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Europace Advance Access originally published online on October 19, 2008
Europace 2008 10(12):1415-1420; doi:10.1093/europace/eun282
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Atrial fibrillation

Paroxysmal atrial fibrillation is associated with increased intra-atrial conduction delay

Mariusz Pytkowski1,*, Agnieszka Jankowska1, Aleksander Maciag1, Ilona Kowalik1, Maciej Sterlinski1, Hanna Szwed1 and Richard C. Saumarez2,3,*

1 Coronary Artery Disease Department, Institute of Cardiology, Warsaw, Poland; 2 Department of Engineering, University of Cambridge, Cambridge, UK; 3 Department of Medicine, University of Cambridge, Cambridge, UK

Manuscript submitted 10 January 2007. Accepted after revision 19 September 2008.

* Corresponding authors. Tel/fax: +48 228 449510 (M.P.), Tel: +44 1223 332434 (R.C.S.).E-mail address: mpytkowski{at}ikard.pl (M.P.)or rcsaumarez{at}btinternet.com (R.C.S.)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 Funding
 References
 
Aims: A novel electrophysiological technique, paced electrogram fractionation analysis (PEFA), which measures activation delay of stimulated beats through the myocardium, has shown that long delays in activation are strongly associated with sudden cardiac death due to ventricular fibrillation. The aim of our study was to determine whether there are differences in intra-atrial conduction in patients with and without paroxysmal atrial fibrillation (PAF) using PEFA. Twenty patients (15 women) in the mean age 54.7 ± 16.6 years, scheduled for transcatheter ablation of their arrhythmias, were divided into two groups: 10 controls without PAF and 10 patients with PAF.

Methods and results: During PEFA, pacing and recording catheters were placed in the coronary sinus (three sites: distal, mid, and proximal) and at four right atrium sites: crista terminalis (one site), RA isthmus (one site), and interatrial septum (two sites). The PEFA protocol involves pacing from one site and recording electrograms from other six sites. A decremental sequence, delivered at one site, had a cycle length of 490 ms (S1S1) with an extrastimulus inserted every third beat whose coupling interval (S1S2) is reduced by 1 ms on each occasion. This process is repeated from each atrial site. The S1S2 at which electrogram duration starts to prolong, and the increase in electrogram duration is determined at all sites. In three patients from the PAF group, atrial fibrillation was induced during PEFA and it was terminated by electrical cardioversion. No other complications were noted. The patients with PAF, compared with the control group, have abrupt increases in the electrogram duration, which occur, at significantly longer S1S2 (P < 0.0001). There were also significantly longer intra-atrial delays in the intrinsic deflection of the electrogram in PAF patient vs. control group (P < 0.0001).

Conclusions: Comparison of PAF and non-AF patient groups showed that intra-atrial conduction delay start in the PAF group earlier (with longer S1S2 intervals) and they are significantly longer in the PAF group. This suggests that atria in patients with PAF are diffusely diseased and that the measured activation delays form one component of an arrhythmogenic substrate.

Key Words: Paced electrogram fractionation analysis (PEFA), Atrial fibrillation


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 Funding
 References
 
Atrial fibrillation (AF) is a growing problem in countries with an ageing population in which 2–4% of population older than 60 years suffers from AF. Furthermore, AF is often refractory to medical therapy and causes appreciable morbidity and mortality.1Go

Re-entry is thought, on the basis of clinical and experimental evidence, to be one of the basic mechanisms of AF.2Go,3Go Although the triggers for AF appear to be located in the pulmonary veins,4Go established AF has regions of slowed conduction and activation block in other regions of the atria5Go and these contribute to the changing macro-re-entry circuits within the atria.

The initiation of re-entrant tachycardias requires a substrate of one or more areas of slowed conduction and activation block.6Go,7Go In classical, well-characterized re-entrant arrhythmias, slowed conduction and block can be inferred from the activation sequence of induction, reset, or termination of the arrhythmia by precisely timed extrastimuli. In contrast to these arrhythmias with a specific anatomical substrate, ventricular fibrillation (VF), while a re-entrant arrhythmia, arises from a functional substrate created by a dynamically changing pattern of refractoriness and activation5Go that is difficult to study clinically. Against this background, a technique, paced electrogram fractionation (PEFA), was developed8Go to identify a substrate for VF by timing the activation of ventricular sites in response to increasingly premature extrastimuli. This technique is based on the hypothesis that diseased tissue, which might contain a substrate for VF, would show fractionated potentials with increasing delay within recorded electrograms (‘fractionation’), created by tortuous activation paths around fibrous tissue and that these effects could be accentuated by local conduction block as the extrastimulus coupling interval was reduced. This hypothesis has been tested in 450 patients with a variety of non-coronary diseases and a strong association between the risk of long QT syndrome (LQTS) and electrogram fractionation was found in hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy, LQTS, and idiopathic VF.9Go–11Go Although these studies have shown that there is a physiological effect that is compatible with the presence of substrate for VF, the mechanisms by which it arises is unlikely to be the same in different diseases. The structural changes in HCM, extensive fibrosis, and disarray12Go are likely to create delays due to tortuous conduction; whereas in the LQTS, there is a local block due to the dispersion of the action potential duration.13Go We hypothesized that similar changes may occur in the atria and that these could be detected by analysing the fractionation of atrial electrograms in patients with PAF.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 Funding
 References
 
Patient groups
The study group consisted of 20 patients (15 women) with a mean age of 54.7 ± 16.6 years scheduled for electrophysiological study and transcatheter ablation (TA) of supraventricular arrhythmias. The patients were divided into two groups: 10 controls without paroxysmal atrial fibrillation (PAF) and 10 patients with a 4–15 year history of between 4 and 30 attacks of PAF per year. Patients with AF in comparison with controls were older (controls 47.6 ± 17.6 years; AF group 66.8 ± 7.0 years; P = 0.0077), had poorer ejection fraction of the left ventricle [echocardiographic left ventricular ejection fraction (LVEF) (%): controls 66 ± 5; AF patients 53 ± 7; P < 0.0001], and had bigger left atria (controls 36.2 ± 5.3 mm; AF group 41.7 ± 5.2 mm; P = 0.0311). In the AF group, arterial hypertension was more frequent than in the control group (controls n = 2; AF group n = 9; P < 0.01). The clinical characteristics of both patient groups are presented in Table 1.


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  		Table 1 Clinical characteristics of patient's groups with and without atrial fibrillation (AF)

 
The protocol was approved by the local Ethics Committee and patients gave informed, witnessed, and written consent for the procedure.

Electrophysiological study and TA
Electrophysiological studies were performed in a fasting state, and antiarrhythmic drugs were discontinued in five half-life periods before the study. No patient was on amiodarone. These were baseline diagnostic study, and PEFA and TA were indicated. Local analgesics, combined with intravenous benzodiazepines and opiates, gave adequate anaesthesia and sedation.

Paced electrogram fractionation study
After the initial EP study, the catheters with 1 cm spaced, bipolar electrodes were positioned at the RA isthmus, the interatrial septum (two sites), the crista terminalis (one site). Three pairs of electrodes were used to pace and record from the coronary sinus: distal pair 1–2 (CSd), middle pairs 5–6 (CSm), and proximal pair 9–10 (CSp) (Figure 1). The study protocol involved delivering a decremental pacing sequence from one site and recording electrograms from the other six sites. The decremental sequence consisted of a drive train with a cycle length of 490 ms (S1S1) with an extrastimulus inserted every third beat whose coupling interval was decreased by 1 ms on each occasion from 470 to 200 ms or to atrial refractoriness. The electrograms were digitized at 1 kHz and stored for further analysis. This process was repeated from each atrial site yielding seven pacing runs. All stored electrograms were reviewed and those that were unsatisfactory due to fusion or failure to capture were rejected.


Figure 1
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  		Figure 1 Diagram showing the principle of paced electrogram fractionation analysis and the positions of electrodes with the right atrium and coronary sinus. RA1 and RA2, right atrial electrodes; CT, crista terminalis; IS1, septal electrode; CSp, CSm, and CSd, proximal, middle, and distal coronary sinus electrodes. The top right hand panel shows the reduction of a conduction curve to two variables (S1S2crit and {Delta}ED) and the bottom right hand panel shows the final result, obtained by averaging all the measurements of S1S2crit and {Delta}ED made in a single patient.

 
The electrograms were processed in an identical manner to that used in ventricular studies8Go,13Go with the object of reducing the 11 340 electrograms recorded in response to an extrastimulus to an ordinal measure that describes the abnormalities of activation within the atria. Step 1: the peaks in each electrogram in response to an extrastimulus were identified and their delays from the stimulus were determined. Step 2: these delays are plotted against the S1S2 at which the electrogram was obtained to generate intra-atrial conduction curves, examples of which are shown in Figures 2 and 3. These curves describe the way in which atrial activation changes with premature stimulation. Step 3: these curves were characterized by fitting interpolating splines to their upper and lower borders and using these splines to derive two parameters: the S1S2 interval at which electrogram duration starts to increase, S1S2crit, and the difference in electrogram duration, {Delta}ED, between those measured at an S1S2 interval of 350 ms and just below atrial effective refractory period. Step 4: the values for S1S2crit and {Delta}ED are averaged to form a single observation per patient.


Figure 2
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  		Figure 2 An intra-atrial conduction curve in a control patient. See text for details on how this is constructed. There is very little change in electrogram morphology or delay as the S1S2 interval is decreased.

 


Figure 3
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  		Figure 3 An intra-atrial conduction curve from a paroxysmal atrial fibrillation patient. Compared with the control patient, there is an increase in electrogram duration and delay that starts to occur at an S1S2 of 350 ms. This is a characteristic pattern that is commonly seen in the ventricle of sudden cardiac death patients.

 

   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 Funding
 References
 
In three patients from the PAF group, AF was induced during PEFA and it was terminated by electrical cardioversion. In other two patients, short runs of SVT were initiated and terminated by atrial pacing. No other complications were noted.

There was no difference in atrial refractory period measured in sinus rhythm at the high right atrium. Patients with PAF have electrograms that prolong with premature stimulation. Figure 4 shows electrograms from a control and a PAF patient and it is clear that the electrograms in the PAF patient become prolonged, more complex, and change delay relative to each other in response to an extrastimulus. The conduction curves of a control (Figure 2) shows that in a control there is very little change in the electrogram as the S1S2 is reduced. In contrast, the curve from a PAF patient (Figure 3) shows that there is increasing delay and electrogram duration that occurs at a relatively long S1S2 interval. The pattern of delay shown in this curve is similar to that seen in the ventricles in patients at risk of sudden cardiac death.


Figure 4
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  		Figure 4 Electrograms recorded at an S1S2 of 270 ms. The electrograms on the left show an S1 and S2 beat from a control, whereas the electrograms on the right show an S1 and S2 beat from a paroxysmal atrial fibrillation patient. Notice the increased delay, change in activation sequence and the fractionation of the electrograms following an S2 beat.

 
Electrograms become increasingly prolonged with increasing {Delta}ED, indicating dispersion of conduction and the presence of a potential re-entrant substrate. Also the increase in duration in PAF patients starts to occur at a longer S1S2 (S1S2crit) when compared with controls. This is shown graphically for three sites: the intra-atrial septum, the low right atrium, and the distal coronary sinus in Figure 5. There is a clear separation between the PAF and control patients, with the PAF patients having a larger increase in electrogram duration, which occurs at a longer S1S2 compared with controls (P < 0.01 ANOVA). The mean value of {Delta}ED and S1S2crit for all electrodes and pacing runs are shown in Figure 5 and there is clear separation between the controls and the PAF group with a mean S1S2crit of 275 ms and {Delta}ED 17 ms for controls and S1S2crit of 324 and {Delta}ED 25 ms for the PAF group (P < 0.01) (Figure 6).


Figure 5
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  		Figure 5 Scattergram of the mean increase of {Delta}ED of each pacing run in electrogram duration vs. S1S2 at which electrogram duration increases for each patient, S1S2crit (as shown in Figure 1—right hand panels). The data are shown for three channels only (right atrium, crista terminalis, and distal coronary sinus).

 


Figure 6
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  		Figure 6 Position of the {Delta}ED and S1S2crit averaged for all the runs and electrode positions for each patient.

 
Finally, the mean delays with 95% confidence limits of the intrinsic potential and the mean longest delays from the pacing stimulus to the electrogram are plotted in Figure 7. This shows, again, that there are significantly greater delays in atrial activation in PAF patients than controls and, in particular, there may be very long absolute delays in the terminal components of the electrogram.


Figure 7
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  		Figure 7 Diagram showing the mean maximum absolute delay in activation (to intrinsic deflection) and to the terminal electrogram component for all runs in every patient. The bars represent the 95% confidence limits of the distributions of each measurement. There is a significantly greater delay in the paroxysmal atrial fibrillation group compared with controls.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 Funding
 References
 
The objective of PEFA is to detect a substrate for fibrillation without inducing an arrhythmia. There is a strong association between the risk of VF and fractionation in the ventricles and therefore it seemed possible that there would be a similar relationship between AF and fractionation in the atria. The present study has shown that there are definite diffuse abnormalities in the atria that are associated with PAF. Although PAF arises from foci in the pulmonary veins, this study suggests that the atria as a whole show delays that are compatible with re-entry, increasing their vulnerability to AF that is triggered by activity in the pulmonary veins. These data are compatible with, and supports, earlier work that has shown delayed conduction in the atria of patients at risk of PAF.14Go–16Go However, in this study, the duration of fractionated electrograms was also determined, which appear to be important since this represents dispersion of conduction which is a pre-requisite for re-entry, whereas slowed conduction, per se, does not necessarily imply a re-entrant substrate.

The electrodes in the study were placed to record from the right and left atria and, strikingly, there were no sites with increased fractionation compared with the rest unlike the findings of Papageorgiou et al.17Go and Tai et al.18Go Although there is limited information from the left atrium, trans-septal puncture being unjustifiable in a preliminary investigative study, the results suggest that the atria are diffusely diseased in PAF and are capable of causing slowed conduction, with a reduction of effective re-entrant wavelength, and maintaining re-entry as has been shown by intra-operative mapping of AF and experimental preparations. This suggests that linear ablation lesions of sites remote from the pulmonary venous ostia may increase the effectiveness of ablation for established AF.19Go

There are differences between the baseline characteristics of PAF patients and controls, who were generally younger and had higher LVEFs. The onset of PAF may represent more general cardiac disease and the selection of elder patients with evidence of minor functional abnormalities reflects that these patients are more prone to PAF. Despite being a national referral centre, it was found that exact matching of controls was impossible, although there is considerable overlap between the two patient groups. Ideally, a new control group should be studied which has identical blood pressure and LVEF to the PAF group but without AF, although they would have no formal indication for EP study. Therefore, the question of association between conduction abnormalities and PAF is still open as it can be argued that the results may be due to increased age and reduced LVEF of the patient group with respect to the controls rather than the presence of PAF. Another objection is that the changes seen in the PAF group were due to AF itself. Although it is known that there is rapid electrophysiological modelling in AF, which reverses once AF is terminated,20Go none of the patients was, or had recently been, in AF at the time of study. Consequently we would attribute the abnormal fractionation in PAF patients to intrinsic myocardial abnormalities arising from disease as opposed to electrical modelling due to relatively infrequent episodes of AF.

The fractionation technique measures the change in activation as a result of premature stimulation. The absolute delays clearly depend on the path length between the stimulating and recording electrodes, and although there was a small increase in left atrial size in PAF patients, this could not account for the delays seen in the intrinsic potential and terminal components of the electrogram. The fractionation method quantifies dispersion of activation time, which is caused by two effects: the slowing of conduction in the relative refractory period of the tissue and the dynamic increase in path length that is imposed by structural abnormalities or collision with locally refractory tissue. The latter is strongly supported by intense fractionation seen in the LQTS,13Go and by mathematical modelling,21Go and is attributable to dispersion of refractoriness, also suggesting that in diseases where there is a significant structural abnormality, dispersion of refractoriness may cause activation to switch between different routes through the myocardium. This concept is completely compatible with the measurements of the activation interval statistics measured during AF,22Go–25Go which is interpreted as dynamic changes in refractoriness but also includes the changes in activation path lengths between successive activations at a particular point.

There is very little information about the structural and electrophysiological changes in the atria during PAF rather than in established AF. A biopsy study in PAF has shown that there is inflammatory cell infiltration and, in some cases, interstitial fibrosis in the septum, and it was suggested that the cellular changes would cause localized slowed conduction and block so forming an arrhythmic substrate.26Go In post-mortem studies of patients with AF due to a number of causes, there is often substantial interstitial fibrosis with myocyte hypertrophy, which, again, is compatible with a re-entrant substrate. The patients in this study, who had structural abnormalities of the atria and so are at risk of developing established AF, probably have an intermediate form between these two pathologies.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
Funding
 References
 
This study has shown that there are diffuse increased activation delays in the atria of patients prone to AF and that these may act as one component of the substrate for AF. However, in view of the difficulties in obtaining precisely matched controls, other factors such as age and LVEF may also contribute to these changes.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Funding
References
 
This work was supported by The Polish Ministry of Education and Science (3PO5C 008 23) (www.mnisw.gov.pl).

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Funding
 References
 
[1] Flaker GC, Blackshear JL, McBride R, Kronmal RA, Halerin JL, Hart RG. Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation: the Stroke Prevention in Atrial Fibrillation (SPAF) Investigators. J Am Coll Cardiol (1992) 20:527–32.[Abstract]

[2] Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation (1995) 92:1954–68.[Abstract/Free Full Text]

[3] Allessie MA. Reentrant mechanisms underlying atrial fibrillation. In: From Cell to Bedside.—Zipes DP, Jalife J, eds. (1995) Philadelphia: Saunders. 562–6.

[4] Haissaguerre M, Jais P, Shah DC, Takahashia A, Hocini M, Quiniou G, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med (1998) 339:659–66.[Abstract/Free Full Text]

[5] Cox JL, Canavan TE, Schuessler RB, Cain ME, Lindsay BD, Stone C, et al. The surgical treatment of atrial fibrillation: II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg (1991) 101:406–26.[Abstract]

[6] Jalife J. Ventricular fibrillation: mechanisms of initiation and maintenance. Annu Rev Physiol (2000) 62:25–50.[CrossRef][Web of Science][Medline]

[7] Spach MS, Josephson ME. Initiating reentry: the role of non-uniform anisotropy in small circuits. J Cardiovasc Electrophysiol (1994) 5:182–209.[Web of Science][Medline]

[8] Saumarez RC, Camm AJ, Panagos A, Gill JS, Stewart JT, de Belder MA, et al. Ventricular fibrillation in hypertrophic cardiomyopathy is associated with increased fractionation of paced right ventricular electrograms. Circulation (1992) 86:467–74.[Abstract/Free Full Text]

[9] Saumarez RC, Slade AK, Grace AA, Sadoul N, Camm AJ, McKenna WJ. The significance of paced electrogram fractionation in hypertrophic cardiomyopathy. A prospective study. Circulation (1995) 91:2762–8.[Abstract/Free Full Text]

[10] Saumarez RC, Heald S, Gill JS, Slade AK, de Belder MA, Walczak F, et al. Primary ventricular fibrillation s associated with increased paced right ventricular electrogram fractionation. Circulation (1995) 92:2565–71.[Abstract/Free Full Text]

[11] Saumarez RC, Chojnowska L, Derksen R, Pytkowski M, Sterlinski M, Huang CL, et al. Sudden death in noncoronary heart disease is associated with delayed paced ventricular activation. Circulation (2003) 107:2595–600.[Abstract/Free Full Text]

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[13] Saumarez RC, Pytkowski M, Sterlinski M, Hauer RN, Derksen R, Lowe MD, et al. Delayed paced ventricular activation in the long QT syndrome is associated with ventricular fibrillation. Heart Rhythm (2006) 3:771–8.[CrossRef][Web of Science][Medline]

[14] Cosio FG, Palacios J, Vidal JM, Cocina EG, Gomez-Sanchez MA, Tamargo L. Electrophysiologic studies in atrial fibrillation. Slow conduction of premature impulses: a possible manifestation of the background for reentry. Am J Cardiol (1983) 51:122–30.[CrossRef][Web of Science][Medline]

[15] Cosio FG, Llovet A, Vidal JM. Mechanism and clinical significance of atrial repetitive responses in man. Pacing Clin Electrophysiol (1983) 6:53–9.[CrossRef][Medline]

[16] Buxton AE, Waxmman HL, Marchlinski FE, Josephson ME. Atrial conduction: effects of extrastimuli with or without atrial dysrhythmias. Am J Cardiol (1984) 54:755–61.[CrossRef][Web of Science][Medline]

[17] Papageorgiou P, Monahan K, Boyle NG, Seifert MJ, Beswick P, Zebede J, et al. Site-dependent intra-atrial conduction delay: relationship to initiation of atrial fibrillation. Circulation (1996) 94:384–9.[Abstract/Free Full Text]

[18] Tai Ch-T, Chen Sh-A, Tzeng J-W, Kuo BL, Ding YA, Chang MS, et al. Prolonged fractionation of paced right atrial electrograms in patients with atrial flutter and fibrillation. J Am Coll Cardiol (2001) 37:1651–7.[Abstract/Free Full Text]

[19] Calò L, Lamberti F, Loricchio ML, De Ruvo E, Colivicchi F, Bianconi L, et al. Left atrial ablation versus biatrial ablation for persistent and permanent atrial fibrillation. J Am Coll Cardiol (2006) 47:2504–12.[Abstract/Free Full Text]

[20] Hobbs WJC, Fynn S, Todd DM, Wolfson P, Galloway M, Garratt C. Reversal of atrial electrical remodeling after cardioversion of persistent atrial fibrillation in humans. Circulation (2000) 101:1145–51.[Abstract/Free Full Text]

[21] Turner IC, Huang CL-H, Saumarez RC. Numerical simulation of paced electrogram fractionation: relating clinical observations to changes in fibrosis and action potential duration. J Cardiovasc Electrophysiol (2005) 16:151–61.[CrossRef][Web of Science][Medline]

[22] Ramdat Misier AR, Opthof T, van Hemel HF, Defauw JJAM, de Bakker JMT, Janse MJ, et al. Increased dispersion of ‘refractoriness’ in patients with idiopathic paroxysmal atrial fibrillation. J Am Coll Cardiol (1992) 19:1531–5.[Abstract]

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[24] Firouzi M, Ramanna H, Kok B, Jongsma HJ, Koeleman BPC, Doevendans PA, et al. Association of human Connexin40 gene polymorphisms with atrial vulnerability as a risk factor for idiopathic atrial fibrillation. Circ Res (2004) 95:e29–e33.[Abstract/Free Full Text]

[25] Ramanna H, Hauer RNW, Wittkampf FHM, de Bakker JMT, Wever EFD, Elvan A, et al. Identification of the substrate of atrial vulnerability in patients with idiopathic atrial fibrillation. Circulation (2000) 101:995–1001.[Abstract/Free Full Text]

[26] Frustaci A, Chimenti C, Bellocci F, Morqante E, Russo MA, Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation (1997) 96:1180–4.[Abstract/Free Full Text]


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