Carotid Body Ablation Research Articles

Hypertension and Device-Based Therapies for Resistant Hypertension: An Up-to-Date Review.

Hypertension is the most prevalent modifiable risk factor associated with cardiovascular mortality. The World Health Organization (WHO) estimates that hypertension directly or indirectly causes the death of at least nine million people globally every year. The number of people living with hypertension (blood pressure (BP) of ≥140 mmHg systolic or ≥90 mmHg diastolic or on medication) doubled between 1990 and 2019, from 650 million to 1.3 billion. Despite a plethora of antihypertensivedrugs widely available, a sizable part of the antihypertensive population stays uncontrolled. The unmet need of controlling BP in this population may be addressed, in part, by developing new drugs and devices/procedures to treat hypertension and its comorbidities. Several device-based approaches have been introduced to lower BP, and most of these strategies aim to modulate autonomic nervous system activity. Importantly, when considering a device-based treatment, each patient's underlying pathophysiology is considered, and the procedural risks are weighed against the cardiovascular risk attributed to the elevated BP.In November 2023, the FDA approved two renal denervation (RDN) devices. This manuscript discusses current interventional devices and procedures recently approved (RDN) and others in the clinical testing stage for arterial hypertension intervention or management.As we list below, all others have shown promising results and are being evaluated on a larger clinical trial.The new device-based classes are as follows: catheter-based RDN, baroreflex amplification, arteriovenous (AV) malformation, carotid body (CB) ablation, pacemaker-based cardiac neuromodulation, electro-acupuncture, and deep brain stimulation. Baroreflex amplification uses peripheral neuromodulation, while AV malformation leverages AV anastomosis. CB ablation modulates chemoreceptors, and pacemaker-based neuromodulation adjusts atrioventricular intervals. Electro-acupuncture proves potential, and deep brain stimulation offers central nervous system intervention.

Carotid body ablation restores astrocyte/microglia morphology in the NTS and reduces hypertension following long-term intermittent hypoxia

Chronic intermittent hypoxia (CIH) heightened carotid body (CB) chemosensory discharges, which contributes to hypertension development. Previously, we reported that CB ablation significantly reduced blood pressure after 21 days of CIH; however, whether CB-mediated glial cell activation in the caudal Nucleus of the Solitary Tract (cNTS) following long-term CIH contribute to maintain high blood pressure and enhanced ventilatory chemoreflex remains unknown. To test this hypothesis, we exposed male C57BL6 mice to CIH (5% FIO2, 12 times/h, 8 h/day) for 60 days. At 45 days of CIH, CBs were selectively denervated, and animals returned to CIH for 15 more days. At the end of the experimental protocol, we measured arterial blood pressure, hypoxic ventilatory response (HVR) in awake mice and characterized astrocyte and microglia morphological features using Sholl analysis. CIH induces hypertension (MABP: 83.47±1.39 vs. 95.00±2.18 mmHg; Sham vs. CIH), increases the HVR (1.69±0.17 vs. 4.31±0.87 ΔVE/min; Sham vs. CIH), modify cNTS astrocytes phenotype (N° of branches: 13.01±0.66 vs. 11.31±0.52; cable length: 181.00±8.90 vs 148.10±1.48 μm, convex hull: 788.10±37.60 vs. 584.30±23.75 μm3; Sham vs. CIH), and microglia arborization (N° of branches: 196.10±8.35 vs. 376.30±16.80; cable length: 667.4±29.63 vs. 1267±60.47 μm, convex hull: 6177±362 vs. 9721±564 μm3; Sham vs. CIH). Importantly, CB denervation normalized the elevated blood pressure (MABP: 83.47±1.38 mmHg; CIHd), the altered peripheral chemoreflex response (HVR: 1.63±0.43 ΔVE/min; CIHd) and morphological changes in astrocytes (N °of branches: 17.23±0.88, cable length: 231.70±12.87, convex hull: 982.70±55.55 μm3) and microglia located in the cNTS (N° of branches 126.20±13.34; cable length: 126.2±13.3, Convex hull size: 3584±380 μm3; CIHd). Present results suggest that CBs play a crucial role in the maintenance of high arterial pressure and respiratory alterations induced by long-term CIH and may contribute to the formation of a neuroinflammatory niche at the cNTS by modifying glial cell activity. Supported by Fondecyt Grants 1211443 and 1220950. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The carotid body detects circulating tumor necrosis factor-alpha to activate a sympathetic anti-inflammatory reflex

Recent evidence has suggested that the carotid bodies might act as immunological sensors, detecting pro-inflammatory mediators and signalling to the central nervous system, which, in turn, orchestrates autonomic responses. Here, we confirmed that the TNF-α receptor type I is expressed in the carotid bodies of rats. The systemic administration of TNF-α increased carotid body afferent discharge and activated glutamatergic neurons in the nucleus tractus solitarius (NTS) that project to the rostral ventrolateral medulla (RVLM), where many pre-sympathetic neurons reside. The activation of these neurons was accompanied by an increase in splanchnic sympathetic nerve activity. Carotid body ablation blunted the TNF-α-induced activation of RVLM-projecting NTS neurons and the increase in splanchnic sympathetic nerve activity. Finally, plasma and spleen levels of cytokines after TNF-α administration were higher in rats subjected to either carotid body ablation or splanchnic sympathetic denervation. Collectively, our findings indicate that the carotid body detects circulating TNF-α to activate a counteracting sympathetic anti-inflammatory mechanism.

Exercise intolerance in volume overload heart failure is associated with low carotid body mediated chemoreflex drive

Mounting an appropriate ventilatory response to exercise is crucial to meeting metabolic demands, and abnormal ventilatory responses may contribute to exercise-intolerance (EX-inT) in heart failure (HF) patients. We sought to determine if abnormal ventilatory chemoreflex control contributes to EX-inT in volume-overload HF rats. Cardiac function, hypercapnic (HCVR) and hypoxic (HVR) ventilatory responses, and exercise tolerance were assessed at the end of a 6 week exercise training program. At the conclusion of the training program, exercise tolerant HF rats (HF + EX-T) exhibited improvements in cardiac systolic function and reductions in HCVR, sympathetic tone, and arrhythmias. In contrast, HF rats that were exercise intolerant (HF + EX-inT) exhibited worse diastolic dysfunction, and showed no improvements in cardiac systolic function, HCVR, sympathetic tone, or arrhythmias at the conclusion of the training program. In addition, HF + EX-inT rats had impaired HVR which was associated with increased arrhythmia susceptibility and mortality during hypoxic challenges (~ 60% survival). Finally, we observed that exercise tolerance in HF rats was related to carotid body (CB) function as CB ablation resulted in impaired exercise capacity in HF + EX-T rats. Our results indicate that: (i) exercise may have detrimental effects on cardiac function in HF-EX-inT, and (ii) loss of CB chemoreflex sensitivity contributes to EX-inT in HF.

Intermittent Hypoxia-Induced Activation of Endothelial Cells Is Mediated via Sympathetic Activation-Dependent Catecholamine Release.

Obstructive sleep apnea (OSA) is a common breathing disorder affecting a significant percentage of the adult population. OSA is an independent risk factor for cardiovascular disease (CVD); however, the underlying mechanisms are not completely understood. Since the severity of hypoxia correlates with some of the cardiovascular effects, intermittent hypoxia (IH) is thought to be one of the mechanisms by which OSA may cause CVD. Here, we investigated the effect of IH on endothelial cell (EC) activation, characterized by the expression of inflammatory genes, that is known to play an important role in the pathogenesis of CVD. Exposure of C57BL/6 mice to IH led to aortic EC activation, while in vitro exposure of ECs to IH failed to do so, suggesting that IH does not induce EC activation directly, but indirectly. One of the consequences of IH is activation of the sympathetic nervous system and catecholamine release. We found that exposure of mice to IH caused elevation of circulating levels of catecholamines. Inhibition of the IH-induced increase in catecholamines by pharmacologic inhibition or by adrenalectomy or carotid body ablation prevented the IH-induced EC activation in mice. Supporting a key role for catecholamines, epinephrine alone was sufficient to cause EC activation in vivo and in vitro. Together, these results suggested that IH does not directly induce EC activation, but does so indirectly via release of catecholamines. These results suggest that targeting IH-induced sympathetic nerve activity and catecholamine release may be a potential therapeutic target to attenuate the CV effects of OSA.

A Compendium on Hypertension: New Advances and Future Impact.

A Compendium on Hypertension: New Advances and Future Impact.

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.

The Current Status of Devices for the Treatment of Resistant Hypertension.

Arterial hypertension is associated with increased cardiovascular morbidity and mortality. Although blood pressure-lowering therapies significantly reduce the risk of major cardiovascular events, blood pressure control remains unsatisfactorily low. Several device-based antihypertensive therapies have been investigated in patients with treatment-resistant hypertension and in patients unable or unwilling to adhere to antihypertensive medication. As the field of device-based therapies is subject to constant change, this review aims at providing an up-to-date overview of different device-based approaches for the treatment of hypertension. These approaches target the sympathetic nervous system (renal denervation, baroreflex amplification therapy, baroreflex activation therapy, and carotid body ablation) or alter mechanical arterial properties by creating an iliac arteriovenous fistula. Notably, the use of all of these treatment options is not recommended for the routine treatment of hypertension by current guidelines but should be investigated in the context of controlled clinical studies.

Enhanced Carotid Body Chemosensory Discharge is Essential for the Hypertension Induced by Chronic Intermittent Hypoxia

Chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea, enhances carotid body (CB) discharges, leading to sympathetic overflow and hypertension. CIH produces oxidative stress (ROS) in the CB, which contributes to enhance the CB drive to the brainstem and hypothalamic nuclei related to the cardiorespiratory control, such as the nucleus of the tractus solitary (NTS), the rostral ventrolateral medulla (RVLM) and the paraventricular nucleus (PVN). We hypothesized whether the enhanced CB chemosensory drive may increase ROS levels in central cardiovascular nuclei during CIH‐induced hypertension. Accordingly, we studied the effects of CB ablation on ROS formation in the NTS, PVN and RVLM of hypertensive CIH‐rats. Male Sprague‐Dawley rats (200 g) were exposed to CIH (5–6% inspired O2 for 20s, followed by room air for 280s, 12 times/h, 8 h/day), for 28 days. Arterial blood pressure (BP) was measured by radio‐telemetry (DSI, USA). Following 21 days of CIH exposure, rats were anesthetized with isofluorane in 2% O2, and the CBs were cryogenically destroyed bilaterally using a fine‐tipped forcep cooled in liquid N2. Then, rats were maintained in CIH conditions for one more week. Another group of rats were maintained in CIH or Sham conditions for 28 days. At the end of the experiments, all animals were euthanized (pentobarbital 120mg/kg i.p.) and brains were removed and frozen at −20°C. Coronal sections of the NTS, RVLM and PVN were cut and incubated for 30 min in the dark with the ROS sensitive fluorescent probe dihydroethidium (DHE 10μM, Invitrogen USA). DHE fluorescence was measured using epifluorescence microscopy (Olympus Optical, Japan) at an excitation wavelength of 543 nm. Data were analyzed by one‐way ANOVA followed by Bonferroni's test. Compared to Sham rats, CIH‐rats showed a significant increase in mean BP (□ 10 mmHg, p<0.05). The CIH‐induced hypertension was abolished by the ablation of the CBs (CBA). ROS formation was markedly reduced by CBA in the NTS, RVLM and PVN of CIH‐exposed rats (CIH vs. CIH‐CBA: NTS: 6.2±1.5 vs. 1.5±02 au, RVLM: 4.9± 1.5 vs. 2.1±1.6 au, PVN: 5.4±1.8 vs. 1.6±05 au, p <0.05, n= 5–6 rats). Results support the evidence for an essential role of the CBs in the development and maintenance of the CIH‐induced hypertension and oxidative stress present in the NTS, RVLM and PVNSupport or Funding InformationFONDECYT 1150040This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Treatment of Hypertension: A Review

Hypertension is the most common modifiable risk factor for death and disability including stroke, accelerated coronary and systemic atherosclerosis, heart failure, chronic kidney disease, lowering the BP with antihypertensive drugs, and reducing the target organ damage and prevalence of the occurrence of cardiovascular disease. According to the 2017 American college of cardiology (ACC)/American heart association (AHA) hypertension guidelines hypertension is defined as systolic BP is ≥130 mmHg or diastolic BP is ≥80 mmHg. BP should be lower than 130/80 mmHg in patient with CHD, CHF, after renal transplantation, diabetes mellitus and stroke. Recommended lifestyle modification included restriction of dietary sodium intake, weight loss if patient is overweight, regular exercise, moderate alcohol intake and increase consumption of potassium rich foods. The initial antihypertensive agent should be generally selected from one of the following four classes—thiazide diuretics, ACE inhibitors, ARBs, and calcium channel blockers, shown to reduce cardiovascular events. There are two interventional approaches—Renal Denervation and Baroreflex activation therapy, which are used in clinical practice for treatment of several treatment resistant hypertensions. Other interventional approaches are carotid body ablation and AVF placement but none of them prevent cardiovascular disease outcome or death in hypertensive patient.

Modulation of Sympathetic Overactivity to Treat Resistant Hypertension.

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. 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.

1416Transvenous carotid body ablation for resistant hypertension: main results of a multicentre safety and proof-of-principle cohort study

1416Transvenous carotid body ablation for resistant hypertension: main results of a multicentre safety and proof-of-principle cohort study

Guinea Pig as a Model to Study the Carotid Body Mediated Chronic Intermittent Hypoxia Effects.

Clinical and experimental evidence indicates a positive correlation between chronic intermittent hypoxia (CIH), increased carotid body (CB) chemosensitivity, enhanced sympatho-respiratory coupling and arterial hypertension and cardiovascular disease. Several groups have reported that both the afferent and efferent arms of the CB chemo-reflex are enhanced in CIH animal models through the oscillatory CB activation by recurrent hypoxia/reoxygenation episodes. Accordingly, CB ablation or denervation results in the reduction of these effects. To date, no studies have determined the effects of CIH treatment in chemo-reflex sensitization in guinea pig, a rodent with a hypofunctional CB and lacking ventilatory responses to hypoxia. We hypothesized that the lack of CB hypoxia response in guinea pig would suppress chemo-reflex sensitization and thereby would attenuate or eliminate respiratory, sympathetic and cardiovascular effects of CIH treatment. The main purpose of this study was to assess if guinea pig CB undergoes overactivation by CIH and to correlate CIH effects on CB chemoreceptors with cardiovascular and respiratory responses to hypoxia. We measured CB secretory activity, ventilatory parameters, systemic arterial pressure and sympathetic activity, basal and in response to acute hypoxia in two groups of animals: control and 30 days CIH exposed male guinea pigs. Our results indicated that CIH guinea pig CB lacks activity elicited by acute hypoxia measured as catecholamine (CA) secretory response or intracellular calcium transients. Plethysmography data showed that only severe hypoxia (7% O2) and hypercapnia (5% CO2) induced a significant increased ventilatory response in CIH animals, together with higher oxygen consumption. Therefore, CIH exposure blunted hyperventilation to hypoxia and hypercapnia normalized to oxygen consumption. Increase in plasma CA and superior cervical ganglion CA content was found, implying a CIH induced sympathetic hyperactivity. CIH promoted cardiovascular adjustments by increasing heart rate and mean arterial blood pressure without cardiac ventricle hypertrophy. In conclusion, CIH does not sensitize CB chemoreceptor response to hypoxia but promotes cardiovascular adjustments probably not mediated by the CB. Guinea pigs could represent an interesting model to elucidate the mechanisms that underlie the long-term effects of CIH exposure to provide evidence for the role of the CB mediating pathological effects in sleep apnea diseases.

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

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. 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.

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

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. 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 ∼20mmHg 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.

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

The mechanisms underlying long-term (30days) 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 3β (GSK3β) by Akt. A pan-Akt inhibitor prevented LT-IH-induced GSK3β inactivation, elevated Dnmt protein expression and activity, AOE gene methylation, sympathetic activation and hypertension. Long-term exposure to intermittent hypoxia (LT-IH; 30days), 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 3β (GSK3β) 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.

4123Long term effect of transvenous carotid body ablation in the treatment of patients with resistant hypertension

4123Long term effect of transvenous carotid body ablation in the treatment of patients with resistant hypertension

Proceedings from the 2nd European Clinical Consensus Conference for device-based therapies for hypertension: state of the art and considerations for the future.

The interest in RDN for hypertension has fluctuated recently, with a flurry of initial enthusiasm followed by sudden loss of interest by researchers and device manufacturers, with an almost as sudden resurgence in clinical trials activity and device innovation more recently. There is widespread consensus that this therapeutic strategy can be effective, at least for some of the technologies available. Major uncertainties remain as to the clinical role of RDN, and whether any of the emerging technologies such as AV-anastomosis formation, carotid body ablation, carotid bulb expansion, or baroreflex stimulation will have a future as effective treatment options in patients with hypertension. In our first consensus report in 2015, the European Expert Group pointed to the major unmet need of standardization of measurements, trial design and procedural performance.6 With the large number of different technologies currently in the pipeline, this need has even increased. Only through high-quality, collaborative research and openness to new methods for recruitment, patient selection, and assessment of outcomes will it be possible to establish incontrovertibly whether device therapies for hypertension are effective and what are preferred patient populations. Once the proof of concept is established, further studies with a design relevant to clinical reality will be needed to establish the place of new devices in the treatment armoury. The clinical and research community has a large responsibility to prove or disprove the value of new therapies, in order to ensure that antihypertensive devices provide future patients with the greatest benefit and the smallest risk. copy; The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.

First In-Human Evaluation of a Transvenous Carotid Body Ablation Device to Treat Patients with Resistant Hypertension

First In-Human Evaluation of a Transvenous Carotid Body Ablation Device to Treat Patients with Resistant Hypertension