (HT). The carotid body (CB) dysfunction contributes to dysmetabolic states, and the resection of carotid sinus nerve (CSN) prevents and reverts dysmetabolism and HT. Herein, we investigated if CSN denervation ameliorates systemic endothelial dysfunction in an animal model of type 2 diabetes mellitus (T2DM).We used Wistar male rats submitted to HFHSu diet during 25 weeks and the correspondent age-matched controls fed with a standard diet. CSN resection was performed in half of the groups after 14 weeks of diet. In vivo insulin sensitivity, glucose tolerance and blood pressure, ex vivo aortic artery contraction and relaxation and nitric oxide (NO) levels in plasma and aorta, aorta nitric oxide synthase (NOS) isoforms, and PGF2αR levels were evaluated.We demonstrated that, alongside to dysmetabolism and HT reversion, CSN resection restores endothelial function in the aorta and decreases the NO levels in plasma and aorta at the same time that restores normal levels of iNOS in aorta without changing eNOS or PGF2αR levels.These results suggest that the modulation of CB activity can be important for the treatment of HT and endothelial dysfunction related with T2DM.

Device Therapy of Hypertension.

In the past decade, efforts to improve blood pressure control have looked beyond conventional approaches of lifestyle modification and drug therapy to embrace interventional therapies. Based upon animal and human studies clearly demonstrating a key role for the sympathetic nervous system in the etiology of hypertension, the newer technologies that have emerged are predominantly aimed at neuromodulation of peripheral nervous system targets. These include renal denervation, baroreflex activation therapy, endovascular baroreflex amplification therapy, carotid body ablation, and pacemaker-mediated programmable hypertension control. Of these, renal denervation is the most mature, and with a recent series of proof-of-concept trials demonstrating the safety and efficacy of radiofrequency and more recently ultrasound-based renal denervation, this technology is poised to become available as a viable treatment option for hypertension in the foreseeable future. With regard to baroreflex activation therapy, endovascular baroreflex amplification, carotid body ablation, and programmable hypertension control, these are developing technologies for which more human data are required. Importantly, central nervous system control of the circulation remains a poorly understood yet vital component of the hypertension pathway and mandates further investigation. Technology to improve blood pressure control through deep brain stimulation of key cardiovascular control territories is, therefore, of interest. Furthermore, alternative nonsympathomodulatory intervention targeting the hemodynamics of the circulation may also be worth exploring for patients in whom sympathetic drive is less relevant to hypertension perpetuation. Herein, we review the aforementioned technologies with an emphasis on the preclinical data that underpin their rationale and the human evidence that supports their use.

Precision Targeted Ablation of Fine Neurovascular Structures In Vivo Using Dual-mode Ultrasound Arrays.

Carotid bodies (CBs) are chemoreceptors that monitor and register changes in the blood, including the levels of oxygen, carbon dioxide, and pH, and regulate breathing. Enhanced activity of CBs was shown to correlate with a significant elevation in the blood pressure of patients with hypertension. CB removal or denervation were previously shown to reduce hypertension. Here we demonstrate the feasibility of a dual-mode ultrasound array (DMUA) system to safely ablate the CB in vivo in a spontaneously hypertensive rat (SHR) model of hypertension. DMUA imaging was used for guiding and monitoring focused ultrasound (FUS) energy delivered to the target region. In particular, 3D imaging was used to identify the carotid bifurcation for targeting the CBs. Intermittent, high frame rate imaging during image-guided FUS (IgFUS) delivery was used for monitoring the lesion formation. DMUA imaging provided feedback for closed-loop control (CLC) of the lesion formation process to avoid overexposure. The procedure was tolerated well in over 100 SHR and normotensive rats that received unilateral and bilateral treatments. The measured mean arterial pressure (MAP) exhibited measurable deviation from baseline 2-4 weeks post IgFUS treatment. The results suggest that the direct unilateral FUS treatment of the CB might be sufficient to reduce the blood pressure in hypertensive rats and justify further investigation in large animals and eventually in human patients.

Plasticity of cardiovascular chemoreflexes after prolonged unilateral carotid body denervation: implications for its therapeutic use.

Unilateral carotid body denervation has been proposed as treatment for sympathetic-related human diseases such as systolic heart failure, hypertension, obstructive sleep apnea, and cardiometabolic diseases. The long-term therapeutic effects of carotid body removal will be maintained if the remnant "buffer nerves," that is, the contralateral carotid nerve and the aortic nerves that innervate second-order neurons at the solitary tract nuclei (NTS), do not modify their contributions to the cardiovascular chemoreflexes. Here, we studied the cardiovascular chemoreflexes 1 mo after unilateral carotid body denervation either by excision of the petrosal ganglion (petrosal ganglionectomy, which eliminates central carotid afferents) or exeresis of a segment of one carotid nerve (carotid neurectomy, which preserves central afferents). Cardiovascular chemoreflexes were induced by intravenous (iv) injections of sodium cyanide in pentobarbitone-anesthetized adult cats. After 1 mo of unilateral petrosal ganglionectomy, without significant changes in basal arterial pressure, the contribution of the contralateral carotid nerve to the chemoreflex increases in arterial pressure was enhanced without changes in the contribution provided by the aortic nerves. By contrast, after 1 mo of unilateral carotid neurectomy, the contribution of remnant buffer nerves to cardiovascular chemoreflexes remained unmodified. These results indicate that a carotid nerve interruption involving denervation of second-order chemosensory neurons at the NTS will trigger cardiovascular chemoreflex plasticity on the contralateral carotid pathway. Then, unilateral carotid body denervation as therapeutic tool should consider the maintenance of the integrity of carotid central chemoafferents to prevent plasticity on remnant buffer nerves.NEW & NOTEWORTHY Unilateral carotid body denervation has been proposed as treatment for sympathetic hyperactivity-related human disorders. Its therapeutic effectiveness for maintaining a persistent decrease in the sympathetic outflow activity will depend on the absence of compensatory chemoreflex plasticity in the remnant carotid and aortic afferents. Here, we suggest that the integrity of central afferents after carotid body denervation is essential to prevent the emergence of plastic functional changes on the contralateral "intact" carotid nerve.

Aorticopulmonary Paraganglioma With Symptomatic Postoperative Bradycardia.

Aorticopulmonary paragangliomas are rare middle mediastinal masses that are often treated with surgery. In addition to the technical challenge of resection due to location near critical structures, these paragangliomas can have postoperative complications due to resection of cardiac sympathetic innervation. We present a patient with a nonfunctional aorticopulmonary paraganglioma who suffered from postoperative hypotension and heart block, with inability to tolerate his prior alpha and beta blockade on discharge.

Selective denervation of the aortic and carotid baroreceptors in rats.

NEW FINDINGS: What is the central question of this study? The traditional surgical approach for sino-aortic denervation in rats leads to simultaneous carotid baroreceptor and chemoreceptor deactivation, which does not permit their individual study in different situations. What is the main finding and its importance? We have described a new surgical approach capable of selective denervation of the arterial (aortic and carotid) baroreceptors, keeping the carotid bodies (chemoreceptors) intact. It is understood that this technique might be a useful tool for investigating the relative role of the baro- and chemoreceptors in several physiological and pathophysiological conditions. ABSTRACT: Studies have demonstrated that the traditional surgical approach for sino-aortic denervation in rats leads to simultaneous carotid baroreceptor and chemoreceptor deactivation. The present study reports a new surgical approach to denervate the aortic and the carotid baroreceptors selectively, keeping the carotid bodies (peripheral chemoreceptors) intact. Wistar rats were subjected to specific aortic and carotid baroreceptor denervation (BAROS-X) or sham surgery (SHAM). Baroreflex activation was achieved by i.v. administration of phenylephrine, whereas peripheral chemoreflex activation was produced by i.v. administration of potassium cyanide. The SHAM and BAROS-X rats displayed significant hypertensive responses to phenylephrine administration. However, the reflex bradycardia following the hypertensive response caused by phenylephrine was remarkable in SHAM, but not significant in the BAROS-X animals, confirming the efficacy of the surgical procedure to abolish the baroreflex. In addition, the baroreflex activation elicited by phenylephrine increased carotid sinus nerve activity only in SHAM, but not in the BAROS-X animals, providing support to the notion that the baroreceptor afferents were absent. Instead, the classical peripheral chemoreflex hypertensive and bradycardic responses to potassium cyanide were similar in both groups, suggesting that the carotid body chemoreceptors were preserved after BAROS-X. In summary, we describe a new surgical approach in which only the baroreceptors are eliminated, while the carotid chemoreceptors are preserved. Therefore, it is understood that this procedure is potentially a useful tool for examining the relative roles of the arterial baroreceptors versus the chemoreceptors in several pathophysiological conditions, for instance, arterial hypertension and heart failure.

The carotid body and associated tumors: updated review with clinical/surgical significance.

Purpose: The carotid body functions as a chemoreceptor and receives richer blood supply, by weight, than any other organ in the body. We review the literature regarding the anatomy, histology, and function of the carotid body and the incidence, functionality, and clinical relevance of carotid body tumors and paragangliomas. These lesions are often nonfunctional but can be associated with catecholamine secretion. Most patients are asymptomatic or present initially with a cervical mass. As the tumors grow, they can impinge on nearby cranial nerves. Although there is some debate, the dominant clinical strategy is to surgically resect these tumors as early as possible. If they are resected early, the risk of postoperative neurovascular injury is minimized. Methods: Literature search was performed using the PubMed database with focus on articles including descriptions of the carotid body and associated tumors. Results: We reviewed recent literature that related to the anatomy of the carotid body while also including carotid pargangliomas and associated diagnosis with treatment interventions. Conclusion: As the carotid body serves as a vital modulator of cardiovascular and respiratory functions, illustrates the importance of identifying potential carotid paragangliomas due its ability to impede function of the carotid body. By understanding carotid paraganglioma's distinct etiologies while also understanding proper diagnosis of tumors allows for early detection and appropriate treatment options.

Importance of the commissural nucleus of the solitary tract in renovascular hypertension.

The rodent renovascular hypertension model has been used to investigate the mechanisms promoting hypertension. The importance of the carotid body for renovascular hypertension has been demonstrated. As the commissural NTS (cNTS) is the first synaptic site in the central nervous system that receives information from carotid body chemoreceptors, we evaluated the contribution of cNTS to renovascular hypertension in the present study. Normotensive male Holtzman rats were implanted with a silver clip around the left renal artery to induce two-kidney, one-clip (2K1C) hypertension. Six weeks later, isoguvacine (a GABAA agonist) or losartan (an AT1 antagonist) was injected into the cNTS, and the effects were compared with carotid body removal. Immunohistochemistry for Iba-1 and GFAP to label microglia and astrocytes, respectively, and RT-PCR for components of the renin-angiotensin system and cytokines in the NTS were also performed 6 weeks after renal surgery. The inhibition of cNTS with isoguvacine or the blockade of AT1 receptors with losartan in the cNTS decreased the blood pressure and heart rate of 2K1C rats even more than carotid body removal did. The mRNA expression of NOX2, TNF-α and IL-6, microglia, and astrocytes also increased in the cNTS of 2K1C rats compared to that of normotensive rats. These results indicate that tonically active neurons within the cNTS are essential for the maintenance of hypertension in 2K1C rats. In addition to signals from the carotid body, the present results suggest that angiotensin II directly activates the cNTS and may also induce microgliosis and astrogliosis within the NTS, which, in turn, cause oxidative stress and neuroinflammation.

Carotid body removal normalizes arterial blood pressure and respiratory frequency in offspring of protein-restricted mothers.

The aim of this study is to evaluate the short-term and long-term effects elicited by carotid body removal (CBR) on ventilatory function and the development of hypertension in the offspring of malnourished rats. Wistar rats were fed a normo-protein (NP, 17% casein) or low-protein (LP, 8% casein) diet during pregnancy and lactation. At 29 days of age, the animals were submitted to CBR or a sham surgery, according to the following groups: NP-cbr, LP-cbr, NP-sham, or LP-sham. In the short-term, at 30 days of age, the respiratory frequency (RF) and immunoreactivity for Fos on the retrotrapezoid nucleus (RTN; brainstem site containing CO2 sensitive neurons) after exposure to CO2 were evaluated. In the long term, at 90 days of age, arterial pressure (AP), heart rate (HR), and cardiovascular variability were evaluated. In the short term, an increase in the baseline RF (~6%), response to CO2 (~8%), and Fos in the RTN (~27%) occurred in the LP-sham group compared with the NP-sham group. Interestingly, the CBR in the LP group normalized the RF in response to CO2 as well as RTN cell activation. In the long term, CBR reduced the mean AP by ~20 mmHg in malnourished rats. The normalization of the arterial pressure was associated with a decrease in the low-frequency (LF) oscillatory component of AP (~58%) and in the sympathetic tonus to the cardiovascular system (~29%). In conclusion, carotid body inputs in malnourished offspring may be responsible for the following: (i) enhanced respiratory frequency and CO2 chemosensitivity in early life and (ii) the production of autonomic imbalance and the development of hypertension.

Modulation of Sympathetic Overactivity to Treat Resistant Hypertension.

PURPOSE OF REVIEW: To review the role and evidence for sympathetic overactivity in resistant hypertension and review the therapies that have been studied to modulate the sympathetic nervous system to treat resistant hypertension, with a focus on non-pharmacologic therapies such as renal denervation, baroreflex activation therapy, and carotid body ablation. RECENT FINDINGS: Based on the two best current techniques available for assessing sympathetic nerve activity, resistant hypertension is characterized by increased sympathetic nerve activity. Several device therapies, including renal denervation baroreflex activation therapy and carotid body ablation, have been developed as non-pharmacologic means of reducing blood pressure in resistant hypertension. With respect to renal denervation, the technologies for renal denervation have evolved since the unfavorable results from the HTN-3 study, and the revised technologies are being actively studied. Data from the first phase of the SPYRAL HTN Clinical Trial Program have been published. Results from the SPYRAL HTN-OFF MED trial suggest that ablating renal nerves can reduce blood pressure in patients with untreated mild-to-moderate hypertension. The SPYRAL HTN-ON MED trial demonstrated the safety and efficacy of catheter-based renal denervation in patients with uncontrolled hypertension on antihypertensive treatment. Interestingly, there was a high rate of medication non-adherence among patients with hypertension in this study. One attractive alternative to radiofrequency ablation is the use of ultrasound for renal denervation. Proof of concept data for the Paradise endovascular ultrasound renal denervation system was recently published in the RADIANCE-HTN SOLO trial. The results of this trial indicate that, among patients with mild to moderate hypertension on no medications, renal denervation with the Paradise system results in a greater reduction in both SBP and DBP at 2months compared with a sham procedure. Overall reductions were similar in magnitude to those noted in the SPYRAL HTN-OFF MED study. With respect to carotid body ablation, there is an ongoing proof of concept study that is investigating the safety and feasibility of ultrasound-based endovascular carotid body ablation in 30 subjects with treatment-resistant hypertension outside of the USA. The sympathetic nervous system is an important contributor to resistant hypertension. Modulation of sympathetic overactivity should be an important goal of treatment. Innovative therapies using non-pharmacologic means to suppress the sympathetic nervous system are actively being studied to treat resistant hypertension.

Human carotid bodies as a therapeutic target: new insights from a clinician's perspective.

From the physiological point of view, carotid bodies are mainly responsible for the ventilatory response to hypoxia; however, they also take part in the regulation of sympathetic tone. According to preclinical data, these structures likely contribute to the development and progression of sympathetically mediated diseases. Moreover, carotid body deactivation in animal models improved blood pressure control in hypertension and reduced mortality in heart failure, along with reducing sympathetic activity. On this basis, two first-in-man studies have been recently performed to investigate the safety and feasibility of such an approach in humans. In this review we summarise the current knowledge regarding the function of carotid bodies, the prevalence of their abnormalities, and the consequences of their excision in human hypertension and heart failure.

Carotid Body Ablation: a New Target to Address Central Autonomic Dysfunction.

PURPOSE OF REVIEW: An abnormal heightened carotid body (CB) chemoreflex, which produces autonomic dysfunction and sympathetic overactivation, is the common hallmark of obstructive sleep apnea (OSA), resistant hypertension, systolic heart failure (HF), and cardiometabolic diseases. Accordingly, it has been proposed that the elimination of the CB chemosensory input to the brainstem may reduce the autonomic and cardiorespiratory alterations in sympathetic-associated diseases in humans. RECENT FINDINGS: A growing body of evidence obtained in preclinical animal models support that an enhanced CB discharge produces sympathetic hyperactivity, baroreflex sensitivity and heart rate variability impairment, breathing instability, hypertension, and insulin resistance. The elimination CB chemosensory input reduces the sympathetic hyperactivity, the elevated arterial blood pressure in OSA and hypertensive models, abolishes breathing instability and improves animal survival in HF models, and restores insulin tolerance in metabolic models. These results highlight the role played by the enhanced CB drive in the progression of sympathetic-related diseases and support the proposal that the surgical ablation of the CB is useful to restore the autonomic balance and normal cardiorespiratory function in humans. Accordingly, the CB ablation has been used in pilot human studies as a therapeutic treatment for resistant hypertension and HF-induced sympathetic hyperactivity. In this review, I will discuss the supporting evidence for a crucial contribution of the CB in the central autonomic dysfunction and the pros and cons of the CB ablation as a therapy to revert autonomic overactivation. The CB ablation could be a useful method to reverse the enhanced chemoreflex in HF and severe hypertension, but caution is required before extensive use of bilateral CB ablation, which abolished ventilatory responses to hypoxia and may impair baroreceptor function.

Diagnosis and management of resistant hypertension: state of the art.

Resistant hypertension is defined as a lack of ambulatory blood pressure response to optimized medical treatment after exclusion of secondary hypertension in patients who are fully adherent to antihypertensive therapy. Patients with resistant hypertension are at high risk of complications, particularly cardiovascular events, and optimization of medical treatment remains the cornerstone of their management. Such optimization should be based on simple algorithms and include the use of aldosterone antagonists. The available data from clinical trials do not support the use of device-based approaches such as renal denervation, baroreflex activation therapy or arteriovenous anastomosis for the treatment of resistant hypertension in the majority of patients. Therefore, device treatment remains a last-resort for patients with truly resistant hypertension in the context of clinical research in highly skilled tertiary referral centres. Future research should focus on improving understanding of the intrinsic (physiological and psychological factors) and extrinsic (environmental stressors) mechanisms that contribute to a lack of response to blood-pressure-lowering drugs in adherent patients. The use of biomarkers to identify patients with early target organ damage and new technologies, such as renal nerve stimulation, to predict blood pressure responses to renal denervation could aid the selection of patients who might benefit from device therapies.

Variable role of carotid bodies in cardiovascular responses to exercise, hypoxia and hypercapnia in spontaneously hypertensive rats.

KEY POINTS: Carotid bodies play a critical role in maintaining arterial pressure during hypoxia and this has important implications when considering resection therapy of the carotid body in disease states such as hypertension. Curbing hypertension in patients whether resting or under stress remains a major global health challenge. We demonstrated previously the benefits of removing carotid body afferent input into the brain for both alleviating sympathetic overdrive and reducing blood pressure in neurogenic hypertension. We describe a new approach in rats for selective ablation of the carotid bodies that spares the functional integrity of the carotid sinus baroreceptors, and demonstrate the importance of the carotid bodies in the haemodynamic response to forced exercise, hypoxia and hypercapnia in conditions of hypertension. Selective ablation reduced blood pressure in hypertensive rats and re-set baroreceptor reflex function accordingly; the increases in blood pressure seen during exercise, hypoxia and hypercapnia were unaffected, abolished and augmented, respectively, after selective carotid body removal. The data suggest that carotid body ablation may trigger potential cardiovascular risks particularly during hypoxia and hypercapnia and that suppression rather than obliteration of their activity may be a more effective and safer route to pursue. ABSTRACT: The carotid body has recently emerged as a promising therapeutic target for treating cardiovascular disease, but the potential impact of carotid body removal on the dynamic cardiovascular responses to acute stressors such as exercise, hypoxia and hypercapnia in hypertension is an important safety consideration that has not been studied. We first validated a novel surgical approach to selectively resect the carotid bodies bilaterally (CBR) sparing the carotid sinus baroreflex. Second, we evaluated the impact of CBR on the cardiovascular responses to exercise, hypoxia and hypercapnia in conscious, chronically instrumented spontaneously hypertensive (SH) rats. The results confirm that our CBR technique successfully and selectively abolished the chemoreflex, whilst preserving carotid baroreflex function. CBR produced a sustained fall in arterial pressure in the SH rat of ∼20 mmHg that persisted across both dark and light phases (P < 0.001), with baroreflex function curves resetting around lower arterial pressure levels. The cardiovascular and respiratory responses to moderate forced exercise were similar between CBR and Sham rats. In contrast, CBR abolished the pressor response to hypoxia seen in Sham animals, although the increases in heart rate and respiration were similar between Sham and CBR groups. Both the pressor and the respiratory responses to 7% hypercapnia were augmented after CBR (P < 0.05) compared to sham. Our finding that the carotid bodies play a critical role in maintaining arterial pressure during hypoxia has important implications when considering resection therapy of the carotid body in disease states such as hypertension as well as heart failure with sleep apnoea.

Role of the carotid body chemoreceptors in glucose homeostasis and thermoregulation in humans.

The carotid bodies (CBs) are multi-modal sensory organs located bilaterally at the bifurcation of the carotid artery and innervated by the carotid sinus nerve (Hering's nerve), a branch of the IX cranial nerve. While the CBs (or embryologically analogous structures) are well known as the dominant oxygen-sensing organ in vertebrates, in mammals there is evidence that the CBs may also sense glucose and temperature, and respond to circulating hormones and other factors. Additionally, the CBs likely participate in regulating baseline levels of sympathetic tone. In this brief review, we focus on the evolution of our efforts to understand 'what else' beyond oxygen sensing the CBs do in humans.

DNA methylation in the central and efferent limbs of the chemoreflex requires carotid body neural activity.

KEY POINTS: The mechanisms underlying long-term (30 days) intermittent hypoxia (LT-IH)-evoked DNA methylation of anti-oxidant enzyme (AOE) gene repression in the carotid body (CB) reflex pathway were examined. LT-IH-treated rats showed increased reactive oxygen species (ROS) levels in the CB reflex pathway. Administration of a ROS scavenger or CB ablation blocked LT-IH-evoked DNA methylation and AOE gene repression in the central and efferent limbs of the CB reflex. LT-IH increased DNA methyltransferase (Dnmt) activity through upregulation of Dnmt1 and 3b proteins by ROS-dependent inactivation of glycogen synthase kinase 3ß (GSK3ß) by Akt. A pan-Akt inhibitor prevented LT-IH-induced GSK3ß inactivation, elevated Dnmt protein expression and activity, AOE gene methylation, sympathetic activation and hypertension. ABSTRACT: Long-term exposure to intermittent hypoxia (LT-IH; 30 days), simulating blood O2 profiles during sleep apnoea, has been shown to repress anti-oxidant enzyme (AOE) gene expression by DNA methylation in the carotid body (CB) reflex pathway, resulting in persistent elevation of plasma catecholamine levels and blood pressure. The present study examined the mechanisms by which LT-IH induces DNA methylation. Adult rats exposed to LT-IH showed elevated reactive oxygen species (ROS) in the CB, nucleus tractus solitarius (nTS) and rostroventrolateral medulla (RVLM) and adrenal medulla (AM), which represent the central and efferent limbs of the CB reflex, respectively. ROS scavenger treatment during the first ten days of IH exposure prevented ROS accumulation, blocked DNA methylation, and normalized AOE gene expression, suggesting that ROS generated during the early stages of IH activate DNA methylation. CB ablation prevented the ROS accumulation, normalized AOE gene expression in the nTS, RVLM, and AM and blocked DNA methylation, suggesting that LT-IH-induced DNA methylation in the central and efferent limbs of the CB reflex is indirect and requires CB neural activity. LT-IH increased DNA methyl transferase (Dnmt) activity through upregulation of Dnmt1 and 3b protein expression due to ROS-dependent inactivation of glycogen synthase kinase 3ß (GSK3ß) by protein kinase B (Akt). Treating rats with the pan-Akt inhibitor GSK690693 blocked the induction of Dnmt activity, Dnmt protein expression, and DNA methylation, leading to normalization of AOE gene expression as well as plasma catecholamine levels and blood pressure.

Translating carotid body function into clinical medicine.

The carotid body (CB) is considered the main O2 chemoreceptor, which contributes to cardiorespiratory homeostasis and ventilatory acclimatization. In clinical medicine, the most common pathologies associated with the CB are tumours. However, a growing body of evidence supports the novel idea that an enhanced CB chemosensory discharge contributes to the autonomic dysfunction and pathological consequences in obstructive sleep apnoea (OSA), hypertension, systolic heart failure (HF) and cardiometabolic diseases. Heightened CB chemosensory reactivity elicited by oxidative stress has been involved in sympathetic hyperactivity, cardiorespiratory instability, hypertension and insulin resistance. CB ablation, which reduces sympathetic hyperactivity, decreases hypertension in animal models of OSA and hypertension, eliminates breathing instability and improves animal survival in HF, and restores insulin tolerance in cardiometabolic models. Thus, data obtained from preclinical studies highlight the importance of the CB in the progression of sympathetic-related diseases, supporting the idea that appeasing the enhanced CB chemosensory drive may be useful in improving cardiovascular, respiratory and endocrine alterations. Accordingly, CB ablation has been proposed and used as a treatment for moderating resistant hypertension and HF-induced sympathetic hyperactivity in humans. First-in-human studies have shown that CB ablation reduces sympathetic overactivity, transiently reduces severe hypertension and improves quality of life in HF patients. Thus, CB ablation would be a useful therapy to reverse sympathetic overactivation in HF and severe hypertension, but caution is required before it is widely used due to the crucial physiological function played by the CB. Further studies in preclinical models are required to assess side-effects of CB ablation.

Carotid Body Denervation Markedly Improves Survival in Rats With Hypertensive Heart Failure.

BACKGROUND: Hypertension is a major cause of heart failure. Excessive sympathoexcitation in patients with heart failure leads to poor prognosis. Since carotid body denervation (CBD) has been shown to reduce sympathetic nerve activity in animal models of hypertension and heart failure, we examined if bilateral CBD attenuates the progression of hypertensive heart failure and improves survival. METHODS: We randomly allocated Dahl salt-sensitive rats fed a high-salt diet from 6 weeks of age into CBD (n = 31) and sham-operation (SHAM; n = 50) groups, and conducted CBD or SHAM at 7 weeks of age. We examined the time course of 24-hour urinary norepinephrine (uNE) excretion, blood pressure (BP) and the percent fractional shortening assessed by echocardiography, and estimated the pressure-natriuresis relationship at 14 weeks of age. Finally, we assessed hemodynamics, histological findings, and survival at 16 weeks of age. RESULTS: Compared to SHAM, CBD significantly reduced 24-hour uNE at 12, 14, and 16 weeks of age, shifted the pressure-natriuresis relationship leftward without changing its slope, and attenuated the increase in BP. CBD preserved percent fractional shortening (34.2 ± 1.2 vs. 29.1 ± 1.3%, P < 0.01) and lowered left ventricular end-diastolic pressure (5.0 ± 0.9 vs. 9.0 ± 1.4 mm Hg, P < 0.05). Furthermore, CBD significantly attenuated myocardial hypertrophy (P < 0.01) and fibrosis (P < 0.01). Consequently, CBD markedly improved survival (relative risk reduction: 64.8%). CONCLUSIONS: CBD attenuated the progression of hypertension and worsening of heart failure possibly through sympathoinhibition, and markedly improved survival in a rat model of hypertensive heart failure.

Intact blood pressure, but not sympathetic, responsiveness to sympathoexcitatory stimuli in a patient with unilateral carotid body resection.

Despite rapidly growing interest in the therapeutic resection of the carotid body (CB) chemoreceptors, few physiologic studies exist on the consequences of unilateral CB resection. We present a case of an otherwise healthy postmenopausal female who underwent unilateral CB resection for a paraganglioma. Approximately 4 years postoperatively, she underwent analysis of her sympathetic and hemodynamic responses to hypoxia, lower body negative pressure, cold pressor test (CPT), and ischemic hand grip exercise and postexercise ischemia (IHE/PEI). Hypoxic ventilatory response and baroreflex sensitivity were relatively normal. Hemodynamic responses to IHE/PEI and CPT showed characteristic increases in cardiac output (from 3.9 L/min to 5.2 L/min [IHE/PEI] and 4.9 L/min [CPT]) and blood pressure (from 126/72 mmHg to 161/87 mmHg [IHE/PEI] and 171/93 mmHg [CPT]). However, muscle sympathetic nerve activity (microneurography of the peroneal nerve) decreased from baseline during IHE/PEI and CPT (burst incidence nadir of 45% and 40% of baseline, respectively) and there was no observable change in total peripheral resistance (from 24 mmHg*min/L to 22 mmHg*min/L [IHE/PEI] and 25 mmHg*min/L [CPT]). These findings illustrate intact blood pressure responsiveness despite attenuated sympathoexcitation, possibly due to an increase in cardiac output and/or adaptive inhibitory effect of the baroreflex on peripheral sympathetic activity.

Surgical management of carotid body tumor - Is Shamblin classification sufficient to predict surgical outcome?

Background The study aims to conduct a review of the surgical management of carotid body tumor. Methods Consecutive patients with CBT who received surgical interventions from January 1994 to January 2014 at our institution were reviewed. Clinical, operative, pathological and follow up information were reported. Results Twenty patients (four males; median age was 36) with 21 CBT operations were recorded during the period. One patient undertook sequential operations for bilateral CBTs. Patients had 19 neck mass, 1 incidental finding and 1 facial nerve palsy. Six CBTs (28.6%) were Shamblin class I, ten (47.6%) were class II and five (23.8%) were class III. Nine CBTs had preoperative conjunctive embolization. Two operations required internal carotid artery resection and reconstruction. Four patients received subtotal resections, while 17 achieved complete resection. Complications included two major strokes, three hoarse voice and two Horner's syndrome. Shamblin class was significant predictor of operative time, blood loss, and whether complete resection accomplished, but could not predict postoperative complication. With median follow up period of 94 months, there was no tumor recurrence found in those had complete resection. Conclusions This small cohort showed that Shamblin class was significant in predicting technical difficulties but could not predict occurrence of complications.