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Modulation of Sympathetic Overactivity to Treat Resistant Hypertension

  • Mechanisms of Hypertension (M Weir, Section Editor)
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Abstract

Purpose of Review

To review the role and evidence for sympathetic overactivity in resistant hypertension and review the therapies that have been studied to modulate the sympathetic nervous system to treat resistant hypertension, with a focus on non-pharmacologic therapies such as renal denervation, baroreflex activation therapy, and carotid body ablation.

Recent Findings

Based on the two best current techniques available for assessing sympathetic nerve activity, resistant hypertension is characterized by increased sympathetic nerve activity. Several device therapies, including renal denervation baroreflex activation therapy and carotid body ablation, have been developed as non-pharmacologic means of reducing blood pressure in resistant hypertension. With respect to renal denervation, the technologies for renal denervation have evolved since the unfavorable results from the HTN-3 study, and the revised technologies are being actively studied. Data from the first phase of the SPYRAL HTN Clinical Trial Program have been published. Results from the SPYRAL HTN-OFF MED trial suggest that ablating renal nerves can reduce blood pressure in patients with untreated mild-to-moderate hypertension. The SPYRAL HTN-ON MED trial demonstrated the safety and efficacy of catheter-based renal denervation in patients with uncontrolled hypertension on antihypertensive treatment. Interestingly, there was a high rate of medication non-adherence among patients with hypertension in this study. One attractive alternative to radiofrequency ablation is the use of ultrasound for renal denervation. Proof of concept data for the Paradise endovascular ultrasound renal denervation system was recently published in the RADIANCE-HTN SOLO trial. The results of this trial indicate that, among patients with mild to moderate hypertension on no medications, renal denervation with the Paradise system results in a greater reduction in both SBP and DBP at 2months compared with a sham procedure. Overall reductions were similar in magnitude to those noted in the SPYRAL HTN-OFF MED study. With respect to carotid body ablation, there is an ongoing proof of concept study that is investigating the safety and feasibility of ultrasound-based endovascular carotid body ablation in 30 subjects with treatment-resistant hypertension outside of the USA.

Summary

The sympathetic nervous system is an important contributor to resistant hypertension. Modulation of sympathetic overactivity should be an important goal of treatment. Innovative therapies using non-pharmacologic means to suppress the sympathetic nervous system are actively being studied to treat resistant hypertension.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988–2008. JAMA. 2010;303(20):2043–50. https://doi.org/10.1001/jama.2010.650.

    Article  CAS  PubMed  Google Scholar 

  2. Moriarty JM, Tung R, Bradfield JS, McWilliams J, Lee EW, Kuo MD. Renal denervation: a novel therapy at the crossroads of imaging, intervention, and innovation. Journal of laboratory automation. 2016;21(2):312–6. https://doi.org/10.1177/2211068215605838.

    Article  PubMed  Google Scholar 

  3. Persell SD. Prevalence of resistant hypertension in the United States, 2003–2008. Hypertension. 2011;57(6):1076–80. https://doi.org/10.1161/hypertensionaha.111.170308.

    Article  CAS  PubMed  Google Scholar 

  4. Whelton PK, Carey RM. The 2017 American College of Cardiology/American Heart Association Clinical Practice Guideline for high blood pressure in adults. JAMA cardiology. 2018;3(4):352–3. https://doi.org/10.1001/jamacardio.2018.0005.

    Article  PubMed  Google Scholar 

  5. Rimoldi SF, Messerli FH, Bangalore S, Scherrer U. Resistant hypertension: what the cardiologist needs to know. Eur Heart J. 2015;36(40):2686–95. https://doi.org/10.1093/eurheartj/ehv392.

    Article  PubMed  Google Scholar 

  6. Smith SM, Huo T, Delia Johnson B, Bittner V, Kelsey SF, Vido Thompson D, et al. Cardiovascular and mortality risk of apparent resistant hypertension in women with suspected myocardial ischemia: a report from the NHLBI-sponsored WISE study. J Am Heart Assoc. 2014;3(1):e000660. https://doi.org/10.1161/jaha.113.000660.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Brambilla G, Bombelli M, Seravalle G, Cifkova R, Laurent S, Narkiewicz K, et al. Prevalence and clinical characteristics of patients with true resistant hypertension in central and Eastern Europe: data from the BP-CARE study. J Hypertens. 2013;31(10):2018–24. https://doi.org/10.1097/HJH.0b013e328363823f.

    Article  CAS  PubMed  Google Scholar 

  8. Tsioufis C, Dimitriadis K, Tousoulis D. Sympathetic nervous system activation and left ventricular hypertrophy: reflections of the same portrait of resistant hypertension? Hell J Cardiol. 2015;56(6):507–9.

    Google Scholar 

  9. Modolo R, de Faria AP, Moreno H. Resistant hypertension: a volemic or nervous matter? J Am Soc Hypertens. 2015;9(5):408–9. https://doi.org/10.1016/j.jash.2015.01.014.

    Article  PubMed  Google Scholar 

  10. Oliva RV, Bakris GL. Sympathetic activation in resistant hypertension: theory and therapy. Semin Nephrol. 2014;34(5):550–9. https://doi.org/10.1016/j.semnephrol.2014.08.009.

    Article  PubMed  Google Scholar 

  11. • Townsend RR. Pathogenesis of drug-resistant hypertension. Semin Nephrol. 2014;34(5):506–13. https://doi.org/10.1016/j.semnephrol.2014.08.004. Comprehensive review discussing the pathogenesis of resistant hypertension.

    Article  CAS  PubMed  Google Scholar 

  12. Manolis AJ, Poulimenos LE, Kallistratos MS, Gavras I, Gavras H. Sympathetic overactivity in hypertension and cardiovascular disease. Curr Vasc Pharmacol. 2014;12(1):4–15.

    Article  CAS  PubMed  Google Scholar 

  13. Tsioufis C, Kordalis A, Flessas D, Anastasopoulos I, Tsiachris D, Papademetriou V, et al. Pathophysiology of resistant hypertension: the role of sympathetic nervous system. Int J Hypertens. 2011;2011:642416–7. https://doi.org/10.4061/2011/642416.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hering D, Schlaich M. The role of central nervous system mechanisms in resistant hypertension. Curr Hypertens Rep. 2015;17(8):58. https://doi.org/10.1007/s11906-015-0570-0.

    Article  PubMed  Google Scholar 

  15. Bruno RM, Di Giulio A, Bernini G, Virdis A, Ghiadoni L, Taddei S. Device-based therapies for resistant hypertension. Curr Pharm Des. 2013;19(13):2401–8.

    Article  CAS  PubMed  Google Scholar 

  16. Zygmunt A, Stanczyk J. Methods of evaluation of autonomic nervous system function. Arch Med Sci. 2010;6(1):11–8. https://doi.org/10.5114/aoms.2010.13500.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Esler M. The 2009 Carl Ludwig Lecture: pathophysiology of the human sympathetic nervous system in cardiovascular diseases: the transition from mechanisms to medical management. J Appl Physiol (Bethesda, Md : 1985). 2010;108(2):227–37. https://doi.org/10.1152/japplphysiol.00832.2009.

    Article  CAS  Google Scholar 

  18. Guyenet PG. The sympathetic control of blood pressure. Nat Rev Neurosci. 2006;7(5):335–46. https://doi.org/10.1038/nrn1902.

    Article  CAS  PubMed  Google Scholar 

  19. Victor RG, Shafiq MM. Sympathetic neural mechanisms in human hypertension. Curr Hypertens Rep. 2008;10(3):241–7.

    Article  CAS  PubMed  Google Scholar 

  20. Grassi G, Ram VS. Evidence for a critical role of the sympathetic nervous system in hypertension. J Am Soc Hypertens. 2016;10(5):457–66. https://doi.org/10.1016/j.jash.2016.02.015.

    Article  CAS  PubMed  Google Scholar 

  21. Grassi G, Mark A, Esler M. The sympathetic nervous system alterations in human hypertension. Circ Res. 2015;116(6):976–90. https://doi.org/10.1161/circresaha.116.303604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Esler M. Sympathetic nervous system moves toward center stage in cardiovascular medicine: from Thomas Willis to resistant hypertension. Hypertension. 2014;63(3):e25–32. https://doi.org/10.1161/hypertensionaha.113.02439.

    Article  PubMed  Google Scholar 

  23. Fisher JP, Fadel PJ. Therapeutic strategies for targeting excessive central sympathetic activation in human hypertension. Exp Physiol. 2010;95(5):572–80. https://doi.org/10.1113/expphysiol.2009.047332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Skrzypecki J, Ufnal M. Drug resistant hypertension—no simple way out. Kidney Blood Press Res. 2015;40(1):66–76. https://doi.org/10.1159/000368483.

    Article  CAS  PubMed  Google Scholar 

  25. Sica DA. Centrally acting antihypertensive agents: an update. J Clin Hypertens (Greenwich, Conn). 2007;9(5):399–405.

    Article  CAS  Google Scholar 

  26. Grassi G. Counteracting the sympathetic nervous system in essential hypertension. Curr Opin Nephrol Hypertens. 2004;13(5):513–9.

    Article  PubMed  Google Scholar 

  27. Grassi G. Sympathomodulatory effects of antihypertensive drug treatment. Am J Hypertens. 2016;29(6):665–75. https://doi.org/10.1093/ajh/hpw012.

    Article  CAS  PubMed  Google Scholar 

  28. Grassi G, Seravalle G, Mancia G. Sympathetic activation in cardiovascular disease: evidence, clinical impact and therapeutic implications. Eur J Clin Investig. 2015;45(12):1367–75. https://doi.org/10.1111/eci.12553.

    Article  Google Scholar 

  29. Wray DW, Supiano MA. Impact of aldosterone receptor blockade compared with thiazide therapy on sympathetic nervous system function in geriatric hypertension. Hypertension. 2010;55(5):1217–23. https://doi.org/10.1161/hypertensionaha.109.147058.

    Article  CAS  PubMed  Google Scholar 

  30. Brinkmann J, Heusser K, Schmidt BM, Menne J, Klein G, Bauersachs J, et al. Catheter-based renal nerve ablation and centrally generated sympathetic activity in difficult-to-control hypertensive patients: prospective case series. Hypertension. 2012;60(6):1485–90. https://doi.org/10.1161/hypertensionaha.112.201186.

    Article  CAS  PubMed  Google Scholar 

  31. Krum H, Sobotka P, Mahfoud F, Bohm M, Esler M, Schlaich M. Device-based antihypertensive therapy: therapeutic modulation of the autonomic nervous system. Circulation. 2011;123(2):209–15. https://doi.org/10.1161/circulationaha.110.971580.

    Article  PubMed  Google Scholar 

  32. Petkovich BW, Vega J, Thomas S. Vagal modulation of hypertension. Curr Hypertens Rep. 2015;17(4):532. https://doi.org/10.1007/s11906-015-0532-6.

    Article  CAS  PubMed  Google Scholar 

  33. Victor RG. Carotid baroreflex activation therapy for resistant hypertension. Nat Rev Cardiol. 2015;12(8):451–63. https://doi.org/10.1038/nrcardio.2015.96.

    Article  PubMed  Google Scholar 

  34. Grassi G, Seravalle G, Brambilla G, Cesana F, Giannattasio C, Mancia G. Similarities and differences between renal sympathetic denervation and carotid baroreceptor stimulation. Curr Vasc Pharmacol. 2014;12(1):63–8.

    Article  CAS  PubMed  Google Scholar 

  35. • 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. https://doi.org/10.1056/NEJMoa1402670. This study is the first randomized controlled study evaluating renal denervation in the USA. This study was different from prior trials in that control subjects were masked and underwent a sham procedure.

    Article  CAS  PubMed  Google Scholar 

  36. Esler M. Illusions of truths in the Symplicity HTN-3 trial: generic design strengths but neuroscience failings. J Am Soc Hypertens. 2014;8(8):593–8. https://doi.org/10.1016/j.jash.2014.06.001.

    Article  PubMed  Google Scholar 

  37. Mahfoud F, Edelman ER, Bohm M. Catheter-based renal denervation is no simple matter: lessons to be learned from our anatomy? J Am Coll Cardiol. 2014;64(7):644–6. https://doi.org/10.1016/j.jacc.2014.05.037.

    Article  PubMed  Google Scholar 

  38. Denker MG, Cohen DL. Resistant hypertension and renal nerve denervation. Methodist DeBakey Cardiovasc J. 2015;11(4):240–4. https://doi.org/10.14797/mdcj-11-4-240.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kandazari DE, Kario K, Mahfoud F, Cohen SA. 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. 2016;171(1):82–91.

  40. •• Townsend RR, Mahfoud F, Kandzari DE, Kario K, Pocock S, Weber MA, 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(10108):2160–70. https://doi.org/10.1016/s0140-6736(17)32281-x. This is the proof-of-concept trial using the Spyral catheter that suggests that ablating renal nerves can reduce blood pressure in patients with untreated mild-to-moderate hypertension.

    Article  PubMed  Google Scholar 

  41. •• Kandzari DE, Bohm M, Mahfoud F, Townsend RR, Weber MA, Pocock S, 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; https://doi.org/10.1016/s0140-6736(18)30951-6. This is the proof-of-concept trial using the Spyral catheter that demonstrated the safety and efficacy of catheter-based renal denervation in patients with uncontrolled hypertension on antihypertensive treatment.

    Article  Google Scholar 

  42. Ewen S, Ukena C, Linz D, Kindermann I, Cremers B, Laufs U, et al. Reduced effect of percutaneous renal denervation on blood pressure in patients with isolated systolic hypertension. Hypertension. 2015;65(1):193–9. https://doi.org/10.1161/hypertensionaha.114.04336.

    Article  CAS  PubMed  Google Scholar 

  43. Krum H, Schlaich M, Sobotka P, Bohm M, Mahfoud F, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet. 2014;383:622–9. https://doi.org/10.1016/S0140-6736(13)62192-3.

    Article  PubMed  Google Scholar 

  44. •• Azizi M, Schmeider R, Mahfoud F, Weber M. Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a muticentre, international, single-blind, randomised, sham-controlled trial. Lancet. 2018;391:2335–45. This is a single-blind, randomized, proof-of-concept study indicating that, among patients with mild to moderate hypertension on no medications, renal denervation with the Paradise endovascular ultrasound renal denervation system results in a greater reduction in both SBP and DBP at 2 months compared with a sham procedure.

    Article  PubMed  Google Scholar 

  45. Mauri L, Kario K, Basile J, Daemen J, Davies J, Kirtane AJ, et al. A multinational clinical approach to assessing the effectiveness of catheter-based ultrasound renal denervation: the RADIANCE-HTN and REQUIRE clinical study designs. Am Heart J. 2018;195:115–29. https://doi.org/10.1016/j.ahj.2017.09.006.

    Article  PubMed  Google Scholar 

  46. Scheffers IJ, Kroon AA, Tordoir JH, de Leeuw PW. Rheos Baroreflex Hypertension Therapy System to treat resistant hypertension. Expert Rev Med Devices. 2008;5(1):33–9. https://doi.org/10.1586/17434440.5.1.33.

    Article  PubMed  Google Scholar 

  47. Bisognano JD, Bakris G, Nadim MK, Sanchez L, Kroon AA, Schafer J, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled Rheos Pivotal Trial. J Am Coll Cardiol. 2011;58(7):765–73. https://doi.org/10.1016/j.jacc.2011.06.008.

    Article  PubMed  Google Scholar 

  48. Bakris GL, Nadim MK, Haller H, Lovett EG, Schafer JE, Bisognano JD. Baroreflex activation therapy provides durable benefit in patients with resistant hypertension: results of long-term follow-up in the Rheos Pivotal Trial. J Am Soc Hypertens. 2012;6(2):152–8. https://doi.org/10.1016/j.jash.2012.01.003.

    Article  PubMed  Google Scholar 

  49. Alnima T, de Leeuw PW, Kroon AA. Baroreflex activation therapy for the treatment of drug-resistant hypertension: new developments. Cardiol Res Pract. 2012;2012:587194–7. https://doi.org/10.1155/2012/587194.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Hoppe UC, Brandt MC, Wachter R, Beige J, Rump LC, Kroon AA, et al. Minimally invasive system for baroreflex activation therapy chronically lowers blood pressure with pacemaker-like safety profile: results from the Barostim neo trial. J Am Soc Hypertens. 2012;6(4):270–6. https://doi.org/10.1016/j.jash.2012.04.004.

    Article  PubMed  Google Scholar 

  51. • Narkiewicz K, Ratcliffe LE, Hart EC, Briant LJ, Chrostowska M, Wolf J, et al. Unilateral carotid body resection in resistant hypertension: a safety and feasibility trial. JACC Basic Transl Sci. 2016;1(5):313–24. https://doi.org/10.1016/j.jacbts.2016.06.004. This is the proof-of-concept study for unilateral carotid body resection involving 15 patients with resistant hypertension.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Neuzil P, Reddy V, Malek F, Kmonicek P, Sievert H, Zeller T, et al. Long term effect of transvenous carotid body ablation in the treatment of patients with resistant hypertension. Eur Heart J. 2017;38(Suppl_1):ehx504.4123.

    Article  Google Scholar 

  53. Schlaich, et al. J Hypertens. 2017;35(e-Supplement 2):e64.

    Article  Google Scholar 

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Correspondence to Raven Voora.

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Dr. Hinderliter receives grant support from ReCor Medical for participation in the RADIANCE-HTN trial. Dr. Voora declares no conflicts of interest relevant to this manuscript.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Voora, R., Hinderliter, A.L. Modulation of Sympathetic Overactivity to Treat Resistant Hypertension. Curr Hypertens Rep 20, 92 (2018). https://doi.org/10.1007/s11906-018-0893-8

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