HYPERTENSION Renal nerve ablation Luca Donazzan, Felix Mahfoud, Stephan H Schirmer, Michael Böhm ▸ Additional references are published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ heartjnl-2013-304702). Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany Correspondence to Professor Michael Böhm, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Kirrberger Str. 1, Geb. 40, Homburg/Saar D-66421, Germany; Michael.Boehm@uks.eu To cite: Donazzan L, Mahfoud F, Schirmer SH, et al. Heart Published Online First: [ please include Day Month Year] doi:10.1136/ heartjnl-2013-304702 Five years have passed since the first study on per- cutaneous renal denervation (RDN) to treat resist- ant hypertension was published. 1 During its short life this technique has demonstrated its safety and efficacy in reducing blood pressure (BP), and also its appreciable indirect effects on cardiovascular remodelling and pleiotropic effects on other path- ologies characterised by high sympathetic activity. Some questions about renal nerve distribution, pre- dictors of BP response, and indices of effective denervation still remain unanswered. Moreover, the results of the Symplicity HTN-3 study are in con- trast with previous findings and have raised many questions. Over time, new devices have been devel- oped that permit a faster and more complete ablation. RENAL NERVE ANATOMY Sympathetic fibres to the kidneys descend the spinal cord from the brain until they reach the lower thoracic and upper lumbar spinal nerves. Fibres then pass to the adjacent ganglia in the sym- pathetic trunks, continuing in the postganglionic fibres which form a circumferential ‘basket-weave plexus’ w1 in the adventitia of the renal artery (RA). Afferent fibres from the kidneys follow similar routes in the reverse direction. There is still debate regarding the location and distribution of renal nerves around the RA, with some authors affirming that they are mostly distal and included in a radius of 2 mm, w2 and others demonstrating their proximal distribution with the largest nerve density between 1–4 mm around the RA (R Virmani, presented at Transcatheter Cardiovascular Therapeutics (TCT), 23 October 2012, Miami, Florida, USA) ( figure 1). The latter theory is also supported by findings in animal studies. w3 SYMPATHO–RENAL AXIS Sympathetic outflow to the kidneys and other organs is regulated by the central nervous system in the nucleus tractus solitarius located in the mid- brain. w4 Stimulation of α1A receptors in the renal vasculature mediates vasoconstriction and reduces renal blood flow. Adrenergic fibres are also evident in the juxtaglomerular apparatus; their activation starts the renin–angiotensin system cascade. Moreover, stimulation of α1B adrenergic receptors induces sodium and water retention in the tubular segment of the nephron. w4 All these events contrib- ute to a rise in BP. Afferent fibres also play an important role in water homeostasis. They are activated by either ischaemic renal damage or by ionic and osmolar concentration changes, and transfer information from the renal interstitium to the brain. 2 w5 Herewith, a self-maintaining sympathetic activation loop is created with important effects not only on the BP, but also on other target organs. RENAL DENERVATION FOR RESISTANT HYPERTENSION Hypertension is a worldwide and growing disease condition, affecting millions of people every year. w6–w8 It is called ‘the silent killer’ due to its high cardiovascular morbidity and mortality, w9 despite its frequent asymptomatic presentation. The most severe form of hypertension is resistant hyper- tension, defined as a persistence of hypertensive BP (ie, BP >140/90 mm Hg) even if patients are treated with ≥3 antihypertensive drugs at optimal doses, including a diuretic, or with four or more medica- tions regardless of BP. 3 Its prevalence is approxi- mately 10–20% of all hypertensive patients. w10 w11 There is much evidence that sympathetic overdrive is the spark and driving force of most types of hypertension. w12 The first surgical experiences of renal nerve interruption with paralumbar sym- pathectomy w13–w15 were affected by many proced- ure related complications and abandoned because of the contemporary development of effective anti- hypertensive drugs. However, interest in renal denervation is now increasing following the devel- opment of percutaneous ablation systems. RDN has proven to be safe in many randomised controlled trials, 3–5 and efficacy data from trials involving dif- ferent denervation systems have shown a mean reduction in office BP of at least -20/-10 mm Hg 6 months after RDN. 6–9 Long term follow-up (36 months) data of the Symplicity HTN-1 confirm these findings, 9 with interesting evidence of a growing response over time (of the 44 subjects who were initially non-responders, 83% were responders at 3 years) ( figure 2). This phenomenon could most probably be explained by progressive cardiovascular remodelling secondary to RDN, which induces a significant reduction in arterial stiffness. w16 Furthermore, RDN has demonstrated its efficacy by reducing BP on ambulatory BP monitoring (ABPM) in true resistant hypertension 10 and by improving the BP response to physical exercise and at recovery. 11 The results of Symplicity-HTN3 12 contrast with the results of previous studies (table 1). In this first trial characterised by a 2:1 randomisation to RDN or sham procedure, the BP reduction at 6 months was significant in both groups with respect to base- line, but the difference in the two groups (-2.39 mm Hg) was lower than that required to meet the primary efficacy endpoint. On ABPM a difference of -1.96 mm Hg did not reach the Donazzan L, et al. Heart 2014;0:1–9. doi:10.1136/heartjnl-2013-304702 1 Education in Heart Heart Online First, published on June 4, 2014 as 10.1136/heartjnl-2013-304702 Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd (& BCS) under licence. group.bmj.com on June 5, 2014 - Published by heart.bmj.com Downloaded from