Renal Denervation: Where to Now?
Abstract
Resistant hypertension remains a growing problem worldwide. Renal sympathetic denervation was thought to be a new method for the treatment for resistant hypertension. Early studies demonstrated a marked benefit in patients who underwent renal denervation procedures, but the pivotal SYMPLICITY 3-HTN trial, the only sham-controlled randomized trial performed, did not show a benefit for patients treated with the procedure compared to sham. There is still much to learn about the physiology and anatomy of renal sympathetic pathways as well as careful attention to medication adherence in order to understand the role of renal sympathetic denervation in treating hypertensive patients. While renal denervation technology remains available in clinical practice outside of the USA, we expect further development of this technology in the upcoming years and the continued evaluation of this technology in patients with hypertension as well as other disease states to fully understand its role.
Keywords
Renal denervation Hypertension Randomized clinical trialNotes
Compliance with Ethical Standards
Conflict of Interest
Neil J. Wimmer has no conflicts of interest.
Laura Mauri reports grants from Abbott, Boston Scientific, Cordis, Medtronic, Eli Lilly, Daiichi Sankyo, Sanofi-Aventis, Boehringer Ingelheim, and Biotronik, other from AstraZeneca and Sanofi, and personal fees from Recor.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Sarafidis PA, Georgianos P, Bakris GL. Resistant hypertension—its identification and epidemiology. Nat Rev Nephrol. 2013;9(1):51–8.CrossRefPubMedGoogle Scholar
- 2.Murray CJ, Lauer JA, Hutubessy RC, Niessen L, Tomijima N, Rodgers A, et al. Effectiveness and costs of interventions to lower systolic blood pressure and cholesterol: a global and regional analysis on reduction of cardiovascular-disease risk. Lancet. 2003;361(9359):717–25.CrossRefPubMedGoogle Scholar
- 3.Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, 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):e510–26.CrossRefPubMedGoogle Scholar
- 4.Kumbhani DJ, Steg PG, Cannon CP, Eagle KA, Smith Jr SC, Crowley K, et al. Resistant hypertension: a frequent and ominous finding among hypertensive patients with atherothrombosis. Eur Heart J. 2013;34(16):1204–14.CrossRefPubMedGoogle Scholar
- 5.Egan BM, Zhao Y, Axon RN, Brzezinski WA, Ferdinand KC. Uncontrolled and apparent treatment resistant hypertension in the United States, 1988 to 2008. Circulation. 2011;124(9):1046–58.PubMedCentralCrossRefPubMedGoogle Scholar
- 6.•Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373(9671):1275–81. The landmark proof-of-concept study demonstrating the feasibility and possible effectiveness of catheter-based renal denervation for resistant hypertension.CrossRefPubMedGoogle Scholar
- 7.Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376(9756):1903–9.CrossRefPubMedGoogle Scholar
- 8.Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34(28):2159–219.CrossRefPubMedGoogle Scholar
- 9.••Bhatt DL, Kandzari DE, O'Neill WW, D'Agostino R, Flack JM, Katzen BT, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370(15):1393–401. The most pivotal clinical study in the field of renal denervation. This manuscript describes the results from the only large, sham-controlled trial of renal denervation for the treatment of resistant hypertension.CrossRefPubMedGoogle Scholar
- 10.Johns EJ, Kopp UC, DiBona GF. Neural control of renal function. Compr Physiol. 2011;1(2):731–67.PubMedGoogle Scholar
- 11.Mancia G, Grassi G. The autonomic nervous system and hypertension. Circ Res. 2014;114(11):1804–14.CrossRefPubMedGoogle Scholar
- 12.Bradford JR. The innervation of the renal blood vessels. J Physiol. 1889;10(5):358–432. 318.PubMedCentralCrossRefPubMedGoogle Scholar
- 13.Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension; results in 1,266 cases. J Am Med Assoc. 1953;152(16):1501–4.CrossRefPubMedGoogle Scholar
- 14.Atherton DS, Deep NL, Mendelsohn FO. Micro-anatomy of the renal sympathetic nervous system: a human postmortem histologic study. Clin Anat. 2012;25(5):628–33.CrossRefPubMedGoogle Scholar
- 15.Worthley SG, Tsioufis CP, Worthley MI, Sinhal A, Chew DP, Meredith IT, et al. Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial. Eur Heart J. 2013;34(28):2132–40.PubMedCentralCrossRefPubMedGoogle Scholar
- 16.Bakris GL, Townsend RR, Liu M, Cohen SA, D'Agostino R, Flack JM, et al. Impact of renal denervation on 24-hour ambulatory blood pressure: results from SYMPLICITY HTN-3. J Am Coll Cardiol. 2014;64(11):1071–8.CrossRefPubMedGoogle Scholar
- 17.Bakris GL, Townsend RR, Flack JM, Brar S, Cohen SA, D'Agostino R, et al. 12-month blood pressure results of catheter-based renal artery denervation for resistant hypertension: the SYMPLICITY HTN-3 trial. J Am Coll Cardiol. 2015;65(13):1314–21.CrossRefPubMedGoogle Scholar
- 18.Azizi M, Sapoval M, Gosse P, Monge M, Bobrie G, Delsart 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(9981):1957–65.CrossRefPubMedGoogle Scholar
- 19.•Kandzari DE, Bhatt DL, Brar S, Devireddy CM, Esler M, Fahy M, et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur Heart J. 2015;36(4):219–27. An explanatory paper that attempts to reconcile the conflicting earlier positive trials that suggested benefit treatment of patients with resistant hypertension with renal denervation with the results from the SYMPLICITY HTN-3 trial.CrossRefPubMedGoogle Scholar
- 20.Sakakura K, Ladich E, Cheng Q, Otsuka F, Yahagi K, Fowler DR, et al. Anatomic assessment of sympathetic peri-arterial renal nerves in man. J Am Coll Cardiol. 2014;64(7):635–43.CrossRefPubMedGoogle Scholar
- 21.Bohm M, Mahfoud F, Ukena C, Hoppe UC, Narkiewicz K, Negoita M, et al. First report of the Global SYMPLICITY Registry on the effect of renal artery denervation in patients with uncontrolled hypertension. Hypertension. 2015;65(4):766–74.CrossRefPubMedGoogle Scholar
- 22.Fadl Elmula FE, Hoffmann P, Larstorp AC, Fossum E, Brekke M, Kjeldsen SE, et al. Adjusted drug treatment is superior to renal sympathetic denervation in patients with true treatment-resistant hypertension. Hypertension. 2014;63(5):991–9.CrossRefPubMedGoogle Scholar
- 23.Jin Y, Jacobs L, Baelen M, Thijs L, Renkin J, Hammer F, et al. Rationale and design of the Investigator-Steered Project on Intravascular Renal Denervation for Management of Drug-Resistant Hypertension (INSPiRED) trial. Blood Press. 2014;23(3):138–46.PubMedCentralCrossRefPubMedGoogle Scholar
- 24.Ukena C, Bauer A, Mahfoud F, Schreieck J, Neuberger HR, Eick C, et al. Renal sympathetic denervation for treatment of electrical storm: first-in-man experience. Clin Res Cardiol. 2012;101(1):63–7.CrossRefPubMedGoogle Scholar
- 25.Remo BF, Preminger M, Bradfield J, Mittal S, Boyle N, Gupta A, et al. Safety and efficacy of renal denervation as a novel treatment of ventricular tachycardia storm in patients with cardiomyopathy. Heart Rhythm. 2014;11(4):541–6.PubMedCentralCrossRefPubMedGoogle Scholar
- 26.Pokushalov E, Romanov A, Corbucci G, Artyomenko S, Baranova V, Turov A, et al. 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. 2012;60(13):1163–70.CrossRefPubMedGoogle Scholar
- 27.Linz D, Mahfoud F, Schotten U, Ukena C, Hohl M, Neuberger HR, et al. Renal sympathetic denervation provides ventricular rate control but does not prevent atrial electrical remodeling during atrial fibrillation. Hypertension. 2013;61(1):225–31.CrossRefPubMedGoogle Scholar
- 28.Linz D, Mahfoud F, Schotten U, Ukena C, Neuberger HR, Wirth K, et al. Renal sympathetic denervation suppresses postapneic blood pressure rises and atrial fibrillation in a model for sleep apnea. Hypertension. 2012;60(1):172–8.CrossRefPubMedGoogle Scholar
- 29.Bohm M, Ewen S, Kindermann I, Linz D, Ukena C, Mahfoud F. Renal denervation and heart failure. Eur J Heart Fail. 2014;16(6):608–13.CrossRefPubMedGoogle Scholar
- 30.Floras JS. Sympathetic nervous system activation in human heart failure: clinical implications of an updated model. J Am Coll Cardiol. 2009;54(5):375–85.CrossRefPubMedGoogle Scholar
- 31.Petersson M, Friberg P, Eisenhofer G, Lambert G, Rundqvist B. Long-term outcome in relation to renal sympathetic activity in patients with chronic heart failure. Eur Heart J. 2005;26(9):906–13.CrossRefPubMedGoogle Scholar
- 32.Brandt MC, Mahfoud F, Reda S, Schirmer SH, Erdmann E, Bohm M, et al. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol. 2012;59(10):901–9.CrossRefPubMedGoogle Scholar
- 33.Verloop WL, Beeftink MM, Nap A, Bots ML, Velthuis BK, Appelman YE, et al. Renal denervation in heart failure with normal left ventricular ejection fraction. Rationale and design of the DIASTOLE (DenervatIon of the renAl Sympathetic nerves in hearT failure with nOrmal Lv Ejection fraction) trial. Eur J Heart Fail. 2013;15(12):1429–37.CrossRefPubMedGoogle Scholar
- 34.Davies JE, Manisty CH, Petraco R, Barron AJ, Unsworth B, Mayet J, et al. First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study. Int J Cardiol. 2013;162(3):189–92.CrossRefPubMedGoogle Scholar
- 35.Alberti KG, Zimmet P, Shaw J. The metabolic syndrome—a new worldwide definition. Lancet. 2005;366(9491):1059–62.CrossRefPubMedGoogle Scholar
- 36.Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112(17):2735–52.CrossRefPubMedGoogle Scholar
- 37.Huang WC, Fang TC, Cheng JT. Renal denervation prevents and reverses hyperinsulinemia-induced hypertension in rats. Hypertension. 1998;32(2):249–54.CrossRefPubMedGoogle Scholar
- 38.Mahfoud F, Schlaich M, Kindermann I, Ukena C, Cremers B, Brandt MC, et al. Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation. 2011;123(18):1940–6.CrossRefPubMedGoogle Scholar
- 39.Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest. 1995;96(4):1897–904.PubMedCentralCrossRefPubMedGoogle Scholar
- 40.Witkowski A, Prejbisz A, Florczak E, Kadziela J, Sliwinski P, Bielen P, et al. Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension. 2011;58(4):559–65.CrossRefPubMedGoogle Scholar