Effect of renal sympathetic denervation on the inducibility of atrial fibrillation during rapid atrial pacing
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- Zhao, Q., Yu, S., Zou, M. et al. J Interv Card Electrophysiol (2012) 35: 119. doi:10.1007/s10840-012-9717-y
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Atrial fibrillation (AF) is associated with activity of renin–angiotensin–aldosterone system (RAAS). Reduction in renal noradrenaline spillover could be achieved after renal sympathetic denervation (RSD). The relationship between RSD and AF is unknown.
The objective of the study was to investigate the inducibility of AF during atrial rapid pacing after RSD.
Thirteen dogs were used for the study as follows: control group (seven dogs) and RSD group (six dogs). In the control group, dogs were subjected to atrial pacing at 800 beats/min for 7 h, and atrial effective refractory period (AERP) was measured every hour in the status of non-pacing. Subsequently, pacing was stopped and the burst pacing (500 bpm) was repeated to induce AF three times. In the RSD group, after each renal artery ablation, the procedure of pacing and electrophysiological measurement was exactly same as in the control group. Blood was collected before and after pacing to measure the levels of renin, angiotensin II and aldosterone.
There was a persistent decrease in AERP in both groups. However, 7 h after cessation of pacing, the induced number of times and duration of AF were higher in the control group than that in the RSD group (1.0 ± 1.26 vs 3.14 ± 2.54, P = 0.03; 16.5 ± 25.1 vs 86.6 ± 116.4, P = 0.02). The plasma aldosterone concentration increased significantly 7 h after rapid pacing in control group (renin, 119.8 ± 31.1 vs 185.3 ± 103.5 pg/ml, P < 0.01; aldosterone, 288.2 ± 43.1 vs 369.6 ± 109.8 pg/ml, P = 0.01). The levels of renin and aldosterone showed a decreasing trend in RSD group, but this did not attain statistical significance.
Episodes of AF could be decreased by renal sympathetic denervation during short-time rapid atrial pacing. This effect might have relationship with decreased activity of RAAS.
KeywordsRenal sympathetic nerveAblationRenin–angiotensin–aldosterone systemAtrial fibrillation
The fundamental mechanisms underlying atrial fibrillation (AF) have long been debated, but electrical and structural remodelling are each important synergistic contributors to the AF substrate, and these changes further perpetuate the existence and maintenance of AF [1–3]. Much attention has been devoted in the past few years to assess the role of renin–angiotensin–aldosterone system (RAAS) in AF [4–6]. Studies have indicated that angiotensin II (Ang II) and aldosterone might be involved in atrial structural and electrical remodelling in patients with AF [7, 8]. The inhibition of the RAAS might have protective effect on remodelling .
Studies have demonstrated that the cross talk between the kidney and the heart includes the upregulated sympathetic nerve system, activation of the RAAS and vasopressin release. It has been shown that compromised hemodynamics during AF leads to an increase in catecholamines and sympathetic tone with parasympathetic withdrawal . The activation of sympathetic nervous system is related to the effects of circulating renin released from the kidneys. In the previous study, Nakashima et al. showed that the inhibition of endogenous Ang II prevented atrial effective refractory period (AERP) shortening during rapid atrial pacing . Whether renal sympathetic denervation could decrease the released renin and the initiation of AF during rapid atrial pacing is unknown. In the present study, we used a rapid atrial-paced canine model to examine the effect of renal sympathetic innervation on acute atrial remodelling process and inducibility AF by catheter-based renal denervation.
2.1 Experimental animals
2.2 Study protocol
Thirteen dogs, divided into two groups, were used for the study as follows: control group (seven dogs) and renal sympathetic denervation (RSD) group (six dogs). In the control group, dogs were subjected to atrial pacing at 800 beats/min for 7 h, and AERP was measured at every hour in the status of non-pacing. Subsequently, pacing was stopped and the burst pacing (500 beats/min) was repeated to induce AF each hour for three times. In the RSD group, 6 F ablation catheter was introduced (Biosense Webster, Inc., Diamond Bar, CA, 91765, USA) into each renal artery via femoral artery. We applied discrete, radiofrequency ablations lasting up to 80 s each and of 6 W or less within each renal artery. During ablation, the catheter was advanced and retreated three times. The catheter system monitored tip temperature and impedance, altering radiofrequency energy delivery in response to a predetermined algorithm. The procedure of pacing and electrophysiological measurement in RSD group was exactly same as in the control group.
In another three dogs, we measured different parameters during the radiofrequency procedure. We did this measurement to test the safety and effectiveness of the device in achieving efferent RSD.
2.3 Induction of atrial fibrillation and biochemical studies
S1S1 (120 ms cycle length) programmed stimulus method was adopted to induce AF. The duration of S1S1 stimulation lasted for 5 s. AF was defined as irregular atrial rates faster than 500 bpm, lasting >5 s.
Four millilitres of venous blood was collected in EDTA vacutainers and centrifuged at 2,310×g for 10 min at 4 °C (Beckman Coulter, Avanti J-E) before and after pacing. The serum was separated and kept in microtubes and stored at −80 °C until assay. The levels of renin, Ang II and aldosterone were examined by ELISA.
2.4 Statistical analysis
Values are shown as mean + SD. Statistical comparisons were made using ANOVA. Paired and unpaired comparisons were conducted using Student’s t test. Unpaired t tests were used to compare the means of nerve densities. Statistical significance was assumed if P values were <0.05.
In the control and RSD groups, the systolic and diastolic blood pressures were stable during the entire period of experiments. When compared with control dogs, RSD dogs had the same blood pressure after ablation and throughout the 7-h pacing period.
3.1 Effect of renin sympathetic ablation
3.2 Changes of AERP and initiation of AF
In the RSD group (Fig. 5), there was no significant difference in AERP before and after RSD and there were no significant differences in the changes of AERP between the two groups. AERP decreased from 129.0 ± 16.8 to 117.7 ± 22.3 ms (P > 0.05) during the first 1 h to 109.2 ± 17.8 ms before cessation of pacing (P < 0.05). After pacing for 1 h, AF cannot been induced by burst pacing (500 beats/min). After cessation of 7 h of pacing, AF was induced in three dogs and the duration of AF was 5, 34 and 60 s, respectively, by burst pacing (500 beats/min). Compared with control dogs, RSD dogs had lower induced number of times (1.0 ± 1.26 vs 3.14 ± 2.54, P = 0.03) and shorter duration of AF (16.5 ± 25.1 vs 86.6 ± 116.4, P = 0.02) after 7-h pacing by burst pacing (500 beats/min). The mean duration and induced times of AF in each hour were shown in Fig. 6.
3.3 Changes of renin, Ang II and aldosterone
4.1 Major findings
This study demonstrated for the first time that episodes and duration of AF could be decreased by renal sympathetic denervation during short-time rapid atrial pacing. Decreased inducibility of AF might have associated with decreased activity of RAAS.
4.2 Effect of intracardiac and extracardiac denervation on inducibility of AF
Initial study on total efferent vagal denervation via epicardial fat pad ablation indicated that such a dedicated approach may prevent AF in dogs produced by atrial pacing . Transvascular atrial parasympathetic nerve system modification by radiofrequency current catheter ablation abolishes vagally mediated AF has been reported . Recently, Tan et al. demonstrated that cryoablation of the superior cardiac branches of vagal nerve eliminated episodes of AF . No matter what the intracardiac ganglionated plexi, extracardiac stellate ganglia or branches of vagal nerve, all these nerves go directly to innervate atrial myocardium. Whether renal sympathetic nerve which has no direct afferent cardiac nerve fibres has impact on AF is not clear.
In the present study, we first observed the inducibility of AF during rapid atrial pacing with or without renal sympathetic denervation. Just as the previous report, rapid atrial pacing can facilitate the initiation and maintenance of AF with the prolonged time . Surprisingly, after renal sympathetic denervation, the average duration and induced episodes of AF were nearly same as that in the control group in the initial 3 h, but average duration and induced episodes of AF decreased significantly after pacing for 4 h. These data highlight the importance of renal sympathetic nerve as an exacerbated factor during rapid atrial pacing.
4.3 RAAS and acute atrial electrical remodelling
Previous studies have demonstrated that high-frequency pacing increases intracellular calcium levels in cardiac myocytes, and intracellular calcium overload is thought to contribute to this phenomenon [1, 15]. Calcium channel blockade prevents AERP shortening during rapid atrial pacing . It has been shown that Ang II increases the intracellular calcium concentration significantly in atrial myocytes in rat heart . Previous study has reported that the inhibition of endogenous Ang II prevented AERP shortening during rapid atrial pacing . Recently, Laszlo et al. demonstrated that selective mineralocorticoid receptor antagonism (eplerenone) influenced ICa,L in the early tachycardia-induced atrial electrical remodelling . Therefore, it is possible that the blockade of RAAS could attenuate atrial fibrillation-induced electrical remodelling, probably by preventing calcium overload. The present study indicated that during atrial rapid pacing, levels of the plasma renin and aldosterone were increased. Although there was no significant difference in the levels of plasma Ang II before and after pacing, the levels of Ang II showed an increasing trend in the control group and decreasing trend in the RSD group. However, in the present study, AERP decreased after rapid pacing in both the two groups. Thus, the relevance of these, at the moment only observational alterations, is likely and has to be further evaluated.
4.4 Renal sympathetic nerve, RAAS and AF
The kidney receives a dense innervation of sympathetic and sensory fibres and can be both a target of sympathetic activity and a source of signals that drive sympathetic tone. It is well-known that renal sympathetic stimulation induces renin release; conversely, Ang II appears to have important actions in modulating sympathetic nerve activity. The RAAS is involved in myocardial fibrosis and increased Ang II production causes marked atrial dilation with focal fibrosis and AF [7, 19]. Under AF, development and persistent sympathetic nerve and RAAS are activated and each condition predisposes to the other. Our study showed that the average duration and induced episodes of AF were longer significantly in control dogs than in renal sympathetic denervation dogs at 7 h after cessation of pacing. This phenomenon might be explained by reduced ‘RAAS activity’ due to renal sympathetic denervation.
4.5 Catheter-based renal denervation as a new strategy for AF management
Despite a long history of medical exploration of AF, many aspects of the management of AF remain controversial . The long-term efficacy of currently available antiarrhythmic drugs for the prevention of AF recurrence is far from ideal because of limited efficacy and potential side effects, particularly proarrhythmia . Since Haissaguerre et al. reported that triggers arising from the pulmonary veins are responsible for the majority of paroxysmal AF , catheter ablation of AF is now a realistic therapeutic option across a broad spectrum of patients—from patients with paroxysmal AF to those with long-lasting persistent AF . Although the superiority of catheter ablation over antiarrhythmic drug therapy has been demonstrated in middle-aged patients with paroxysmal AF, the role of the procedure in other patient subgroups such as those with long-standing persistent AF has not been well-defined [24, 25]. Currently, ganglionated plexi (GP) ablation has been employed for both paroxysmal and persistent AF, and GP ablation appears to be an efficacious method to improve pulmonary vein (PV) isolation in patients with AF [26, 27]. However, ablation-induced atrial or ventricular proarrhythmia has been reported and anatomic GP modification appears to carry a higher risk of iatrogenic left atrial tachycardias than PV isolation [28, 29]. Furthermore, studies have shown that fat pad ablation did not achieve long-term suppression of AF induction in canine model [30, 31]. We demonstrated in the present study that inducibility of AF can be decreased by renal sympathetic denervation during short-time rapid atrial pacing. The effectiveness and safety of catheter-based renal denervation had been demonstrated in patients in recent years [32, 33]. The present findings further support the assertion that ablation of extracardiac nerves can be an effective alternative to ablation of intracardiac nerves by atrial ablation for the treatment of AF .
5 Study limitations
The present study has several limitations. First, we did not observe the long-time effect of renal sympathetic denervation on inducibility of AF and atrial substrate remodelling because renal sympathetic nerve has no direct afferent nerve fibres to dominate cardiac function. Whether renal sympathetic denervation downregulated the activation of RAAS then decreased the generation of renin and Ang II and delayed the progress of atrial fibrosis and remodelling should be further investigated. Second, we did not perform stimulation of renal sympathetic nerves; therefore, we could not determine the relative importance of renal sympathetic nerve activation and inducibility of AF. Third, except for RAAS, renal sympathetic nerve activity has effect on the release of other neurohormones, such as bradykinin, prostaglandin, etc. Whether there are changes of plasma neurohormones after renal sympathetic denervation and have effect on atrial remodelling are unknown. Finally, the intracellular calcium concentration was not measured. Thus, further experiments with single cells isolated from atrial myocardium will be needed to evaluate the effect of RSD on intracellular calcium overload during rapid atrial pacing.
We thank Dr. Hongyao Hu for his support; Xiaohong Wang and Huafen Liu for their assistance; and Yu Liu for providing the multi-polar electrode catheters used in this study. This work was supported by National Natural Science Foundation of China (81070144).
Conflict of interests
The authors have no conflict of interests to disclose.