The Carotid Body as a Therapeutic Target for the Treatment of Sympathetically Mediated Diseases

Paton, Julian F. R.; Sobotka, Paul; Fudim, Marat; Engelman, Zoar J.; Hart, Emma C J; McBryde, Fiona D; Abdala, Ana Paula; Marina, N; Gourine, Alexander V.; Lobo, Mel; Patel, Nikunj K.; Burchell, Amy E; Ratcliffe, Laura E K; Nightingale, Angus K

doi:10.1161/hypertensionaha.111.00064

Cited by 252 publications

(251 citation statements)

References 64 publications

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“…The decrease in arterial pressure was accompanied by a decrease in sympathetic vasomotor tone (blood pressure response to ganglionic blockade). Carotid body modulation 30 in the form of carotid body excision is being evaluated for treatment of patients with cardiac failure (NCT01653821 at http://clinicaltrials.gov) and hypertension (NCT01729988 at http://clinicaltrials.gov).…”

Section: Carotid Body Modulationmentioning

confidence: 99%

Sympathetic Nervous System and Hypertension

2013

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With the development and implementation of device-based therapeutic interventions to decrease renal and systemic nerve activity in patients with resistant hypertension, there has been an increase in research dealing with the role of the sympathetic nervous system in hypertension. These interventions have produced substantial decreases in blood pressure in patients wherein pharmacological treatments, including agents which inhibit the effects of the renin-angiotensin-aldosterone system, have failed serves to confirm and reassert the essential role of the sympathetic nervous system in hypertension. This review will encompass recent publications dealing with the sympathetic nervous system and hypertension, focusing on those recently published in Hypertension. Sympathetic Activation in Animal Models Obesity-Related HypertensionAlthough there has been a debate as to whether sympathetic activation is a cause or consequence of obesity, the studies noted below support the view that it is the obesity that leads to sympathetic activation. The importance of this sympathetic activation for the development of the hypertension is supported by the finding that renal denervation prevents the development of obesity hypertension in the dog.Studies have now focused on the developmental phase of obesity hypertension regarding the renal sympathoexcitation. In rabbits fed high-fat diets, body weight, plasma insulin and leptin concentrations, mean arterial pressure, heart rate, and renal sympathetic nerve activity were all increased after 1 week.1 Mean arterial pressure and body weight continued to increase over 3 weeks of high-fat diet, whereas heart rate and renal sympathetic nerve activity did not change further. Arterial baroreflex control of renal sympathetic nerve activity was attenuated from the first week of the high-fat diet. Excitatory responses to air jet stress diminished over 3 weeks of high-fat diet. Resumption of normal diet normalized glucose, insulin, leptin, and heart rate, but body weight, visceral fat content, mean arterial pressure, and renal sympathetic nerve activity remained elevated. Increased renal sympathetic nerve activity and its impaired baroreflex control, which occur with 1 week of high-fat feeding, seem integral to the rapid development of obesity hypertension. Increased plasma leptin and insulin may contribute to the initiation of hypertension but are not required for maintenance of the hypertension, which is related to the sustained increase in renal sympathetic nerve activity. As the air jet stress response is transduced by hypothalamic neurons, the authors speculate that this site is involved in the maintenance phase of the hypertension with a sustained increase in renal sympathetic nerve activity.The early effects of diet-induced fat accumulation on lumbar sympathetic nerve activity were also examined in rats over 15 days.2 Increases in brown and white adipose tissue (but not body weight) were accompanied by increases in plasma leptin (but not glucose) concentration and heart rate; however, mean a...

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Section: Carotid Body Modulationmentioning

confidence: 99%

Sympathetic Nervous System and Hypertension

2013

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“…In our human study and that of others, successful RDN treatment did not lower SBP to target levels in the majority of patients (<140 mm Hg; 38% at 6 months in Symplicity-1 14 ) or reduce BP to levels that allowed removal of antihypertensive medication. 9,14 Clearly, other factors are involved and may include poor cerebral perfusion, 48,49 excessive carotid body activity, 50,51 activation of the innate immune system, 31,52 and alterations in arterial baroreceptor input.…”

Section: Perspectives: One Size Does Not Fit Allmentioning

confidence: 99%

Translational Examination of Changes in Baroreflex Function After Renal Denervation in Hypertensive Rats and Humans

et al. 2013

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Abstract-Renal denervation has shown promise in the treatment of resistant hypertension, although the mechanisms underlying the blood pressure (BP) reduction remain unclear. In a translational study of spontaneously hypertensive rats (n=7, surgical denervation) and resistant hypertensive human patients (n=8; 5 men, 33-71 years), we examined the relationship among changes in BP, sympathetic nerve activity, and cardiac and sympathetic baroreflex function after renal denervation. In humans, mean systolic BP (SBP; sphygmomanometry) and muscle sympathetic nerve activity (microneurography) were unchanged at 1 and 6 months after renal denervation (P<0.05). Interestingly, 4 of 8 patients showed a 10% decrease in SBP at 6 months, but sympathetic activity did not necessarily change in parallel with SBP. In contrast, all rats showed significant and immediate decreases in telemetric SBP and lumbar sympathetic activity (P<0.05), 7 days after denervation. Despite no change in SBP, human cardiac and sympathetic baroreflex function (sequence and threshold techniques) showed improvements at 1 and 6 months after denervation, particularly through increased sympathetic baroreflex sensitivity to falling BP. This was mirrored in spontaneously hypertensive rats; cardiac and sympathetic baroreflex sensitivity (spontaneous sequence and the Oxford technique) improved 7 days after denervation. The more consistent results in rats may be because of a more complete (>90% reduction in renal norepinephrine content) denervation. We conclude that (1) renal denervation improves BP in some patients, but sympathetic activity does not always change in parallel, and (2) baroreflex sensitivity is consistently improved in animals and humans, even when SBP has not decreased. Determining procedural success will be crucial in advancing this treatment modality.

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“…This has motivated the investigation of nonpharmacologic approaches 7, 10, 11, 12. The present study investigated the safety and efficacy of a pacemaker‐based therapy that takes advantage of the fact that ventricular pressure generation is preload dependent and that preload can be manipulated by altering atrioventricular pacing delay.…”

Section: Discussionmentioning

confidence: 99%

“…These include baroreceptor activation therapy,17, 18, 19 renal denervation,7, 20 arteriovenous shunting,10, 21 carotid body resection or denervation,12, 22 and mechanical stimulation of the baroreceptors 23. Prior review articles have provided overviews and comparisons of these different approaches and will not be repeated here,24, 25 other than to say that treatment of isolated systolic hypertension (ie, patients with office diastolic blood pressure <90 mm Hg), which is characterized by increased vascular stiffness, has proved to be particularly challenging for some of these approaches, with such patients excluded from the recently complete SPYRAL HTN‐OFF MED study 19, 26.…”

Section: Discussionmentioning

confidence: 99%

Pacemaker‐Mediated Programmable Hypertension Control Therapy

Neužil

Merkely

Ērglis

et al. 2017

JAHA

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BackgroundMany patients requiring a pacemaker have persistent hypertension with systolic blood pressures above recommended levels. We evaluated a pacemaker‐based Programmable Hypertension Control (PHC) therapy that uses a sequence of variably timed shorter and longer atrioventricular intervals.Methods and ResultsPatients indicated for dual‐chamber pacing with office systolic blood pressure (oSBP) >150 mm Hg despite stable medical therapy were implanted with a Moderato™ pulse generator that delivers PHC therapy. Patients were followed for 1 month (Run‐In period) with conventional pacing; those with persistent oSBP >140 mm Hg were included in the study and had PHC therapy activated. The co‐primary efficacy end points were changes in 24‐hour ambulatory systolic blood pressure and oSBP between baseline and 3 months. Safety was assessed by tracking adverse events. Thirty‐five patients met the initial inclusion criteria and underwent Moderato implantation. At 1 month, oSBP was <140 mm Hg in 7 patients who were excluded. PHC was activated in the remaining 27 patients with baseline office blood pressure 166±11/80±10 mm Hg despite an average of 3.2 antihypertensive medications. During the Run‐In period, oSBP and 24‐hour ambulatory systolic blood pressure decreased by 8±13 and 5±12 mm Hg (P<0.002), respectively. Compared with pre‐PHC activation measurements, oSBP decreased by another 16±15 mm Hg and 24‐hour ambulatory systolic blood pressure decreased by an additional 10±13 mm Hg (both P<0.01) at 3 months. No device‐related serious adverse effects were noted.ConclusionsIn pacemaker patients with persistent hypertension despite medical therapy, oSBP and 24‐hour ambulatory systolic blood pressure are decreased by PHC therapy. Initial indications are that this therapy is a safe and promising therapy for such patients.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02282033.

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The Carotid Body as a Therapeutic Target for the Treatment of Sympathetically Mediated Diseases

Cited by 252 publications

References 64 publications

Sympathetic Nervous System and Hypertension

Sympathetic Nervous System and Hypertension

Translational Examination of Changes in Baroreflex Function After Renal Denervation in Hypertensive Rats and Humans

Pacemaker‐Mediated Programmable Hypertension Control Therapy

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