Contemporary ReviewRenal sympathetic denervation for treatment of patients with atrial fibrillation: Reappraisal of the available evidence
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)
- et al.
Autonomic nerve activity and atrial fibrillation
Heart Rhythm
(2007) - et al.
Unique autonomic profile of the pulmonary veins and posterior left atrium
J Am Coll Cardiol
(2007) - et al.
Left stellate ganglion and vagal nerve activity and cardiac arrhythmias in ambulatory dogs with pacing-induced congestive heart failure
J Am Coll Cardiol
(2007) - et al.
Competing autonomic mechanisms precede the onset of postoperative atrial fibrillation
J Am Coll Cardiol
(2003) - et al.
Patterns of baseline autonomic nerve activity and the development of pacing-induced sustained atrial fibrillation
Heart Rhythm
(2011) - et al.
Roles of adrenergic and cholinergic stimulation in spontaneous atrial fibrillation in dogs
J Am Coll Cardiol
(2004) - et al.
Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation
Heart Rhythm
(2005) - et al.
Cryoablation of stellate ganglia and atrial arrhythmia in ambulatory dogs with pacing-induced heart failure
Heart Rhythm
(2009) - et al.
Effects of renal sympathetic denervation on the development of atrial fibrillation substrates in dogs with pacing-induced heart failure
Int J Cardiol
(2013) - et al.
Renal sympathetic denervation suppresses atrial fibrillation induced by acute atrial ischemia/infarction through inhibition of cardiac sympathetic activity
Int J Cardiol
(2016)
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
Renal denervation for improving outcomes of catheter ablation in patients with atrial fibrillation and hypertension: early experience
Heart Rhythm
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
Atrial fibrillation pathophysiology: implications for management
Circulation
Neural mechanisms of atrial arrhythmias
Nat Rev Cardiol
Neural substrate for atrial fibrillation: implications for targeted parasympathetic blockade in the posterior left atrium
Am J Physiol Heart Circ Physiol
Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial
Lancet
SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension
N Engl J Med
Calcium and arrhythmogenesis
Physiol Rev
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
Role of autonomic tone in the initiation and termination of paroxysmal atrial fibrillation in patients without structural heart disease
J Cardiovasc Electrophysiol
Altered complexity and correlation properties of R-R interval dynamics before the spontaneous onset of paroxysmal atrial fibrillation
Circulation
Differences in heart rate dynamics before the spontaneous onset of long and short episodes of paroxysmal atrial fibrillation
Ann Noninvasive Electrocardiol
Intrinsic cardiac nerve activity and paroxysmal atrial tachyarrhythmia in ambulatory dogs
Circulation
Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation
Circulation
Evidence for increased atrial sympathetic innervation in persistent human atrial fibrillation
Pacing Clin Electrophysiol
Cited by (19)
Is renal denervation still a treatment option in cardiovascular disease?
2020, Trends in Cardiovascular MedicineCitation 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 DiseasesCitation 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.
A potential and lionhearted soldier for atrial fibrillation accompanied with heart failure: Renal denervation
2017, International Journal of CardiologyEffects of renal sympathetic denervation on the stellate ganglion and brain stem in dogs
2017, Heart RhythmCitation 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.