Evaluation of renal nerve morphological changes and norepinephrine levels following treatment with novel bipolar radiofrequency delivery systems in a porcine model

Cohen-Mazor, Meital; Mathur, Prabodh; Stanley, James; Mendelsohn, Farrell O.; Lee, Henry; Baird, Rose; Zani, Brett G.; Markham, Peter; Rocha‐Singh, Krishna

doi:10.1097/hjh.0000000000000236

Cited by 35 publications

(26 citation statements)

References 14 publications

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Section: Discussionmentioning

confidence: 89%

“…These findings corroborate recent studies showing significant reductions in renal norepinephrine 8 weeks after RDN in obese hypertensive dogs 19 and 1 and 4 weeks after RDN in normal pigs. 18 In addition, after RDN we found inhibition of the afferent response to electric stimulation and decreased levels of CGRP staining.Interestingly, we found that by 5.5 months after RDN there was almost complete functional and anatomic reinnervation, and by 11 months after denervation there were no differences in the responses to electric stimulation, renal distribution of TH and CGRP, or renal norepinephrine levels compared with nondenervated controls. Importantly, by demonstrating unambiguously different responses to stimulation of the proximal and distal ends of the cut renal nerve we were able to demonstrate normalization of both the afferent and efferent responses to stimulation of the intact renal nerves.…”

mentioning

confidence: 89%

“…Studies in humans after renal transplants have found variable rates of reinnervation, 16,17 probably because human tissue was often derived from failed transplants. In recent studies in porcine 18 and canine 19 models, RDN using Symplicity and alternative catheters was associated with 81%, 59%, and 47% reductions in kidney norepinephrine content at 1, 4, and 8 weeks after denervation, respectively. Although these studies suggest significant denervation followed by potential reinnervation early after RDN, functional responsiveness and anatomic distribution of afferent and efferent renal nerves were not assessed.…”

Section: February 2015mentioning

confidence: 99%

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Reinnervation of Renal Afferent and Efferent Nerves at 5.5 and 11 Months After Catheter-Based Radiofrequency Renal Denervation In Sheep

et al. 2015

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T here is extensive evidence that renal afferent and efferent nerves play a critical role in the control of renal function and in setting the level of arterial blood pressure.1 This includes the findings that in experimental and human hypertension there are increases in renal sympathetic nerve activity (RSNA) and renal norepinephrine spillover, respectively. In addition, surgical renal denervation (RDN) reduces blood pressure in hypertensive animals and patients, 1-4 although in patients this was associated with several side effects. 4 The development of catheter-based radiofrequency RDN has resulted in a resurgence of interest in RDN as a treatment for resistant hypertensive patients. Initial trials demonstrated reductions in office systolic blood pressure 5,6 and in the 36-month follow-up from the first trial 93% of patients showed reductions in office systolic blood pressure of ≥10 mm Hg after RDN. 7 In contrast, the recent Symplicity HTN-3 trial did not demonstrate reductions in systolic blood pressure beyond that observed in sham control patients 6 months after RDN, 8 although there is still debate on factors that may have led to the lack of effect, such as procedural and population variability.It would be expected that destruction of the renal nerves reduces blood pressure because the efferent renal nerves play a major role in stimulating renin release, causing renal vasoconstriction and inducing sodium retention.1 It is also plausible that in hypertension, increased afferent renal nerve activity may cause a reflex increase in sympathetic outflow and worsening hypertension.9,10 Such actions are supported by findings that in some hypertensive patients, catheter-based RDN reduced the level of muscle SNA 11,12 and plasma norepinephrine. 13 Despite these proposed mechanisms, it is unknown how Abstract-Previous studies indicate that catheter-based renal denervation reduces blood pressure and renal norepinephrine spillover in human resistant hypertension. The effects of this procedure on afferent sensory and efferent sympathetic renal nerves, and the subsequent degree of reinnervation, have not been investigated. We therefore examined the level of functional and anatomic reinnervation at 5.5 and 11 months after renal denervation using the Symplicity Flex catheter. In normotensive anesthetized sheep (n=6), electric stimulation of intact renal nerves increased arterial pressure from 99±3 to 107±3 mm Hg (afferent response) and reduced renal blood flow from 198±16 to 85±20 mL/min (efferent response). In a further group (n=6), immediately after denervation, renal sympathetic nerve activity was absent and the responses to electric stimulation were abolished. At 11 months after denervation (n=5), renal sympathetic nerve activity and the responses to electric stimulation were at normal levels. Immunohistochemical staining for renal efferent (tyrosine hydroxylase) and renal afferent nerves (calcitonin gene-related peptide), as well as renal norepinephrine levels, was normal 11 months after denervation. Findings at 5.5...

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Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 89%

Section: February 2015mentioning

confidence: 99%

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Reinnervation of Renal Afferent and Efferent Nerves at 5.5 and 11 Months After Catheter-Based Radiofrequency Renal Denervation In Sheep

et al. 2015

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“…14,17,18 Effective RF nerve ablation has been previously shown to decrease NE levels in large animal models. 19,20 In this study, the norepinephrine levels measured in the single ablation animals demonstrated a significant NE decrease at all time points compared to naïve kidneys. The dramatic drop at 7 and 30 days, interestingly, is attenuated at 90 days, albeit still statistically decreased compared to controls.…”

Section: Discussionmentioning

confidence: 94%

“…14,[24][25][26] The high degree of distal nerve atrophy observed at 7 and 30 days in this study reported at chronic time points in other large animal experiments where RF ablation of renal nerves was performed. 14,20 It is necessary to further establish if the apparent morphological "recovery" of distal nerves could be responsible for the late increase in NE levels and whether this partial recovery may or may not produce a physiologic increase in blood pressure. The available clinical data though suggest sustained blood pressure lowering effects up to 36 months following the procedure.…”

Section: Discussionmentioning

confidence: 99%

Sub-acute Safety and Efficacy Evaluation of Single versus Double Treatment Cycles of a Monopolar Radiofrequency Catheter-Based Renal Nerve Ablation and its Chronic Evolution in a Large Animal Model

Hubbard¹,

Sakaoka²,

Brants³

et al. 2016

J.ATAMIS

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Aims:We aimed to evaluate the transcatheter renal denervation(RDN) effects delivered by a mono-electrode catheter in a large animal model including safety implications of delivery of one cycle versus two cycles of ablations.Methods and Results:18 animals underwent bilateral RDN; 4 untreated naïve swine were enrolled as controls for norepinephrine levels(NE) only. Animals recieved 120-second (follow up-7,30 and 90 days) or 240-second cycles ablations (follow up-7 days). Norepinephrine evaluation, histology and immunohistochemistry evaluation was performed. No luminal obstruction was observed at follow up. A 70% decrease in NE levels (76.68±57.87ng/g) was observed at 7 days, 81% at 30 days(49.05±45.81ng/g), and 51% at 90 days(12.7±73.2 ng/g) compared to naïve controls(254.1±54.1ng/g;p<0.05). Histologically, the thermal effect extended to a complete circumferential involvement with a depth ~8mm. The primary histological feature at 7 days was nerve necrosis and distal atrophy; at 30 days, necrosis was replaced by healing changes of fibrosis. Neuromatous regeneration was apparent at 30 days at RF treated levels. At 90 days these features progressed to become more conspicuous. There were no appreciable differences in depth and circumferential extent of RF injury between one and two cycle treatment groups.Conclusion:RDN performed with a mono-electrode catheter (Iberis) appears to be safe following single or double-cycle RF ablation.NE decrease following RDN was demonstrated at 7, 30, and 90 days compared to naïve controls, suggesting efficient nerve ablation with the device as intended for human use.

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Acute changes in histopathology and intravascular imaging after catheter‐based renal denervation in a porcine model

Sakaoka

Takami

Onimura

et al. 2017

Cathet Cardio Intervent

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Evaluation of renal nerve morphological changes and norepinephrine levels following treatment with novel bipolar radiofrequency delivery systems in a porcine model

Cited by 35 publications

References 14 publications

Reinnervation of Renal Afferent and Efferent Nerves at 5.5 and 11 Months After Catheter-Based Radiofrequency Renal Denervation In Sheep

Reinnervation of Renal Afferent and Efferent Nerves at 5.5 and 11 Months After Catheter-Based Radiofrequency Renal Denervation In Sheep

Sub-acute Safety and Efficacy Evaluation of Single versus Double Treatment Cycles of a Monopolar Radiofrequency Catheter-Based Renal Nerve Ablation and its Chronic Evolution in a Large Animal Model

Acute changes in histopathology and intravascular imaging after catheter‐based renal denervation in a porcine model

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