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General Review

Therapeutic Ultrasound for the Heart: State of the Art

P. Greillier a, , C. Bawiec a , F. Bessire a,b , C. Lafon a
a Univ Lyon, Universit Claude Bernard Lyon 1, Centre Lon Brard, INSERM, UMR1032, LabTAU, 69003 Lyon, France
b Hospices Civils de Lyon, Hpital Cardiovasculaire Louis Pradel, 69500 Lyon, France

Received 21 September 2017; received in revised form 10 November 2017; accepted 13 November 2017

Abstract
This work describes the use of therapeutic ultrasound as a treatment of cardiovascular disease including recent, state of the art approaches.
Therapeutic ultrasound researchers have made recent advances in the highly dynamic and changing world of interventional cardiology where they
are confronted with several challenges, such as of the complexity of ultrasound propagation in the highly heterogeneous environment of the thorax
or the complexity of the heart (in term of motion and physiology). It is believed that with these recent innovations, therapeutic ultrasound for
cardiac applications will soon have a place in the toolkit of cardiologists.
2017 Published by Elsevier Masson SAS on behalf of AGBM.

Keywords: Ultrasound therapy; Cardiovascular disease treatments; HIFU; Ultrasound ablation

1. Introduction A wide range of techniques combining the use of medica-

Cardiovascular disease (CVD) is a major concern for current
global health. According to the American Heart Association
(AHA) [1] and the European Society of Cardiology [2], CVD
is the number one cause of death in Western countries.
CVD affects the heart and surrounding blood vessels and can
be divided into two classes:
Structural disorders. These affect the anatomical function
of the heart such as malfunctioning valves, coronary artery
blockage or congenital heart defects.
Electrical disorders. These concern all mechanisms in-
volved in an abnormal production or propagation of elec-
trical waves through the heart. Electrical disorders could
be the consequence of isolated cells malfunctioning, scar
tissues and/or other perturbations in tissue electrophysio-
logical structures.
* Corresponding author.
E-mail address: paul.greillier@inserm.fr (P. Greillier).
https://doi.org/10.1016/j.irbm.2017.11.004
1959-0318/ 2017 Published by Elsevier Masson SAS on behalf of AGBM.
tion, surgery and other interventional means (e.g. stents) are
used to cure CVD. Cardiology research is under a constant state
of rapid evolution leading to improved outcomes for CVD pa-
tients [3].
Direct, real-time and inexpensive, ultrasound imaging is al-
ready utilized as a routine clinical procedure for cardiology,
often coupled with contrast agents [4]. Advances in ultrasonic
imaging systems have improved diagnostic abilities by incor-
porating new imaging enhancement technologies such as ultra-
fast imaging (allowing for elastography and electromechanical
imaging) [5] and 3D/4D imaging [6] allowing for a better un-
derstanding and monitoring of tissue properties.
Therapeutic ultrasound (TU), using ultrasound as a treat-
ment as opposed to a diagnostic, is seen as an emerging tech-
nology in the cardiovascular field as well. Over the last decades,
many researches have highlighted that TU could provide al-
ternatives to the existing radiofrequency or cryotherapy-based
catheters thanks to its versatility. As an extremely versatile tool,
TU can be used for a large variety of applications [7]. These
applications include thermal ablation, distant scalpel, and even
drug delivery.
In the following, after a quick summary of the bio-effects
capable of being induced using TU, we review the different
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techniques applied to the treatment of CVD and their current
status. We also consider their challenges and limitations to find
a way to their clinical viability.
2. Therapeutic ultrasound: principle
A summary of the bio-effects associated with TU is provided
to help the reader. Compared with other imaging modalities
such as CT-scanning, ultrasound imaging has lower risks of
side-effects due to the relatively low acoustic intensities used
(e.g. 430 mW/cm2 spatial-peak, time-averaged intensity for car-
diac diagnostic ultrasound device [8]). However, if the energy
level is increased, ultrasound does have the potential to induce
cellular and tissue level changes in the body. A large part of ul-
trasound research has been and continues to be done to evaluate
and regulate the induced biological effects [8,9]. In the case of
TU, these effects are especially important as the energy levels
that are used can modify the tissue structure. Ultrasound bio-
effects can be divided into two broad categories, thermal and
mechanical, which are described in greater detail below.
2.1. Thermal effects
The thermal effects of the US are due to the acoustic absorp-
tion of the waves which is converted into heat [10]. It is directly
related to the exposure time and intensity of the ultrasound field.
One common way to quantify thermal exposimetry is the ther-
mal dose, which is described by the following equation defined
as the cumulative equivalent minutes at 43 C [11,12]:
t
CEM 43 C = R T 43 dt (1)
0 ena interact with each other, creating combinatory effects [20].
where T is the temperature and R is 0.5 above 43 C and 0.25
below 43 C.
CEM 43 C quantifies the biologically equivalent heating time
at 43 C that the tissue undergoes. This thermal dose vari-
able expresses only the equivalence between specific time
temperature exposure configurations. It does not describe the
mechanisms of the tissue and cellular level changes induced by
the heat. The hyperthermia effect on the cellular behavior un-
der long exposure and mild temperature (e.g. alteration on the
cancerous cells proliferation under 45 for 1 h [13]) and the
thermal lesion caused by high temperature for a short time (e.g.
protein coagulation, tissue inflammation and cell necrosis).
Thermal effects are commonly produced by continuous
(or quasi-continuous) sonication with relatively low intensi-
ties (102 W/cm2 spatial-peak, temporal-average intensity).
High intensity ultrasound (HIFU) transducers concentrate the
US beam energy in a small focal region (focal lengths range
from 2 to 135 mm [10]). The lesions created are often small
(on the order of 12 wavelengths [10]), precise and placed with-
out damaging the surrounding tissue.
2.2. Non-thermal effects
Non-thermal effects are attributed to mechanically induced
effects of the ultrasonic pressure wave, mainly due to cavita-
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tion phenomenon in TU and secondly to radiation force. Non-
thermal effects can be produced by short exposure (<0.05 ms)
with relatively high pressure (>20 MPa) [14] or with longer
exposure and relatively low pressure (55 kPa [15]) to not
induce heating. Transducers used are either focalized as HIFU
or non-focused.
Cavitation phenomenon is the expansion and contraction of
the natural gas voids [16]. This phenomenon is triggered when
there are gas voids in the tissue in the presence of an acous-
tic field. Gas bubbles can dissolve in physiological tissue, but
when the tissue is under an ultrasound field, the compression
and especially rarefaction waves can cause the bubbles to grow,
a phenomenon known as rectified diffusion [17].
Cavitation divides into two forms [17]:
Stable cavitation describes a sustainable, periodic and non-
linear expansion and contraction of a gas bubble.
Inertial cavitation refers to the violent collapse of bubbles.
During this collapse, local pressure and temperature are in-
stantly increased, producing micro-jets and light emission
which can cause tissue fragmentation, free radical produc-
tion and shock-waves.
The second main non-thermal mechanism is the radiation
force. The radiation force is a period-averaged force exerted on
the medium by a sound wave. It induces the generation of fluid
streaming [18] and tissue displacements [19].
2.3. Combinatory effects
Still, it must be noted that all of the aforementioned phenom-
For example, a temperature increase induces bubble formation
which forms an acoustic mirror due to the impedance mismatch
between tissues (1.5 Mrayls) and air (415 rayls), increasing
cavitation effect (boiling histotripsy [14]).
3. Thermal ablation and arrhythmias
3.1. Anatomy and physiology of the arrhythmias
A complex electrical network runs through the heart causing
its contractions: from the sinoatrial node in the right atrium,
electrical impulses travel through the heart, first in the atria
then descending to the ventricles through the atrioventricular
node. Alteration of the normal pattern of electricity causes ar-
rhythmias often due to unwanted tissues which create abnormal
electrical pathways. These lead to shortcuts, re-entrant circuits,
or ectopic pulsing nodes [21] which encompass several diseases
including atrial fibrillation, the most prevalent one [22].
Arrhythmias treatments include medication, heart resyn-
chronization (pacemaker), catheter intervention and/or surgery.
In lieu of conventional surgery cardiologists more commonly
prefer the use of catheter ablation [23]. As with surgery, thermal
ablation attempts to treat arrhythmias through the destruction of
the abnormal electrical zone.
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P. Greillier et al. / IRBM ()
Current thermal ablative techniques are catheter-based, us-
ing radiofrequency (RF) [23] or cryoenergy [24]. RF thermal
ablation consists in passing electrical currents heating up an
electrode in contact with the abnormal tissues. Cryoablation
burns targeted tissues by freezing them using cooled down nee-
dles with circulating refrigerant fluids. These techniques, al-
though widely used [3], still have limitations: the need for a
direct contact between the tip of the catheter and the tissue, no
direct visualization of the created lesions and the difficulty to
produce complete coagulation near large blood vessels [23].
The success of these procedures depends on the energy dif-
fusion into the desired area: in the case of thick myocardium,
a low rate of therapy success is expected.
On the contrary, High Intensity Focused Ultrasound (HIFU)
is a cardiac ablative therapy that offers some potential advan-
tages over current methods. First, the invasiveness can be re-
duced by placing US transducers away from the target as was
proposed with the transesophageal and transthoracic methods.
Second, even if the focal zone is small, dynamic focusing or
specially designed or custom fit transducer shape may be ap-
plied to manage the sonicated zone shape [25,26].
HIFU monitoring can be combined with ultrasound [27] and
MRI imaging modalities providing the clinician real-time imag-
ing of the treatment [28].
3.2. Endovascular devices
Much like existing ablative techniques, the first ultrasonic
devices were aimed at accessing the heart through an endovas-
cular approach. This approach consists of positioning the ab-
lative device inside the heart chambers, through a catheter in-
serted in the vessels. The first experiments in 1990s on car-
diac ablation used a flat transducer mounted on intracardiac
catheters [29,30]. Using such transducers, He et al. were able
to produce deep lesions in the myocardium at 10-MHz in vivo
in dog hearts, albeit not without complications. The poor ultra-
sonic directivity of the planar transducer led Hynynen et al. to a
new cylindrical design [31], which improved the energy deposi-
tion abilities. Hynynen et al. demonstrated the feasibility of this
transducer in vivo by producing 48 mm deep lesions. Large le-
sions were produced by both types of transducers though the
maximum power output was limited by the transducer self-
heating.
The first commercial HIFU device for cardiac applications
was developed to treat atrial fibrillation [32] (ProRythm). It
consisted of a catheter system with a combination of two bal-
loons at the end focusing the ultrasound energy in a circular
shape.1 The combination of the two balloons permitted to over-
come the limitations of the previous US catheters. It could
handle the energy deposition more precisely, while reducing
the self-heating effect. It created circumferential ablative le-
sions on the atrium of the pulmonary veins to isolate pulmonary
veins, which is the most frequent ectopic node zone in atrial
fibrillation [33]. This technology was the first to reach human
1 The reader is referred to Fig. 1 Nakagawa et al. [32] for a schema of the
probe.
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3
trials. Its benefit was to create deeper and larger lesions than
radiofrequency catheters could produce. However, by attempt-
ing reaching deeper lesions, the surrounding tissues such as the
esophagus were put at increased risk, leading to an unfortunate
event. Indeed, the death of two patients during clinical trials
ended the development of this new catheter [34,35]. The deaths
were induced by atrioesophageal fistulas which are a feared but
rare complication [36] caused by undesired energy deposit on
neighboring targeted tissues.
To better manage the safety concerns, a more recent study
presented the feasibility of similar cylindrical and planar trans-
ducers guided and monitored by MRI thermometry [28]. The
use of MRI thermometry in beating hearts was described by
Toupin et al. [37]. The use of such modality, while being expen-
sive, can answer safety concerns about atrioesophageal fistula.
These experiments successfully demonstrated their utility on
Zerdine ultrasound phantom gels (CIRS, Norfolk, Virginia) and
in vitro pig heart samples. Further research in vivo will likely
demonstrate additional benefit of this new modality.
Another team proposed to use a combination of a dual-mode
transducer with a robotic catheter named Low Intensity Col-
limated Ultrasound (LICU) [38]. The treatment management
they proposed combined an atrium geometry scan using the
same transducer as an imaging device and as an automated
treatment. They demonstrated the safety and the efficacy of
their design in vivo on 19 swines. Thanks to a lower inten-
sity creating a gradual lesion (maximum acoustic intensity of
2.5 W mm2 ), they asserted that LICU is safer than HIFU
considering the atrioesophageal fistula risk. However, more re-
search is needed to demonstrate and verify the full safety of this
device.
Though endovascular devices are the most straightforward
because of their similarities with existing methods, the deaths
due to an imperfect management of the energy deposition,
I slowed down and even stopped their development. However,
new techniques using MRI or robotics might give this approach
future hope.
3.3. Epicardial devices
Unlike the endovascular approach, epicardial devices target
a pathological area being outside the heart. The Epicor de-
vice (St Jude Medical, Saint Paul, MN) was the first HIFU
device that obtained FDA approval for treating arrhythmias
through sternotomy. The system consisted of an array of ul-
trasonic transducers that was placed at the back surface of the
left atrium to encircle the pulmonary veins [39]. Despite pos-
itive results [40,41], its invasiveness and its lack of versatility
(only for treating atrial fibrillation) did not create a real break-
through in the market of cardiac devices. It is no longer being
used in the clinic [22,42].
Recently, Nazer et al. [43] demonstrated in vivo, on 10 pigs,
the ability of an epicardial HIFU catheter to deliver transmu-
ral ablation through thick myocardium. This study combined
A-mode ultrasound imaging and therapy, which improved tar-
geting by helping the physician to direct the therapy ultrasonic
beam to the myocardium, avoiding damaging surrounding tis-
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4 P. Greillier et al. / IRBM ()
sues. Compared to previous endocardial catheter, the catheter
used in this study had an irrigation balloon reducing the self-
heating effect. This leads to the capacity to create large lesions.
Moreover, the use of A-mode gives a more precise control for
the ablation. Nevertheless, the invasive external use questioned
the usefulness of such a catheter, which could be used inside
the heart if its dimensions were reduced.
The epicardial approaches use larger devices and conse-
quently more power enabling potential improved treatment
compared with endocardial devices, yet they must demonstrate
a favorable riskbenefit ratio since they are more invasive.
3.4. Transesophageal devices
Other cardiac ablation devices are being designed for deliv-
ering HIFU by means of a transesophageal approach. In clini-
cal practice, transesophageal echocardiography uses the acous-
tic window as echocardiography between the esophagus and
the heart for imaging. Transesophageal therapy uses the same
acoustic window with an endoscope containing either a phased-
array [44] or a spherical therapeutic transducer [45].
This approach reduces the invasiveness when compared with
other catheter-based solutions. It combines ultrasound dynamic
focusing, aimed at creating thermal lesions in the heart with-
out damaging the esophagus, and an ultrasound imaging trans-
ducer for anatomical guidance. Several studies have been con-
ducted demonstrating this method in simulation [4648], and
with in vitro and in vivo trials [45,49] on swine models. Atri-
oesophageal fistula is prevented by the use of a cooling system
that also acts as an acoustic coupling between the transducer
and the heart [49]. While it highlighted the feasibility of the
method, in vivo trials were limited by the animal model used.
Anatomical differences between humans versus swines in the
heart/lung disposition affected the results [49]. Future experi-
ments will require new models, e.g. non-human primates [50].
As mentioned earlier, some transesophageal devices were
also combined with ultrasound imaging [45] which can improve
treatment by allowing real-time adjustments. Kwiencinski et al.
[51] demonstrated with shear-wave elastography (SWE) that
myocardium stiffness increased with the applied thermal dose.
SWE was coupled with the transesophageal imaging system in
order to assess the lesion formation in real-time [52].
Even though the results were promising, improvements in
the focusing accuracy and flexibility are still needed, as well as
technical enhancements in the image-guided ultrasound phased
arrays [53].
3.5. Ablation and transthoracic approaches
Transthoracic access refers to sonication through the thorax.
Sonication was proven feasible even though it is highly chal-
lenging to transmit ultrasound through the acoustic fences of
the ribs and lungs [54]. The feasibility of transthoracic abla-
tion to produce precise lesion was first demonstrated in vivo
in 39 dogs in 1997 [55]. The team used a spherical therapy
transducer with a 63.5 mm radius guided by a single element
imaging transducer in its center. The probe was mounted on
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a three-dimensional positioning system to target the different
parts of the organ because of the absence of dynamic focus-
ing. Newer experiments confirmed these results with equivalent
methods and were able to successfully generate septal ablation
[56] and complete heart block [57].
While it could be considered as the least invasive HIFU tech-
nique, there are few current applications of this thermal method
of HIFU. Other works discussing transthoracic approaches,
which concern different therapeutic ultrasound techniques such
as histotripsy and cardiac pacing, are described in the next sec-
tions.
4. Histotripsy
Histotripsy uses inertial cavitation to purposefully disinte-
grate or liquefy tissue by short pulses with HIFU transducers
[14]. Histotripsy cavitation occurs when a high negative pres-
sure threshold is reached (for example <28 MPa for most tissue
with a single-pulse shock produced by a 750 kHz transducer
[58]) in the focal area. The goal of histotripsy is to create what
is called a cavitation cloud, a dense cloud of cavitation bubbles
created during the continued application of the HIFU. Since the
focus of the HIFU transducer is controllable so is the region
where the cavitation cloud is formed. Therefore, the cloud can
be seen as having sharp boundaries where the tissue is dis-
integrated at the subcellular level [59]. The ability of precisely
defining and treating a targeted area has led histotripsy to be
considered a precise non-thermal ultrasonic scalpel.
In the heart, researchers have been meaning to use his-
totripsy as a therapeutic tool in order to replace open heart
surgery [60]. Xu et al. [60] first demonstrated the feasibility
of creating atrial septal defects (ASD) on an open-chest dog
model using histotripsy. ASD is usually created before open-
heart surgery via the Rashkind atrial septostomy procedure, for
mixing blood in newborn child with hypoplastic left heart syn-
drome, or transposition of the great arteries [61]. In vivo trials
on pigs later demonstrated the ability of histotripsy to be per-
formed through the rib cage, increasing the interest of such
an approach [62]. Extracorporal histotripsy therapy was suc-
cessfully demonstrated in fetal sheep organs in utero [63]. The
same team demonstrated a 1-month intermediate safety in 15
neonatal pigs that underwent cardiac histotripsy. The aim was
to analyze the risks of embolism provoked by ejection of sep-
tum pieces (i.e. debris larger than small vessels that may cause
strokes or pulmonary embolism) after histotripsy [64]. Recent
studies focused on improving the in vivo technique accuracy by
integrating real-time motion tracking, synchronized with ultra-
sound beam steering [65].
Research on histotripsy for ASD is limited to a very spe-
cific and restrictive population: pediatric patients with congen-
ital heart diseases. To the best of our knowledge, publication
concerning histotripsy in this field seem to have slowed down,
maybe because of the population-related restriction.
Recent research on this field has also demonstrated the po-
tential of histotripsy for chordal cutting [66] aiming at reducing
ischemic mitral regurgitation. A part of the current surgical
management consists of cutting the basal chord to improve
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P. Greillier et al. / IRBM ()
the closure of the mitral leaflets [67]. On 5 in vitro explanted
beating sheep hearts and 7 in vivo open-chest sheep hearts,
Villemain et al. used 3D echo monitoring for guided histotripsy
and succeeded at performing chordal cutting without open heart
surgery. By avoiding heat diffusion, effectively eliminating the
issue of reaching the thermal denaturation threshold, their tech-
nique gained more precision compared to previous experiments
on chordal cutting [68] and valve ablation [69].
Current research on the histotripsy in the heart reached a
high progress status in preclinical studies. The next step will
be the clinical study.
5. Microbubbles, ultrasounds and heart
Combining ultrasound contrast agents with cavitation has
generated new possibilities for therapeutic applications, such
as targeted drug delivery and micro-ablation.
Ultrasound contrast agents (UCAs) are used to enhance clin-
ical diagnosis, by enabling the visibility of micro-vasculature
or deep absorbing tissue [4]. In the case of the heart, contrast
agents are currently used for ventricular cavity opacification
and endocardial definition [70] in order to define the ejection
fraction, or to determine the presence of a thrombus. Many
different commercial products have been created for this ap-
plication and are approved for clinical use [71] (i.e. SonoVue,
Sonazoid, etc.).
Typically the microbubble structure is composed of a li-
pidic, polymeric or protein shell encapsulating a high molecular
weight gas, such as perfluoropropane [72]. Microbubbles work
as an acoustic reflector due to their impedance mismatch with
tissue, enhancing the image quality where they are present.
They also increase the likelihood of cavitational events. This
is because in the presence of a high-pressure US field micro-
bubbles act as a cavitation nuclei, which increases the intrinsic
risk of damage during diagnostic procedures [4]. Thus, previous
research aimed to diminish the UCAs cavitational events since
its purpose was for imaging. However, in the past few years,
coupling UCAS with TU has proved to be a promising way for
micro-ablation and targeted drug delivery.
5.1. Ultrasound for drug and gene delivery
The principle behind gene transfection is to incorporate part
of genetic information into the cells of interest to reprogram
defective behavior. The first trials on patients [73], showed
that gene therapy had the potential to be very promising and
it became a new paradigm for the treatment of chronic dis-
eases. However, its efficacy has been limited because of the
difficulties of getting genetic agents through the cell mem-
brane and the risks of mutagenesis events [74]. One promising
method of delivering the genes through the cell membrane is
sonoporation [75] (transient openings in the cell membrane in-
duced by ultrasound) [76], which allows the penetration of large
molecules into cells and facilitate external material to reach
the cell DNA. Ultrasound-targeted mediated delivery (UTMD)
is the coupling of sonoporation, gene therapy and microbub-
bles.
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5
Three methods were studied in the literature [74,77]:
Simultaneously injecting genetic agent and microbubbles
Encapsulating drug(s) into the microbubbles shell or inte-
rior
Incorporating targeting cationic activated proteins to the
shell of the microbubble shell [78]
In these methods, ultrasound was applied on the targeted
zone creating sonoporation while the desired molecules were
released as the bubbles underwent destruction. Ultrasound in-
duced cavitation is generally produced by an imaging probe
with short bursts of increased output power [74]. This is per-
mitted by the lowered cavitation threshold ensuing from the
contrast agent presence.
Cardiac application of UTMD has been mainly studied in
the case of cardiac ischemia. Its main cause is infarction: a
blockage of the coronary arteries leading to a lowering of
the cell oxygenation and then to cell apoptosis. UTMD re-
searchers targeted cardioprotective effects in cardiomyopathy
infarctions through genetic approaches such as growth factor
transfer, stem-cell mobilizing genes and anti-apoptotic gene. To
combat infarction, UTMD researchers have targeted the pro-
cess of angiogenesis to compensate the loss of the infarcted
tissue functions. Kondo et al. [79] delivered plasmids of the
hepatocyte growth factor gene into rat hearts. Fujii et al. [80]
team focused on implanted stem-cells. Both showed an im-
proved left ventricle ejection fraction and reduced surface area
of the scar formation. Other teams successfully attempted to
elucidate a response involving the apoptotic process progres-
sion in rats with doxorubicin-induced cardiomyopathy [81].
The researchers transfected the anti-apoptotic gene Survivin
into the rodents and the gene attenuated the occurrence of my-
ocyte apoptosis and reduced left ventricular systolic dysfunc-
tion. More recent experiments on swine have also demonstrated
the feasibility of UTMD in more realistic cardiac models than
rats [82].
UTMD for gene therapy seemed to be promising for the
healing of cardiac infarction. However, the research that has
been performed on large animal (more realistic cardiac) mod-
els is limited. This is yet another step that must be performed
before human studies.
5.2. Myocardial Cavitation-Enabled Therapy (MCET)
Myocardial Cavitation-Enabled Therapy (MCET) is a tech-
nique that consists of inducing cavitation inside the heart mus-
cle using ultrasound contrast agents with high and short ul-
trasound pulses (peak rarefactional pulse of 2.3 MPa during
1.45 s) [83]. As we explained in the section on ultrasound
bio-effects, micro-bubbles in these high-pressure ultrasound
fields oscillate and collapse, damaging the neighboring tissue
by means of inertial cavitation effects.
In the realm of therapeutic ultrasound for cardiac treatment,
Miller et al. [83] investigated these effects as a possible tool and
not as an unwanted byproduct, by applying ultrasound to the
myocardium with contrast agents present. These experiments
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6 P. Greillier et al. / IRBM ()
aimed at the treatment of hypertrophic cardiomyopathy, i.e. a
thickening of the ventricular septum, which results in an out-
flow tract obstruction and an increased risk of sudden death.
The two current strategies consist of a surgical septal myomec-
tomy, i.e. surgical ablation reducing the septum thickness [84]
or catheter embolization of septal coronaries with alcohol [85].
What MCET proposes to do is reduce the cardiac wall thick-
ness by means of an accumulation of micro-lesions through
cavitation. Three main factors impact the density of micro-
lesions and the size of the macro-lesion induced: concentration
of contrast agent, acoustic pressure delivery and insonication
time [86,87].
Methods were developed to study these micro-lesions in 3D
with Evans blue staining [88]. This study showed that after 6
weeks the micro-lesions progressed into a permanent loss of
myocardial tissue, replaced by scar fibrosis tissue [89]. How-
ever, no reduction of the heart wall thickness was revealed. Lu
et al. claimed that a pharmaceutical solution could be used to
reduce this scar tissue or that a longer time of maturation would
reveal a wall thinning similar to what is found with alcohol sep-
tal ablation [90], without its limitations.
6. Cardiac pacing
Cardiac pacing aims to accelerate slow heart rhythm which
generates unstable hemodynamic status [91]. Cardiac pacing
devices or pacemakers (PMs) can be used permanently or tem-
porarily. Permanent devices are implanted surgically and elec-
trodes are screwed into the endocardium or more rarely stitched
on the epicardium. Temporary PMs are mainly used for urgent
situations to maintain a minimal heart rhythm in various cases
of severe brachycardia. In this procedure, the PM leads need to
be inserted quickly into the heart by an endovascular approach
[92]. When faced with an extremely urgent situation, external
patches are applied on the rib cage in order to perform external
pacing. It is barely tolerable for patients as electrical stimula-
tion is painful and often requires sedation [92]. As opposed to
internal invasive applications, external ultrasound pacing of the
heart has been considered as an alternative solution in urgent
situations requiring cardiac stimulation by producing ventricu-
lar contraction. This is advantageous considering that insonica-
tion through the rib cage could be painless and as effective as
conventional methods.
Dalecki et al. demonstrated that HIFU pulses of 1.2 MHz of
5 ms may cause premature ventricular contraction (PVC) [93]
and that heating was not the reason for their generation [94].
Questions still remain on what is involved in the phenomenon.
The proposed mechanisms were: (1) cavitation, (2) acoustic ra-
diation force, (3) shear-stress activating mechano-sensitive cells
of the cardiac tissue or (4) direct vibration at a cellular level
[95].
Since the discovery of ultrasound induced PVC, many ex-
periments have been conducted in vivo on small animals. In
2016 Marquet et al. [96] demonstrated that this method was
successful on a larger animal. In 10 ex vivo Langendorff pig
hearts and four swines, they triggered repetitive and predictable
PVCs (90% of success rate) without causing damage to the
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heart tissue. They also confirmed that two factors were criti-
cal for a proper heart pacing: a correct pressure level (>4 MPa
at 1 MHz) and a minimal length of insonication time >10 ms.
7. Conclusions, limitations and challenges of therapeutic
ultrasound
Various therapeutic ultrasound applications with regard to
the heart were reviewed. Each of them have faced and still
need to overcome a variety of challenges before being useful
in a clinical environment. Thermal ablation through catheteri-
zation HIFU seems to be the most straightforward technique of
TU. Indeed, it follows the same interventional surgery approach
and enables larger lesions than the current reference techniques
used in clinic. However, clinical trials and a lack of commer-
cial success of the endocardiac procedure have slowed down its
progression. The precision and safety of the endovascular pro-
cedure need to be better manage for future investigations. New
approaches currently being studied, such as transesophageal
[49], have proven their feasibility but are still immature. They
need to complete in vivo evaluation and begin clinic trials to
fully demonstrate the interest of such an approach. Also, ques-
tion remains about the safety for the esophagus which need to
be answered to convince the cardiologist. Teams working on
histotripsy have promising results in vivo, proving its useful-
ness as a non-invasive scalpel and an alternative surgery [62].
Their techniques are quite new and last experiments proved the
capability of histotripsy to be used non-invasively with a strong
precision. Research on drug and gene delivery through ultra-
sound applications within the cardiac organ are still ongoing
and far from clinical trials. The same could be said for cardiac
pacing and MCET, as the research is still underway.
TU still has a long way to go before being considered a ref-
erence technique, however if it is able to overcome some of
the challenges laid out here, it has potential to be in the fu-
ture. The first challenge encountered by many teams was the
thorax anatomy. Depending on the method/location of delivery,
different biological structures can interfere with the treatment
and behave as ultrasonic fences prohibiting efficient energy
deposit in the tissue. The heart, for example, is blocked on
some sides by an ultrasonic fence (lungs, trachea, ribs, etc.).
For both transesophageal and transthoracic methods of delivery,
as we noted, lung presence may block the acoustic field. Fur-
thermore, ultrasound (if not properly applied) may incidentally
harm the surrounding targeted tissue causing unwanted side-
effects. This can sometimes be reinforced by the mirror effect
caused by the high acoustic impedance mismatch between air
and tissue. It was this phenomenon which ended some attempts
at endocardial HIFU ablation. It is known that correctly admin-
istered ultrasound can allow a physician to apply the treatment
through tissue without harming it, but it is important to keep in
mind that a poorly managed energy deposition could produce
deleterious side effects and may cause harm to un-targeted tis-
sue with unwanted results.
This problem of complex anatomy is made worse by the
physiological behavior of the heart itself. Since it is a constantly
moving organ, it is intrinsically a challenge for current clini-
JID:IRBM AID:477 /REV
P. Greillier et al. / IRBM ()
cal technology, including the ultrasound approach. While most
clinical techniques use contact with a therapeutic probe for en-
ergy deposition, here, with ultrasound, this contact is no longer
needed. Yet this also comes with associated challenges, such
as the necessity to aim at a moving target. Heart motions are
complex and relatively fast. Most of the time, a simple synchro-
nization on the electrocardiogram can be enough (and may be
mandatory), however, a non-continuous ultrasound deliverance
may drastically reduce energy deposition and create a need for a
longer treatment time. As suggested, new progress in transducer
designs such as those used in phased-array transducers may be
the solution. Coupled with real-time motion tracking [97,98],
new devices should have the capability of real-time tracking of
the targeted zone.
As described in this review, TU has the potential to treat
many different kinds of heart disease. The example of the Epi-
cor system is interesting in that they demonstrated good re-
sults of their therapeutic approach but were unable to convince
the clinic/clinicians. Their invasiveness limited the commercial
spreading of their device/technique as it was not shown to be
better than radiofrequency ablation which remains the reference
method. We can conclude that the medical field needs more than
potential to adopt new techniques when current reference ones
already exist. TU techniques will have to demonstrate their effi-
cacy and safety but also their cost-effectiveness benefits for the
cardiologist to choose them. It is necessary to both overcome
the technical hurdles and fully demonstrate the advantages for
TU to reach a more global acceptance. And it is believed that
with the recent advances in ultrasound research, therapeutic ul-
trasound for cardiac applications will soon have a place in the
tool kit of the cardiologists.
Conflict of interest statement
The authors declare that they have no competing interests.
Acknowledgements
The authors would like to acknowledge support provided by
the French Federation of Cardiology and the Focused Ultra-
sound Foundation.
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