Renal sympathetic denervation
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]
Synonyms and keywords: RDN, renal denervation
Overview
Renal denervation (RDN) is a minimally invasive, endovascular catheter-based procedure invented to treat patients with severe resistant hypertension.[1] Preliminary data suggest that renal denervation is safe and results in a sustained blood pressure reduction of approximately 30 mm Hg at a three-year follow up.[2][3] However, in light of the negative results from SYMPLICITY HTN-3, the beneficial effect of renal denervation remains uncertain.
Rationale
A treatment catheter is introduced into the renal artery and energy is applied circumferentially at several ablation points within each renal artery to target the sympathetic endings in the adventitia of the vessel wall.[4][5] The drop in blood pressure presumably results from a reduction in norepinephrine release from the nerve endings and an overall decrease in sympathetic activity, which culminates in diminished renin secretion, vasoconstriction, and sodium reabsorption.[5][1] Renal denervation might also be beneficial in comorbidities of hypertension such as congestive heart failure, chronic kidney disease, and metabolic syndrome.[6]
History
Prior to pharmacological management of hypertension, surgical sympathectomy was a recognized treatment for hypertension. Before modern pharmacotherapy, the mortality rate within 5 years of malignant hypertension was close to 100%.[1] Surgical treatment of hypertension was suggested by several independent researchers in 1923, yet the first patient with malignant hypertension to be treated with surgical sympathectomy wasn't until 1925, by Adson. [5] [7] Isolated bilateral renal denervation was only performed in 1934 by Page and Heuer, however, because the results were considered unsatisfactory, surgical renal denervation was replaced by a more aggressive technique, the surgical removal of splanchnic nerves or splanchnicectomy, which showed effective results. Subsequently, thoracolumbar splanchnicectomy became the procedure of choice for malignant hypertension, which did not respond to diet and limited pharmacological therapy of the time, for the following 2 decades. [5] Between 1938 and 1947, other studies were made by Smithwick and Thompson, who published results from studying 3500 patients with malignant hypertension. Of those, 2400 were treated with thoracolumbar splanchnicectomy, while the others took the pharmacological therapy available at the time. The group who underwent the surgical procedure had an inferior mortality rate and substantial blood pressure reduction, when compared to the pharmacologically treated group. [5] This technique was often successful in reducing blood pressure but due to its non-selective nature, the high operative mortality and side effects were considerable. [1] These included orthostatic hypotension, palpitations, anhidrosis, intestinal disturbances, impotence, thoracic duct injuries and atelactasis. [8][9]
It was only until mid-1950's that the first oral antihypertensive medication became available. This allowed for a well-tolerated treatment regimen that patients could follow on the long term. For the last 50 years, medication has improved the control of hypertension in thousands of patients throughout the world, however, evidence from the National Health and Nutrition Examination Survey along with large randomized clinical trials shows that an estimated 20% to 30% of hypertension cases require up to 3 or more antihypertensive drugs to achieve blood pressure targets. [5][6][10] Recent data from National Health and Nutrition Examination Survey shows that 12.8% of hypertensive patients fulfill the criteria for resistant hypertension, which represents about 120 million patients worldwide. [5] Failure to reach normal blood pressure values puts these patients at an increased risk for development of major cardiovascular complications. [11]
During this time, a major effort in understanding the role of the SNS in hypertension has been made, particularly the role of renal sympathetic nerves in this process. [5] Several models are pointing to a considerable role of the SNS overactivity in the development and maintenance of hypertension, to which renal sympathetic nerves are an important contributor. This overactivity is involved in several other diseases, described below, which justifies the need for more studies to evaluate how relevant this procedure might be for the treatment of other conditions. [5]
Device
As of today, several percutaneous renal sympathetic nerve ablation systems are being studied and tested, 6 of them have already received CE marking to be used for renal nerve ablation: [1][5][12][13][14][15]
- Medtronic's Simplicity™ System - produced by Medtronic (formerly Ardian), was the first device to be used in humans, receiving market approval in 2010. It uses a radio frequency catheter (6F) inserted percutaneously through a femoral sheath, under fluoroscopic control. Despite being easily used, it has a tendency to create lesions with a less predictable pattern. This device now has over 5 years of clinical experience and 3 years of follow up data. The device has received favourable reviews on WhichMedicalDevice™, but concerns have been reported regarding availability and financial reimbursement for the procedure.
- St. Jude's EnligHTN system - also uses a radio frequency catheter inserted percutaneously through a femoral sheath, under fluoroscopic control, however, is equipped with 4 electrodes on a basket structure. This allows it to create lesions in a more circumferential pattern, being able to create thermal injury and fiber interruption in a more predictable way.
- Vessix's V2 system - also uses a radio frequency catheter inserted percutaneously through a femoral sheath, under fluoroscopic control, however, the electrodes are mounted in a balloon, allowing for a good distribution of the energy.
- Covidien's One Shot system - also uses a radio frequency catheter inserted percutaneously through a femoral sheath, under fluoroscopic control, however, the electrodes are mounted in a balloon, allowing for a good distribution of the energy.
- Iberis system - also uses a radio frequency catheter and a 4-French shaft, enabling radial access.
- Recor's Paradise system - uses an ultrasound technology catheter inserted percutaneously through a femoral sheath.
Any of these systems must be manipulated by skilled operators, in an appropriately equipped catheterization lab. [6] Currently they are available in parts of Europe, Asia, Africa, Australia and the Americas. So far, no renal denervation device has had FDA approval.
Procedure
Overview
Considering the factors: drug-resistant hypertension, SNS involvement in hypertension, importance of renal nerves for the overall sympathetic activity of the body, along with the ease of approach of the renal nerves through catheter techniques, hypertension is thought to be a good candidate for a catheter-based interventional approach. Knowing that sympathetic nerve fibers are located in the adventitia of the renal arteries, they can be easily reached by a catheter through a transvascular approach and interrupted using thermal energy. However, considering that sympathetic nerves share their location with C-pain fibers, analgesia and sedation, but not anesthesia, are mandatory for this procedure. [1][5]
Pre-procedure
- This technique must take place in a well equipped catheterization lab center, with skilled operators, experienced in handling possible surgical complications.
- Preprocedural examinations require the exclusion of secondary hypertension, as a "hidden cause" of resistance, as well as confirmation of uncontrolled blood pressure, while on medical treatment. This last criterion may involve the testimonial of a third party, confirming that the patient took the medication, since a common cause of "resistance" is noncompliance with the regimen. [6]
- Renal artery suitability must be assessed, which is done with a duplex ultrasound or MRI, and adequate anticoagulation should be attained and confirmed by activated clotting time test (with a target of 200-250 seconds). Ideally the renal artery must be >20 mm in length and >4 mm in diameter.
- Renal function tests are also required to confirm kidney's ability to sustain preprocedural contrast medium exposure. [6][9][11]
During procedure
- Vital signs such as blood pressure, heart rate and oxygen saturation must be monitored and continuous transcutaneous oxygen should be provided. [9]
- Although not confirmed by clinical trials, it has been suggested the administration of periprocedural anti-platelet therapy, for up to 4 weeks after the procedure, to prevent thrombus formation. [11]
Technique
- Under fluoroscopic guidance, through a femoral sheath, the electrode is positioned in each of the renal arteries.
- In patients with single renal arteries, 4 ablation points are recommended. The catheter should be placed at the periphery of the second order renal artery branch point, with the help of a guide wire. The lesions made in the artery wall should have a circumferential pattern, to decrease the risk of artery stenosis, which can be achieved by rotating the catheter while pulling it back to the ostium of the artery, at the same time that the energy is being delivered. For a successive and safe ablation, the points of lesion should be distanced by >5 mm. In areas of atherosclerotic plaque, the ablation should be avoided. [11] The energy used for the ablation also generates heat within the vessels, yet the system is cooled by the high rate of blood flow. [6] The procedure lasts for about 30 to 60 minutes. [11]
- Up until now, the devices used for this procedure have used either a single-tip electrode catheter, or a multielectrode system. The multielectrode systems have simplified this process by making it less painful and faster than the single-tip electrode version. [5][1]
Post-procedure
- After the procedure, the patient should be monitored until the sedation wears off, and closely followed to access the safety and efficacy of the procedure. Some studies also recommend the evaluation of the renal arteries, using duplex ultrasound, in order to exclude renal artery stenosis. Despite having been reported in single cases, this complication might not be due to the technique itself, but to pre-existing atherosclerotic plaques. [6]
Outcomes
The safety and efficacy of renal denervation were first investigated in a proof-of-concept study on 45 patients with resistant hypertension.[16] Office blood pressures after procedure were reduced by –14/–10, –21/–10, –22/–11, –24/–11, and –27/–17 mm Hg at 1, 3, 6, 9, and 12 months, respectively. These data led to the following trials:
SYMPLICITY HTN-1
This was designed to be a first-in-human observational evaluation of the efficacy and safety of selective renal sympathetic denervation. [11] It looked at outcomes of 45 patients, with a mean age of 58 ± 9 years and mean blood pressure of 177±20/101±15 mm Hg, taking on average 5 antihypertensive drugs, who underwent catheter-based renal denervation. [11]
The patients were then evaluated at 1, 3, 6, 9 and 12 months. The procedure was noted to be associated with a significant decrease in office blood pressure, with mean decreases of: [11]
- 1st month: 14±4/10±3 mm Hg
- 3rd month: 21±7/10±4 mm Hg
- 6th month: 22±10/11±5 mm Hg
- 9th month: 24±9/11±5 mm Hg
- 12th month: 27±16/17±11 mm Hg.
Three-year follow-up data have demonstrated an average blood pressure reduction of 33/19mm Hg. This trial confirmed the durability of the procedure, contradicting the hypothesis that sympathetic nerve regrowth would nullify the effect. It has also noted a reduction of 47% in renal norepinephrine spillover, accompanied by a decrease in overall body norepinephrine spillover, confirming a reduction in central sympathetic activity after the renal denervation. [2][6]
In terms of safety, in this trial, renal angiography was performed at the 14th and 30th day post procedure and MRI angiography at the 6th month, which showed no sign of renal artery aneurysm or stenosis. [11]
Despite being of great value, this study was too small, lacked control groups and relied on office blood pressure, instead of ambulatory values. [5]
SYMPLICITY HTN-2
This was a randomized, controlled trial, with a total of 106 patients from Australia and Europe, that compared 54 control patients with 52 active treatment patients, who underwent catheter-based renal denervation. Prior to the study, both groups had similar characteristics and antihypertensive treatment regimens, except for the estimated glomerular filtration rate, which was inferior in the active treatment group. [11]
- After the procedure, the difference in office blood pressure for these two groups at 6 months was:
- Active treatment group - mean blood pressure of 147/84 mm Hg, from 178/96 mm Hg
- Control group - no change, with a mean blood pressure of 179/96 mm Hg, from 178/97 mm Hg
- After the procedure, the difference in ambulatory blood pressure for these two groups at 6 months was:
- Active treatment group - confirmed the observed office changes, with reductions of 20±17 mm Hg for systolic and 12±11 mm Hg for diastolic blood pressure
- Control group - confirmed the absence of changes, with 2±13 mm Hg for systolic and 0±7 mm Hg for diastolic blood pressure
The trial showed that 20% of patients in the active treatment group had reductions in drug treatment before the 6 month period and that 39% of these, saw their blood pressure controlled to values <140 mm Hg, whereas the patients in the control group, only 6% had this reduction of drug treatment and only 3% saw their blood pressure controlled. At the same time, 8% of the patients in the active treatment group had an increase in the drug treatment regimen, before the 6 month follow-up visit, while 12% of the patients in the control group had this increase. [11] At the 6 months follow-up, the initial control group underwent the same renal denervation procedure, which led them to experience the same blood pressure drops as the initial active treatment group. [6] At 12 months the effects from the renal denervation were still present. [5]
It is important to notice that blood pressure lowerings usually take weeks to months to to settle in, which suggests a slow resetting of SNS regulation. This should be kept in mind and transmitted to the patient, in order to avoid unrealistic expectations. Also the procedure is intended to improve blood pressure control in patients with resistant hypertension, therefore, it is important to inform the patient that he will most likely continue the pharmacological therapy. [9]
Meta-analyses of renal denervation have yielded conflicting results. [17] Although in blood pressure-lowering trials using pharmacological approaches, office and ambulatory blood pressure results are normal to show disparities, in this particular case there was a considerable difference between blood pressure levels in office and ambulatory data. [11] The reasons for this disparity are so far unclear. Proposed theories include renal denervation obliterating the white coat response, thereby disproportionately reducing clinic values,[17] or the disparity rather being an anomaly due to deficiencies in renal denervation trial designs to date.
In these two previous trials patient awareness of the differences in treatment, along with a possible influence of observer bias might have been a contributor to the results observed, therefore a new study was designed: [11]
SYMPLICITY HTN-3
SYMPLICITY HTN-3 is a multi-center, prospective, single-blind, randomized, sham-controlled study on efficacy and safety of renal sympathetic denervation in patients with severe resistant hypertension (Clinical Trial No. NCT01418261).[18][19] A total of 535 patients were randomized in a 2:1 ratio to receive renal denervation or sham procedure. There was no significant reduction in office and ambulatory SBP or differences in safety between the two groups.
- Mean changes in office systolic blood pressure (SBP) at 6 months were as follows, for a difference of –2.39 mm Hg:
- Renal denervation group: –14.13±23.93 mm Hg (p<0.001)
- Sham procedure group: –11.74±25.94 mm Hg (p<0.001)
- Mean changes in 24-hour ambulatory systolic blood pressure (SBP) at 6 months were as follows, for a difference of –1.96 mm Hg:
- Renal denervation group: –6.75±15.11 mm Hg (p<0.001)
- Sham procedure group: –4.79±17.25 mm Hg (p<0.001)
Risks
The Symplicity HTN-1 and HTN-2 trials have demonstrated a good safety profile for catheter-based renal denervation. [5] Patients may experience pain during application of radiofrequency pulses and intraprocedural bradycardia requiring atropine, has also been reported.[3] Other documented procedure-related complications include small hematomas, renal artery stenosis, vasospasm of the renal artery following the procedure, femoral artery pseudoaneurysm and renal artery dissection. A concern about this technique was if renal function would be affected. So far data show only minor deterioration of eGFR and increase in serum creatinine. [5]
A particular concern is the theoretical risk of damage to renal arteries during the delivery of radiofrequency energy. Some published data mentioned that the applied energy could result in acute cellular swelling, transient local de-endothelization, connective tissue coagulation and possible thrombus formation, hence the advised concomitant administration of antiplatelet therapy. [9] An animal study using swines showed no damage to the renal arteries at 6 month follow up. This finding is further supported in human studies in the HTN-1 and HTN-2 trial where follow up imaging has not demonstrated renal vascular damage.[20]
Two case reports were published, following reports of rise in blood pressure secondary to renal sympathetic denervation, caused by progression of renal artery stenosis. However, it is still yet to be confirmed whether this evolution was due to the procedure or the natural progression of the disease process. [9]
Uses of Renal Denervation Beyond Hypertension
Potential benefits of renal denervation are being investigated in comorbidities of hypertension that are associated with exaggerated sympathetic activity, including:
- Atrial fibrillation[21][22][23][24][25]
- Diabetes mellitus[26]
- Heart failure[27]
- Sleep apnea[28][29][30]
- Polycystic ovary disease[31]
- Ventricular tachycardia[32]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Thukkani, A. K.; Bhatt, D. L. (2013). "Renal Denervation Therapy for Hypertension". Circulation. 128 (20): 2251–2254. doi:10.1161/CIRCULATIONAHA.113.004660. ISSN 0009-7322.
- ↑ 2.0 2.1 Symplicity HTN-1, Investigators (2011 May). "Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months". Hypertension. 57 (5): 911–7. doi:10.1161/HYPERTENSIONAHA.110.163014. PMID 21403086. Check date values in:
|date=(help) - ↑ 3.0 3.1 Symplicity HTN-2, Investigators (2010 Dec 4). "Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial". Lancet. 376 (9756): 1903–9. doi:10.1016/S0140-6736(10)62039-9. PMID 21093036. Unknown parameter
|coauthors=ignored (help); Check date values in:|date=(help) - ↑ Esler, MC (2010 Dec 4). "Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomized controlled trial". Lancet. 376 (9756): 1903–9. doi:10.1016/S0140-6736(10)62039-9. PMID 21093036. Unknown parameter
|coauthors=ignored (help); Check date values in:|date=(help) - ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 5.15 Papademetriou, V.; Rashidi, A. A.; Tsioufis, C.; Doumas, M. (2014). "Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions". Circulation. 129 (13): 1440–1451. doi:10.1161/CIRCULATIONAHA.113.005405. ISSN 0009-7322.
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 Böhm M, Linz D, Urban D, Mahfoud F, Ukena C (2013). "Renal sympathetic denervation: applications in hypertension and beyond". Nat Rev Cardiol. 10 (8): 465–76. doi:10.1038/nrcardio.2013.89. PMID 23774592.
- ↑ Doumas, M (2009 Apr 11). "Interventional management of resistant hypertension". Lancet. 373 (9671): 1228–30. doi:10.1016/S0140-6736(09)60624-3. PMID 19332354. Unknown parameter
|coauthors=ignored (help); Check date values in:|date=(help) - ↑ Doumas, M (2010 Feb 15). "Renal sympathetic denervation and systemic hypertension". The American journal of cardiology. 105 (4): 570–6. doi:10.1016/j.amjcard.2009.10.027. PMID 20152255. Unknown parameter
|coauthors=ignored (help); Check date values in:|date=(help) - ↑ 9.0 9.1 9.2 9.3 9.4 9.5 Mahfoud, F.; Luscher, T. F.; Andersson, B.; Baumgartner, I.; Cifkova, R.; DiMario, C.; Doevendans, P.; Fagard, R.; Fajadet, J.; Komajda, M.; LeFevre, T.; Lotan, C.; Sievert, H.; Volpe, M.; Widimsky, P.; Wijns, W.; Williams, B.; Windecker, S.; Witkowski, A.; Zeller, T.; Bohm, M. (2013). "Expert consensus document from the European Society of Cardiology on catheter-based renal denervation". European Heart Journal. 34 (28): 2149–2157. doi:10.1093/eurheartj/eht154. ISSN 0195-668X.
- ↑ Calhoun, DA (2008 Jun 24). "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. 117 (25): e510–26. doi:10.1161/CIRCULATIONAHA.108.189141. PMID 18574054. Unknown parameter
|coauthors=ignored (help); Check date values in:|date=(help) - ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 11.11 11.12 Schlaich MP, Schmieder RE, Bakris G, Blankestijn PJ, Böhm M, Campese VM; et al. (2013). "International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension". J Am Coll Cardiol. 62 (22): 2031–45. doi:10.1016/j.jacc.2013.08.1616. PMID 24021387.
- ↑ WhichMedicalDevice. Symplicity Catheter System (Overview). http://www.whichmedicaldevice.com/by-manufacturer/113/198/symplicity-catheter-system
- ↑ Medtronic. RDN Brochure. http://www.medtronicrdn.com/mediakit/RDN%20Brochure.pdf
- ↑ Medgadget. Medtronic Starts Trial with Symplicity Renal Denervation System for Chronic Heart Failure and Renal Impairment. http://medgadget.com/2012/02/medtronic-starts-trial-with-symplicity-renal-denervation-system-for-chronic-heart-failure-and-renal-impairment.html
- ↑ WhichMedicalDevice. Symplicity Catheter System (User Reviews). http://www.whichmedicaldevice.com/by-manufacturer/113/198/symplicity-catheter-system
- ↑ Krum, H.; Schlaich, M.; Whitbourn, R.; Sobotka, PA.; Sadowski, J.; Bartus, K.; Kapelak, B.; Walton, A.; Sievert, H. (2009). "Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study". Lancet. 373 (9671): 1275–81. doi:10.1016/S0140-6736(09)60566-3. PMID 19332353. Unknown parameter
|month=ignored (help) - ↑ 17.0 17.1 Doumas, Michael; Anyfanti, Panagiota; Bakris, George (2012). "Should ambulatory blood pressure monitoring be mandatory for future studies in resistant hypertension". Journal of Hypertension. 30 (5): 874–876. doi:10.1097/HJH.0b013e328352c3c7. ISSN 0263-6352.
- ↑ Bhatt, Deepak L.; Kandzari, David E.; O'Neill, William W.; D'Agostino, Ralph; Flack, John M.; Katzen, Barry T.; Leon, Martin B.; Liu, Minglei; Mauri, Laura; Negoita, Manuela; Cohen, Sidney A.; Oparil, Suzanne; Rocha-Singh, Krishna; Townsend, Raymond R.; Bakris, George L. (2014). "A Controlled Trial of Renal Denervation for Resistant Hypertension". New England Journal of Medicine. 370 (15): 1393–1401. doi:10.1056/NEJMoa1402670. ISSN 0028-4793.
- ↑ Renal Denervation in Patients With Uncontrolled Hypertension (SYMPLICITY HTN-3). ClinicalTrials.gov Identifier: NCT01418261 http://clinicaltrials.gov/ct2/show/NCT01418261
- ↑ Rippy, MK (2011 Dec). "Catheter-based renal sympathetic denervation: chronic preclinical evidence for renal artery safety". Clinical research in cardiology : official journal of the German Cardiac Society. 100 (12): 1095–101. doi:10.1007/s00392-011-0346-8. PMID 21796327. Unknown parameter
|coauthors=ignored (help); Check date values in:|date=(help) - ↑ Scherlag, MA.; Scherlag, BJ. (2013). "A randomized comparison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension". J Am Coll Cardiol. 62 (12): 1129–30. doi:10.1016/j.jacc.2013.05.068. PMID 23810880. Unknown parameter
|month=ignored (help) - ↑ Linz, D.; Mahfoud, F.; Schotten, U.; Ukena, C.; Neuberger, HR.; Wirth, K.; Böhm, M. (2012). "Renal sympathetic denervation suppresses postapneic blood pressure rises and atrial fibrillation in a model for sleep apnea". Hypertension. 60 (1): 172–8. doi:10.1161/HYPERTENSIONAHA.112.191965. PMID 22585944. Unknown parameter
|month=ignored (help) - ↑ Linz, D.; Mahfoud, F.; Schotten, U.; Ukena, C.; Hohl, M.; Neuberger, HR.; Wirth, K.; Böhm, M. (2013). "Renal sympathetic denervation provides ventricular rate control but does not prevent atrial electrical remodeling during atrial fibrillation". Hypertension. 61 (1): 225–31. doi:10.1161/HYPERTENSIONAHA.111.00182. PMID 23150501. Unknown parameter
|month=ignored (help) - ↑ Pokushalov, Evgeny; Romanov, Alexander; Corbucci, Giorgio; Artyomenko, Sergey; Baranova, Vera; Turov, Alex; Shirokova, Natalya; Karaskov, Alexander; Mittal, Suneet; Steinberg, Jonathan S. (2012). "A Randomized Comparison of Pulmonary Vein Isolation With Versus Without Concomitant Renal Artery Denervation in Patients With Refractory Symptomatic Atrial Fibrillation and Resistant Hypertension". Journal of the American College of Cardiology. 60 (13): 1163–1170. doi:10.1016/j.jacc.2012.05.036. ISSN 0735-1097.
- ↑ Ukena, Christian; Bauer, Axel; Mahfoud, Felix; Schreieck, Jürgen; Neuberger, Hans-Ruprecht; Eick, Christian; Sobotka, Paul A.; Gawaz, Meinrad; Böhm, Michael (2011). "Renal sympathetic denervation for treatment of electrical storm: first-in-man experience". Clinical Research in Cardiology. 101 (1): 63–67. doi:10.1007/s00392-011-0365-5. ISSN 1861-0684.
- ↑ Mahfoud, F.; Schlaich, M.; Kindermann, I.; Ukena, C.; Cremers, B.; Brandt, MC.; Hoppe, UC.; Vonend, O.; Rump, LC. (2011). "Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study". Circulation. 123 (18): 1940–6. doi:10.1161/CIRCULATIONAHA.110.991869. PMID 21518978. Unknown parameter
|month=ignored (help) - ↑ Davies, JE.; Manisty, CH.; Petraco, R.; Barron, AJ.; Unsworth, B.; Mayet, J.; Hamady, M.; Hughes, AD.; Sever, PS. (2013). "First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study". Int J Cardiol. 162 (3): 189–92. doi:10.1016/j.ijcard.2012.09.019. PMID 23031283. Unknown parameter
|month=ignored (help) - ↑ Witkowski, A.; Prejbisz, A.; Florczak, E.; Kądziela, J.; Śliwiński, P.; Bieleń, P.; Michałowska, I.; Kabat, M.; Warchoł, E. (2011). "Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea". Hypertension. 58 (4): 559–65. doi:10.1161/HYPERTENSIONAHA.111.173799. PMID 21844482. Unknown parameter
|month=ignored (help) - ↑ Fisher, James P.; Young, Colin N.; Fadel, Paul J. (2009). "Central sympathetic overactivity: Maladies and mechanisms". Autonomic Neuroscience. 148 (1–2): 5–15. doi:10.1016/j.autneu.2009.02.003. ISSN 1566-0702.
- ↑ Witkowski, A.; Prejbisz, A.; Florczak, E.; Kadziela, J.; Sliwinski, P.; Bielen, P.; Michalowska, I.; Kabat, M.; Warchol, E.; Januszewicz, M.; Narkiewicz, K.; Somers, V. K.; Sobotka, P. A.; Januszewicz, A. (2011). "Effects of Renal Sympathetic Denervation on Blood Pressure, Sleep Apnea Course, and Glycemic Control in Patients With Resistant Hypertension and Sleep Apnea". Hypertension. 58 (4): 559–565. doi:10.1161/HYPERTENSIONAHA.111.173799. ISSN 0194-911X.
- ↑ Schlaich, MP.; Straznicky, N.; Grima, M.; Ika-Sari, C.; Dawood, T.; Mahfoud, F.; Lambert, E.; Chopra, R.; Socratous, F. (2011). "Renal denervation: a potential new treatment modality for polycystic ovary syndrome?". J Hypertens. 29 (5): 991–6. doi:10.1097/HJH.0b013e328344db3a. PMID 21358414. Unknown parameter
|month=ignored (help) - ↑ Ukena, C.; Bauer, A.; Mahfoud, F.; Schreieck, J.; Neuberger, HR.; Eick, C.; Sobotka, PA.; Gawaz, M.; Böhm, M. (2012). "Renal sympathetic denervation for treatment of electrical storm: first-in-man experience". Clin Res Cardiol. 101 (1): 63–7. doi:10.1007/s00392-011-0365-5. PMID 21960416. Unknown parameter
|month=ignored (help)