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Focal atrial tachycardia Insights concerning the arrhythmogenic substrate based on analysis of intracardiac electrograms and inflammatory markers Ioan Liuba Division of Cardiology Department of Medicine and Care Faculty of Health Sciences Linköping University, Sweden ISBN 978-91-7393-556-2 ISSN 0345-0082 Printed by LiU-Tryck, Linköping 2009 “…I turned my mind to know and to search out and to seek wisdom and the sum of things…” Ecclesiastes 7:25 – The Bible To Laura TABLE OF CONTENTS LIST OF PAPERS………………………………………………………………………....…8 INTRODUCTION………………………………………………………………………........9 Incidence…………………………………………………………………………......... 9 Diagnosis…………………………………………………………………………….....9 Mechanism……………………………………………………………………….…...14 Anatomical localization………………………………………………………………17 Clinical features………………………………………………………………………18 Natural history………………………………………………………………………..18 Complications………………………………………………………………………...19 Pharmacological therapy………………………………………………….…….....….19 Catheter ablation……………………………………………………………………....21 AIMS OF THE STUDY………………………………………………………………….…27 MATERIAL AND METHODS…..…………………………………………………………..………...29 Patients…………………………………………………………………………….......29 Methods…………………………………………………………………….……....…30 Statistical analyses………………………………………………………….…………34 RESULTS………………………………………………………………………….………..35 GENERAL DISCUSSION…………………..……………………………………………...58 The role of inflammation in the pathogenesis of atrial fibrillation and focal atrial tachycardia………………………………………………………………..…………...59 The electrophysiologic proprieties of the atrial substrate in patients with focal atrial tachycardia………………………………………………………….……..63 The impact of the method of estimating activation time during the mapping of focal atrial tachycardia…………………………………………………….………68 3 Observer variability in activation time determination during mapping of focal atria tachycardia ………………………………………………..….70 CONCLUSIONS…………………………………………………………………………....73 REFERENCES……………………………………………………………………………...75 ORIGINAL PAPERS……………………………………………………………………….97 4 Abstract Background: Focal atrial tachycardias are tachycardias characterized by a radial spread of activation from a discrete area of the atrial myocardium. They account for 10-15% of supraventricular tachycardias and are generally poorly responsive to pharmacological treatment. The pathophysiologic substrate of these arrhythmias remains poorly understood. Computational studies suggest that a certain degree of intercellular uncoupling and anisotropy are important prerequisites for the development of focal arrhythmias. The anisotropy and intercellular uncoupling could promote focal arrhythmias by minimizing the suppressive effect of the surrounding atrial muscle on the pacemaking process in the focus. This hypothesis would be in agreement with the fact that fractionated electrograms, a marker of anisotropy and reduced intercellular coupling, are often recorded at the site of earliest activated site. Reduced intercellular coupling could be induced by factors enhancing the amount of intracardiac connective tissue, such as advancing age or cardiac disease states. Indeed, focal inflammatory processes have been reported in atrial specimens resected from patients with focal tachycardia undergoing arrhythmia surgery. Methods: In a group of patients with paroxysmal and permanent atrial fibrillation we sought to assess whether there is a link between inflammation and the occurrence of atrial arrhythmia. We therefore analyzed different inflammatory markers (C-reactive protein and interleukin-6 and 8) in the systemic and pulmonary circulation as well as in the heart in these patients. In addition, we assessed the extent of intercellular uncoupling in the vicinity of tachycardia origin in patients with focal atrial tachycardia. We also assessed the impact of electrogram fractionation on the method of activation time determination, by comparing different methods for estimating activation time with regard to the appearance of the resultant 5 activation maps and the location of the foci. We also assessed the observer variability in the estimation of activation time during mapping of these tachycardias. Results: There was no evidence of elevated circulatory levels of inflammatory markers in patients with paroxysmal atrial fibrillation. However, patients with permanent atrial fibrillation had increased levels of inflammatory markers (interleukin-8) in the systemic circulation but not in the pulmonary circulation or in the heart. In patients with focal atrial tachycardia, a higher degree of electrogram fractionation existed in the region surrounding the earliest activation site and activated within the first 15 ms as compared with the remaining atrium. Moreover, within this region, from the periphery towards the earliest activated site, there was a gradual increase in electrogram fractionation as well as a gradual decrease in the peak-to-peak voltage. When comparing different methods for estimating local activation time we found that different methods can generate activation maps with different appearances and foci with different locations. However, regardless of the method of activation time determination, the foci tend to cluster within relatively large areas of low-amplitude fractionated electrograms. In addition we found significant observer variability in the estimation of the local activation time. Conclusion: Patients with paroxysmal atrial fibrillation (and probably focal atrial tachycardia) do not have elevated levels of inflammatory markers. The increased levels of interleukin-8 in the systemic circulation suggest a link between long-lasting arrhythmia and inflammation. A relatively wide area of increased electrogram fractionation exists around the site of origin of focal atrial tachycardia. These findings suggest a sizeable atrial region with particular electrophysiological proprieties and raise the possibility of an anatomical substrate of the tachycardia. Increased electrogram fractionation can impact the process of activation 6 determination, as suggested by the fact that different methods compute foci with different locations. In addition, there is significant observer variability in the estimation of local activation time in these patients. 7 LIST OF PAPERS This thesis is based on the following papers, referred to in the text by their Roman numerals: I. Liuba I, Ahlmroth H, Jonasson L, Englund A, Jönsson A, Säfström K, Walfridsson H. Source of inflammatory markers in patients with atrial fibrillation. Europace 2008;10:848-53. II. Liuba I, Walfridsson H. Focal atrial tachycardia: increased electrogram fractionation in the vicinity of the earliest activation site. Europace. 2008;10:1195-204. III. Liuba I, Walfridsson H. Activation mapping of focal atrial tachycardia: The impact of the method for estimating activation time. J Interv Card Electrophysiol. (In press). IV. Liuba I, Jönsson A, Walfridsson H. Electroanatomic mapping of focal atrial tachycardia: Reproducibility of activation time measurement and focus localization. Submitted. 8 INTRODUCTION Atrial tachyarrythmias are arrhythmias involving the working atrial myocardium but not the atrioventricular junction. According to the electrophysiologic mechanism and the anatomic substrate, atrial tachycararrhythmias can be divided into regular tachycardias (focal and macroreentrant atrial tachycardias and tachycardias involving the sinus node) and atrial fibrillation (AF).1,2 The term “focal” refers to tachycardias with a radial spread of activation from a discrete region of atrial myocardium (usually <1cm with the currently available catheters)3 and which are thus amenable to focally directed ablation.. Incidence Focal atrial tachycardia (FAT) accounts for 5-17% of the supraventricular tachycardias observed in electrophysiological laboratory.3,4 The incidence seems higher in young children and in patients aged 60 or more.3 Interestingly, in a group of 3554 young asymptomatic males applying for pilot license, 12 (0.43%) had ECG elements consistent with the diagnosis of FAT.5 Diagnosis Traditionally, these tachycardias have been recognized by the presence of distinct P waves with abnormal morphology/axis separated by an isoelectric baseline (Figure 1) and the existence of sporadic (spontaneous or pharmacologically induced) atrioventricular block that does not affect the tachycardia.6-8 A history of cardiac disease, an incessant pattern, prior failed cardioversions, identical morphology of the first and the subsequent P waves during 9 tachycardia and large variations of the rate and PR interval on ECG lend further support to the diagnosis of FAT.3,6-9 Figure 1. Twelve-lead ECG from a patient with focal AT originating in the superolateral aspect of the tricuspid annulus. Note the positive P waves in lead V1, suggesting a right atrial focus. Also, the P waves are positive in lead –aVR, indicating a lateral origin in the right atrium (Cabrera leads are used: -aVR instead of aVR). Arrows indicate the P waves. The ECG provides a rough estimate of the origin of the tachycardia (Figure 2). On of the most useful ECG leads in this regard is V1. Thus, a negative or biphasic P-wave in V1 is associated 10 with 100% specificity for a right atrial focus. A positive P-wave in lead V1 is associated with a 100% sensitivity for a the left atrial focus.11,12 Tachycardias originating in the right 10 superior pulmonary vein generate narrow, positive P-waves in leads I and aVL; a transition from a biphasic P during sinus rhythm to a positive and narrower P in V1 during tachycardia can be observed at the onset of tachycardia (Figure 3).11,13 A positive P in the inferior leads can differentiate superior from inferior foci.11,14,15 Furthermore, a negative P wave in aVR suggests a focus situated along the crista terminalis.14 In the electrophysiology laboratory, FAT is recognized by: a) an atrial activation sequence different from that during sinus rhythm b) tachycardia initiation independent of atrioventricular nodal conduction c) persistence of tachycardia despite sporadic atrioventricular block. The diagnosis of FAT will finally require the demonstration of a radial spread of activation from a discrete atrial region.3,16 However, in FAT with 1:1 atrioventricular conduction, if the site of origin is situated in the Koch’s triangle, further work-up is necessary in order to exclude a tachycardia involving a septal accessory pathway or atrioventricular nodal reentry tachycardia. Several pacing techniques may be used in this regard. The following findings support the diagnosis of atria tachycardia: a) an ‘atrial-atrial-ventricular’ sequence upon cessation of transient ventricular overdrive pacing with 1:1 ventriculoatrial conduction during tachycardia b) a different atrial activation sequences during ventricular pacing and during tachycardia c) ventriculoatrial dissociation during transient ventricular overdrive pacing (provided that tachycardia is not interrupted during pacing) d) a ventriculoatrial interval during tachycardia different than the ventriculoatrial interval of the return cycle length after transient atrial overdrive pacing.17-20 11 The diagnosis of atrial tachycardias (and hence FAT) is excluded when: a) tachycardia can be reset by delivering a ventricular premature beat during His refractoriness b) tachycardia can be terminated by a ventricular premature beat or ventricular overdrive pacing without depolarizing the atria c) an atrial-ventricular sequence is observed upon cessation of transient ventricular overdrive pacing with 1:1 ventriculoatrial conduction.18,19 12 Positive P in I, aVL or Negative/bifasic/isoelectric P in V1 yes no RA LA Negative/isoelectric P in aVR (positive P in Cabrera leads) Negative P in II, III, aVF yes no yes MEDIAL TA or SEPTAL Negative P in V1 yes no P wave duration in II, III, aVF ratio tachycardia/sinus<0.85 yes Negative P in II, III, aVF SUPERIOR CT SUPERIOR LA RAA or LATERAL TA CT yes INFERIOR LA no APEX OF KOCH TRIANGLE no no no OTHER SEPTAL SITES or MEDIAL TA INFERIOR CT Figure 2. Stepwise algorithm for localization of ectopic foci. Modified from Tang et al. 11, Fitzgerald et al. 12, Tada et al. 14 and Hsieh et al. 20. RA= right atrium; LA=left atrium; CT= crista terminalis; TA= tricuspid annulus. 13 Figure 3. Left panel: twelve–lead ECG showing a focal AT with P-P interval 220 ms and sporadic AV block (Cabrera leads are used: –aVR instead of aVR). Right panel: atrial bigeminy with extrabeats (arrows) showing the same P wave morphology as during tachycardia. The focus was situated at the ostium of the right superior pulmonary vein. Note that in lead V1 the P waves are biphasic during sinus rhythm and positive during tachycardia and extrabeats. Arrows indicate the extrabeats. Mechanism Three possible electrophysiological mechanisms are involved in the genesis of FAT. Automaticity refers to spontaneous impulse initiation due to diastolic depolarization in subsidiary pacemakers (enhanced normal automaticity) or in working atrial cells without pacemaking capability but whose membrane potential is partially depolarised to levels of -70 -40mV by some pathological process (abnormal automaticity).21 Subsidiary pacemakers have been identified in several atrial regions such as the crista terminalis, the coronary sinus ostium, the junction of the right atrium and the inferior vena cava, the pulmonary veins, as 14 well as in the mitral and tricuspid anulus 21. Automatic tachycardias can be facilitated by adrenergic surge. Triggered activity refers to oscillations of the membrane potential (afterdepolarizations) appearing either during repolarization (that is, phase 2 and 3 of the action potential - early afterdepolarization) or after repolarization is completed (that is, phase 4 - delayed afterdepolarization). When these oscillations reach a certain threshold level they initiate an action potential.21 Such tachycardias may play a role during digitalis toxicity.22 Microreentry. In isolated human atrial myocardium with nonuniform anisotropic proprieties, Spach et al. 23 were able to induce stable reentrant ATs in areas as small as 1.6 mm2. In the intact human heart these tachycardias may arise due to an increase in the fibrous connective tissue between cardiac fibers, which results in a disruption of the gap junctional communication between adjacent cells 23,24. This will augment the normal difference in the cell-to-cell current transfer capabilities over the transverse and longitudinal directions, rendering such regions susceptible for conduction block and reentry. The direct demonstration of the electrophysiological mechanism in clinical tachycardias has been reported only in patients undergoing surgical ablation. Automatic discharges were detected by means of microelectrode recordings in atrial specimens resected from some patients with medically refractory FAT,25-27 while microreentry was directly evidenced only in the ventricle, during simultaneous multisite mapping procedures, in patients with previous myocardial infarction and ventricular tachycardias.28 In the clinical electrophysiology laboratory, however, such sophisticated recording techniques cannot be used, and therefore 15 the mechanism can be inferred indirectly on the basis of ECG appearance and the response to pacing or pharmacological substances. In this regard, automaticity is suggested by: a) the impossibility of tachycardia initiation with pacing22 b) a gradual acceleration immediately after initiation and slowdown before termination (“warm-up” and “slow-down” phenomena)22 c) impossibility of entrainment or termination with pacing 29,30; however, the pacing may suppress such tachycardias with their resumption after pacing termination (“transient suppression”). The differentiation between triggered activity and micro-reentry is more difficult, since both can be initiated and terminated with electrical stimulation.31 Reentry may be suspected in the presence of the following findings: a) tachycardia can be initiated and terminated reproducibly with pacing22 b) tachycardia can be entrained (although sometimes entrainment is difficult to demonstrate de to the small size of the circuit). Triggered activity, on the other hand, is suggested by the following criteria: a) initiation with pacing along with the demonstration of cycle-length dependency22 b) impossibility to entrain the tachcardia c) some authors were able to demonstrate afterdepolarizations on monophasic action potential recordings immediately before the onset of tachycardia.17 Concerning the response to pharmacological substances Chen et al17 demonstrated that adenosine and verapamil cannot terminate tachycardias due to automaticity but can interrupt most triggered activity and microreentry tachycardias (Table 1). Propranolol, on the other side, could terminate all types of focal tachycardias. 16 Table 1 Electrophysiological and pharmacological patterns of atrial tachycardias Mechanism Induction Propranolol Induction with pacing with ISO Term Reinduc Verapamil Term Reinduc Automaticity 0% 100% 100% 0% 0% 100% Trig. activity 100% 22% 100% 66% 100% 0% Reentry 100% 48% 100% 96% 11% 2/10 pts* Adapted from Chen et al. 17. Trig activity =Triggered activity; ISO = isoprenalin; Term = termination of the tachycardia; Reinduc = reinduction of the tachycardia under drug infusion. * Isoprenalin needed to sustain the tachycardia in 2 patients It has to be mentioned, however, that, at present, the clinical relevance of the data concerning the underlying mechanism remains unknown. The immediate outcome of the catheter ablation in these tachycardias does not seem to depend on the putative electrophysiologic mechanism.17 Anatomical localization The ectopic foci are not randomly distributed but seem to cluster in certain regions, such as along the crista terminalis, around the coronary sinus ostium or the atrioventricular rings and around the ostia of or inside the pulmonary veins. This preferential distribution may be related to local particularities in cardiac fiber arrangement and cell-to-cell coupling accounting for anisotropic conduction, as will be discussed in the next chapters.1,2 17 Clinical features FAT has been reported in subjects with structurally normal hearts as well as in patients with ischemic or congenital heart disease, hypertrophic cardiomyopathy, atrial tumors, myocarditis, septal or appendage aneurysms and valvular, metabolic and bronchopulmonary diseases.4,32-37 The clinical presentation may be paroxysmal (episodes with abrupt onset and termination, lasting minutes to hours), repetitive (brief, frequent episodes separated by short runs of sinus beats), or incessant (tachycardias that are present more than 90% of the day).1,7,8 Symptoms are described more frequently in incessant and/or fast tachycardias and they can range from palpitations to exercise intolerance, fatigue, dizziness, presyncope and even syncope.8,38 Some patients may by asymptomatic, especially small children and patients with not very fast tachycardias.36,39 Natural History In some patients a spontaneous remission of the tachycardia may occur.4,5,39,40 Klersy et al4 found that the age is the only independent factor predicting the possibility of remission: in a group of 46 patients, disappearance of tachycardia was observed in 55% of patients under 25 years of age and in only 14% of patients aged 25 years or older. During a follow-up period that ranged of 3-11 years, Poutianien et al5 noted that, in some patients, the ECG showed a slowdown of the ectopic rate and a change in the P-wave morphology, suggesting fusion of sinus and ectopic beats. The authors hypothesized therefore that the substrate of remission might be a progressive degeneration of the focus with a gradual slowdown of the firing rate. 18 Complications FAT are frequently incessant and refractory to pharmacological therapy 8,34,41. Therefore, if uncontrolled, they may lead to a form of dilated cardiomyopathy referred to as tachycardiainduced cardiomyopathy or tachycardiomyopathy. It was estimated that FAT account for 14% of cases of tachycardiomyopathy in children and 5% in adults; however, curative catheter ablation is generally followed by a rapid improvement of both the clinical and echocardiographic picture.36,39,42-49 Pharmacological therapy The effect of pharmacological therapy on FAT is difficult to assess because of the small series of patients that have been published, different endpoints (rate control of rhythm control) and lack of controlled trials. The general agreement in the literature is that single drugs are frequently ineffective, especially in incessant forms. Therefore, in order to avoid aggressive antiarrhythmic therapy, patients who fail short trials with mild drugs should be referred early to catheter ablation. However in small children without cardiomyopathy and in patients who fail ablation, the antiarrhythmics remain the main alternative and a review of the available data in the literature in this regard becomes relevant. a). Digoxin, class IA and class IV antiarrhythmics. Digoxin is ineffective in most cases in suppressing the tachycardia 50-53. Class IA and IV (calcium blockers) are also generally ineffective 7,40, although in one study on adults, verapamil iv could terminate some forms of focal AT.17 However, digoxin and calcium channel blockers may slow down the ventricular rate during the tachycardia.54 19 b). Beta-blockers seem to have variable effects both in children and adults.8,38,39,52 As mentioned previously, in their study on 36 patients with AT, Chen et al.17 reported that Propranolol iv (0,2 mg/kg) could interrupt all tachycardias due to automaticity and DADs as well as 48% of reentrant tachycardias, suggesting thus a mechanism-dependent effect (table 2). Nevertheless, after Propranolol, 66% of the tachycardias due to triggered activity could be reinduced, possibly due to the fact that the ionic channels involved in triggered activity tachycardias are less dependent on beta adrenergic stimulation. Beta-blockers are generally used as first-line agents both acutely and chronically, alone or in combination with other antiarrhythmics.52,55 c). Class IC antiarrhythmics. Compared to beta-blockers, class IC antiarrhythmics appear to be more frequently effective in these tachycardias. For propafenone, the success rate in children ranges between 33 and 89%.52 The lack of simultaneous heart disease and age <1year are associated with greater efficacy.52,56 The efficacy of flecainide varies between 25100%.52,57 These drugs could be used as second line agents (after beta-blockers).37,52,54,55,58,59 d). Class III. The efficacy of amiodarone in focal ATs ranges between of 45-100%.52,60 It appears to be better tolerated by pediatric patients (especially small children) than in adult patients, where it is metabolized more slowly.8,60-62 Nevertheless, amiodarone is known to have potentially serious non-cardiac side effects, which appear more frequently during longterm therapy. For these reasons, it should be reserved for patients who are refractory to other antiarrhythmic drugs and in whom radiofrequency catheter ablation is unsuccessful or not indicated. In cases of severe left ventricular dysfunction it may be started intravenously.52,54 20 Regarding the efficacy of sotalol, fewer reports are available in the literature. In five studies on children reviewed by Luedtke et al,63 tachycardia termination or at least rate control were reported in 33-100% of cases. In another study, sotalol was ineffective in controlling the tachycardia.39 Some authors consider it to have the same efficacy and safety as class IC antiarrhythmics and recommend it as a second-line agent.54,58 In children, on the other hand, Luedtke et al52 expressed concerns regarding side effects and recommended it only in cases refractory to betablockers and class IC antiarrhythmics. Catheter Ablation Because of the high success rate and low risk of complications, radiofrequency catheter ablation tends to be the first line therapy in focal ATs. The clinical tachycardia should be well documented prior to the electrophysiological study (resting and stress ECG, Holter or oesophageal ECG) in order to assess the probable location of foci (depending on the P-wave morphology) and to establish the target tachycardia, since aggressive induction protocols in the electrophysiology laboratory may initiate non-clinical tachycardias. When tachycardia is not present at baseline, or is not sufficiently sustained, several provocative maneuvers may be employed: Isoprenaline in increasing doses, atropine, epinephrine, theophylline, orciprenalin, programmed electrical stimulation from different atrial sites and even vagal maneuvers (Valsalva, carotid sinus massage).3,64,65 Nevertheless, such procedures are not always successful. Occasionally, this may be due to residual antiarrhythmic drug effects, premedication or pharmacological substances administered during the EP study. 21 Some authors have reported that Propofol anaesthesia has also a suppressant effect on these tachycardias.66 Conventional Mapping Detailed mapping is necessary during tachycardia in order to locate and delineate the focus. Several multipolar catheters are deployed in the atrium in order to obtain stable endocardial electrogram references, including a multipolar catheter inside the coronary sinus that will record signals from the left atrium. The mapping catheter is successively moved during tachycardia, targeting the site of earliest atrial activation preceding the surface P-wave or a stable intracardiac reference electrogram (“activation mapping”).67,68 There is a variant of this technique, in which 2 mapping catheters are used: while one found an early and stable electrogram, the other is moved in order to find an even earlier potential (“encircling mapping”).68 If such an early zone is located in the atrial septum, the left atrium should also be mapped.67,68 Radiofrequency current is applied at the site of the earliest activation (usually preceding the Pwave onset by 10-75 ms)67-69 or at the site displaying a paced P-wave and/or endocardial atrial activation matching the P-wave and/or the endocardial sequence of activation during tachycardia. A QS-like unipolar signal with a sharply negative initial deflection is highly predictive of a successful ablation site 68. If necessary, mapping of the left atrium is performed through a transseptal puncture or a patent foramen ovale. The endpoints are the termination of tachycardia and inability for reinduction. 22 Electroanatomic Mapping Two nonfluoroscopic mapping systems have been used in patients with focal ATs. The CARTO system (Biosense Webster) consists of an ultra low magnetic field source and a special roving catheter containing a miniature magnetic field sensor at its distal end. The location and orientation of the catheter are accurately determined in the magnetic field during the same part of each cardiac cycle, without the use of fluoroscopy. For each acquired point the system records its spatial location, the local bipolar and unipolar electrograms and the local activation time (LAT). Both the spatial and electrophysiological information are used to reconstruct the 3D geometry of the atrium and a colour-coded map of the endocardial activation (Figures 4 and 5). The site of earliest activation site is identified, with the rest of the myocardium displaying progressively later activation times. Figure 4. Left panel. Modified left anterior oblique view of the activation map of the both atria during a septal FAT. Right panel. The left atrium viewed in an anteroposterior projection. Tubular icons depict pulmonary veins. Both sides of the septum are activated earlier than other atrial sites. However, the left septum activation (where tachycardia was successfully ablated) preceded the right side activation with 15 ms. 23 The possibility of displaying both the anatomical and electrophysiological information, to tag different cardiac structures or previous ablation points and to renavigate the catheter to previously acquired points are very useful. Generally the fluoroscopy time is less than 30 minutes, depending on the mapping strategy and the level of operator experience. The main limitation of this system is the fact that, employing a point-to-point mapping approach, the procedure requires an incessant tachycardia or at least frequent monofocal extrabeats. Figure 5. FAT originating at the ostium of the left superior pulmonary vein. Left atrium viewed in a posteroanterior (left panel) and superior projection (right panel). Blue dots indicate points where double potentials were recorded. The EnSite system (St Jude Medical) uses multi-electrode array catheter that is capable of recording far-field endocardial signals. By processing the signals using a mathematical equation, the system is able to compute and interpolate instantaneously over 3000 virtual 24 electrograms from the entire mapped chamber.70 The information is presented as isopotential or isochronal maps superimposed on the geometry of the atrium. The advantage of using the Ensite system resides in its ability to simultaneously compute electrograms from multiple sites during one cycle of the tachycardia, allowing for mapping of tachycardias that are not sustained or are poorly tolerated. Nevertheless, as previous studies have shown, the accuracy of electrogram reconstruction is influenced by filtering settings and the distance from the multielectrode catheter to the endocardium.71-73 Ablation Results and Complications According to an analysis performed by the author on 713 patients who underwent catheter ablation of FAT reported in 28 studied, the pooled success rate was 88%. 9,64,67-69,74-97 The recurrence rate was 8%. Complications are reported in 1% of patients and consist of damage of the right or left phrenic nerve, sinus node dysfunction (during ablation of high cristal tachycardias) and atrioventricular block (ablation of septal tachycardias).3 In agreement with our estimations, the recent AHA/ACC/ESC guidelines for the management of patients with supraventricular arrhythmias report an overall acute success rate of 86% and a recurrence rate of 8%.55 In children, one report mentions an immediate success rate of 88% with a recurrence rate of 25% over 4 years.98 It should be remarked that due to a high rate of spontaneous remission and concerns about the long-term effects of radiofrequency catheter ablation on an immature myocardium, there is a tendency to avoid radiofrequency ablation in children without tachycardiomyopathy or severe antiarrhythmic drug side effects.54,58,98,99 On the contrary, in adults with recurrent episodes of tachycardias, radiofrequency catheter ablation is 25 recommended as first line-therapy.37,52,55,100,101 Moreover, in cases with incessant tachycardias, ablation should be undertaken even in asymptomatic patients.55 In patients with tachycardias refractory to pharmacological treatment and in whom radiofrequency catheter ablation has failed, AV node ablation and pacemaker implantation may be considered.68 26 AIMS OF THE STUDY As mentioned above, the pharmacological therapy is often not effective53 and catheter ablation is therefore recommended as first-line therapy for patients with recurrent symptomatic arrhythmias and for those with incessant forms, at risk of developing tachycardia-induced cardiomyopathy.55 The acute success rate of catheter ablation is 88%.9,64,67-69,74-97 In comparison, the success rate for other supraventricular tachycardia ranges between 95 and 98%.55 In addition, the long-term recurrence rate of FAT after a successful catheter ablation is considered significant.93,102 The lower success rate of catheter ablation in patients with FAT as compared with patients with other supraventricular tachycardias and the relatively high recurrence rate may have several explanations, such as: a poor understanding of the pathogenesis of FAT, the possibility of a large anatomic substrate,93,102 the existence of concomitant inflammatory processes and other associated structural heart disease, the limitations of the current mapping technology, and the poor accuracy of the methods of activation time determination used at present in the electrophysiology laboratory. It was the aim of this research project to provide insights into these issues. Specifically, we attempted to answer the following questions: • Is there a link between FAT and inflammation? Are there evidences of an inflammatory process in the atrial myocardium in patients with FAT? • Are there evidences of an electrophysiologic and anatomic substrate of the tachycardia? What is the size of this region? Is this region indeed discrete as commonly regarded? • What is the impact of different methods of activation time determination on the resultant activation maps and on the location of the earliest activated site? Do these 27 methods agree with one another with respect of the location of the earliest activated site? What is the observer variability associated with these methods? Four studies were carried out in order to answer these questions. The first study aimed at assessing the presence of a possible inflammatory reaction in the heart in patients with focal arrhythmias. The second study aimed at assessing the electrophysiological proprieties and the size of the atrial substrate in patients with FAT. The third study aimed at comparing several methods of LAT estimation with regard to the size and location of the resulting focus. The fourth study aimed at assessing the observer variability of different methods of LAT determination. 28 MATERIAL AND METHODS Patients All patients were referred for catheter ablation at the Department of Cardiology, University Hospital Linköping due to symptomatic arrhythmias. Paper I Ten patients with paroxysmal AF and eight patients with permanent AF were investigated. The control group consisted of ten patients with Wolf-Parkinson-White syndrome due to leftsided accessory pathways. None of the controls or of the patients had other concomitant heart and inflammatory conditions according to standard history, physical examination, transthoracic echocardiography, and routine laboratory tests. Exclusion criteria were previous cardiac surgery or percutaneous catheter ablation within 90 days, history of infection within 90 days, structural heart disease, diabetes mellitus, neoplasia, and use of lipid-lowering medication. Papers II-IV In study II thirteen patients who underwent electroanatomic mapping and catheter ablation of FAT were investigated. In study III one further patient with FAT was assessed. This patient together with the thirteen patients included in study II comprise the subjects for study III, which therefore included fourteen patients. In study IV one further patient with FAT was included. This patient together with the fourteen patients included in study III constituted the patients investigated in study IV. No patient had undergone previous catheter ablation. One patient (included in studies II-IV) had combined aortic valve and coronary artery disease, while no evidence of structural heart 29 disease was demonstrated in the remaining 12 patients. All antiarrhythmic drugs were discontinued >5 half-lives prior to ablation. Methods In study I, the presence of inflammation in AF patients was assessed by measuring the plasma levels of C-reactive protein (CRP), interleukin 6 (IL-6) and interleukin 8 (IL-8). The study was performed in the electrophysiology laboratory prior to mapping and ablation. The inflammatory markers were assessed in blood samples from the femoral vein, the right atrium, the coronary sinus, and the upper pulmonary veins. Elevated levels of CRP, IL-6, or IL-8 at any of these sites were considered to indicate the presence of an inflammatory reaction. In patients with FAT, a detailed analysis of bipolar and unipolar electrograms was performed. All patients underwent electroanatomic mapping with the CARTO system (Biosense Webster, California). The aim of paper II was to assess whether the electrophysiology of the region surrounding the focus differed from the remaining atrium. This was indirectly inferred from differences in the morphology of unipolar and bipolar electrograms in the two regions. We assessed the amplitude, the degree of electrogram fractionation, and the duration of the signals (Figure 6). The degree of electrogram fractionation was assessed on the basis from the number of negative deflections.103 The degree of electrogram fractionation was assessed on the basis of the number of the negative deflections (Figure 6).102,104 A deflection was defined as a positive or negative excursion from baseline of at least 0.07 mV (the noise limit of the CARTO system in our laboratory) and consistently recorded during a time window of 2 seconds. Bipolar 30 electrograms were categorized as electrograms with 1, 2, and ≥ 3 negative deflections. The incidence of electrograms with multiple (2 and ≥3) negative deflections in a certain atrial region was considered to indicate the degree of electrogram fractionation in that region; when comparing different atrial regions, the region with the highest degree of electrogram fractionation was defined as the region with the highest incidence of electrograms with multiple negative deflections. The peak-to-peak voltage was measured automatically between the positive peak and the negative peak. The measurements were adjusted manually whenever necessary. The duration of electrograms was measured from their onset to their end, with onscreen calipers. The onset of the electrograms was defined as the instant of the earliest electrical activity leaving the baseline at an angle of at least 45°.105 The end of the electrograms was defined as the instant when the last deflection returned to baseline. Isochrones (5 ms steps) were drawn on the electroanatomic activation maps and the shell of the left atrium was thus divided in small regions bounded by two consecutive isochrones. Electrograms characteristics were compared among these regions. In paper III, a comparison of different methods of LAT determination was performed with respect to the size and location of the foci in the resulting electroanatomic activation maps. Three different methods of LAT determination were used: (1) the peak amplitude of the bipolar electrogram (Bi-peak), either above or below the isoelectric line;106 (2) the instant of the steepest downslope of the bipolar electrogram (Bi-dslope),107-109 and (3) the onset of the bipolar electrogram, defined as the onset of the first deviation leaving the baseline at ≥ 45° (Bi-on) (Figure 7).106 For electrograms containing multiple peak amplitudes or steep downslopes, Bi-peak and Bi-dslope were arbitrarily assigned on the earliest peak and steepest downslope, respectively. To ensure accuracy of data, for each algorithm, the LAT was measured twice at each site (first and second measurement) and a mean LAT was then 31 calculated. Figure 6. Analysis of unipolar and bipolar electrograms in paper II. ECG lead II, the bipolar electrogram and the tip unipolar electrogram recorded by the mapping catheter are shown. For the bipolar electrograms we assessed the peak-to-peak voltage (vertical dotted line), duration of electrogram (horizontal dotted line), and the number of negative deflection (digits). For unipolar electrograms only the number of negative deflections (digits) was determined. The electroanatomic maps obtained with Bi-peak, Bi-dslope, and Bi-on were analyzed with respect to: 1) the diameter of the focus, defined as the maximum distance between the points with the earliest activation generated by a given method of LAT determination; when there was only 1 point of earliest activation, the diameter of the focus was considered equal to the diameter of the catheter (2.5 mm); 2) the distance between foci determined by the three methods. The distance between points was calculated automatically by the CARTO system. 32 We also assessed the existence of regions of complex electrophysiological proprieties in maps generated by different methods of LAT determination. To this aim we assessed the degree of electrogram fractionation, peak-to-peak voltage, and duration of electrograms, both in the vicinity of the focus assessed with the three methods of LAT determination and in the remaining atrium. The degree of fractionation, the peak-to-peak voltage, and the duration was assessed as described for paper II. Again, isochrones (5 ms steps) were drawn on the electroanatomic activation maps and the shell of the left atrium was thus divided in small regions bounded by two consecutive isochrones. Electrograms characteristics were compared among these regions. Paper IV aimed at assessing the reproducibility of different methods of LAT determination with respect to the resulting activation times and location of the focus in electroanatomic maps. We studied the same three methods of LAT determination as in paper III. Three experienced observers ascribed the LAT at each recorded site, without knowledge of each other’s results. In addition, the one observer ascribed the LAT on two electrograms at each recorded site. Intraobserver variability was assessed by comparing the LAT assigned by the first observer to the two electrograms at each site. Interobserver variability was calculated by comparing the average value of the first observer with the measurements of the second and the third. 33 Figure 7. Different methods for LAT estimation used in paper III. Statistical analyses Normally distributed variables were expressed as mean ± SD. They were compared by Student’s t test or a one-way analysis of variance followed by Tukey’s post hoc test. Nonnormally distributed parameters were expressed as median and interquartile range or as media and range. They were compared by Kruskal-Wallis test. In paper I, the AF patients were compared with the control group by means of one-way ANOVA or Mann-Whitney test, as appropriate. Clinical parameters were compared using the chi-square test. Correlation between plasma levels of inflammatory markers at different locations was assessed by Spearman rank correlation method. In paper II and III, bipolar peak-to-peak voltage was nonnormally distributed and was therefore analyzed with the Kruskal-Wallis test. Differences in 34 the number of electrogram deflections were assessed with the χ2 test. Pearson's correlation coefficients were used to assess the agreement among the methods of LAT determination. In paper IV, intraobserver variability was assessed by comparing the LAT assessed twice by the same observer. Interobserver variability was calculated by comparing the average value of this observer with the measurements of the second and the third. Intra- and interobserver variability was calculated as the standard deviation (SD) of the absolute difference of the two measurements divided by the average value and then expressed as a percentage, according to the method described by Bhullar et al.110,111 In addition, the absolute mean difference, the 95% confidence interval (CI), and the limits of agreement are reported according to the method described by Bland and Altman.112 For focus location, the variability is expressed by the mean and SD of relative distance between foci generated by the three observers with each algorithm. All analyses were performed with JMP (JMP, version 5.1.1, SAS Institute Inc.) and Statview software (version 5.0, SAS Institute Inc.). RESULTS Paper I There were no significant differences between the 3 groups of patients with respect to: age, gender, body mass index, and history of hypertension. Five patients with paroxysmal AF were in AF during the blood sampling while the remaining 5 were in sinus rhythm. There were no differences between the patients with paroxysmal AF and controls in any of the inflammatory markers at any of the sampling sites. The patients with permanent AF and the controls had similar CRP and IL-6 levels. (Table 2, Figure 8). However, the IL-8 levels in the femoral vein, right atrium, and coronary sinus were greater in patients with permanent AF than 35 in controls (Table 2, Figure 8). No IL-8 differences were found in the samples from the pulmonary veins. Therefore, an IL-8 concentration gradient existed in patients with permanent AF with the IL-8 levels in the femoral vein, right atrium, and coronary sinus greater than the levels in the pulmonary veins (P=0.023, Figure 8). A close correlation existed between the IL-8 levels in the femoral vein and right atrium (Spearman’s rank correlation coefficient R=0.929, P=0.014), and between the IL-8 levels in the femoral vein and coronary sinus respectively (Spearman’s rank correlation coefficient R=0.976, P=0.009) (Figure 9). However, no significant correlation existed between the IL-8 levels at these locations and the IL-8 levels in the pulmonary veins. 36 Table 2 Inflammatory markers in the three groups of patients Controls Patients with paroxysmal AF Patients with permanent AF P n =10 n = 10 P n=8 Value* Value** CRP (mg/l) Fe V 0.96 (0.55 - 1.62) 1.03 (0.38 - 2.65) 0.762 0.69 (0.51 - 6.83) 0.594 Fe V 1.21 (0.66 - 2.62) 1.28 (0.86 - 2.27) 0.762 2.33 (1.03 - 6.70) 0.155 RA 0.90 (0.52 - 1.66) 1.02 (0.63 - 1.73) 0.706 2.13 (0.93 - 5.27) 0.091 CS 0.91 (0.36 - 1.91) 0.90 (0.77 - 1.90) 0.564 2.00 (0.82 - 5.29) 0.115 LSPV 0.99 (0.53 - 1.98) 0.99 (0.70 - 1.83) 0.807 2.38 (0.90 - 5.06) 0.050 RSPV 0.98 (0.61 - 1.89) 1.15 (0.73 - 1.76) 0.870 2.39 (0.91 - 5.19) 0.083 Fe V 2.58 (2.15 - 3.81) 2.97 (1.49 - 3.68) 0.940 4.66 (3.86 - 6.13) 0.003 RA 2.30 (1.97 - 3.71) 3.06 (1.43 - 4.27) 0.999 3.93 (3.39 - 5.64) 0.013 CS 2.85 (2.36 - 3.67) 3.15 (1.91 - 4.16) 0.923 4.07 (3.53 - 4.99) 0.016 LSPV 2.90 (2.18 - 3.10) 1.81 (1.58 - 3.52) 0.462 3.03 (1.96 - 3.72) 0.424 RSPV 2.78 (2.42 - 2.96) 2.12 (1.50 - 3.68) 0.624 2.81 (1.80 - 3.54) 0.894 IL-6 (pg/ml) IL-8 (pg/ml) Fe V : femoral vein; RA : right atrium; CS : coronary sinus; LSPV : left superior pulmonary vein; RSPV : right superior pulmonary vein. Data are expressed as median values and interquartile ranges * =paroxysmal versus control ; **=permanent versus control 37 Figure 8. The levels of CRP, IL-6, ad IL-8 at different sampling sites in patients controls (WPW patients), in patients with paroxysmal AF (PAF) and in patients in permanent AF (CAF). Compared to controls and patients with paroxysmal AF, patients with permanent AF had higher levels of IL-8 in the femoral vein, right atrium, and coronary sinus (asterisk). No differences were noted for the IL-8 levels from the pulmonary veins. P values are indicated in red. 38 Figure 9. A close correlations existed among IL-8 levels in the femoral vein, right atrium, and coronary sinus. Due to skewed distribution, the values had to be logarithmic transformed before computing these plots. A similar high-degree correlation existed even for untransformed data, as revealed by the Spearman rank correlation. However, no significant correlation existed between IL-8 from the femoral vein, coronary sinus and right atrium on one hand and the left and right upper pulmonary veins (PV) on the other hand. Paper II A number of 1205 bipolar and 1021 unipolar electrograms were suitable for analysis (77 ± 61 bipolar electrograms per patient and 72 ± 63 unipolar electrograms per patient respectively). We found that the regions surrounding the earliest activation site and activated within the first 15 ms differ from the remaining atrium in terms of peak-to-peak voltage and degree of electrogram voltage. 39 Thus, the incidence of bipolar electrograms with multiple negative deflections significantly higher in the region activated within the first 15 ms than the remaining atrium (P<0.0001). Similarly, the incidence of unipolar electrograms with multiple negative followed was higher in the former region than in the latter one (P =0.0001, Figure 10). The bipolar voltage was lower (1.33 ± 0.99 mV) in the region activated within the first 15 ms than in the remaining atrium (1.61 ± 1.11 mV) (P <0001). The unipolar voltage was also lower in the former region (1.75 ± 0.92 mV) than in the latter one (1.95 ± 1.11 mV) (P =0.0188, Figure 10). Bipolar electrogram duration did not differ significantly between the 2 atrial regions (49.53 ± 12.46 ms vs 48.56 ± 10.98, P =0.1800). Moreover, within the region activated during the first 15 ms, there was a consistent gradient in both the number of negative deflections and peak-to-peak voltage. Thus, the incidence of both unipolar and bipolar electrograms with multiple negative deflections increased progressively (P<0.0001), while the unipolar and bipolar peak-to-peak voltage decreased progressively (P<0001) from the region activated between 10 and 15 ms towards the earliest activation site (Figure 11). The maximum incidence of unipolar and bipolar electrograms with multiple negative deflections and the minimum value of the peak-to-peak voltage were reached in the region activated between 0 and 5 ms and at the earliest activation site. The surface of the region activated within the first 15 ms was 4.88 ± 3.59 cm2 (range: 0.9 cm2 – 12.5 cm2). Analyzing the activation pattern in the region activated within the first 15 ms we found irregular isochrones suggestive of anisotropic conduction. One example is shown in fig 12. 40 Figure 10. Panels A and B. Incidence of bipolar and unipolar electrograms according to the number of negative deflections. The incidence of electrograms with multiple negative deflections is higher in the region activated within the first 15 ms (region 0-15 ms) than in the remaining atrium. Panels C and D. Bipolar and unipolar electrogram voltage in the region 015 ms and in the remaining atrium. Frequency distribution of electrogram voltage in the 2 regions is presented in the lower panels. Electrograms in the region 0-15 ms have a lower voltage than in the remaining atrium. Error bars represent standard error of the mean. 41 Figure 11. Panels A and B. Incidence of unipolar and bipolar electrograms with 1, 2, and ≥3 negative defections in the earliest activation site (focus), in the regions activated between 0 and 5 ms (region 0-5 ms), 5 and10 ms (region 5-10 ms), and 10 and 15 ms (region 10-15 ms) respectively, and in the remaining atrium. The incidence of electrograms with 1 negative deflection decreased gradually while the incidence of electrograms with 2 and ≥3 negative deflections increased gradually towards the earliest activation site. Panels C and D. Bipolar and unipolar voltage in the same atrial regions. Bipolar voltage decreases gradually towards the earliest activation site. 42 Figure 12. Isochronal activation maps during FAT originating in the right interatrial septum (right atrium viewed in left lateral projection). Isochrone lines were plotted at 5 ms intervals. The following regions are shown: region activated between 0 and 5 ms, colored in red; region activated between 5 and10 ms, colored in green; region activated between 10 and 15 ms, colored in blue. The remaining atrium is depicted in violet. Irregular, closely aligned isochrones in the vertical direction suggest anisotropic conduction in the region surrounding the point of earliest activation. This is concordant with the increased incidence of electrograms with multiple negative deflections in this region, as showed in the insets. The bipolar and unipolar peak-to-peak voltage decreased towards the region activated between 0 and 5 ms and the earliest activation site. Blue ring indicate the position of the tricuspid annulus; red dot indicates a site where a His-bundle potential was recorded. 43 Paper III A total of 1289 bipolar electrograms (92 ± 63 electrograms per patient) were selected for analysis. A strong correlation existed among the activation times computed by the three bipolar methods for estimating LAT (P<0.0001, Table 3). Also, there was a strong correlation between the activation times computed by the bipolar methods and the instant of the steepest downslope of the unipolar electrogram (P<0.0001, Table 3). The three bipolar methods of LAT determination computed foci with similar diameters: 3.13 ± 2.17 mm for Bi-peak, 2.81 ± 0.78 mm for Bi-dslope, and 2.54 ± 0.14 mm for Bi-on (P=0.60). However, the three algorithms generated foci in different locations. In only one patient the foci of the three algorithms coincided perfectly. The distances between the foci generated by each method were 4.36 ± 4.91 mm (Bi-peak - Bi-dslope), 7.21 ± 5.11 mm (Bi-peak - Bi-on), and 7.21 ± 5.87 mm (Bi-dslope - Bi-on) (P=0.26). The distances between foci were not correlated with the number of points sampled during mapping (P ranging between 0.2331 and 0.8219). The diameter and the distance between the foci in each patient are detailed in Table 4. 44 Table 3 Comparison among different methods for determining local activation time (LAT) Correlation Method of LAT Difference determination (mean ± standard deviation) Coefficient (R2) P value Bi-peak vs. Bi-dslope 1.64 ± 4.28 ms 0.983 <0.0001 Bi peak vs. Bi-on 14.87 ± 6.58 ms 0.961 <0.0001 Bi-dslope vs. Bi-on 13.21 ± 6.75 ms 0.959 <0.0001 Bi-peak vs. Uni 2.53 ± 5.14 ms 0.976 <0.0001 Bi-dslope vs. Uni 0.89 ± 5.59 ms 0.972 <0.0001 Bi-on vs. Uni 12.34 ± 6.58 ms 0.962 <0.0001 Bipolar vs. bipolar Bipolar vs. unipolar Bi-peak=peak amplitude of the bipolar electrograms; Bi-dslope=instant of the steepest downslope of the bipolar electrograms; Bi-on=onset of the bipolar electrograms; Uni=instant of the steepest downslope of the unipolar electrograms Although the foci generated by the three algorithms had different locations, they tended to cluster within areas of low amplitude electrograms with a higher degree of fractionation. Thus, when comparing electrogram characteristics among different atrial regions, regardless of the algorithm of LAT determination, the region surrounding the focus and activated within the first 15 ms had lower peak-to-peak voltage and higher incidence of electrograms with multiple negative deflections than did the rest of the 45 atrium (Table 5, Figure 13). Significant differences in electrogram duration between the 2 regions existed only when LAT was assigned according to Bi-on (Table 5). On electroanatomic maps, electrograms activated during the first 15 ms were recorded at up to 3.4 cm around the foci generated by each of the three algorithms, within a region of 3.81 ± 2.34 cm2 (in electroanatomic maps computed by Bi-peak), 3.38 ± 2.12 cm2 (in maps computed by Bi-dslope), and 4.76 ± 3.01 cm2 (in maps computed by Bi-on) (P=0.34). 46 47 2.5 2.5 10 2.5 2.5 10 11 12 13 14 2.5 2.5 2.5 4 2.5 2.5 2.5 2.5 2.5 2.5 2.5 5 2.5 2.5 Bi-dslope Diameter of the foci (mm) 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 3 2.5 2.5 2.5 2.5 Bi-on * 0 9 5 0 6 4 3 0.5 7 6 5 19.5 6 9 10 4 0 * 0 12 6 12 0 5 1.5 15 0 4 13 Bi-peak - Bi-on Distance between foci (mm) Bi-peak - Bi-dslope In patient 6, the foci generated by the three methods coincided perfectly. * 2.5 2.5 6 9 2.5 5 2.5 2.5 4 8 2.5 3 2.5 2.5 2 7 2.5 Bi-peak 1 Patient * 7 3 0 19.5 0 6 9 4 0 12 13 12 4 12 Bi-dslope - Bi-on Table 4 The diameter and the distance between the foci defined by the three methods for determining local activation time 48 on=onset of the bipolar electrograms Bi-peak=peak amplitude of the bipolar electrograms; Bi-dslope=instant of the steepest downslope of the bipolar electrograms; Bi- 49 Duration (ms) deflections (%) Incidence of electrograms with multiple negative Peak-to-peak voltage (mV) Bi-dslope Duration (ms) deflections (%) Incidence of electrograms with multiple negative Peak-to-peak voltage (mV) Bi-peak three methods of activation time determination 49 ± 11 81 1.61 ± 1.13 49 ± 11 79 48 ± 12 86 1.26 ± 0.93 48 ± 12 88 1.34 ± 0.95 during the first 15 ms atrium 1.59 ± 1.13 Region activated Remaining 0.5797 0.0053 <0.0001 0.4850 0.0002 0.0008 P value Table 5 Characteristics of the electrograms in the region activated during the first 15 ms and in the remaining atrium for each of the 50 48 ± 11 80 1.59 ± 1.13 49 ± 11 86 1.37 ± 0.98 0.0492 <0.0001 0.0035 on=onset of the bipolar electrograms Bi-peak=peak amplitude of the bipolar electrograms; Bi-dslope=instant of the steepest downslope of the bipolar electrograms; Bi- Duration (ms) deflections (%) Incidence of electrograms with multiple negative Peak-to-peak voltage (mV) Bi-on Table 5 continued Figure 13. Bipolar voltage and incidence of electrograms according to the number of negative deflections in the region activated within the first 15 ms (Region 0-15 ms) and in the remaining atrium. Regardless of the method of definition of LAT, the former region had a lower peak-peak voltage and a greater number of negative deflections. 51 Paper IV A total of 1438 bipolar electrograms (96 ± 61 electrograms per patient) were analyzed. For all the three bipolar algorithms, we assessed the intra- and interobserver variability. Intraobserver and interobserver variability of Bi-peak There was no significant difference in LAT assigned by the same observer (difference 2.29 ± 3.74 ms, P=0.98). There was no significant difference in LAT assigned by the three independent observers (difference 1.47 ± 2.75 ms, P= 0.99; interobserver variability 1.15%). For the intraobserver variability, the limits of agreement were ±8.60 ms and the 95% CI was 029 and 0.17 ms (Figure 14). For the interobserver measurements, the limits of agreement were ±6.11 ms and the 95% CI were -0.17 and 0.02 ms (Figure 15). Intraobserver and interobserver variability of Bi-dslope There was no significant difference in LAT assigned by the same observer (difference 2.47 ± 4.17 ms; P=0.80). There was no significant difference in LAT assigned by the two independent observers (difference 2.15 ± 3.89 ms; P= 0.52). For the intraobserver variability, the limits of agreement were ±9.47 ms, the 95% CI was -0.09 and -0.59 (Figure 14). For the interobserver variability, the limits of agreement were ±8.51 ms and the 95% CI were -1.06 and -0.80 ms (Figure 15). Intraobserver and intraobserver variability of Bi-on There was no significant difference in LAT assigned by the same observer (difference 3.16 ± 4.48 ms, P=0.98). However, there were significant differences in LAT assigned by the three independent observers (difference 3.00 ± 4.86 ms; P<0.00001). For the intraobserver variability, the limits of agreement were ±10.76 ms, the 95% CI was -0.30 and 0.26 ms 52 (Figure 14). For the interobserver measurements, the limits of agreement were ±8.62 ms and the 95% CI was -1.10 ms and -0.84 ms (Figure 15). Comparison among the activation times assessed by the three algorithms When comparing the intra- and interobserver agreement in the LAT assessed with the three algorithms, we found significant differences. Thus, the intraobserver mean absolute differences in LAT assessed by the three methods were 2.29 ± 3.74 ms (Bi-peak) vs 2.47 ± 4.17 ms (Bi-dslope) vs 3.16 ± 4.48 (Bi-on) (P<0.0001). The interobserver mean absolute differences in LAT assessed by the three methods were 1.47 ± 2.75 ms (Bi-peak) vs 2.15 ± 3.89 ms (Bi-dslope) vs 3.00 ± 4.86 ms (Bi-on) (P<0.0001). Distance between foci computed by the three algorithms The three observers tended to compute different foci. Thus, the interobserver difference in the location of the foci computed with the three algorithms was 3.57 ± 3.81 mm (Bi-peak) vs 5.47 ± 4.98 mm (Bi-dslope) vs 6.57 ± 6.94 mm (Bi-on) (P=0.0025). The maximal range was 0- 13 mm (Bi-peak) vs 0-16 mm (Bi-dslope) vs 0-25 mm (Bi-on). The three observers computed foci with similar diameters. Thus, the interobserver difference in the diameter of the foci computed by the observers were 3.23 ± 2.73 mm (Bi-peak) vs 3.27 ± 4.05 mm vs 4.54 ± 6.42 (Bi-dslope) mm vs (Bi-on) (P=0.32). The maximal range was 2.5 – 11 mm (Bi-peak) vs 2.5 – 19 mm (Bi-dslope) vs 2.5 – 29 mm (Bi-on). 53 Comparison of bipolar voltage and number of negative deflections between the region surrounding the focus and the remaining Atrium For all three observers, regardless of the algorithm of LAT estimation, we noted that the region surrounding the focus and generally activated within the first 15 ms had a lower peakto-peak voltage and a greater number of negative deflections than did the remaining atrium (Table 6). Figure 14. Bland-Altman graphs showing the intraobserver variability of LAT. The graphs plot the difference of each pair of measurements of LAT (Intraobserver dif LAT) assessed by Bi-peak, Bi-dslope, and Bi-on respectively against the average value. The reference lines indicate the mean value of the difference (middle line) and the limits of agreement (the upper and lower reference lines). The wider spread of points around the mean difference in case of Bi-on suggests poorer intraobserver agreement for this method as compared to Bi-peak and Bi-dslope. 54 Figure 15. Bland-Altman graphs presenting the interobserver variability of LAT. Each graph plots the difference of each pair of measurements of LAT (Interobserver dif LAT) assessed by Bi-peak, Bi-dslope, and Bi-on respectively against the average value. The reference lines indicate the mean value of the difference (middle line) and the limits of agreement (the upper and lower reference lines). As in the case of intrabserver variability, the wider spread of points around the mean difference in case of Bi-on suggests poorer interobserver agreement for this method as compared to Bi-peak and Bi-dslope. 55 Table 6. Bipolar voltage and number of negative deflections in the region surrounding the earliest activated site and in the remaining according to the method of activation time determination Remaining Focus area P Value atrium Observer #1 Bi-peak Voltage (mV) 1.61 ± 1.30 1.30 ± 0.93 <0.0001 No. neg. deflections 2.05 ± 0.76 2.26 ± 0.71 <0.0001 Voltage (mV) 1.59 ± 1.11 1.33 ± 0.98 <.0001 No. neg. deflections 2.07 ± 0.76 2.21 ± 0.77 0.003 Voltage (mV) 1.64 ±1.12 1.27 ± 0.95 <0.0001 No. neg. deflections 2.06 ± 0.73 2.21 ± 0.78 0.002 Voltage (mV) 1.62 ± 1.13 1.28 ± 0.91 <0.0001 No. neg. deflections 2.05 ± 0.75 2.26 ± 0.72 <0.0001 Voltage (mV) 1.59 ± 1.12 1.34 ± 0.97 <0.0001 No. neg. deflections 2.05 ± 0.75 2.26 ± 0.74 <0.0001 Bi-dslope Bi-on ‘ Observer #2 Bi-peak Bi-dslope 56 Remaining Focus area P-Value atrium Observer #2 Bi-on Voltage (mV) 1.63 ± 1.13 1.32 ± 0.95 <0.0001 No. neg. deflections 2.05 ± 0.73 2.22 ± 0.76 0.0001 Voltage (mV) 1.61 ± 1.13 1.34 ±0.95 <0.0001 No. neg. deflections 2.05 ± 0.77 2.22 ± 0.70 <0.0001 Voltage (mV) 1.62 ±1.12 1.28 ± 0.94 <0.0001 No. neg. deflections 2.07 ± 0.76 2.21 ± 0.72 0.002 1.62 ± 1.13 1.34 ± 0.97 <0.0001 2.03 ± 0.0.74 2.23 ± 0.75 <0.0001 Observer #3 Bi-peak Bi-dslope Bi-on Voltage (mV) No. neg. deflections 57 GENERAL DISCUSSION Spontaneous diastolic depolarizations can occur in several regions of the heart. Normally, these include the sinoatrial node, the dominant pacemaker region, but also structures like the atrioventricular node and the Purkinje systems, whose intrinsic automaticity is normally suppressed by the faster activity of the sinoatrial node. In addition, other regions of the heart (e.g. the coronary sinus, the atrioventricular annuli, the right and left atrial appendage, and the pulmonary veins) may under some pathological conditions express spontaneous electrical activity. Successful propagation of the action potential from these regions to the rest of the heart will lead to focal tachycardias. In order for a focus to drive the surrounding atrial muscle, it must be electrically coupled to it.113,114 However, the quiescent atrial cells have a resting membrane potential more negative than the maximum diastolic potential of the focus cells and, because of electrotonic interactions between the two tissues (as a result of the same intercellular electrical coupling), the pacemaking activity in the focus cells tend to be suppressed.113-115 This so called “loading effect” is modulated by the size of the focus and the magnitude and spatial distribution of intercellular electrical coupling among the focus cells and among the cells in the surrounding atrial myocardium.113,114,116,117 Computer simulations show that a weak electrical coupling between the focus and the atrial muscle is required in order to minimize the electrotonic interactions between the two tissues and to protect the pacemaking process.114 In addition, the presence of anisotropy (that is, varying intercellular electrical coupling in different directions) and the presence of resistive barriers in the surrounding tissue due to strands of connective tissue or scars is required for the propagation out of the ectopic activity.114,117,118 58 The role of inflammation in the pathogenesis of atrial fibrillation and focal atrial tachycardia In keeping with the above mentioned theoretical studies, clinical data also suggest an association between focal tachycardias and regions characterized by relative electrical uncoupling and anisotropy.119 Such conditions exist naturally at the crista terminalis, the triangle of Koch, the tricuspid and mitral valve annuli or the pulmonary veins.120-125 These sites are frequently reported as sources of FAT.126,127 Intercellular uncoupling could be further augmented by factors enhancing the amount of intracardiac connective tissue, such as advancing age or cardiac disease states.128-131 Indeed, inflammatory infiltrates and increased connective tissue have been observed in atrial specimens resected from patients undergoing surgery for incessant FAT.132-134 Interestingly, in two such patients with apparently normal hearts, histological examination of the excised atrial tissue showed focal atrial myocarditis, while examination of ventricular endomyocardial biopsies showed no abnormalities.135 Focal areas of myocardial interstitial inflammation and fibrosis have also been reported at postmortem examination in one infant with multifocal atrial tachycardia who died abruptly.136 Inflammatory infiltrates has been reported even in patients with focal ventricular tachycardias. Thus, in a young patient with left aortic sinus cusp focal tachycardia, magnetic resonance imaging revealed signs suggestive of a subacute inflammatory process of the myocardium affecting mainly the septum and the adjacent wall of the aortic root.137 Moreover, these signs persisted nine months after a successful catheter ablation of the tachycardia. Collectively, these data suggest that some focal atrial inflammatory processes might provide the pathophysiologic substrate for FAT. Inflammatory changes have also been reported in atrial biopsies from patients with paroxysmal lone AF.138 In addition, expression of IL-8 mRNA was reported in atrial samples 59 from some patients with permanent AF,139 while elevated circulating levels of CRP and IL-6 have been demonstrated in patients with paroxysmal and persistent AF with the highest levels in the latter group.140,141 Furthermore, baseline CRP levels have found to predict the risk of developing AF in the future.142,143 These findings suggest a link between inflammation and AF, although it remains unclear whether inflammation is a cause of AF or merely a consequence. Sata et al144 attempted to establish causality between inflammation and onset of AF in 15 patients with PAF who were enrolled into a study where CRP, IL-6, and TNF-α were measured both at baseline and 2 weeks after successful cardioversion and compared with 11 patients with normal sinus rhythm. Baseline CRP, IL-6, and TNF-α were greater in the AF group and did not normalize 2 weeks after cardioversion, suggesting that inflammation could be an independent risk factor for AF.144,145 Electrophysiological studies have shown that most paroxysms of AF are initiated by rapid focal arrhythmias originating in the muscular sleeves around the pulmonary veins ostia.146 Therefore, and in view of the above mentioned data suggesting a possible link between inflammation and AF and FAT, we hypothesized that inflammation is involved in the pathogenesis of AF by triggering focal tachycardias in the region of the pulmonary veins. We attempted to provide evidence for such an inflammatory process by measuring different biomarkers of inflammation in the heart as well as in the systemic and pulmonary circulation in patients with paroxysmal and permanent AF. We assumed that a concentration gradient would exist among these locations, possibly with the highest levels of inflammatory markers in the pulmonary circulation (provided that the inflammatory process would be localized to the pulmonary veins). In order to minimize the role of any confounders, only patients with AF and no other co-morbidities were included. As control group we studied patients with WPW syndrome and no evidence of AF. 60 However, as presented in paper I, there were no differences in any of the inflammatory markers studied between controls any patients with paroxysmal AF. This finding was independent on the cardiac rhythm during blood sampling (sinus rhythm or AF). Although based on a small number of patients, our data concerning the CRP levels are in line with those reported recently by Elllinor et al,147 who studied a larger cohort of patients with idiopathic paroxysmal and permanent AF, with and without hypertension. As in our study, the authors found no differences in the CRP levels between healthy controls and patients with idiopathic AF without hypertension. However, significantly elevated CRP levels were found in patients with AF and hypertension. Subsequent statistical analysis revealed that these differences were attributable to the differences in the body mass index between the two groups of patients. In our study there were no differences in the body mass index between controls and patients with paroxysmal AF, explaining the similar levels of CRP in the two groups. Our findings are also consistent with those reported in some recent studies on patients with permanent AF. Thus, in this group of patients, Conway et al.148 and Roldan et al.149 found no evidence of raised levels of CRP and IL-6 after adjusting for associated comorbidities. Collectively, these studies along with our data seem to support the concept that AF (and hence FAT) itself is not associated with elevated circulatory levels of inflammatory markers, and that the increased levels of CRP and IL-6 reported in previous studies are probably related to some co-morbid conditions that might exist in these patients. It should be stressed however that our results do not exclude that inflammation is important in the pathogenesis of AF or of focal atrial arrhythmias. They might rather suggest that more sensitive indexes of inflammation be required to detect the presence of the presence of inflammation in these patients. A possible explanation for our results could be that a previous inflammatory reaction, resolved at the moment of blood sampling, might have produced 61 structural and electrical changes in the pulmonary veins and/or the atria that triggered thereafter focal arrhythmias and AF. A novel finding of our study, however, is that patients with permanent AF had raised levels of IL-8 in the samples from the femoral vein, right atrium, and coronary sinus. Moreover, a concentration gradient was noted among the different vascular beds studied, with higher IL-8 levels in the femoral vein, right atrium, and coronary sinus and lower levels in the pulmonary veins. In addition, there was a high-degree correlation among the IL-8 levels from the femoral vein, right atrium, and coronary sinus, while no correlation existed among IL-8 levels from these sites and IL-8 levels from the pulmonary veins. Along with the normal levels of CRP and IL-6, these findings suggest a low-grade inflammatory process originating mainly in the systemic circulation and not associated with an acute phase reaction. In addition, the elevated levels of IL-8 in patients with permanent AF but not in those with paroxysmal AF suggest a link between inflammation and long-lasting AF. One could speculate about the significance of the raised IL-8 levels in patients with permanent AF. Elevated biomarkers of vascular endothelial damage/dysfunction have been reported in patients with permanent AF.150,151 This could suggest that the vascular endothelium in the systemic circulation could have been a source of IL-8 in our patients. Possibly, the elevated levels of IL-8 in the right atrium and coronary sinus were associated with increased amounts of IL-8 in the cardiac tissue. IL-8 is an powerful activator and chemoattractant for neutrophiles,152 thereby promoting neutrophil-mediated organ injury.153,154 Therefore, it could be hypothesized that a direct toxic effect of IL-8 on the atrial tissue might have played a role in arrhythmia maintenance in patients with permanent AF in the present study. This hypothesis 62 raises the question whether IL-8 lowering therapy might have an effect on the prevention of AF permanence in patients with paroxysmal AF. The electrophysiologic proprieties of the atrial substrate in patients with focal atrial tachycardia In paper II we aimed to assess the extent of electrogram fractionation in the vicinity of tachycardia origin, as defined by electroanatomic mapping. As previously mentioned, computer simulations suggest that the initiation and propagation of ectopic activity would require an arrhythmogenic substrate characterized by a certain degree of intercellular uncoupling and anisotropy.113,116,117,155,156 This hypothesis is in agreement with the fact that low-voltage fractionated bipolar electrograms are often recorded at the site of earliest activation during mapping of clinical focal tachycardias.157 Experimental and theoretical studies show that such electrograms are markers of increased anisotropy and pour intercellular coupling.158-160 Indeed, our data show that the morphology of both bipolar and unipolar electrograms recorded around the tachycardia origin differed from those recorded in other atrial regions. Thus, compared to electrograms from the remaining atrium, electrograms recorded in the vicinity of the site of origin of the tachycardia and activated during the first 15 ms had lower amplitude and higher degree of fractionation. The area of this region varied between 0.9 cm2 and 12.5 cm2. Moreover, within this region, from its centre to the periphery, we noticed a gradual change in both the amplitude and the degree of fractionation. Specifically, we observed that the amplitude of electrograms decreases progressively whereas the degree of fractionation increases progressively towards the site with earliest activation. Furthermore, the isochronal 63 maps showed that the activation wavefront in this region propagated highly asymmetrically, with crowded isochrones in certain directions. In addition the edge of the activation wavefront is extremely irregular. Collectively, these data suggest a pronounced electrical anisotropy in this area. The pattern of bipolar electrogram fractionation in this region was similar with the pattern of unipolar electrogram fractionation. This fact suggests a real fractionation due to local electrical activation, rather than artifactual findings secondary to the directional sensitivity of the bipolar electrograms.161 According to experimental studies, fractionated electrograms result from asynchronous activation of poorly interconnected viable myocardial fibres separated by strands of connective tissue.158,160 The relative scarcity of myocardium would contribute to the lower amplitude of electrograms. The spread of the activation in such conditions would be highly anisotropic. Therefore, the results of our study suggests that the region surrounding the origin of tachycardia has indeed particular electrical and structural characteristics as compared to the remaining atrium, and that these characteristics are due to a poorer intercellular coupling. This would seem consistent with the above mentioned data from computational studies. We did not attempt to obtain information on the electrophysiologic mechanism of the tachycardias studied and, therefore, it remains unclear whether these tachycardias were due to automaticity, triggered activity or microreentry. However, the above mentioned findings seem consistent with both automaticity and reentry as possible mechanisms. Thus, the gradual transition in electrical and structural proprieties around the site of origin of the tachycardia, as suggested by the by the gradient in electrogram amplitude and fractionation around the site of earliest activation reminds of the architecture of the sinoatrial node. The amount of connective 64 tissue is higher and the degree of intercellular coupling is weaker in the sinoatrial node as compared to the atrial myocardium.162 In addition, from the centre of the node (where the leading pacemaker site is located) to the periphery (next to the atrial myocardium), there is gradual transition in cell types, membrane proprieties, and intercellular coupling.162-164 This seems to be an essential design feature for the proper function of the sinoatrial node. The weaker intercellular coupling within the node would protect the central part of the node (that is, the leading pacemaker cells) form the inhibitory effects of the atrial myocardium.114,115 The gradual change in the intercellular coupling within the node would explain how a small sinoatrial node could drive the much larger mass of the atrial myocardium. Computer models show that a gradual increase in intercellular the border between the node and the atrium, allow a relatively small node to exhibit pacemaking and to drive the larger mass of the surrounding atrial myocardium, whereas an abrupt change in intercellular coupling would render the node quiescent or unable to drive the atrium.114 In view of these data, one can speculate that an ectopic focus, just like the sinoatrial node, is an entity with complex electrophysiologic proprieties and architecture. The earliest activated site would correspond to the leading pacemaker site in the node. The poorer intercellular coupling in the region surrounding the earliest activated site as compared with the remaining atrium, would protect the cells from the central part of the focus from the hyperpolarizing inhibitory effect of the surrounding atrial quiescent cells, allowing the pacemaking process. The gradual transition in intercellular coupling would explain how a small focus is able to drive the much larger mass of atrial myocardium. Local heterogeneity in electrophysiological proprieties and intercellular coupling are associated with increased dispersion of local action potential duration and susceptibility of 65 reentry.165,166 It appears therefore reasonable to speculate that the varying electrophysiologic proprieties and intercellular coupling in the region surrounding the earliest activation site, as suggested by the electrogram characteristics in this region, could provide a substrate not only for automaticity but also for functional reentry. In this case, the higher degree of electrogram fractionation and the lower voltage encountered in the central part of this region might correspond to a discrete area of depressed electrical activity, which might serve as the pivot point around which the activation wave rotates. The relation between these findings and triggered activity, as a third possible underlying mechanism for tachycardias in the group of patients, remains unclear. The present study raises nevertheless the question whether the difference in electrogram characteristics between the region surrounding the tachycardia origin and the remaining atrium could be observed not only during the tachycardia but also during sinus rhythm. This would confirm that that the differences in electrophysiologic proprieties between the two regions do not dependent on the direction of activation and on the heart frequency and would further support the existence of an anatomical substrate of FAT. Indeed, limited data from two of our patients (#11 and 13; figure 16) who underwent mapping both during tachycardia and during sinus rhythm suggests that this hypothesis is true. Further studies are however warranted in this respect. 66 Figure 16. Electrogram characteristics in patients #11 and #13 from paper II. These patients underwent mapping both during tachycardia and during sinus rhythm within the same ablation procedure. Therefore, we could assess electrogram parameters during rhythms. Left panel presents electrogram characteristics during tachycardia, in the region around the focus (region activated during the first 15 ms) and in the remaining atrium. The peak-to-peak voltage in the region around the focus is less than the peak-to-peak voltage in the remaining atrium. In addition, a higher incidence of electrograms with multiple negative deflections exits in the former region as compared with the later one. Right panel presents the characteristics of the electrograms recorded during sinus rhythm in the same regions. Again, the peak-to-peak voltage in the region surrounding the focus is less than the peak-to-peak voltage in the remaining atrium and the incidence of electrograms with multiple negative deflections is higher in the former region as compared with the later one. Collectively, the data presented in panel A and B suggest that the differences in electrogram characteristics between the atrial region harboring the focus and the remaining atrium are not dependent on the heart frequency, thereby supporting the hypothesis concerning an underlying anatomic substrate for FAT. 67 In conclusion, the results of the present study seem consistent with the concept that the area around the point of earliest activation and generally activated within the first 15 ms may play an important role in the process of focal activity. In this case, the size of this region (up to 12.5 cm2 in this study) would suggest that the substrate of FAT is in fact a sizeable atrial region with complex, gradually changing electrophysiologic proprieties and not just a pointlike area, as commonly regarded.167 The impact of the method of estimating activation time during the mapping of focal atrial tachycardia Successful ablation of FAT requires accurate estimation of the LAT for each recorded bipolar electrogram, which is to represent the moment of local depolarization of the myocardium in the vicinity of the recording electrode. The activation times from all electrograms are displayed in a color-coded map that depicts the spatiotemporal spread of activation wavefront. The problem in cardiac mapping is that it is not possible to conclude with absolute certainty which components of a bipolar electrogram are due to the activation of the myocardium in the immediate proximity of the recording electrode and which are due to remote electrical activity. 168 This is especially true for electrograms with increased fractionation that are often encountered in the region of tachycardia origin, as described above. Therefore, no consensus exists on how to assign the LAT. Based on some theoretical data,169 mapping of atrial tachycardia has been performed by marking the LAT on bipolar electrograms at the peak absolute amplitude,89 the moment of the maximal downslope,89,170 and the onset of the first deflection leaving the baseline at ≥ 45°.78,171-173 However, the extent to which these landmarks reflect the instant of electrical activation in clinical settings remains unknown. This is particularly relevant in patients with FAT, because different methods of LAT estimation 68 might generate activation maps with different appearances and different earliest activation sites. We addressed this issue in the study presented in paper III. We found that the activation times corresponding to the peak amplitude, the maximal downslope, and the onset of bipolar electrograms are correlated strongly with another. However, the activation maps and the location of the foci computed by these algorithms are not identical. In fact, the distances between the foci generated by each algorithm varied between 0 and 2 cm. In only one patient there was perfect agreement among the three methods with respect to the location of the focus. Interestingly, regardless of the method of LAT estimation, the foci are situated within a region of low voltage, fractionated electrograms having an area of several square centimeters. This finding further supports the concept of an anatomic substrate of the tachycardia due to a relatively wide atrial region with reduced intercellular coupling. In this case, our study suggests that, despite the differences among these methods with regard to the location of the focus, all methods are able to identify the anatomical substrate of the tachycardia and accurately place the focus within this region. It is noteworthy that the maximum distance between the foci computed by the three algorithms was 2 cm. Experimental studies show that the mean width of an ablation lesion generated by conventional catheter is 10 mm,174 while irrigated tip catheters create lesions with a mean width of 16 mm.175 Consequently, an ablation targeting a focus inaccurately located by one method of LAT determination might “miss” a focus that would have been accurately located by another method. In view of this concern, and due to potential 69 inaccuracies with each of these methods as well as the possibility of a wider anatomic substrate of the tachycardia, it appears reasonable to speculate that more aggressive ablation techniques may be more successful, regardless of the method of LAT estimation. Such ablation techniques might involve large-tip or irrigated-tip catheters, higher energy output, and energy delivery to larger areas in the vicinity of the earliest activation. Our findings suggests that bipolar voltage map could also assist the mapping and ablation procedure by displaying the region of lower bipolar voltage (that is, the substrate of the tachycardia) and its relation with the site of earliest activation. With electroanatomic mapping, a possible approach would be to incrementally adjust the voltage settings to higher values until a compact region of lower voltage is delineated. If the radiofrequency current directed to the earliest activation site fails to stop the tachycardia (presumably secondary to an inaccurately detected focus by a certain method of LAT estimation or secondary to a larger anatomical substrate of the tachycardia), a reasonable approach would be to attempt to ablate an increasingly larger area around the earliest site, within the borders of the region of lowbipolar voltage. This will ensure that a sufficiently area of the substrate of the tachycardia is ablated, thus increasing the chance for tachycardia termination and diminishing the risk of recurrence. Observer variability in the estimation of activation time determination during mapping of focal atrial tachycardia Due to the lack of reliable criteria for activation detection and due to the susceptibility of automatic detecting algorithms to artifacts and remote electrical activity, mapping of clinical tachycardias often requires visual inspection of electrograms activation time assignment by 70 experienced observers.168 Such an approach introduces nevertheless an unavoidable element of subjectivity, which can affect the selection of the site of earliest activation that has to be targeted by ablation. The reproducibility of LAT measurement with different algorithms in patients with FAT remains unknown. Therefore in paper IV we assessed the intra and interobserver variability of LAT estimation in patients with FAT. Three experienced observers were asked to review bipolar electrograms recorded from fifteen patients with FAT. The observers ascribed the LAT without the knowledge of each other’s results. One observer ascribed the LAT twice on two electrograms per recorded site. The LAT was sequentially assigned to the peak amplitude, sharpest downslope, and the onset of the bipolar electrograms. The observer variability was assessed by both quantitative and qualitative criteria. We found significant differences among the three algorithms. Thus, the best intra- and interobserver reproducibility was found when the LAT was assigned on the peak amplitude while the poorest existed when the LAT was assigned on the onset of electrograms. The LAT assigned on the maximal downslope of electrogram had an intermediate reproducibility. These findings might be explained by the fact that the peak amplitude and the maximal downslope are often situated in the major deflection, which is readily visually recognized in most bipolar electrograms.105 In addition, the major deflection correlates well with the most rapid part of the intrinsic deflection of the corresponding unipolar electrograms,105 which, at least under ideal conditions, is closely timed with the maximum slope of the upstroke of the local transmembrane potential, the marker of local electrical activation.158,176 This would not only explain the better reproducibility of the peak amplitude and the maximal downslospe, but 71 it would also suggest that the LAT estimated based on these two landmarks might be more accurate than the LAT estimated based on the onset of the electrogram. The poorer reproducibility of LAT assigned to the onset of electrograms might also reflect some particularities of the morphology of the electrograms recorded in patients with FAT. Possibly, such electrograms often have low-amplitude, slow slew rate initial components rendering the onset more difficult to define by the operator. We also demonstrate that the differences in the interobserver reproducibility of LAT measurement are associated with differences in the interobserver reproducibility of the focus location. Again, the best reproducibility was found when LAT was assigned to the peak amplitude and the poorest when the LAT was ascribed to the onset of the electrograms. The range in the relative distance between the foci found by different observers was 0-13 mm for the peak amplitude, 0-16 mm for the sharpest downslope and 0-23 mm for the onset of the electrograms. As previously mentioned, the width of an ablation lesion for conventional catheters is 10 mm174 and 16 mm for irrigated tip catheters.175 This would suggest that, even if irrigated tip catheters are employed, the risk for ablation failure is larger when LAT is assessed according to the onset of electrograms than when LAT is assigned to the peak amplitude and maximal downslope. In conclusion, at least for the patients assessed in this study, the intra- and interobserver variability in LAT estimation is likely to be smaller when LAT is assigned to the peak amplitude and the maximal downslope than when LAT is assigned on the onset of electrograms. 72 CONCLUSIONS • Patients with paroxysmal AF (and probably FAT) do not have evidence of elevated inflammatory markers in the systemic or pulmonary circulation or in the heart. However, patients with permanent have elevated IL-8 plasma levels in the systemic circulation, which along with the normal CRP and IL-6 levels, suggest a low-grade inflammatory reaction with a possible source of inflammation in the systemic circulation in these patients. • In FAT patients, a high incidence of electrograms with increased fractionation and low peak-to-peak voltage exists in the region surrounding the site of earliest activation. The area of this region is up to several square centimeters. This finding suggests the existence of wide anatomic substrate of the tachycardia due to reduced intercellular coupling. This is in agreement with data from computational studies indicating that a certain degree of intercellular uncoupling is required for the development of FAT. • Electrogram fractionation in FAT patients may impact the process of activation time determination • Different algorithms of activation time determination, althoug highly correlated with one another, can generate foci with different locations. However, the foci tend to cluster within relatively large areas of low-amplitude fractionated electrograms. During mapping, this region can be roughly delineated by all three methods of activation time estimation. However, details concerning the activation pattern within the region and the location of the focus vary among the algorithms. 73 • Significant observer variability exists among different algorithms, which tend to compute different LAT and foci with different locations. 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