Abstract
The seventeenth century London neuroanatomical school headed by Thomas Willis published the first images of the sympathetic nervous system. Nineteenth century European physiologists characterised these as the “pressor nerves”. Von Euler’s demonstration that the sympathetic transmitter was norepinephrine brought the field into the modern era. Sympathetic nervous system responses are regionally differentiated; human regional sympathetic activity is best studied by recording from postganglionic sympathetic efferents directed to the skeletal muscle vasculature (clinical microneurography) and by measurement of organ-specific norepinephrine release to plasma from sympathetic nerves (regional “norepinephrine spillover”). With these techniques, the sympathetic nervous system became accessible to clinical scientists, allowing the demonstration that sympathetic nervous system activation is crucial in the development and outcomes of cardiovascular disorders, most notably heart failure and essential hypertension. Activation of the renal sympathetic outflow is pivotal in the pathogenesis of essential hypertension. An important goal for clinical scientists is translation of knowledge of pathophysiology, such as this, into better treatment for patients. Although disputed, the case is strong that in hypertension, we are now on the cusp of effective “mechanisms to management” transition, with the use of catheter-based renal sympathetic nerve ablation for treating drug-resistant hypertension.
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Hamilton WF, Richards DW. Output of the heart. In: Fishman AP, Richards DW, editors. Circulation of the blood. Men and ideas. Bethesda: American Physiological Society; 1982. p. 87–90.
Peet MM, Isberg MM. The surgical treatment of arterial hypertension. JAMA. 1946;130:467–73.
Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension; results in 1,266 cases. J Am Med Assoc. 1953;152:1501–4.
Paton WDM, Zaimis EJ. Paralysis of autonomic ganglia by methonium salts. Brit J Pharmacol. 1951;6:155–68.
van Zwieten PA. Development of antihypertensive drugs: from the bench to the clinic. In: Birkenhager WH, Robertson JIS, Zanchetti A, editors. Handbook of hypertension, chapter 22; hypertension in the twentieth century: concepts and achievements. Amsterdam: Elsevier; 2004. p. 457–86.
Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens. 2009;27:2121–58.
Esler M, Jennings G, Korner P, et al. The assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover. Hypertension. 1988;11:3–20.
Anderson EA, Sinkey CA, Lawton WJ, et al. Elevated sympathetic nerve activity in borderline hypertensive humans. Evidence from direct intraneural recordings. Hypertension. 1989;14:177–83.
Yamada Y, Miyajima E, Tochikubo O, et al. Age-related changes in muscle sympathetic nerve activity in essential hypertension. Hypertension. 1989;13:870–7.
Grassi G, Colombo M, Seravalle G, et al. Dissociation between muscle and skin sympathetic nerve activity in essential hypertension, obesity, and congestive heart failure. Hypertension. 1998;31:64–7.
Grassi G, Dell’Oro R, Quarti-Trevano F, et al. Neuroadrenergic and reflex abnormalities in patients with the metabolic syndrome. Diabetologia. 2005;48:1359–65.
Rumantir MS, Vaz M, Jennings GL, et al. Neural mechanisms in human obesity-related hypertension. J Hypertens. 1999;17:1125–33.
Huggett RJ, Burns J, MackIntosh AF, et al. Sympathetic neural activation in nondiabetic metabolic syndrome and its further augmentation by hypertension. Hypertension. 2004;44:1–6.
Lambert E, Straznicky N, Schlaich MP, et al. Differing patterns of sympathoexcitation in normal weight and obesity-related hypertension. Hypertension. 2007;50:862–8.
DiBona GF, Kopp UC. Neural control of renal function. Physiol Rev. 1997;77:76–197.
DiBona GF, Esler M. Translational medicine: the antihypertensive effect of renal denervation. Am J Physiol Regul Integr Comp Physiol. 2012;298:R245–53.
de la Sierra A, Segura J, Banegas JR, et al. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension. 2011;57:898–902. The definitive evaluation of how often blood pressure is drug-resistant, based on a large-scale, community based Spanish evaluation, utilising ambulatory pressure monitoring.
Persell SD. Prevalence of resistant hypertension in the United States, 2003–2008. Hypertension. 2011;57:1076–80.
Bisognano JD, Bakris G, Nadim MK, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension. J Am Coll Cardiol. 2011;58:765–73.
Krum H, Schlaich MP, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:1275–81.
Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomized controlled trial. Lancet. 2010;376:1903–309.
Brest AN, Wiener L, Bachrach B. Bilateral carotid sinus nerve stimulation in the treatment of hypertension. Am J Cardiol. 1972;29:821–5.
Esler M, Jennings G, Korner P, et al. Measurement of total and organ-specific norepinephrine kinetics in humans. Am J Physiol 1984;247 (Endocrinol Metab 10): E21-E28.
Oldham JB. Denervation of the kidney. Hunterian lecture of the Royal College of Surgeons, England. 9th March, 1950. Ann R Coll Surg Engl. 1950;7:222–45.
Sakakura K, Ladich E, Cheng Q, et al. Anatomical distribution of human renal sympathetic nerves: pathological study. J Am Coll Cardiol 2014; 63(12_S): doi:10.1016/S0735-1097(14)62154-9. This is a detailed anatomy of the human renal nerves. The study indicates the efferent, sympathetic nerves and the afferent, sensory nerves do not run parallel paths in juxtaposition to the renal arteries, a finding relevant to where energy should be directed in catheter-based renal denervation procedures. The renal sympathetic nerves converge on the renal arteries distally, closer to the renal artery branch points. The afferent nerves are rather remote from the renal arteries as they emerge from the kidneys, but converge on the proximal renal arteries, near the aortic take-off.
Rippy MK, Zarins D, Barman NC, et al. Catheter-based renal sympathetic denervation: chronic preclinical evidence for renal artery safety. Clin Res Cardiol. 2011;100:1095–101.
Krum H, Schlaich MP, Bohm M, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet. 2013. doi:10.1016/S0140-6736(13)62192-3.
Esler MD, Krum H, Schlaich M, et al. Renal denervation for treatment of drug-resistant hypertension. One-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation. 2012;126:2976–82.
Investigators Symplicity HTN-1. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension. 2011;57:911–7.
Worthley SG, Tsioufis CP, Worthley MI, et al. Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial. Eur Heart J. 2013. doi:10.1093/eurheartj/eht197.
Mabin T, Sapoval M, Cabane V, et al. First experience with endovascular ultrasound renal denervation for the treatment of resistant hypertension. EuroIntervention. 2013;8:57–61.
Esler M. Illusions of truths in the Symplicity HTN-3 trial: generic design strengths but neuroscience failings. J Am Soc Hypertens. 2014. doi:10.1016/j.jash.2014.06.001. This critique of the Symplicity HTN-3 renal denervation trial provides new evidence that the level of sympathetic denervation typically achieved in RF renal denervation studies is incomplete, probably suboptimal, and differs widely between individual patients. These observations have particular relevance to the Symplicity HTN-3 study, where there are now known to have been procedural failings in RF energy delivery, which was not to all quadrants of the renal artery circumference in the majority of patients, this being a protocol prerequisite.
Meredith IT, Esler MD, Cox HS, et al. Biochemical evidence of sympathetic denervation of the heart in pure autonomic failure. Clin Auton Res. 1991;1:187–94.
Bhatt D, Kandzari D, O’Neill, et al. A controlled trial of renal denervation for resistant hypertension. New Engl J Med. 2014;370:1393–401. The published report of the highly influential, sham-controlled, US pivotal renal denervation trial, which did not meet the primary efficacy endpoint. For a critique see reference 32.
Kandzari D, lecture on behalf of the Symplicity HTN-3 Investigators. Symplicity HTN-3 Trial: analysis of potentially confounding factors. EuroPCR 2014, Paris.
Shun-Shun M, Howard J, Francis D. Removing the hype from hypertension. BMJ. 2014;348:g1937. doi:10.1136/bmj.g1937.
Hering D, Lambert EA, Marusic P, et al. Substantial reduction in single sympathetic nerve firing after renal denervation inpatients with resistant hypertension. Hypertension. 2013;61:457–64. The sympathetic activation in severe, drug-resistant hypertension is partly generated by a renal injury signal relayed to the CNS by renal afferent nerves. This paper demonstrates that RF renal ablation, by abolishing this brain input, reduces central sympathetic outflow.
Campese VM, Kogosov E. Renal afferent denervation prevents hypertension in rats with chronic renal failure. Hypertension. 1995;25:878–82.
Zoccali C, Mallamaci F, Parlongo S, et al. Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease. Circulation. 2002;105:1354–9.
Hering D, Mahfoud F, Walton AS, et al. Renal denervation in moderate to severe CKD. J Am Soc Nephrol. 2012;23:1250–7. This paper reports a favorable pilot study of renal denervation in renal hypertension.
Schlaich MP, Bart B, Hering D, et al. Feasibility of catheter-based renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease. Int J Cardiol. 2013. doi:10.1016/j.ijcard.2013.01.218. This paper similarly reports a favorable pilot study of renal denervation, in the hypertension accompanying end-stage renal disease. The low blood flow in the atrophic kidneys did cause technical difficulties in some patients, with catheter tip over-heating.
Meredith IT, Friberg P, Jennings GL, et al. Regular exercise lowers renal but not cardiac sympathetic activity in man. Hypertension. 1991;18:575–82.
Esler M, Eikelis N, Schlaich M, et al. Chronic mental stress is a cause of essential hypertension: presence of biological markers of stress. Clin Exp Pharm Physiol. 2008;35:498–502.
Esler M, Eikelis N, Schlaich M, Lambert G, et al. Human sympathetic nerve biology: parallel influences of stress and epigenetics in essential hypertension and panic disorder. Annals of New York Academy of Science 2008;1148: Renal responses to mental stress and epinephrine in man. Am J Physiol. 1989;257:F682–9.
Tidgren B, Hjemdahl P. Renal responses to mental stress and epinephrine in man. Am J Physiol. 1989;257:F682–9.
Roman RJ, Cowley AW. Characterisation of a new model for the study of pressure natriuresis in the rat. Am J Physiol Renal Physiol. 1985;248:F190–8.
Acknowledgments
The author is a Senior Director of the Baker IDI Heart and Diabetes Institute, Melbourne, and Conjoint Professor of Medicine Monash University, Melbourne. His primary funding is by a Senior Principal Research Fellowship of the Australian National Health and Medical Research Council. He discloses research funding and receipt of consultancy fees from Medtronic.
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The author has received consultancy and travel fees from Medtronic. He holds no shares in the company, or patent rights for renal denervation.
Human and Animal Rights and Informed Consent
Human research performed by the author and reported here, was done with the approval of the Alfred Hospital Research Ethics Committee, after participating subjects provided written informed consent.
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This article is part of the Topical Collection on Blood Pressure Monitoring and Management
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Esler, M. The Sympathetic Nervous System in Hypertension: Back to the Future?. Curr Hypertens Rep 17, 11 (2015). https://doi.org/10.1007/s11906-014-0519-8
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DOI: https://doi.org/10.1007/s11906-014-0519-8