Experimental Ablation of Outflow Tract Muscle With a Thermal Balloon Catheter
Background Pulmonary balloon valvuloplasty has been performed in selected patients with tetralogy of Fallot as an alternative to surgical palliation; this technique is limited, however, by the fact that the balloon has little effect on the dynamic, muscular contribution to outflow tract obstruction. In an experimental model, we used a new thermal balloon catheter to ablate right ventricular outflow tract muscle. We evaluated the acute efficacy and muscle ablation parameters of this technology and its effects after myocardial healing.
Methods and Results A prototype electrolyte-filled balloon catheter, heated by radiofrequency energy, was constructed. Studies were conducted to determine the optimum electrolyte solution needed to minimize balloon heating time with an unmodified, commercially available radiofrequency generator. In vivo ablations of right ventricular outflow tract muscle with the thermal balloon were performed in lambs that were divided into three groups (n=5 each) according to the duration of thermal energy delivery (20, 40, and 60 seconds, respectively). Ablated lesion volume increased (460±63 to 1156±256 mm3) as the energy delivery time increased (20 to 60 seconds) and was correlated with delivered energy, temperature integral, and maximum epicardial surface temperature (r=.85, .82, and .72, respectively). All five lesions in the 60-second group showed an acute decrease of the wall thickness. Additional in vivo ablations were performed in 6 animals in which survival studies showed muscle thinning, healing by fibrosis, and no evidence of aneurysm formation.
Conclusions Thermal energy can be used with a balloon catheter delivery system to ablate myocardium. This study suggests that this energy delivery technology might be useful for relief of muscular outflow tract obstruction and that further studies are warranted.
Primary surgical repair of such lesions as tetralogy of Fallot (TOF) is performed with excellent early and late results.1 2 3 4 In certain patients, however, particularly neonates with small pulmonary arteries, primary repair is associated with higher operative morbidity and mortality.5 In these cases, palliative aortopulmonary shunts or patch outflow tract augmentation is performed, and repair is delayed until the pulmonary arteries increase in size.6 The technique of pulmonary balloon valvuloplasty has been performed for palliation of the valvular component of right ventricular (RV) outflow tract obstruction with acceptable results in selected patients with TOF; this technique provides an alternative to aortopulmonary shunts or palliative RV outflow tract patch reconstruction for the relief of severe cyanosis.7 8 9 10 However, isolated pulmonary valvular stenosis is the site of RV outflow tract obstruction in only 5% to 15% of patients with TOF.11 12 The remaining 85% to 95% of patients with TOF have muscular infundibular stenosis, which may not be palliated well by pulmonary balloon valvuloplasty alone.
In additional settings, muscular obstruction can complicate certain lesions, such as double-inlet left ventricle/ventricular septal defect/transposition of the great arteries, in which obstruction at the level of the ventricular septal defect (“bulboventricular foramen”) produces the functional equivalent of subaortic stenosis. This can be a significant source of morbidity and mortality in the management of such single-ventricle lesions.13
Radiofrequency energy has been successfully applied directly to the heart for treatment of arrhythmias and has been shown to be a safe and effective energy source for the thermal ablation of endocardial arrhythmogenic foci and accessory pathways.14 15 16 Catheter-delivered radiofrequency energy causes thermal injury due to radiofrequency-induced heating of tissue water and with increasing delivered energy can cause well-demarcated myocardial coagulation necrosis.17 We initially hypothesized that direct application of radiofrequency energy to an outflow tract would be efficacious for ablation of large areas of outflow tract muscle. However, as noted in the “Discussion,” pilot studies suggested that this may not be feasible for producing lesions over a sufficiently large area and volume of outflow tract muscle.
Alternatively, we hypothesized that balloon-delivered thermal energy applied to an obstructed outflow tract may cause myocardial ablation sufficient to improve the obstructive hemodynamics and achieve interim palliation. We used a thermal ablation balloon catheter heated by radiofrequency energy and of sufficient size for ablation of infant outflow tract muscle. The purpose of these initial experimental studies is (1) to determine optimum thermal balloon design parameters, (2) to evaluate the efficacy of this technology for ablating myocardial muscle, (3) to determine the relation between thermal energy application and muscle ablation when evaluated in an acute model, and (4) to determine the chronic effects of thermal ablation of outflow tract muscle after myocardial healing has occurred.
This study includes (1) an in vitro protocol to evaluate catheter design, (2) an acute in vivo protocol to examine the ablation efficacy and parameters, and (3) a chronic in vivo protocol to assess anatomic effects after the ablated outflow tract heals and potential complications such as late ventricular rupture. The protocols for the in vivo experiments were carried out in an ovine model and were approved by the Subcommittee on Animal Care, Massachusetts General Hospital. All animals received humane care according to “Principles of Laboratory Animal Care” formulated by the National Society for Medical Research and the “Guide for the Care and Use of Laboratory Animals” published by the National Institutes of Health [DHEW Publication (NIH) 80-23, revised 1985, Office of Science and Health Reports, DRR.NIH, Bethesda, MD 20205].
Radiofrequency Thermal Balloon Catheter
Fig 1⇓ shows the design of our prototype radiofrequency-heated thermal balloon catheter, produced in our laboratory for this experimental study. This prototype, a 14F, 30-cm-long catheter, contains two modified unipolar electrodes for delivery of radiofrequency energy (model 6985, Medtronic, Inc), a wire-type copper/constantan thermocouple probe for continuous monitoring of balloon temperature (type IT-18, Sensortek, Inc), a small-lumen catheter (20-gauge) used for balloon inflation/deflation, and a thin latex balloon with an 18-mm diameter and 22-mm length when inflated with 2 mL of electrolyte solution. The electrodes are separated by a 10-mm gap, and the tip of the thermocouple is positioned in the balloon cavity at the midpoint of the two electrodes. Radiofrequency energy is delivered via the two electrodes to heat the electrolyte solution (discussed later) within the balloon. The radiofrequency energy field produces a driving force on the ions in the electrolyte solution within the balloon, causing ionic motion at the frequency of the radiofrequency alternating current. The resulting ionic motion heats the electrolyte solution by molecular friction.18
Radiofrequency Energy Source
Radiofrequency energy was supplied by a commercially available radiofrequency lesion generator system (model RFG-3C, Radionics, Inc), which delivers alternating current in a sine-wave pattern at a frequency of 500 kHz. The output power varies as a function of the circuit impedance. Power and voltage were recorded on a strip-chart recorder (model 7758A, Hewlett Packard) connected to the radiofrequency generator. Delivered energy (in joules) was calculated by measuring the area under the power curve during energy delivery. Mean power was determined by dividing calculated energy by the duration of delivery. The thermocouple probe in the catheter was connected to an electronic thermometer (Sensortek), and balloon temperature was recorded on the chart recorder. The “effective ablation temperature integral” was defined as the area under the temperature-versus-time curve above 50°C during energy delivery.
In Vitro Experimental Protocol
To determine the optimal balloon electrolyte solution for in vivo use, we compared normal saline (0.9% sodium chloride solution) and a commercially available high-concentration sodium chloride solution (2.5 mEq/mL, 14.6% solution, Abbott Laboratories) (H-NaCl) with respect to balloon heating. One and 2 mL of each solution were used for balloon inflation while the balloon was immersed in a 37°C water bath. Radiofrequency current was delivered between two electrodes at 80% of the maximum generator output, and balloon temperature was recorded as a function of time. Ten determinations were made for each volume (1 or 2 mL) of each electrolyte solution.
In additional in vitro experiments, an alternative source of radiofrequency energy was used for balloon heating. In these experiments using H-NaCl, the electrodes were connected to a commercially available electrosurgical unit (model SSE2-K, Valleylab Corp) used in the “coagulate” mode.
Acute In Vivo Surgical Preparation
In this study using a prototype balloon catheter, the RV outflow tract was accessed in an open-chest model. Eighteen lambs of either sex, 5 to 17 days old and weighing 5.5 to 9.8 kg (mean, 7.6±1.4 SD), were anesthetized with sodium pentobarbital (30 mg/kg IV). Animals were then intubated and ventilated with 100% oxygen (Ohio Anesthesia Ventilator, Ohio Medical Products) with a tidal volume of 15 mL/kg. Respiratory rate was adjusted to maintain Paco2 between 35 and 40 mm Hg. Systemic temperature was maintained at 37°C with heating lamps. An arterial catheter for hemodynamic monitoring was placed via the right femoral artery, and arterial pressure was continuously monitored. A venous catheter for infusion was placed in the right femoral vein. To maintain a constant level of anesthesia after induction, sodium pentobarbital was continuously infused (2 mg · kg−1 · h−1). A right thoracotomy was performed in the fourth intercostal space, the pericardium was opened, and a pericardial cradle was created to support the heart.
After administration of heparin (1.5 mg/kg IV), the radiofrequency thermal balloon catheter was inserted into the RV cavity via the RV apex and advanced into the outflow tract. The balloon was then briefly inflated with 2 mL of electrolyte solution and positioned so that the balloon was palpable 1 cm below the pulmonic valve annulus. A needle-type thermocouple probe (Needle Microprobe Type T, Cole-Parmer Instrument) was inserted tangentially just below the epicardium at the level of the balloon, and the balloon was deflated; subepicardial surface temperature was recorded continuously. A bolus of lidocaine (1.5 mg/kg IV) was administered just before thermal ablation.
Thermal Ablation Protocol
H-NaCl (2 mL) was injected into the balloon, and the balloon position against the RV outflow tract free wall was confirmed by palpation to ensure balloon contact. Immediately after balloon inflation, radiofrequency energy was delivered at 80% of the maximum generator output. In this in vivo study, “effective energy delivery time” was defined as the duration over which the balloon temperature was ≥50°C. Animals were randomized into one of three groups of 5 lambs so that radiofrequency current was delivered during one of the following effective energy delivery times: 20, 40, and 60 seconds. After the procedure, the catheter was immediately deflated and withdrawn from the right ventricle.
In 3 additional control lambs, balloon inflation was carried out for 60 seconds without application of radiofrequency energy to determine the effects of the balloon itself on the outflow tract muscle.
Lesion Size Evaluation
Three hours after thermal ablation, animals were euthanatized, and the hearts were excised and washed in saline solution. The hearts were then cut into slices 4 mm thick in a plane perpendicular to the RV outflow tract long axis. The slices were incubated in a 1% solution of triphenyltetrazolium chloride (TTC) in buffered saline at 37°C for 15 minutes.19 The slice with the deepest myocardial lesion was then sectioned at the deepest point in a perpendicular plane to determine the maximum lesion depth. The area of the lesion identified by TTC staining was measured for each slice by projecting photographs of each slice on a screen and using planimetry technique. The lesion volume of a slice was calculated by multiplying the measured area by the slice thickness. The sum of the lesion volumes of all slices represented an estimate of the total lesion volume. Total RV muscle volume, which was defined in this study as the sum of both RV free-wall muscle and intraventricular septal muscle, was also assessed by the same method; the septum was included, since some lesions extended onto the intraventricular septum. The percentage of RV muscle that was ablated was calculated as the ratio of lesion volume to RV muscle volume. In some slices, thermal energy appeared to cause myocardial thinning, resulting in a decrease in RV free-wall thickness with a TTC staining pattern illustrated schematically in Fig 2⇓. In such cases, preablation RV free-wall thickness was estimated by averaging the RV free-wall thickness of the undamaged muscle portion immediately adjacent to each side of the area of TTC staining. The estimated volume of myocardial loss (“desiccated volume”) was quantified by planimetry. After staining, all slices were photographed and fixed in 1% formalin solution; the tissues were embedded in paraffin, sectioned, and stained with hematoxylin and eosin for further histopathological examination.
Chronic In Vivo Preparation and Protocol
Six additional lambs of either sex, 8 to 11 days old and weighing 6.0 to 7.4 kg (mean, 6.9±0.5 kg), were anesthetized by breathing halothane (4%) in oxygen. After endotracheal intubation, anesthesia was maintained by ventilation with halothane (1.0% to 1.5%) in oxygen. Central venous pressure (CVP) was measured with a catheter inserted percutaneously into the right jugular vein. Under sterile technique, a right thoracotomy was performed, and the chest was entered in the fourth intercostal space. The pericardium was opened parallel to the phrenic nerve, and the right ventricle was exposed. CVP catheter position was confirmed by palpation; CVP was measured before and after thermal ablation of the RV outflow tract. A purse-string suture of 4-0 polypropylene was placed in the RV apex. A 2- to 3-mm ventriculotomy was made, and the radiofrequency thermal balloon catheter was advanced into the RV outflow tract; the purse-string suture was tightened to secure hemostasis around the shaft of the catheter at its penetration into the right ventricle. Lidocaine (1.5 mg/kg IV) was administered, the balloon was inflated, and its position in the outflow tract was confirmed by palpation. Radiofrequency energy was then applied as previously described, and thermal ablation was carried out for either 40 seconds (3 lambs) or 60 seconds (3 lambs). The balloon was then deflated, the catheter was withdrawn, and the right ventriculotomy was closed by tying the purse-string suture. The pericardium was reapproximated with interrupted sutures. An intercostal block was placed at ribs 2 through 6 with 0.5% bupivacaine (Marcaine, Sanofi Winthrop Pharmaceuticals) for postoperative analgesia. The chest was closed after insertion of a temporary chest drain. Lambs were allowed to awaken and were extubated and returned to the animal care facility for recovery. Additional analgesia, if needed, was provided with meperidine (1 mg/kg IM) until lambs were freely ambulatory.
After 8 weeks had elapsed, each lamb was reanesthetized with sodium pentobarbital, as described for the acute in vivo protocol. The chest was entered again via a right thoracotomy. The pericardium was opened and suspended to form a cradle. The right ventricle was visually assessed, with particular reference to the presence of aneurysmal dilatation or dyskinetic wall motion. Echocardiographic gel was then placed on the surface of the heart, and a plastic film was used to create a well in the chest over the heart. The well was filled with saline, which was used as an echocardiographic medium. Echocardiography was performed with a 4.0-MHz probe (Acuson model S3194 with Acuson console model 128XP/10). RV function was evaluated, and the RV outflow tract was evaluated for wall motion; pulmonic and tricuspid valve functions were assessed.
Lambs were then euthanatized, and the hearts were excised and sectioned as previously described. Outflow tract minimal wall thickness was measured, excluding epicardial fat; for comparison, wall thickness in adjacent, nonablated outflow tract muscle was also measured.
All data are expressed as mean±SD. In the in vitro study, a Student’s t test was used to compare the times necessary to heat each electrolyte solution up to 90°C. In the acute in vivo study, the lesion volume was correlated with delivered energy, maximum balloon temperature, and effective ablation temperature integral by linear regression analysis. Differences in lesion volumes and depths due to increasing effective energy delivery time were tested by one-way ANOVA and the Student-Newman-Keuls test for multiple comparisons. In the chronic in vivo study, wall thicknesses in ablated muscle and adjacent unablated muscle were compared by a paired t test. Statistical significance was defined as P<.05.
In Vitro Study
As shown in Fig 3⇓, radiofrequency heated H-NaCl more rapidly than normal saline in this in vitro model at both electrolyte volumes tested. Resistance and delivered voltage were lower for H-NaCl than for normal saline, and as shown in Table 1⇓, more power could be delivered with H-NaCl. Consequently, H-NaCl was chosen for use in the in vivo experiments.
In contrast to the observations made when a radiofrequency generator designed for electrophysiological ablations was used, when an electrosurgical radiofrequency generator was used for balloon heating, it produced boiling of the solution in the balloon, and the resulting gas formation produced intermittent electrode contact. This resulted in an initial rapid phase of balloon heating followed by intermittent slow heating to the final balloon temperature.
Acute In Vivo Study
The prototype radiofrequency thermal balloon catheter remained intact after a total of 21 energy deliveries. In the 15 acute experiments with thermal ablation, delivered power ranged from 26.4 to 31.7 W, with a mean value of 27.8±3.3 W. Mean delivered energy values were 914±53, 1267±184, and 1885±27 J for the 20-, 40-, and 60-second effective energy delivery groups, respectively (P<.001). Balloon temperature increased rapidly and exceeded 50°C 8 to 10 seconds after radiofrequency energy was applied. The effective energy delivery time began when the balloon temperature was ≥50°C. Thus, total energy delivery time was 8 to 10 seconds longer than the effective energy delivery time. The maximum balloon temperature ranged from 79.1°C to 98.7°C, and the averages of maximum temperature in the 20-, 40-, and 60-second groups were 88.0±1.8°C, 88.3±6.3°C, and 94.3±4.0°C, respectively. There were no statistically significant differences among them. The averages of maximum epicardial surface temperature for the 20-, 40-, and 60-second groups were 59.8±5.3°C, 59.8±8.1°C, and 69.5±8.1°C; there were no statistically significant differences among them.
In all 15 hearts subjected to acute thermal ablation, lesions were observed and evaluated. In 13 of 15 hearts, thermal lesions were produced on both the RV outflow tract free wall and the interventricular septum (see example in Fig 6⇓), and in the other 2 hearts, which belonged to the 20-second group, lesions occurred only on the RV outflow tract free wall. All five lesions in the 60-second group were transmural on the free wall and could be visually identified on the epicardial surface of the heart. The diameters of the lesions on the epicardial surface were approximately 10 mm. Only two lesions in the 40-second group were transmural, and no transmural ablation occurred in the 20-second group. As shown in Fig 4⇓, lesion volume increased from 460±63 to 1156±256 mm3 as the effective energy delivery time increased from 20 to 60 seconds. There were statistically significant differences between the 60-second group and the 20- and 40-second groups (P<.001) but no statistically significant difference between the 20- and 40-second groups. The lesion volume as a percentage of RV muscle volume showed the same tendency. The values were 3.4±1.0% in the 20-second group, 4.0±1.1% in the 40-second group, and 7.0±2.3% in the 60-second group. There were statistically significant differences between the 60-second group and the other two groups (P<.01). As shown in Fig 5⇓, a positive correlation existed between delivered energy and lesion volume (r=.85) as well as between the effective ablation temperature integral or maximum epicardial surface temperature and lesion volume (r=.82 and r=.72, respectively). However, the correlation between maximum balloon temperature and lesion volume was weak (r=.58). As illustrated in the example in Fig 6⇓, RV free-wall thickness decreased acutely because of focal myocardial desiccation or balloon compression and heat fixation on the endocardial surface in 7 animals: 1 in the 20-second group, 1 in the 40-second group, and all 5 in the 60-second group. Desiccated volume was calculated and ranged from 26 to 120 mm3, and when compared among the three groups, it resulted in statistically significant differences (Table 2⇓). Estimated lesion depths were also calculated. In contrast to the measured lesion depth, as shown in Table 2⇓, there were statistically significant differences between the 20-second group and the other groups (versus 40-second group, P<.01; versus 60-second group, P<.005). Estimated lesion depths correlated with the delivered energy and the effective ablation temperature integral (r=.77 and r=.75, respectively) but did not correlate with either maximum balloon temperature or epicardial surface temperature (r=.34 and r=.57, respectively). In the 3 control lambs, no lesions were observed. Furthermore, when heart slices from control lambs were examined, there was no evidence of free-wall thinning or outflow tract dilation.
During balloon inflation, mean blood pressure decreased significantly, from 70.3±8.0 to 45.9±11.1 mm Hg (P<.001). In this acute model, 9 lambs (8 with thermal ablation and 1 control) developed ventricular fibrillation 35 to 50 seconds after balloon inflation and required cardioversion. After thermal ablation (or after cardioversion), hemodynamic parameters returned to baseline.
With TTC staining, all lesions produced by thermal ablation were distinguishable as an unstained white area compared with the viable TTC red-stained area (Fig 6⇑). Lesion length on the endocardial surface ranged from 11 to 18 mm. The macroscopic margin between the TTC-stained and -unstained areas was sharply demarcated and was identical to the microscopically determined margin; at 3 hours after ablation, there was no histological evidence of edema. Fig 7⇓, a photomicrograph of a thermal lesion, illustrates the narrow and sharply demarcated border zone between normal and necrotic myocardium; contraction band necrosis is evident within the thermal lesion region, neutrophil infiltration is noted, and there is no histological evidence of edema.
Chronic In Vivo Study
All 6 lambs subjected to this protocol survived for subsequent reexamination; during this ablation protocol, none of the lambs exhibited ventricular fibrillation. CVP did not change significantly after thermal ablation (preablation, 3.1±0.9 mm Hg; postablation, 3.6±1.1 mm Hg; P=NS) All lambs appeared clinically well after surgery, and at the time of reexamination, the mean body weight had increased 178%, to 19.2±2.6 kg. There were no pericardial effusions, and filmy pericardial adhesions were noted in all lambs, consistent with prior surgery; they were uniformly distributed over the surface of the heart. Echocardiography demonstrated normal pulmonic and tricuspid valve function in all animals. There was no visual or echocardiographic evidence of dyskinetic wall motion or aneurysm formation. Echocardiographic assessment of RV function showed well-preserved overall function and a well-localized area of impaired contraction in the outflow tract that was most marked in the lambs ablated for 60 seconds.
Visual inspection of heart slices demonstrated a fibrous endocardial scar at the site of thermal ablation, as illustrated in Fig 8⇓. Wall thickness at the ablation site decreased compared with adjacent unablated muscle: 40-second group, 3.4±0.5 versus 5.2±0.4 mm, P<.05; 60-second group, 2.5±0.5 versus 4.8±0.6 mm, P<.005. In the 60-second group, 2 of the 3 hearts demonstrated visible epicardial thermal lesions immediately after the procedure; transmural scar was noted after healing, and thus in these hearts, the measured wall thickness was entirely scar (Fig 8⇓). In all 6 hearts, pulmonic and tricuspid valve leaflets appeared normal.
This study demonstrates that radiofrequency energy can be used with a balloon catheter delivery system to create significant thermal myocardial lesions in the RV outflow tract. This finding suggests that this energy delivery technology might be applied to relieve outflow tract obstruction by muscle ablation for palliating congenital heart defects.
Radiofrequency energy is used for the ablation of endocardial arrhythmogenic foci and accessory conduction pathways.14 15 16 Direct catheter-delivered radiofrequency energy can cause well-demarcated myocardial coagulation necrosis.17 However, the efficacy of current catheters and energy generators for direct radiofrequency delivery for large-volume myocardial ablation is limited. An important limitation includes coating of the catheter electrode with coagulated myocardium and degenerated plasma proteins, which can cause an abrupt increase in impedance and a consequent decrease in delivered energy.20 21 Another limitation is the small electrode tip size in currently available electrodes, which requires repeated energy applications and catheter manipulations to achieve a radiofrequency lesion of sufficient size22 23 ; thus, if direct application of radiofrequency energy is to be used, it must produce a lesion over a relatively large area of the endomyocardium to result in decreased outflow tract contractility and obstruction. Recent studies have suggested that even electrodes >8 mm in length may not facilitate the production of large ablation lesions.24 With increasing electrode size, inconsistent contact between the electrode and the endomyocardial surface may limit energy transfer and may predispose to charring of the electrode surface. This may be a particular concern in the case of direct radiofrequency application in dynamic outflow tract obstruction, when electrode position and contact may be more difficult to control.
In pilot studies, we designed and used large-surface-area electrodes of various sizes and shapes with a commercially available radiofrequency generator in an attempt to directly apply radiofrequency energy to the outflow tract to achieve lesions similar in size to those achieved in the present study. When sufficient energy was applied, it resulted in tissue desiccation, electrode coating, and an abrupt rise in electrode impedance during energy delivery that limited total delivered energy. Because of such observations in pilot studies, we believe that direct energy application to a significant area of outflow tract muscle using currently available radiofrequency energy delivery catheters is not likely to be efficacious for reducing outflow tract obstruction. In contrast, our prototype radiofrequency thermal balloon catheter uses radiofrequency energy to heat only the electrolyte solution within the balloon; it does not ablate myocardial tissue by direct application of radiofrequency energy. Because electrolyte solutions such as saline do not contain organic compounds, the electrode surfaces inside the thermal balloon do not become covered with degenerated organic material; as a result, the sudden rise in impedance and subsequent decrease in energy delivery that plague catheters used for direct radiofrequency energy application do not occur.
Before the application of this radiofrequency thermal balloon catheter in in vivo experiments, we conducted pilot studies to help optimize the prototype design. First, the balloon used in this prototype was made of latex, unlike angioplasty and valvuloplasty balloons, which are made of polyethylene or polyvinyl chloride.25 Latex was selected to produce a balloon that is very compliant and capable of conforming to the irregularities of the endomyocardial surface, thus optimizing heat transfer.
Second, we examined factors that would help limit the time needed to achieve effective ablation temperature. We tested two commercially available electrolyte solutions in in vitro experiments. H-NaCl was heated more rapidly than normal saline and is consequently more desirable for this thermal balloon catheter, since it diminishes the time in which the balloon may occlude the outflow tract during ablation. H-NaCl posed no toxicity in the volume used in this study, even when administered intravenously as a bolus. The 2 mL of H-NaCl used to dilate the balloon does not result in significant positive pressure; the volume was chosen to allow sufficient balloon-endocardium contact to generate lesions of sufficient size. Nonetheless, we recently examined other sodium chloride concentrations for use as the electrolyte solution in this catheter system. In additional subsequent in vitro experiments, the optimum sodium chloride concentration was found to be 7%, and it produced the same rate of heating as the 14.6% solution used in the present study.
Finally, we examined other means of achieving more rapid balloon heating. If excessive amounts of radiofrequency power are applied to such a thermal balloon from an electrosurgical energy source, gas formation occurs that can increase impedance and thus inhibit heating; gas bubbles within the balloon may also decrease the rate of heat transfer to the myocardium. Because the heating electrodes were placed inside the catheter shaft as shown in Fig 1⇑ and balloon temperature was limited to <95°C, in this prototype there was less gas formation at high levels of radiofrequency power.
No increases in impedance were observed in either the in vitro or in vivo studies; no coating of the balloon surface was noted in the in vivo studies. This catheter was designed and tested with a commercially available radiofrequency lesion generator (model RFG-3C, Radionics). Such a device provides continuous readout of delivered power, and it also has the option for feedback control of balloon temperature with an integral thermocouple. This may be an important safety consideration, particularly when the balloon is being used at the high temperatures employed in this study. Finally, radiofrequency generators are relatively inexpensive compared with other sources of heat energy, such as laser.
Thermal lesions in our model are created by the conduction of heat at the balloon-endomyocardial interface. Studies of direct radiofrequency ablation have suggested that lesion size is correlated well with the electrode-tissue interface temperature.26 27 However, our results show that the maximum balloon temperature was not a good predictor of lesion volume in the outflow tract. An explanation for this observation may be that the peak balloon temperature achieved in all three groups was well above the 46°C to 50°C necessary to cause myocardial injury.22 26 As a result, the energy delivery time of the three groups becomes the more important variable, since it determines the depth of heat penetration. We have defined the “effective ablation temperature integral,” as described in the “Methods” section, on the basis of reports22 26 showing that the temperature at the border of viable and nonviable tissue was 46°C to 50°C during direct radiofrequency energy delivery. The effective ablation temperature integral is a good predictor of lesion volume, as well as delivered energy, since it takes into consideration both radiofrequency energy delivery time and temperature. Our data demonstrate a strong positive correlation between the effective ablation temperature integral and delivered energy (r=.94).
Ablated, nonviable infundibular myocardium loses its ability to contract, and as shown in the chronic protocol, healing results in outflow tract thinning and scar formation. Thus, in instances of dynamic obstruction, this should decrease obstruction during systole. Our prototype radiofrequency thermal balloon catheter was designed to ablate a significant portion of the infundibular myocardium and to dilate and remold the outflow tract into a larger lumen, as noted in the example shown in Fig 8⇑. The appearance of the “desiccated volume” in the acute study suggests that dilation and ablation by heating may also produce heat fixation of the outflow tract lumen, resulting in an immediate increase in outflow tract dimensions, in addition to the delayed effect observed when ablated muscle underwent necrosis and healing. Similar observations have been made in blood vessels, in which thermal balloon angioplasty can reduce the elastic recoil of acutely dilated vessel walls.28 29 In coronary angioplasty, the combination of persistent balloon inflation and thermal exposure allows the stretched vessel wall to “set” at the inflated balloon diameter.30 The mechanisms by which elastic recoil of the vessels is altered with heat include a combination of collagen denaturation and tissue desiccation.31
This study addressed not only the acute effects of thermal ablation but also the chronic effects noted after ventricular healing. As illustrated in Fig 8⇑, healing of ablated muscle resulted in endocardial scar formation. In the 6 lambs studied, although wall thickness decreased significantly, there was no evidence of aneurysm formation or ventricular rupture, even in lambs in which full-thickness ablation occurred. This may be related, in part, to the fact that RV pressure is low compared with LV pressure; thus, the physical forces that can result in further wall thinning after ablation are much less than those that produce the clinically observed left ventricular rupture or aneurysm formation that may occur after transmural myocardial infarction.
Critique and Limitations of the Methods
Although our acute in vivo model with a normal outflow tract was not designed to show relief of a preexisting outflow tract gradient, the decrease of the RV outflow tract free-wall thickness and loss of contractile function associated with myocardial necrosis imply acute enlargement of the outflow tract luminal diameter. The amount of desiccated volume (range, 26 to 120 mm3) was small compared with total lesion volume; however, in the hearts in which desiccated volume was present, the average of the estimated lesion depth was 1.5 mm larger than that of the measured lesion depth. This observed difference, plus the effects on regional contractility, should reduce dynamic outflow tract obstruction, particularly in a neonatal or infant heart. Furthermore, as suggested by the example shown in Fig 8⇑, with healing, additional outflow tract enlargement may occur. Further studies are needed to determine whether an adequate volume of tissue can be ablated to reduce the gradient in a hypertrophied RV outflow tract.
In this study, thermal ablation, even at application times of 60 seconds, did not produce any significant change in global RV function, as judged by a lack of increase in CVP after the procedure and by preserved global RV function as determined by echocardiography. This is consistent with what would be expected with localized lesions in the outflow tract, with preserved function in the inlet and trabecular portions of the right ventricle, and with a normal pulmonary circulation. A detailed, quantitative assessment of regional RV function is very difficult to achieve by echocardiography; in this study, thermal ablation produced lesions well localized to the RV outflow tract. When thermal ablation is ultimately applied for relief of RV outflow tract obstruction, its efficacy should be judged primarily by relief of gradient rather than by assessment of its effects on regional function. Nonetheless, a thorough analysis of the clinical efficacy of this technique would benefit from having not only a noninvasive measure of the contractility of remaining tissue but also a noninvasive measure of the mass of ablated tissue.
One question raised by this study is how long the outflow tract can be completely occluded by balloon inflation. Previous reports have shown that most patients who undergo pulmonary balloon valvuloplasty can tolerate 20 to 25 seconds of complete RV outflow tract occlusion.32 33 With the energy delivery system used in the present study, to achieve substantial acute remolding of the RV outflow tract, up to 40 seconds of effective energy delivery time was necessary in our in vivo model. With the 20-second effective energy delivery time, obvious lesions could be created in all 5 hearts; however, the lesions were small, without an acute decrease in RV outflow tract free-wall thickness. Fortunately, most patients likely to benefit from this procedure as a palliative intervention are neonates and infants with congenital heart disease, in whom smaller balloons may be used and smaller cardiac dimensions may favor clinical efficacy with shorter thermal application times; since our in vitro study demonstrates that small quantities of electrolyte solution can be heated with radiofrequency energy to ablation temperature faster than large quantities, a smaller balloon size will result in shorter inflation times than those used in our study (Fig 2⇑). Concomitant intracardiac shunts, such as a ventricular septal defect, a patent foramen ovale, or a patent ductus, also may make balloon inflation more readily tolerated. Ultimate clinical application may require a balloon in which initial heating to an effective ablation temperature (>50°C) is achieved more rapidly than in the present study or use of a staged approach with multiple short thermal balloon applications; the latter may also permit titration of the relief of outflow tract obstruction, thus minimizing the risk of excessive pulmonary blood flow when applied to lesions such as tetralogy of Fallot.
Nine lambs in the acute in vivo study developed ventricular fibrillation during thermal balloon ablation at balloon inflation times >35 seconds; while this may have been a direct effect of tissue damage, the occurrence during balloon inflation in 1 lamb not subjected to thermal ablation suggests that RV outflow tract obstruction, RV distension, and decreased systemic pressure may have contributed to ventricular fibrillation, particularly in this model with a normal heart and no intracardiac shunts. The use of direct application of radiofrequency energy for the treatment of ventricular arrhythmias results in muscle ablation by heating and is usually not associated with ventricular fibrillation.34 Prevention of cardiac arrhythmias during application of this technology will be essential and warrants further study.
The prototype radiofrequency-heated thermal balloon catheter used in this study has several limitations. The balloon membrane material selected was elastic latex, as previously described. While this material can alter its shape to conform to the endomyocardial surface to optimize heat transfer, elasticity may not be not ideal for the dilatation of a fibrotic, obstructed outflow tract. Less elastic material may be more desirable for dilating such an outflow tract.
The ideal radiofrequency-heated thermal balloon catheter must be small enough to allow percutaneous insertion in a neonate or infant. In this laboratory-built prototype, a 14F catheter was used. Future studies in a closed-chest model are necessary to determine how ablation parameters might differ in a closed-chest model in which there is no air-tissue interface at the surface of the right ventricle to affect thermal boundary conditions. For such studies and for clinical applications, fabrication on a smaller shaft (5F to 7F) will be required to permit percutaneous access to the neonatal RV outflow tract.
This preliminary study suggests the possibility that catheter-delivered thermal ablation might be useful for managing dynamic, muscular outflow tract obstruction. Further experimental studies, including additional chronic animal studies and eventual clinical trials, are warranted.
We thank John T. Fallon, MD, PhD, for assistance with histological examination, Myang-Yong Lee, MD, for assistance in echocardiographic examination, and Tracy A. Svizzero for her technical assistance.
Reprint requests to Gus J. Vlahakes, MD, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114-2696.
- Received October 24, 1994.
- Accepted November 29, 1994.
- Copyright © 1995 by American Heart Association
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