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 ( 30 ) is inserted into the renal artery ( 10 ) as, for example, by advancing the distal end of a catheter ( 18 ) bearing the transducer into the renal artery. The ultrasonic transducer emits unfocused ultrasound so as to heat tissues throughout a relatively large impact volume ( 11 ) as, for example, at least about 0.5 cm3 encompassing the renal artery to a temperature sufficient to inactivate nerve conduction but insufficient to cause rapid ablation or necrosis of the tissues. The treatment can be performed without locating or focusing on individual renal nerves.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims the benefit of the filing date of U.S. Provisional Patent Application Nos. 61/256,429, filed on Oct. 30, 2009, and 61/292,618, filed on Jan. 6, 2010, the disclosures of which are hereby incorporated herein by reference. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    Successful treatment of hypertension is important for many reasons. For example, successful treatment of hypertension has significant clinical benefits in preventing or limiting conditions caused by or exacerbated by hypertension, such as renal disease, arrhythmias, and congestive heart failure, to name a few. While drug therapy can be used to treat hypertension, it is not always successful. Some people are resistant to drug therapy treatment or experience significant side effects from drug therapy treatment. 
         [0003]    Hypertension can be treated by inactivating conduction of the renal nerves surrounding the renal artery. Sympathetic renal nerve activity plays a significant role in the initiation and maintenance of hypertension. When the brain perceives increased renal nerve activity, signaling low blood volume or a drop in blood pressure, it compensates by increasing sympathetic nerve activity to the heart, the liver, and the kidneys, which results in increased cardiac output; insulin resistance; and most importantly, increased renin production by the kidneys. Renin stimulates the production of angiotension, which causes blood vessels to constrict, resulting in increased blood pressure and stimulates the secretion of aldosterone. Aldosterone causes the kidneys to increase the reabsorption of sodium and water into the blood, increasing blood volume thereby further increasing blood pressure. 
         [0004]    It has been established for years that surgically cutting renal nerves results in a decrease in blood pressure and water retention to normal levels; thereby allowing the patients&#39; heart, liver, and kidneys to also return to healthier functioning. It has also been shown a disruption of the renal nerves has no serious ill effects. However, surgically cutting the renal nerves requires a major surgical procedure with risks of undesirable side effects. It would be desirable to produce the same result without major surgery. 
         [0005]    In order to explain the difficulties associated with accomplishing this task without causing other damage, the anatomy of the renal arteries and nerves will be described now. Shown in  FIG. 1  is an illustration of the renal nerves  8  that surround the renal artery  10 , which is connected to the kidney  6 . The sympathetic renal nerves  8  include both the afferent sensory renal nerves from the kidney  6  to the brain and the efferent sympathetic renal nerves from the brain to the kidney  6 . In addition,  FIG. 2  shows a cross-section of a renal artery  10 . The renal artery wall includes layers: the intima  3 , which includes an inner single layer of endothelial cells; the media  5 , which is in the center of the artery wall; and the adventitia  4 , which is the outside layer. Also shown are the renal nerves  8  that lie within the aventitia  4 , on the surface of the renal artery  10 , and adjacent to the renal artery  10 . As can be seen from these two figures, the renal nerves  8  surround the renal artery  10 . Different individuals have the renal nerves  8  in different locations around the renal artery. Thus, the renal nerves may be at different radial distances R from the central axis A of the renal artery, and also may be at different locations around the circumference C of the renal artery. It is not practical to locate the renal nerves by referring to anatomical landmarks. Moreover, it is difficult or impossible to locate individual renal nerves using common in vivo imaging technology. 
         [0006]    The inability to locate and target the renal nerves  8  makes it difficult to disconnect the sympathetic renal activity using non-surgical techniques without causing damage to the renal artery  10  or causing other side effects. For example, attempts to apply energy to the renal nerves can cause effects such as stenosis, intimal hyperplasia, and necrosis. Other side effects can include thrombosis, platelet aggregation, fibrin clots and vasoconstriction. In addition, the inability to target and locate the renal nerves  8  makes it difficult to ensure that sympathetic renal nerve activity has been discontinued enough to achieve an acceptable therapeutic treatment. 
         [0007]    U.S. Pat. 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. Moreover, the RF energy source must contact the intima to be able to heat the renal nerves, which may cause damage or necrosis to the single layer endothelium and the intima, potentially causing intimal hyperplasia, renal artery stenosis, and renal artery dissection. 
         [0008]    The &#39;005 Patent also suggests the use of high-intensity focused ultrasound to deactivate the renal nerves. The described high-intensity focused ultrasound energy source assertedly emits ultrasound energy in a 360° pattern around the axis of the renal artery, and does not need to contact the intima  3 . However, the high-intensity focused ultrasound source applies concentrated energy in a thin focal ring surrounding the artery. It is difficult or impossible to align this thin ring with the renal nerves because it is difficult or impossible to visualize and target the renal nerves with current technology, and because the renal nerves may lie at different radial distances from the central axis of the renal artery. The latter problem is aggravated in patients who have renal arteries with large variations in shape or thickness. Moreover, the thin focal ring can encompass only a small segment of each renal nerve along the lengthwise direction of the nerves and artery. Since nerves tend to re-grow, a small treatment zone allows the nerves to reconnect in a shorter period of time. 
         [0009]    For many years ultrasound has been used to enhance cell repair, stimulate the growth of bone cells, enhance delivery of drugs to specific tissues, and to image tissue within the body. In addition, high-intensity focused ultrasound has been used to heat and ablate tumors and tissue within the body. Ablation of tissue has been performed nearly exclusively by high-intensity focused ultrasound because the emitted ultrasound energy is focused on a specific location to allow precise in-depth tissue necrosis without affecting surrounding tissue and intervening structures that the ultrasound energy must pass through. 
         [0010]    U.S. Pat. No. 6,117,101, to Diederich, discusses use of highly collimated ultrasound energy rather than high intensity focused ultrasound for ablating tissue to create a scar ring within the pulmonary vein for blocking the conduction of electrical signals to the heart. 
         [0011]    US Patent Publication No. 20100179424 (application Ser. No. 12/684,067), the disclosure of which is incorporated by reference herein, uses unfocused ultrasound for the treatment of mitral valve regurgitation. In the &#39;474 Publication, unfocused ultrasound energy is used to heat and shrink the collagen associated with the mitral annulus. This apparatus uses an inflatable balloon in order to place the ultrasound transducer into the correct location, thereby targeting the mitral annulus. In this apparatus, a part of the balloon contacts the tissue to be heated. 
       BRIEF SUMMARY OF THE INVENTION 
       [0012]    One aspect of the invention provides 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 adapted for insertion into a renal artery of the mammalian subject. The ultrasound transducer desirably is arranged to transmit unfocused ultrasound energy. The apparatus according to this aspect of the invention desirably also includes an actuator electrically connected to the transducer. The actuator most preferably is adapted to control the ultrasound transducer to transmit unfocused ultrasound energy into an impact volume of at least approximately 0.5 cm 3 , encompassing the renal artery so that the unfocused ultrasound energy is applied at a therapeutic level sufficient to inactivate conduction of renal nerves throughout the impact volume. As discussed further below, such therapeutic level is below the level required for tissue ablation. 
         [0013]    The apparatus may further include a catheter with a distal end and a proximal end, the transducer 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. The catheter may be constructed and arranged to hold the transducer out of contact with the wall of the renal artery. 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 may be adapted to transmit the ultrasound energy in a 360° cylindrical pattern surrounding a transducer axis, and the catheter may be constructed and arranged to hold the axis of the transducer generally parallel to the axis of the renal artery. 
         [0014]    A further aspect of the invention provides methods for inactivating renal nerve conduction in a mammalian subject. A method according to this aspect of the invention desirably includes the steps of inserting an ultrasound transducer into a renal artery of the subject and actuating the transducer to transmit therapeutically effective unfocused ultrasound energy into an impact volume of at least approximately 0.5 cm 3  encompassing the renal artery. The ultrasound energy desirably is applied so that the therapeutically effective unfocused ultrasound energy inactivates conduction of all the renal nerves in the impact volume. For example, the step of actuating the transducer 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 42° C. 
         [0015]    Because the impact volume is relatively large, and because the tissues throughout the impact volume preferably reach temperatures sufficient to inactivate nerve conduction, the preferred methods according to this aspect of the invention can be performed successfully without determining the actual locations of the renal nerves, and without targeting or focusing on the renal nerves. The treatment can be performed 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 inactive relatively long segments of the renal nerves, so as to reduce the possibility of nerve recovery which would re-establish conduction along the inactivated segments. 
         [0016]    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 
         [0017]      FIG. 1  is an anatomical view of a typical renal artery and associated structure. 
           [0018]      FIG. 2  is a diagrammatic sectional view depicting a portion of a renal artery and nerves. 
           [0019]      FIG. 3  is a diagrammatic view depicting components of apparatus in accordance with one embodiment of the present invention. 
           [0020]      FIG. 4  is a fragmentary diagrammatic perspective view depicting a portion of the apparatus shown in  FIG. 3 . 
           [0021]      FIG. 5  is a diagrammatic view depicting a portion of the apparatus of  FIGS. 3 and 4  in conjunction with a renal artery. 
           [0022]      FIG. 6  is a functional, block diagrammatic view depicting portions of a component used in the apparatus of  FIGS. 3 and 4 . 
           [0023]      FIG. 7  is a flow chart depicting the steps used in a method according to one embodiment of the present invention. 
           [0024]      FIG. 8  is a diagrammatic view depicting portions of the apparatus of  FIGS. 3 and 4  during operation in accordance with the method of  FIG. 7 . 
       
    
    
     DETAILED DESCRIPTION 
       [0025]    Apparatus according to one embodiment of the invention ( FIG. 3 ) includes a sheath  12 . The sheath  12  generally may be in the form of an elongated tube having a proximal end  14 , a distal end  16  and a proximal-to-distal axis  15 . As used in this disclosure with reference to elongated elements for insertion into the body, the term “distal” refers to the end which is inserted into the body first, i.e., the leading end during advancement of the element into the body, whereas the term “proximal” refers to the opposite end. 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  17  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  15 . 
         [0026]    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  15  of the sheath. The proximal end  20  of the catheter desirably is relatively stiff such that it may transmit torque. Thus, by turning the proximal end  20  of the catheter  18 , distal end  22  of the catheter  18  can be rotated about the proximal-to-distal axis of the catheter  18 . 
         [0027]    The distal end  22  of the catheter  18  is preformed so that when the distal end of the catheter is outside of the sheath  12 , the distal end tends to assume a hooked configuration as indicated in broken lines at  22 ′ in  FIG. 3 . In this condition, rotational motion of the distal end  22 ′ will swing the curved section around the proximal-to-distal axis. Thus, by rotating the proximal end of the catheter  18 , the distal end  22 ′ of the catheter  18  can be positioned in any radial direction. 
         [0028]    Catheter  18  has a balloon  24  mounted at the distal end  22 . In its inflated condition ( FIG. 4 ), 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. 
         [0029]    An ultrasound transducer  30  ( FIGS. 3 and 5 ) is mounted adjacent the distal end  22  of catheter  18  within balloon  24 . Transducer  30 , which is desirably formed from a ceramic piezoelectric material, is of a tubular shape and has an exterior emitting surface  31  in the form of a cylindrical surface of revolution about the proximal-to-distal axis  33  of the transducer  30 . The transducer  30  typically has an axial length along axis  31  of approximately 2-10 mm, and preferably 6 mm. The outer diameter of the transducer  30  is approximately 1.5-3 mm in diameter, and preferably 2 mm. The physical structure of the transducer and its mounting to the catheter may be, for example, as described in U.S. Pat. Nos. 7,540,846 and 6,763,722, the disclosures of which are incorporated by reference herein. The transducer  30  also has conductive coatings (not shown) on its interior and exterior surfaces. Thus, the transducer may be physically mounted on a metallic support tube  84  ( FIG. 5 ), which in turn is mounted to the catheter. The coatings are electrically connected to ground and signal wires  32 . Wires  32  extend from the transducer  30  through a lumen  34 . The lumen  34  extends between the proximal end and the distal end of a catheter  18 , while the wires  32  extend from the transducer  30 , through the lumen  34 , to the proximal end of the 14 catheter  18 . 
         [0030]    Transducer  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 ultrasonic energy directed toward the interior of the transducer so that the reflected energy reinforces the ultrasonic vibrations at the exterior surface. For example, support tube  84  and transducer  30  may be configured so that the interior surface of the transducer  30  is spaced apart from the exterior surface of the support tube, which is formed from metal, by a gap (not shown). The distance across the gap, between the interior surface of the transducer and the exterior surface of the support tube may be one half the wavelength of the ultrasound energy emitted by the transducer, to promote efficient operation of the transducer  30 . In this embodiment, the ultrasound energy generated by the transducer  30  is reflected at the water gap to reinforce ultrasound energy propagating from the transducer  30 , thereby ensuring the ultrasound energy is directed outwardly from an external surface of the transducer  30 . 
         [0031]    Transducer  30  is also arranged to convert ultrasonic waves impinging on the exterior surface  31  into electrical signals on wires  32 . Stated another way, transducer  30  can act either as an ultrasonic emitter or an ultrasonic receiver. 
         [0032]    The transducer  30  is designed to operate, for example, at a frequency of approximately 1 MHz to approximately a few tens of MHz, and typically at approximately 9 MHz. The actual frequency of the transducer  30  typically varies somewhat depending on manufacturing tolerances. The optimum actuation frequency of the transducer may be encoded in a machine-readable or human-readable element (not shown) such as a digital memory, bar code or the like affixed to the catheter. Alternatively, the readable element may encode a serial number or other information identifying the individual catheter, so that the optimum actuation frequency may be retrieved from a central database accessible through a communication link such as the internet. 
         [0033]    An ultrasound system  20 , also referred to herein as an actuator, is releasably connected to catheter  18  and transducer  30  through a plug connector  88  ( FIG. 3 ). As seen in  FIG. 6 , ultrasound system  20  may include a user interface  40 , a control board  42  incorporating a programmable control device such as a programmable microprocessor (not shown), an ultrasound excitation source  44 , and a circulation device  48 . The user interface  40  interacts with the control board  42 , which interacts with the excitation source  44  to cause transmission of electrical signals at the optimum actuation frequency of the transducer to the transducer  30  via wires  32 . The control board  42  and ultrasound source  44  are arranged to control the amplitude and timing of the electrical signals so as to control the power level and duration of the ultrasound signals emitted by transducer  30 . Excitation source  44  is also arranged to detect electrical signals generated by transducer  30  and appearing on wires  32  and communicate such signals to control board  42 . 
         [0034]    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 liquid, preferably an aqueous liquid, 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 refrigerating coil (not shown), or the like for providing a supply of liquid to the interior space of the balloon  24  at a controlled temperature, desirably at or below body temperature. The control board  42  interfaces with the circulation device  48  to control the flow of fluid into and out of the balloon  24 . For example, the control board  42  may include motor control devices linked to drive motors associated with pumps for controlling the speed of operation of the pumps  37 . Such motor control devices can be used, for example, where the pumps  37  are positive displacement pumps, such as peristaltic pumps. Alternatively or additionally, the control circuit may include structures such as controllable valves connected in the fluid circuit for varying resistance of the circuit to fluid flow (not shown). The ultrasound system  20  may further include two pressure sensors  38 , to monitor the liquid flow through the catheter  18 . One pressure sensor monitors the flow of the liquid to the distal catheter  18  to determine if there is a blockage while the other monitors leaks in the catheter  18 . While the balloon is in an inflated state, the pressure sensors  38  maintain a desired pressure in the balloon preferably at approximately 3 pounds per square inch (20 KPa). 
         [0035]    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 board  46 . As discussed above, the machine-readable element on the catheter may include information such as the operating frequency of the transducer  30  in a particular catheter  18 , and the control board  42  may use this information to set the appropriate frequency for exciting the transducer. Alternatively, the control board may be arranged to actuate excitation source  44  to measure the transducer operating frequency by energizing the transducer at a low power level while scanning the excitation frequency over a pre-determined range of frequencies for example 8.5 Mhz-9.5 Mhz, and monitoring the response of the transducer to such excitation. 
         [0036]    The ultrasonic system  20  may be similar to that disclosed in U.S. Provisional Patent Application No. 61/256,002, filed Oct. 29, 2009, entitled “METHOD AND APPARATUS FOR PERCUTANEOUS TREATMENT OF MITRAL VALVE REGURGITATION (PMVR),” the disclosure of which is incorporated by reference herein. 
         [0037]    A method according to an embodiment of the present invention is depicted in flowchart form in  FIG. 7 . 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  30  in inserted into the renal artery (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 within the sheath until the distal end of the catheter projects from the sheath as schematically depicted in  FIG. 8 . Because the distal end  22  of the catheter  18  is pre-formed like a hook, the distal end  22  of the catheter  18  may slide into the renal artery  10  when the tip is rotated inside the aorta towards the renal artery  10  branches and then slightly pushed forward and pulled backwards. This action is facilitated by the typical angle of the renal artery/aorta bifurcation. Based on the hooked shape of the distal end  22 , the distal end  22  of the catheter  18  may tend to catch in the renal artery  10  side branch when pulled back inside the aorta. 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. 
         [0038]    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  FIGS. 4 and 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 ( FIG. 5 ) 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. 
         [0039]    In the next step  58 , the ultrasound system  20  uses transducer  30  to measure the size of the renal artery  10 . Control board  42  and ultrasound source  44  actuate the transducer  30  to “ping” the renal artery  10  with a low-power ultrasound pulse. The ultrasonic waves in this pulse are reflected by the artery wall onto transducer  30  as echoes. Transducer  30  converts the echoes to echo signals on wires  32 . The ultrasound system  20  then determines the size of the artery  10  by analyzing the echo signals. For example, the ultrasound system  20  may determine the time delay between actuation of the transducer to produce the “ping” and the return of echo signals. In step  60 , the ultrasound system  20  uses the measured artery size to set the acoustic power to be delivered by transducer  30  during application of therapeutic ultrasonic energy in later steps. For example, control board  42  may use a lookup table correlating a particular echo delay (and thus artery diameter) with a particular power level. 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  30 , may cause a range of time delay in the echo signals. The ultrasound system  20  may take an average of the range to determine the average size of the renal artery  10  and make adjustments to the power level based on the average size. 
         [0040]    The physician then initiates the treatment (step  60 ) through the user interface  40 . In the treatment (step  64 ), the ultrasonic system or actuator  20 , and particularly the control board  42  and ultrasonic source  44 , actuate transducer  30  to deliver therapeutically effective ultrasonic waves to an impact volume  11  ( FIG. 5 ). The ultrasound energy transmitted by the transducer  30  propagates generally radially outwardly and away from the transducer  30  encompassing a full circle, or 360° of arc about the proximal-to-distal axis  33  of the transducer  30  and the axis A of the renal artery. 
         [0041]    The selected operating frequency, unfocused characteristic, placement, size, and the shape of the ultrasound transducer  30  allows the entire renal artery  10  and renal nerves to lie within the “near field” region of the transducer  30 . Within this region, an outwardly spreading, unfocused omni-directional (360°) cylindrical beam of ultrasound waves generated by the transducer  30  tends to remain collimated and has an axial length approximately equal to the axial length of the transducer  30 . For a cylindrical transducer, the radial extent of the near field region is defined by the expression L 2 /λ, where L is the axial length of the transducer  30  and λ is the wavelength of the ultrasound waves. At distances from the transducer  30  surface greater than L 2 /λ, the beam begins to spread axially to a substantial extent. However, for distances less than L 2 /λ, the beam does not spread axially to any substantial extent. Therefore, within the near field region, at distances less than L 2 /λ, the intensity of the ultrasound energy decreases linearly, in proportion to distance from the transducer  30  surface, as the unfocused beam spreads radially. As used in this disclosure, the term “unfocused” refers to a beam, which does not increase in intensity in the direction of propagation of the beam away from the transducer  30 . 
         [0042]    The impact volume  11  is generally cylindrical and coaxial with the renal artery. It extends from the transducer surface to an impact radius  39 , where the intensity of the ultrasonic energy is too small to heat the tissue to the temperature range that will cause inactivation of the renal nerves  8 . The impact radius  39  is determined by the dosage of ultrasound energy transmitted from the transducer  30 . The volume V of impact volume  11  is determined by the following equation: 
         [0000]    
       
      
       V=πr 
       2 
       2 
       h−πr 
       1 
       2 
       h  
      
     
         [0043]    where
       r 1 =the radius of the transducer  30     r 2 =the radius of the impact zone  11     h=length of the transducer  30         
 
         [0047]    As discussed above, the length of the transducer  30  may vary between 2 mm and 10 mm, but is preferably 6 mm to provide a wide inactivation zone of the renal nerves. The diameter of the transducer  30  may vary between 1.5 mm to 3.0 mm, and is preferably 2.0 mm. The dosage is selected not only for its therapeutic effect, but also to allow the radius  39  of the impact volume  11  to be between preferably 5 mm to 7 mm in order to encompass the renal artery  10 , and adjacent renal nerves, all of which lie within an average radius of 3-4 mm, without transmitting damaging ultrasound energy to structures beyond the renal artery  10 . This will result in an impact volume  11  of at least 0.5 cm 3 , with the length of renal nerve inactivation closely corresponding to the length of the transducer  32 . 
         [0048]    The power level desirably is selected so that throughout the impact volume, solid tissues are heated to about 42° C. or more for at 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. 
         [0049]    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  3  ( FIG. 2 ) 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 of the renal artery  10  and not at the intimal layer  3 . In addition, the circulation of cooled liquid through the balloon  24  containing the transducer  30  may also help reduce the heat being transferred from the transducer  30  to the intimal layer  3  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. 
         [0050]    In order to generate the therapeutic dosage of ultrasound energy, the acoustic power output of the transducer typically is approximately 10 watts to approximately 100 watts, more typically approximately 20 to approximately 30 watts. The duration of power application typically is approximately 2 seconds to approximately a minute or more, more typically approximately 10 seconds to approximately 20 seconds. The optimum dosage used with a particular system to achieve the desired temperature levels may be determined by mathematical modeling or animal testing. 
         [0051]    The impact volume  11  of the unfocused ultrasound energy encompasses the entire renal artery  10 , including the adventitia and closely surrounding tissues, and hence encompasses all of the renal nerves surrounding the renal artery. Therefore, the placement in the renal artery  10  of the transducer  30  may be indiscriminate in order to inactivate conduction of all the renal nerves  8  surrounding the renal arteries  10  in the subject. As used in this disclosure “indiscriminate” and “indiscriminately” mean without targeting, locating, or focusing on any specific renal nerves. 
         [0052]    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  10  and performs the entire treatment again for that artery  10 , (step  72 ). After completion of the treatment, the catheter  18  is withdrawn from the subject&#39;s body (step  74 ). 
         [0053]    Numerous variations and combinations of the features discussed above can be utilized. For example, the ultrasound system  20  may control the transducer  30  to transmit ultrasound energy in a pulsed function during application of therapeutic ultrasonic energy. The pulsed function causes the ultrasound transducer  30  to emit the ultrasound energy at a duty cycle of, for example, 50%. Pulse modulation of the ultrasound energy is helpful in limiting the tissue temperature while increasing treatment times. 
         [0054]    In a further variant, the steps of measuring the renal artery size and adjusting the dose (steps  58  and  72 ) may be omitted. In this instance, the transducer is simply operated at a preset power level sufficient for the renal arteries of an average subject. In a further variant, the renal artery diameter can be measured by techniques other than actuation of transducer  30  as, for example, by radiographic imaging using a contrast agent introduced into the renal artery or magnetic resonance imaging or use of a separate ultrasonic measuring catheter. In this instance, the data from the separate measurement can be used to set the dose. 
         [0055]    In the particular embodiment discussed above, the transducer  30  is centered in the renal artery by the non-circular element  80  of expansible balloon  24 . Other centering arrangements can be used. For example, an expansible balloon encompassing the transducer may be a balloon of circular cross-section slightly smaller in diameter than the renal artery  10 . Such a balloon allows blood to continue to flow through the renal artery  10 , but maintains the transducer  30  roughly centered in the renal artery  10 . In this embodiment, the balloon  24  is dynamic rather than fitted to the renal artery  10  because the flow of blood around the balloon  24  causes small back and forth movements. This dynamic nature allows the blood to continue to reach all parts of the renal artery  10 , thereby providing cooling and minimizing damage to the intima  3 . In other embodiments, the distal end of the catheter can include expansible structures other than balloons, such as a wire basket or wire mesh structure which can be selectively brought to a radially expanded condition, such as by compressing the structure in the axial direction. The wire basket may be non-reflecting to ultrasound, or may be mounted on the catheter at a position axially offset from the transducer  30 . 
         [0056]    In a further variant, the balloon  24  may be formed from a porous membrane or include holes, such that cooled liquid being circulated within the balloon  24  may escape or be ejected from the balloon  24  into the blood stream within the renal artery  10 . The escaping or ejected cooled liquid from the balloon  24  that enters the blood flow may support further cooling of the inner lining of the renal artery  10 , which is in contact with the flowing blood. 
         [0057]    Typically, catheter  18  is a disposable, single-use device. The catheter  18  or ultrasonic system  20  may contain a safety device that inhibits the reuse of the catheter  18  after a single use. Such safety devices per se are known in the art. 
         [0058]    In yet another variant, the catheter  18  itself may include a steering mechanism which allows the physician to directly steer the distal end  22  of the catheter. The sheath may be omitted. 
         [0059]    Another variation may be that an energy emitter unit at the distal end of the catheter  18 , which includes the ultrasound transducer  30 , may be positioned in the renal vein, and the ultrasound transducer  30  may include reflective or blocking structures for selectively directing ultrasound energy from the transducer  30  over only a limited range of radial directions to provide that ultrasound energy desirably is selectively directed from the transducer  30  in the renal vein toward the renal artery  10 . When the venous 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  30  arrangement. For example, the ultrasound transducer  30  may have a construction and be operated to emit directed ultrasound energy  5  similarly as disclosed in US Provisional Application No. 61/256,002, filed Oct. 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 venous approach may be utilized to take advantage of the potential for reduced closure issues after catheter  18  withdrawal. 
         [0060]    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.