Does Renal Sympathetic Denervation Decrease Sympathetic Nerve Activity?

Mini Review

Austin Neurosurg Open Access. 2015;2(1): 1025.

Does Renal Sympathetic Denervation Decrease Sympathetic Nerve Activity?

Alexander Cole, Scott Nankervis, Guat-Siew Chew, Mark Myers, Fadi Charchar and Yutang Wang*

School of Applied and Biomedical Sciences, Federation University Australia, Australia

*Corresponding author: Yutang Wang, School of Applied and Biomedical Sciences, Federation University Australia, Mount Helen, VIC 3353 Australia

Received: May 07, 2015; Accepted: May 29, 2015; Published: June 01, 2015

Abstract

One major development in the field of sympathetic nerve research is the recent invention of catheter-based Renal Sympathetic Denervation (RSD) for the treatment of resistant hypertension. A large number of clinical trials have shown the effectiveness of RSD in lowering blood pressure. However, the recent Symplicity HTN-3 trial, the first trial on RSD with a single-blinded and shamcontrolled design, failed to show a blood-pressure-lowering effect of RSD. One of reasons explaining this discrepancy may be that sympathetic denervation in some patients is not complete. Therefore, investigating methods to verify the completeness of RSD has high clinical importance. This article reviewed the correlation between RSD and the noradrenaline content/spillover as well as Muscle Sympathetic Nerve Activity (MSNA), discussed the value of using noradrenaline and MSNA in predicting blood pressure response to RSD, and pointed out some future directions.

Keywords: Blood pressure; Muscle sympathetic nerve activity; Noradrenaline; Renal sympathetic denervation

Introduction

In hypertensive patients, renal sympathetic nerve activity is increased and high renal sympathetic nerve activity may be a major mechanism for the development of hypertension [1]. One major development in the field of sympathetic nerve research is the recent invention of catheter-based Renal Sympathetic Denervation (RSD) for the treatment of resistant hypertension. Since the first clinical trial on RSD was published in 2009 [2], a large number of clinical investigations have shown the effectiveness of RSD in lowering blood pressure. However, the recent Symplicity HTN-3 trial, the first trial on RSD with a single-blinded and sham-controlled design, failed to show a blood-pressure lowering effect of RSD [3]. One major limitation in the current clinical trials on RSD is the lack of a method to verify the completeness of sympathetic denervation in the renal artery [4]. The Simplicity catheter is required to be moved and rotated ≥4 times to cover the circumference of the renal artery, which makes RSD operator-dependent [4]. In addition, long-term side effects of RSD are not yet known [5-7]. Therefore, investigating methods to verify the completeness of RSD has high clinical importance [8-10]. This article reviewed the correlation between RSD and the noradrenaline content/spillover as well as Muscle Sympathetic Nerve Activity (MSNA), and discussed the value of using noradrenaline and MSNA in predicting the response of blood pressure to RSD.

Renal Sympathetic Denervation

Resistant hypertension is blood pressure that remains above the reduction goal despite concurrent use of three antihypertensive drugs at optimal doses, including a diuretic. Resistant hypertension contributes to an increased risk of cardiovascular events [11], and affects ≈ 6 million people in the United States [12,13]. Patients with resistant hypertension had few therapeutic options before 2007.

Renal sympathetic nerves include efferent and afferent nerves which lie adjacent to the adventitia layer of the renal artery [14]. Renal sympathetic nerves are crucial for production of catecholamines which can lead to hypertension [14]. Increased renal efferent sympathetic nerve activity can increase renin secretion and increase sodium absorption [15,16], consequently leading to increased fluid retention and hypertension. In addition, an increase in renin can activate the renin-angiotensin-aldosterone system, which contributes to the formation of hypertension [15,16]. On the other hand, increased renal afferent nerve activity can stimulate central sympathetic outflow, which can increase systemic vascular resistance and hypertension [15,16].

RSD is a catheter-based endovascular procedure to disconnect renal sympathetic nerves in the renal arteries. Therefore, RSD may lower blood pressure of hypertensive patients where renal sympathetic nerve activity is commonly increased [1]. This hypothesis was first investigated in 2007 by Krum et al. [2]. In this proof-of-principle Symplicity HTN-1 trial (N=45) [2], the authors showed that RSD decreased office systolic blood pressure by 22 mm Hg at 6 months in patients with resistant hypertension, and similar results were observed in the randomised but not sham-controlled nor blinded Symplicity HTN-2 trial (N=106) in 2010 [17]. The results of these two trials brought hope for patients with resistant hypertension. Subsequently, RSD has become a treatment option for resistant hypertension in many countries. It is increasingly clear that not every patient will respond to RSD. For example, the non response rate (a decrease in office systolic blood pressure of < 10 mm Hg) at 12 months was 15% in the Symplicity HTN-1 trial [18]. The randomised Symplicity HTN-3 trial (N=530), the first trial on RSD with a single-blinded and sham-controlled design, recently showed that RSD failed to lower blood pressure in patients with resistant hypertension 6 months after the procedure [3]. The reasons for the discrepancy between the Symplicity HTN-3 trial and a large number of other trials are not fully understood, although it has been suggested that incomplete sympathetic denervation of the renal artery may, at least in part, explain the failure of the Symplicity HTN-3 trial [19]. However, this needs to be investigated in the future.

The procedure of RSD is previously described [20]. In brief, a catheter connected to a radiofrequency generator is inserted percutaneously and advances into the lumen of the renal artery. The typical inserting point is the right femoral artery and anatomic eligibility for the procedure is confirmed by renal angiography. The treatment catheter is introduced into each renal artery. Then discrete radiofrequency ablations lasting up to 2 min each are applied, and catheter is required to be moved and rotated ≥4 times to cover the circumference of each renal artery [4,20].

The renal artery anatomy is one of the criteria for a patient to be eligible for RSD. The expert consensus document from the European Society of Cardiology states that eligibility of renal arteries for RSD includes no polar or accessory arteries, no renal artery stenosis, and no prior revascularization [21]. Given that RSD may lead to renal artery stenosis [6] and long-term effects of RSD are unknown, exclusion of patients with this unfavorable renal artery anatomy from RSD is crucial.

Renal Sympathetic Denervation and Noradrenaline

RSD applies radio frequency energy to the renal arterial lumen, aiming to destroy both the afferent and efferent sympathetic nerves in the renal arteries [2,3,17]. Therefore, parameters on the renal sympathetic nerve activity are important to assess the success of the RSD procedure. One such parameter is renal noradrenaline spillover. A Pubmed search for clinical trials on RSD that contained noradrenaline data was conducted and five articles were identified (Table 1) [2,22-25].

Citation: Cole A, Nankervis S, Guat-Siew Chew, Myers M, Charchar F and Wang Y. Does Renal Sympathetic Denervation Decrease Sympathetic Nerve Activity?. Austin Neurosurg Open Access. 2015;2(1): 1025.