Vicente Climent,
MD, PhD*, Aquilino Hurlé, MD, PhD, FETCS†, Siew Yen
Ho, PhD, FRCPath, FESC‡,
Damián Sánchez-Quintana, MD, PhD*
*Departamento de Anatomía
Humana, Facultad de Medicina, Universidad de Extremadura, Badajoz,
Spain
†Departamento de Cirugía Cardiaca del Hospital
General Universitario de Alicante, Alicante, Spain
‡National
Heart and Lung Institute, Imperial College, and Royal Brompton and
Harefield Hospitals, London, UK
Address for
correspondence: Siew Yen Ho, Paediatrics, National Heart and
Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY.
United Kingdom. E-mail:
yen.ho@imperial.ac.uk
Abstract
Until recently
the treatment of atrial fibrillation (AF) consisted primarily of
palliation, mostly in the form of pharmacological intervention. However
because of recent advances in nonpharmacologic therapies, the current
expectation of patients and referring physicians is that AF will be
cured, rather than palliated. In recent years there has been a rapid
expansion in the availability and variety of energy sources and devices
for ablation. One of these energies, microwave, has been applied
clinically only in the last few years, and may be a promising technique
that is potentially capable of treating a wide range of ventricular and
supraventricular arrhythmias. The purpose of this study was to review
microwave energy ablation in surgical treatment of AF with special
interest in histology and ultrastructure of lesions produced by this
endocardial ablation procedure.
Keywords: atrial fibrillation; microwave ablation
Introduction
Atrial fibrillation is known to be the commonest cardiac rhythm
disturbance and a significant source of associated mortality and
morbidity
1-3.
Its medical treatment with antiarrhythmic drugs has proved rather
disappointing, with reported failure rates for maintaining sinus rhythm
exceeding 80% in the medium to long term. Thus, the direct consequence
of this poor therapeutic efficacy of antiarrhythmic drugs to restore
sinus rhythm is to limit pharmacological treatment of chronic AF to the
prevention of thromboembolic events and heart rate control in most
instances.
Surgical Procedures in AF treatment
In recent
years, efforts have been made to develop more efficient surgical
options to treat AF. During the decade of the 1980´s, Cox and
colleagues
4-6
conducted some pioneering electrophysiologic research that lead to the
development of the so-called Maze procedure
7,
a surgical technique (modified in three occasions) that basically
consisted of performing a set of transmural surgical incisions at
precise locations of both atria in such a way that the resulting
fibrous scars would produce lines of electrical isolation, so
interrupting all possible re-entrant circuits necessary to perpetuate
AF.
The
outstanding results obtained with this technique
8,9, with reported success rates above 90%
for curing the arrhythmia, justified its adoption as the gold standard
for the surgical treatment of AF. However, this “cut and sew” Maze
procedure did not gain great popularity among surgeons as it is
complex, time consuming and not without potentially dangerous
associated complications. So, further clinical and technological
research was necessary in order to develop simpler, quicker and safer
surgical techniques to deal with AF.
The complex
conventional Maze III procedure
10
included left atrial lesions encircling all four pulmonary veins,
extending towards the mitral annulus (the so-called left atrial
isthmus) and towards the left atrial appendage, which was excised.
Also, several right sided lesions, along the crista terminalis with
extensions towards interatrial septum and also towards the free atrial
wall and tricuspid annulus and excision of the right atrial, were
described for this procedure.
However, the
debate is now open on whether all atrial lesions described for the
conventional Maze procedure are necessary in order to achieve optimal
results in terms of reversion of AF into sinus rhythm. The relevant
studies carried out by Haissaguerre et al
11
demonstrated that paroxysmal (intermittent) AF is induced by triggers
located in the pulmonary veins in about 90% of cases. Consequently, the
great majority of patients with paroxysmal AF could be cured by just
electrically isolating the pulmonary veins, thus, simplifying
considerably the lesion pattern described for the Maze procedure.
A different
approach should be made regarding chronic (permanent) AF. The drivers
that sustain chronic AF are also a matter of debate. Some authors
12,13 support the idea
that AF drivers are located, as are the triggers, within the pulmonary
veins and, on this basis, simple pulmonary vein isolation should be
enough to treat chronic AF, as was the case with intermittent AF. Other
authors
14 describe some
macro-reentrant circuits on both atria, a phenomenon known as atrial
electrical remodelling, as the drivers for permanent AF. If this was
the case, pulmonary vein isolation alone would not be quite enough to
cure the arrhythmia as the procedure would interrupt the triggers that
initiate AF, but not the drivers that perpetuate it.
From the
clinical point of view, the so-called partial or mini-Maze procedures,
that is, procedures that include only left atrial lesions, have proved
less effective than the Maze procedure itself, with reported success
rates in the range of 60 to 80%
15.
Furthermore, postoperative atrial
tachycardia secondary to re-entrant circuits around the mitral or
tricuspid annuli can be expected in about 10% of patients treated with
this limited approaches.
From all these
data, we could conclude that: a) pulmonary vein
isolation should be performed in all instances, b) paroxysmal AF
requires further lesion lines in left atrial isthmus and cavo-tricuspid
isthmus to prevent postoperative atrial re-entry tachycardia and c)
permanent AF requires additional right-sided lesions to interrupt
macro-reentry
16.
Another line
of research on the surgical treatment of AF deals with the
method to produce atrial lesions. Performing surgical incisions and
subsequent suturing, as described for the conventional Maze procedure,
guarantee transmurality but increase technical complexity and potential
hazards. This is why, in recent years, several alternative forms of
energy have been introduced with the aim of producing transmural atrial
lesions that result in fibrous scars, similar to those described for
the Maze procedure, but in a simpler, quicker and safer manner. These
energy sources include radiofrequency, cryoenergy and microwaves, all
of them available for clinical use, and others, such as laser energy or
ultrasounds, which are at present being tested on experimental grounds.
Recent data demonstrate that these energy sources are just as effective
as surgical incisions to produce the desired atrial lesions
17-19 and
considerably shortened the time taken for creating the maze in
comparison to the Cox´s maze procedure.
20
Therefore, the
conventional “cut and sew” technique has now been abandoned by most
surgeons, even by Dr. Cox himself. Microwave and radiofrequency
ablation yield similar results in terms of restoration of sinus rhythm
following the Cox Maze III line concept, even in patients requiring
complex double, or triple, valve procedures
21.
Histology of the lesions produced
by means of microwave energy
Microwave
ablation is based on the effect of
high frequency electromagnetic radiation on the atrial wall. These
electromagnetic waves, when applied to the atrial endocardial or
epicardial surface, interact with tissue dipolar molecules, mainly with
water molecules, inducing their oscillation at a very high speed, so
converting electromagnetic energy into kinetic energy. This high speed
vibration favours friction between water molecules within the
myocardial wall, which results in an increase of myocardial tissue
heat
22. Microwave ablation
has been demonstrated effective for the
treatment of atrial arrhythmias and because microwave antennas may be
made into flexible linear applicators, they may be well suited to the
ablation of AF and the production of catheter-based maze procedures.
Thus, following these mechanisms, microwave energy has proved capable
to produce histologically demonstrated transmural atrial lesions
23,24.
A search of
the main medical journals was carried out to review the
application of microwave on the epicardial or endocardial surfaces
(
Table 1). Some authors
9,25,29,31,32 prefer an epicardial
approach which might allow reduction, or even elimination, of the
aortic cross-clamp time and permits a surgeon to avoid an atriotomy
when it not required for treating intracardiac pathology
23. In
general, epicardial ablation is safer than endocardial ablation because
the energy source is directed into the atrial chamber rather than
outward into adjacent mediastinal structures, and it also allows the
operator to center the energy of application on the structures that
contain more water and overcome fat tissue barriers. In spite of that,
the endocardial application of microwaves is most widely used
26,30,33,34 (
Table
1) in clinical series due to the great number of
cases of chronic AF requiring surgical interventions on the mitral
valve (repairs or replacements).
Table
1
RN= Reference number. Exp:
Experimental animal.
A/V: Atrial/Ventricle. LA: Left Atrium. RA: Right Atrium. RA: Right
Atrial Appendage.
PV: Pulmonary Veins. LV: Left ventricle
Epi/End: Epicardium/Endocardium
Comp: Complications. Rec: Recurrences
SSS: Sick Sinus Syndrome.
SB: Sinus Bradycardia. AF= Atrial fibrillation
SIS: Systemic Inflammatory Syndrome
The
electromagnetic fields can propagate through blood, desiccated
tissue or scar and be deposited directly in the deeper tissue. The
penetration depth depends upon several factors, including the
dielectric properties of the tissue, frequency of the microwave energy,
and antenna design.
25,26
Several studies
27,28 have shown how the
composition and thickness of the cardiac layers are major determinants
in the formation of the lesion after ablation.
Similarly,
Santiago et al
27 reporting
on epicardial radiofrequency (RF)
applications suggest that the thickness and the composition of the
epicardium and the myocardium play an important role in the formation
of the tissue lesion, and that this may account the large variability
in the clinical results from different groups working in RF ablation.
From a biophysical point of view, it is likely that atrial tissues with
different compositions (more or less fat, connective and myocardial
tissues, intercellular space, etc) will have different electrical
properties. Fuller and Wood
28
in an experimental study using RF
ablation suggested that the flow through an intramural coronary artery
may play a role in preserving the myocardium around the vessel, and it
is necessary to have a high tissue temperature to overcome the effect
of intramural vascular cooling. They found the volume of preserved
myocardium correlated directly with arterial flow rate through the
lesion
Microwave
energy has been used at frequencies of 0.915 GHz and
2.450 GHz for the myocardial ablation of arrhythmias (
Table 1).
Normally the energy is set around 65W in humans, and the application
time is 45 seconds when applied endocardially on pulmonary veins. Other
authors apply microwave energy epicardially for longer time (90
seconds) on the right atrial appendage (human),
23
or pulmonary veins
(mongrel dogs).
29
Keane et
al
26 evaluated the effect
of the microwave energy on a
phantom tissue (which have similar properties to myocardium) and on
ventricles of goats. It has been demonstrated (on the phantom tissue)
that the antenna is capable of heating the tissue-equivalent material
to at least 48°C and this was the temperature required for
irreversible tissue damage and a depth of 8 mm. The desired result was
achieved with a 2 minutes microwave exposure time at antenna power
levels ranging from 22 to 34 watts (
Table
1). Shorter exposure times of
30 and 60 seconds resulted in reduced penetration depth. At present,
therefore, given the widespread microscopic injury by microwave
ablation, additional data using different antennas and frequencies are
needed to demonstrate the safety and efficacy of microwave.
Santiago and
colleagues
27 reporting on
tissue damage
by heating induced by RF ablation in patients with mitral valve disease
obtained similar lesions depth with 80-90°C in epicardial
applications and 70°C in endocardial applications. The percentage
of transmural lesions in this study was 8%, although according to other
workers
23 it is not clear
whether transmurality is a prerequisite for a
lesion to be effective. The interruption of an electrical pathway may
be effective although not all the fibres are destroyed. A thinner
tissue might conduct slow enough to interrupt re-entrance phenomena and
be sufficient to restore regular atrial activity.
Most
histological investigations of effects of microwave on
tissues are made using light microscopy with stain techniques which
distinguish clearly between extracellular and muscular tissue (Masson
or Jones trichrome, elastic van Gieson, etc) and they compare samples
of preablation with postablation or control tissues (
Fig. 1). As can be
seen in
Table 1, few data are
available regarding the histologic
acute-, short- and long-term changes of the myocardium after microwave
hyperthermic exposure. The histologic examination of acute morphologic
effects
24 after microwave
endocardial ablation demonstrated that left
atrial wall thickness appeared reduced when compared with preablation
samples (
Table 1). The samples
after microwave ablation revealed a
transmural lesion. Nevertheless, some apparently viable cells were
observed near the epicardial side
24.
Atrial or ventricular myocytes in
postablation showed severe myolysis, intramyocardial edema and
intramural haemorrhage or foci of coagulative necrosis
23-26,29,34 (
Table
1 and Fig.1).
Figure 1. Histologic samples from
the left atrial wall showing the myocardium prior to microwave ablation(a,c,e) compared with
immediately after ablation(b,d,f).
Note that hypertrophy, irregular shape, damage to myocytes (arrows),
edema, and increased distance between cells are more evident in
postablation samples. CT= Connective tissue, MY= Myocyte. The bar
indicates 50µm
Using immunohistochemical staining procedures,
we assessed the expression and organization of contractile and
cytoskeletal proteins of myocytes and extracellular matrix damaged
before and after of microwave ablation procedure
24. The acute changes
of the atrial myocytes in endocardial post-ablation samples showed
severe and complete loss of regularly arranged contractile material
with an irregular proliferation or accumulation of one or more
cytoplasmic components such as mitochondria (which were unusually small
with the occasional giant mitochondria) and glycogen granules replacing
the myofibrillar elements (
Fig. 2).
The majority of the small
intramyocardial vessels staining with CD34 and CD31 antibodies within
the zone of the ablation lesion showed distinct occlusion of their
lumens and severe disruption of endothelial or adventitial layers (
Fig.
2).
Figure 2. Immunohistochemical
staining for desmin (a,b),
mitochondria (c,d) and CD 34 (e,f) comparing before (a,c,e) and after (b,d,f) microwave ablation. Tissues
after ablation showed more clear foci of coagulative necrosis with
accumulation of mitochondria (thin arrows), and myolysis areas
replacing the myofibrillar elements (thick arrows). The majority of the
small intramyocardial vessels staining with CD 34 antibodies showed
distinct occlusion of their lumens postablation (arrowheads in f). Panels a, b
and e are at the same
magnification. Panels c and d are at the same magnification.
Ultrastructural observations obtained before microwave ablation showed
only focal alterations such as focal loss of contractile elements,
abnormally shaped mitochondria, large and highly lobulated nuclei,
intercalated disk disruption and basement membrane disruption (
Fig.3).
However, acute ultrastructural changes in myocyte endocardial
post-ablation samples demonstrated irregular or complete loss of
membranous borders, loss or very irregular shape of nuclei,
mitochondrial swelling, disruption of endothelial cells of the
capillary vessels, and signs of inflammation shown by the presence of
macrophages
24 (
Fig. 3). These are morphologic
features of irreversible
injury indicative of non viable cells. Nonetheless, severely
degenerated myocytes were isolated from other cells by fibrous tissue
but occasionally were connected by junctional areas to only moderately
degenerated cells. It is unclear whether these myocytes would remain
viable over time to be capable of delivering electrical activity
associated with AF. For these reasons, it is necessary to explore
short- and long-term histologic changes following microwave energy
ablation to evaluate it the full thickness lesion is a prerequisite for
a lesion set to be effective.
Figure
3. Transmission electron photomicrograph of samples preablation (a,c,e) and postablation using
microwave (b,d,f) showing the
architecture of contractile elements and basement membrane (a,b). The capillary vessel(CV) in (d) shows severe disruption of
endothelial and adventitial layers compared with the vessel in
preablation sample(c). In panel
(e) the extracellular matrix
show in preablation an collagen fibers with a fibroblast(open arrow) in
the same field. A severely degenerated myocyte in postablation sample
shown in (f) has severe
disruption of nuclear and basement membranes, disarray and loss of
contractile filaments and condensation of heterochromatin.
Magnification: (a)x6000 (b)x4800 (c)x3790 (d)5910 (e)x5800 (f)x7540
BM=basement membrane; CF=collagen fibers; MI=mitochondria; MY=myocyte;
N=nucleus.
Watanabe et al.
25 observed 2 days after application of
epicardial
microwave energy at the free wall of the left ventricle of mongrel dogs
necrotic muscle with intramural hemorrhage that was demarcated from the
normal myocardium by young granulation tissue on the border zone of
ablated lesion. At 1 month, the necrosis was present only in the center
of the lesion, and most of the necrotic muscle was replaced by fibrotic
tissue. Similar results were found by Van Brakel et al
29 (
Table
2).
Healing by fibrosis was complete by 3 months and fatty tissue
infiltrated a small area of the ablated lesion. After 6 months, the
necrotic myocardium healed to a white-colored hard scar tissue which
was sharply demarcated from normal myocardium. At 12 months the scar
tissue consisted of collagen fibres and was infiltrated by fatty
tissue
25. However, little
information is available on the thinner
atrial wall regarding the histologic changes long-term after microwave
ablation.
In summary, it
seems that microwave ablation creates transmural lesions
with only a few proarrhythmic events occurring during ablation, and
suggests that application of this energy can be particularly useful in
the treatment of tachyarrhythmias arising from deep foci of ventricular
myocardium. Further studies are required to assess the use of this
energy on atrial wall that is irregular in thickness.
35,36
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