Europace Advance Access originally published online on May 9, 2007
Europace 2007 9(7):490-495; doi:10.1093/europace/eum039
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ATRIAL FIBRILLATION ABLATION
Platelet activation and myocardial necrosis in patients undergoing radiofrequency and cryoablation of isthmus-dependent atrial flutter
Herz-Zentrum Bad Krozingen, Suedring 15, 79189, Bad Krozingen, Germany
Manuscript submitted 15 January 2007. Accepted after revision 22 February 2007.
* Corresponding author. Tel: +49 7633 402 725; fax: +49 7633 402 425. E-mail address: willibald.hochholzer{at}herzzentrum.de
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Abstract |
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Aims Lower platelet activation by cryoenergy compared with radiofrequency (RF) energy was recently demonstrated immediately following ablation procedures of cardiac arrhythmias. Due to the delayed occurrence of cryolesions it is currently unknown, if cryoenergy and RF energy are associated with similar platelet activation and myocardial necrosis in the days after the procedure.
Methods and results We enrolled 38 patients with common atrial flutter undergoing cavotricuspid isthmus ablation with either RF energy (n = 23) or cryoenergy (n = 13). Ten patients undergoing RF ablation and receiving aspirin served as antiplatelet control group. Troponin T and platelet surface protein expression of P-selectin were determined before and immediately after ablation as well as on day 1 and 2 thereafter. Rise in troponin T was amplified after RF ablation (0.50 ± 0.37 µg/L) when compared with cryoablation (0.24 ± 0.20 µg/L; P = 0.024). In patients without aspirin, a significant increase in P-selectin expression was observed on day 1 after intervention in RF ablation compared with cryoablation (80 ± 26 vs. 63 ± 16 arbitrary units; P = 0.048). Platelet activation was attenuated in patients receiving aspirin.
Conclusion Successful ablation of atrial flutter with cryoenergy is associated with less myocardial necrosis and platelet activation compared with ablation with RF energy. Increased platelet activation following RF ablation can be attenuated by concomitant treatment with aspirin.
Key Words: Cryoablation, Radiofrequency ablation, Platelets, Necrosis, Atrial flutter
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Introduction |
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Radiofrequency (RF) ablation as catheter therapy for cardiac arrhythmias has been introduced in clinical medicine in the mid-1980s and has become the treatment of choice for a wide variety of arrhythmias.1
–3 One of those, common atrial flutter, is a macroreentrant tachycardia propagating counter-clockwise or clockwise through the cavotricuspid isthmus.4,5 Radiofrequency ablation of this arrhythmia is associated with high cure rates during long-term follow-up.6,7 Although RF ablation has proven to be safe in general, thromboembolic events including stroke occur in 0.6–5.6% of patients despite appropriate use of oral anticoagulation and heparin, especially in left-sided procedures.3,8–11 The crucial role of platelet activation by myocardial necrosis or by heating and destruction of blood cells during ablation procedure is a matter of debate.8,9,12 Such platelet activation can be suppressed by antiplatelet therapy as demonstrated in patients receiving aspirin. These patients showed a significant decrease of several indirect markers of platelet activation and a blunted increase of D-dimer.13–15
Transvenous cryoenergy is a new technique for the ablation of supraventricular arrhythmias.16–18 It seems to be associated with a lower thrombogenicity due to less endothelial disruption and preservation of the extracellular matrix.19–21 A first study investigating the effects of RF and cryoenergy on the activation of thrombocytes and the coagulation system showed a significantly lower platelet activation with cryoablation during the procedure as well as immediately thereafter.22 However, one of the major mechanisms of cryolesion formation is the occlusion of small blood vessels inducing a subsequent ischaemic necrosis, which develops with a delay of several hours after the ablation procedure.23 It is therefore desirable to study the post-procedural time course of platelet activation and markers of myocardial necrosis in patients undergoing cryoablation to get a full estimate of the thrombogenic potential of this procedure.
We therefore designed this study to test the hypothesis that cryoablation is associated with less post-procedural myocardial necrosis and platelet activation compared with RF ablation. Further on, we investigated the impact of antiplatelet therapy with aspirin on the effects of RF ablation.
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Methods |
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Patient selection
Our study enrolled consecutive patients with persistent or paroxysmal common atrial flutter scheduled for an ablation of the cavotricuspid isthmus. Patients were eligible for the study if they were on chronic treatment with oral anticoagulants without antiplatelet co-medication and underwent either RF or cryoablation, as decided by the operator. Oral anticoagulation was continued for at least 4 weeks after the procedure. Ten patients receiving chronic treatment with aspirin (
100 mg per day) undergoing RF ablation were enrolled as antiplatelet control group. We excluded patients with previous cardiac ablation therapy or MAZE procedure, patients with a history of previous cardio-embolic events, patients with planned additional ablation due to arrhythmia other than atrial flutter, patients with severe concomitant diseases (e.g. malignant tumour or terminal renal failure), and patients with any contraindication to heparin. All patients gave written informed consent. The study was performed according to the principles of the Declaration of Helsinki, and our institutional ethics committee approved the study protocol.
Ablation therapy
Vascular access was obtained through the right femoral vein. A 10-pole mapping catheter (Lifewire®, St. Jude Medical, Eschborn, Germany) was positioned in the lateral right atrium and a quadripolar catheter in the His position. Mapping of the isthmus and the coronary sinus was performed by the steerable ablation catheter. Participation of the cavotricuspid isthmus in the re-entrant circuit was confirmed by entrainment mapping in all patients.24 For this purpose, atrial flutter was induced in patients in sinus rhythm by programmed atrial stimulation.
Ablation was performed through the isthmus in a point by point fashion starting at the ventricular side and moving to the inferior vena cava. Radiofrequency energy was delivered with an irrigated tip ablation catheter (Thermocooled, Biosense Webster, Diamond Bar, CA, USA) with a target temperature of 50°C, a maximum output of 40 W and an irrigation rate of 16 mL/min. For RF ablation, we used a drag method with an application time of 2 min. Cryoablation was delivered with a deflectable, 6.5-mm tip, 10F catheter using the CryoCorTM cryoablation system (CryoCor Inc., San Diego, CA, USA) with a minimum temperature of minus 90°C. The length of each cryoapplication was 6 min.
Goal of the ablation was a complete conduction block which was confirmed by change of the activation sequence of the lateral wall during pacing from the coronary sinus and of the septum during pacing of the low right atrium, respectively. Furthermore, the line was checked for double potentials along the line during pacing of the low right atrium as close as possible to the line. Conduction block was re-evaluated after a 30-min wait.
Blood sampling
Blood samples for platelet function assays were drawn by puncture of an antecubital vein with a 19-gauge needle using minimal venous occlusion and not via the venous sheath from the femoral vein to prevent artificial platelet activation. The first 5 mL of blood were discarded. Samples were collected in tubes containing 3.8% buffered sodium-citrate for platelet function analyses while cardiac troponin was measured in serum (Sarstedt AG, Germany). We obtained the first blood sample before catheterization, the second sample immediately after the ablation procedure and two further blood samples 24 and 48 hours thereafter.
Cardiac troponin T measurement
Troponin T was determined using the troponin T STAT electrochemiluminescent immunoassay on an Elecsys 2010 system (Roche Diagnostics, Mannheim, Germany). The analytical range extends from 0.01 to 25 µg/L. The coefficient of variation (imprecision) of this assay is 6% at 0.09 µg/L, 7% at 0.06 µg/L, 10% at 0.03 µg/L, and 30% at 0.01 µg/L. The cut-off value for diagnosis of myocardial infarction according to ESC/ACC guidelines is 0.03 µg/L.
Flow cytometry
Blood samples were processed immediately (<10 min). Expression of P-selectin (CD62P-PE, Coulter, Krefeld, Germany), and activated GP IIb/IIIa (PAC-1-FITC, Becton Dickinson, Heidelberg, Germany) was determined by flow cytometry as previously described.25,26 Concisely, platelets were identified by size and a platelet-specific monoclonal antibody (CD41-PC7, Coulter, Krefeld, Germany) in whole blood to prevent platelet activation by further processing. After incubation with antibodies for 30 min, 300 µL phosphate-buffered saline (Sigma-Aldrich, Taufkirchen, Germany) containing para-formaldehyde was added for dilution and fixation. Samples were analysed immediately after fixation. A four channel flow cytometer equipped with a 488 nm argon laser (FACSCalibur, Becton Dickinson, Heidelberg, Germany) was used and 10 000 events were analysed from each sample. The mean channel of fluorescence intensity was taken as a measure for the antibody binding, and thus antigen surface exposure. To determine the cut-off for platelets with surface exposure of P-selectin or activated GP IIb/IIIa (equal positive cells) we tested blood samples of 10 healthy volunteers without cardiovascular disease and took the 97th percentile of the mean cell distribution as cut-off.
Statistical analysis
For all statistical analyses, we used the SPSS software package, version 13.0 (SPSS Inc., Chicago, USA). Continuous variables were tested for normal distribution by Kolmogorov–Smirnov test. Discrete variables are reported as counts (percentages) and continuous variables as mean ± SD. We tested differences between groups with the 
2 test for discrete variables and with one-way ANOVA followed by Scheffe's test for continuous variables. In the two-tailed test, a P value < 0.05 was regarded as significant.
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Results |
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Study cohort and ablation therapy
Our study enrolled 38 consecutive patients scheduled for elective cavotricuspid isthmus ablation between April 2004 and June 2005. Thirteen patients with oral anticoagulation and without antiplatelet therapy were scheduled for RF ablation and 15 patients for cryoablation. Ten patients with concurrent aspirin therapy (8 of 10 without oral anticoagulation) undergoing RF ablation served as an antiplatelet therapy group. Baseline characteristics of the patient cohorts are shown in Table 1. Isthmus ablation therapy was indicated due to paroxysmal common atrial flutter in the majority of patients (92%). Paroxysmal atrial fibrillation was present in about 50% of patients.
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Cavotricuspid isthmus ablation was successful in all patients. One patient with initially unsuccessful cryoablation of the cavotricuspid isthmus was shifted to successful RF ablation. In patients undergoing RF ablation, the mean procedure time was 143 ± 63 min, mean ablation time 30 ± 13 min, and mean total energy 87 ± 35 kJ. Similar results were obtained in patients with cryoablation, where the mean procedure time was 142 ± 57 min, and mean ablation time was 34 ± 16 min. No thromboembolic events occurred during the procedure or the systematic follow-up of 30 days. Furthermore, no recurrence of common atrial flutter was recorded during this follow-up period. After this period, two patients were readmitted to our hospital with a relapse of isthmus-dependent atrial flutter (one patient at day 287 after cryoablation and the other patient at day 555 after RF ablation).
Myocardial necrosis
In patients undergoing RF ablation the time course of troponin T displayed an early peak immediately after ablation procedure and decreased thereafter (Figure 1). The increase in troponin T in patients with cryoablation was delayed with the maximal increase occurring on the first post-procedural day. Radiofrequency ablation caused significantly higher troponin levels after ablation (P = 0.026) which in 21 of the 23 patients investigated (91%) exceeded 0.3 µg/L (10 x over the cut-off value for diagnosis of myocardial infarction) compared with 8 of the 15 patients (53%) undergoing cryoablation (P = 0.009). A more substantial increase in troponin T (>1.0 µg/L) was observed in four patients undergoing RF ablation (17%) compared with only one patient with cryoablation (7%; P = 0.067). No significant differences could be found between patients undergoing RF ablation with or without antiplatelet therapy (data not shown).
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) and with cryoablation (
). Comparison between cohorts by one-way ANOVA.Platelet activation
Mean expression of P-selectin, a marker of platelet degranulation and activation, increased significantly in patients undergoing RF ablation without aspirin, whereas it displayed a contrary trend in patients undergoing cryoablation (Figure 2). P-selectin was significantly higher in RF patients at day 1 after ablation compared with cryoablation patients (P = 0.048). Radiofrequency ablation caused no alteration in P-selectin expression in aspirin treated patients.
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), and in patients undergoing cryoablation (The surface expression of the activated receptor for fibrinogen (GP IIb/IIIa), a marker of advanced platelet activation, also decreased after cryoablation, while it was not altered by RF ablation in patients with or without concomitant aspirin-treatment (Figure 3).
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To define the proportion of patients with a significant rise in platelet activation after ablation therapy, we analysed the number of patients with an increase of > 100% in platelets positive for either P-selectin or activated GP IIb/IIIa (Figure 4). Patients undergoing RF ablation without antiplatelet therapy experienced an increase of P-selectin positive platelets four times more often than patients with cryoablation (53.8% vs. 13.3%; P = 0.022). A blunted increase of positive platelets was found in aspirin-treated patients. The increase of platelets positive for activated GP IIb/IIIa displayed a similar trend (Figure 4).
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Discussion |
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Main findings
This study investigated the extent of myocardial necrosis and platelet activation in patients undergoing RF ablation or cryoablation of the cavotricuspid isthmus. Furthermore, the effect of treatment with aspirin (
100 mg per day) was determined in patients undergoing RF ablation. There are three major findings of this study: First, cryoablation is associated with less marked and delayed myocardial necrosis compared with RF ablation. Second, while RF ablation is associated with a significant increase in expression of platelet surface proteins, this effect was not found with cryoablation. Third, the extent of platelet activation caused by RF ablation can be diminished by concomitant therapy with aspirin.
Myocardial necrosis
A post-procedural rise in troponin as a highly specific and sensitive marker for myocardial necrosis could be demonstrated in all patients. In RF ablation, peak troponin levels were observed immediately after the intervention with a subsequent decrease at day one and two. The latter time course indicates that maximum formation of necrosis already occurs during the procedure. In contrast, the peak in troponin T levels in patients undergoing cryoablation occurred at the first post-procedural day. This finding might be the consequence of the occlusion of small blood vessels which is regarded as one of the major mechanisms of cryolesion formation.23 Myocardial necrosis following cryoablation is not only the result of intracellular ice formation and coalescence of ice crystals into larger ice crystals during early rewarming phase, but is also due to the formation of microthrombi in small vessels caused by endothelial damage. A previous study demonstrated that about 4 h after thawing, small blood vessels were occluded which results in a delayed ischaemic necrosis.23
Nevertheless, the extent of the myocardial necrosis was smaller after cryoablation even though this procedure displayed similar success rates with respect to occurrence of atrial flutter. This can be explained by the homogeneous histological structure of cryolesions with smoother and sharper demarcation from intact myocardium compared with RF lesions. It is suggested that the latter effect might also be responsible for the observed lower incidence of complications like AV block during cryoablation.18
Platelet activation
Radiofrequency ablation caused an increased expression of platelet activation markers which confirms the results of several previous studies investigating platelet activation by indirect markers.14,21,27–29 In contrast to the findings regarding RF ablation, cryoablation caused increased platelet activation only in a minority of patients while the mean of the cohort displayed a trend towards decreased platelet activation after ablation with cryoenergy. Our results extend the findings of a recently published study investigating platelet activation in patients undergoing pulmonary vein ablation with either RF or cryoenergy.22 Tse and co-workers reported in their study a significant platelet activation directly after RF ablation but not after cryoablation. We now demonstrate that RF ablation causes immediate platelet activation, while this effect is delayed and attenuated after cryoablation. The observed platelet activation following RF ablation can be diminished by antiplatelet treatment using aspirin.
The exact mechanism responsible for the lower platelet activation and the subsequent reduction in thrombus formation by cryoenergy is unknown, so far. One possible reason for our findings might be that cryoenergy results in lower thrombus formation as shown in experiments with cryoablation in dogs.19 One may also speculate that the lower level of thrombus formation may be attributed to the size of the cryolesions, but Khairy et al. failed to demonstrate any correlation between extent of cryolesion and thrombus formation.19
Other studies focused on the relationship between hypothermia and platelet function. Experimental settings using ex vivo as well as in vivo methods showed decreased platelet function at decreased temperatures.30,31 Several mechanisms for temperature dependent impaired platelet function have been demonstrated such as diminished production of the arachidonic acid metabolite thromboxane A2, decreased 
-degranulation, and decreased surface expression of GP Ib-V-IX complex (receptor for von Willebrand factor).30
Increased platelet activation induced by myocardial necrosis has been described in other clinical situations such as myocardial infarction.32,33 Therefore, it may be speculated that the attenuated myocardial necrosis caused by cryoablation—as demonstrated in our study—is responsible for the attenuated expression of surface proteins indicative for platelet activation. Moreover, the histology of cryolesions reveals a sharply delineated necrosis zone with preserved ultrastructure of the underlying tissue and extracellular matrix19 and minimal surface exposure of the intracellular components activating thrombocytes (e.g. collagen).
Limitations
Due to the limited number of patients, we cannot draw firm conclusions about the clinical impact of our findings. Furthermore, only effects of the applied procedures on platelet activation were determined. As platelet activation is only one factor triggering activation of the coagulation system, a complete assessment of the effects of RF and cryoablation on the coagulation cascade and therefore on the overall thromboembolic risk associated with these procedures is beyond the scope of the present investigation.
Conclusions
Successful ablation of the cavotricuspid isthmus with cryoenergy compared with an ablation using RF is associated with less and delayed myocardial necrosis and lower platelet activation. The results of this study support the clinical impression that cryoablation might be associated with a lower thromboembolic risk compared with RF ablation. Platelet activation caused by RF ablation procedures can be diminished by antiplatelet therapy with aspirin. The latter finding might be of superior clinical importance in ablation procedures with higher risk for thromboembolic events, such as left-sided ablations.
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The study was supported by a grant from the Herz-Zentrum, Bad Krozingen.
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References |
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