Renal sympathetic denervation: Difference between revisions
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During the procedure, [[vital signs]] such as [[blood pressure]], [[heart rate]] and [[oxygen saturation]] must be monitored and continuous transcutaneous [[oxygen]] should be administered. <ref name="MahfoudLuscher2013">{{cite journal|last1=Mahfoud|first1=F.|last2=Luscher|first2=T. F.|last3=Andersson|first3=B.|last4=Baumgartner|first4=I.|last5=Cifkova|first5=R.|last6=DiMario|first6=C.|last7=Doevendans|first7=P.|last8=Fagard|first8=R.|last9=Fajadet|first9=J.|last10=Komajda|first10=M.|last11=LeFevre|first11=T.|last12=Lotan|first12=C.|last13=Sievert|first13=H.|last14=Volpe|first14=M.|last15=Widimsky|first15=P.|last16=Wijns|first16=W.|last17=Williams|first17=B.|last18=Windecker|first18=S.|last19=Witkowski|first19=A.|last20=Zeller|first20=T.|last21=Bohm|first21=M.|title=Expert consensus document from the European Society of Cardiology on catheter-based renal denervation|journal=European Heart Journal|volume=34|issue=28|year=2013|pages=2149–2157|issn=0195-668X|doi=10.1093/eurheartj/eht154}}</ref> | During the procedure, [[vital signs]] such as [[blood pressure]], [[heart rate]] and [[oxygen saturation]] must be monitored and continuous transcutaneous [[oxygen]] should be administered. <ref name="MahfoudLuscher2013">{{cite journal|last1=Mahfoud|first1=F.|last2=Luscher|first2=T. F.|last3=Andersson|first3=B.|last4=Baumgartner|first4=I.|last5=Cifkova|first5=R.|last6=DiMario|first6=C.|last7=Doevendans|first7=P.|last8=Fagard|first8=R.|last9=Fajadet|first9=J.|last10=Komajda|first10=M.|last11=LeFevre|first11=T.|last12=Lotan|first12=C.|last13=Sievert|first13=H.|last14=Volpe|first14=M.|last15=Widimsky|first15=P.|last16=Wijns|first16=W.|last17=Williams|first17=B.|last18=Windecker|first18=S.|last19=Witkowski|first19=A.|last20=Zeller|first20=T.|last21=Bohm|first21=M.|title=Expert consensus document from the European Society of Cardiology on catheter-based renal denervation|journal=European Heart Journal|volume=34|issue=28|year=2013|pages=2149–2157|issn=0195-668X|doi=10.1093/eurheartj/eht154}}</ref> | ||
Under [[fluoroscopic]] guidance, 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. The energy used for the ablation also generates heat within the [[vessels]], yet the system is cooled by the high rate of [[blood flow]]. <ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592 }} </ref> | 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. The energy used for the ablation also generates heat within the [[vessels]], yet the system is cooled by the high rate of [[blood flow]]. <ref name="pmid23774592">{{cite journal| author=Böhm M, Linz D, Urban D, Mahfoud F, Ukena C| title=Renal sympathetic denervation: applications in hypertension and beyond. | journal=Nat Rev Cardiol | year= 2013 | volume= 10 | issue= 8 | pages= 465-76 | pmid=23774592 | doi=10.1038/nrcardio.2013.89 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23774592 }} </ref> | ||
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. <ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref><ref name="ThukkaniBhatt2013">{{cite journal|last1=Thukkani|first1=A. K.|last2=Bhatt|first2=D. L.|title=Renal Denervation Therapy for Hypertension|journal=Circulation|volume=128|issue=20|year=2013|pages=2251–2254|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.004660}}</ref> | 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. <ref name="PapademetriouRashidi2014">{{cite journal|last1=Papademetriou|first1=V.|last2=Rashidi|first2=A. A.|last3=Tsioufis|first3=C.|last4=Doumas|first4=M.|title=Renal Nerve Ablation for Resistant Hypertension: How Did We Get Here, Present Status, and Future Directions|journal=Circulation|volume=129|issue=13|year=2014|pages=1440–1451|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.005405}}</ref><ref name="ThukkaniBhatt2013">{{cite journal|last1=Thukkani|first1=A. K.|last2=Bhatt|first2=D. L.|title=Renal Denervation Therapy for Hypertension|journal=Circulation|volume=128|issue=20|year=2013|pages=2251–2254|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.113.004660}}</ref> | ||
==Outcomes== | ==Outcomes== | ||
Revision as of 03:33, 13 April 2014
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. It most commonly uses a radiofrequency energy source and aims to treat hypertension in selected patients whose blood pressure can't be controlled with a combination of lifestyle changes and antihypertensive therapy. A patient is said to have resistant hypertension when despite these changes and taking 3 or more antihypertensive drugs, including a diuretic drug, at their maximal tolerated doses, without secondary hypertension, has a baseline systolic blood pressure of more that 160 mm Hg (or more that 150 mm Hg, in case of concomitant type 2 diabetes mellitus). [1] This treatment is based on the fact that these patients have an increase in sympathetic outflow. [2] By applying radiofrequency energy pulses to the renal arteries, the nerves in the vascular wall (adventitia layer) can be ablated. This causes a reduction of renal sympathetic afferent and efferent activity with the intent to decrease blood pressure. [3] This specific interruption of the renal sympathetic nerves appears to offer a durable blood pressure decrease, without severe consequences. [1] Early data from international clinical trials shows promising results, demonstrating an average blood pressure reduction of approximately 30mm Hg at three year follow up in patients with treatment-resistant hypertension. [4][5] Since 2007, over 4000 patients have undergone catheter-based renal denervation with the Medtronic Symplicity™ Renal Denervation System. [6] Despite its importance in drug-resistant hypertensive patients, by reducing renal sympathetic nerve flow, this procedure will also reduce overall sympathetic activity, thereby affecting multiple organs, which is why renal denervation might also be beneficial in other disease states, such as congestive heart failure, chronic kidney disease, metabolic syndrome and others. [7] Until now, few complications have been reported, being inconsequential. It's long-term efficacy is still yet to be determined, however, studies show a permanence of effect at least of 2 to 3 years. [2][8]
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 was only treated with surgical sympathectomy, by Adson in 1925. [2] [9] Isolated bilateral kidney 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 the limited pharmacological therapy of the time, for the following 2 decades. [2] 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. [2] 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.[10][11] 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. [2][7][12] 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. [2] Failure to reach normal blood pressure values puts these patients at an increased risk for development of major cardiovascular complications. [8] Subsequently, the number of hypertensive patients being referred for splanchnicectomy has decreased considerably in recent years. 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. [2] 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 others diseases, described below, which justifies the need for more studies to evaluate how relevant this procedure might be in the treatment of other conditions. [2]
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][2][13][14][15][16]
- 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. [7] Currently they are available in parts of Europe, Asia, Africa, Australia and the Americas.[6] So far, no renal denervation device has had FDA approval.
Procedure
Considering the factors: drug therapy resistance of 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 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][2] 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 the resistance, as well as confirmation of uncontrolled blood pressure, while on medical treatment. This last requisition 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. Before the procedure can take place, renal artery suitability must be assessed, which is done with a duplex ultrasound or MRI. 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. [7][11] During the procedure, vital signs such as blood pressure, heart rate and oxygen saturation must be monitored and continuous transcutaneous oxygen should be administered. [11]
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. The energy used for the ablation also generates heat within the vessels, yet the system is cooled by the high rate of blood flow. [7] 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. [2][1]
Outcomes
The two biggest studies to date have been the Symplicity HTN-1 and HTN-2 trials, conducted with Medtronic's Symplicity RDN System.
Symplicity HTN-1 [4] looked at outcomes in 153 patients that underwent catheter-based renal denervation. Three-year follow-up data have demonstrated an average blood pressure reduction of -33/-19mm Hg.
Symplicity HTN-2 [5] was a randomized, controlled trial that compared 54 control patients with 52 patients who underwent catheter-based renal denervation. Six month follow-up data 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. Longer follow-up, more patients, and improved study design are necessary to further validate catheter-based renal denervation. Currently the Symplicity HTN-3 trial is underway in the US. This is a 530-patient, multi-centre, prospective, single-blind, randomized, controlled study (Clinical Trial No. NCT01418261).[17]
Meta-analyses of renal denervation have yielded conflicting results.[18] Whilst office systolic blood pressure reductions typically average around 30 mmHg, reductions observed on ambulatory blood pressure monitoring are typically much smaller, around 10 mmHg.[19] The reasons for this disparity are so far unclear. Proposed theories include renal denervation obliterating the white coat response, thereby disproportionately reducing clinic pressures,[18] or the disparity rather being an anomaly due to deficiencies in renal denervation trial designs to date.[19]
Risks
The Symplicity HTN-1 and HTN-2 trials have demonstrated a good safety profile for catheter based renal denervation. Patients may experience pain during application of radiofrequency pulses and intraprocedural bradycardia requiring atropine has also been reported.[5] Other documented procedure related complications include femoral artery pseudoaneurysm and renal artery dissection.
Of particular concern is the theoretical risk of damage to renal arteries during delivery of radiofrequency energy. An animal study using swine 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]
Uses of Renal Denervation beyond Hypertension
Hypertension is associated with an overactive sympathetic drive and renal denervation is the ablation of the renal nerves stopping the cross-talk between the kidneys and brains, thus reducing the sympathetic drive. Similar to hypertension, congestive heart failure (CHF), left ventricular hypertrophy (LVH), atrial fibrillation (AF), obstructive sleep apnea (OSA), and insulin resistance/type 2 diabetes mellitus (DM) all have been associated with an overactive sympathetic drive. Current clinical trials are researching the effect of renal denervation in these clinical conditions as well. [21]
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.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 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.
- ↑ 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) - ↑ 4.0 4.1 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) - ↑ 5.0 5.1 5.2 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) - ↑ 6.0 6.1 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.
- ↑ 7.0 7.1 7.2 7.3 7.4 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.
- ↑ 8.0 8.1 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.
- ↑ 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) - ↑ 11.0 11.1 11.2 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) - ↑ WhichMedicalDevice. Symplicity Catheter System (Overview). http://www.whichmedicaldevice.com/by-manufacturer/113/198/symplicity-catheter-system [Accessed online April 5, 2012]
- ↑ Medtronic. RDN Brochure. http://www.medtronicrdn.com/mediakit/RDN%20Brochure.pdf [accessed online 7 April 2012].
- ↑ Medgadget. Medtronic Starts Trial with Symplicity Renal Denervation System for Chronic Heart Failure and Renal Impairment. [Published online 12 Feb 2012] [Accessed online 5 Apr 2012] 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 [Accessed online April 5, 2012]
- ↑ Renal Denervation in Patients With Uncontrolled Hypertension (SYMPLICITY HTN-3). ClinicalTrials.gov Identifier: NCT01418261 http://clinicaltrials.gov/ct2/show/NCT01418261. [Accessed online 7 Apr 2012].
- ↑ 18.0 18.1 http://www.ncbi.nlm.nih.gov/pubmed/22495128
- ↑ 19.0 19.1 http://heart.bmj.com/content/early/2013/09/12/heartjnl-2013-304238.abstract
- ↑ 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) - ↑ www.renaldenervationworld.org