WO2014022777A1

WO2014022777A1 - Method and apparatus for treatment of hypertension through an ultrasound imaging/therapy catheter

Info

Publication number: WO2014022777A1
Application number: PCT/US2013/053429
Authority: WO
Inventors: Reinhard Warnking
Original assignee: Sound Interventions, Inc.
Priority date: 2012-08-03
Filing date: 2013-08-02
Publication date: 2014-02-06

Abstract

Apparatus and methods for deactivating renal nerves extending along a renal artery of a mammalian subject to treat hypertension and related conditions. An ultrasonic transducer configuration (30) or micro wave antenna is inserted into the renal artery (10) or alternatively the ureter as, for example, by advancing the distal end of a catheter (18) bearing the transducer configuration into the renal artery. The ultrasonic transducer configuration emits therapeutic ultrasound so as to heat tissues throughout a impact volume which has been identified in a A mode, 2D image or color Doppler image to a temperature sufficient to inactivate nerve conduction but insufficient to cause rapid ablation or necrosis of the tissues. The 2D image control provides the user with an acute procedural endpoint.

Description

METHOD AND APPARATUS FOR TREATMENT OF HYPERTENSION THROUGH AN ULTRASOUND IMAGING/THERAPY CATHETER

BACKGROUND OF THE INVENTION

[0001] Successful treatment of hypertension is important since hypertension presents a significant, growing global health issue. Successful treatment of hypertension has significant clinical benefits in preventing or limiting conditions caused by chronic high blood pressure, such as heart disease, increased risk of stroke and renal disease. While drug therapy can be used to treat hypertension, efficacy is low due to various reasons. Some patients are resistant to drug therapy treatment or experience significant side effects from drug therapy treatment. There are also issues with non compliance with the prescribed drug therapy.

[0002 ] Recently developed by Ardian, Inc. Palo Alto, CA, hypertension can be treated by inactivating conduction of the renal nerves surrounding the renal artery. Sympathetic renal nerve activity plays an important role in the initiation and maintenance of hypertension. Clinical studies have confirmed the safety and efficacy of the percutaneous catheter based renal denervation procedure with a mono polar RF catheter.

[ 0003] Although revolutionary, this renal denervation procedure with RF has procedural and efficacy issues. Procedural issues include ablation time and catheter positioning. A high non responder rate of over 20% represents a limitation in efficacy.

[0004] This limitation might be caused by the irregular location of nerves and therewith incomplete ablation with a point by point RF ablation approach. Different individuals have the renal nerves in different locations around the renal artery. Thus, the renal nerves may be at different radial distances from the central axis of the renal artery, and also may be at different locations around the circumference of the renal artery. The location of nerves varies greatly along the axis of the renal artery. Within a few mm the number, size and location of renal nerves (4) can vary greatly as shown in Fig 1A and IB. US Patent No. 7,617,005 suggests the use of a radio frequency ("RF") emitter connected to a catheter, which is inserted in the renal artery. The RF emitter is placed against the intima and the RF energy is emitted to heat the renal nerves to a temperature that reduces the activity of renal nerves which happen to lie in the immediate vicinity of the emitter. In order to treat all the renal nerves surrounding the renal arteries, the RF emitter source must be repositioned around the inside of each renal artery multiple times. The emitter may miss some of the renal nerves, leading to an incomplete treatment.

[Ό005] The above mentioned procedural difficulties with a mono polar, single electrode RF approach have been addressed by arranging several RF electrodes in circumferential fashion on a balloon or basket type catheter. Bipolar or mono polar electrode arrangements are being utilized. However, while the procedural issues are being addressed complete denervation remains an issue even with these multi electrode devices. The heat generated with an RF electrode depends on the density of the electrical field between RF electrode and ground electrode or between bipolar electrode pairs. The highest density and therewith heat is generated in immediate vicinity of the electrode tissue contact area. In order to ablate deeper lying nerves heat needs to travel or be conducted to the nerve location. This mechanism makes it very challenging to avoid overheating the intima while ablating the deeper lying renal nerves. This problem can be overcome as described in Sound PCT/US2010/054637 through the use of unfocused ultrasound throughout a predetermined impact volume. In this case heat is generated throughout the impact volume wherever ultrasound interacts with tissue and the dose is chosen to ablate nerves but not tissue within this volume (dosimetry) . The heating mechanism of ultrasound is caused by mechanical vibration of tissue molecules. Since acoustic properties of body tissues (muscle, connective tissue, fat) are very similar a rather homogenous (compared to RF) heating effect can be achieved within a treatment volume. Of course ultrasound intensity will diminish with distance from the ultrasound transducer. In case of a cylindrical transducer configuration the intensity will decrease with 1/r, r being the distance from the transducer. In addition tissue will attenuate ultrasound intensity. The RF energy distribution or heating effect is much more difficult to control, since the intensity around a spherical electrode decreases according to 1/rr. In addition blood acts not only as a heat sink but also as an RF energy sink, since blood conducts electricity better than soft tissue. Another advantageous energy source in comparison to RF is microwave energy to create above described treatment or impact volumes. Heat is generated through friction resulting from alignment of water molecules and charged ions. Of course blood needs to be displaced for example by inflating a balloon around the antenna to avoid coagulation.

[ 0006] Only a homogenous, circumferential ablation or impact volume around the renal artery has the potential to ablate all or most of the nerves within this impact volume. Such treatment volume around the renal artery can be generated with ultrasound as described in PCT 2010, 054637. However, it is difficult to generate homogenous treatment volumes due to manufacturing challenges of cylindrical ultrasound transducers in particular cylindrical higher frequency transducers and difficulties to precisely center the transducer inside the renal artery and to coaxially align the transducer due to the tortuous nature of the renal artery. [0007] The renal nerve (bundles) (4) vary greatly in size from, less than 100 microns to 500 microns (sometimes to mm range) in diameter (see FIG 1A and IB) . The small dimensions (100 microns) are currently not resolved with typical medical imaging equipment like MRI, CT or extracorporeal ultrasound. Therefore a catheter based ultrasound transducer configuration is proposed to image and ablate renal nerve bundles. This transducer configuration can operate either as a therapeutic denervation- or a diagnostic imaging- device. To the user therapy and monitoring (i.e. imaging) will occur simultaneously by utilizing an interlaced mode of operation.

[0008] If one uses focused ultrasound as for example described in Ardian US Pat 7,617,005 and 7,653,438 the difficulty or impossibility arises to target the tiny renal nerves with current imaging methods like CT, MRI or conventional ultrasound imaging systems. Further these focused ultrasound treatment volumes are being proposed as symmetric circumferential volumes. Since the renal nerves are not arranged symmetrically at the same distance around the renal arteries the focused treatment volume will cause tissue damage in the surrounding tissue as well as nerve ablation. Nerve ablation is at best partial but in any case coincidental.

[0009] If one uses unfocused ultrasound to treat an impact volume which likely contains the renal nerves (as described in Sound PCT 2010,054637) dosimetry is of utmost importance to select an energy level just sufficient to ablate nerves but to spare tissue. This requires highly uniform ultrasound fields. Given the current state of the art in transducer manufacturing this is very difficult and expensive to achieve with cylindrical transducers as described in Sound ITV PCT 2010, 054637

[0010] In addition to the need for a homogeneous ultrasound impact volume, alignment of the ultrasound source within the renal artery is of outmost importance in order to achieve a homogenous treatment volume and therewith complete denervation within this treatment volume (see FIG 2). Since in blood or cooling fluid the ultrasound energy decreases with 1/r, r being the distance from the transducer axis, a homogenous treatment volume (1A) can be achieved only by aligning the transducer axis with the vessel axis (see 1A in FIG 2). This way a high energy decrease occurs over the first mm' s of cooling fluid or blood while the energy decay is less pronounced within the treatment volume beyond the first few mm' s . In other words the more linear portion of the 1/r function can be utilized to form the treatment volume, while the initial steep decay of 1/r is positioned within the blood vessel. Since ultrasound is non thrombogenic the high energy levels close to the transducer are not causing blood clots or have any other negative effect. IB shows a very uneven treatment volume due to miss alignment.

[0011] Therefore a need exists for successful renal denervation with ultrasound to generate more homogenous ultrasound fields which can be . much better controlled and targeted as described in the prior art. What is needed are transducer configurations which can modify the geometry of the ultrasound impact volume based on anatomical-dimensions or -variability between individuals or location of certain structures prone to injury without making the transducer manufacturing process impossible or extremely expensive. Also what is needed is a transducer configuration which can be used therapeutically to denervate and diagnostically to image. This allows the user to target nerves (at least larger nerve bundles) or groups of nerves and adjust the treatment volume accordingly. Also, surrounding vital structures can be visualized and the treatment volume adjusted to avoid damage. Lastly, imaging allows the user to determine an acute endpoint to the procedure since larger nerve bundles and surrounding tissue will change their echo structure when ablated.

BRIEF SUMMARY OF THE INVENTION

[0012 ] One aspect of the invention provides an apparatus for inactivating renal nerve conduction in a human or non- human mammalian subject. The apparatus according to this aspect of the invention preferably includes an ultrasound transducer configuration adapted for insertion into a renal artery or the ureter of the mammalian subject. The ultrasound transducer configuration desirably is arranged to transmit unfocused, softly focused or focused ultrasound energy. The apparatus according to this aspect of the invention desirably also includes an actuator electrically connected to the transducer configuration which can excite the ultrasound transducer configuration in different ways to create unfocused, softly focused or focused therapeutic ultrasound fields and operate the transducer configuration in diagnostic imaging(2D) modes, Doppler modes, and diagnostic amplitude (A) modes. The catheter may have an expansible element such as a balloon, wire basket or the like mounted adjacent the distal end. For example, the transducer configuration may be controlled by the actuator to transmit the ultrasound energy in a 360° cylindrical pattern surrounding a transducer axis. If it has been determined through an A mode measurement through the transducer configuration that the catheter axis is offset from the vessel axis the 360 degree ultrasound field power can be modulated angularly to compensate for this offset and virtually center the catheter inside the vessel. This is shown in FIG 7A where the off axis position of the transducer is being compensated by increasing or decreasing the acoustic intensity as symbolized by the line density in the drawing. This virtual acoustic centering of the catheter is of utmost importance to avoid vessel wall injuries and to obtain a homogenous treatment volume and therewith complete denervation.

[0013] A further aspect of the invention provides methods for ablating renal nerves in a mammalian subject. A method according to this aspect of the invention desirably includes the steps of inserting an ultrasound transducer configuration into a renal artery or the ureter of the subject and actuating the transducer configuration to transmit therapeutically effective ultrasound energy. This energy can be applied in a cylindrical volume (impact volume) with a radius of about 5 to 15 mm encompassing the renal artery. The ultrasound energy desirably is dosed based on a diagnostic imaging and an A mode run, so that the therapeutically effective ultrasound energy is centered and selected to inactivate conduction of all the renal nerves in the impact volume while sparing the tissue in particular the vessel wall. For example, the step of actuating the transducer configuration may be so as to maintain the temperature of the renal artery wall below 65°C while heating the solid tissues within the impact volume, including the renal nerves in the impact volume, to above 50°C. Energy levels will be chosen based on the vessel diameter measured in A mode and nerve location of larger nerve bundles which can be resolved (distance from the transducer configuration) based on 2 D imaging.

[0014] Because the impact volume is relatively large, and because the tissues throughout the impact volume reaches temperatures sufficient to ablate nerves but not high enough to necrose tissue the preferred methods according to this aspect of the invention can be performed successfully without determining the actual location of individual renal nerves. The treatment can be performed by determining the average distance of larger visible nerve bundles from the catheter axis without measuring the temperature of tissues. Moreover, the treatment preferably is performed without causing stenosis of the renal artery, intimal hyperplasia, or other injuries that would require intervention. The preferred methods and apparatus can inactivate relatively long (several mm) segments of the renal nerves, so as to reduce the possibility of nerve recovery which would re-establish conduction along the inactivated segments.

[ 0015] Instead of a circumferential impact volume a treatment sector can be generated and based on the 2 D image aligned with nerve locations without targeting individual nerve fibers. Energy levels will depend on vessel diameter and catheter position within the vessel and distance of larger nerve bundles targeted from the catheter axis. The advantage of this approach is that the overall dose can be minimized in particular if the nerves are concentrated in a few locations around the renal artery as it often occurs.

[ 0016] At least larger nerve bundles can be imaged through the transducer configuration and therewith provide the operator with a real time nerve ablation feedback and therewith a procedural endpoint. In case larger nerves cannot be identified changes in tissue brightness will provide the acute endpoint. Ablated tissue and nerves are more echogenic than normal tissue and nerves. Based on extensive animal work it is safe to assume that when larger nerves are ablated tiny nerves within the same treatment volume are ablated as well.

[ 0017 ] Further aspects of the invention provide probes which can be used in the method and apparatus discussed above, and apparatus incorporating means for performing the steps of the methods discussed above.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A and IB show two cross sections of the renal artery with surrounding nerves just a few mm apart demonstrating the irregular location and distribution of renal nerves.

FIG. 2 demonstrates the impact centering and coaxial alignment has on generating a homogenous treatment volume. FIG. 3 is an anatomical view of a typical renal artery, kidney, aorta and the iliac arteries with a sheath inserted to position the distal end of the treatment catheter inside the renal artery.

FIG. 4 is an anatomical view of the renal artery, kidney, aorta and iliac arteries with a treatment catheter positioned inside the ureter.

FIG. 5 is a three dimensional drawing showing a transducer configuration with non circular cooling balloon at the distal catheter end.

FIG. 6A shows a cross section of the apparatus shown in FIG. 5 and comparing it with a cross section of a transducer configuration of the prior art shown in FIG 6 B.

FIG. 7 A is a cross sectional view depicting a cross sectional portion of the apparatus of FIG. 5 inside a renal artery demonstrating the virtual acoustic centering of the catheter. FIG 7 B shows the selective targeting of nerve clusters

FIG. 8 shows typical examples of imperfect intensity distributions of a cylindrical ultrasound transducer of the prior art.

FIG. 9 is a diagrammatic view of another transducer configuration .

FIG. 10 shows a power modulation scheme to keep the temperature constant in the treatment volume.

FIG. 11 is a functional block diagram showing the major components of the ultrasound system or actuator

FIG. 12 is a flow chart depicting the steps used in a method according to one embodiment of the present invention.

FIG 13A and B show pre and post ultrasound images of the renal artery cross section treated for renal denervation. The echogenic difference between pre and post treatment is clearly visible . [ 0018] DETAILED DESCRIPTION

[0019] Apparatus according to one embodiment of the invention (FIG. 3) includes a sheath 12. The sheath 12 may be a steerable sheath. Thus, the sheath may include known elements such as one or more pull wires (not shown) extending between the proximal and distal ends of the sheath and connected to a steering control (not shown) arranged so that actuation of the steering control by the operator flexes the distal end 16 of the sheath in a direction transverse to the axis .

[0020 ] The apparatus also includes a catheter 18 having a proximal end 20, a distal end 22 and a proximal-to-distal axis which, in the condition depicted in FIG. 3 is coincident with the proximal-to-distal axis of the sheath.

[0021] Catheter 18 has a balloon 24 mounted at the distal end 22. Water is circulated in the balloon in order to cool the ultrasound transducer configuration. In its inflated condition (FIG. 5), balloon 24 has a partially non-circular profile in which one part 82 of the balloon is smaller in diameter than the renal artery, whereas another part 80 of the balloon 24 is noncircular in shape. The noncircular part has a major diameter D_MAJ equal to or just slightly less than the internal diameter of the renal artery, and has a minor diameter D_MIN smaller than the major diameter.

[0022 ] An ultrasound transducer configuration 30 (FIG. 5) is mounted adjacent the distal end 22 of catheter 18 within balloon 24. Transducer configuration 30 consists of a phased array structure formed into a cylindrical shape around its short axis or elevation. The process of forming such cylindrical linear or phased arrays is well known and described in prior art see Eberle US 6,049,958. The plated transducer material typically PZT is bonded to a metalized polyimide layer. The bonding material (for example die attach film) as well as the polyimide are chosen so, that they act as 1^st and 2^nd acoustic matching layers so that Z 1 = SR (Z PZT x Z Poly) . The individual transducer elements are mechanically and electrically separated through a dicing operation as well known in transducer manufacturing. Now the linear array is being only held together by the outer matching layer and it can be rolled into the desired cylindrical shape. The inside of the cylindrical array (or a portion thereof) is then filled with backing material to optimize the imaging performance of the array. One advantage of the described process is a acoustically very homogeneous array since the elements are diced out of a flat ceramic material. Such flat PZT structures can be very well controlled as far thickness, poling and material consistency are concerned. In comparison it is very difficult and expensive to control wall thickness of a cylindrical tube transducer in particular of a higher frequency transducer. A 10 MHz transducer would require a wall thickness of only about 75 microns. Therefore the cylindrical linear or phased array structure as described above will have superior acoustic homogeneity compared to cylindrical tube transducers as utilized in the prior art, see Sound

ProRhythm.... , Diederich.... or Lesh Fig. 8 shows a typical intensity distribution of a cylindrical tube transducer. It is easily appreciated that circumferentially as well longitudinally the intensity fluctuates significantly due to manufacturing tolerances mainly dimensionally . These intensity fluctuations can result in inconsistent efficacy of the denervation procedure and or injury to vital structures due to intensity hotspots. The transducer configuration 30 typically has an axial length of approximately 2-10 mm, and preferably 6 mm. The outer diameter of the transducer configuration 30 is approximately 2-4 mm in diameter. The linear elements of transducer configuration 30 also have conductive coatings (not shown) on its interior and exterior surfaces. The coatings are electrically connected to ground and signal wires. The wires extend from the transducer 30 through a lumen between the proximal end and the distal end of the catheter 18 and terminate in a connector 32 shown in Fig.3.

[0023] Transducer configuration 30 is arranged so that ultrasonic energy generated in the transducer is emitted principally from the exterior emitting surface. Thus, the transducer may include features arranged to reflect or absorb ultrasonic energy directed toward the interior of the transducer. In case of reflection, reflected energy reinforces the ultrasonic vibrations at the exterior surface. Reflection can be achieved as well known in the art by air backing or a metal reflector coupled by fluid.

[0024] Transducer configuration 30 is also arranged to convert ultrasonic waves impinging on the exterior surface into electrical signals on wires and connector 32. Stated another way, transducer 30 can act either as an ultrasonic emitter or an ultrasonic receiver.

[0025] The thickness of the transducer configuration 30 is designed to operate, for example, at a freguency of approximately 1 MHz to approximately a few tens of MHz, and typically at approximately 10 to 15 MHz. Typically the transducer thickness is chosen to be lambda/2 of the operating freguency. The attenuation of ultrasound in tissue is an exponential function of the path length and freguency. At 10 MHz in connective tissue the ultrasound intensity decreases due to attenuation and geometry by approximately 1/rr. This limits the treatment volume to a cylinder with a radius of about 5 to 15 mm which is appropriate given the nerve location in and on the renal artery adventitia. At frequencies of 10 to 15 MHz the steep intensity decrease protects neighboring structures like the ureter and bowl from collateral damage. Cylindrical transducers of the prior art as described in Sound , ProRhythm.... , Diederich and Lesh are very difficult to produce at higher freguencies since the wall thickness of the cylindrical transducer needs to be thinner than 75 microns for frequencies greater than 10 MHz. These dimensions are very difficult to control and lead to transducer non uniformities and therewith to inhomogeneous ultrasound fields as shown in FIG 8.

[ 0026] As shown in Fig. 6 A element spacing is chosen to be approximately or less than lamda/2 in order to allow for beam- forming or phased array effects (lamda/2 is about 75 micron for 10 MHz) . A 8 F catheter would allow for 96 elements at a pitch of 88 microns which is very feasible from a manufacturing standpoint, given that electronic IVUS catheters (as manufactured by Volcano) require a pitch of about 50 microns. These dimensions are different from the spacing chosen in US 2011/0257562 or US 2012/0095372 which will not allow for beam-forming or phased array effects as shown in Fig.6 B. As can be appreciated from Fig. 6 B and described for example by Matthew O'Donnell et al, Synthetic Phased Arrays for Intraluminal Imaging of Coronary Arteries, IEEE Transactions on Ultrasonics, May 1997; element sizes significantly above lamda/2 create independent ultrasound beams which do not allow for phased array beam-forming. An array as shown in FIG. 6 B cannot be utilized for imaging and therapeutic targeting of larger nerve bundles or beam steering to avoid collateral damage of neighboring vital structures as for example bowl tissue or tissue imaging to obtain an acute procedural endpoint.

[0027 ] An ultrasound system 20, also referred to herein as an actuator, is releasably connected to catheter 18 and transducer 30 through a plug connector 32 (FIG. 3) . The multitude of transducer elements of transducer configuration 30 is preferably connected through flex circuit strip lines to the connector pins of connector 32. An alternative method is to employ multiplexer IC' s at the distal assembly and connect a reduced number of wires to the ultrasound system (i.e. in the case of a 96 element transducer configuration only 12 wires need to be run to the system when a 8 to 1 multiplexer is utilized) . As seen in FIG. 11, ultrasound system 20 may include a user interface 40, a control module 42 incorporating a programmable control device such as a programmable microprocessor (not shown) , an ultrasound excitation source 44, a beam-former 43 and a water circulation device 48. The user interface 40 interacts trough the control module 42 with the beam-former 43, which interacts with the excitation source 44 to cause transmission of electrical signals at the optimum actuation seguence to the transducer 30 via connector 32. The beam-former 43 and ultrasound source 44 are arranged to control the amplitude and timing of the electrical signals so as to control the power level and geometry of the ultrasound fields emitted by transducer configuration 30. Excitation source 44 is also arranged to detect electrical signals generated by transducer 30 and appearing on connector 32 and communicate such signals to an image display.

[0028 ] The circulation device 48 is connected to lumens (not shown) within catheter 18 which in turn are connected to balloon 24. The circulation device is arranged to circulate a liguid, preferably an agueous liguid, through the catheter 18 to the transducer 30 in the balloon 24. The circulation device 48 may include elements such as a tank for holding the circulating coolant 35, pumps 37, a ref igerating coil (not shown) , or the like for providing a supply of liguid to the interior space of the balloon 24 at a controlled temperature, desirably at or below body temperature. The control module 42 interfaces with the circulation device 48 to control the flow of fluid into and out of the balloon 24.

[0029] The ultrasound system 20 incorporates a reader 46 for reading a machine-readable element on catheter 18 and conveying the information from such element to control module 42. As discussed above, the machine-readable element on the catheter may include information such as the operating frequency; array spacing etc of the transducer configuration 30 in a particular catheter 18, and the control board 42 may use this information to set the appropriate frequency and beamforming for exciting the transducer.

[ 0030 ] A method according to an embodiment of the present invention is depicted in flow chart form in FIG. 12. After preparing a human or non-human mammalian subject such as a patient (step 50) , preparation of an arterial access site such as a location on the femoral artery (step 52), and connecting the catheter 18 to the ultrasound system 20 (step 54),. the ultrasound transducer configuration 30 in inserted into the renal artery under angiographic visualization (step 56) by inserting the distal end of the sheath 12 through the access site into the aorta. While the distal end of the sheath is positioned within the aorta, the catheter 18 is advanced under angiographic guidance within the sheath until the distal end of the catheter projects from the sheath as schematically depicted in FIG. 3. The balloon 24 on the catheter desirably is maintained in a deflated condition until the distal end of the catheter is disposed at a desired location within the renal artery. During insertion of the catheter 18 and the transducer 30 (step 56) , the physician may verify the placement of the transducer 30 to be within the renal artery 10, although before the kidney 6 or any branches of the renal artery 10 that may exist. Such verification can be obtained using x-ray techniques such as fluoroscopy.

[ 0031] Once the distal end of the catheter is in position within a renal artery, pumps 37 bring balloon 24 to an inflated condition as depicted in FIG. 5. In this condition, the non-circular portion 80 of the balloon engages the artery wall, and thus centers transducer 30 within the renal artery, with the axis 33 of the transducer approximately coaxial with the axis A of the renal artery. However, the balloon does not block blood flow through the renal artery. In this condition, the circulation device 48 maintains a flow of cooled aqueous liquid into and out of balloon 24, so as to cool the transducer 30. The cooled balloon also tends to cool the interior surface of the renal artery. Moreover, the continued flow of blood through the renal artery helps to cool the interior surface of the renal artery. The liquid flowing within the balloon may include a radiographic contrast agent to aid in visualization of the balloon and verification of proper placement.

[0032 ] In the next step 58, the ultrasound system 20 uses transducer configuration 30 to measure the size of the renal artery 10 and catheter position within the renal artery. Control module 42 and ultrasound source 44 actuate the transducer configuration 30 to image the renal artery 10 with low-power ultrasound pulses. The ultrasonic waves in this pulse are reflected by the artery wall onto transducer configuration 30 as echoes. This of course can be accomplished only with an array type Tx not with a cylindrical Tx as proposed by Sound...., Prorhythm, Diederich and Lesh , since a cylindrical Tx lacks spatial resolution. Transducer configuration 30 converts the echoes to echo signals on wires terminated in connector 32. The ultrasound system 20 then determines the size of the renal artery and catheter position within the artery 10 by analyzing the echo signals. For example, the ultrasound system 20 may determine the time delay between transmit actuation of the transducer to the return of echo signals. Alternatively, the received echos are displayed in 2 dimensional format and the user carries out the measurements on the screen in the 2 D image. In step 60, the ultrasound system 20 uses the measured artery size and the position of the catheter within the artery to acoustically center the catheter in the artery by varying the power circumferentially . Generally, the larger the artery diameter, the more power should be used. Variations in the shape of the renal artery 10, or in the centering of the transducer configuration 30, may cause a range of time delays in the echo signals and is compensated for with varying power levels for each transducer beam or angle.

[0033] The physician then visualizes surrounding structures and adjusts the treatment volume or the catheter position to avoid injury to vital structures like bowl or ureter (step 61) . The physician then initiates the treatment (step 62 and 64) . While the therapeutically effective dose is being applied the physician monitors the ablation effect on larger nerve bundles or surrounding tissue to determine the acute procedural endpoint (step 65) . In section B of the FIG 12 an optional second ablation is described before the opposite artery is treated.

[0034] As discussed above, the length of the transducer configuration 30 may vary between 2mm and 10mm, but is preferably 6mm to provide a wide inactivation zone of the renal nerves. In order to optimize the 2D image the transducer length can be subdivided to allow for electronic elevation focusing in order to optimize the beam elevation width for nerve visualization. In another embodiment a relatively small section (i.e. 2mm) of the axial length is utilized (and optimized; i.e. backing) for imaging while the longer length is utilized for therapeutic operation. The diameter of the transducer 30 may vary between 2 mm to 4.0mm, and is preferably 2.7mm. The dosage is selected not only for its therapeutic effect, but also to allow the radius of the impact volume to be between preferably 5mm to 15 mm in order to encompass the renal artery 10, and adjacent renal nerves, all of which lie within or on the adventitia, without transmitting damaging ultrasound energy to structures beyond the renal artery 10.

[0035] The power level desirably is selected so that throughout the impact volume, solid tissues are heated to about 50°C or more for several seconds or more, but desirably all of the solid tissues, including the intima of the renal artery remain well below 65°C. Thus, throughout the impact region, the solid tissues (including all of the renal nerves) are brought to a temperature sufficient to inactivate nerve conduction but below that which causes rapid necrosis of the tissues .

[0036] Research shows that nerve damage occurs at much lower temperatures and much faster than tissue necrosis. See Bunch, Jared. T. et al. "Mechanisms of Phrenic Nerve Injury During Radiofrequency Ablation at the Pulmonary Vein Orifice, Journal of Cardiovascular Electrophysiology, Volume 16, Issue 12, pg. 1318-1325 (Dec. 8, 2005), incorporated by reference herein. Since, necrosis of tissue typically occurs at temperatures of 65°C or higher for approximately 10 sec or longer while inactivation of the renal nerves 8 typically occurs when the renal nerves 8 are at temperatures of 42 °C or higher for several seconds or longer, the dosage of the ultrasound energy is chosen to keep the temperature in the impact volume 11 between those temperatures for several seconds or longer. The dosage of ultrasonic energy desirably is also less than that required to cause substantial shrinkage of collagen in the impact volume. Operation of the transducer thus provides a therapeutic dosage, which inactivates the renal nerves 8 without causing damage to the renal artery 10, such as, stenosis, intimal hyperplasia, intimal necrosis, or other injuries that would require intervention. The continued flow of blood across the inside wall of the renal artery 10 ensures the intimal layer 1 (FIGs. 1A and IB) of the renal artery is cooled. This allows the ultrasound energy transmitted at the therapeutic dosage to be dissipated and converted to heat principally at the outer layers (media 2 and adventitia 3) of the renal artery and not at the intimal layer 1. In addition, the circulation of cooled liquid through the balloon 24 containing the transducer configuration 30 will prevent heat being transferred from the transducer configuration 30 to the intimal layer 1 and to the blood flowing past the transducer. Hence, the transmitted therapeutic unfocused ultrasound energy does not damage the intima and does not provoke thrombus formation, providing a safer treatment compared to RF treatments.

[0037] The placement of the unfocused cylindrical impact volume or volumes in case of treatment sectors or focused beams is done under 2 D imaging guidance from transducer configuration 30 to avoid heat damage to vital structures. Optionally, the physician may then reposition the catheter 18 and transducer 30 along the renal artery (step 66) and reinitiate the treatment 68 to retransmit therapeutically effective unfocused ultrasound energy (step 70) . This inactivates the renal nerves at an additional location along the length of the renal artery, and thus provides a safer and more reliable treatment. The repositioning and retransmission steps optionally can be performed multiple times. Next the physician moves the catheter 18 with the transducer 30 to the other renal artery and performs the entire treatment again for that artery, (step 72). After completion of the treatment, the catheter 18 is withdrawn from the subject's body (step 74) .

[0038 ] Numerous variations and combinations of the features discussed above can be utilized. For example, the ultrasound system 20 may control the transducer configuration 30 to transmit ultrasound energy in a pulsed function interleaved with imaging pulses to give the user a simultaneous operation of imaging and therapy. During the therapeutic application of ultrasonic energy an additional pulsed function causes the ultrasound transducer configuration 30 to emit the ultrasound energy at initially a long duty cycle until certain temperatures are reached and the duty cycle is reduced accordingly as shown in FIG 10. Pulse modulation of the ultrasound energy is helpful in limiting the tissue temperature while increasing treatment times see example in FIG. 10.

[0039] Another variation may be that an ultrasound energy emitter and imaging unit at the distal end of the catheter 18, may be positioned in the ureter as shown in FIG.4, and the ultrasound transducer configuration may include directional, reflective or blocking structures or phased array steering for selectively directing ultrasound energy from the transducer over only a limited range of radial directions to provide that ultrasound energy desirably is selectively directed from the transducer configuration in the ureter toward the renal artery 10. When the ureter approach is utilized, the ultrasound energy is directed into a segment or beam propagating away from an exterior surface of the transducer 30, commonly known as a side firing transducer arrangement. For example, the ultrasound transducer may have a construction and be operated to emit directed ultrasound energy similarly as disclosed in US Provisional Application No. 61/256002, filed October 29, 2009, entitled "METHOD AND APPARATUS FOR PERCUTANEOUS TREATMENT OF MITRAL VALVE REGURGITATION (PMVR)," incorporated by reference herein. In this variation, the route by which the catheter 18 is introduced into the body, and then positioned close to the kidneys 6, is varied from the atrial approach discussed above. A ureter approach may be utilized to take advantage of the potential for elimination of closure issues after catheter withdrawal. A central lumen with open proximal and distal ends can be utilized to pass an angioscope for visualization and guidance of catheter insertion through the catheter. This lumen or an additional lumen serves also as a channel for cooling fluid irrigation once the catheter is in position. The cooling fluid can simply be irrigated since the ureter /will drain the fluid into the bladder of the patient. Active cooling is critical for denervation from the ureter in order to avoid injury to the ureter wall.

[ 0040 ] 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 .

Claims

Claims :

1. Apparatus for inactivating renal nerve conduction in a mammalian subject comprising:

an ultrasound transducer configuration adapted for insertion into a renal artery of the mammalian subject and for transmitting ultrasound energy; and

an actuator electrically connected to the transducer configuration, the actuator being adapted to control the ultrasound transducer to transmit ultrasound energy into an impact volume at a therapeutic level sufficient to inactivate conduction of renal nerves throughout the impact volume.

2. The apparatus of claim 1, wherein the actuator controls the transducer configuration to transmit unfocused ultrasound energy in circumferential fashion at an acoustic power level of approximately 10 to approximately 30 watts for approximately 10 to approximately 30 seconds to provide an absorbed dose of approximately 100 to approximately 900 joules in the circumferential impact volume without geometrically targeting individual nerves or nerve bundles.

3. The apparatus of claim 1 wherein the actuator controls the transducer configuration to transmit ultrasound energy in an angular segment to target nerve clusters or to avoid vital neighboring structures.

4. The apparatus of claim 1 wherein the actuator controls the transducer configuration to transmit energy in one or several angularly sharply focused beam(s) to target individual nerve bundles

5. The apparatus of claim 1, wherein the actuator is adapted to control the transducer configuration so as to maintain the temperature of the renal artery wall below 65 °C while achieving a temperature above 50 °C throughout the impact volume.

6. The apparatus of claim 1, where the transducer configuration is a phased array arranged in circumferential fashion around the catheter axis.

7. The apparatus of claim 6, where the transducer configuration is separated axially into a lightly backed therapeutic ring optimized for energy efficiency and a heavy backed diagnostic ring to optimize for imaging performance .

8. The apparatus of claim 1, where the transducer configuration is a rotatable flat rectangular transducer with a long axis aligned with the catheter axis.

9. The apparatus of claim 1, wherein the actuator is adapted to operate the transducer configuration in A mode to determine vessel dimensions and catheter position within the vessel and to acoustically center the catheter by varying the power based on catheter vessel wall distance angularly.

10. The apparatus of claim 1, wherein the actuator is adapted to operate the transducer configuration in 2 dimensional imaging (B) mode to visualize the renal artery and surrounding structures to avoid collateral damage .

11. The apparatus of claim 10, wherein the 2 dimensional image provides the user with an acute procedural endpoint based on changes of echogenic tissue reflectivity.

12. The apparatus of claim 10, wherein the 2 dimensional image provides the user with an acute procedural endpoint based on changes of the echogenic reflectivity of larger nerve bundles.

13. The apparatus of claim 10, wherein the 2 dimensional image and the therapeutic treatment volume are generated through interlaced pulse series, giving the user a simultaneous mode of diagnostic/therapeutic operation .

14. The apparatus of claim 1, wherein the actuator is adapted to operate the transducer configuration in color Doppler imaging mode to visualize the renal artery, surrounding structures and blood flow.

15. The apparatus of claim 1, wherein the actuator is adapted to control the ultrasound transducer configuration to transmit the ultrasound energy in a pulsed function after reaching a target temperature and to maintain that target temperature.

16. The apparatus of claim 1, wherein the ultrasound transducer configuration is adapted to transmit the ultrasound energy in a pattern having a length of at least approximately 2 mm along the axis of the renal artery.

17. The apparatus of claim 1, wherein the transducer configuration is adapted to apply the ultrasonic energy at the therapeutic level throughout an impact volume having a length of at least approximately 2 mm along the axis of the of the renal artery.

18. The apparatus of claim 1, further comprising a catheter with a distal end and a proximal end, the transducer configuration being mounted to the catheter adjacent the distal end, the catheter and transducer being constructed and arranged to allow a substantial flow of blood through the renal artery while the ultrasound transducer is positioned within the renal artery.

19. The apparatus of claim 7, wherein the catheter is constructed and arranged to hold the transducer configuration out of contact with the wall of the renal artery.

20. The apparatus of claim 8, wherein the ultrasound system is adapted to control the ultrasound transducer configuration to vary the acoustic power used to transmit the therapeutically effective unfocused ultrasound energy depending on the determined size of the renal artery.

21. A method for inactivating renal nerve conduction in a mammalian subject comprising the steps

Of:

inserting an ultrasound transducer configuration into a ureter of the mammalian subject; and actuating the transducer to transmit therapeutically effective ultrasound energy into an impact volume of at least approximately 0.5 cm³, encompassing the renal artery so that the therapeutically effective unfocused ultrasound energy inactivates conduction of all the renal nerves in the impact volume.

22. The method of claimi^?- 21, wherein the ultrasound energy is transmitted at an acoustic power level of approximately 10 to approximately 30 watts for approximately 10 to approximately 30 seconds to provide an absorbed dose of approximately 100 to approximately 900 joules throughout the impact volume.

23. The method of claim 21, wherein the step of transmitting ultrasound energy is performed so as to maintain the temperature of the ureter wall below 65 °C while heating the renal nerves in the impact region to above 50 °C.

24. The method of claim 21, wherein the steps of inserting the ultrasound transducer configuration into the ureter and actuating the transducer to transmit ultrasound energy are performed without determining the actual locations of renal nerves but placing the impact volume around the renal artery visualized in color Doppler imaging mode.

25. The method of claim 21, wherein the step of actuating the transducer configuration is performed so that a single application of the ultrasound energy in each ureter is effective to inactivate conduction of all the renal nerves surrounding that renal artery.

26. The method of claim 21, further comprising the steps of: repositioning the ultrasound transducer configuration in the ureter after the step of actuating the transducer; and then

repeating the step of actuating the transducer configuration .

27. The method of claim 21, wherein the step of actuating the transducer configuration is performed so that the ultrasound energy is transmitted in a pulsed function to maintain a certain target temperature.

28. The method of claim 21, wherein the step of inserting the ultrasound transducer configuration into the ureter is performed so that the transducer does not contact the wall of the ureter .

29. Apparatus for inactivating renal nerve conduction in a mammalian subject comprising:

means for positioning an micro wave antenna in a renal artery of the mammalian subject; and

means for actuating the antenna to transmit therapeutically effective unfocused micro wave energy into an impact volume of at least approximately 0.5 cm³, encompassing the renal artery so that the therapeutically effective unfocused micro wave energy inactivates conduction of all the renal nerves in the impact volume.

30. The apparatus of claim 6 where the transducer configuration is formed from a diced, flat PZT material with superior uniformity compared to cylindrical

transducers .