TREATMENT OF CARDIAC VALVE INSUFFICIENCY

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of the filing date of U.S. Provisional Patent Application Nos. 61/256,002, filed on October 29, 2009, and 61/256,438, filed on October 30, 2009, the disclosures of which are hereby incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to treatment of valves in mammalian subjects. More particular, the invention relates to percutaneous and non-invasive treatment of mitral valve insufficiency in the heart of a mammal.

BACKGROUND OF THE INVENTION

[0003] The heart of a human and other mammals includes a valve known as a mitral valve. The mitral valve, when properly operating, prevents blood flow from the left ventricle of the heart into the left atrium during contraction of the left ventricle.

[0004] When the mitral valve is in a diseased state, commonly known as mitral valve insufficiency or mitral valve regurgitation, the mitral valve does not close properly during contraction of the heart. Consequently, in the presence of mitral valve insufficiency, when the left ventricle of the heart contracts as part of the pumping action of the heart, a significant portion of the blood in the left ventricle may flow back from the left ventricle, through the mitral valve and into the left atrium. Such flow of blood during contraction of the heart is undesired, and may cause injury to the mammal .

[0005] Mitral valve insufficiency often is treated by surgery on the heart to repair or replace the mitral valve. Such surgery may expose a patient to risk and complications. [0006] Alternatively, mitral valve insufficiency may be treated by introducing a catheter including an energy emitter into the body, and operating the emitter to heat collagen fibers that are included in the mitral annulus of the mitral valve. Heating of the collagen fibers causes the collagen fibers to delink or become reconfigured, which in turn may shrink the annulus. In practice, however, there are difficulties in accurately positioning an energy emitter in contact with the mitral annulus during a mitral valve repair procedure, to obtain desired heating of the collagen fibers of the mitral annulus, while maintaining contact between the emitter and the mitral annulus despite rapid movement of the annulus, such that damage to other internal tissue or cells surrounding or near the mitral valve or the emitter may be avoided .

[0007] In another alternative, it has been proposed to treat mitral valve insufficiency by bringing an ultrasound transducer into proximity with the mitral annulus. In this treatment approach, direct contact between the transducer and the annulus is not required. The ultrasound transducer is positioned, by means of a positioning balloon, in the posterior/lateral portion of the mitral annulus, so that ultrasonic energy emitted by the transducer impinges on the annulus. This treatment approach, however, still requires a left-side of the heart procedure, which has its associated risks for stroke, perforation during performance of a transeptal puncture, etc. Further, preclinical work involving this treatment approach has shown that it may be difficult to limit catheter movement, which in turn may result in unwanted energy deposition superior and inferior to the mitral annulus. In addition, this treatment approach may include a risk of damaging the mitral leaflets and chordae tendineae, either due to unwanted energy deposition or physical contact of the balloon or catheter with the mitral annulus that results from manipulation of the catheter or a guide wire associated with the catheter. In addition, this treatment approach may direct energy from the inside of the heart outwardly, thereby resulting in a risk of collateral damage in neighboring organs or structures, for example, AV node damage or atrio esophageal fistulae .

[0008] Therefore, there exists a need to shrink the mitral annulus of a mitral valve without placing a catheter in the left side of the heart, and to avoid contact of an apparatus, which may provide for deposition of heat in the mitral annulus, with the mitral leaflets, chordae tendinae or other delicate structures.

BRIEF SUMMARY OF THE INVENTION

[0009] In accordance with an aspect of the invention, a method of treating a mitral valve of a mammalian subject includes positioning an energy emitter at a location inside the coronary sinus of the subject adjacent the mitral annulus of the mitral valve. The method may further include, while the energy emitter is disposed at the location, emitting therapeutic energy from the energy emitter so that a substantial portion of the therapeutic energy is absorbed by the mitral annulus.

[0010] In accordance with another aspect of the invention, a method of treating mitral valve insufficiency may include preferentially applying energy to a posterior/lateral portion of a mitral annulus of a mammalian subject adjacent a coronary sinus to heat and contract collagen in the posterior/lateral portion, wherein the applied energy is emitted from an energy emitter positioned within the coronary sinus of the subject.

[0011] In accordance with another aspect of the invention, an apparatus for treating a cardiac valve of a mammalian subject may include an elongated catheter having proximal and distal regions; and an energy emitter including an ultrasonic transducer and an expansible structure carried on the distal region of the catheter. The expansible structure may be adapted to hold the transducer spaced apart from an inner lining of the coronary sinus of the subject in which the energy emitter is disposed and to cool the transducer.

[0012] In accordance with another aspect of the invention, apparatus for treating a cardiac valve of a mammalian subject may include an elongated catheter having proximal and distal regions; and an energy emitter including at least one of a radio frequency and optical energy emitter and an expansible structure carried on the distal region of the catheter. The expansible structure may be adapted to expand to an expanded state to cause the energy emitter to contact the coronary sinus wall .

[0013] In accordance with another aspect of the invention, a method of repairing a mitral valve of a mammalian subject may include the steps of: (a) inserting an ultrasonic energy emitter including an ultrasonic transducer and a cooling balloon structure including a balloon surrounding the transducer in the coronary sinus of the subject; (b) inflating the balloon structure surrounding the ultrasonic transducer with a liquid; (c) positioning a distal portion of the balloon structure in the coronary sinus at a first location adjacent to a selected portion of the annulus of the mitral valve of the subject; (d) applying ultrasonic energy emitted from the ultrasonic emitter to the selected portion of the annulus to shrink tissue in the selected portion of the annulus of the mitral valve; and (e) positioning the transducer within the coronary sinus and offset from the first location by about one transducer length and repeating step (d) .

[0014] In accordance with another aspect of the invention, a method of treating a cardiac valve of a mammalian subject may include positioning an energy emitter inside the esophagus of the subject in proximity with the valve; and emitting therapeutic energy from the energy emitter so that a substantial portion of the therapeutic energy is absorbed by the annulus of the valve.

[0015] In accordance with another aspect of the invention, method of treating a valve insufficiency in a mammal may include non-invasively applying radiation energy emitted from a gamma knife to a predetermined region of the valve.

[0016] In accordance with another aspect of the invention, an apparatus for treating a mitral valve of a mammalian subject may include means for insertion into the coronary sinus of the subject having proximal and distal regions. The apparatus may also include means for energy emission carried on the distal region of the insertion means. The energy emission means may include means for positioning the energy emitter means at a location inside the coronary sinus of the subject adjacent the mitral annulus of the mitral valve, and while the energy emission means is disposed at the location, emitting therapeutic energy from the energy emission means so that a substantial portion of the therapeutic energy is absorbed by the mitral annulus.

[0017] In accordance with another aspect of the invention, an apparatus for treating a mitral valve of a mammalian subject may include means for insertion into an esophagus of the subject having proximal and distal regions. The apparatus may further include means for energy emission carried on the distal region of the insertion means. The energy emission means may be operable to apply therapeutic ultrasonic energy to a predetermined region of the cardiac valve so that a substantial portion of the therapeutic energy is absorbed by the mitral annulus of the mitral valve.

[0018] Further objects, features, and advantages of the present invention will be more readily apparent from the detailed described embodiments set forth below, taken in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG. 1 is a block diagram, schematic view of an exemplary apparatus for treating a mitral valve insufficiency, in accordance with an aspect of the present invention.

[0020] FIG. 2 is a cross-sectional view of an exemplary embodiment of a treatment catheter, in accordance with an aspect of the present invention.

[0021] FIG. 3 is a diagrammatic, sectional view of a human heart with an exemplary embodiment of a treatment catheter in an operative condition, in accordance with an aspect of the present invention.

[0022] FIG. 4 is diagrammatic, axial sectional view of a human heart with an exemplary embodiment of a treatment catheter in an operative position, in accordance with an aspect of the present invention.

[0023] FIG. 5 is a diagrammatic, sectional view of a human heart with an exemplary embodiment of a treatment catheter in a plurality of operative positions, in accordance with an aspect of the present invention.

[0024] FIG. 6 is a cross-sectional view of another embodiment of a treatment catheter, in accordance with an aspect of the invention.

[0025] FIG. 7 is a cross-sectional view of a heart with a treatment probe in an operative position within the esophagus, in accordance with an aspect of the present invention.

[0026] FIG. 8 is a cross-sectional view of an embodiment of a treatment probe, in accordance with an aspect of the present invention .

[0027] FIG. 9 is a cross-sectional view of an embodiment of a treatment probe, in accordance with an aspect of the present invention .

[0028] FIG. 10 is a partial schematic view of the heart showing a treatment probe in an operative position, in accordance with an aspect of the present invention. [0029] FIG. 11 is block diagram of an apparatus for treating a valve insufficiency, in accordance with an aspect of the invention.

DETAILED DESCRIPTION

[0030] In accordance with an aspect of the present invention, referring to FIGs. 1-6, a valve treatment apparatus 100 may include a treatment catheter 5, a pull wire control unit 8, an energy generator control unit 15, a fluid circulation control unit 16, an energy emitter unit 50 and a monitoring and imaging system 200. Each of the pull wire control unit 8, the energy generator control unit 15, the fluid circulation control unit 16, the generator 15 and the monitoring and imaging system 200 may include a processor and a memory including instructions executable by the processor to perform operations that implement functions associated with the respective units and the inventive apparatus and method as described below, in accordance with aspects of the present invention .

[0031] Referring to FIG. 1, the treatment catheter 5 may be an elongated structure having a proximal end 22, a distal end 24 and a proximal-to-distal axis. The catheter 5 may define a bore 21 extending from the proximal end 22 to the distal end 24 that may accommodate a guide wire. In one embodiment, the catheter 5 may have a relatively stiff proximal wall section 28 and a relatively flexible distal wall section 32, and include a transition 26 between the proximal and distal wall sections .

[0032] Referring to FIG. 1, a pull wire 9 may be slidably mounted in or to the proximal wall 28 of the catheter 5 and be connected to the distal wall 32 of the catheter 5. The pull wire 9 may be linked at its proximal end to the pull wire control unit 8. The pull wire control unit 8 may provide for control of movement of the pull wire 9. For example, a user may manipulate the pull wire 9, using the control unit 8, to pull on the wire 9 and bend the distal end 24 of the catheter 5 in a predetermined direction transverse to its proximal-to-distal axis, as shown schematically by dashed- lines in FIG. 1. In one embodiment, the pull wire 9 may be controlled as set forth in U.S. Published Patent Application No. 2006-0270976 ("the '976 Publication"), the disclosure of which is incorporated by reference herein.

[0033] In one embodiment, the catheter 5 may be adapted such that the distal end 24of the catheter 5 may be disposed in any position by the combination of pulling the pull wire 9 and rotating the catheter 5 about its proximal-to-distal axis.

[0034] In one embodiment, referring to FIG. 4, the pull wire control unit 8 (shown in phantom) may include a lever 18 coupled to the pull wire 9, and the pull wire control unit 8 including the lever 18 may be part of a handle unit 20 which is physically attached to the proximal end 22 of the catheter 5. See, for example, '976 Publication. Thus, a user may maneuver the catheter 5 to any desired position by actuating the pull wire control unit 8 using the lever 18 and turning the handle 20, desirably with one hand, during a valve repair procedure, such as a mitral valve repair procedure, in accordance with aspects of the present invention. In a further embodiment, the fluid control unit 16 and the energy generator unit 15 also may be connected to the catheter 5 through the handle 20, as schematically shown in FIG. 4.

[0035] The energy emitter unit 50 may be mounted on the catheter 5 at the distal end 24. Referring to FIG. 2, in one embodiment, the emitter unit 50 may include one or more energy emission elements 11 mounted along the length of the catheter 5. The emission element 11 may be a bipolar or monopolar RF electrode for generating RF energy signals, a microwave antenna for generating microwave energy signals or a medium through which optical energy signals may be transmitted ("optical window") . In one embodiment, a plurality of RF electrodes may be mounted along the length of the catheter 5. In another embodiment, a single microwave antenna or a single optical window may be mounted at the distal end 24 of the catheter 5.

[0036] In another embodiment, the emitter unit 50 may be slidably mounted on the catheter 5, such that the emitter unit 50 may be moved axially along a length of and relative to the catheter .

[0037] In another embodiment, referring to FIG. 1, the emitter unit 50 may include an ultrasonic transducer 52 for generating ultrasonic energy signals mounted on the distal end 24 of the catheter 5. The ultrasonic energy signals generated by the ultrasonic transducer may be, for example, at about 5- 12 MHz and about 10-100 Watts of acoustic power.

[0038] In the embodiment of FIG. 1, the emitter unit 50 may include the ultrasonic transducer 52 having a tubular, cylindrical configuration. An ultrasonic reflector 53, such as a brass or other metal body, may be positioned on one side of the transducer 52. Ultrasonic waves generated by the transducer 52 propagate generally radially outwardly, transverse to the axis of the transducer. The reflector 53 may be positioned at a distance of one-half of the wavelength of the ultrasonic energy signals generated by the transducer 52, on one side of the transducer 52, to reflect ultrasonic energy signals generated by the transducer 52 propagating to the one side. Based on the ultrasonic energy signals reflected by the reflector 53 and the other ultrasonic energy signals generated by the transducer 52 propagating opposite the one side, most of the generated ultrasound energy signals may be directed into a segment 14, thereby creating a segmental treatment field. As discussed below, the transducer 52 may be positioned to cause the segment 14 to overlap a section of the mitral annulus of a mitral valve of a mammalian heart which is to be treated, in accordance with aspects of the present invention.

[0039] In still other embodiments, focusing devices, such as lenses and diffractive elements, may be used in conjunction with the transducer 52 to cause the generated ultrasonic energy to be directed in the form of the segment 14.

[0040] In an alternative embodiment, the ultrasonic transducer 52 may be a planar transducer with a molded lens which helps to direct most of the ultrasonic energy generated into the segment 14, and thus create a segmental treatment field. In addition, the transducer 52 may include an air backing or light composite backing on the back side of the transducer 52. In one embodiment, metallic coatings on interior and exterior surfaces of the transducer 52, or on front and back surfaces of a planar design transducer 52, may be connected to a ground wire and a signal wire in cable 55.

[0041] In one embodiment, the emitter unit 50 may have an ultrasonic emitter operable to provide both imaging and therapy functionalities. The ultrasonic emitter may be a single ultrasound transducer. The transducer may be operated to detect thickness of the mitral annulus and position of the transducer relative to the mitral annulus, using detected ultrasound energy signals which are reflections of ultrasound energy signals emitted by the transducer. The ultrasound transducer may be connected to an ultrasound energy monitoring apparatus included in the system 200, which processes electrical signals supplied from the ultrasound transducer which are representative of ultrasound energy signals detected at the transducer that are reflections of ultrasound energy signals emitted by the transducer.

[0042] For example, the ultrasound energy monitoring apparatus of the system 200 may determine the thickness of the mitral annulus of the heart of a mammal, by determining the time interval between reflected ultrasound energy signals corresponding to reflections from the proximal and distal walls of the mitral annulus . The annulus thickness is proportional to the time interval between detection of the proximal and distal reflections. In addition, the ultrasound transducer may be operated to emit ultrasound energy signals, and the ultrasound monitoring apparatus may determine whether the reflected ultrasound signals detected at the transducer indicate a characteristic motion, or signature, of the mitral valve leaflets. When the mitral valve leaflet signature is indicated, the ultrasound energy field, such as the segment 14, of the transducer is directed into the mitral annulus, such that the emitter unit 50 is desirably positioned in alignment with the mitral annulus for treatment by application of ultrasound energy signals from the transducer.

[0043] The generator unit 15 may be connected to the emitter unit 50 by a cable 55. The cable 55 is a suitable energy, energy signal or current conveying medium for conveying, respectively, energy, energy signals or voltages

(current) from the generator unit 15 to the emitter unit 50. In one embodiment where the emitter unit 50 is an optical window, the cable 55 is an optical fiber.

[0044] In another embodiment where the emitter unit 50 is an ultrasound transducer, the cable 55 may be a twisted pair that is attached to the ground wire and the signal wire of the ultrasound transducer. In such embodiment, the cable 55 may convey electric signals from the generator unit 15 to the emitter unit 50 to cause ultrasound energy to be generated from the transducer, and convey from the emitter unit 50 to the generator unit 15 electric signals representative of ultrasound energy signals detected at the transducer.

[0045] In a further embodiment where the emitter unit 50 is an RF electrode or a microwave antenna, the cable 55 is a coaxial cable for conveying RF signals or microwave signals. [0046] The generator unit 15 may be a signal generator for generating RF signals or microwave signals to cause generation, respectively, of RF energy by an RF electrode or microwave energy by a microwave antenna. Alternatively, the generator 15 may be an optical energy generator, such as a laser, for generating optical energy. In another embodiment, the generator 15 may be an ultrasonic transducer excitation source that generates electrical current (voltage) to actuate an ultrasonic transducer. In a further embodiment, the generator unit 15 may be adapted to output to the system 200 electrical signals which are the same as or representative of the electrical signals supplied to the generator unit 15 from the emitter unit 50, such as from an ultrasonic transducer of the emitter unit, over the cable 55.

[0047] The monitoring and imaging system 200 may include an ultrasound imaging system as described above, which provides functionalities for determining thickness of the mitral annulus and position of an ultrasound transducer relative to the mitral annulus using reflected ultrasound energy signals. In addition, the system 200 may include a magnetic resonance imaging system, a transesophageal echocardiography (TEE) imaging system and a biplane fluoroscopy system.

[0048] The fluid circulation unit 16 may operate to supply aqueous fluid, such as water or a contrast fluid, and also remove fluid.

[0049] In one embodiment, referring to FIG. 1, the proximal end 22 of the catheter 5 may include a transition 18 that extends obliquely to the proximal-to-distal axis of the catheter 5 and is connected to the fluid circulation unit 16. The circulation unit 16 may be operable to supply fluid through the catheter 5 to the distal end 24 of the catheter, and also to remove fluid from within the catheter 5.

[0050] In one embodiment, the fluid circulation unit 16 may include an inflow pump and an outflow pump. The inflow pump may be connected to an inflow passage 17 extending through the catheter 5 to the distal end 24, and the outflow pump may be connected to a separate outflow passage 19 extending through the catheter 5 to the distal end 24. For example, water supplied by the unit 16 may be utilized to irrigate RF electrodes 11 at the distal end 24 of the catheter 5 while the RF electrodes are generating RF energy, thereby cooling them and any tissue contacting the catheter 5 at the distal end 24.

[0051] In still a further embodiment, referring to FIGs. 2 and 6, the distal end 24 of the catheter 5 may include an expansible balloon 30 or like expansible structure. The distal end 24 may be adapted to provide that, when the balloon 30 is inflated, and the energy emitter emits a form of thrombogenic energy, such as RF or optical energy, the balloon 30 causes the energy emitter to be in contact with tissue, such as the wall of the coronary sinus in which the catheter is positioned. The balloon 30 further may be adapted to provide that, when deflated, the balloon 30 may fold into a relatively small diameter structure.

[0052] In one embodiment, the inflow pump of the unit 16 may be connected to the inflow passage 17 extending through the catheter 5 to an interior space of the balloon 30, and the outflow passage 18 may extend through the catheter 5 also to the interior space of the balloon 30. Referring to FIGs. 2 and 6, the balloon 30 may be supplied with fluid from the circulation unit 16 to inflate the balloon 30, while ultrasound energy signals are being generated by the ultrasound transducer 52, to cause the balloon 30 to contact, and desirably surround, at least a portion of the transducer 52. The fluid within the balloon 30, thus, may cool the transducer 52, and also make the transducer 52 be easily visible, such as by using fluoroscopy, based on contrast material within the fluid. In one embodiment, during operation of the apparatus 100, the circulation unit 16 may continuously circulate aqueous fluid through the balloon 30 and maintain the balloon 30 under a desired pressure and at a desired temperature. In one embodiment, a space between the transducer 52 and the reflector 53 may be in communication with the interior space within the balloon 30, which provides additional cooling for the transducer 52, desirably with fluid supplied by the circulation unit 16.

[0053] An exemplary operation of the apparatus 100 for treating a mitral valve insufficiency in a beating heart 222 of a mammal or human is described with reference to FIGs. 4 and 5. A guiding or delivery sheath 70 may be advanced by a user, such as a physician, over a guide-wire or a coronary sinus catheter (not shown) placed in a coronary sinus 220 of the heart 222, until the distal end of the sheath 70 extends into the coronary sinus entrance 221 in the right atrium of the heart. The coronary sinus catheter may then be withdrawn, and the treatment catheter 5 may be advanced through the guiding sheath 70 into the right atrium, and inserted into the coronary sinus 220.

[0054] In an alternative embodiment, the treatment catheter

5 may be advanced over the guide-wire. In one embodiment, the catheter 5 may have a shape similar to that of a coronary sinus catheter and may be advanced directly without a sheath into the coronary sinus.

[0055] In an alternative embodiment, the coronary sinus 222 may be accessed either femorally through the inferior vena cava 224, as shown in FIG. 3, or subclavially through the superior vena cava.

[0056] In another embodiment, the catheter 5 may be pre- shaped to facilitate advancement into the coronary sinus ostium, such as similar to the shape of a coronary sinus catheter, and may be inserted directly into the coronary sinus, with or without a guide wire and/or sheath. [0057] After the distal end 24 of the catheter 5 is within the coronary sinus 220, the user may rotate the catheter 5 so that the emitter unit 50, such as the emitter element (s) 11, faces the mitral annulus 226 of the mitral valve 228, thereby placing the catheter 5 with the emitter unit 50 in an operative position. When the catheter 5 with the emitter unit 50 is in an operative position, the emitter unit 50 may be operated to emit energy. For example, optical energy generated at the generator unit 15 may be supplied over optical fiber cable 55 and be emitted through an optical window 11 of the emitter unit 50. Alternatively, the emitted energy may be ultrasound energy, microwave energy or RF energy, respectively, generated by an ultrasonic transducer, microwave antenna or RF electrode contained within the emitter unit 50. The emitter unit 50 may be adapted such that the emitted energy propagates away from the catheter 5 substantially within the segment 14. The emitter unit 50 may be positioned within the coronary sinus 220 to align the segment 14 with the mitral annulus 226 of the mitral valve 228 of the heart, such that a substantial portion of the emitted energy, such as at least about 80 percent of the emitted energy, is absorbed by the mitral annulus.

[0058] In one embodiment, the segment 14 may be aligned with the mitral annulus, such that emitted energy is applied over about five percent of the circumference of the mitral annulus during a single actuation of the emitter unit 50.

[0059] In a further embodiment, the state of the mitral annulus may be monitored by the imaging and monitoring system 200, such as by ultrasound imaging, during treatment using the catheter 5. During treatment by applying ultrasound energy to the mitral annulus, the physical properties of the collagenous tissue in the mitral annulus change, and thus the ultrasound energy reflectivity of the mitral annulus changes. The changes in ultrasound energy reflectivity of tissue may be observed using ultrasonic imaging of the system 200, to monitor whether a desired lesion is formed in the mitral valve annulus .

[0060] In one embodiment, the emitter unit 50 may be an ultrasound transducer operable to detect reflections of ultrasound energy signals emitted therefrom. The detected reflected ultrasound energy signals may be used by the system 200 to align the segment 14 of the transducer with the mitral annulus, and also determine an amount of ultrasound energy to be supplied by the transducer as therapy. In addition, the system 200 may be used to determine when the detected reflections indicate a characteristic signature of the mitral valve leaflets, while the catheter 5 with the emitter unit 50 is rotated in the coronary sinus 220. When the characteristic signature is obtained, the ultrasound transducer is positioned such that the segment 14 is aligned with the mitral annulus 226. In addition, for such alignment position of the emitter unit 50, the thickness of the mitral annulus may also be determined by the system 200, based on the time difference between the proximal and distal ultrasound reflections of the mitral annulus.

[0061] The ultrasound energy generated by the ultrasound transducer as a therapeutic dose may be controlled according to the determined mitral annulus thickness. In one embodiment, the system 200 may supply control signals to the generator unit 15 to provide that the generator unit 15 controls actuation of the ultrasound transducer 52 to generate the desired therapeutic dose of energy to be deposited in the mitral annulus. In one embodiment, the transducer 52 may be operated to provide for therapeutic application of ultrasound energy in an interleaved timing mode with respect to ultrasound energy emitted for imaging applications. In another embodiment, the emitter unit 50 may include an array of ultrasound transducers to provide for two dimensional (2D) ultrasound imaging, and also for therapeutic application of ultrasound energy, quasi-simultaneously or interleaved with emission of ultrasound energy for imaging applications.

[0062] In one embodiment, orientation of the emitter unit

50 to achieve optimal energy deposit in the mitral annulus may be controlled by fluoroscopy or TEE (3D) functionalities included in the system 200.

[0063] Referring to FIG. 4, which shows the anatomy of the mitral annulus 226 in relation the coronary sinus 220, the coronary sinus 220 typically is located slightly above the posterior/lateral portion 230 of the mitral annulus 226 and extends along and generally parallel to only the posterior/lateral portion 230 of the mitral annulus. The coronary sinus does not extend along the anterior portion of the mitral annulus. Advantageously, in accordance with the present invention, energy, such as ultrasound, radio frequency, optical energy or microwave energy, emitted from the emitter unit 50 may be preferentially directed into the posterior/lateral portion 230 of the mitral annulus 226, which results in preferential heating of the posterior and lateral aspects of the mitral annulus 226. Such directed heating of the posterior and lateral portions of the mitral annuls is particularly desirable, because the posterior and lateral portions are rich in collagen and, therefore, tend to shrink preferentially with heating. The heat energy de-links the collagen fibers or breaks up cross-links, which orient collagen molecules or triple helixes in a parallel fashion in the mitral annuls. The breaking up of the cross-links, in turn, breaks up the parallel structure of collagen molecules, thereby causing shrinkage of the mitral annulus.

[0064] Further, such directed heating by operation of the inventive treatment catheter, which is obtained in view of the spatial relation between the coronary sinus and the mitral annulus, minimizes risk of damage to aortic valve structures, such as the aorta 232, or the conduction system, such as the bundle of Hiss or the AV node, which lie close to the anterior mitral annulus 234. In addition, since coronary sinus movement is very much in synchronization with movement of the mitral annulus, the energy may be deposited mainly in the mitral annulus, and collateral damage to the mitral valve leaflets or other structures due to heart movement may be minimized, during application of the energy emitted from the emitter unit 50.

[0065] Further, by directing the emitted energy substantially in the form of the segment 14, leaflet damage in the mitral valve is highly unlikely, because the emitted energy is mostly absorbed within the mitral annulus before the energy can reach the leaflets of the mitral valve.

[0066] FIG. 5, which shows the heart 222 in an axial view from the top with the atria and associated structures removed for ease of illustration, shows desired positions of an emitter element 11 of an emitter unit. Referring to FIG. 5, in one embodiment, the catheter 5 may be advanced by one emitter element 11, or about one emitter unit length, at a time, between operation of the apparatus 100 to emit energy from the emitter unit 50, anywhere along the length of the coronary sinus 220, to provide for a series of energy deposits in the mitral annulus 226 of the mitral valve 228. The emitter unit may be advanced in step-by-step manner until the entirety of the posterior and lateral portion 230 of the mitral annulus has been exposed to sufficient energy treatment at each emitter unit location. Advantageously, step-by-step energy deposition provides that the amount of energy emitted may be adjusted in accordance with mitral annulus thickness, and the position of the emitter unit within the coronary sinus in relation to the mitral annulus may be optimized for each energy application. As described above, annulus thickness, and the position of an ultrasound transducer in relation to the mitral annulus, so as to provide for alignment of the segment 14 with the mitral annulus, may be determined by operation of the ultrasound transducer to detect ultrasound energy signals which are reflections of ultrasound energy signals emitted from the transducer and imaging performed with the system 200.

[0067] Referring to FIG. 2, in a further embodiment in which the emitter unit 50 emits a form of thrombogenic energy and includes a plurality of emission elements 11, such as RF electrodes, inflation of the balloon 30 may serve as a positioning device that pushes the portion of the catheter 5 at which the RF electrodes 11 are disposed into contact with the coronary sinus wall facing the mitral annulus to avoid blood coagulation.

[0068] In one embodiment, the catheter 5 may be positioned such that, when the emitter unit emits RF or optical energy, the emitter unit is forced by inflation of the balloon into contact with the inner coronary sinus wall during emission of a form of thrombogenic energy, such as RF or optical energy.

[0069] In one embodiment in which the emitter unit 50 includes the ultrasonic transducer 52, the ultrasonic excitation source 15 may be operated to actuate the transducer 52 to emit ultrasonic waves, which have a frequency of about 5-12 MHz, and the transducer 52 may be driven to emit, for example, about 10-100 Watts of acoustic power for about 10 seconds. In addition, the transducer 52 may be actuated continuously for about 10 seconds to about a minute. In one embodiment, the actuation of the transducer 52 may be repeated several times. In another embodiment, the frequencies, power levels and actuation times of the transducer 52 may be varied, as suitable based on thickness measurements of the mitral annulus and/or the resulting shrinkage of annulus, as determined from imaging performed by two-dimensional or three- dimensional TEE or biplane fluoroscopy at the monitoring and imaging system 200.

[0070] In another embodiment, the transducer 52, when in an operative position, may be within the balloon 30 which is filled with fluid. In such embodiment, ultrasonic waves generated by the transducer 52, which may include ultrasonic waves reflected by the reflector 53, propagate generally radially outwardly from the transducer 52 aligned with the segment 14. The ultrasonic waves in the segment 14 propagate through the liquid within the balloon 30 to, and then through, the wall of the balloon, and then into the surrounding blood and tissue. The ultrasonic waves then may impinge on the tissues of the heart that are surrounded by the coronary sinus and also upon the mitral annulus . Advantageously, propagation of the ultrasonic waves from the transducer 52 into the mitral annulus 226 is essentially independent of contact between the balloon 30, or the transducer 52, and the solid tissues of the heart, such as the coronary sinus wall facing the mitral annulus, because ultrasound energy is a form of non- thrombogenic energy. The composition of the tissues surrounding the balloon 30 may provide that the liquid within the balloon 30 and the blood surrounding the balloon 30 have approximately the same acoustic impedance, such that there is little or no reflection of ultrasonic waves at (i) interfaces between the liquid within the balloon 30 and the blood outside the balloon 30; (ii) interfaces between the blood and the tissue; or (iii) the interface between the fluid, such as saline, within the balloon 30 and the solid tissue in areas where the balloon 30 contacts the coronary sinus.

[0071] In another embodiment, the transducer 52 may be positioned in an operative position such that essentially all of the mitral annulus lies within a near field region of the transducer 52. Within the near field region, the outwardly spreading beam of ultrasonic waves in the segment 14 tends to remain collimated and have an axial length approximately equal to the axial length of the transducer 52. Based on the location of the coronary sinus relative to the mitral annulus, advantageously the posterior and lateral regions of the mitral annulus, which contain particularly high concentrations of collagen fibers, receive substantially all of the ultrasonic energy in the segment 14, while very little or none of the ultrasonic waves in the segment 14 reach the anterior and septal regions of the mitral annulus. As discussed above, the ultrasonic energy directed into posterior and lateral portions of the mitral annulus is particularly effective in shrinking the mitral annulus. Further, the posterior and lateral position of the coronary sinus in relation to the transducer 52 avoids damage to sensitive structures, such as the aortic valve disposed in proximity to the anterior and septal aspects of the mitral annulus.

[ 0072 ] Preclinical work has shown that the shrinkage in the mitral valve occurs principally in the lateral and posterior aspects of the mitral annulus. The coronary sinus limits movement of the catheter 5 of the apparatus 100 to an axial dimension only, thereby making positioning of the emitter unit 50 of the catheter 5 according to the present invention during a mitral valve treatment procedure to be relatively simple and reliable. Also, it has been observed in experimentation that the mitral annulus tends to shrink immediately upon application of the ultrasonic energy, and that the typical shrinkage reduces the mitral valve area about 20%-30%. It has been observed that such shrinkage of the mitral annulus, in turn, tends to improve the sealing action of the leaflets of mitral valve and reduce or cure mitral valve insufficiency. See, Heuser, R. et al . , Journal of Interventional Cardiology, Vol. 21 p. 180 (April 2008), incorporated by reference herein. [0073] Further, the present invention advantageously provides that the surface of the coronary sinus in contact with blood does not become damaged, and hence does not provoke thrombus formation. This result is obtained because non- thrombogenic energy, such as ultrasonic energy, emitted from the emitter unit 50 within the coronary sinus is dissipated and converted to heat principally inside the mitral annulus, rather than in blood. In addition, circulation of cooled liquid through a balloon of the treatment catheter 5 during a treatment procedure may help to cool the emitter unit, which may be within or exterior to the balloon, and avoid direct heat transfer between the emitter unit, such as the ultrasonic transducer 52, and the intima lying at the surface of the coronary sinus where the lining contacts the balloon. Such cooling of the emitter unit may avoid thrombus formation, which may be caused by heating of the emitter unit during a treatment application. Further, in embodiments in which a form of thrombogenic energy, such as RF or optical energy, is emitted from the emitter unit, a positioning balloon 30 may provide that the energy emitter unit is in direct contact with the coronary sinus wall.

[0074] After completion of an energy deposition ( s ) by the emitter unit 50, the catheter 5 may be withdrawn from the subject's body. In an embodiment where the catheter 5 includes the balloon 30, the balloon 30 may be deflated prior to withdrawal of the catheter 5.

[0075] In another embodiment where the emitter unit 50 is slidably mounted on the catheter 5, the catheter may be positioned in an operative position and the emitter unit may be moved axially along the catheter between energy applications, in increments equal to the length of the emitter, while the catheter is maintained fixed at the operative position. [0076] Referring to FIG. 2, in an embodiment in which several emitter units 50, such as RF electrodes or ultrasound transducers 11, are mounted on the catheter 5 at the distal end 24 in a chain like fashion, energy may be emitted over a length of the catheter 5 which has been inserted into the coronary sinus. In such embodiment, the emitter units may be arranged on the distal end 24 of the catheter to extend along substantially the entire length of the coronary sinus or about 10 cm. In this embodiment, treatment of the mitral valve by application of energy, such as in a plurality of segments 14, does not require axial movement of the catheter during treatment. In addition, the several emitter units may be activated sequentially, or all or some of the emitter units may be activated at the same time.

[0077] In an alternative embodiment, the system 100 may include other imaging modalities which detect heating and, thus, can also be used to monitor the treatment. For example, magnetic resonance imaging, which can detect changes in temperature and may be a functionality of the system 200, may be used to monitor the treatment.

[0078] Thus, according to the present invention, mitral valve insufficiency may be treated percutaneously, without accessing the left sided heart. The emitter unit mounted on a catheter may be positioned in proximity with the mitral annulus, without having to place any device inside the mitral valve annulus. Such positioning avoids impacting blood flow through the annulus and difficulties with positioning due to rapid movement of the annulus and valves. In the absence of a need to place any device inside the mitral annulus and even on the left side of the heart, many potential side effects associated with other treatments of mitral valve insufficiency, such as stroke, mitral valve or chordae tendineae damage and perforations, may be avoided or reduced significantly . [0079] In accordance with a further aspect of the present invention, referring to FIGs. 7-10, a valve treatment apparatus 400 may include a treatment probe 410, an energy generator control unit 412 and a monitoring and imaging system 414.

[0080] The probe 410 may be an elongated structure having a proximal end 422 and a distal end 424. An energy emitter unit 426 may be mounted on the probe 410 at the distal end 424. In one embodiment, the emitter unit 426 may include an array of ultrasound transducers 428, which are adapted for imaging, and an array of ultrasound transducers 430, which are adapted for therapy by applying a suitable dosage of ultrasound energy to a tissue or organ.

[0081] An electrical signal conveying cable 455 may connect the generator unit 412 to the ultrasound transducers of the probe 422.

[0082] The generator unit 412 may be operable to transmit electrical signals for selectively actuating the imaging and therapy ultrasound arrays, and to receive electrical signals representative of ultrasound energy signals from the imaging transducers. In addition, the generator unit 412 is coupled to the system 414, and may provide to the system 414 electrical signals representative of detected ultrasound energy signals, similarly as described above for the apparatus 100.

[0083] The system 414 is operable to perform ultrasound imaging functionalities, such as TEE imaging, and control operation of the generator unit 412 to actuate the emitter unit 426, similarly as described above regarding operation of the system 200 with the generator unit 15 in the apparatus 100.

[0084] In one embodiment, referring to FIG. 8, the imaging transducers 428 may be configured in a phased array to provide that a three dimensional ("3D") image of a target region, such as the region of the heart including the mitral valve, may be generated at the system 414, based on ultrasound signals detected at the transducers 428. By use of 3D imaging, and based on movement of the probe 410 within the esophagus by a user, a 2D imaging plane 460 may be generated at the system 414 that shows all or substantially all of the mitral annulus of a mitral valve of the heart of a mammal.

[0085] An exemplary operation of the apparatus 400 for treatment of a mitral valve insufficiency in a mammalian heart is described with reference to FIG. 7. FIG. 7 shows a cross- section through the left ventricle 236 and left atrium 238 of the heart 222 to illustrate the position of the mitral valve 228 in relation to the esophagus 240, in which the probe 410 may be inserted in accordance with an aspect of the invention. In addition, for reference purposes, the pulmonary artery 242 and the aorta 232 of the heart 222 are also shown in FIG. 7. A treatment procedure using the apparatus 400 may include inserting the probe 410 into the esophagus 240 of the mammal. The probe 410 may be moved within the esophagus 240 to position the emitter unit 426, which includes the ultrasound transducers 428 and 430, behind the heart 222 and desirably in proximity with the mitral annulus. The positioning may be guided by imaging, such as TEE, provided by the system 414.

[0086] In one embodiment, the imaging system 414 and the generator 412 may be adapted to control actuation of the imaging transducers 428 of the probe 410 to provide that the system 414 may generate and graphically display on a display screen (not shown) 2D image planes 460 of the mitral valve region and a virtual therapy beam 462 overlaid on the 2D image plane 460. The virtual beam 462 includes a focal point or region 464, and corresponds to the ultrasound energy beam expected to be generated, from ultrasound energy generated at the therapy ultrasound transducers 430, at the position of the probe 410 within the esophagus 240 currently shown in the 2D image plane 460.

[0087] Referring to FIG. 10, the 2D image plane 460 on the display may graphically show a portion of the esophagus 240 and a portion of the heart 222 including such structures as the inferior vena cava 224, the coronary sinus 220, the aorta 232, the pulmonary artery 242, the mitral annulus 226, the anterior papillary muscle 246, the posterior papillary muscle 248, the posterior cusp 250 of the mitral valve, the anterior cusp 252 of the mitral valve and chordae verdinae 254. In addition, the display may show the virtual therapy beam 462, and in particular, the position of the focal point 464 of the beam 462, in relation to the structures of the heart. By observing the images on the display while moving the probe 410, a user may determine a position of the probe 410 that may result in ultrasound energy generated from the probe 410, by the therapy transducers 430, being applied with precision only to the annulus 226 of the mitral valve 228, to heat and, as result, cause shrinkage of the mitral annulus 226. By moving the probe 410 within the esophagus 240, the focal point 464 of the therapeutic beam 462 may be moved successively around the posterior/lateral portion 230 of the mitral annulus 226, such that therapeutic ultrasound energy may be applied to selected portions of the mitral annulus by actuation of the transducers 430 at desired positions.

[0088] In one embodiment, the user, guided by 2D or 3D images on the display obtained from actuation of the imaging transducers 428, may adjust the position of the focal point 464 after each actuation of the therapy transducers 430, so that selected locations of the posterior/lateral portion 230 of the mitral annulus 226 are treated. The amount of ultrasound energy generated, and thus the amount of energy applied as a therapy dose to the portion of the mitral annulus positioned at the focal point, may be controlled and optimized based on a determination of the annulus thickness at the focal point, where the ultrasound transducers 426 are used to detect reflections of ultrasound energy signal emitted by the transducers 426, similarly as described above for the apparatus 100. Based on such application of ultrasound energy precisely at selected points on the posterior/lateral portion of the mitral annulus, the anterior portion of the annulus may not be subjected to deposition of energy, thereby avoiding risk of damage to the conduction system (AV node, bundle of His) in the heart.

[0089] In addition, 2D and 3D images obtained from TEE imaging using the ultrasound transducers of the probe 410 may be used by the user to monitor the degree of shrinkage of the mitral annulus at the focal region, during a treatment procedure, and the application of ultrasound energy by the transducers may be suitably controlled during the procedure in view of the observed shrinkage.

[0090] In a further embodiment, referring to FIG. 9, the probe 410 may have a single array of ultrasound transducers 432 mounted at the distal end 424. The imaging system 414 and generator unit 412 may be adapted such that the transducers 432 are actuated and used to perform both imaging and therapy. In one embodiment, some or all of the transducers 432 may be actuated to generate ultrasound energy for imaging and applying therapeutic doses of energy to the mitral annulus.

[0091] In one embodiment, the probe 410 having the single array of transducers 432, or having the imaging transducers 428 and the therapy transducers 430, may be operated in an alternating mode of imaging and therapy, to avoid cluttering the image with representations of high power therapeutic ultrasound energy bursts, and to provide substantially real time image guidance of the therapeutic ultrasound beam, which makes operation of the probe 410 easier and safer. [0092] In one embodiment, the system 414 and generator 412 may be adapted to automatically control transmission of a desired therapeutic dose of ultrasound energy to the focal point 464, which desirably is positioned at the location of the mitral annulus of the heart, thereby providing a safe, simple and reliable treatment of mitral valve insufficiency. The controlled transmission of therapeutic doses may be in accordance with a control signal generated by a software application included in the system 414.

[0093] The system 414 may automatically adjust the emitted dose of ultrasound energy by the ultrasound transducers, to compensate for expected attenuation of the therapy beam at varying focal depths in the heart at which the focal point 464 of the therapy beam may be positioned, as shown on a screen display .

[0094] In a further embodiment, the system 414 may control the actuation of the therapeutic ultrasound transducers 430, and the combined imaging/therapeutic transducer 432, to generate ultrasound energy at a power level and for a time interval that provides a therapeutic dosage within the focal point 464, which is positioned at the mitral annulus, to shrink collagen within the mitral annulus, without causing damage to the esophageal wall 241 through which the ultrasound beam 462 is transmitted. The amount of ultrasound energy generated may be determined with respect to research findings that shrinkage of collagen occurs at lower levels of applied energy than the levels of energy that cause tissue necrosis.

[0095] In one embodiment, the operating frequency of the ultrasound transducers of the probe 410 for imaging as well as therapy is about 5-10 MHz range, and preferably about 7.5 MHz.

[0096] In a further embodiment, the system 414 may be adapted to have an EKG functionality that may be used to monitor heart movement. When the probe 410 is in an operative position within the esophagus, the system 414 may control actuation of the transducers of the probe 410 to cause ultrasound energy to be emitted synchronized with heart movement, as monitored using the EKG functionality.

[0097] In another aspect of the invention, referring to

FIG. 11, an apparatus 500 for treating a valve insufficiency in a mammalian subject, such as a mitral valve insufficiency of the heart, completely non-invasively may include a gamma radiation system 502, commercially known as a "gamma knife," and a monitoring and imaging system 504 connected to the gamma knife 502.

[0098] The gamma knife 502 may be operated to accurately focus beams of gamma radiation onto a desired position. The gamma knife 502 desirably is adapted to provide imaging data to the imaging system 504 indicating the position at which the beams would be focused on a subject, during operation of the gamma knife 502 to direct radiation onto the subject.

[0099] The system 504 may be adapted to display images of a region to which radiation from the gamma knife 502 would be directed, based on imaging data provided by the gamma knife 502. In addition, the system 504 may include EKG functionalities to monitor heart movement of the subject, as described above. The system 504 and gamma knife 502 may be adapted to provide that the system 504 controls application of energy by the gamma knife 502 based on monitoring information, such as obtained from monitoring of heart movement using the EKG functionality of the system 504.

[0100] In operation of the apparatus 500, the gamma knife

502, which is completely external to a mammal to which gamma radiation from the knife 502 is to be applied, may be controlled by the system 504 to apply energy, synchronized with heart movement of the mammal, to the mitral annulus of the mammal's heart. In one embodiment, the gamma radiation generated by the gamma knife 502 may be accurately deposited within about 0.5 mm of a desired target location in the mitral annulus of the heart, thereby causing shrinkage of the mitral annulus .

[0101] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the appended claims .