Author + information
- †Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany
- ‡Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts
- §Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- ↵∗Reprint requests and correspondence:
Dr. Felix Mahfoud, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
- renal denervation catheters
- renal nerve ablation
- renal sympathetic nerve distribution
- therapy resistant hypertension
- treatment recommendation
Hypertension remains the most prevalent cardiovascular risk factor around the globe, and a large body of previously published literature examined the impact of the sympathetic nervous system on hypertension and vascular disease (1). In humans, sympathetic nerve activity is increased in almost all forms of hypertension and its comorbidities when measured according to muscle sympathetic nerve activity (2,3). Catheter-based approaches to renal sympathetic denervation may provide new treatment options for patients with resistant hypertension and bring the sympathetic nervous system back to center stage in cardiovascular medicine (1).
The relevance and variation in distribution and density of the renal sympathetic nervous system in humans have not been investigated sufficiently in the past, and treatment recommendations for catheter-based renal denervation have therefore been based on what now appears anecdotal or inappropriate extrapolation from other organ systems. In this issue of the Journal, Sakakura et al. (4) thoroughly define and explain mechanistic insight into how and when catheter-based renal denervation can be beneficial. The authors investigated the anatomic distribution of renal sympathetic nerves in human autopsy subjects (40 renal arteries from 20 patients) and provided the following insight:
1. The maximum average number of nerves was observed in the proximal and middle segments of the renal artery and the least number in the distal segments.
2. The mean distance from the lumen to nerve was highest in the proximal and lowest in the distal segments.
3. The circumferential distribution was greatest in the ventral region and least in the dorsal regions.
4. The density of efferent fibers was far higher than afferent fibers.
5. Accessory renal arteries are surrounded by sympathetic nerves.
6. No differences in nerve anatomy in hypertensive subjects compared with nonhypertensive subjects were observed.
These data suggest that asymmetric targeting is required to achieve denervation of renal afferent and efferent nerves and that the variability in target anatomy plays a causative role in achieving effective treatment. The flipside of the argument also prevails as to whether the present findings can or should impact our clinical practice in performing the procedure. The ablation depth of the currently available radiofrequency renal denervation systems varies between 2 and 4 mm, which in fact limits the accessibility of renal nerves by radiofrequency energy delivery in some regions of the renal artery. The density of renal nerves is higher in proximal segments compared with distal segments of the renal arteries, although with increasing distance from the aorta, radial nerve and ganglia distributions are localized closer to the lumen (Figs. 1A to 1C). The cumulative percentile of nerves at 3 mm is ∼50% in the proximal and middle segment and 75% in the distal segment. Therefore, one could argue that energy delivery should focus on the proximal part of the renal arteries, where the density of the nerves (efferent and afferent) is highest (Fig. 1A). However, the distance from the arterial lumen to nerves is shorter in the distal segment, which might translate into more effective and complete ablations, given the treatment pattern of the available radiofrequency devices (Fig. 1C). The situation is even more complex because there also seem to be differences in the circumferential location of the nerves, with the greatest number of nerves in the ventral region (11.0 ± 3.5 per section) compared with the dorsal region (6.2 ± 3.0 per section; p < 0.001).
Due to the high variability in renal nerve density, the efficacy of intravascular renal denervation within a given renal artery segment, particularly by single electrodes, seems to be dependent on the circumferential location and depth from the luminal surface of sympathetic nerves and ganglia. Indeed, the available evidence suggests that renal denervation reduces renal sympathetic activity (5) as well as reduces office and ambulatory blood pressure in open-label registries and randomized controlled trials (6–11) in certain, but not all, patients. It was well understood that the small, single-center studies which suggested the effects of renal denervation in resistant hypertension required validation in the arena of full-fledged clinical trials and real-world studies (12,13). Thus, the first blinded, sham-controlled Symplicity HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) study, which investigated renal denervation compared with invasive sham treatment in patients with severe therapy-resistant hypertension, met its primary safety endpoint but failed to reach its primary efficacy endpoint (14). The difference in office and ambulatory systolic blood pressure between the renal denervation group and the sham group did not reach statistical significance. Indeed, blood pressure response after renal denervation varies, and in the Symplicity HTN-1 trial (Percutaneous renal denervation in patients with treatment-resistant hypertension), response to renal denervation was arbitrarily defined as a systolic blood pressure reduction of >10 mm Hg 6 months after treatment. This threshold was thought to represent a clinical meaningful reduction of blood pressure that would translate into a reduction in cardiovascular risk (15). The Symplicity HTN-3 trial failed, but using this definition, 58% of the patients treated with renal denervation and 48% of patients in the sham group (p = 0.04) met the 10–mm Hg blood pressure reduction at the 6-month follow-up.
In addition, other procedural outliers may have been potential reasons for no or minor blood pressure changes after renal denervation (15). In Symplicity HTN-3, a total of 535 patients were recruited in 88 centers, but 111 operators performed 364 renal denervation procedures (14). On average, operators performed ∼3 procedures, but a reasonable number of investigators performed even fewer and many only 1. The procedures were performed by using the first-generation technology, a single electrode mono-polar catheter system (Symplicity Flex, Medtronic, Inc., Minneapolis, Minnesota) that deployed radiofrequency energy to the vessel wall. There were no means of assessing proper wall contact or effective destruction of renal sympathetic nerves intraprocedurally (16). Those who use radiofrequency ablation of arrhythmias are aware that radiofrequency lesion formation depends on good electrode–tissue contact, power delivery, electrode–tissue interface temperature, target tissue impedance, and the size of the catheter’s active electrode (17). This is important because specific catheter refinements and scientifically sound treatment recommendations might help to beneficially influence treatment success. However, one of the (anecdotal) procedural recommendations using the Symplicity Flex catheter was to start the denervation procedure distally inferior and, by pulling and rotating the catheter tip, to perform at least 4 focal treatments with an inferior, anterior, superior, and posterior orientation of the catheter tip with a distance of ≥5 mm between each location (18). Are these treatment recommendations supported by biology? Can treatment success be increased by concentrating our ablation efforts on a specific region? How many nerves need to be affected to significantly decrease noradrenaline kidney tissue content in animals and, even more importantly, sympathetic nerve activity and thereby blood pressure in humans: 10%, 50%, or 100%?
Certainly, additional preclinical and clinical studies are required to understand whether 1 size fits all or whether we will have to customize and refine treatments according to specific catheter features and, potentially, patient characteristics in the future. Despite the request to optimize treatment efficacy, new and revised devices have to show favorable safety profiles because an intensified treatment algorithm could potentially induce or promote renal artery stenosis. New renal denervation catheter developments and scientifically sound treatment recommendations might help to further increase treatment success. The results of Symplicity HTN-3 have provided valuable momentum. The renal denervation procedure may be technically easy; however, it is becoming more obvious that the importance of the complex underlying anatomy and physiology as well as the biophysics of radiofrequency lesion formation have been widely underestimated. The findings presented in this issue of the Journal (4) provide interesting information but above all should stimulate investigators and device manufactures to perform rigorous preclinical and clinical studies to resolve essential questions and to allow the field to determine how, when, and why effects can be anticipated.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Drs. Mahfoud and Böhm were investigators of the Symplicity HTN-1 and HTN-2 trials. Dr. Mahfoud is supported by Deutsche Hochdruckliga und Deutsche Gesellschaft für Kardiologie. Drs. Mahfoud and Böhm have received research grants, speaker honorarium, and consultancy fees from Medtronichttp://dx.doi.org/10.13039/100004374/Ardian, St. Jude Medicalhttp://dx.doi.org/10.13039/100006279, Boston Scientific, and/or Cordishttp://dx.doi.org/10.13039/100006479. Dr. Edelman is supported in part by grants from the U.S. National Institutes of Health (GM 49039).
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