Ablation of Ventricular Tachycardia Using Multiple Sequential Transcatheter Application of Radiofrequency Energy

Ablation of Ventricular Tachycardia Using Multiple Sequential Transcatheter Application of Radiofrequency Energy MICHAEL OEFF, JONATHAN J. LANGBERG, MICHAEL C. CHIN, WALTER E. FINKBEINER,* and MELVIN M. SGHEINMAN From the Departments of Medicine and * Pathology. University of California San Francisco, San Francisco, California OEFF, M., ET AL.: Ablation of Ventricular Tachycardia Using Multiple Sequential Transcatheter Applica-

tion of Radiofrequency Energy. Multiple sequentiai radio/requency energy was applied in (he left and right ventricles of 24 dogs fo produce large ablated areas limited to endocardial and subendocardial regions. Endocardial ablation was performed in nine dogs with normal ventricles and 15 that had survived remote myocardial in/arcts, three with inducible sustained monomorphic ventricular tachycardia. A quadripolar catheter was positioned either at the site of earliest ventricular activation during induced monomorphic ventricular tachycardia or at circumscribed areas of the left ventricle. Radiofrequency energy was delivered between two adjacent poles of the catheter, successively applying radio/requency energy to the distal, middle, and proximal electrode pairs; this was repeated 9 to 11 times with the catheter in a slightly different position. A cumulative energy of 9,688 ± 4,191 joules resulted in an ablated endocardial/subendocardial surface area of 4.7 ± 2.2 cm^ (range 2.4-10 cm^, maximum depth 4 mmj. Sustained tachycardia was not inducible by aggressive programmed ventricular stimulation in the dogs with previously inducible tachycardia, indicating successful ablation of the tachycardia foci. Only seven normal dogs were available for eiectrophysiological studies; three were used in acute and four in chronic studies. Ventricular tachycardia was not induced in the remaining dogs either before or after radiofrequency ablation, indicating the lack of an arrhythmogenic effect of this method. Histologic examination was performed in all nine normal dogs (five were sacrificed for acute pathological examination] as well as in the 15 with myocardial infarction. The late pathological examination of the radiofrequency lesion in these 19 animals showed homogeneous areas of coagulation necrosis and endocardial proliferation. Thus, this modified technique of radiofrequency ablation produced large homogeneous endocardial/subendocardial scars suitable for treating ventricular tachycardia and showed no evidence of an arrhythmogenic influence. [PACE, Vol. 15, August 1992J ventricular tachycardia, ablation, radiofrequency energy Introduction Catheter ablation has been performed in selected patients to treat drug refractory ventricular

This work was suppored by a grant from the Deutsche Forschungsgemeinschaft (DFG). Germany. Address for reprints: Michael OetT, M.D.. Klinikum Steghtz. Freie Universitat Berlin. Cardiopulmonary Dept.. Hindenburgdamm 30. D 1000 Berlin 45. Germany. Fax: 49-30-798-4141. Received February 22.1991; revision July 1,1991; revision January ;n. 1992; revision March 18. 1992; accepted March 19. 1992.

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tachycardia [VT). High energy direct current shocks delivered at the site of earliest endocardial activation during tachycardia produced variable long-term results.^"* Desiccation of ventricular endocardial tissue hy radiofrequency current causes circumscribed homogeneous coagulation necrosis without barotrauma;"' " the size and effect of injury can be controlled to a limited degree by titrated delivery parameters/'^"^ However, the disadvantage of the radiofrequency technique is that only a small tissue lesion resulted after unipolar or bipolar application.'"-^

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Successful operative ablation of VT foci includes removal or destruction of large areas by either endocardial resection,^^ laser photocoagulation,^^-''* or cryoablation.^^ The aim of this study was to examine the feasibility, therapeutic results, and adverse side effects of catheter ablation of ventricular arrhythmogenic foci by use of application of multiple sequential radiofrequency energy via a multipolar electrode catheter in order to enlarge the zone of myocardial ablation. This technique of producing large ablated endocardial areas was investigated with respect to suppression of inducible tachycardia in animals with sustained VTs after myocardial infarction. Possible arrhythmogenic effects using programmed ventricular stimulation were studied in normal dogs and in animals with chronic infarction but no inducible tachycardia.

Methods Animals All studies were performed in accordance with the guidelines of the American Physiological Society. Thirty-one mongrel dogs of either sex weighing 14 to 29 kg (mean 21.3 ± 4.4 kg) were included in this study. Nine dogs had normal hearts, while an experimental myocardial infarction was induced in 22 animals. Of the nine normal dogs, five were sacrificed after the acute studies, and four were allowed to recover for chronic investigation. Of the 22 dogs with myocardial infarction, one died intraoperatively due to refractory ventricular fibrillation, and six others died suddenly within 24 hours of the procedure. Thus, 15 dogs with remote experimental myocardial infarction underwent programmed stimulation in an effort to induce monomorphic ventricular tachycardia, which was successful in only three animals. Experimental Myocardial Infarction The method was described previously.^ In brief, myocardial infarcts were produced in 22 dogs by a modification of a method described by Garan et 81.^*" The loft anterior descending coronary artery was dissected from surrounding tissues immediately distal to the first diagonal

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branch and partially occluded for 20 minutes. It was then ligated along with all visible epicardiai branches in the left ventricular apical area originating from the left circumflex or posterior descending coronary arteries. Fifteen of 22 dogs survived this procedure and were included in the long-term experiments. Ligation proximal to the first diagonal branch of the left anterior descending artery in the first few animals of this series proved fatal within 24 hours after infarction. Thus, the infarct area was diminished by ligating just distal to the diagonal branch. Programmed Ventricular Stimulation Programmed ventricular stimulation was performed before, approximately 30 minutes after, and 20.1 ± 10.0 days [range: 4-38 days) after radiofrequency ablation in the normal and infarcted animais. The infarct age in the latter group was 21.4 ± 6.5 days (range 11-35 days) at the time of the control programmed stimulation and radiofrequency ablation. A programmable stimulator (DTU-101, Bloom and Associates, Reading, PA, USA) was used to apply impulses to three sites (right ventricular apex and outflow tract and left ventricular apex) at twice the diastolic threshold with two basic drive cycle lengths (350 and 280 msec) and up to three extrastimuli. The stimulation was repeated with isoproterenol infusion (4 |j.g/min) or after repeated procainamide application (150 to 250 mg IV) in animals with normal and infarcted ventricles if tachycardia had not been previously induced. Catheter Mapping, Pace Mapping In the dogs with induced sustained monomorphic VT, the site of earliest endocardial ventricular activation during sustained monomorphic VT was localized by catheter mapping at 12 or more different sites and up to 20 different catheter positions with high spatial resolution at sites with early activation. These positions were marked on biplane fluoroscopic screens. Additionally, ventricular pacing was performed at the site of earliest activation to confirm the configuration of the spontaneous tachycardia in the surface ECG leads. The surface ECC and the endocardial electrograms were recorded (Honeywell, Electronics for Medicine VR-16, Pleasantvillo, NY, USA) at a paper speed of 100 mm/sec.

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Radiofrequency Energy System

Unmodulated radiofrequency current of 750 kHz was delivered using a constant voltage power source [Bicap, Model 4005 [Microvasive Inc., Milford, MA, USA]). A custom-made controller device (Mansfield Scientific, Watertown, MA, USA) was used to measure duration, voltage, current strength, power, and delivered energy during radiofrequency energy application. The maximum delivery time for single applications was set at 30 seconds. Surface electrocardiogram leads I, III, Vi and Vs, arterial blood pressure, and energy delivery parameters were recorded continuously (Honeywell, Electronics for Medicine VR-16] at a paper speed of 25 mm/sec during and at least 15 seconds before and after application. A custom-made lowpass filter also allowed surface electrocardiographic recordings during radiofrequency delivery. Uni- and bipolar endocardial electrograms were recorded from the electrodes, which delivered the radiofrequency energy before and after ablation. Technique for Applying Multiple Sequential Radiofrequency Energy

Radiofrequency lesions were created in the left ventricle of the 19 dogs in the chronic [four with normal and 15 with infarcted ventricles] and the five in the acute [with normal ventricles] experiments. Additional lesions were created in the right ventricle of six normal dogs. Standard 6 French quadripolar catheters with 0.5-cm interelectrode spacing [USCI, Div CR Bard Inc., Billerica, MA, USA] were used for application of multiple sequential bipolar radiofrcquency energy. The radiofrequency energy was applied in a circumscribed area at the site of earliest endocardial activation during ventricular tachycardia [three dogs) or at the anterolateral wall, the apex or the septum of the left ventricle, and the anterior wall of the right ventricle in all remaining animals. Applications were applied sequentially between poles 1 [distal electrode] and 2, then between poles 2 and 3, and 3 and 4 [proximal electrode) without changing the catheter position. After marking the position of the catheter on the fluoroscope screen, the catheter was removed, cleaned, and repositioned at a slightly different site, and the sequence was repeated 9 to 11 times in an at-

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Figure 1. Catheter position during multiple sequential radio/requency apphcation (o enlarge ahlated ventricular endocardia! surface. Sequenlial bipolar radio/requency energy application between Ihree adjacent pairs o/eJec(rodes of a standard quadripolar eJectrode catheter, repeated many times with the catheter in slighfJy di//erent positions.

tempt to achieve a perpendicular pattern for the sequential lesions [Fig. 1]. Morphometric and Morphological Examinations At the end of the study, triphenyl-tetrazolium chloride solution (5%, 60 mL] was infused intravenously over 30 minutes to stain viable myocardial tissue for differentiation from ablated or infarcted tissue.'^ The heart volume was measured before and after fixation in 10% buffered formalin solution (pH 7.4) to calculate the shrinkage. After gross examination, the heart was sectioned serially in 2mm slices proceeding from the apex to the base of the ventricles. A planimeter was used to measure the area of the left ventricular myocardium, the infarct area and the area of the radiofrequency ablation lesions in the apical and basal view of each

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slice after sixfold magnification. The volume of the entire left ventricle and of the infarcted or ablated tissue was calculated from these areas. The endocardial surface of the ablation necrosis was marked separately in the apical and basal view of each slice, and the total surface area of the ablated endocardium was calculated. The ablation lesions were distinguished around or within the infarcted myocardium hy a brownish discoloration of the eudocardial surface and the ablated myocardium. Representative samples were taken from all lesions, embedded in paraffin, sectioned using a rotary microtome, and stained with hematoxylin-eosin and trichrome stains.

recorded at infero-apical, septal, and apico-septai locations 70, 85, and 90 msec before the onset of the surface QRS. Pace mapping in this area showed pace induced QRS configurations identical to the induced tachycardia configuration in all recorded leads.

Statistical Analysis

Multiple Sequential Application of Radiofrequency Energy

The tabular data are expressed as means ± standard deviation. Differences of independent quantitative samples were tested with Student's ttest for paired or unpaired values. Results Inducibility of Ventricular Tachycardia Prior to Ablation Normal AnimaJs Two of these dogs with normal hearts did not receive the complete stimulation protocol and thus were excluded from the electrophysiological results, but not from pathological examination. In five of the remaining seven dogs, a maximum of two echo complexes were inducible hy programmed ventricular stimulation, while two dogs developed ventricular fibrillation in response to three extrastimuli. Animols with Inducible Ventricular Tachycardia Sustained monomorphic ventricular tachycardia was inducible in three of the 15 surviving dogs with remote myocardial infarction. The rates were between 285 and 320/min. The VT was hemodynamically and morphologically stable and was reproducibly inducible at least twice after termination by ventricular extrastimuli or overdrive pacing. During left ventricular endocardial mapping, the earliest endocardial activation was

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AnimaJs with Remote Myocardial Infarction without Inducible Tachycardia Sustained monomorphic VT was not inducible in the remaining 12 dogs. However, nonsustained monomorphic (7 to 15 beats, n = 3) or polymorphic VT (n = 3) or ventricular flutter/fibrillation (n ^ 6) was induced.

All dogs had radiofrequency energy delivered in a bipolar fashion at 31 ± 2 different sites in the left or right ventricle. The preset power was 16 ± 5 watts and varied hetween 7 aud 35 watts. During the total of 930 single applications, an impedance rise occurred in 64% after a mean application time of 6.2 ± 5.9 seconds. During this time, 98.9 ± 104.8 joules were delivered to the endocardium. In 36% of applications, however, the preset time was reached without a change of impedance, and 507.7 ± 139 joules were delivered. Thus, the applied mean energy was 247 ± 229 joules for a single application and exceeded 600 joules in only 1.3% of all applications. The mean cumulative energy after multiple sequential radiofrequency application amounted to 9,688 ± 4,191 joules (range 3,965-20,634 joules). A total of 3,609 ± 1,602 joules (range 1,597-5,878 joules) were delivered in the right ventricle. Changes in the endocardial electrograms manifested themselves as reduction of the R wave amplitude and/or elevation of the ST segment and were observed after ablation in 79% of all applications. No hemodynamic complications (i.e., hypotension or low output state) were observed during the procedure. Arrhythmogenic Effects During Radiofrequency Energy Applications There was no difference in the prevalence of acute arrhythmias in normal and infarct dogs.

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Their data are, therefore, combined for purposes of analysis. For the group as a whole, ventricular arrhythmias were observed at the onset of energy delivery for single radiofrequency application or during impedance rise. Single or < 4 repetitive ventricular premature beats (VPBs) were observed in 39% of all 930 applications, while prolonged or sustained episodes of VT occurred in 15% and ventricular fibrillation in 1.6%. Of the 20 episodes of sustained VT or ventricular fibrillation, four occurred a few seconds after completion of the radiofrequency application. All sustained tachyarrhythmias could be terminated by electrical countershock. Ablation of VT Sustained monomorphic VT was inducible in only three of the 15 dogs with myocardial infarction. Sustained monomorphic VT was no longer inducible in these three dogs in the acute study after radiofrequency ablation; however, nonsustained VT (four and eight successive ventricular complexes) could be induced in two and only a single ventricular complex in one. The chronic testing in these three dogs, performed 25 to 38 days after ablation, revealed inducibility of nonsustained tachycardias (three and four beats} in two animals and ventricular flutter in one animal (with triple extrastimuli plus isoproterenol infusion).

Animals with Remote Myocardial Infarction without Previously InducibJe Tachycardia For the 12 animals with chronic myocardial infarction and no previously inducible VT, it was possible in one dog to induce sustained VT immediately after ablation, while nonsustained VT had been inducible beforehand. In the other 11 dogs, nonsustained monomorphic (three and six beats, n = 2) or polymorphic VT (n = 4) or ventricular flutter/fibrillation (n = 5) was inducible immediately after ablation. During late restudy of these 12 dogs, nonsustained monomorphic (three to eight beats, n = 4) or polymorphic VT(n = 4] or ventricular flutter/fibrillation (n = 4) could be induced, but sustained VT was not inducible. These arrhythmias were poorly reproducible and were seen in different animals when comparing the acute and the chronic experiment. Gross Pathological Findings Myocardial Infarcts The volume of the infarcted tissue was 12.1% ± 4.8% of the total left ventricular volume in the three dogs with and 11.5% ± 2.4% in the 12 dogs without inducible tachycardia (NS]. Animals that died within 24 hours postoperatively had a significantly larger infarct than the surviving ones (22.3% ± 8.2% of total left ventricular size vs 11.6% ± 2.8%, P = 0.0001). Gross Effects of Radio/requency Lesions

Latent Arrhythmogenic Effects of Radiofrequency Energy Applications The latent arrhythmogenicity of ablation was determined in all remaining animals without inducible VT prior to ablation. Normal Animals In the seven normal animals studied acutely after radiofrequency application, the ventricular response immediately after ablation was nonsustained polymorphic VT (maximum 3 sec) in four, and a maximum of four ventricular ectopics in the other three animals. In the long-term study, only ventricular ectopics (maximum three beats) could be induced in the four dogs allowed to recover for chronic investigation.

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To study the pathological effects of multiple sequential radiofrequency ablation 24 animals were available: five normal dogs for the acute study (two of them not included in the electrophysiological evaluation), while the chronic study included four normal dogs and 15 dogs with remote myocardial infarction. Ablation resulted in large areas of homogeneous endocardial necrosis in the short-term experiments (Fig. 2) and the development of large confluent scars in the longterm study (Fig. 3). In only one of 24 animals was the lesion covered by loose thrombotic debris; this was found behind the posterior papillary muscle in the chronic study of a normal ventricle. Most radiofrequency lesions revealed a brownish discoloration at the endocardial surface of normal or infarcted tissue. The radiofrequency lesion was

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tion of VT foci ranged between 4.3 and 6.8 cm^. The ablated area in the right ventricle could not be determined due to its extensive trabeculation. AbJated MyocardiaJ Volume The volumes of the radiofrequency induced lesions in the left or right ventricle were similar and ranged from 0.3 to 2.4 cm^ (mean 1.1 ± 0.6 cm^]. They were 1.1 to 2.1 cm"* in the left ventricles of the three dogs with ablated VT. The correlation between the ablated volume and the cumulated radiofrequency energy applied was weak (r = 0.3, NS). Histologic Results Recent Lesions

Figure 2. Cross section of the normal heart after in vivo calheter ablation using a cumulative radiofrequency energy of 5.965 joules. The muItipJe sequentiaJ ablation resuJted in extensive necrosis limited to the endocardium/subendocardium wifh a surface area of 4.1 cm^ (dotted line).

limited to the subendocardium with a sharp horder between the normal or infarcted tissue and could be differentiated from the transmural infarcted scar by the discoloration due to the ablative energy and/or enhanced hemorrhage (Fig. 3). Transmural necrosis was not observed in the left ventricle. Radiofrequency lesions were at the border zone of the myocardial infarcts in all animals with a successfully ablated tachycardia focus. All right ventricular lesions were concentrated in one area and displayed three to six small transmural scars due to single applications. AbJated Endocardiai Surface In 24 dogs, the area of the ablated endocardial/ subendocardial surface either in the acute or longterm experiments ranged from 2.4-10.0 cm^ with a mean of 4.7 ± 2.2 cm^ The mean depth of the myocardial necrosis was 2.3 mm, the maximum depth 4 mm. The area suitahle for successful abla-

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The immediate effects of endocardial ablation included a coagulation necrosis surrounded by a narrow hemorrhagic border, thus providing a sharp homogeneous demarcation from normal myocardial tissue. Long-Term Reaction Chronic radiofrequency lesions consisted of coagulation necrosis, presence of chronic inflammatory cells, hemorrhage, myocardial scarring, proliferation of the fibroblasts, and thickening of the endocardium. Histologic examination of the focus of VT showed collagen bundles, fibroblasts, macrophages, collapsed blood vessels, and hemorrhage. Several bundles of normal or only slightly damaged myocardial cells were embedded in this connective tissue with a diameter of approximately 5 to 30 cells. These bundles were also found in the scars of hearts without previously inducible tachycardia, but less frequently. However, an accurate quantitative comparison was not performed. At low power magnification, the radiofrequency lesions revealed a homogeneous border with normal tissue and could thus be distinguished from the diffuse, scattered scarring of the transmural infarction, which had an inbomogeneous border with viable cells surrounded by fibrous tissue (Fig. 4). Catheter Condition No catheter showed gross evidence of insulation or electrode damage, but often thin layers of

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Figure 3. Left venlricJe with chronic anterior infarcfion after multiple sequenfial radiofrequency ablation of the inferoapical region (38 days after abiafionj with a large abiofed area farrows, surface area: 5.4 cnr} limited to the endocardiai/siibendocardia] Jayer at the site of earliest endocardia] activation during monomorphic ventricular tachycardia. The chordae tendineae of the anteWor papillary muscle were cut for better visibility.

blood coagulum or small tissue particles were found on the electrodes, particularly after impedance rise had occurred.

Discussion In this report we show that multiple sequential bipolar radiofrequency application allowed for ablation of large endocardial/suhendocardial surface areas in healthy and diseased myocardium. A mean cumulative energy of 9,688 joules applied at a target site yielded an ablated surface area of up to 10 cm^ (mean 4.7 ± 2.2 cm^) with an average depth of 2.3 mm and a maximum depth of 4 mm. No transmural involvement of the left ventricle was observed. The right ventricle exhibited tiny transmural scars without perforation comparable to prior studies using unipolar applications.^ In addition, we showed that this method successfully ablated the VT focus in the three animals with inducible sustained VT. Despite induction of frequent ventricular ar-

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rhythmias (56% of all dogs) during or just after radiofrequency application, no long-term arrhythmogenic effect was found. No animal died after radiofrequency ablation, and none had inducible VT during chronic restudy performed 3 weeks after radiofrequency ablation using an aggressive stimulation protocol. The induction of polymorphic VT or ventricular flutter/fibrillation immediately after ablation was poorly reproducible in the chronic experiments, probably indicating a nonspecific response. The gross and histologic examination after long-term experiments revealed a homogeneous myocardial scar at the area of radiofrequency ablation covered by proliferated, thickened endocardium. This differed significantly from the infarct area, which exhibited an inhomogeneous border zone with viable cells contained in fibrous tissue. The ablated area in all animals with inducible tachycardia involved ischemic and normal myocardium. Histologic evaluation of the tissue of the

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Figure 4. Photomicrograph of a chronic endocardial radio/requency lesion at the border of the chronic myocardiaJ infarct (site of earliest endocardial activation during tachycardia). The radiofrequency lesion (right) shows coagu]ation necrosis, scarring, and hemorrhage with a sharp border with narmal (issue (bottom, white arrows) containing chronic inflammatory cells. The proliferation af the endocardium is aiso evident. The myocardiaJ infarct (left] shows a discontinuous border zone to normai tissue (at the cut artifact, black arrows) including parts of viable tissue. (Hematoxylin and eosin, x 50)

VT foci revealed bundles of normal myocardial cells embedded in connective tissue, as described for human endocardial specimens resected surgiUse of Radiofrequency Energy for Endocardial

Ablation Radiofrequency energy has been used experimentally and clinically for ablation of the sinoatrial node,^^ intraatrial ablation,'' induction of chronic incomplete atrioventricular block,•'•^"•^^ ablation of accessory pathways^^'^' or in the canine coronary sinus,^^ ablation of bundle branch reentry,^^ and intraventricular ablation.''"^•"•'•^'^' However, an early rise of impedance at the catheter/tissue interface due to charring of tissue and/or formation of a blood coagulum often limited the amount of delivered energy and the lesion .^'^ In our experience, an impedance rise oc-

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curred in 64% of all applications after a mean of 6 seconds. The linear relation between delivered energy and lesion size^'^" renders only single radiofrequency energy applications inappropriate in patients with VT. Even the stepwise increase of the radiofrequency power level with sufficient exposure duration at each level to allow for stabilization^° only results in slight increases in the lesion size. Thus, tbe use of multiple bipolar radiofrequency energy seemed necessary, since the unipolar application appeared unlikely to achieve the destruction of tissue volume required to ablate reentrant VT. Efficacy of Ablation of Large Endocardial Surfaces for Treatment of VT Map-guided subendocardial resection usually involves removal of 10 to 16 cm^ of tissue to a

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depth of 3 to 4 mm.^^ Regions of subendocardial scars have been burned off to an area of 16 to 60 cm^ by Nd:YAG laser pbotocoagulation," and subendocardial lesions produced by cryoablation produce lesion areas of 20 cm^ to a depth of 3 to 6 mm.^"'' Transcoronary chemical ablation of VT may also produce large transmural lesions.^" Thus, enlargement of the ablated endocardial area by the transcatheter application technique described here may be the key to successful tachycardia focus ablation.

Limitations The effectivity of single bipolar radiofrequency applications after VT mapping was not tested by repetitive programmed stimulation during the multiple ablation procedure. Thus, it remains unclear whether single applications were already capable of ablating the VT focus.

Clinical Implications Our results demonstrate that multiple sequential catheter ablation by application of radiofrequency energy at the site of earliest ventricular activation during sustained monomorphic VT destroyed the tachycardia focus by producing large endocardial surface necrosis. There is no evidence of a proarrhythmic effect of this method in the long-term experiments. However, sustained tachyarrhythmias occurring during or shortly after radiofrequency application may complicate the procedure. Thrombus formation was observed only rarely. But the occurrence of thin layers of coagulum may produce embolism in patients, thus necessitating systemic anticoagulation. Ablation necrosis was always limited to the endocardium/subendocardium of the left ventricle, suggesting that ventricular perforation is unlikely. Right ventricular ablation is recommended with caution, since transmural scars—though never perforation— were observed in tbe right ventricular myocardium.

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