Pathology of Renal Artery Ablation: Impact of Therapeutic Methods

Sep 26, 2018   |  

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Hypertension is a common disease associated with cardiovascular mortality.1,2 Catheter-based renal sympathetic denervation was introduced to interrupt renal sympathetic nerve signaling, thereby lowering blood pressure in patients with uncontrolled hypertension. Using this procedure, the SYMPLICITY HTN-1 and SYMPLICITY HTN-2 (Renal Denervation in Patients With Uncontrolled Hypertension) trials3,4 and the DENER-HTN (Renal Denervation for Hypertension) trial5 showed a marked reduction in blood pressure. On the other hand, the randomized, sham-controlled SYMPLICITY HTN-3 trial failed to demonstrate a reduction of blood pressure at 6 months in patients who underwent renal denervation.6 After the SYMPLICITY HTN-3 trial, several potential confounders were identified that might explain the lack of benefit observed following the intervention, including inadequate patient selection, operator inexperience, insufficient procedure performance (lack of proper placement of denervation), uncontrolled changes in antihypertensive medications, and poor medication adherence.

Overall, historical data on surgical sympathectomy indicate a beneficial effect on blood pressure levels.7,8 Given that renal sympathetic activation plays a role in the pathogenesis of hypertension, an improvement in methodology may modulate the results following renal denervation. Although it is extremely important to elucidate the procedures involved, the suitable placement of renal denervation had not been established prior to the SYMPLICITY HTN-3 trial. Our group assessed the anatomical distribution of peri-arterial sympathetic nerves around human renal arteries.9 A total of 10,329 nerves was identified from 20 patients. Mean nerve distance to the arterial lumen was the greatest in proximal segments (3.40 ± 0.78 mm), followed by middle segments (3.10 ± 0.69 mm), and the least in distal segments (2.60 ± 0.77 mm) (p < 0.001). The cumulative incidence of nerve distance from the arterial lumen based on proximal, middle, and distal segments is shown in Figure 1, and the circumferential peri-arterial nerve location is shown in Figure 2.9 Our study suggests that renal denervation for the distal renal artery may be more effective for the reduction of blood pressure because of a shorter distance from the arterial lumen to nerves. Furthermore, it suggests that less thermal energy may be required to achieve nerve damage. In light of this anatomical study, the recent SYMPLICITY HTN trials recommended treating all accessible renal arteries, including branch vessels and accessory arteries, as well as the main renal artery with as many 4-quadrant treatments as needed.10 Subsequently, the renal denervation system (Symplicity Spyral [Medtronic, Inc.; Minneapolis, MN]) has been improved; it includes a mounted 4-electrode array that self-expands into a helical configuration, with electrodes located at 90 degrees from each other circumferentially. The SPYRAL HTN-OFF MED (Investigation of Catheter-Based Renal Denervation in Patients With Uncontrolled Hypertension in the Absence of Antihypertensive Medications) and SPYRAL HTN-ON MED (Investigation of Catheter-Based Renal Denervation in Patients With Uncontrolled Hypertension in the Presence of Antihypertensive Medications) trials showed a significant reduction in blood pressure.11,12

Figure 1: Cumulative Distribution of Nerves at Distance From Lumen

Figure 1
Modified and reproduced with permission from Sakakura et al.9

Figure 2: Proposed Diagram of Renal Artery and Circumferential Peri-Arterial Nerve Location

Figure 2
Although there were fewer nerves surrounding the renal artery in the distal segments compared with the proximal and middle segments, the mean distance from renal artery lumen to nerve location is least in the distal segments compared with the proximal and middle segments. Reproduced with permission from Sakakura et al.9

Currently, several types of renal denervation devices are available. EnligHTN (St. Jude Medical; St. Paul, MN) is a radiofrequency system that is an expandable, multi-electrode basket renal denervation catheter. Mahfoud et al. investigated the efficacy of renal denervation in the distal main renal artery using the EnligHTN catheter versus the main renal artery with branches using the Symplicity Spyral. They showed that compared with a Spyral catheter, distally focused treatment of the main renal artery using an EnligHTN catheter seems to be equally effective in reducing tissue norepinephrine levels.13

The Paradise ultrasound denervation system (ReCor Medical; Palo Alto, CA) is a catheter-based device designed to deliver ultrasound energy for targeted, circumferential denervation of renal sympathetic nerves. An animal study using the Paradise system demonstrated circumferential ablation.14 Recently, the RADIANCE-HTN SOLO (A Study of the ReCor Medical Paradise System in Clinical Hypertension) trial showed the efficacy of renal denervation using the Paradise endovascular ultrasound renal denervation system.15 The RADIANCE-HTN trials included two separate cohorts: patients with mild to moderate hypertension who underwent randomization while off antihypertensive medications (SOLO cohort) and patients on three antihypertensive medications (TRIO cohort). The SOLO cohort included 146 patients and showed a significant reduction in daytime ambulatory systolic blood pressure in the renal denervation group compared with the sham group (-8.5 ± 9.3 mmHg vs. -2.2 ± 10.0 mmHg; baseline-adjusted difference between groups: -6.3 mmHg; 95% confidence interval, -9.4 to -3.1; p = 0.0001).15

The Peregrine System Infusion Catheter (Ablative Solutions, Inc.; San Jose, CA) is a renal denervation device using chemical neurolysis with percutaneous perivascular alcohol infusion. A single-blinded, randomized study that assessed the efficacy of renal denervation with alcohol infusion compared with a single-electrode radiofrequency catheter using a porcine model showed a significantly greater ablation area in the alcohol infusion group than that in the radiofrequency ablation group.16 In addition, renal tissue norepinephrine concentration was lower in the alcohol infusion group than in historical controls.

Until now, the efficacy of renal denervation has been demonstrated only in the short term (2-6 months). It is unknown whether the benefits of renal denervation will be sustained over longer periods of time. The assessment of pathological changes with sympathetic renal nerves over time may help understand the mechanisms resulting in sustained blood pressure reduction. Sakakura et al. assessed a total of 49 renal arteries from 28 animals at 4 different time points (7, 30, 60, and 180 days).17 Nerve injury after radiofrequency renal denervation was the greatest in the sub-acute phase (7 days) than in the transitional phase (30 and 60 days) and chronic phase (180 days), with peak functional nerve damage seen at 30 days. The healing process of nerves is likely to be species-dependent and to influence the effect of renal denervation. For example, the duration of healing may be longer in humans than in pigs, thereby leading to a more sustained effect of renal denervation.

In conclusion, recently published randomized sham-controlled trials have shown the efficacy of renal denervation for up to 6 months. A pathological assessment, including the anatomy of the renal nerves, has helped expand and refine the methods of renal denervation. Larger studies with longer follow-up are required to determine whether this procedure may lead to a reduction in cardiovascular events.

References

  1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet 2005;365:217-23.
  2. Lloyd-Jones DM, Evans JC, Levy D. Hypertension in adults across the age spectrum: current outcomes and control in the community. JAMA 2005;294:466-72.
  3. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009;373:1275-81.
  4. Symplicity HTN-2 Investigators, Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376:1903-9.
  5. Azizi M, Sapoval M, Gosse P, et al. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial. Lancet 2015;385:1957-65.
  6. Bhatt DL, Kandzari DE, O'Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370:1393-401.
  7. Allen EV. Sympathectomy for essential hypertension. Circulation 1952;6:131-40.
  8. Morrissey DM, Brookes VS, Cooke WT. Sympathectomy in the treatment of hypertension; review of 122 cases. Lancet 1953;1:403-8.
  9. Sakakura K, Ladich E, Cheng Q, et al. Anatomic assessment of sympathetic peri-arterial renal nerves in man. J Am Coll Cardiol 2014;64:635-43.
  10. Kandzari DE, Kario K, Mahfoud F, et al. The SPYRAL HTN Global Clinical Trial Program: Rationale and design for studies of renal denervation in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications. Am Heart J 2016;171:82-91.
  11. Townsend RR, Mahfoud F, Kandzari DE, et al. Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial. Lancet 2017;390:2160-70.
  12. Kandzari DE, Böhm M, Mahfoud F, et al. Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial. Lancet 2018;391:2346-55.
  13. Mahfoud F, Pipenhagen CA, Boyce Moon L, et al. Comparison of branch and distally focused main renal artery denervation using two different radio-frequency systems in a porcine model. Int J Cardiol 2017;241:373-8.
  14. Sakakura K, Roth A, Ladich E, et al. Controlled circumferential renal sympathetic denervation with preservation of the renal arterial wall using intraluminal ultrasound: a next-generation approach for treating sympathetic overactivity. EuroIntervention 2015;10:1230-8.
  15. Azizi M, Schmieder RE, Mahfoud F, et al. Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial. Lancet 2018;391:2335-45.
  16. Bertog S, Fischel TA, Vega F, et al. Randomised, blinded and controlled comparative study of chemical and radiofrequency-based renal denervation in a porcine model. EuroIntervention. 2017;12:e1898-e1906.
  17. Sakakura K, Tunev S, Yahagi K, et al. Comparison of histopathologic analysis following renal sympathetic denervation over multiple time points. Circ Cardiovasc Interv 2015;8:e001813.

Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Prevention, Interventions and Imaging, Angiography, Nuclear Imaging, Hypertension

Keywords: Angiography, Hypertension, Renal Artery, Denervation, Medication Adherence


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