TECHNICAL FIELD

[0001] The invention relates to systems and methods for non-invasive stimulation, and more particularly to systems and methods using extracorporeal mechanical waves or pulses to stimulate a heart non-invasively.

BACKGROUND

[0002] The predominant technique for temporary cardiac pacing is invasive and consists in the insertion of intra-cardiac catheters. Although pacing with intra-cardiac catheters has been successfully used clinically for about 60 years, these catheters are associated with inherent risks due to the nature of interventional procedures and also due to costs (single-use devices, need of a sterile environment). Further, long-term complications with intra-cardiac catheters are not negligible; therefore, ways to stimulate the heart without leads are intensively sought after. The predominant non-invasive method currently used is the transcutaneous transthoracic electrical stimulation. However, this technique is frequently rejected by subjects due to the discomfort of the subcutaneous stimulation of the thoracic musculature as effective cardiac pacing requires high intensity pulses in most instances.

[0003] There is therefore a need for an improved system and method for stimulating non- invasively an area of interest of a subject’s body.

SUMMARY

[0004] According to a first broad aspect, there is provided a mechanical wave generating system comprising: a generator device for generating mechanical waves; at least two mechanical waveguides each extending along a longitudinal axis between a proximal end and a distal end, the proximal end being operatively connected to the generator device for receiving the mechanical waves therefrom; and a coupling device operatively connected to the distal end of the at least two mechanical waveguides for receiving and outputting the mechanical waves, wherein the at least two mechanical waveguides are oriented so that the longitudinal axes intersect at a focal point. [0005] In one embodiment, the generator device comprises a plurality of mechanical wave generator, each operatively connected to the proximal end of a respective one of the at least two mechanical waveguides.

[0006] In one embodiment, the mechanical wave generators comprise piezoelectric transducers.

[0007] In one embodiment, the at least two mechanical waveguides have a fixed position relative to the generator device and the coupling device.

[0008] In another embodiment, the at least two mechanical waveguides have a movable position relative to at least one of the generator device and the coupling device so as to vary a position of the focal point.

[0009] In one embodiment, the mechanical wave generating system further comprises at least two actuators each operatively connected to a respective one of the at least two mechanical waveguides to adjust the movable position thereof.

[0010] In one embodiment, the at least two actuators comprise one of linear actuators and rotational actuators.

[0011] In one embodiment, the coupling device comprises a flexible abutting portion for conforming to a shape of a subject.

[0012] In one embodiment, the coupling device comprises a hollow enclosure filled with acoustically conductive material.

[0013] In one embodiment, the acoustically conductive material comprises one of water, degassed water and ultrasound gel.

[0014] In one embodiment, the hollow enclosure is a flexible bag.

[0015] In one embodiment, the bag is made of rubber.

[0016] In one embodiment, the distal end of the at least two mechanical waveguides is inserted into the flexible bag. [0017] In one embodiment, the at least two mechanical waveguides are hermetically secured to the flexible bag.

[0018] In one embodiment, the at least two mechanical waveguides comprise a central mechanical waveguide and additional mechanical waveguides, the additional mechanical waveguides being arranged according to a frusto-conical configuration.

[0019] In one embodiment, the at least two mechanical waveguides comprise a central mechanical waveguide and additional mechanical waveguides, the additional mechanical waveguides being arranged according to a frusto-pyramidal configuration.

[0020] According to another broad aspect, there is provided a method for stimulating an area-of-interest of a heart, the method comprising: acquiring and displaying an image of the heart; acquiring a heartbeat of the heart; locating the area-of-interest of the heart using the displayed image of the heart; determining an adequate time for stimulating the area-of-interest of the heart using the heartbeat; and stimulating the area-of-interest of the heart by generating and propagating mechanical waves up to the area-of-interest of the heart.

[0021] In one embodiment, the step of generating the mechanical waves up to the area-of- interest of the heart is performed extracorporeally.

[0022] In one embodiment, the step of acquiring the image of the heart is performed using at least one of a magnetic resonance imaging, an ultrasound medical imaging and an X-ray medical imaging.

[0023] In one embodiment, the method further comprises displaying a visual representation of the acquired heartbeat.

[0024] In one embodiment, the step of generating and propagating mechanical waves comprises focusing the mechanical waves on the area-of-interest of the heart.

[0025] It should be understood that a mechanical wave may have an arbitrary amplitude, duration, waveform, frequency, and/or the like. For example, a mechanical wave may have a high/low amplitude, a short/long duration, different waveforms, and any frequency content. [0026] For the purpose of the present description, a mechanical pulse should be understood as a short duration mechanical wave. The duration of a mechanical pulse is of the order of about l/fc, where fc is the center frequency of the wave. In one embodiment, the center frequency fc is comprised between 20 kHz and 10 MHz, preferably between 100 kHz and 2 MHz.

[0027] Furthermore, a mechanical waveguide should be understood as a waveguide adapted to propagate mechanical waves or pulses along its length. In the present description, the expressions“waveguide”,“mechanical waveguide” and“transmission member” may be used interchangeably. The shape and dimension of a waveguide may vary. For example, a waveguide may have a cylindrical shape. The diameter of the waveguide may be constant along its length. Alternatively, the diameter of the waveguide may vary along its length. For example, the diameter of a waveguide may decrease along its length so that the waveguide corresponds to a taper.

[0028] In one embodiment, a mechanical waveguide may comprise a single elongated element adapted to propagate mechanical waves and/or pulses therealong. In another embodiment, a mechanical waveguide may comprise a plurality of elongated elements each adapted to propagate mechanical waves and/or pulses therealong.

BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Having thus generally described the nature of the invention, reference will now be made to the accompanying drawings, showing by way of illustration example embodiments thereof and in which:

[0030] Figure 1 is a block diagram illustrating a system for non-invasive stimulation of a region of interest of a subject, in accordance with an embodiment;

[0031] Figure 2 is a side view of a system for non-invasive stimulation of a region of interest of a subject, in accordance with an embodiment;

[0032] Figure 3 is a see-through perspective view of the system of Figure 2; [0033] Figure 4 is a flow chart illustrating a method for non-invasive stimulation of a region of interest of a subject, in accordance with an embodiment;

[0034] Figure 5a is an exemplary graph representing a left ventricular electrocardiogram signal (in mV) as a function of time during a focal non-invasive stimulation of the left ventricle;

[0035] Figure 5b is an exemplary graph representing an intraventricular pressure (in mmHg) as a function of time during a focal non-invasive stimulation of the left ventricle;

[0036] Figure 5 c is an exemplary graph representing the amplitude of a mechanical pulse (in Pa) as a function of time during a focal non-invasive stimulation of the left ventricle;

[0037] Figure 6a is an exemplary graph representing an atrial electrocardiogram signal (in mV) as a function of time during a focal non-invasive atrial stimulation;

[0038] Figure 6b is an exemplary graph representing an intraventricular pressure (in mmHg) as a function of time during a focal non-invasive atrial stimulation; and

[0039] Figure 6c is an exemplary graph representing the amplitude of a mechanical pulse (in Pa) as a function of time during a focal non-invasive atrial stimulation.

DETAILED DESCRIPTION

[0040] With reference to Figure 1, there is described a system 100 for non-invasive cardiac stimulation by providing mechanical waves or mechanical pulses to the heart of a subject’s body or any other animal.

[0041] The system 100 comprises a mechanical pulse generator 102 configured to generate a high amplitude and short duration mechanical wave or mechanical pulse.

[0042] In one embodiment, the high amplitude and short duration mechanical pulse produced by the pulse generator 102 has a center frequency (fc) comprised between about 20 kHz and about 10 MHz. In one embodiment, the duration of the mechanical pulse generated by the mechanical pulse generator 102 is less than 10 microseconds, preferably around 1 microsecond, and may have an amplitude greater than 5 MPa, preferably greater than 10 MPa. In this embodiment, the short duration mechanical pulses produced by the pulse generator 102 provide an increased ability for the mechanical energy to stimulate the heart with sufficient energy. Further, the microsecond pulses produced by the pulse generator 102 lower the risks of damaging the cells, tissue(s), organ(s) and/or lesion(s) to be treated due to cavitation and/or heating effects as compared to ultrasound, such as in the case of high intensity focused ultrasound (FUFU), for which energy bursts duration are typically in the millisecond range. As such, the use of mechanical waves or mechanical pulses for stimulating the heart provides a better overall safety profde as compared with the use of FUFU for example.

[0043] A non-invasive stimulation system such as described herein and may therefore be useful to optimize the safety of a subject whose heart is in arrhythmia, i.e., not in sinus rhythm, with resulting deleterious cardiac output reduction. Single or dual chambers atrial and/or ventricular stimulation would allow ventricles to pump blood more effectively through the body and optimize cardiac output. Cardiac stimulation may also be also performed during surgery, pacing, cardiac resynchronisation, diagnostic or therapeutic electrophysiology procedures, targeting cardiac arrhythmias. Non-invasive stimulation could potentially also target neurological (nerves, spine, brain) and digestive and gastrointestinal diseases.

[0044] The pulse generator 102 may comprise at least one broadband source and/or at least one narrow band source. Either of the narrowband or broadband source may be an electromechanical transducer that converts electrical energy into mechanical energy. The broadband source is centered at a frequency fb, comprised between about 20 kHz and about 10 MHz, and is able to produce a pulse of duration l/fb, while the narrowband source is centered at a frequency fn, also comprised between about 20 kHz and about 10 MHz, and has a bandwidth typically less than 1/10 to 1/100 of fn.

[0045] In one embodiment, the pulse generator 102 may comprise a plurality of broadband sources and/or a plurality of narrowband sources. The outputs of several sources covering adjacent frequency bands are combined to generate the mechanical wave or mechanical pulse. In one embodiment, the outputs of at least two broadband sources, i.e. the mechanical pulses generated by the at least two broadband sources, are combined together. In another embodiment, the outputs of at least one broadband source and at least one narrowband source are combined together.

[0046] In another embodiment, the system 100 comprises a pulse focusing device 104 for focusing the mechanical wave or mechanical pulse output of a large broadband source toward a focal zone. It should be understood that the outputs of more than one large broadband source may be concurrently focused on the same focal zone.

[0047] In one embodiment, the pulse focusing device 104 is a spatial concentrator, an acoustic lens, an acoustic mirror and/or the like.

[0048] In a further embodiment, a high amplitude mechanical wave or mechanical pulse may be generated by spatially and/or temporally focusing or combining mechanical waves or mechanical pulses sequentially emitted by a single broadband source using a reverberating cavity. It should be understood that the mechanical waves or mechanical pulses generated by more than one broadband source may be spatially and/or temporally focused or combined together by a reverberating cavity to provide the high amplitude mechanical wave or mechanical pulse.

[0049] In still another embodiment, high amplitude and short duration mechanical pulses may be generated by using a dispersive medium and/or a dispersive geometry to focus or combine the component waves emitted sequentially by a single broadband source. It should be understood that the mechanical waves or mechanical pulses generated by more than one source may be combined or focused together using the dispersive medium or the dispersive geometry.

[0050] In still another embodiment, the mechanical wave or mechanical pulse may be amplified. In an embodiment in which a temporal concentrator is present, the mechanical wave becomes a mechanical pulse for which the amplitude is greater than that of each component wave of the mechanical wave. In an embodiment in which a spatial concentrator is present, the amplitude of a mechanical wave or mechanical pulse is increased while propagating through the spatial concentrator. In another embodiment in which a spatial concentrator is present, different mechanical waves or mechanical pulses are combined to generate a greater amplitude mechanical wave or mechanical pulse, i.e. that the different mechanical waves or mechanical pulses add to each other.

[0051] The system 100 further comprises at least one guiding device 106 connected, at a proximal end thereof, to the pulse focusing device 104 and directed or oriented, at the distal end thereof, towards a subject’s body 108. The guiding device 106 is configured for transmitting or propagating, from the proximal end to the distal end thereof, the mechanical waves or mechanical pulses generated by the pulse generator 102 or outputted by the focusing device 104, if any. The guiding device 206 is further configured for directing or orienting the mechanical waves or mechanical pulses towards an anatomical target, which comprises cells, tissue(s), organ(s) and/or lesion(s) to be treated on the subject’s body 108.

[0052] In one embodiment, the guiding device 106 comprises at least a mechanical waveguide, a guidewire or any other guide known in the art that is suitable for transmitting or propagating mechanical energy along its body and transferring the mechanical energy to an anatomical target of a subject’s body 108.

[0053] In one embodiment, the anatomical target to be treated is the heart 110 of a subject or a given region of interest of the heart of a subject.

[0054] In one embodiment, the system 100 comprises only one guiding device or mechanical waveguide 106 operatively coupled to the pulse generator 102 and configured for directing or orienting the mechanical waves or mechanical pulses generated by the pulse generator 102 towards the anatomical target to be treated (e.g. the heart 110) on the subject’s body 108.

[0055] In one embodiment where only one guiding device 106 is used, the guiding device 106 is inserted into the subject’s body 108 until the distal end of the guiding device 106 is positioned adjacent the cells, tissue(s), organ(s) and/or lesion(s) to be treated while being outside of the subject body such that the mechanical waves or mechanical pulses are directed or oriented towards same. In this case, the system 100 is used for a non- invasive treatment method. [0056] In another embodiment, the distal end of the guiding device 106 may alternatively be positioned within the subject body so that the distal end of the guiding device 106 be adjacent to the region to be treated such as cells, tissue(s), organ(s) and/or lesion(s) to be treated or abuts against the region to be treated in order for the mechanical waves or mechanical pulses to be directed or oriented towards the region to be treated. In this case, the system 100 is used in an invasive or minimally invasive treatment method. When it abuts against the region to be treated, the distal end of the guiding device 106 is in physical contact with the region to be treated, which may include a lateral contact.

[0057] In one embodiment, the system 100 comprises a plurality of guiding devices 106 each operatively coupled to the pulse generator 102 and each configured, via a focusing guide 107, for directing or orienting the mechanical waves or mechanical pulses generated by the pulse generator 102 to the anatomical region to be treated (e.g. the heart 110) on the subject’s body 108.

[0058] In one embodiment, each of the guiding devices 106 of the plurality of guiding devices are coupled at the proximal end thereof to a 500 kHz piezoelectric transducer that is itself connected to the pulse generator 102, which is configured to deliver a voltage between 300 V and 600 V, adjustable in increments of 50 volts for example.

[0059] In an embodiment in which the system 100 comprises a plurality of guiding devices 106, each of the guiding device 106 is physically arranged or disposed in relation to one another so that each of the mechanical wave or mechanical pulse transmitted or propagated by each of the guiding device 106 is directed or oriented towards a focal point or focal region where all the mechanical waves or mechanical pulses converge. The focal point/region is the point/region where the energy of the mechanical waves or mechanical pulse emitted by the guiding devices 106 is focused or concentrated.

[0060] While in the below description, it is referred to a focal point, it should be understood that the expression“focal point” also includes a focal region and should not be limited to a discrete point. [0061] In an embodiment in which the system 100 comprises a plurality of the guiding devices 106, the guiding devices 106 are disposed according to a truncated- conical arrangement about a focal axis. In this arrangement, the guiding devices 106 each emit mechanical pulses towards a focal point located along the focal axis.

[0062] In one embodiment, the amplitude of the mechanical wave or mechanical pulse reaching the distal end of the guiding device(s) 106 is comprised between about 1 MPa and about 1000 MPa. In one embodiment, the amplitude of the mechanical wave or mechanical pulse reaching the distal end of the guiding device(s) 106 is about 10 MPa to about 35 MPa. In one embodiment, the duration of the short mechanical wave or mechanical pulse reaching the distal end of the guiding device 106 is in the order of l/fc.

[0063] In one embodiment, the guiding device(s) 106 is made of medical grade biocompatible material such as stainless steel, nitinol or a titanium alloy, although other materials known in the art may be used. The guiding device(s) 106 may further be provided with radiopaque material or a radiopaque marker positioned at the distal end thereof. The opaque marker is made of a material that blocks the propagation of X-rays so that the opaque marker may be visible on an X-ray image.

[0064] In one embodiment, the system 100 may be used in in vivo applications on an anatomical target region, such as the heart 110 of the subject’s body 108. For an invasive use, the guiding device(s) 106 may be positioned to be adjacent, to abut or to be in physical contact, including a lateral contact, with the region to be treated within the body. For a non- invasive use of the system 100, the distal end of the guiding device(s) 106 may be submerged into an acoustically conductive material such as degassed water enclosed in a container which may be designed to conform to the anatomy of the body area where it is to be in contract with the skin. In one embodiment, the container adapted to conform to the anatomy of the body is a rubber bag having a wall thickness of about 0.5 mm. An acoustic gel applied at the interface between the container and the skin may improve the transmission of the mechanical waves into the body.

[0065] In one embodiment, the use of degassed water may prevent the occurrence of cavitation that may be produced by mechanical waves or mechanical pulses. Such cavitation may reduce the energy transmission performance between the guiding device(s) 106 and the targeted area to be treated.

[0066] In one embodiment, the system 100 may be used in ex vivo applications on an anatomical target to be treated, such as an explanted heart 110. In an embodiment in which the system 100 comprises only one guiding device 106, the single guiding device 106 may be submerged into a physiological buffer containing the heart 110 and positioned to be adjacent, to abut or to be in physical contact with the area of the heart 110 to be treated. In an embodiment in which the system 100 comprises a plurality of guiding devices 106, the distal ends of the guiding devices 106 may be submerged in a physiological buffer containing the heart 110 and the guiding devices 106 may be positioned so that the focal point be positioned on the area of the heart 110 to be treated, such as the left ventricle and the anterior side of the atrium.

[0067] Figures 2 and 3 illustrate one embodiment of a system 200 for generating and propagating mechanical waves such as high amplitude and short duration mechanical pulses non-invasively into a subject’s body. It should be understood that he system 200 represents a particular implementation of the system 100. The system 200 comprises a wave generator device 202 for generating mechanical waves such as mechanical pulses, a plurality of mechanical waveguides 204 for propagating the generated mechanical waves and a guiding or coupling device 206.

[0068] As illustrated in Figure 3, each mechanical waveguide 204 is provided with a cylindrical shape and extends longitudinally between a proximal end operatively connected to the wave generator device 202 for receiving mechanical waves generated by the wave generator device 202, and a distal end connected to the coupling device 206. The mechanical waveguides 204 are geometrically arranged so that their longitudinal axes intersect at a focal point or region 208 positioned along a focal axis E.

[0069] In the illustrated embodiment, the mechanical waveguides 204 comprise a central mechanical waveguide aligned with the focal axis E while the other mechanical waveguides 204 are arranged according to a truncated-conical configuration, i.e. the longitudinal axes of the mechanical waveguides 204 form a cone and intersect at a same geometrical point, i.e. the focal point 208 positioned along the focal axis E.

[0070] In one embodiment, the wave generator device 202 comprises a plurality of mechanical wave generators such as plurality of electromechanical or piezoelectric transducers and the proximal end of each mechanical waveguide 204 is operatively connected to a respective mechanical wave generator so that the mechanical waves generated by each mechanical wave generator are at least partially coupled into a respective mechanical waveguide 204.

[0071] The coupling device 206 is designed to contact the body of the subject to be treated and is acoustically conductive. The distal end of the mechanical waveguides 204 is operatively connected to the coupling device 206 so that mechanical waves generated by the wave generator device 202 and propagating along the mechanical waveguides 204 may be coupled into the coupling device 206 and propagate therethrough up to the subject’s body. The coupling device 206 allows for positioning the system 200 relative to the subject’s body, abutting the system 200 against the subject’s body and/or improving the coupling of the mechanical waves from the mechanical waveguides 204 to the subject’s body.

[0072] In the illustrated embodiment, the coupling device 206 comprises a hemispherical body 210 and a circular plate 212. It should be understood that the circular plate 212 may be omitted so that the coupling device 206 may only comprise the hemispherical body 210.

[0073] In one embodiment, the distal end of the mechanical waveguides 204 abuts against the coupling device 206 so as to be in physical contact with the circular plate 212 or the hemispherical body 210 if the circular plate 212 is omitted.

[0074] In one embodiment, the distal end of the mechanical waveguides 204 is movably connected to the coupling device 206 so that the relative position between the distal end of the mechanical waveguides 204 and the coupling device 206 may vary. For example, the distal end of the mechanical waveguides 204 is movably secured to the coupling device 206. [0075] In another embodiment, the distal end of the mechanical waveguides 204 is fixedly secured to the coupling device 206 so that the relative position between the distal end of the mechanical waveguides 204 and the coupling device 206 cannot vary.

[0076] In one embodiment, the hemispherical body 210 is hollow and forms an enclosure with the circular plate 212. In one embodiment, the enclosure contains an acoustically conductive material. For example, the enclosure may house water, degassed water, ultrasound gel or the like for helping propagate the mechanical waves emitted by the mechanical waveguides 204.

[0077] In one embodiment, the hemispherical body 210 and/or the circular plate 212 are made of acoustically conductive material.

[0078] In one embodiment, the hemispherical body 210 and the circular plate 212 are made of rigid or semi-rigid materials. In another embodiment, at least the hemispherical body 210 is made of flexible material to form a flexible bag to conform to the anatomy of the subject to be treated.. For example, the hemispherical body may be made of rubber to form a rubber or polymer bag into which an acoustically conductive fluid is enclosed.

[0079] In an embodiment in which the coupling device 206 contains an acoustically conductive fluid such as when the coupling device 206 is a bag, the distal end of the mechanical waveguides 204 may be penetrate into the coupling device 206 and the distal section of the mechanical waveguides 204 is then hermetically secured to the coupling device 206.

[0080] In one embodiment, the system 200 further comprises a housing 214 extending between a proximal end secured to the wave generator device 202 and a distal end secured to the coupling device 206 for enclosing the mechanical waveguides 204 therein. While in the illustrated embodiment, the housing 214 is provided with a truncated conical shape, it should be understood that other adequate shapes may be envisioned.

[0081] In one embodiment, the proximal end of the mechanical waveguides 204 is fixedly secured to the wave generator device 202 and the distal end of the mechanical waveguides 204 is fixedly secured to coupling device 206 so that the position of the focal point 208 along the focal axis E may not be varied.

[0082] In another embodiment, the mechanical waveguides 204 are movably secured to the wave generator device 202 and/or the coupling device 206 so that the 3D position of the focal point 208 may be varied. For example, the mechanical waveguides 204 may be rotatably secured to the wave generator device 202 and/or the coupling device 206 so that the angle Q between the longitudinal axis of the mechanical waveguide 204 and the focal axis E may be varied in order to adjust the position of the focal point 208 along the focal axis E to a desired position.

[0083] In one embodiment, the angle Q for each mechanical waveguide 204 may be independently changed in order to modify the axial location, the radial location, the angular location and/or the focal size of the focal point 208.

[0084] In another embodiment, the central mechanical waveguide 204 aligned with the axis E has a fixed position while the angle Q for the other mechanical waveguides 204 may concurrently and evenly be varied so that the position of the focal point 208 (i.e. the depth of the focal point 208) may translate along the axis E.

[0085] In one embodiment, the system 200 comprises a linear actuator for each mechanical waveguide 204 in order to modify the angle Q associated with each mechanical waveguide 204. In an embodiment in which the central mechanical waveguide 204 has a fixed position, the system 200 comprises no linear actuator for the central mechanical waveguide 204. For example, the linear actuator may be an electric, electromechanical, pneumatic or hydraulic linear actuator.

[0086] In another embodiment, the system 200 comprises an angular or rotational actuator for each mechanical waveguide 204 in order to modify the angle Q associated with each mechanical waveguide 204. In an embodiment in which the central mechanical waveguide 204 has a fixed position, the system 200 comprises no angular or rotational actuator for the central mechanical waveguide 204. For example, the angular or rotational actuator may be an electric, electromechanical, pneumatic or hydraulic linear actuator. [0087] In an embodiment in which the system 200 comprises an electromechanical transducer for each mechanical waveguide 204 and the mechanical waveguides may move relative to the coupling device 206, each electromechanical transducer may be fixedly secured at the proximal end of its respective mechanical waveguide 204 and each electromechanical transducer may be connected to a respective assembly formed by a respective mechanical waveguide 204 and its respective electromechanical transducer so that the assembly can be moved by the electromechanical transducer. For example, when the coupling device 206 is a flexible bag filled with an acoustically conductive fluid and the distal end of the mechanical waveguides 204 hermetically penetrates into the coupling device 206, the position of the focal point 208 can be changed by moving the assemblies formed by the mechanical waveguides 204 and their respective electromechanical transducers.

[0088] While the above description refers to mechanical waveguides 204, it should be understood that any adequate device adapted for propagating mechanical waves may be used in replacement of the mechanical waveguides. For example, guide wires or shock wires may be used.

[0089] In one embodiment, a mechanical wave sensor such as pressure transducer or a hydrophone may be used for detecting the focal point 208.

[0090] In one embodiment, the system 200 may be used for stimulating a heart. In this case, the focal point 208 is to be focused on an area-of-interest of the heart 110 to be treated in order for the focused mechanical waves or mechanical pulses to stimulate the heart by inducing a depolarisation and beating of same. In one embodiment, the area-of-interest is the left ventricle and/or anterior side of the atrium.

[0091] While in the illustrated embodiment, the mechanical waveguides 204 are arranged or disposed circumferentially about the focal axis E according to a truncated conical configuration, it should be understood that other geometrical arrangements allowing for the focusing of the mechanical waves or pulses at a focal point may be used. For example, the mechanical waveguides 204 may be geometrically positioned according to a truncated pyramidal arrangement. [0092] In an embodiment in which the system 200 is used to stimulate a heart, the amplitude of a mechanical pulse reaching the distal end of the mechanical waveguides has a frequency of about 2 Hz (120 OdC / min) for about 30 seconds successively on the atrium and the left ventricle.

[0093] In one embodiment, the mechanical waveguides 204 have a cylindrical shape, a length of about 915 mm and a diameter of about 25 mm. However, it should be understood that the mechanical waveguides 204 may be provided with any other adequate shape. Similarly while the cross-sectional shape and size are constant along the length of the mechanical waveguides 204, it should be understood that the cross-sectional shape and/or size may vary along the length of the mechanical waveguides 204. For example at least one of the mechanical waveguides 204 may have a tapered shape.

[0094] In one embodiment, the focal point 208 is located at a focal distance of about 150 mm along the focal axis from the distal ends of the mechanical waveguides 204. In the case of in vivo applications, the focal point and the focal distance may be determined by measurements under 2D fluoroscopy and 3D rotational angiography without injection of contrast medium. In the case of ex vivo applications, the focal point and the focal distance may be determined by direct physical measurements using, for example, a ruler or any other measuring device(s) know in the art.

[0095] Figure 4 illustrates one embodiment of a method 300 of using the system 100 or 200 for non-invasive cardiac stimulation by providing mechanical waves or mechanical pulses to a heart of a subject’s body in in vivo applications, or to an explanted heart of a subject’s body 108 in ex vivo applications. It should be understood that the method 300 may be used not only on a human being, but also on an animal with appropriate modifications.

[0096] At step 202, an image of at least a portion of the heart is acquired and displayed on a display unit. The image may be acquired using any medical imaging technique known in the art such as magnetic resonance imaging (MRI), ultrasound medical imaging, X-ray medical imaging and/or the like. It should be understood that the acquired image contains the area-of- interest of the heart to be stimulated, such as for example the left ventricle and the anterior side of the atrium. [0097] At step 304, the heartbeat of the subject is monitored and acquired by an electrocardiography monitoring unit and a visual representation of the heartbeat, such as an electrocardiogram (ECG), is displayed on an electrocardiography display unit. It should be understood that any adequate method for determining the heartbeat of a subject may be used. For example, in one embodiment, the heartbeat is acquired by electrocardiography. In this case, a plurality of electrodes, e.g. surface electrodes, are placed on the skin of the subject such as over the limbs and the chest and are connected to the electrocardiography monitoring unit. Over time and at each heartbeat, the electrodes record the electrical depolarization of the heart which is used to generate an ECG that is received by the electrocardiography monitoring unit and displayed on the electrocardiography display unit.

[0098] In one embodiment, the image of the at least a portion of the heart, as well as the ECG are both displayed on a same unit. Alternatively, the image of the at least a portion of an anatomical target and the ECG may be displayed on separate display units.

[0099] In one embodiment, the display of the image of the at least a portion of an anatomical target and the display of the ECG are performed in a substantially real-time and concurrent fashion so that both displays are synchronized in time.

[00100] At step 306, the localization of the area-of-interest of the heart imaged at step 302 is performed by a 2D or 3D imaging and/or navigation unit. In one embodiment, the localization of the area-of-interest is performed automatically by the 2D or 3D imaging and/or a navigation unit. Alternatively, the localization of the area-of-interest is performed manually by the user of the method 300 or by any medical personnel.

[00101] In one embodiment where the localization of the area-of-interest has been determined and a plurality of guiding devices 106, 204 is used, the plurality of the guiding devices 106, 204 is adjusted or positioned relative to the subject’s body so that the focal point is positioned on the area of the anatomical target to be treated. In one embodiment, the focal point is located at a focal distance of about 150 mm along the focal axis from the distal ends of the plurality of guiding devices 106, 204. Also, the positioning of the focal point on the area-of-interest is performed by measurements under 2D fluoroscopy and 3D rotational angiography without injection of contrast medium. It should be understood that any other adequate focal distance may be used by the system 100, 200 to focus the energy of the mechanical waves of mechanical pulses on the area of the heart to be treated.

[00102] At step 308, an adequate time for stimulating the area of the heart to be treated is determined using ECG synchronization. In one embodiment, the step of determining the adequate stimulation time may be chosen at a predefined cardiac activation time after the absolute refractory period by the user manually. In another embodiment, the step of determining the adequate stimulation time may be chosen at a predefined cardiac activation time after the absolute refractory period by the electrocardiography monitoring unit automatically. For example, the synchronization between the adequate time for stimulating the area to be treated and the ECG is performed by a an electronic circuit or a computer.

[00103] In one embodiment, the adequate time for stimulation is indicated visually on the electrocardiography display unit and/or by a sound. For example, the indication may be a visual indication and/or a sound indication.

[00104] At step 310, using the system 100, the guiding device 106 is positioned and oriented so as to target the area-of-interest of the heart. If the system 200 is used, the coupling device 206 is positioned and oriented so as to target the area-of-interest of the heart. A high amplitude and short duration pulse or a series of high amplitude and short duration pulses is then generated at the adequate time determined at step 308. The generated pulse propagate through the guiding device(s) 106, 204 before penetrating into the body of the subject and reach the area-of-interest of the heart. Each mechanical pulse arriving at the area of interest triggers a cardiac depolarization. When a sequence of pulses is generated, it is possible to obtain a synchronized stimulation in line with the heart depolarization of the subject.

[00105] It should be understood that the frequency and phase of the mechanical waves or mechanical pulses generated by the pulse generator may be modified as desired and may not be in pace with the natural heartbeats of the subject’s heart.

EXAMPLE: EX VIVO CARDIAC STIMULATIONS

[00106] The system 200 and the method 300 were used to assess the feasibility of using mechanical pulses for cardiac stimulation ex vivo. [00107] Hearts were explanted from two common pigs each weighing approximately 40 Kg according to the Langendorff s isolated and perfused heart assay, while maintaining the flow by cannulation of the aorta and the artery pulmonary. Ex vivo cardiac stimulation experiments were performed on each beating heart using the system 200 comprising seven mechanical waveguides 204, and the focal point was adjusted to about 150 mm from the distal end of the mechanical waveguides 204. Then, the seven mechanical waveguides 204 were directly submerged into the physiological buffer solution containing the individual beating heart and the focal point was focused by direct physical measurements successively on the left ventricle and the anterior side of the atrium. According to the method 300, the hearts were automatically stimulated at a predefined cardiac activation time after the absolute refractory period.

[00108] Figures. 5a-5c and Figures 6a-6c illustrate experimental results. Figures 5a-5c illustrate the application of a mechanical pulse on the anterior face of the left ventricle of a heart and the electrical and mechanical response of the heart. As illustrated in Figure 5 c, a mechanical pulse 400 is propagated on the left ventricle of the heart at a given time. Following the propagation of the mechanical pulse 400, the electrocardiogram of Figure 5a exhibits a peak 402 showing an electrical depolarisation of the heart. As illustrated in Figure 5b, the heart also shows a mechanical response following the propagation of the mechanical pulse since the pressure within the heart presents a peak 404 indicative of a premature beat of the heart.

[00109] Figures 6a-6c illustrate the application of a mechanical pulse on the atrium of a heart and the electrical and mechanical response of the heart. As illustrated in Figure 6c, a mechanical pulse 410 is propagated on the atrium of the heart at a given time. Following the propagation of the mechanical pulse 410, the electrocardiogram of Figure 6a exhibits a peak 412 showing an electrical depolarisation of the heart. As illustrated in Figure 6b, the heart also shows a mechanical response following the propagation of the mechanical pulse 410 since the pressure within the heart presents a peak 414 indicative of a premature beat of the heart.

[00110] As reported in Table 1, the success rate of the non-invasive ventricular and atrial stimulation, by the electrocardiographic ventricular bipolar electrical response (ECG) followed by the visual mechanical heart contraction and resulting ventricular pressure response in the explanted hearts was proportional to the voltage applied to the pulse generator to generate the mechanical waves or mechanical pulses.

Table 1 : Correlation between the success rate (in %) of eliciting an ECG beating response and associate pressure response and the strength of the mechanical waves or mechanical pulses used for stimulating the explanted hearts.

[00111] Also, the risk of cardiac defibrillation was investigated by stimulating repeatedly at a maximal voltage of 600 V the explanted beating hearts with two fast pulses between the R and T waves of the ECG. In this experiment, no fibrillation could be triggered.

[00112] The embodiments described above are intended to be exemplary only. The scope of the invention is therefore intended to be limited solely by the appended claims.