ClinicalAblationCellular damage, platelet activation, and inflammatory response after pulmonary vein isolation: A randomized study comparing radiofrequency ablation with cryoablation
Introduction
Transvenous pulmonary vein isolation (PVI) is a new effective treatment for atrial fibrillation (AF).1, 2, 3 However, rare but potentially life-threatening complications such as thromboembolism,4, 5 pulmonary vein (PV) stenosis,6, left atrium–esophageal fistula,7 and inflammatory syndromes8 have been described. In an attempt to reduce the incidence of complications, alternatives to the traditionally used radiofrequency (RF) energy have been investigated. Cryoenergy has been used since the mid-1970s for the surgical management of arrhythmia substrates.9, 10 It was first introduced as a catheter-based technology in 2000.11 Cryoablation has been shown to result in lesions characterized by dense homogeneous fibrosis with well-delineated border zones and preservation of the extracellular matrix and tensile strength,12 as well as to reduce endothelial disruption and thrombus formation.13, 14 Therefore, cryoablation appears to represent the ideal energy for safe creation of lesions in the left atrium. To further assess the differential effects of cryoablation vs RF energy in patients undergoing PVI, we measured markers of tissue damage, platelet activation, and inflammatory response before and up to 48 hours after the procedure. We hypothesized that cryoablation would be associated with a favorable safety profile compared to RF energy.
Section snippets
Patients and methods
Between April 2007 and April 2009, 60 patients with highly symptomatic, drug-refractory paroxysmal or persistent episodes of AF referred to our center were randomly assigned to undergo transseptal PVI using either an open irrigated-tip radiofrequency catheter (RF group) or a cryoballoon catheter (Cryo group). Exclusion criteria were long persistent AF (>12 months), left atrial diameter >55 mm, intracardiac thrombi determined by transesophageal echocardiography, myocardial infarction or cardiac
Results
The clinical and baseline characteristics of patients treated with cryoablation or RF ablation are listed in Table 1. After an AF history of 5.2 ± 3.6 years and a mean number of 2.8 ± 1.0 unsuccessful antiarrhythmic drugs, 38 patients presented with paroxysmal AF and 22 with persistent AF. Nineteen patients (32%) had a history of structural heart disease, and 27 (45%) had arterial hypertension.
Procedural parameters
Procedural time was significantly shorter using the cryoballoon (177 ± 30 minutes) compared to using RF catheters (200 ± 46 minutes, P = .028), but fluoroscopy time was similar (38 ± 12 minutes vs 37 ± 16 minutes respectively, P = .827). RF was applied over 52 ± 21 minutes to achieve isolation of all 4 veins (total delivered energy 87,584 ± 35,953 J). In the Cryo group, 21 patients were ablated using a 28-mm balloon, 7 with a 23-mm balloon, and 2 using both sizes. Ten patients required
Cellular damage
Myocardial damage as indicated by a significant increase in hs-TnT was observed both after cryoablation and after RF ablation (Figure 1). The total release of hs-TnT over time as calculated by the area under the time course up to 48 hours after ablation provided similar figures for both methods (32.7 ± 11.5 ng/mL*h–1 vs 37.8 ± 15.3 ng/mL*h–1 for Cryo and RF, respectively; P = .153). Compared to patients who did not need supplementary focal cryoablations, patients who received touch-ups
Platelet activation
Significant activation of platelets could be detected 24 and 48 hours after ablation in both groups (optical aggregometry, surface expression of P-selectin and GP IIb/IIIa). No significant differences were found between treatment groups (Figure 3).
Inflammatory response
There was a significant inflammatory response after both cryoablation and RF as represented by an increase in hs-CRP 24 and 48 hours after the procedure. There was a trend toward a higher peak value after 48 hours after RF ablation (28.6 ± 22.7 mg/L vs cryoablation 20.5 ± 23.3 mg/L, P = .175), with no statistically significant differences after correction for repeated measurements (Figure 4).
Table 3 provides an overview of the global effect of ablation on the different laboratory parameters in
Follow-up
After median follow-up of 12 months (range 3–29 months), 24 patients (80%) after RF ablation and 19 (63%) after cryoballoon ablation were free of AF without antiarrhythmic drugs (P = .15; Figure 5). One patient in the Cryo group presented with typical AV nodal reentrant tachycardia that was successfully ablated 2 months after the index procedure; another patient had a single recurrence of AF 10 months after catheter ablation in the context of a manifest hyperthyroidism. Two patients in the RF
Discussion
In this randomized study, we showed that PVI procedures produce tissue damage, inflammatory response, and platelet activation. Both cryoenergy and RF energy resulted in a comparable rise in all laboratory markers, not supporting a safety benefit of cryoenergy over RF.
Influence of lesion size
This finding contrasted with our previous findings, suggesting reduced platelet activation after ablation of cavotricuspid-dependent atrial flutter using cryoenergy.21 However, in that study, troponin release was significantly lower after cryoablation than after RF ablation, suggesting a lesser extent of lesions. In addition, recently published randomized trials using different energies for treatment of typical right-sided flutter showed a significantly higher recurrence rate after focal
Microparticles
Circulating procoagulant MPs are small membrane vesicles that are shed from virtually all cells in response to activation, thermic injury, and/or apoptosis. Apart from being a reliable probe of vascular injury, circulating procoagulant MPs, mainly of platelet, leukocyte, and endothelial origins, provide an additional phospholipidic surface for the assembly of blood coagulation factors, thereby promoting the coagulation cascade and thrombin generation. Using real-time intravital microscopy to
Platelet activation
RF ablation procedures bear a low but clinically significant risk of thromboembolic events.32 Previous studies have already shown that RF ablation induces activation of platelet function.21, 33 In vitro studies pointed out that cryolesions displayed lower thrombus formation than RF lesions.14 Further clinical studies found lower platelet activation using cryoenergy compared to RF energy,21, 23 suggesting that cryoenergy might be a safer alternative to RF energy, especially for left-sided
Inflammatory response
Previous studies using RF have demonstrated that ablation triggers inflammation response, frequently associated with generalized edema.8 Histopathologic studies have established that RF ablation induces necrosis followed by inflammatory infiltrates leading to a fibrotic scar.
In the present study, we confirmed that leukocyte-derived MPs, a reliable probe of leukocyte stimulation, and hs-CRP significantly rose following ablation. However, no differences could be evidenced between patients ablated
Clinical implications
Cryoballoon ablation is a powerful method for creating circumferential lesions around the PVs, as indicated by significant hs-TnT release and a clinical success rate comparable to PVI performed with a standard irrigated-tip catheter. Moreover, procedural time was significantly shorter using the cryoballoon. However, the safety arguments initially favoring the use of cryoenergy might not be valid when using the cryoballoon. We could not detect any important difference in tissue damage, platelet
Study limitations
Cryoballoon and irrigated-tip RF PVI involve use of a sheath and a catheter of very different sizes. Those technical disparities could have influenced platelet activation and inflammation parameters.
Intraprocedural blood sampling was performed from the vascular sheath in the right atrium and postprocedural blood sampling from a peripheral vein. The site and method of sampling could have influenced the measurement of biomarkers, but it would have affected both groups in the same manner.
Our study
Conclusion
In this prospective randomized trial, the cryoballoon and the irrigated-tip RF catheter induced a similar rise in systemic sensitive laboratory markers of cell damage, platelet activation, and inflammation after PVI. Lesion size rather than ablation method appears to be responsible for the magnitude of the systemic procoagulant and inflammatory response.
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The first 2 authors contributed equally to this study. This study received financial support from CryoCath. Dr. Herrera Siklódy received consulting and speaking fees from Medtronic, Biosense Webster, and St. Jude. Dr. Arentz received consulting and speaking fees from Medtronic and St. Jude. ClinicalTrials.gov identifier: NCT00773539.