Comparison of Histopathologic Analysis Following Renal Sympathetic Denervation Over Multiple Time Points

Sakakura, Kenichi; Tunev, Stefan; Yahagi, Kazuyuki; O’Brien, Amanda J.; Ladich, Elena; Kolodgie, Frank D.; Melder, Robert J.; Joner, Michael; Virmani, Renu

doi:10.1161/circinterventions.114.001813

Cited by 51 publications

(50 citation statements)

References 22 publications

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“…These features are consistent with the current literature describing the histopathologic observations following RF ablation with other devices. 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.…”

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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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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“…In a recent study, the Simplicity renal ablation system was used to investigate chronological changes in the renal arteries after radiofrequency renal denervation in the swine model (75). A total of 49 renal arteries from 28 animals with 4 different time points (7, 30, 60, and 180 days) were examined.…”

Section: Other Potential Determinants Of the Antihypertensive Responsmentioning

confidence: 99%

Renal denervation for the treatment of resistant hypertension: review and clinical perspective

Iliescu

Lohmeier

Tudorancea

et al. 2015

American Journal of Physiology-Renal Physiology

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When introduced clinically 6 years ago, renal denervation was thought to be the solution for all patients whose blood pressure could not be controlled by medication. The initial two studies, SYMPLICITY HTN-1 and HTN-2, demonstrated great magnitudes of blood pressure reduction within 6 mo of the procedure and were based on a number of assumptions that may not have been true, including strict adherence to medication and absence of white-coat hypertension. The SYM-PLICITY HTN-3 trial controlled for all possible factors believed to influence the outcome, including the addition of a sham arm, and ultimately proved the demise of the initial overly optimistic expectations. This trial yielded a much lower blood pressure reduction compared with the previous SYMPLICITY trials. Since its publication in 2014, there have been many analyses to try and understand what accounted for the differences. Of all the variables examined that could influence blood pressure outcomes, the extent of the denervation procedure was determined to be inadequate. Beyond this, the physiological mechanisms that account for the heterogeneous fall in arterial pressure following renal denervation remain unclear, and experimental studies indicate dependence on more than simply reduced renal sympathetic activity. These and other related issues are discussed in this paper. Our perspective is that renal denervation works if done properly and used in the appropriate patient population. New studies with new approaches and catheters and appropriate controls will be starting later this year to reassess the efficacy and safety of renal denervation in humans. denervation; hypertension; pathophysiology; renal nerves; resistance RESISTANT HYPERTENSION IS defined as failure to achieve a guideline-driven blood pressure of less than 140/90 mmHg in patients who are adherent to maximally tolerated doses of at least three antihypertensive drugs, including a diuretic appropriate for kidney function (13). Population-based studies published over the last decade indicate that anywhere from 3 to 12% of hypertensive patients in the United States have resistant hypertension, despite the abundance of efficacious blood pressure-lowering agents belonging to over seven drug classes (11,20,68). Moreover, in addition to the cardiovascular mortality risk directly linked to the extent of blood pressure elevation, resistant hypertensive patients frequently have additional risk factors such as obesity, diabetes, chronic kidney disease, and age over 55 and are therefore more likely to die from stroke, myocardial infarction, heart failure, and end-stage renal disease (47, 76).Since increased sympathetic activity was believed to be present in many patients with resistant hypertension, renal denervation was thought to be the solution for all patients whose blood pressure could not be controlled by medication and was introduced for clinical use 6 years ago. In the open label, uncontrolled SYMPLICITY HTN-1 and SYMPLICITY HTN-2 trials, undertaken in patients with resistant hypertension, redu...

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“…Short-term 6 month Bp results or incomplete follow-up (34) cannot be extrapolated into durability of the Bp response or the prevention of cardiovascular complications. This is particularly the case in view of a recent report describing renal reinnervation within 60 days after renal nerve ablation in an experimental model (35). The DENERHTN investigators will soon report whether or not the need to continue or intensify antihypertensive drug treatment after RDN limits the cost-effectiveness of the procedure (9).…”

Section: -H Sbpmentioning

confidence: 99%

Meta-analysis of randomized controlled trials of renal denervation in treatment-resistant hypertension

et al. 2015

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Objective . The blood pressure (BP)-lowering effect of renal sympathetic nervous denervation (RDN) in resistant hypertension (rHT) shows large variation among studies. Methods. We meta-analyzed summary statistics of randomized clinical trials on RDN in rHT. For continuous outcomes, we assessed heterogeneity by Cochran ' s Q test and used random-effect models weighted for the inverse of the variance. We assessed safety by assessing the risk of major adverse events from stratifi ed contingency tables. Results. Of 5652 patients screened in seven trials, 985 (17.4%) qualifi ed and were randomized to control ( n ϭ 397) or RDN with SYMPLICITY ™ catheters ( n ϭ 588). Follow-up was 6 months. In both control and RDN patients, antihypertensive treatment was continued or optimized. At enrolment, age averaged 58.1 years, systolic/ diastolic offi ce and 24 h BP 168.5/93.3 mmHg and 151.8/86.1 mmHg, respectively, and estimated glomerular fi ltration rate (eGFR) 79.3 ml/min/1.73 m ² . For BP outcomes, there was heterogeneity among trials. Pooled effects (control minus RDN) were Ϫ 4.9/ Ϫ 3.5 mmHg (95% confi dence interval, Ϫ 20.9 to 11.1/ Ϫ 8.9 to 1.9) for offi ce BP, Ϫ 2.8/ Ϫ 1.5 mmHg ( Ϫ 6.5 to 0.8/ Ϫ 3.3 to 0.4) for 24 h BP and 0.81 ml/min/1.73 m ² ( Ϫ 1.69 to 3.30) for eGFR. Removing one trial at a time produced confi rmatory results. Adverse events occurred in 7.4% and 9.9% of control and RDN patients, respectively ( p ϭ 0.24). Conclusion. In selected rHT patients maintained on antihypertensive drugs, RDN with the SYMPLICITY systems does not signifi cantly decrease BP but is safe. Future trials with next-generation catheters should aim at identifying responders in patients with evidence of sympathetic nervous overactivity.

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Comparison of Histopathologic Analysis Following Renal Sympathetic Denervation Over Multiple Time Points

Cited by 51 publications

References 22 publications

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

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

Renal denervation for the treatment of resistant hypertension: review and clinical perspective

Meta-analysis of randomized controlled trials of renal denervation in treatment-resistant hypertension

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