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

Hart, Emma C J; McBryde, Fiona D; Burchell, Amy E; Ratcliffe, Laura E K; Stewart, Lesley Q.; Baumbach, Andreas; Nightingale, Angus K; Paton, Julian F. R.

doi:10.1161/hypertensionaha.113.01261

Cited by 57 publications

(49 citation statements)

References 53 publications

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“…Given the current clinical interest and application of renal denervation (RD) in the treatment of drug-resistant hypertension [25][26][27][28][29] , we have characterized the interaction between CSD and RD in combination to establish the type of interaction: summative, occlusive or facilitatory. Given that T lymphocytes have been shown to contribute to both angiotensin II and neurally mediated chronic hypertension 30,31 , we have assessed immune function following CSD.…”

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The carotid body as a putative therapeutic target for the treatment of neurogenic hypertension

et al. 2013

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In the spontaneously hypertensive (SH) rat, hyperoxic inactivation of the carotid body (CB) produces a rapid and pronounced fall in both arterial pressure and renal sympathetic nerve activity (RSA). Here we show that CB de-afferentation through carotid sinus nerve denervation (CSD) reduces the overactive sympathetic activity in SH rats, providing an effective antihypertensive treatment. We demonstrate that CSD lowers RSA chronically and that this is accompanied by a depressor response in SH but not normotensive rats. The drop in blood pressure is not dependent on renal nerve integrity but mechanistically accompanied by a resetting of the RSA-baroreflex function curve, sensitization of the cardiac baroreflex, changes in renal excretory function and reduced T-lymphocyte infiltration. We further show that combined with renal denervation, CSD remains effective, producing a summative response indicative of an independent mechanism. Our findings indicate that CB de-afferentation is an effective means for robust and sustained sympathoinhibition, which could translate to patients with neurogenic hypertension.

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The carotid body as a putative therapeutic target for the treatment of neurogenic hypertension

et al. 2013

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“…A third reason may be because of the variation in the blood pressure response to renal denervation. The responder rates (a decrease in systolic blood pressure of ≥10 mm Hg) were only 33% and 50%, respectively, in the reports from Fadl Elmula et al 2 and Hart et al, 3 and these values were lower than those in the Symplicity HTN-1 study. These studies highlight that a big variation in the response of blood pressure to renal denervation exists, and that in some patients blood pressure may increase.…”

Section: To the Editormentioning

confidence: 72%

More Research Is Needed to Investigate the Effect of Denervation on Blood Pressure

Wang

2014

Hypertension

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“…Short-term studies in rodents and humans for example indicate that cardiac and sympathetic baroreflex functions improve after RDN, even when no change in blood pressure was achieved. 13 In conclusion, the work of Booth et al 1 provides a critical step forward in our understanding of the chronic effects of RDN, applying the same device as used in human clinical trials to a large animal model, and carefully documenting anatomical and functional evidence for successful initial denervation, and both renal afferent and efferent reinnervation over an 11-month time frame. Although this work suggests that correct and careful adherence to the RDN procedure can ensure a successful denervation, it does not lend support to long-term denervation being the mechanism underlying sustained effects, and this is where future research efforts must now be directed.…”

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confidence: 99%

What Underlies the Prolonged Hypotensive Effect of Catheter-Based Renal Denervation in Humans?

Phillips

2015

Hypertension

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276I n this issue, Booth et al 1 use a unique combination of functional, anatomical, and biochemical techniques to determine the effectiveness of percutaneous catheter-based radiofrequency renal denervation (RDN) on the destruction of the renal nerves and the long-term pattern of functional reinnervation. Their work is timely given the failure of the only appropriately powered, blinded, sham-controlled RDN clinical study to meet its primary end points, 2,3 and indeed the future of the technique as the panacea for the treatment of resistant hypertension is now being questioned. 4,5 Although issues of procedural competency and suboptimal denervation have been raised, 6 it is now more important than ever for the basic mechanisms underlying RDN to be clarified because specific patient cohorts may still show better responsiveness to therapy, 5 and secondary benefits of RDN in conditions such as diabetes mellitus, chronic kidney disease, and heart failure are still under investigation. 4 Whether primary beneficial effects are because of removal of afferent (sensory), efferent (sympathetic), or both components of the renal nerve also remains to be elucidated. One of the more puzzling issues associated with the procedure is the reported time frame of effectiveness, with data from the Symplicity HTN-1 and HTN-2 studies suggesting long-term changes in blood pressure in patients with treatment-resistant hypertension out to 36 months post RDN. 7,8 This is despite strong evidence in small animal models that reinnervation of both the sensory and the sympathetic renal nerves occurs over a relatively rapid time course (2-4 months) with functional capacity.9-11 A limitation in translating work from small animal models to human clinical treatments is the methodology used to achieve denervation, which in the experimental situation typically involves the use of full surgical exposure of the renal nerves, stripping of the renal nerves, and the application of a 10% solution of phenol.9 Such an approach achieves full denervation when compared with catheter-based RDN, which in controlled studies in humans has been shown to achieve a mean efficacy of 47%, as determined by renal noradrenaline spillover methods. 6 Booth et al 1 tackle these questions head on, using a large animal ovine model to examine not only the immediate impact of RDN on both the renal afferent and the efferent nerves but also the degree of reinnervation at 5.5 and 11 months post RDN. In the first instance, they demonstrate that 1 week after RDN using the Symplicity RDN System, renal sympathetic and afferent nerve functions in the sheep are abolished. Critically, they then show in further cohorts of animals that at 11 months post denervation, both levels of renal sympathetic nerve activity, as determined by direct recording, and physiological responses to sympathetic and sensory renal nerve electric stimulation, have returned to normal levels. This was supported by immunohistochemical assessment of the anatomic distribution of afferent and efferent nerves within the ...

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

Cited by 57 publications

References 53 publications

The carotid body as a putative therapeutic target for the treatment of neurogenic hypertension

The carotid body as a putative therapeutic target for the treatment of neurogenic hypertension

More Research Is Needed to Investigate the Effect of Denervation on Blood Pressure

What Underlies the Prolonged Hypotensive Effect of Catheter-Based Renal Denervation in Humans?

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