Elsevier

Heart Rhythm

Volume 13, Issue 12, December 2016, Pages 2388-2394
Heart Rhythm

Contemporary Review
Renal sympathetic denervation for treatment of patients with atrial fibrillation: Reappraisal of the available evidence

https://doi.org/10.1016/j.hrthm.2016.08.043Get rights and content

Afferent renal sympathetic nerve signaling regulates central sympathetic outflow. In this regard, renal sympathetic denervation has emerged as a novel interventional strategy for treatment of patients with resistant hypertension. Despite the disappointing results of the Simplicity HTN-3 randomized controlled trial, promoters of renal denervation argue that the negative results were due to ineffective denervation technique and poor patient selection. Yet, long-term “pathologic” increase of efferent sympathetic nerve activity is observed in many chronic disease states characterized by sympathetic overactivity, such as arrhythmia, heart failure, insulin resistance, and chronic kidney disease. In this review, we highlight the contemporary evidence on the safety/efficacy of renal denervation in the treatment of patients with atrial fibrillation.

Introduction

Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia, with robust association to morbidity and mortality.1 The development of electrophysiologic and structural substrate for AF results from an interplay of various mechanisms: atrial stretch and dilation, interstitial fibrosis, oxidative stress, and disturbed intracellular calcium homeostasis.2 Moreover, the autonomic nervous system has been implicated to play a significant role in the genesis and sustainability of AF.3, 4 During the past decade, increasing evidence highlighted the importance of the pulmonary veins and posterior left atrium in harboring potential foci for generating AF. This region has distinctive anatomic, molecular, and electrophysiologic properties that favor the development and maintenance of AF. The contribution of sympathetic and parasympathetic innervation of the pulmonary veins and posterior left atrium to the occurrence of AF has also been studied.5, 6, 7 Renal sympathetic denervation (RDN) has emerged as a novel approach for treatment of patients with resistant hypertension. Despite the initial encouraging results of the open-label Simplicity HTN-2 trial, the results of the larger blinded Simplicity HTN-3 trial were disappointing. Reduction of 6-month systolic pressure with RDN was comparable to sham procedure.8, 9 This review summarizes the available evidence on the therapeutic outcome of RDN in the treatment of patients with AF.

Section snippets

Role of the autonomic nervous system in creating AF substrate

The autonomic nervous system (both sympathetic and parasympathetic) plays a crucial role in creating a “dynamic” substrate for atrial arrhythmia, both in normal heart and in structural heart disease. Sympathetic stimulation predisposes to arrhythmia by Ca influx and Ca release from the sarcoplasmic reticulum, thus enhancing automaticity and triggered activity (Figure 1).10 On the other hand, vagal activation induces nonhomogeneous shortening of the atrial effective refractory period (AERP),

Renal sympathetic interaction

Sympathetic innervation of the kidneys arises from the second sympathetic ganglion; sympathetic fibers travel through the adventitia of the renal arteries to reach the kidneys.24 The renal efferent sympathetic fibers terminate in the glomerular arterioles, renal proximal tubules, and juxtaglomerular apparatus.25 Renal efferent sympathetic signaling mediates vasoconstriction and reduced renal blood flow; sodium and fluid retention; and renin release.24, 26 On the other hand, stimulation of

Experimental studies of renal denervation in AF

In a canine model of pacing-induced heart failure, animals that previously underwent RDN (8 weeks before) had no significant decrease of AERP, no increase in atrial dimensions (vs baseline), fewer episodes of induced AF with a shorter duration of episodes, less atrial fibrosis, and less neurohormonal activation (vs animals that underwent pacing without RDN).36 Possible mechanisms of decreasing AF inducibility were shown in another study of a similar model.37 RDN was associated with less P-wave

Clinical studies of renal denervation in AF

Little clinical evidence exists for the efficacy and safety of RDN in preventing/treating AF. In a first-in-man small pilot randomized study (n = 27), Pokushalov et al49 compared pulmonary vein isolation (PVI) alone vs PVI combined with RDN in patients with a history of symptomatic AF refractory to ≥2 antiarrhythmic medications and drug-resistant hypertension (systolic blood pressure >160 mm Hg despite ≥3 antihypertensive medications) referred for PVI. All had paroxysmal AF (67% also had

Reappraisal of the available evidence

A growing body of evidence—mainly derived from experimental studies—supports the safety and possible benefit of RDN in the setting of AF at intermediate-term follow-up. In animal models of AF, RDN was associated with reduction of both spontaneous and inducible AF with shorter duration of AF episodes, less shortening of AERP, less P-wave dispersion, increased atrial conduction velocity, less neurohormonal activation, less atrial fibrosis and inflammation, less atrial sympathetic innervation, and

References (53)

  • E. Pokushalov et al.

    A randomized comparison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension

    J Am Coll Cardiol

    (2012)
  • E. Pokushalov et al.

    Renal denervation for improving outcomes of catheter ablation in patients with atrial fibrillation and hypertension: early experience

    Heart Rhythm

    (2014)
  • A.J. Camm et al.

    2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation--developed with the special contribution of the European Heart Rhythm Association

    Europace

    (2012)
  • Y.K. Iwasaki et al.

    Atrial fibrillation pathophysiology: implications for management

    Circulation

    (2011)
  • M.J. Shen et al.

    Neural mechanisms of atrial arrhythmias

    Nat Rev Cardiol

    (2012)
  • R. Arora et al.

    Neural substrate for atrial fibrillation: implications for targeted parasympathetic blockade in the posterior left atrium

    Am J Physiol Heart Circ Physiol

    (2008)
  • M.D. Esler et al.

    Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial

    Lancet

    (2010)
  • D.L. Bhatt et al.

    SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension

    N Engl J Med

    (2014)
  • H.E. Ter Keurs et al.

    Calcium and arrhythmogenesis

    Physiol Rev

    (2007)
  • R. Arora

    Recent insights into the role of the autonomic nervous system in the creation of substrate for atrial fibrillation: implications for therapies targeting the atrial autonomic nervous system

    Circ Arrhythm Electrophysiol

    (2012)
  • T. Tomita et al.

    Role of autonomic tone in the initiation and termination of paroxysmal atrial fibrillation in patients without structural heart disease

    J Cardiovasc Electrophysiol

    (2003)
  • S. Vikman et al.

    Altered complexity and correlation properties of R-R interval dynamics before the spontaneous onset of paroxysmal atrial fibrillation

    Circulation

    (1999)
  • S. Vikman et al.

    Differences in heart rate dynamics before the spontaneous onset of long and short episodes of paroxysmal atrial fibrillation

    Ann Noninvasive Electrocardiol

    (2001)
  • E.K. Choi et al.

    Intrinsic cardiac nerve activity and paroxysmal atrial tachyarrhythmia in ambulatory dogs

    Circulation

    (2010)
  • J.V. Jayachandran et al.

    Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation

    Circulation

    (2000)
  • P.A. Gould et al.

    Evidence for increased atrial sympathetic innervation in persistent human atrial fibrillation

    Pacing Clin Electrophysiol

    (2006)
  • Cited by (19)

    • Is renal denervation still a treatment option in cardiovascular disease?

      2020, Trends in Cardiovascular Medicine
      Citation Excerpt :

      The mechanism underlying the potential anti-arrhythmic effects of RDN is not fully delineated yet. Nammas et al. [47] described that the potential mechanism underlying the initiation of arrhythmias through activation of the cardiorenal axis may be elicited by activation of the mechanoreceptors in the renal pelvic wall and chemoreceptors in the renal interstitium with stimuli, such as ischemia, hypoxia or intrinsic renal disease. Stimulation of these receptors may lead to renal afferent sympathetic signaling through the hypothalamus, followed by increased central sympathetic outflow and efferent sympathetic nerve signaling to the heart, which may lead to enhanced automaticity and triggered activity.

    • Pathophysiology and Risk of Atrial Fibrillation Detected after Ischemic Stroke (PARADISE): A Translational, Integrated, and Transdisciplinary Approach

      2018, Journal of Stroke and Cerebrovascular Diseases
      Citation Excerpt :

      The prevention of this “neurogenic to cardiogenic AFDAS shift” is one of the main targets for reducing the consequences of both recurrent AF and AF-related cardiac structural changes. Therefore, interventions such as anti-inflammatory agents,60-62 aldosterone antagonists,63 modulators of autonomic64 and catecholamine65 surges, and suppressors of the renin-angiotensin system66 could be tested first in the animal model and then in humans. In terms of economics, identifying patients at higher risk of developing AFDAS immediately after stroke will help allocate diagnostic technologies more efficiently.

    • Effects of renal sympathetic denervation on the stellate ganglion and brain stem in dogs

      2017, Heart Rhythm
      Citation Excerpt :

      These findings are consistent with the results of the present study, which showed that RD suppressed PAT episodes through SG damages. Our study helps to provide a mechanistic basis of the antiarrhythmic effects of RD.3 In addition, RD may be helpful in controlling other types of arrhythmias known to be controllable by SG ablation. Absence of BP effects has been observed in the present study and in previous clinical studies,6,30 suggesting that hypotension may not be a side effect of RD.

    View all citing articles on Scopus
    View full text