Cardiovascular Research

Cardiovascular Research 2002 54(2):470-475; doi:10.1016/S0008-6363(02)00239-0
© 2002 by European Society of Cardiology

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Copyright © 2002, European Society of Cardiology

Endovascular stimulation within the left pulmonary artery to induce slowing of heart rate and paroxysmal atrial fibrillation

Benjamin J. Scherlag^a,*, William S. Yamanashi^a, Patrick Schauerte^b, Michael Scherlag^a, Ying-Xian Sun^a, Yuemei Hou^c, Warren M. Jackman^a and Ralph Lazzara^a

^aCardiac Arrhythmia Research Institute at the University of Oklahoma Health Sciences Center, Department of Veterans Affairs Medical Center, 1200 Everett Drive, Room UH6E103, Oklahoma City, OK 73104, USA
^bTechnical University RWTH, Aachen, Germany
^cXinjiang Medical University, Urumuqi, PR China

^* Corresponding author. Tel.: +1-405-271-9696; fax: +1-405-271-7455 benjamin_scherlag{at}ouhsc.edu

Received 7 September 2001; accepted 27 December 2001

	Abstract

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion Acknowledgments References

 
Objective: In recent years there have been many reports dealing with basic models for sustained atrial fibrillation (AF), however few animal models exist for paroxysmal AF which closely simulate that seen clinically. Methods: In 12 dogs, anesthetized with sodium pentobarbital, a right thoracotomy was performed. We stabilized a basket electrode catheter within the left pulmonary artery (LPA) through a purse string suture in the right ventricle. Electrode catheters were sutured to multiple atrial sites including the four pulmonary veins and the right and left atrial appendages, along Bachman's bundle and the coronary sinus. Results: Continuous pulses of electrical stimulation (20 Hz square wave stimuli, each 0.1 ms in duration, voltage range 1–40 V) across adjacent splines of the five arms of the basket induced slow heart rates (at lower voltages) and then initiated atrial premature depolarizations (APDs), atrial tachycardia (AT) and AF (at higher voltages). To avoid possible direct activation of atrial myocardium, we also applied a train (50–100 ms duration) of high frequency stimuli (200 Hz) coupled to each atrial paced beat so that the train fell within the atrial refractory period. Stimulation in the LPA at an average of 14±7 V induced heart rate slowing, APDs were seen followed by AT/AF at a voltage of 20±6 V, P=0.002. Stimulation in the LPA resulted in APDs arising from a variety of sites including the left pulmonary veins (superior or inferior) and the left atrial appendage. After β-blockade (intravenous esmolol or propranolol, 1 mg/kg) the voltage threshold for induction of AF rose from 14±7 to 25±10 V, P=0.02. Upon the addition of intravenous atropine (1–2 mg) the arrhythmic response (AF) to stimulation was completely abolished. Atrial pacing threshold was unchanged after autonomic blockade. Local application of radiofrequency energy (average number=3±2) across the metallic splines of the basket catheter in the LPA (70–80 V for 60 s) caused abolition of both the slowing and the arrhythmic response to LPA stimulation. Conclusion: These data suggest that stimulation of autonomic nerves in the LPA causes slowing of the heart rate followed by paroxysmal APD/AT/AF simulating the spontaneously occurring paroxysmal AF syndrome, associated with bradycardia, reported in patients.

KEYWORDS Ablation; Adrenergic (ant)agonists; Arrhythmia (mechanisms); Autonomic nervous system; Bradycardia; Muscarinic (ant)agonists

	1 Introduction

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion Acknowledgments References

 
Atrial fibrillation (AF) has been recognized as the most common supraventricular arrhythmia found clinically. Its prevalence is mainly in the elderly, i.e. in those aged 50–80 and particularly affects men in that age group [1]. There are suggestions in the literature that sustained, chronic AF begins with episodic AF and that more frequent episodes lead to an electrophysiological remodeling of the atria, i.e. chronic shortening of the atrial refractory period, eventually leading to establishment of chronic AF. This process has been termed "AF begets AF" [2].

Recently we have developed a new experimental model for induction of the PAF syndrome, i.e. atrial premature depolarizations (APDs), atrial tachycardia (AT) and AF, via endovascular stimulation of autonomic nerves in the superior vena cava [3]. These preliminary findings not only suggest that activation of both parasympathetic and sympathetic nerves to the atria can induce PAF in structurally normal hearts but also provides: (1) insight into a neural–electrophysiologic mechanism for induction of PAF, (2) may provide a diagnostic test for determining those at risk for developing PAF and (3) may allow for the determination of key neural sites involved in the development of PAF and therefore particularly susceptible for radiofrequency ablation and prevention of PAF occurrences. In the present study, we have found that endovascular stimulation within the LPA, presumably of the autonomic neural elements overlying this vessel can initially induce slowing of the heart rate. Then, with higher voltages, APDs, AT and AF can be induced.

	2 Methods

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion Acknowledgments References

 
Twelve adult mongrel dogs (weighing 18–30 kg) were anesthetized with sodium pentobarbital (30 mg/kg) administered intravenously. A 50–100-mg amount was injected hourly in order to maintain a surgical plane of anesthesia. The animals were intubated and ventilated with room air. A catheter was inserted into the left external jugular vein for drug delivery. Blood pressure was monitored via a sheath inserted in the left common carotid artery. A quadripolar electrode catheter with 2 mm interelectrode spacing was introduced into the left common carotid artery and advanced to the aortic root to record His bundle electrograms. Two standard ECG leads were monitored continuously.

Using a right lateral thoracotomy at the 4th intercostal space, a pericardiotomy allowed access to the atria and base of the ventricles. Several octapolar electrode catheters (2 mm interelectrode spacing) were attached by sutures to contact the four pulmonary veins, Bachman's bundle, the coronary sinus and the right and left atrial appendages. All tracings were amplified and digitally recorded on a computer-based Bard Labsystem. ECG filter settings ranged between 0.1 and 250 Hz, whereas bipolar electrograms were filtered at 30–250 Hz.

2.1 Stimulation within the left pulmonary artery (LPA)
A purse string suture was placed in the right ventricular outflow tract. A basket electrode catheter (Biosense-Webster, Diamond Bar, CA, USA) (Fig. 1) was inserted through the purse-string and advanced into the left pulmonary artery. The five splines of the basket were specially formed of uninsulated metal so that adjacent splines could be used for bipolar stimulation and individual splines used for radiofrequency ablation in conjunction with a skin patch. The impedance of the naked spline was in the range of 180–270 . Stimulation of presumed autonomic neural elements was achieved by continuous delivery of high frequency square waves at 20 Hz, with each stimulus 0.05–0.1 ms in duration. The appropriate site of stimulation was indicated by a marked slowing of the atrial rate at voltages between 1 and 40 V. The features of the PAF syndrome appeared in the higher voltage range and consisted of APDs/AT leading to runs of AF.

View larger version (17K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Schematic depiction of the basket electrode catheter used for autonomic nerve stimulation and ablation within the left pulmonary artery. The basket is composed of metallic splines (five, only four shown in two dimensions) with a central pull-string which can be used to expand and contract the basket. Stimulation was applied as a bipolar lead across adjacent splines. Ablation was accomplished by delivery of radiofrequency energy to each spline with a skin patch as the grounding electrode.

 
2.2 Administration of autonomic blocking agents
In order to assess the involvement of either or both arms of the autonomic nervous system in the pacing induced PAF syndrome, β-blockade was induced by the administration of either esmolol 1 mg/kg or propranolol 1 mg/kg intravenously. For muscarinic receptor blockade atropine, 1–2 mg, was given by the same route.

All animal studies were reviewed by the local Animal Studies Subcommittee and approved by the Research and Development Committee of the Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma. The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US Nationals Institutes of Health (NIH Publication No. 85-23, revised 1996).

	3 Results

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion Acknowledgments References

 
The PAF syndrome could be induced by electrical stimulation within the LPA. At an appropriate site stimulation resulted in marked slowing of the atrial rate prior to the induction of APD/AT/AF. Fig. 2 shows a typical example, in which continuous pulsed stimulation was applied across a pair of splines of the expanded basket catheter in the LPA. At a stimulation intensity of 8 V the sinus cycle length of 420 ms (heart rate 143/min) was prolonged to 496 ms (heart rate 121/min) initially, Fig. 2A). When the voltage was raised to 26 V the atrial cycle length increased from 448 (heart rate 134/min) to 1072 ms (heart rate 56/min) but then was followed by single and multiple APDs and AT (Fig. 2B). In Fig. 2C, at a voltage level of 30 V, APDs leading to AT then AF occurred in quick succession.

View larger version (27K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Electrophysiology features of the PAF syndrome could be induced by electrical stimulation within the LPA. Traces from the top: ECG lead I, electrograms from the right atrial appendage (RAA) and his bundle (Hb) region. (A) In contrast to induction of PAF in the superior vena cava, LPA stimulation at an appropriate site always resulted in marked slowing of the atrial prior to induction of APD/AT/AF. Continuous stimulation applied across specific pairs of adjacent splines of the expanded basket catheter induced an increase of the A–A cycle length from 420 to 496 ms. The parameters of stimulation were frequency, 20 Hz; duration of each stimulus, 0.1 ms; intensity, 8 V. (B) When the voltage was increased to 26 V the slowing effect was more profound. The cycle length increased from 448 to 1072 ms followed by APDs and AT. (C) At an intensity of stimulation of 30 V, APD/AT/AF was rapidly induced. The Hb electrograms were omitted in (B) and (C) to simplify the figure.

 
Atrial ectopy leading to AF could also be induced by coupling trains of high frequency (200 Hz) stimuli to atrial paced beats. Fig. 3 shows two separate arrays of electrogram recordings from the multiple electrode catheters sutured to various sites in the right and left atria and pulmonary veins. The two beats shown in right panel and left panel are the same atrial paced beats viewed from different multiple electrode arrays. Note that the earliest electrical ectopic activation after the end of the high frequency pulse (duration 100 ms) arises from the electrodes at the left atrial appendage (LAA, asterisks) even though the highest voltage was applied closest to the left superior pulmonary vein (LSPV, arrow) in the left pulmonary artery. Of the four dogs in whom the high frequency trains were delivered during atrial pacing, two showed the site of earliest ectopic activation at the left atrial appendage; one near the left superior pulmonary vein and one which arose earliest from the left inferior pulmonary vein.

View larger version (58K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 Induction of atrial ectopy during atrial pacing, from the left atrium. Each atrial pacing stimulus was coupled to a train of high frequency stimuli (200 Hz, train duration=100 ms, each square wave 0.1 ms in duration) delivered across adjacent splines of the basket catheter in the LPA. The right and left panels display the multiple bipolar electrograms recorded from the right and left superior and inferior pulmonary veins (RSPV, LSPV, RIPV, LIPV, respectively), left atrial appendage (LAA), right atrium (RA), coronary sinus (CS) and Bachman's bundle (Bach). ECG lead aVR was also recorded (top). The atrial paced electrogram can be seen at the beginning of the onset of stimuli. Note that the earliest ectopic atrial activity arises at the LAA (asterisks) although the high frequency trains were delivered in the LPA closest to the left superior vein (LSPV, arrow). See text for further discussion.

 
Ten of the twelve dogs showed inducible APD/AT/AF which was still inducible after intravenous administration of β-blockers but the voltage required to induce AF increased significantly from 14±7 to 25±10 V, P<0.05 (Table 1). However, after administration of atropine, none of the dogs were inducible (0/10, Table 1), moreover, atrial pacing thresholds were unchanged from the control state. In eight of ten inducible dogs, radiofrequency current (75 V) applied for 60 s at the splines, at which stimulation induced slowing and AF, abolished both slowing of the heart rate and AF inducibility even when continuous pulsed stimulation was increased to the highest voltage (40 V). The average number of radiofrequency application was 3±2.

View this table: [in this window] [in a new window]   Table 1 Effect of local cardiac autonomic nerve stimulation in the left pulmonary artery on inducibility on the paroxysmal atrial fibrillation syndrome

 

	4 Discussion

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion Acknowledgments References

 
These experiments provide evidence suggesting that autonomic nerve stimulation close to the heart can induce the electrophysiologic manifestation seen clinically as the paroxysmal atrial fibrillation (PAF) syndrome. The latter is characterized by frequent atrial premature beats, followed by runs of atrial tachycardia eventually degenerating, episodically, to AF. In those patients with no structural heart disease, the syndrome has been defined as lone AF.

In the present study continuous pulsed electrical stimulation in the left pulmonary artery in the normal dog heart induced slowing of the heart rate. This finding provides strong evidence that parasympathetic stimulation of preganglionic fibers from the left vagosympathetic trunk is part of the mechanism underlying this effect. Randall and Armour in 1977 [4] provided meticulous studies tracing the para- and sympathetic fibers which course over the pulmonary artery in the dog, the baboon and in man. Interestingly, they alluded to "stimulation of a small branch arising immediately below the caudal cervical ganglion. During or immediately following cessation of stimulation, atrial fibrillation occurred and persisted for periods varying from a few seconds to several minutes." They also state that "Identical stimulation of comparably sized branches rostral or caudal to it did not produce the response, although stimulation of the vagal trunk did."

Furthermore, they go on to state that this response "was not sufficiently consistent to identify any specific nerve as an ‘atrial fibrillation nerve,’ but the concept of such a morphological–functional entity is of such importance as to merit much additional research." [4]

The stimulation site mentioned by Randall and Armour is found in the plexus of fibers forming the vagosympathetic input to the heart which runs over the left pulmonary artery [4]. Thus, it appears that stimulation of these nerves via endovascular stimulation would activate both para- and sympathetic efferents to the heart. The former being responsible for the heart rate slowing and the latter for triggering the ectopic beats. These ectopic beats, in turn, could serve as the initiators of AT/AF in the context of the markedly shortened atrial refractory period caused by autonomic nerve stimulation, mainly the response to parasympathetic stimulation [5].

Some question can be raised as to whether the induction of atrial ectopy is mediated by autonomic nerve stimulation or direct stimulation of underlying left atrial tissues or both. Even the use of the trains of stimuli, coupled to atrial pacing, and falling in the refractory period can be challenged. For, if autonomic stimulation, particularly parasympathetic stimulation, shortens atrial refractoriness therefore, even a short duration, 50 ms, train can become a depolarizing stimulus albeit falling during the relative refractory period and perhaps inducing EADs or closely coupled stimulation in the atrial vulnerable period. Perhaps, more convincing evidence that there is a predominant autonomic bases for the atrial ectopy, is the response seen after β-blockers or after atropine administration. First, there was a significant increase in the voltage required to induce AF suggesting that β-stimulation contributed to the induction of the atrial ectopy. Secondly, the complete abolition of inducible APD, AT/AF by atropine, even at the highest applied voltages, indicated the critical role of the parasympathetic influence in the induction of PAF. Of importance, there was no change in the atrial pacing threshold before and after autonomic blockade.

4.1 Clinical implications
Experimental animal studies over several decades have shown that increased parasympathetic tone can predispose to AF [6–8]. The role of the autonomic nervous system in relation to paroxysmal atrial fibrillation has not been precisely defined but several suggestive clinical studies have been forthcoming. Specifically, recent studies have shown that the sympathovagal balance, as indicated by altered values of heart rate variability, are significantly different in those patients with recurrence of AF after cardioversion than in those without early recurrences [9,10]. Both these studies indicated that an increased sympathetic tone was associated with the enhanced chances of AF recurrence. In patients with paroxysmal focal AF originating in the pulmonary veins and superior vena cava, β-adrenergic stimulation (isoproterenol infusion) could initiate AF [11,12] whereas increasing parasympathetic tone (phenylephrine infusion) suppressed focal activity mainly in the pulmonary veins [13]. The latter authors explained the apparent contradiction by hypothesizing that accentuated antagonism caused by increased parasympathetic tone could decrease automaticity and suppress focal firing [13].

Coumel described two forms of autonomically based paroxysmal atrial fibrillation [14]. The adrenergic form was associated with exercise or emotional stress occurred during the daytime and occurred at sinus rates around a heart rate of 90 beats/min—β-blockade was an effective treatment. In contrast, the PAF of vagal origin occurred mostly at night, particularly during sleep and was associated with bradycardia. β-Blockade was contraindicated since it tended to increases PAF episodes presumably by enhancing the parasympathetically induced bradycardia during sleep.

The form of PAF induced in the present study appears to be an experimental counterpart of clinical patients described by Coumel with bradycardia induced PAF. Admittedly, this is an uncommon form of PAF but there might be a possible use of this experimental means for AF induction, clinically. In some patients, brought to the electrophysiology laboratory for ablation of PAF, the arrhythmia is difficult to induce, many times requiring the infusion of isoproterenol in order to activate episodes of PAF [11,12]. The use of endovascular stimulation within the LPA, particularly during atrial pacing, could be an adjunctive means for inducing PAF.

Also, the possibility that ablation of localized neural elements by applying radiofrequency energy to the successful stimulation sites in the LPA may actually decrease or eliminate the PAF syndrome in those susceptible patients. Of course, studies are needed to ascertain the safety and efficacy of such ablation procedures.

Time for primary review 25 days.

	Acknowledgments

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion Acknowledgments References

 
We thank Mrs. Andrea K. Moseley for her technical assistance and her dedicated efforts in the preparation of the manuscript.

Supported by a research grant from the Helen and Wil Webster Fund of the Oklahoma University Foundation and Biosense-Webster, Diamond Bar, CA, USA

	References

Top Abstract 1 Introduction 2 Methods 3 Results 4 Discussion Acknowledgments References

 

1. Zipes D.P. Atrial fibrillation, from cell to bedside. J Cardiovasc Electrophysiol (1997) 8:927–938.[Web of Science][Medline]
2. Wijffels M.C.E.F., Kirchof C.J.H.J., Dorland R., Allessie M.A. Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats. Circulation (1995) 92:1954–1968.[Abstract/Free Full Text]
3. Scherlag B.J., Schauerte P., Scherlag M.A., et al. Radiofrequency ablation at the junction of the superior vena cava and right atrium terminates neurally induced atrial fibrillation. PACE (1999) 22:II724. (abstract).
4. Randall W.C., Armour J.A. Neural regulation of the heart. Randall W.C., ed. (1977) New York: Elsevier Science. Chapter 2.
5. Hoffman B.F., Cranefield P.F. The atrium. In: Electrophysiology of the heart (1960) New York: McGraw Hill. Chapter 3.
6. Hoff H.E., Geddes L.A. Cholinergic factor in atrial fibrillation. J Appl Physiol (1955) 8:177–192.[Free Full Text]
7. Burn J.H., Williams E.M.V., Walker J.M. The effects of acetylcholine in the heart–lung preparation including production of auricular fibrillation. J Physiol (1955) 128:277–293.[Free Full Text]
8. Sharifov O.F., Zaitzev A.V., Rosenshtraukh L.V., et al. Spatial distribution and frequency dependence of arrhythmogenic vagal effects in canine atria. J Cardiovasc Electrophysiol (2000) 11:1029–1042.[Web of Science][Medline]
9. Lombardi F., Colombo A., Basilico B., et al. Heart rate variability and early recurrence of atrial fibrillation after electrical cardioversion. J Am Coll Cardiol (2001) 37:157–162.[Abstract/Free Full Text]
10. Michelucci A., Lazzeri C., Padeletti L., et al. Altered values of heart rate variability in patients with relapse of atrial fibrillation during the first week after electrical cardioversion. Ital Heart J (2001) 2:435–440.[Medline]
11. Haissaguerre M., Jais P., Shah D., et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. New Engl J Med (1998) 339:659–666.[Abstract/Free Full Text]
12. Hsieh M.H., Tai C.T., Tsai C.F., et al. Preliminary vein electrogram characteristics in patients with focal sources of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol (2000) 11:953–959.[Web of Science][Medline]
13. Tai C.T., Chiou C.W., Wen Z.C., et al. Effect of phenylephrine on focal atrial fibrillation originating in the pulmonary veins and superior vena cava. J Am Coll Cardiol (2000) 36:788–793.[Abstract/Free Full Text]
14. Coumel P. The atrium in health and disease. Atteul P., Coumel P., Janse M.J., eds. (1989) Mt. Kisco, NY: Futura. 213–232.

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