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Interventional Cardiology

Renal Denervation: Paradise Lost? Paradise Regained? Deepak Padmanabhan, DM, 1 Ameesh Isath, MBBS, 1,2 and Bernard Gersh, MB, ChB, D Phil, FRCP, MACC 1 1. Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN; 2. Department of Internal Medicine, Mount Sinai St Luke’s Hospital, New York, NY

Abstract Renal denervation is a relatively recent concept whose initial promising results suffered a setback following the SYMPLICITY 3 trial, which did not show a significant blood pressure-lowering effect in comparison to sham. In this review article, we begin with the history including the physiological basis behind the concept of renal denervation. Furthermore, we review the literature in support of renal denervation, including the recently published SPYRAL HTN-OFF MED, which demonstrated significant blood pressure reduction in the absence of antihypertensive medication. We further touch upon the potential pitfalls and possible future directions of renal denervation.

Keywords Renal denervation, trials, hypertension, electroporation, blood pressure, review Disclosure: The authors have no conflicts of interest to declare. Acknowledgements: We wish to thank Kevin M Youel of the media department for help with the illustrations. Received: January 6, 2018 Accepted: April 5, 2018 Citation: US Cardiology Review 2018;12(2):78–86. DOI: https://doi.org/10.15420/usc.2018.1.2 Correspondence: Dr Bernard Gersh, Professor of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E: gersh.bernard@mayo.edu

Endovascular techniques for renal denervation (RDN) as a treatment for hypertension were initially highly encouraging with reductions in blood pressure (BP) in the range of 30 mmHg.1 However, these high expectations received a major setback following the unexpected results of the sham-controlled Renal Denervation in Patients With Uncontrolled Hypertension (SYMPLICITY HTN-3) trial. This promising procedure was faced with a major roadblock and, in general, the expectations that this would stand the test of time were markedly tempered.2 Like all good trials, SYMPLICITY HTN-3 provided answers, but also generated new questions, particularly in regard to procedural and technical issues. This, in turn, has led to a series of new and ongoing trials, which hopefully will resolve the issue of whether this procedure will become a routine aspect of hypertension management. In the present article, we review the literature in support of the RDN concept as well as emphasize the potential pitfalls and possible future direction of RDN.

Proof of Concept: A Historical Perspective The renal system, through the maintenance of fluid–electrolyte balance and its interplay with the autonomic nervous system, plays an essential role in the pathophysiology of hypertension. Increased sympathetic nervous system activity as a cause and result of hypertension has been proven in various human experiments.3 The activation of the efferent sympathetic system via the postganglionic sympathetic neuronal chain relayed to the kidneys over the renal vasculature results in one or all of three effects; increased renin secretion from the juxtaglomerular apparatus; renal vasoconstriction decreasing renal blood flow; and enhanced sodium and water absorption. This contributes to an increased intravascular volume and arteriolar vasoconstriction adding to hypertension.4,5

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Renal structures are also richly innervated with baroreceptors and chemoreceptors. Stimulation of these nerves by metabolites like adenosine, which form under conditions of ischemia and oxidative stress, result in increased input into the hypothalamus augmenting the sympathetic outflow, not only to the kidneys, but also to other structures like the heart and peripheral arteries, resulting in neurogenic hypertension.5–7 Interruption of this neural traffic underlies the concept of RDN for the treatment of hypertension. Esler et al. demonstrated increased renal sympathetic nervous activity in adults with essential hypertension. His assessment of renal norepinephrine spillover using isotope dilution measurements showed elevated levels in comparison to normal individuals.8 Also, this increase was higher in young adults (<40 years) with essential hypertension compared to older individuals. On comparison of 34 patients with essential hypertension and 23 normal patients, Esler et al. demonstrated than in those with hypertension, plasma concentration of noradrenaline and rate of release of noradrenaline into plasma was 32 % and 38  % higher, respectively, than in normal individuals.9 Schlaich further demonstrated a sustained decrease in BP from 161/107 to 127/81 mmHg at 12 months following bilateral renal artery ablation (Figure 1).10 One of the earliest treatment modalities for hypertension preceding the use of medications was surgical RDN. Smithwick and Thompson followed up 1,266 cases of thoracolumbar sympathetic splanchnicectomy over a minimum of 5 years. They compared the management of hypertension in these patients with that of in 467 medically treated controls to assess the mortality and efficacy of surgery as treatment for hypertension.11 Sympathetic splanchnicectomy decreased all-cause mortality in contrast to medically treated controls. However, this nonselective sympathectomy technique resulted in very severe debilitating

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