(Circulation. 1999;100:203-208.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Extracardiac Ablation of the Canine Atrioventricular Junction by Use of High-Intensity Focused Ultrasound
From the Division of Cardiology (S.A.S., T.T., F.M.) and the Department of Biomedical Engineering (J.-U.A.K., C.C.), University of Michigan, Ann Arbor.
Correspondence to S. Adam Strickberger, MD, University of Michigan Medical Center, 1500 E Medical Center Dr, Box 0022, Ann Arbor, MI 48109.
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Abstract |
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Background—High-intensity focused ultrasound has been applied to internal organs from outside the body to ablate tissue. No published study has assessed the feasibility of ablating cardiac tissue within the beating heart by use of this type of therapeutic ultrasound. The purpose of this study was to determine whether high-intensity focused ultrasound can be used to ablate the atrioventricular (AV) junction within the beating heart.
Methods and Results—Ten dogs were anesthetized and underwent a thoracotomy. The heart was covered with a polyvinyl chloride membrane. The thorax above the membrane was perfused with degassed water, which functioned as a coupling medium for the ultrasound. A 7.0-MHz diagnostic ultrasound probe was affixed to a spherically focused 1.4-MHz high-intensity focused ultrasound transducer with a 1.1x8.3-mm focal zone 63.5 mm from the ablation transducer. The diagnostic ultrasound probe was calibrated such that the location of the focal zone of the ablation transducer was identifiable on the 2-dimensional ultrasound image. Target sites were identified with the diagnostic ultrasound. The maximum ultrasound intensity for ablation (2.8 kW/cm2) was delivered to the AV junction only during electrical diastole and for a total of 30 seconds. Complete AV block was achieved in each of the 10 dogs with 6.5±5.6 (range, 3 to 21) 30-second applications of therapeutic ultrasound. Gross inspection showed that the mean lesion volume was 124±143 mm3, with a depth of 6.7±3.6 mm, a length of 5.7±2.5 mm, and a width of 4.7±1.8 mm. Four hours after the dogs were killed, histopathological study demonstrated a well-demarcated area of necrosis and early inflammation.
Conclusions—High-intensity focused ultrasound produces well-demarcated lesions and appears to be a feasible energy source to create complete AV block within the beating heart without damaging the overlying or underlying cardiac tissue. This energy source may allow for a noninvasive approach to ablation of cardiac arrhythmias.
Key Words: ablation • atrioventricular node • arrhythmias
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Introduction |
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High-intensity focused ultrasound has been used to ablate deep tumors.1 2 3 4 5 This type of therapeutic ultrasound energy offers the advantage of being applied from outside the body to create a lesion of essentially any size and geometry.6 High-intensity ultrasound can also be focused up to 15 cm within the body without heating or damaging the intervening tissue.6 Therapeutic ultrasound has been used to treat a variety of conditions.1 2 4 5 7 8 9 10 11 12 13 14 However, the use of extracardiac ultrasound to ablate functioning myocardium has not been reported. The purpose of this study was to determine whether extracorporeal focused ultrasound can be used to create atrioventricular (AV) block within the beating canine heart.
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Methods |
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Experimental Preparation
The University of Michigan Committee on the Use and Care of Animals approved the protocol. Ten mongrel dogs of either sex (37±7 kg; range, 27 to 50 kg) were used for this study. The dogs were anesthetized with sodium pentobarbital 10 to 30 mg/kg IV and then underwent endotracheal intubation and mechanical ventilation. General anesthesia was maintained with supplemental doses of sodium pentobarbital. Arterial blood gases were evaluated periodically, and ventilation was adjusted to maintain the arterial pH at 7.35 to 7.45. A hemostatic sheath was inserted into a jugular vein, and another was inserted into a carotid artery to allow for arterial blood pressure monitoring. A sternotomy was performed, and a retractor was positioned to expose the pericardium (Figure 1
). A polyvinyl
chloride membrane was positioned over the heart and lungs. To exclude
air bubbles and to improve the acoustic coupling, saline was applied to
the surface of the heart and the underside of the polyvinyl chloride
membrane. The thoracic cavity was perfused at 600 mL/min with degassed
water above the membrane. The degassed water functioned as an
ultrasound coupling medium. The ultrasound ablation system was placed
inside the thorax in the degassed water and positioned over the AV
groove. The surface ECG and the arterial blood pressure
were displayed and recorded on a multichannel recorder
(Electronics for Medicine VR 16).
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Combined Diagnostic/Ablation Ultrasound System
The diagnostic ultrasound component of the combined
ultrasound system used a conventional 2-dimensional (2D) ultrasound
machine (Diasonics VST Master Series, Diasonics/Vingmed Ultrasound Inc)
with a 7.0-MHz probe that was affixed to the ablation ultrasound
transducer (Figure 1
). The ablation ultrasound transducer was a
spherically focused single piezoelectric element (Etalon). The radius
of curvature was 63.5 mm, and the focal point was 63.5 mm
from the transducer. The operating frequency of the transducer was 1.44
MHz, and the focal zone (-6 dB) was 1.1 mm wide and 8.3 mm
long. In all experiments, the continuous-wave spatial peak temporal
average intensity was 2.8 kW/cm2. This is orders
of magnitude greater than that associated with diagnostic
and transcatheter ablation ultrasound. The spherically
focused ablation transducer exposed tissue to high-intensity focused
ultrasound energy in a cone shape. The input impedance of the ablation
transducer was electrically matched to the 50-
output impedance from
the linear amplifier. The high-intensity focused ultrasound transducer
was driven by a function generator (model 23, Wavetek) and a high-power
amplifier (300-W maximum; AP 400B, ENI). The high-power amplifier and
the function generator produced a gated sinusoidal waveform at 1.44
MHz. The ablation ultrasound transducer was positioned 63.5 mm
from the target by use of a 3-axis mechanical manipulator.
Calibration of the Ablation Ultrasound Transducer to the
Ultrasound Image
A 63.5-mm-long pointer, a length identical to the distance to
the focal point of the ablation ultrasound transducer, was attached to
the ablation ultrasound transducer. The combined ablation and imaging
fixture was placed in a degassed water bath. The location of the tip of
the pointer, relative to the diagnostic ultrasound image,
was noted on the ultrasound imaging monitor. This location was
displayed on the imaging monitor throughout the experiment and defined
the location of the focal point of the ablation transducer within the
2D ultrasound image (Figure 2). This
allowed the identification of ablation targets by use of the ultrasound
image.
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Ablation Protocol
The 2D ultrasound images were used to identify the AV junction
(Figure 2). All target sites were identified directly from the
2D ultrasound image. The calibration mark indicating the focal zone of
the ablation transducer was positioned at the summit of the
interventricular septum. A computer interface (Gateway
2000) was used to control the duration and timing of each energy
application. Because of cardiac motion and the desire to create
well-defined lesions at the AV junction, applications of ablative
energy were gated to the QRS complex and delivered only during
electrical diastole, as defined by the average preablation
heart rate. Mechanical ventilation and diagnostic
ultrasound imaging were continued during applications of ablative
energy. The ablation ultrasound energy was applied for a total of 30
seconds. The total number of applications per target site (119.7±7.7)
required to achieve a total application duration of 30 seconds depended
on the sinus cycle length (384±36 ms). The initial target site was
selected at the summit of the interventricular septum. If
complete AV block did not develop with a 30-second application of
ablative ultrasound energy, a new target slightly below or adjacent to
the previous target site was selected by use of the 2D ultrasound
image, and an additional 30-second application of energy was delivered.
This was repeated until complete AV block was induced.
After completion of the experimental protocol, the animals were
euthanized by an intravenous injection of supersaturated
potassium chloride. The heart was removed, and the lesion in the AV
junction was localized grossly. The 3 dimensions of the lesion were
measured, and the lesion volume was calculated according to the
following equation, which describes an ellipsoid: Lesion
volume=(4/3)
xlength/2xdepth/2xwidth/2.
Microscopic Evaluation
Pathological examination was completed in 4 animals. Lesions
from 3 animals were sent for microscopic evaluation immediately after
euthanasia. One additional animal was killed 4 hours after complete AV
block was created to allow evolution of the lesion.
Representative blocks of tissue encompassing the lesion
and including the epicardium and the surrounding myocardium
were identified by visual inspection. These blocks were fixed in 10%
formalin and embedded in paraffin. Sections were subsequently stained
with hematoxylin and eosin.
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Results |
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Main Findings
Complete AV block was created in each of the 10 animals with 30-second applications of ablative ultrasound at a mean of 6.5±5.6 target sites (range, 3 to 21; Table
; Figures 2 and 3). Junctional ectopy preceded complete
AV block in each animal. The mean escape rate was 61.4±12.8 bpm
(range, 40 to 80 bpm), with a QRS duration of 105±13 ms. The mean
lesion volume was 124±143 mm3, with a depth
of 6.7±3.6 mm (range, 1 to 15 mm), a length of 5.7±2.5
mm (range, 1 to 9 mm), and a width of 4.7±1.8 mm (range, 3
to 8). Lesion appearance was accompanied by the formation of an
echo-dense area at the targeted focal zone in each animal (Figure 2). Three animals developed ventricular fibrillation
during an application of ablative ultrasound energy. Sinus rhythm was
restored with electrical defibrillation in each instance.
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Gross and Microscopic Pathology
By gross inspection, each lesion was well demarcated and
surrounded by normal adjacent tissue (Figure 3). The
myocardium between the ultrasound ablation transducer and
the lesion was unaffected (Figure 3). Anatomically, the location
of lesions always was consistent with the target sites
identified by 2D ultrasound.
Pathological examination was completed in 4 animals. Microscopic
examination of tissue from the 3 animals killed immediately after
complete heart block was achieved showed a well-demarcated area of very
acute inflammation. The adjacent tissue was
histologically normal. Microscopic examination of
tissue from the 1 animal killed at 4 hours demonstrated a
well-demarcated lesion (Figure 4). The
myocardium immediately adjacent to the lesion, including
the tissue between the lesion and the ablation ultrasound transducer,
was histologically normal. Within the lesion, necrosis
was clearly evident, with increased eosinophilia of myocyte cytoplasm,
prominent contraction bands, and an incipient leukocytic response
(Figure 4).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Main Findings
This study demonstrates that extracardiac ablation of the AV junction can be achieved in the beating heart by use of high-intensity focused ultrasound. Applications of ablative ultrasound energy produced well-demarcated lesions that demonstrated thermal coagulation. Lesion formation was consistently associated with the development of a small echo-dense area on the 2D ultrasound image. The myocardium adjacent to the lesions, including the tissue between the lesion and the ablation ultrasound transducer, was unaffected by the ablative ultrasound energy.
Pathology and Mechanism of Lesion Formation
The lesions created in this study with high-intensity focused
ultrasound were well demarcated. Similar lesions have been observed
when high-intensity focused ultrasound was used to create lesions in
noncardiac tissue.1 5 7 11 15 The pathology of the acute
lesions noted in the present study is similar to that of the
well-demarcated lesions created with radiofrequency
energy.16 17 18 This type of well-demarcated lesion is not
believed to be associated with a risk of proarrhythmia.
However, the effect of time on cardiac lesions created with
high-intensity focused ultrasound energy has not been evaluated.
Imaging of Ablation Targets and Lesions
Intracardiac ultrasound imaging has been used to direct
applications of radiofrequency energy and to observe the development of
lesions generated by radiofrequency catheter
ablation.19 20 In animals subjected to radiofrequency
catheter ablation, the lesion size noted with intracardiac ultrasound
correlates well with the lesion size observed
postmortem.20 In the present study,
diagnostic ultrasound was used to select ablation target
sites and to monitor lesion formation. Lesion formation was associated
with the development of an echo density at the target site. These
preliminary data suggest that combining diagnostic
ultrasound imaging with ultrasound ablation may provide a technique for
identifying target sites and for recognizing when an energy application
has resulted in lesion formation.
Comparison With Transcatheter Ultrasound
Ablation
Ultrasound cardiac ablation has been performed in dogs with
a 7F catheter.21 22 The lesion depth and volume were
similar to those created with radiofrequency catheter
ablation.18 21 22 Catheter-based ultrasound ablation
requires 
10 MHz to produce adequate tissue absorption. Approximately
1 W of acoustic power is needed; there is direct tissue contact, and
lesion depth is 
8 to 10 mm.21 22 In the
present study, target sites for ablation were selected with
conventional, noninvasive, 2D ultrasound, and tissue contact was not
required. The high-intensity ultrasound used 120 W of total acoustic
power that was focused and used to ablate tissue at a distance of 6.3
cm from the transducer without damaging the intervening tissue.
High-intensity focused ultrasound has been used in an in vitro system
to create lesions of various sizes and shapes, in a variety of
locations, within the complex anatomy of the canine
heart.23 A phased-array therapeutic ultrasound system
composed of tens or hundreds of ultrasound elements may be used to
create lesions at specific target depths up to 15 cm, without
significant heating of the intervening tissue.6
Phased-array systems may be suitable for noninvasive cardiac ablation
because of the ability to control for the position of the target site
by switching between different beam patterns at electronic speed, to
correct for aberrations due to complex inhomogeneous
intervening tissue, such as the ribs and lungs, and the ability to
change the effective aperture dimensions during treatment by adjusting
the driving signals.6 24 25
Previous Studies Using High-Intensity Ultrasound
Previous investigators have evaluated noninvasive high-intensity
focused ultrasound in vivo and in vitro for the treatment of a variety
of disorders.1 2 4 5 9 11 14 26 Catheter-based ultrasound
ablation has been used to dissolve clots in patients with acute
myocardial infarctions, and externally delivered ultrasound has proved
effective for recanalizing thrombosed ileofemoral arteries in
rabbits.26 27 The present study is the first to report
that high-intensity ultrasound energy can be focused from outside the
beating heart to a desired location within this organ without damage to
intervening tissue.
Technological Limitations of Ultrasound Ablation
A spherically focused single-element ultrasound ablation system,
as used in the present study, cannot be used to ablate cardiac
tissue through a closed chest. However, modeling studies of a human
chest phantom demonstrated the feasibility of using a phased-array
ultrasound system for precise beam formation within the thorax and
around the ribs.24 In addition, many
parameters, such as frequency, the ratio between the
aperture size and focal depth, and duration of energy application, can
affect lesion size and volume. These factors need to be more completely
understood to optimize lesion formation. In addition, lesion volume
varied between animals. Differences in biological factors may have
contributed to this variation, or perhaps the variable lesion size
resulted from applications that did not form lesions, from overlap of
successive target sites, or because the focal zone was small.
Conclusions and Implications
These results demonstrate that extracardiac application of
ablative ultrasound energy gated to the cardiac cycle and guided by
diagnostic 2D ultrasound can be accurately aimed at the AV
junction and can create complete AV block in the beating canine heart
without damaging adjacent tissue. The lesions are well-demarcated and
consistent with thermal necrosis. This technology may form the
basis of extracorporeal application of an ablative energy that can
create controlled lesions of various sizes and shapes. Theoretically, a
combined diagnostic and therapeutic phased-array ultrasound
system may allow for noninvasive ablation of cardiac
arrhythmias.
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Acknowledgments |
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Dr Tokano was supported in part by Research Fellowship Award 17F967 from the American Heart Association of Michigan. The authors greatly appreciate the assistance of Gerald D. Abrams, MD, of the Department of Pathology at the University of Michigan.
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Footnotes |
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Drs Strickberger and Cain are stockholders in a company developing a noninvasive ablation system.
Received December 22, 1998; revision received March 18, 1999; accepted March 31, 1999.
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Circulation. 1997;95:1411–1416.High-intensity focused
ultrasound can be applied externally to ablate internal tissue. No
published study has assessed the feasibility of ablating cardiac tissue
within the beating heart from outside the body with high-intensity
focused ultrasound. The purpose of this study was to determine whether
high-intensity focused ultrasound guided by conventional 2-dimensional
diagnostic ultrasound can be used to create complete AV
block within the beating heart. After undergoing a thoracotomy, 10 dogs
successfully underwent ablation of the AV junction with extracardiac
application of therapeutic ultrasound. Gross lesions were obvious, and
histopathological evaluation demonstrated a well-demarcated area of
necrosis. High-intensity focused ultrasound may provide a technique for
noninvasive cardiac ablation.
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