Editorial by Dr Sebastian Mafeld, Radiology Specialist Registrar, and Dr Phil Haslam, Consultant Interventional Radiologist, both of the Freeman Hospital, Newcastle upon Tyne
Hypertension is a global problem affecting approximately 1 billion people (2000 estimate) and this number is set to increase by a further 500 million by 2025. Although frequently a ‘silent’ disease, hypertension is associated with the development of cardiovascular risk factors. Pharmacological management forms the mainstay of treatment but treatment resistant hypertension (blood pressure above desired range despite three concurrent anti-hypertensives one of which should be a diuretic) is a common problem and challenging for clinicians to manage. Renal sympathetic denervation has been proposed as a treatment option in these cases. Since 2007, over 4000 patients have undergone the procedure using the Medtronic (formerly Ardian) Symplicity renal denervation system (click here for the Which Medical Device overview of this and other newer devices). This editorial reviews the rationale, evidence, complications and future implications of renal sympathetic denervation (RSD).
Rationale
The aetiology of hypertension is multifactorial but renal sympathetic input is an established contributor. Efferent sympathetic stimulation results in sodium and water retention, reduced renal blood flow and increased rennin release.4, The afferent renal sympathetic nerves are also involved through their central nervous system interaction which can ultimately increase sympathetic nervous system activity and raise blood pressure. This pathophysiology has long been understood and prior to pharmacological treatment, surgical sympathectomy (subdiaphragmatic spanchnicectomy) was successful at reducing blood pressure but associated with significant side effects (postural hypotension, syncope, impotence, mobility disturbance) making it an unattractive procedure. With the advent of pharmacological therapy, this procedure was abandoned.
Pharmacological therapy alone is not enough, currently, resistant hypertension may have a prevalence as high as 20-30% of all hypertension cases, therefore new innovations are needed to combat this problem.2
Modern endovascular catheter based access to the renal arteries allows for application of radiofrequency energy to selectively denervate the renal efferent and afferent sympathetic nerves located in the renal arteries’ adventitia. At a theoretical level this should lower blood pressure, but what is the evidence?
Summary of Evidence
Outside of small single institution reports, there are three studies that form the body of evidence for RSD.
1. Krum et al (2009). – This was a proof of principle international trial which analysed data for 45 patients treated with RSD. 12 month follow up demonstrated blood pressure reduction by -27/-17mm Hg. This study was limited by lack of a control group, suboptimal candidate exclusion criteria and small patient numbers.
2. Symplicity HTN-1 Trial – This study built upon the previous cohort by increasing the patient numbers and including follow up data up to 24 months. 153 patients were included and demonstrated an average blood pressure reduction -32/-14mm Hg at 24 months.
3. Symplicity HTN-2 Trial 5 – This study was a randomised control trial of 106 participants where 52 underwent RSD and 54 were controls. Data at six months demonstrated a blood pressure reduction of -32/12mm Hg in the treated group compared with a change of 1/0 mm Hg in the control group. Further 12 month data from the treated group demonstrated a sustained blood pressure reduction of -28/-9.7 mm Hg.
Procedural Information and Safety Implications
The Symplicity HTN-1 Trial used an average of 4 ablations in each renal artery. During the ablations patients experienced pain, but this did not persist post procedure. There were complications in 4/53 cases which included, 1 renal artery dissection upon catheter placement and 3 groin pseudoaneurysms. 6 month imaging follow up demonstrated no vascular abnormality at the site of ablation. No change in renal function was seen at 12 month follow up.
The Symplicity HTN-2 Trial demonstrated minor adverse events associated with the procedure in 5/52 cases. These included: 1 pseudoaneurysm, 1 post procedural drop in BP requiring pharmacological intervention, 1 urinary tract infection, 1 prolonged hospitalisation for investigation of paraesthesia, 1 back pain managed with analgesia which resolved within 1 month. Follow up imaging demonstrated no vascular abnormality at ablation site, however, 1 case showed progression of a pre-existing renal artery stenosis.
Theoretical Concerns
Although RSD has demonstrated a good intra procedure safety profile, two theoretical long term concerns exist:
Firstly, given current follow up data only exist to 24 months, it has been suggested that sympathetic nerve re-growth could diminish long term blood pressure reduction.5 Renal transplant data suggests sympathetic efferent nerves may be able to re-grow although the extent to which this will influence blood pressure is unclear.9 On the other hand, afferent sympathetic fibres are not thought to regrow.5,9
Secondly, the renal sympathetic system is an important physiological regulator, by denervating, regulatory mechanisms other than blood pressure could be negatively impacted. Ukena et al. investigated the cardiorespiratory response to exercise after RSD. It was found RSD “reduces blood pressure during exercise with improvements in heart rate recovery without blood pressure dysregulation, ventilatory effects, or chronotropic incompetence”.12
Future Implications
Sympathetic drive has been implicated in multiple clinical conditions. Data is emerging to suggest that RSD may have beneficial effects in other conditions; left ventricular hypertrophy, altered glucose metabolism, congestive heart failure and chronic kidney disease. 4,6, Before RSD can be integrated into mainstream clinical practice, further longer term data and larger study numbers are required – the Symplicity HTN-3 will attempt to address these issues.
As with all medical interventions, cost-benefit analyses are also necessary to determine financial feasibility. The Medtronic Symplicity Renal Sympathetic Denervation system is currently the only device of its kind on the market but further innovations in medical devices for the treatment of hypertension (e.g Rheos System; CVRx) may increase market competition.
References
1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005 Jan 15-21;365(9455):217-23.
2. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008;117(25):e510–526.
3. Medtronic. MEDTRONIC SYMPLICITY™ RENAL DENERVATION SYSTEM DEMONSTRATES SIGNIFICANT AND SUSTAINED BLOOD PRESSURE REDUCTION OUT TO THREE YEARS. [Press Release]. Retrieved from: http://www.medtronicrdn.com/pdfs/RDN_ACC_Press_Release_FINAL_03_25_12.pdf. April 4 2012.
4. Schlaich MP, Hering D, Sobotka P, Krum H, Lambert GW, Lambert E, Esler MD. Effects of renal denervation on sympathetic activation, blood pressure, and glucose metabolism in patients with resistant hypertension. Front Physiol. 2012;3:10. Epub 2012 Feb 2.
5. 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 Dec 4;376(9756):1903-9. Epub 2010 Nov 17.
6. Doumas M, Faselis C, Papademetriou V. Renal sympathetic denervation and systemic hypertension. Am J Cardiol. 2010 Feb 15;105(4):570-6.
7. Doumas M, Douma S. Interventional management of resistant hypertension. Lancet. 2009 Apr 11;373(9671):1228-30. Epub 2009 Mar 28.
8. Ukena C, Mahfoud F, Kindermann I, Barth C, Lenski M, Kindermann M, Brandt MC, Hoppe UC, Krum H, Esler M, Sobotka PA, Böhm M. Cardiorespiratory response to exercise after renal sympathetic denervation in patients with resistant hypertension. J Am Coll Cardiol. 2011 Sep 6;58(11):1176-82.
9. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009 Apr 11;373(9671):1275-81. Epub 2009 Mar 28.
10. Symplicity HTN-1 Investigators. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension. 2011 May;57(5):911-7. Epub 2011 Mar 14.
11. Murray D. Esler, Henry Krum, Markus Schlaich, Roland Schmieder, Michael Bohm, Paul Sobotka. RENAL SYMPATHETIC DENERVATION FOR TREATMENT OF RESISTANT HYPERTENSION: ONE YEAR RESULTS FROM THE SYMPLICITY HTN-2 RANDOMIZED CONTROLLED TRIAL. Journal of the American College of Cardiology, Volume 59, Issue 13, Supplement, 27 March 2012, Page E1705.
12. Ukena C, Mahfoud F, Kindermann I, Barth C, Lenski M, Kindermann M, Brandt MC, Hoppe UC, Krum H, Esler M, Sobotka PA, Böhm M. Cardiorespiratory response to exercise after renal sympathetic denervation in patients with resistant hypertension. J Am Coll Cardiol. 2011 Sep 6;58(11):1176-82.
13. Brandt MC, Mahfoud F, Reda S, Schirmer SH, Erdmann E, Böhm M, Hoppe UC. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol. 2012 Mar 6;59(10):901-9.
Further Information
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