Author + information
- Received August 3, 2015
- Revision received October 23, 2015
- Accepted November 19, 2015
- Published online April 1, 2016.
- Bernard Lim, MD, PhDa,∗ (, )
- K.L. Venkatachalam, MDb,
- Benhur D. Henz, MDc,
- Susan B. Johnson, BSd,
- Arshad Jahangir, MDe and
- Samuel J. Asirvatham, MDd,f
- aPrairie Cardiovascular Consultants, Springfield, Illinois
- bCardiovascular Diseases, Department of Medicine, Mayo Clinic, Jacksonville, Florida
- cInstituto Brasília de Arritmia, Brasília, Brazil
- dDivision of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
- eAurora Health Care, Center for Integrative Research on Cardiovascular Aging (CIRCA), Milwaukee, Wisconsin
- fDepartment of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota
- ↵∗Reprint requests and correspondence:
Dr. Bernard Boon Chye Lim, Prairie Cardiovascular Consultants, Baylis Medical Building, 747 North Rutledge Street, Springfield, Illinois 62702.
Objectives This study reports on a novel method to prevent coagulum formation by continuously delivering a negative charge to the catheter tip to repel negatively charged fibrinogen molecules during RF ablation.
Background Radiofrequency (RF) ablation for cardiac arrhythmias is associated with a 70% incidence of coagulum formation on the catheter tip during ablation and a 10% incidence of thromboembolic events. Catheter tip thrombus can impede RF energy to the tissue, reducing efficacy and increasing procedure times.
Methods A novel circuit was built to deliver a negative, fixed-offset, direct current-based charge using a 9-V battery, placed in parallel with an RF delivery unit during RF ablation. In in vivo canine experiments, standard ablation catheters were advanced into atria and ventricles under fluoroscopic guidance. The presence of thrombus with and without RF delivery was identified with intracardiac echocardiography.
Results Scanning electron microscopy of the catheter tips showed clot coverage of the catheter tip to be 90% for noncharged catheters compared to 0% (p < 0.01) in negatively charged catheters. Volume of clot formed on the catheter tip decreased with increased amount of charge (140 ± 5.3 arbitrary units with no charge vs. 0 arbitrary units with a 100-μA current delivering negative charge, p < 0.01). Application of a negative charge did not affect the quality of the intracardiac electrogram or induce malignant ventricular arrhythmias.
Conclusions Negative-charge delivery to ablation catheter tips and tissue during RF ablation is feasible and safe and can eliminate coagulum formation, potentially reducing thromboembolic complications.
- charge delivery
- clot prevention
- radiofrequency ablation
Coagulum formation on catheter tips and denuded tissue during radiofrequency (RF) ablation can lead to thromboembolism and stroke. Much effort has been directed toward the development of strategies to prevent this devastating complication (1). Many different approaches have been used either to vary the intensity of anticoagulation with intravenous heparin (1–3) or to limit the temperatures obtained during ablation (4–6). In typical high-intensity protocols, activated clotting times that range from 300 s to 350 s (7,8) are achieved. Although coagulum is reduced with these regimens, thrombi and thromboembolic events still occur with high frequency (8). Furthermore, the high-intensity regimens may be associated with a higher risk of bleeding. Irrigation methods have also been used to lower temperature during ablation (9–11). However, coagulum formation is not prevented and furthermore, there may be a problem of embolization of the clot via the process of irrigation itself. Also, the fluid received by heart-failure patients during a typical irrigated-tip ablation places them at increased risk for fluid overload, necessitating ongoing diuresis.
These limitations provide the incentive for the development of new ablation strategies. One such approach would be to deliver a negative charge to repel blood elements (12). One of the key components of blood is fibrinogen, the building block of a clot, which is negatively charged (13,14). We have shown previously that if fibrinogen is allowed to bind to positively charged surfaces, conformational changes occur in the fibrinogen molecule (15,16), which could lead to the release of fibrinopeptides (17) and spontaneous thrombosis (15). We had found that the deposition of a negative charge on catheter surfaces repelled fibrinogen molecules and prevented formation of coagulum. We now extend these preliminary data further by determining whether it is possible to deliver negative charge while simultaneously delivering RF energy, to reduce coagulum formation in live canine ablation experiments.
The experimental protocol was approved by the Mayo Foundation Institutional Animal Care and Use Committee. The authors had full access to the data and take full responsibility for their integrity.
Design of a novel circuit for charge delivery during RF energy delivery
A key requirement of the circuit is to be able to deposit negative charge continuously on the electrodes and the tissue without affecting the electrogram signal amplitude/quality or the ability of the ablation unit to deliver energy to the tissue. This was done by using an arrangement of high-impedance current delivery parallel to the signal processing pathway (Figure 1). A 9-V battery was used as the source of DC current. Matched, precision metal film resistors connected to the negative terminal of the battery were then used to convert this voltage into the required current. High resistor values prevented loading of the signal and ablation voltages. Matching allowed the signal processing circuitry to maintain a high common-mode rejection to minimize electrical interference. The return path for the injected current (charge) was through an external large-area patch on the shaved skin of the dog’s thigh that was connected to the return (positive) electrode of the 9-V battery. The ablation catheters were placed in the atria and ventricles of the dogs via the femoral veins.
General study design
Mongrel dogs (weight, 30 to 40 kg; age, 1 to 3 years) were used for the in vivo study. The dogs received 1 of 2 therapies: RF energy delivery with and without negative charge applied to the catheter tip. The therapy assignments were not random because of staff and equipment availability. Eleven dogs were used.
Animal monitoring/surgical care
The dogs were anesthetized with intravenous ketamine (10 mg/kg) and diazepam (0.5 mg/kg), intubated, and ventilated with a pressure-cycled ventilator. Each animal was monitored continuously with 8 surface electrocardiogram (ECG) leads, along with blood pressure monitoring through a Teflon sheath in a femoral artery. Vascular access was then obtained as previously described (18).
Clinical animal studies
Intracardiac ultrasound imaging
A 10-F, 5.5- to 10.0-MHz ultrasound catheter with multidirection tip deflectability was positioned in the right atrium and interfaced to the input stage of an Acuson Sequoia imaging platform (Siemens Healthcare GmbH, Erlangen, Germany) for complete intracardiac imaging. Intracardiac echocardiography (ICE) was used to guide the catheter placement and to visualize thrombus formation on catheter tips.
Quantification of the amount of charge (current) required to prevent coagulum
Using a potentiometer in series with the voltage source, the quantity of negative charge (current) continuously delivered to the catheter tip was varied by adjusting the current from 7.125 μA to 100 μA and, as control, reversing the polarity of the current to deliver a positive charge to the catheter tip. Current, defined as the rate of flow of electric charge, was measured instead of charge itself, because this was a stable and reproducible surrogate for deposited charge. At the end of the experiments, the catheter tips were examined visually and also processed with sputter coating and critical point drying for field emission scanning electron microscopy (SEM). This portion of the study identified that the minimum negative current (charge) needed to prevent coagulum was 100 μA.
Simultaneous charge delivery-ablate protocol
Standard Boston Scientific EPT Blazer II (Boston Scientific, Marlborough, Massachusetts) 6-F, 4-mm; 8-F, 5-mm; and 7-F, 4-mm closed loop irrigation (Chilli) ablation catheters were advanced from the right femoral vein into the atria and ventricles under ICE and biplane fluoroscopic guidance. In the first series of experiments, each catheter was placed in the right atrium and right and left ventricle and left for 40 min (to simulate time spent performing intracardiac mapping). At the end of 40 min, the catheter tip was visualized with ICE for thrombus and then RF energy was delivered at 55 W and 65°C. No thrombus was found in these first series of experiments and subsequent experiments did not use the 40-min waiting period. The procedure was repeated on a different catheter with RF energy being applied immediately after placement in the heart chambers. For charge delivery, the catheters were attached via a custom designed adaptor to the charge delivery unit shown in Figure 1. The potentiometer was adjusted to deliver a current of 100 microamperes based on the previous experiments with quantification of amount of charge (current) required to prevent coagulum.
One hundred ten lesions were created in total. Fifty percent were with charge, 50% were without charge. All had adequate lesions as judged by area and depth of the lesions. We used 6-F, 4-mm and 8-F, 5-mm catheters in creating 70 of the lesions, 8-F, 8 mm catheters for 10 of the lesions and 7-F, 4 mm closed loop irrigation (Chilli) ablation catheters for 30 of the lesions. The 70 lesions were created with the power of 50 W and with temperatures ranging from 65°C to 95°C and for an ablation duration of 120 seconds. Thirty of the lesions were created with power of 12 W to 15 W and with a temperature of 80°C and with a 120-s duration of ablation. Ten of the lesions were created at 80 W and a temperature of 75°C.
Assessment of catheter tip thrombus
Using the dimensions obtained from online measurements of the ICEs, the volume v of the clot was calculated either from v = 4/3πr3 for a spherical clot or v = πr2h for a cylindrical clot. At the end of the experiments, the catheter tips were visually inspected and photographed. The photographic images were superimposed on an 8 × 9 lattice and the presence or absence of clot, clot surface coverage as well as the 3-dimensional profile (height) or thickness of the clot within each individual square of the lattice was quantified using the National Institutes of Health (NIH) imaging software JI Image. The tips were then placed in Trump’s (a 50/50 mixture of glutaraldehyde and formaldehyde) solution and processed with critical point drying and sputter coating for field-emission SEM (FESEM). The FESEM images were superimposed on an 8 × 9 lattice and the presence or absence of clot, clot surface coverage as well as the 3-dimensional profile (height) or thickness of the clot within each individual square of the lattice was quantified using the NIH imaging software JI Image. The thickest slice was taken across the lattice.
Effect of charge on intracardiac electrograms
The electrogram with and without charge were traced using ultrafine marker pens with red and blue, respectively, onto transparency sheets; the 2 transparencies were then overlaid, and these in turn were overlaid on ECG graph paper. Any pure red or pure blue would be noted against each small square of the graph paper. The total number of small squares would be counted against the total number of small squares spanning the whole electrogram and taken as a percentage match.
Effect of charge on ablation lesions
The locations of the ablation lesions created with and without negative charge application was mapped with ICE. The effect of negative charge placement on the intracardiac ablation lesions was assessed by measuring the area and depth of the lesions obtained with and without charge placement in the explanted heart to calculate the lesion volumes.
For the lesion measurements, medians and interquartile ranges (IQRs) were reported and a Wilcoxon matched-pairs signed-rank test, which does not assume normality in the data, was used to assess if there was a difference in both the area and the volume of ablations after a negative charge or no charge was delivered to each dog.
Application of negative charge during RF ablation
ICE showed the formation of thrombus on the 8-F, 5-mm Blazer II catheter tip during RF energy delivery at 55 W and 65°C without charge (Figure 2A). In Figure 2A, the panel shows the formation of thrombus (n = 20 ablations, average clot volume = 29.39 ± 8 mm3) on the catheter tip during RF ablation without charge. Figure 2B shows that with the application of a negative charge, there is no thrombus formation (n = 15 ablations, clot volume = 0 mm3, p < 0.01). Macroscopic examination of the tips clearly showed an all-or-nothing response to negative charge application during RF energy delivery with the negatively charged catheter tips being completely devoid of coagulum formation (0% clot surface coverage of catheter tip) (Figure 3A, right panel) whereas the uncharged tips had almost complete coverage of the catheter tip (90.7 ± 2.3%, p < 0.01) (Figure 3A, left panel) with coagulum. FESEM at low magnification (original magnification ×100) showed that the uncharged catheter tips during ablation had almost complete surface coverage with clot (90 ± 2.5%) (Figure 3B, left panel) whereas the negatively charged catheter tips showed complete absence of surface clot coverage (0%, p < 0.01) (Figure 3B, right panel). FESEM at high magnification (original magnification ×1,000) showed that with ablation, the classic lace-like pattern of fibrin clots was obliterated, replaced with an amorphous material (Figure 3C, left panel), suggesting that the thermal energy of the ablation had denatured the fibrin clot. In contrast, the negatively charged catheter tips displayed a complete absence of coagulum formation, with the metallic surface of the catheter surface easily discerned (Figure 3C, right panel).
The use of the different catheters did not impact clot formation.
Dose-dependent effect of charge on clot volume
With increasing current delivering negative charge, the thickness of the clot decreased in a nonlinear fashion (Figure 4). There was an initial sharp decrease in the clot thickness (140 ± 5.3 arbitrary units [a.u.] vs. 83.75 ± 4.2 a.u.; p < 0.05; n = 20) with the current increasing from 0 μA to 7.125 μA. An interesting observation was that between currents of 13.96 μA and 67.65 μA there appeared to be a plateau in the effect of negative charge on clot thickness (67.7 ± 6.3 a.u. vs. 48.65 ± 7.6 a.u.; p = NS). There appeared to be a threshold near 100 μA where the formation of coagulum could be prevented (48.65 ± 7.2 a.u. at 67.65 μA vs. 0 a.u. at 100 μA; p < 0.01). When the polarity of the charge was reversed, the clot thickness increased with increasing current, from 140 ± 5.3 a.u. at 0 μA to 145 ± 9.3 a.u. at 7.125 μA (p = NS), to 203 ± 7.5 a.u. at 67.65 μA (p < 0.05), and then to 254 ± 9.6 a.u. at 195 μA (p < 0.05). This showed very clearly the association between both polarity of charge and quantity of charge on the coagulum formation.
Effect of charge on intracardiac electrograms
We have traced the electrogram with and without charge (Figure 5) using ultrafine marker pens with red and blue, respectively, onto transparency sheets; then superimposed the 2 electrograms and overlaid the red and blue electrograms on ECG graph paper. Any pure red or pure blue would be noted against each small square of the graph paper. The total number of small squares would be counted against the total number of small squares spanning the whole electrogram and taken as a percentage match.
We found that the percentage match between the charge and noncharge electrogram was 96 ± 3%.
Effect of charge on ablation lesions
The effect of negative charge placement on the intracardiac ablation lesions was assessed by measuring the area of the lesions (n = 18) obtained with and without charge placement (Figure 6). The median area of the ablation lesions obtained without charge was 24 mm2 with an IQR of 9.22 to 94.86 mm2 whereas the median area of the lesions with charge application was 35 mm2 with an IQR of 8.0525 to 62.3 mm2. The volume of the ablation lesions obtained without charge was 156 mm3 with an IQR of 87 to 386.425 mm3 whereas the volume of the lesions with charge application was 149 mm3 with IQR of 107 to 287.95 mm3 (Figure 7). Using the Wilcoxon matched-pairs signed-rank test, the area of the ablation lesions obtained without charge was 52.89 ± 53.37 mm2 whereas the area of the lesions with charge application was 44.51 ± 40.81 mm2 (p = 0.859). The volume of the ablation lesions obtained without charge was 380.89 ± 314.62 mm3 whereas the volume of the lesions with charge application was 200.38 ± 113.13 mm3 (p = 0.314). This showed that the application of charge did not significantly affect the characteristics of the intracardiac ablation lesions.
In the present study, application of a continuous negative charge during RF energy delivery in a canine heart prevented the formation of coagulum on the catheter tip. The magnitude of the effect was dependent on the amount of charge delivered. The charge could be delivered without significantly affecting the quality of the ICE or inducing malignant arrhythmias.
Coagulum formation during RF ablation occurs frequently despite therapeutic heparinization (19–21). The coagulum can increase the risk of thromboembolism (19,22). Previous studies had suggested this as being relatively uncommon (19). However, recent studies using more sensitive diffusion-weighted magnetic resonance images have documented a 10% incidence of thromboembolic events (23,24). Yet even more recent data suggest that the incidence of clinically silent cerebral lesions may be as high as 52% depending on the type of technology used (25). Although clinically silent (22), patients may go on to develop memory deficits, cognitive decline, and subtle neurological deficits (26–28). With the increasing use of left-sided procedures in atrial fibrillation ablations and ventricular tachycardia, and the use of larger catheter size to deliver more power, the incidence of thromboembolism may increase further. A recent study has shown subtle cognitive impairment after left-sided ablations (29). As such, so-called clinically silent magnetic resonance imaging lesions may not be as benign as was originally thought (30).
It is known that charge application can repel negatively charged blood components (12). Fibrinogen, the building block of a clot, is negatively charged (13,14). We have previously shown that fibrinogen in binding to positively charged surfaces can undergo conformational changes in its molecular structure that lead to spontaneous thrombosis (15,16). Sawyer et al. (31,32) have previously quantified the potential difference between the blood and tissue as being 5 mV. Disruption of the tissue surface through RF ablation would reverse the polarity of this potential and make the blood positive with respect to the tissue adventitia, thus making the tissue surface more likely to bind fibrinogen, leading to the formation of thrombus. We therefore investigated the feasibility of placement of a negative charge on the catheter surface during RF energy delivery (16). The application of negative charge to the catheter surface repelled fibrinogen molecules, possibly by creating a “fibrinogen-free” zone around the catheter electrodes, thus preventing fibrinogen from binding to the surface and also to the tissue and consequently preventing coagulum formation. We have now confirmed the results from our initial in vitro experiments in live canine experiments.
In this study, the absence of charge application resulted in the formation of coagulum on the catheter tip. This happened regardless of whether there was RF energy being delivered or not, suggesting that surface-fibrinogen interactions that induced fibrinogen conformational changes (15) in addition to the effects of temperature induced fibrinogen denaturation (33) may be implicated in coagulum formation. This is supported by our observation that the coagulum not only forms at the distal ablation surface where the temperature is the highest due to ablation but also at the cooler proximal recording electrodes. It has been proposed that the endothelial surface may represent a thrombogenic substrate when it is perturbed (19), thrombus forming via a thrombin dependent pathway that involves tissue factor and coagulation cascade activation. However, we have shown that electrostatic mechanisms (positive attracts negative) starting with the binding of fibrinogen and consequent fibrinogen conformational changes leading to thrombosis can occur (15,16). Thus, in addition to the thrombin-dependent pathway of coagulum formation (19), there may be an additional thrombin-independent pathway via which coagulum forms, via contact and temperature related mechanisms (4). Clot formation occurring in parallel via the two mechanisms (thrombin-dependent and -independent pathways) may explain why heparinization does not abolish the incidence of coagulum formation and thromboembolic events in RF ablation (7,8). Although heparin does reduce the incidence of coagulum formation, even at high activated clotting time levels where increased bleeding starts to be a problem, there is still coagulum formation and thromboembolic events (7,8,34). By placing a negative charge in addition to heparin administration and creating a fibrinogen-free zone, we have shown here that we can dramatically reduce coagulum formation.
In this report, we found that the volume of the clot formed on the catheter surface was inversely related to the magnitude of the current applied. The greater the quantity of negative charge there is, the lesser the amount of clot. Conversely, the greater the amount of positive charge there is, the greater the volume of clot. This observation clearly defines an association between the charge properties of the material surface and coagulum formation. Current electrophysiological ablation procedures are hampered by limitations of energy delivery due to fear of temperature increase and consequent coagulum formation (5,35). Our data showing the relationship between the magnitude of the current delivering the negative charge and clot volume may provide a way around this problem. A threshold of 100 μA under which coagulum appears suggests a role for the titration of the charge delivery to the amount of RF energy delivered, that could potentially lead to higher RF energy delivery without increasing the risk for coagulum formation, thereby increasing procedural success and decreasing procedural time.
The presence of charge with up to a current level of 100 μA did not significantly affect the quality of the intracardiac electrogram. Furthermore, over the range of the current that we used, we did not induce any ventricular fibrillation or tachycardia.
The lesions created by the simultaneous charge-ablate protocol mentioned in this paper were equivalent with or without charge, showing that the application of charge did not significantly affect the characteristics of the intracardiac ablation lesions.
The limitation of this study is that this is a canine model. However, the animals used were large beagles and therefore the current equipment used is what would have been used in a human, making extrapolation to human studies feasible.
We conclude that negative charge delivery to the ablation catheter tip during RF ablation is a feasible and safe technique that can prevent coagulum formation and potentially reduce thromboembolic phenomena.
COMPETENCY IN MEDICAL KNOWLEDGE: The clinical implications of this work are that cardiac electrophysiologists would be provided with a technology above and beyond that of concurrent intravenous heparinization to address one of the most feared complications of an ablation procedure—that of thromboembolic complications.
TRANSLATIONAL OUTLOOK: The challenges in the development of this technology would be testing the safety and efficacy in clinical trials given the current unattractive funding and economic climate.
For supplemental videos and their accompanying legends, please see the online version of the article.
Supported by a grant from Mayo Medical Ventures and Mayo Discovery Translational Award Fund. Drs. Lim, Venkatachalam, Jahangir, Asirvatham, and Ms. Johnson own intellectual property rights and equity pertaining to the novel catheter described herein. Dr. Asirvatham has received honoraria from Abiomed, Atricure, Biotronik, Biosense Webster, Boston Scientific, Medtronic, Medtelligence, St. Jude, Sanofi-Aventis, Wolters Kluwer, Elsevier, and Zoll; and is a co-patent holder with Aegis, Access Point Technologies, Nevro, Sanovas, and Sorin Medical.
- Abbreviations and Acronyms
- field emission scanning electron microscopy
- intracardiac echo
- Received August 3, 2015.
- Revision received October 23, 2015.
- Accepted November 19, 2015.
- 2016 American College of Cardiology Foundation
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