Distribution of the Origin of Adenosine Triphosphate- Sensitive Atrial Tachycardias With the Earliest Activation Recorded in the His Bundle Catheter

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1 Circulation Journal Official Journal of the Japanese Circulation Society ORIGINAL ARTICLE Arrhythmia/Electrophysiology Distribution of the Origin of Adenosine Triphosphate- Sensitive Atrial Tachycardias With the Earliest Activation Recorded in the His Bundle Catheter Are They Limited to the Immediate Vicinity of the His bundle? Tomofumi Nakamura, MD; Hitoshi Hachiya, MD; Yasuaki Tanaka, MD; Atsuhiko Yagishita, MD; Koji Sugiyama, MD; Masahito Suzuki, MD; Mihoko Kawabata, MD; Tetsuo Sasano, MD; Kenzo Hirao, MD; Mitsuaki Isobe, MD Background: The aim of this study was to assess the spatial distribution of the origins of adenosine triphosphate (ATP) sensitive focal atrial tachycardias (AT) that have their earliest activation recorded in the His bundle (HB) catheter. Methods and Results: Catheters were placed according to the standard fashion for an electrophysiologic study of supraventricular arrhythmia, namely, high right atrium, HB, coronary sinus, and right ventricle. The ATs with their earliest activation recorded in the HB catheter and that were terminated by rapid injection of ATP (4.3±2.5 mg), formed the study group (n=12). After catheter ablation of these ATs, the distances between the successful ablation site and the HB area were measured. Only one successful site was near the HB and the other sites were at the noncoronary sinus of Valsalva (n=6), tricuspid annulus (n=3), right atrial septum (n=1), and left atrial septum (n=1). The average distance between the HB catheter and successful site was 10.4±8.8 mm. In 5 of the 12 cases (the 3 tricuspid and 2 septal foci), the distances were greater than 10 mm. Conclusions: When ablating ATP-sensitive AT with the earliest activation recorded in the HB catheter, it is important to perform detailed mapping not only around the HB. (Circ J 2013; 77: ) Key Words: Adenosine triphosphate; Atrial tachycardia; Catheter ablation; His bundle area One of the conventional strategies for ablating focal atrial tachycardia (AT) with radiofrequency (RF) energy is to seek and target the site of earliest activation. This involves conducting detailed baseline mapping within the atrium, and analyzing the sequence of atrial activation of the AT recorded by the intracardiac electrode catheters. For AT originating from the His bundle (HB) area, mapping is carefully performed in the area around the HB. 1 However, the origin of the AT can be distant to the HB area, even if the site of earliest atrial activation among the high right atrium (HRA), HB, and coronary sinus (CS) catheters is observed in the HB catheter. In those cases, meticulous mapping around the HB area may prolong the procedure without helping the operator to achieve ablation success. Adenosine-sensitive AT in which the earliest activation is recorded at the HB is considered to be among ATs arising from the atrioventricular (AV) annulus, 2 but the distribution and actual distance between the HB and successful ablation sites has never been evaluated. Therefore, the objective of this study was to assess the distance between the HB area and successful site of ablation of ATs in which the earliest activation sites were recorded by the HB catheter, among the standard HRA, HB and CS catheters, and their spatial distribution. Methods Patients Characteristics The records of 41 patients who underwent electrophysiological study (EPS) and ablation of focal ATs from 2004 to 2011 were reviewed and 12 patients (29%) in whom the AT was terminated by rapid injection of a small amount of adenosine triphosphate (ATP) and in whom the earliest atrial activation during AT was recorded in the HB catheter among the standard HRA, HB and CS catheters were investigated in this study. Received August 17, 2012; revised manuscript received September 21, 2012; accepted October 23, 2012; released online December 5, 2012 Time for primary review: 19 days Department of Cardiovascular Medicine (T.N., Y.T., A.Y., K.S., M.S., M.K., T.S., M.I.), Heart Rhythm Center (H.H., K.H.), Tokyo Medical and Dental University, Tokyo, Japan Mailing address: Tomofumi Nakamura, MD, Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo , Japan. tomonakamura-tmd@umin.ac.jp ISSN doi: /circj.CJ All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 Origin of ATP-Sensitive ATs 627 Table 1. Patients and Tachycardia-Related Characteristics Patient no. Age, years Sex Structural heart disease TCL, ms ATP, mg Successful ablation site AbA-HisA, ms Ab-HBE, mm AbA-P, ms Inverse relationship in tachycardia induction 1 58 M None NCS Yes 2 77 M None NCS Yes 3 77 F None NCS Yes 4 77 F None NCS NA 5 60 F None NCS Yes 6 60 F None NCS Yes 7 73 F None TA ant Yes 8 63 F None TA ant Yes 9 52 M None TA sep NA F PLSVC HBA Yes F Post AVR SEP sup NA M None SEP mid NA Mean 63.1± ± ± ± ± ±15.8 AbA-HisA, time difference between atrial electrograms of the successful ablation point and His bundle catheter; AbA-P, time difference between atrial electrograms of the successful ablation point and onset of P-wave in lead II of surface ECG; Ab-HBE, distance between successful ablation site and His bundle area; ant, anterior; ATP, adenosine triphosphate; AVR, aortic valve replacement; HBA, His bundle area; mid, middle; NCS, noncoronary sinus of Valsalva; PLSVC, persistent left superior vena cava; SEP, atrial septum; sep, septal; sup, superior; TA, tricuspid annulus; TCL, atrial tachycardia cycle length. Structural heart disease was defined using a history of prior open-heart surgery and echocardiographic criteria, namely, presence of left ventricular (LV) asynergy, reduced LV ejection fraction, abnormal LV hypertrophy, aortic and mitral valve disease, or left atrial dilatation. Verbal and written informed consent for the ablation procedure and study was given by all patients prior to the procedure. The study protocol, including data collection and record keeping, was approved by the hospital s institutional review board. EPS Antiarrhythmic drugs were discontinued for at least 5 halflives prior to the EPS. Three quadripolar 6Fr catheters were inserted via the right femoral vein and advanced to the HRA, HB area, and right ventricle according to the standard fashion for an EPS of supraventricular arrhythmia. A decapolar 6Fr catheter was inserted via the right subclavian vein and advanced through the CS. The proximal electrodes of the CS catheter were positioned at the CS ostium. A quadripolar 4-mm-tip ablation catheter (Ablaze, Japan Lifeline Co, Ltd, Tokyo, Japan or Blazer II, Boston Scientific, Natick, MA, USA or EZ- Steer, Biosense-Webster, Irwindale, CA, USA) was inserted via the right femoral vein. Femoral arterial puncture or the Brockenbrough procedure was performed if activation mapping of left-sided cardiac structures, such as the left atrium or the sinus of Valsalva, was required (eg, exploration of the left side of the heart was performed in the cases of the earliest atrial electrogram recorded by the ablation catheter in the right atrium not preceding that recorded at the HB catheter by >10 ms or the HB electrogram was only recorded at the site of earliest activation). In some patients, an electroanatomical mapping systems (CARTO system, Biosense-Webster or the ENSITE system, St. Jude Medical, St. Paul, MN, USA) was used. Attempts to induce the AT were by programmed atrial extrastimuli at several basic cycle lengths. If the AT was not inducible or not sustained, isoproterenol was administered intravenously until the sinus heart rate increased by at least 20%. ATP (Adetphos-L, Kowa, Nagoya, Japan) was given as an intravenous bolus injection during the AT in increasing amounts from 2 mg to 10 mg until termination of the AT. During the AT, the time between the atrial potential recorded by the HB catheter and the onset of the surface P-wave in lead II was measured. Definitions Standard electrophysiological techniques were used to exclude diagnoses of an accessory pathway or AV nodal reentrant tachycardia. A diagnosis of focal AT was made using the following conventional criteria: (a) abnormal P-wave morphology during the tachycardia, (b) endocardial atrial activation sequence during AT inconsistent with sinus origin and unable to be reproduced by ventricular stimulation, (c) tachycardia induction by ventricular stimulation associated with V-A-A-V sequence, (d) no evidence of a macroreentrant atrial tachycardia, (e) change in the A-A interval during tachycardia preceding any change in the V-V interval, (f) presence of AV conduction block or delay without affecting tachycardia cycle length, (g) dissociation of ventricular activity from the tachycardia, (h) tachycardia initiation independent of a critical prolongation of the AH interval, and (i) termination of the tachycardia without blocking AV nodal conduction. In the patients in whom an electroanatomical mapping system was used, focal AT was defined as follows: (a) conduction pattern radiating in all directions from a single site of earliest activation, and (b) range of activation times less than the tachycardia cycle length. Catheter Ablation RF energy was applied at the site of earliest bipolar activation (maximal temperature: 55 C, duration: 60 s, power: 40 W). The location of the RF energy application was recorded by fluoroscopy and stored for further evaluation, together with the intracardiac electrograms, on an eletrophysiological recording system (LabSystem PRO EP recording system, C.R. Bard, Inc, Lowell, MA, USA). When an electroanatomical mapping system was used, ablation tags were marked on the 3D recon-

3 628 NAKAMURA T et al. Table 2. Distance From the HB to the Successful Ablation Site and the Interval Between the Atrial Electrograms Recorded at the Successful Ablation Site and the HB* Successful ablation site struction for each RF application. The catheter ablation was judged successful if the tachycardia was successfully terminated and was not inducible by programmed and continuous stimulation even with isoproterenol infusion 30 min after the final RF application. Measurement of the Distance The HB area was defined as the interelectrode area where the HB potential was recorded within the HB catheter. In patients for whom an electroanatomical mapping system was used, the distance between the successful ablation site and the HB area was measured by the system. In other patients, the measurement was made under fluoroscopic guidance. Statistical Analysis Continuous data are expressed as mean ± SD. n Distance (mm) Time (ms) Tricuspid annulus Anterior ± ±14.1 Septal Total ± ±15.7 Noncoronary sinus 6 5.2± ±21.1 HB area Atrial septum Right Left *Note that all sites other than the noncoronary sinus and the HB area were separated from the HB by >10 mm. HB, His bundle. Results Patients Characteristics Clinical and tachycardia characteristics of the 12 patients are listed in Table 1. The mean age was 63.1±12.6 years and 8 of the 12 patients were female (66.7%). One patient had a history of open-heart surgery and another patient had persistent left superior vena cava. None of others had structural heart disease. The drugs being taken by the patients prior to the ablation session were recorded: 5 patients were not taking cardiovascular drugs (patient nos. 1, 3, 5, 10, and 12), 1 on verapamil only (patient no. 9), 2 on class I antiarrhythmic drugs only (patient nos. 4 and 6), and 1 on all 3 types of drugs (verapamil, class I antiarrhythmic drug, and β-blocker: patient no. 11). The remaining 3 were on 2 of the 3 types of drugs. Electrophysiological Characteristics The mean tachycardia cycle length was 355.2±55.2 ms. The earliest atrial activation during the AT was recorded by the HB catheter in all patients as per our study inclusion criteria. The atrial potential recorded by the HB catheter during the AT was same or earlier than the onset of the surface P-wave for 24.7±15.8 ms (range 0 45 ms). Likewise, injection of ATP terminated the sustained AT in all patients. The mean dosage of ATP required for AT termination was 4.3±2.5 mg (range 2 10 mg). In 2 of 12 patients, relatively larger amounts of ATP (8 and 10 mg, respectively) Figure 1. Illustration of successful ablation sites in 12 patients with ATP-sensitive atrial tachycardia. Successful ablation was at the noncoronary sinus of Valsalva (NCS) in 6 patients, anterior tricuspid annulus (TA) in 2 patients, septal TA in 1 patient, immediate vicinity of the His bundle (HB) area in 1 patient, right atrial (RA) septal wall in 1 patient and let atrial (LA) septum in 1 patient. Red symbols indicate the successful ablation sites <10 mm from the HB area, black >10 mm. ATP, adenosine triphosphate; LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle. were used compared with previous reports. Nevertheless, because all tachycardias were terminated without blocking AV conduction, they were defined as ATP-sensitive AT. An inverse relationship between the coupling interval of the extrastimulus initiating the AT and the interval from the stimulus to the first complex of the AT was observed in 8 patients, which suggested microre-entry to be the mechanism (patient nos. 1, 2, 3, 5 8, and 10). In the remaining 4 patients, the relationship was not assessed. Successful Ablation Site Catheter ablation was successful in all 12 patients. There was only one patient in whom the successful ablation site was in the immediate vicinity of the HB. In 6 patients, the earliest activation was obtained at the noncoronary sinus of Valsalva (NCS) and ablations performed there were successful in terminating the AT. In the remaining 5 patients, the successful ablation site was at the tricuspid annulus (TA, n=3) or at the atrial septum far from the AV junction (n=2). The distance between the successful ablation site and the HB area averaged 10.4±8.8 mm (range 4 35 mm). The average time by which the atrial potential recorded at the successful ablation site preceded that of the HB catheter was 24.7±16.4 ms (range 0 61 ms). Table 2 summarizes these distance and time differences by site and Figure 1 illustrates the spatial distribution of the foci. Figure 2 is an example of successful ablation of AT in patient no. 7 (in Table 1). The activation map acquired by the CARTO system shows a centrifugal conduction pattern. The successful ablation site was at the anterior part of the TA, which was separated from the HB area by 16 mm (Figure 2A). Intracardiac electrode catheters indicated that the earliest atrial activation was in the HB catheter, except for the ablation catheter. The atrial electrograms recorded at the successful ablation site preceded that of the HB catheter by 28 ms (Figure 2B). Figure 3 shows another example (patient no. 6) in which the successful ablation site existed at the NCS.

4 Origin of ATP-Sensitive ATs 629 Figure 2. Example of successful ablation for ATP-sensitive atrial tachycardia (patient no. 7 in Table 1). (A) CARTO activation map showing centrifugal conduction pattern. Successful ablation was performed at the anterior part of the tricuspid annulus (red marker), which was separated from the His bundle (HB) (yellow marker) by 16 mm. (B) Intracardiac electrograms indicate that the earliest atrial activation was in the HB catheter, except for the ablation catheter. The atrial electrograms recorded at the successful ablation site preceded that of the HB catheter by 28 ms (vertical dotted line). ABL, ablation catheter; ATP, adenosine triphosphate; TA, tricuspid annulus; CS, coronary sinus; HRA, high right atrium. Discussion Distribution of the AT Several years ago, Iesaka et al 1 reported on the existence of adenosine-sensitive atrial microreentrant tachycardia that arose near the HB. They speculated that the AV node or its transitional tissues were part of the reentrant circuit. Since then, it has been found that the foci of such adenosine-sensitive microreentrant ATs may also arise at diverse sites such as the CS ostium, 3,4 TA, 5 mitral annulus, 6 and others. 7 In our study, 6 of 12 ATs were terminated by RF application at the NCS. The distances between the ATs and the HB area were short (5.2±1.5 mm). Ablating at the NCS is a wellknown strategy for this type of AT and has been reported by several authors The RF energy from the site may penetrate through the atrial septum and may be able to ablate the tachycardia circuit without damaging the HB. However, another 3 foci existed along the TA, which may have been caused by AV nodal tissue extending along the AV junction. As shown in Table 2, the foci at the TA were separated from the HB area by an average of 14.3±1.5 mm. It is important to note that the earliest atrial activation was nevertheless recorded by the HB catheter, because the catheters are not placed around the TA in a standard EPS. Therefore, ATs arising from the TA may sometimes be misidentified as para-hisian AT. The mechanisms of the 2 ATs originating from the atrial septum (1 left-, 1 right-sided) were unclear because detailed EPS were not performed. This type of septal AT may also be misdiagnosed as a para-hisian AT, because again, the standard catheters are not placed around the TA. As described in patient no. 7 (Figure 2), 3D electroanatomical mapping was helpful for detailed mapping during AT. 14,15 Mechanism of ATP-Sensitive AT In our present study, 10 of 12 ATs (83.3%) arose from the AV junction. The special nature of the tissue around the junction may play an important role in the occurrence of these ATs. Several investigator have studied the characteristics of AV junctional tissue and have found that it resembles atrial myocardium histologically and extends along the AV valvular annulus However, electrophysiologically, it resembles AV nodal tissue, including its response to adenosine. ATP is rapidly broken down into adenosine in the bloodstream, with a plasma half-life of less than 1s. As a consequence, an intravenous dose of ATP may reach the site of action as adenosine. 19 The effects of adenosine on supraventricular tissue include shortening of the action potential duration mediated by a potassium current (IKAch), and antiadrenergic electrophysiological effects resulting from inhibition of adenyl cyclase, which leads to a reduction of the inward L-type calcium current (ICa- L). 20,21 Therefore, adenosine may transiently terminate conduction through the AV node or inhibit delayed afterpotentials in atrial tissue, which could lead to catecholamine-induced triggered activity. Iesaka et al were the first to report that the circuit of ATPsensitive microreentrant AT might include AV nodal tissue, according to their speculation that the conduction block in the circuit was induced by reduction of the inward calcium current, an effect of ATP. 1 On the other hand, Iwai et al examined the response of 43 patients with AT to adenosine and reported that all focal AT were terminated by rapid injection of adenosine, except for those whose etiologies were due to macroreentry. 20 More recently, based on electrophysiological behavior and response to drugs, they suggested that para-hisian AT was mechanistically consistent with triggered activity. 2 Further investigation is needed to elucidate the mechanism of this type of AT. In our study, 8 patients had an inverse relationship between the coupling interval of the extrastimulus initiating the AT and the interval from the stimulus to the first complex of the AT,

5 630 NAKAMURA T et al. Figure 3. Location of successful ablation site for ATP-sensitive atrial tachycardia (patient no. 6 in Table 1). (Top) Successful ablation was performed at the noncoronary sinus of Valsalva, which was separated from the His bundle (HB) area by 5 mm. (Bottom) Intracardiac electrograms. Ventricular stimulation during tachycardia was performed to clearly determine the atrial potentials. The earliest atrial activation was recorded by the HB catheter, except for the ablation catheter, whereas the atrial electrogram recorded at the successful ablation site preceded that of the HB by 14 ms. ABL, ablation catheter; ATP, adenosine triphosphate; CS, coronary sinus; HRA, high right atrium; RVA, right ventricular apex. which suggested microreentry as the mechanism (patient nos. 1, 2, 3, 5 8, and 10). Clinical Implications When attempting to ablate ATP-sensitive AT, there is a tendency to search for the earliest atrial electrogram mainly around the HB, if the earliest atrial activation of the AT is recorded in the HB catheter among the standard HRA, HB and CS catheters. However, this study shows that nearly half of the successful ablation sites were >10 mm from the HB. We believe knowledge of the distribution and the distance between the origin of the AT and the HB area will facilitate effective and safe ablation of ATP-sensitive focal AT. Conclusion In ATP-sensitive AT that have the earliest activation recorded in the HB catheter among the HRA, HB and CS catheters placed according to the standard fashion for an EPS of supraventricular arrhythmia, it is important to perform detailed mapping not only around the HB, but also the TA and both sides of the septum. Disclosures There is no source of financial support and no conflicts of interest. References 1. Iesaka Y, Takahashi A, Goya M, Soejima Y, Okamoto Y, Fujiwara H,

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