System and method for locating and identifying the functional nerves innervating the wall of arteries and catheters for same
09723998 · 2017-08-08
Assignee
Inventors
Cpc classification
A61B5/0036
HUMAN NECESSITIES
A61B5/4833
HUMAN NECESSITIES
A61B5/0205
HUMAN NECESSITIES
A61B2018/00404
HUMAN NECESSITIES
G16Z99/00
PHYSICS
A61B18/18
HUMAN NECESSITIES
A61B18/1492
HUMAN NECESSITIES
A61B5/4836
HUMAN NECESSITIES
A61B5/24
HUMAN NECESSITIES
International classification
A61B5/0205
HUMAN NECESSITIES
A61B5/20
HUMAN NECESSITIES
A61B5/053
HUMAN NECESSITIES
A61B5/00
HUMAN NECESSITIES
Abstract
System and method for locating and identifying nerves innervating the wall of arteries such as the renal artery are disclosed. The present invention identifies areas on vessel walls that are innervated with nerves; provides indication on whether energy is delivered accurately to a targeted nerve; and provides immediate post-procedural assessment of the effect of energy delivered to the nerve. The method includes at least the steps to evaluate a change in physiological parameters after energy is delivered to an arterial wall; and to determine the type of nerve that the energy was directed to (none, sympathetic or parasympathetic) based on the evaluated results. The system includes at least a device for delivering energy to the wall of blood vessel; sensors for detecting physiological signals from a subject; and indicators to display results obtained using this method. Also provided are catheters for performing the mapping and ablating functions.
Claims
1. A system for mapping a parasympathetic or sympathetic nerve underlying the wall of renal vein, comprising: (i) a catheter configured to deliver electrical current to one or more locations on the inner renal vein wall sufficient to stimulate a nerve underlying said renal vein; (ii) one or more measuring devices for measuring one or more physiological parameters associated with said nerve underlying said renal vein, wherein said physiological parameters are selected from the group consisting of systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate; (iii) a computing device configured to couple to the one or more measuring devices for computing any increase or decrease in the physiological parameters against a baseline; and (iv) a display device for displaying the location or identity of the parasympathetic or sympathetic nerve underlying said renal vein.
2. The system of claim 1, wherein said catheter could also deliver ablative energy selected from the group consisting of radiofrequency, mechanical, ultrasonic, radiation, optical and thermal energies.
3. The system of claim 1, wherein said computing device comprises one or more microcontrollers or computers.
4. A method of using the system of claim 1 for mapping a parasympathetic or sympathetic nerve underlying a renal vein, said mapping comprises: a. introducing the catheter into the lumen of a renal vein such that the tip of said catheter contacts a site on the inner renal vein wall; b. measuring one or more physiological parameters with the measuring devices to obtain baseline measurements before introducing electrical current to the site, said physiological parameters are selected from the group consisting of systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate; c. applying electrical stimulation by introducing electrical current to the site via the catheter, wherein said electrical current is controlled to be sufficient to elicit changes in said physiological parameters when there is an underlying nerve at the site; and d. measuring said physiological parameters at a specific time interval after each electrical stimulation with the measuring device, wherein an increase of said physiological parameters over the baseline measurements after said electrical stimulation would be identified by the computing device as mapping of a sympathetic renal nerve at said site; a decrease of said physiological parameters over the baseline measurements after said electrical stimulation would be identified by the computing device as mapping of a parasympathetic renal nerve at said site; and e. displaying the location or identity of a parasympathetic or sympathetic nerve underlying said renal vein on the display device based on the result of (d).
5. The method of claim 4, said mapping further comprises the step of applying radiofrequency energy through the catheter to the site identified in step (d) for ablation of the underlying nerve to treat disease caused by systemic renal nerve hyperactivity.
6. The method of claim 5, said mapping further comprises repeating the steps (b) to (d) on the ablated site, wherein a lack of change in said physiological parameters confirms nerve ablation.
7. The method of claim 4, wherein the electrical current delivered falls within the following ranges: (a) voltage of between 2 and 30 volts; (b) resistance of between 100 and 1000 ohms; (c) current of between 5 and 40 milliamperes; (d) time of application between 0.1 and 20 milliseconds.
8. A method of using a catheter for mapping parasympathetic or sympathetic renal nerve for treatment of disease caused by systemic renal nerve hyperactivity, said catheter comprises a shaft, the proximal end of said shaft is configured to be connected to an energy source, and the distal end (catheter tip) of said shaft is in the form of a single helix, double helix or multiple prongs having one or more electrodes; said mapping comprises the steps of: a. introducing said catheter into the lumen of a renal vein such that the tip of said catheter contacts a site on the inner renal vein wall; b. measuring one or more physiological parameters to obtain baseline measurements before introducing electrical current to the site, said physiological parameters are selected from the group consisting of systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate; c. applying electrical stimulation by introducing electrical current to the site via the catheter, wherein said electrical current is controlled to be sufficient to elicit changes in said physiological parameters when there is an underlying nerve at the site; and d. measuring said physiological parameters at a specific time interval after each electrical stimulation, wherein an increase of said physiological parameters over the baseline measurements after said electrical stimulation would indicate that a sympathetic renal nerve has been mapped at said site; a decrease of said physiological parameters over the baseline measurements after said electrical stimulation would indicate that a parasympathetic renal nerve has been mapped at said site.
9. The method of claim 8, wherein the electrodes may be activated independently of one another.
10. The method of claim 8, wherein the entire catheter is between 1 and 2 m in length, the catheter tip is between 2 and 8 cm in length and between 0.5 mm and 10 mm in diameter.
11. The method of claim 8, wherein said helix or said prongs comprise coils that are substantially round or flat in shape, and the electrodes are spaced along the length of said coil or prongs, wherein said electrodes are embedded in said coil or prongs, or lie on the surface of said coil or prongs.
12. The method of claim 8, wherein the catheter tip is configured to hold a balloon inflatable to fill the space within the coil of said helix or prongs.
13. The method of claim 8, wherein said prongs are rejoined at the distal end.
14. The method of claim 8, wherein said mapping further comprises the step of applying radiofrequency energy through the catheter to the site identified in step (d) for ablation of the underlying nerve to treat disease caused by systemic renal nerve hyperactivity.
15. The method of claim 14, wherein said mapping further comprises repeating the steps (b) to (d) on the ablated site, wherein a lack of change in said physiological parameters confirms nerve ablation.
16. The method of claim 8, wherein the electrical current delivered falls within the following ranges: (a) voltage of between 2 and 30 volts; (b) resistance of between 100 and 1000 ohms; (c) current of between 5 and 40 milliamperes; (d) time of application between 0.1 and 20 milliseconds.
Description
BRIEF DESCRIPTION OF THE FIGURES
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DETAILED DESCRIPTION OF THE INVENTION
(47) Please note that as referred to throughout this specification, the term “catheter” references the entire length of a catheter apparatus, from the distal portion intended for introduction into the desired target anatomy for ablation or other action, extending through to the juncture where the catheter meets the cable linking the catheter to an RF generator. As referenced to through this specification, the term “catheter tip” is used to reference the distal portion of the catheter which carries electrodes, and performs stimulative, ablative, and mapping functions within the body at a targeted site of action. The term “catheter tip” is used interchangeably with terms referencing the “distal portion” of any recited catheter.
(48) The renal nerve architecture is of paramount consideration before successful ablation can take place; therefore, individual renal nerve architecture must be carefully considered or mapped before catheterization for denervation can be successfully accomplished. The presence of aberrant or unusual renal architecture, as well as normal variation in renal nerve architecture among individuals require mapping of the renal nerves before ablation. In other words, mapping of the renal nerves is required before catheter denervation because the best spots for ablation are “random” in the sense that the best spots for ablation vary from one person to another, and from one artery to another. Optimal ablation thus requires identification or mapping of renal nerves prior to catheter ablation.
(49) This invention provides a system and method for locating sites innervated with functional nerves in the wall of arteries, particularly the renal artery, though persons skilled in the art will appreciate that nerves innervating other arteries or vessels in the human body may be located using this invention. The system comprises one or more devices capable of delivering a dose of energy to the wall of an artery; one or more sensors to receive inputs of physiological signals; one or more devices for analysis of signals from the sensors; and one or more indicators or panels capable of displaying the results of the analysis.
(50)
(51) In one embodiment of the invention, device 101 is an invasive device inserted into an artery capable of delivering energy to a nerve innervating the artery, resulting in nerve stimulation or ablation. In another embodiment, device 101 is made up of two separate entities, one delivering the energy for nerve stimulation, and the other nerve ablation. In a different embodiment, device 101 is a single-electrode catheter or multi-electrode catheter.
(52) In one embodiment, power source 102 delivers energy to the arterial wall via device 101. In another embodiment, energy is delivered remotely through the human body by power source 102 into the arterial wall without device 101. In a further embodiment, power source 102 is a multi-channel power source capable of delivering separate doses of energy independently to distinct locations on the arterial wall. In other embodiments, power source 102 is a single channel power source capable of delivering only 1 dose of energy each time. In another embodiment, the dosage of energy to be delivered by power source 102 is adjustable to induce different effects on a targeted nerve such as stimulation or ablation. In further embodiments, the energy delivered by power source 102 is one or more of electrical, mechanical, ultrasonic, radiation, optical and thermal energies.
(53) In one embodiment, sensors 103 detect signals from physiological parameters comprising blood pressure, heart rate, biochemical levels, cardiac electrical activity, muscle activity, skeletal nerve activity, action potential of cells and other measurable reactions as a result of the above such as pupil response, electromyogram and vascular constriction. In a further embodiment, sensors 103 detect said signals externally with or without contacting any part of the human body. In another embodiment, sensors 103 detect said signals inside the human body by placing into contact with, or in the vicinity of, the lumen of interest such as the renal artery or femoral artery or any other artery. In yet another embodiment, sensor 103 could be a sensor from part of another equipment that is used in conjunction with this invention during the interventional procedure.
(54) In an embodiment, device 104 is one or more microcontrollers or computers capable of digital analysis of the signals arising directly or indirectly from sensor 103.
(55) In one embodiment, indicator 105 is one or more digital viewing panels that display the result from the analysis of device 104. In another embodiment, one or more results of said analysis from multiple locations on the arterial wall are simultaneously displayed on indicator 105. In a further embodiment, indicator 105 also displays one or more the physiological signals from sensor 103; energy related information from power source 102 such as current, frequency, voltage; tissue-electrode interface related information such as impedance; and information related to device 101 such as temperature. In certain embodiments, indicator 105 comprises a set of different colored lights each distinctly representing sympathetic nerve, parasympathetic nerve or no nerve. In other embodiments, indicator 105 represents the result from analysis of device 104 with texts, symbols, colors, sound or a combination of the above.
(56) In certain embodiments, device 4 and indicator 5 are integrated as a single device and, in further embodiments, both device 4 and indicator 5 are integrated into power source 2.
(57) In yet another embodiment, sensor 103, device 104 and indicator 105 exist independently from device 101 and power source 102 such that sensor 103, device 104 and indicator 105 can be used with other external or invasive methods for energy delivery into the vessel wall such as high-intensity focused ultrasound.
(58) The present invention additionally provides a method for identifying the presence of functional sympathetic or parasympathetic nerves innervating a selected area on the arterial wall based on changes in physiological parameters induced by a dose of energy. The method comprises one or more of the steps of preparing a baseline of the physiological parameters to be measured prior to the delivery of a dose of energy to the arterial wall; delivering a dose of energy to the arterial wall; detecting the physiological changes as a result of the delivered energy; rating the change based on a set of empirically pre-determined values; and, based on the ratings, determining if there are functional sympathetic or parasympathetic nerves in the vicinity of the site of energy delivery.
(59)
(60) At step 1, physiological signals from sensor 103 are continuously recorded by device 104 to produce a reliable baseline reflective of any instantaneous changes in the signals.
(61) Energy is then delivered by one of the electrodes in device 101 to the area on the arterial wall that this electrode is in contact with (Step 2). Sensor 103 detects any physiological change caused by the energy delivered, and the change is recorded as signals which are then sent to device 104. (Step 3)
(62) In step 4, device 104 determines the deviation of the physiological signals from the baseline of step 1 and, in step 5, determines the type of nerves innervating the area on the arterial wall based on the deviation from the baseline information.
(63) In one embodiment, the physiological signals detected by sensor 103 comprises one or more of blood pressure, heart rate, biochemical levels, cardiac electrical activity, muscle activity, skeletal nerve activity, action potential of cells and other observable body reactions as a result of the above such as pupil response and vascular constriction.
(64) In an embodiment, the dosage of energy delivered in step 2 is adjustable to induce different interactions with a targeted nerve such as nerve stimulation or nerve ablation.
(65) In certain embodiments, the values of the physiological signals are measured using other external devices and inputted into device 104 prior to the energy delivery to replace the baseline formed by device 104.
(66) In one embodiment, the changes in physiological parameters are detected during or after the energy delivery process in step 2. In another embodiment, the changes in physiological parameters are in the form of numerical values or waveforms. In further embodiments, the deviation from baseline of step 1 is evaluated by subtracting the baseline of step 1 from the signals.
(67) In one embodiment, the empirically pre-determined set of values could be obtained from sets of clinical data or deduced from the experience of clinical physicians. In some embodiments, an area on the arterial wall is considered to be innervated with sympathetic nerves when energy delivered to the area causes an increase in heart rate by 10 beats per minute and/or an increase in blood pressure by 6 mmHg. In other embodiments, an area on the arterial wall is considered to be innervated with parasympathetic nerves when energy delivered to the area causes a decrease in heart rate by 5 beats per minute and/or a decrease in blood pressure by 2 mmHg.
(68) In a further embodiment, the results of step 5 will be displayed on indicator 105.
(69) In one embodiment, the method is used for identifying the suitable sites for nerve ablation in the arterial wall to disrupt baroreflex via sympathetic and parasympathetic nervous systems. In another embodiment, the method provides indication of whether the ablation energy is delivered accurately to the targeted nerves in the arterial wall. In a further embodiment, the method is used for immediate post-procedural assessment of nerve ablation.
(70) The present invention also provides for specially-designed catheters with a steerable distal end (i.e. the catheter tip) in shapes customized to renal architecture, possessing one or more electrodes to map renal nerve distribution, to perform renal ablations and to perform angiography. In certain embodiments, the electrodes of such catheters are sequentially spaced along the length of the catheter tip, where the electrode faces make contact with segmented portions of the renal artery lumen. In certain embodiments, the shape of the catheter tip is a single helix wherein the coil of the helix is either round or flat in shape (
(71) In further embodiments, the catheter tip may comprise an umbrella shape or frame with a closed end (
(72) In another embodiment, the catheter has a steerable catheter tip with a single electrode at its tip (
(73) In certain embodiments, the above catheter tips may be introduced into the arterial architecture to perform the functions of a stent.
(74) In one embodiment, the diameter of these catheter tips, d, may vary from 0.5 mm to 10 mm; the length of the catheter tips, L, may vary from 20 mm to 80 mm; the diameters of coil, D, may vary from 3.0 mm to 7.5 mm; the distances between each coil, 1, may vary from 4 mm to 6 mm; the numbers of coils may vary from 3.3 to 20; and the fully uncoiled lengths of the coils may vary from 31 mm to 471 mm.
(75) The electrodes of the catheters may be activated independently of one another or can be activated in any combination to emit electrical stimulation or radiofrequency energy. The electrodes each have dual functions of delivering electrical stimulation or radiofrequency energy. Electrical stimulation is used to identify and map segments of renal artery lumen beneath which lie renal nerves of importance. Said identification and mapping is accomplished through the monitoring of a physiological response or responses to the applied electrical stimulation, such as changes in blood pressure response and heart rate or muscle sympathetic nerve activity (Schlaich et al., NEJM 2009), or renal norepinephrine spillover (Esler et al. 2009, and Schlaich et al., J Htn. 2009), wherein changes in physiological response indicate the presence of an underlying sympathetic nerve distribution in the vicinity of the activated electrode. In another embodiment, individual electrodes of the catheters may be activated in physician operator-selected combinations in order to assess maximal physiological response, and the consequent locations of underlying renal nerves. The electrodes of the catheters are able to emit not just electrical current of sufficient strength to stimulate renal nerve, but thermal energy such as radiofrequency energy to ablate underlying renal nerve tissue based on renal nerve mapping results. In other embodiments, separate electrodes of the catheters can be selectively activated to emit ablative energy such as high radiofrequency energy wherein the choice of the activated electrodes is based upon the results of the mapping of the nerves. In further embodiments, based on the mapping of the renal nerves, ablative techniques using other types of ablative energy such as laser energy, high intensive focused ultrasound or cryoablative techniques can be utilized on renal artery walls to ablate the sympathetic renal nerves.
(76) In certain embodiments, these catheters are interchangeably used with existing radiofrequency generators which are presently utilized with existing cardiac catheter systems.
(77) In one embodiment, the aforementioned catheter systems may be utilized with any variety of acceptable catheter guidewire previously inserted into the patient's body to guide the catheter tip to the desired location. They may also be used with devices and other instruments that may be used to facilitate the passage of like devices within the cardiovascular and renal vascular systems, such as sheaths and dilators. When required, the aforementioned catheter systems may also be utilized with a puller wire to position the catheter tip.
(78) The present invention also provides methods of using the catheters described herein to map renal nerve distribution, comprising the steps of using electrical stimulation while monitoring changes in physiological responses, such as blood pressure and heart rate, to map renal nerve distribution and identify ablation spots within renal arteries for ideal denervation of renal nerves. These methods comprise activating the independent electrodes of the described catheters to emit an electrical charge to stimulate the underlying renal nerve while monitoring physiological responses such as blood pressure and heart rate; the presence of changes in physiological response indicate the presence of an underlying sympathetic nerve in the vicinity of the activated electrode and a superior location for ablation. An agglomeration of mapping data may take the form of a clinically useful guide respecting renal nerve distribution to assist clinicians in performing ablation.
(79) In one embodiment, the tip of said catheter is optionally moved in a blood vessel according to a specified protocol in order to make contact with desired portions of the renal artery lumen. In one embodiment, the optional protocol for moving the catheter tip in the above method comprises moving the stimulatory or ablative section of the catheter tip from the half of the renal artery closer to the interior of the kidney to the half of the renal artery closer to the aorta and applying one or more electrical stimulation to each of the two halves.
(80) In another embodiment, the optional protocol for moving the catheter tip comprises turning the stimulatory or ablative section of the catheter tip within the renal artery in the following sequence: (a) turning from the anterior wall to the posterior wall of the artery; (b) turning from the posterior wall to the superior wall of the artery; and (c) turning from the superior wall to the inferior wall of the artery, wherein each turn is 90° or less. In one embodiment, one or more electrical stimulations are applied after each turning of the catheter tip within the renal artery.
(81) In one embodiment, the electrical stimulation applied falls within the following parameters: (a) voltage of between 2 to 30 volts; (b) resistance of between 100 to 1000 ohms; (c) current of between 5 to 40 milliamperes; (d) applied between 0.1 to 20 milliseconds.
(82) The present invention also provides a method of ablating renal nerves to treat disease caused by systemic renal nerve hyperactivity, comprising the steps of: (a) applying the mapping method described herein to map renal nerves; (b) applying radiofrequency energy through the catheter to site-specific portions of the renal artery lumen to ablate the mapped renal nerves; and (c) applying stimulation again to assess the effectiveness of ablation. In further embodiments, based on the mapping of the renal nerves, other ablative techniques generally known in the art can be utilized on renal artery walls to ablate the sympathetic renal nerves, e.g. ablative techniques using other ablative energy such as laser energy, high intensive focused ultrasound or cryoablative techniques.
(83) The present invention provides for a catheter adapted to be used in a method for locating or identifying a functional nerve innervating the wall of a blood vessel in a subject, comprising a shaft, wherein the proximal end of said shaft is configured to be connected to an energy source, and the distal end (catheter tip) of said shaft is in the form of a single helix, double helix or multiple prongs having one or more electrodes.
(84) In one embodiment, said catheter comprises one or more electrodes that are configured to emit energy sufficient to stimulate or ablate a nerve on said vessel. In a further embodiment, said electrodes may be activated independently of one another.
(85) In one embodiment, said catheter is between 1 and 2 m in length, wherein the catheter tip is between 2 and 8 cm in length, and between 0.5 mm and 10 mm in diameter.
(86) In one embodiment, said catheter contains helical coils or prongs which are substantially round or flat in shape, and the electrodes are spaced along the length of said coils or prongs, wherein said electrodes are embedded in said coils or prongs, or lie on the surface of said coils or prongs. In one embodiment, the prongs are rejoined at the distal end. In yet another embodiment, the electrodes are evenly spaced along the length of said coils at 90° or 120° from each other.
(87) In one embodiment, said catheter has a catheter tip that is configured to hold a balloon inflatable to fill the space within the coil of said helix or prongs.
(88) The present invention also provides a method of using a catheter to locate or identify a functional nerve innervating the wall of a blood vessel in a subject, comprising the steps of: a) inserting said catheter into said blood vessel and activating the electrodes on the catheter to deliver energy to one or more locations on said vessel wall sufficient to change one or more physiological parameters associated with the innervation of said vessel by a sympathetic or parasympathetic nerve; and b) measuring said one or more physiological parameters after each energy delivery, and determining the change from the corresponding parameters obtained without energy delivery to said vessel; wherein a lack of change in said physiological parameters in step b indicates the absence of a functional nerve at the location of energy delivery, a significant change in said physiological parameters in step b indicates the presence of a functional nerve at the location of energy delivery, and the direction of change in said physiological parameters in step b determines the nerve to be sympathetic or parasympathetic at the location of energy delivery. It is to be understood that a lack of change means that the change would be considered by someone skilled in the art to be negligible or statistically insignificant, and a significant change means that the change would be considered by someone skilled in the art to be meaningful or statistically significant.
(89) In one embodiment, said vessel is an artery, including a renal artery. In one embodiment, the functional nerve is related to baroreflex. In one embodiment, the location where energy is delivered is an area where a nerve has been ablated, wherein a lack of change in said physiological parameters in step b confirms nerve ablation. In another embodiment, the subject used is a human or non-human animal. In another embodiment, the physiological parameters described are selected from blood pressure, heart rate, cardiac electrical activity, muscle activity, skeletal nerve activity, action potential of cells, pupil response, electromyogram, vascular constriction, and levels of biochemicals selected from epinephrine, norepinephrine, renin-angiotensin II and vasopressin. In yet another embodiment, said energy is adjustable and consists of one or more of electrical, mechanical, ultrasonic, radiation, optical and thermal energies. In one embodiment, said energy causes nerve stimulation or nerve ablation. In another embodiment, the functional nerve is a sympathetic or parasympathetic nerve. In yet another embodiment, the energy delivered falls within the following ranges: a) voltage of between 2 and 30 volts; b) resistance of between 100 and 1000 ohms; c) current of between 5 and 40 milliamperes; and d) time of application between 0.1 and 20 milliseconds.
(90) In one embodiment, the catheter used for insertion into a blood vessel is moved in the blood vessel in the following sequence: a) turning 900 or less from the anterior wall to the posterior wall of the artery; b) turning 90° or less from the posterior wall to the superior wall of the artery; and c) turning 90° or less from the superior wall to the inferior wall of the artery.
(91) It will be appreciated by persons skilled in the art that the system and method disclosed herein may be used in nerve ablation of the renal artery to disrupt baroreflex via sympathetic and parasympathetic nervous systems but its application could be extended to any innervated vessels in the body.
(92) The invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific examples are for illustrative purposes only and should not limit the scope of the invention which is defined by the claims which follow thereafter.
(93) It is to be noted that the transitional term “comprising”, which is synonymous with “including”, “containing” or “characterized by”, is inclusive or open-ended and does not exclude additional, un-recited elements or method steps.
EXAMPLE 1
Locating Nerves Innervating an Arterial Wall
(94) A method to locate nerves innervating an arterial wall via examination of the changes in physiological parameters after the delivery of a suitable dose of energy was designed and executed in acute pig experiments. The aims of this experiments are: 1. To test currently existing cardiac ablation catheters (7F,B-Type, spacing 2-5-2 mm, CELSIUS® RMT Diagnostic/Ablation Steerable Catheter, Biosense Webster, Diamond Bar, Calif. 91765, USA) and a radiofrequency generator (STOCKERT 70 RF Generator, Model Stockert GmbH EP-SHUTTLE ST-3205, STOCKERT GmbH, Freiburg, Germany) for the purposes of renal nerve mapping and ablation. 2. To test renal nerve mapping via examination of changes in blood pressure and heart rate during emission of electrical stimulation at different sites within the lumen of the left and right renal arteries. 3. To determine the safe range of high radiofrequency energy to be emitted to renal arteries for renal nerve ablation via examination of visual changes of renal arterial walls and histology. 4. To use changes in blood pressure and heart rate as indices of efficient ablation of renal nerves during renal ablation.
(95) Three pigs (body weight from 50-52 kg) were anesthetized with intravenous injection of sodium pentobarbital at 15 mg/kg. The physiological parameters: systolic blood pressure, diastolic blood pressure, mean arterial pressure and heart rate were monitored. The experimental design and protocol are illustrated in
(96) The ablation catheter used in this set of experiments was the 7F,B-Type, spacing 2-5-2 mm, CELSIUS® RMT Diagnostic/Ablation Steerable Catheter (Biosense Webster, Diamond Bar, Calif. 91765, USA) and a Celsius radiofrequency generator (STOCKERT 70 RF Generator, Model Stockert GmbH EP-SHUTTLE ST-3205, STOCKERT GmbH, Freiburg, Germany).
(97) Baselines for systolic, diastolic and mean arterial blood pressure and heart rate were measured before the delivery of electrical energy to different areas of the renal arterial wall. Mean arterial blood pressure and heart rate were then measured 5 seconds to 2 minutes after the delivery of energy to note for any effects. By recognizing that a significant change in blood pressure and heart rate to be associated with nerve stimulation, it was found that, although the segment of the arterial wall that is innervated varies in each animal, the method described herein has correctly located these areas in each of the animals giving a map of the innervated regions in the renal artery.
EXAMPLE 2
Relationship Between Physiological Parameters and the Nerves Innervating an Arterial Wall
(98) In order to demonstrate that energy delivered to different locations on an arterial wall may result in different effects on physiological parameters such as blood pressure and heart rate, and such characteristics can be capitalized on to identify the type of nerve innervating an arterial wall, electrical energy was delivered to the innervated areas on the renal arterial walls of the pig model according to several strategies. Detailed parameters on the electrical energy delivered to Pig #1, Pig #2 and Pig #3 are shown in Table 1, Table 2 and Table 3 respectively.
(99) In Pig #1, four separate stimulations took place in the left renal artery and two separate stimulations were performed in the right renal artery. As preliminary approaches, on the abdominal side of the left renal artery, two separate doses of electrical energy were delivered: one to the anterior wall and one to the posterior wall of the artery. On the kidney side of the left renal artery, two separate doses of electrical energy were delivered: one to the anterior wall and one to the posterior wall of the artery. Different effects of these energies on blood pressure and heart rate were observed. In the right renal artery, one dose of electrical energy was delivered to the renal artery on the abdominal side and the kidney side, respectively. The same stimulation strategy was used for Pig #2 and Pig #3.
(100) The electrical energy delivered to different locations in the renal artery caused different effects on the systolic blood pressure, diastolic blood pressure, mean blood pressure and heart rate in all of the pigs tested. For instance, in response to the electrical energy delivered to the left kidney, the maximal change in systolic blood pressure was respectively 19.5 mmHg and 29 mmHg in Pig #1 and Pig #3; the minimal change of systolic blood pressure was respectively 2 mmHg and 1 mmHg in Pig #1 and Pig #3. However, in Pig #2, changes in systolic blood pressure were consistent when the electrical energy was delivered to either the abdominal aorta side or the kidney side. Furthermore, the stimulation location which caused the maximal effect or minimal effect varied from animal to animal, indicating that the distribution of renal autonomic nerves is not consistent between animals. These phenomena in systolic blood pressure, diastolic blood pressure, mean arterial blood pressure and heart rate during delivery of electrical energy to wall of the left renal artery were observed and further summarized in Table 4A, 4B, 4C and 4D, respectively. Similar phenomenon in systolic blood pressure, diastolic blood pressure, mean arterial blood pressure and heart rate during electrical stimulation in the right renal artery were also observed and further summarized in Table 5A, 5B, 5C and 5D, respectively.
(101) These data provide proof of concept for locating and identifying nerves innervating an arterial wall—specifically, that a substantial physiological response, in this case, the maximal increase or decrease in measured blood pressure, was induced by delivery of electrical energy via a catheter placed at a defined location where renal nerve branches are abundantly distributed. Averaged data (mean±SD) calculated from Table 4A-D and Table 5A-D are graphically represented in
(102) TABLE-US-00001 TABLE 1 Renal Nerve Stimulation for Mapping Pig #1: Renal Artery Stimulation Site Stimulation Parameters Left Kidney side Anterior Wall 15 V; 0.4 ms; 400 Ohm; 17 mA Posterior Wall 15 V; 0.4 ms; 400 Ohm; 28 mA Abdominal Anterior Wall 15 V; 0.2 ms; 400 Ohm; 28 mA Aorta Side Posterior Wall 15 V; 0.2 ms; 540 Ohm; 28 mA Right Kidney side 15 V; 0.2 ms; 600 Ohm; 25 mA Abdominal Aorta Side 15 V; 0.2 ms; 520 Ohm; 25 mA
(103) TABLE-US-00002 TABLE 2 Renal Nerve Stimulation for Mapping Pig #2: Renal Artery Stimulation Site Stimulation Parameters Left Kidney side 15 V; 0.2 ms; 580 Ohm; 26 mA Abdominal Aorta Side 15 V; 0.2 ms; 480 Ohm; 28 mA Right Kidney side 15 V; 0.2 ms; 520 Ohm; 28 mA Abdominal Aorta Side 15 V; 0.2 ms; 500 Ohm; 28 mA
(104) TABLE-US-00003 TABLE 3 Renal Nerve Stimulation for Mapping Pig #3: Renal Artery Stimulation Site Stimulation Parameters Left Kidney side 15 V; 9.9 ms; 800 Ohm; 28 mA Abdominal Aorta Side 15 V; 9.9 ms; 800 Ohm; 28 mA Right Kidney side 15 V; 9.9 ms; 800 Ohm; 28 mA Abdominal Aorta Side 15 V; 9.9 ms; 800 Ohm; 28 mA
(105) TABLE-US-00004 TABLE 4A Changes in Systolic Blood Pressure (SBP) During Electrical Stimulation in Left Renal Artery Left Renal Stimulation SBP Maximal Responses (mmHg) Minimal Responses (mmHg) Animal Stimulation Stimulation No. Baseline Maximal Δ Location Baseline Minimal Δ Location Pig 1 131.5 151 19.5 AO Side 140 142 2 Renal Side Pig 2 155 159 4 Renal Side 155 159 4 AO Side Pig 3 173 202 29 Renal Side 169 170 1 AO Side Average 153.2 170.7 17.5 154.7 157.0 2.3 SD 20.8 27.4 12.6 14.5 14.1 1.5
(106) TABLE-US-00005 TABLE 4B Changes in Diastolic Blood Pressure (DBP) During Electrical Stimulation in Left Renal Artery Left Renal Stimulation DBP Maximal Responses (mmHg) Minimal Responses (mmHg) Animal Stimulation Stimulation No. Baseline Maximal Δ Location Baseline Minimal Δ Location Pig 1 99 108 9 AO Side 116 117 1 Renal Side Pig 2 112 115 3 Renal Side 114 116 2 AO Side Pig 3 119 139 20 Renal Side 110 115 5 AO Side Average 110.0 120.7 10.7 113.3 116.0 2.7 SD 10.1 16.3 8.6 3.1 1.0 2.1
(107) TABLE-US-00006 TABLE 4C Changes in Mean Arterial Pressure (MAP) During Electrical Stimulation in Left Renal Artery Left Renal Stimulation MAP Maximal Responses (mmHg) Minimal Responses (mmHg) Animal Stimulation Stimulation No. Baseline Maximal Δ Location Baseline Minimal Δ Location Pig 1 112.5 125 12.5 AO Side 123 128 5 Renal Side Pig 2 130 133 3 Renal Side 131 132 1 AO Side Pig 3 141 158 17 Renal Side 136 138 2 AO Side Average 127.8 138.7 10.8 130.0 132.7 2.7 SD 14.4 17.2 7.1 6.6 5.0 2.1
(108) TABLE-US-00007 TABLE 4D Changes in Heart Rate (HR) During Electrical Stimulation in Left Renal Artery Left Renal Stimulation HR Maximal Responses (mmHg) Minimal Responses (mmHg) Animal Stimulation Stimulation No. Baseline Maximal Δ Location Baseline Minimal Δ Location Pig 1 150 151 1 Renal Side 140 130 −10 Renal Side Pig 2 126 132 6 AO Side 132 120 −12 Renal Side Pig 3 138 142 4 Renal Side 159 150 −9 AO Side Average 138.0 141.7 3.7 143.7 133.3 −10.3 SD 12.0 9.5 2.5 13.9 15.3 1.5
(109) TABLE-US-00008 TABLE 5A Changes in Systolic Blood Pressure (SBP) During Electrical Stimulation in Right Renal Artery Right Renal Stimulation SBP Maximal Responses (mmHg) Minimal Responses (mmHg) Animal Stimulation Stimulation No. Baseline Maximal Δ Location Baseline Minimal Δ Location Pig 1 151.5 156 4.5 Renal Side 155 158 3 AO Side Pig 2 153 166 13 Renal Side 157 162 5 AO Side Pig 3 154 167 13 Renal Side 157 162 5 AO Side Average 152.8 163.0 10.2 156.3 160.7 4.3 SD 1.3 6.1 4.9 1.2 2.3 1.2
(110) TABLE-US-00009 TABLE 5B Changes in Diastolic Blood Pressure (DBP) During Electrical Stimulation in Right Renal Artery Right Renal Stimulation DPB Maximal Responses (mmHg) Minimal Responses (mmHg) Animal Stimulation Stimulation No. Baseline Maximal Δ Location Baseline Minimal Δ Location Pig 1 111.5 113 1.5 Renal Side 113 113 0 AO Side Pig 2 113 119 6 Renal Side 114 117 3 AO Side Pig 3 110 113 3 Renal Side 112 110 −2 AO Side Average 111.5 115.0 3.5 113.0 113.3 0.3 SD 1.5 3.5 2.3 1.0 3.5 2.5
(111) TABLE-US-00010 TABLE 5C Changes in Mean Arterial Pressure (MAP) During Electrical Stimulation in Right Renal Artery Right Renal Stimulation MAP Maximal Responses (mmHg) Minimal Responses (mmHg) Animal Stimulation Stimulation No. Baseline Maximal Δ Location Baseline Minimal Δ Location Pig 1 130 130 0 AO Side 131 130 −1 Renal Side Pig 2 130 141 11 Renal Side 132 135 1 AO Side Pig 3 127 130 3 Renal Side 130 131 1 AO Side Average 129.0 133.7 4.7 131.0 132.0 1.0 SD 1.7 6.4 5.7 1.0 2.6 2.0
(112) TABLE-US-00011 TABLE 5D Changes in Heart Rate (HR) During Electrical Stimulation in Right Renal Artery Right Renal Stimulation HR Maximal Responses (beats/min) Minimal Responses (beats/min) Animal Stimulation Stimulation No. Baseline Maximal Δ Location Baseline Minimal Δ Location Pig 1 141 146 5 AO Side 144 135 −9 Renal Side Pig 2 135 147 12 Renal Side 120 117 −3 AO Side Pig 3 129 135 6 Renal Side 126 123 −3 AO Side Average 135.0 142.7 7.7 130.0 125.0 −5.0 SD 6.0 6.7 3.8 12.5 9.2 3.5
(113) TABLE-US-00012 TABLE 6 Possible effects of stimulating renal nerves Change of Change of blood heart rate pressure when when renal Animal renal nerve nerve Publication Model stimulated stimulated Ueda H, Uchida Y and Kamisaka K, “Mechanism Dog decrease N/A of the Reflex Depressor Effect by Kidney in Dog”, Jpn. Heart J., 1967, 8 (6): 597-606 Beacham WS and Kunze DL, Cat decrease N/A “Renal Receptors Evoking a Spinal Vasometer Reflex”, J. Physiol., 1969, 201 (1): 73-85 Aars H and Akre S Rabbit decrease N/A “Reflex Changes in Sympathetic Activity and Arterial Blood Pressure Evoked by Afferent Stimulation of the Renal Nerve”, Acta Physiol. Scand., 1970, 78 (2): 184-188 Ma G and Ho SY, Rabbit decrease Decrease “Hemodynamic Effects of Renal Interoreceptor and Afferent Nerve Stimulation in Rabbit”, Acta Physiol. Sinica, 1990, 42 (3): 262-268 Lu M, Wei SG and Chai XS, Rabbit decrease Decrease “Effect of Electrical Stimulation of Afferent Renal Nerve on Arterial Blood Pressure, Heart Rate and Vasopressin in Rabbits”, Acta Physiol. Sinica, 1995, 47 (5): 471-477
(114) Among all the stimulation experiments performed in pigs according to the previously described protocol, certain locations in the renal arterial wall led to significant decreases in heart rate without causing changes in the blood pressure or the change in blood pressure is minimal in comparison to the decrease in heart rate (
EXAMPLE 3
Ensuring Energy is Directed to a Target Nerve During Ablation
(115) Subsequent to the studies for locating and identifying nerves in an arterial wall, energies at dosage suitable for ablations were also delivered to the innervated spots in the renal arterial wall of the same pigs. Four ablations were each delivered to the left and to the right renal arteries starting from the kidney side and moving to the abdominal aorta side in the order of movement from the anterior, to the posterior, to the superior and then to the inferior wall; each ablation was ≦5 mm apart from the location of the previous ablation and the electrode head (catheter tip) of the ablation catheter was turned 90 degrees after each ablation. Based on the literature (Krum 2009, 2010), low energy level (5-8 watts) should be used for renal ablation; therefore, 5 watts and 8 watts were used for renal ablation. For left renal artery ablation, the energy level applied was 5 watts and the time length of ablation was 120 seconds; for the right renal artery, the ablation energy level applied was 8 watts and the time length was 120 seconds. The temperature at the ablation site was measured to be from 40° C. to 50° C. The physiological parameters: systolic blood pressure, diastolic blood pressure, mean arterial pressure and heart rate were examined during ablations. The data clearly showed that ablation at different locations within the renal artery resulted in differing changes in blood pressure and heart rate, further demonstrating that changes in physiological parameters such as blood pressure and heart rate can be used as indicators for an accurate delivery of ablation energy to a targeted nerve and provided further evidence that distribution of the nerves in the arterial wall varied case by case.
(116) Changes in systolic blood pressure, diastolic blood pressure, mean arterial pressure and heart rate during four separate renal ablations in the renal arteries of the left kidney were summarized in
EXAMPLE 4
Chronic Renal Nerve Ablation Experimental Results
(117) This set of experiments involves methods to determine the safety profile of the energy levels used in existing cardiac ablation catheters in the denervation of renal nerves.
(118) The ablation catheter used in this set of experiments was the 7F,B-Type, spacing 2-5-2 mm, CELSIUS® RMT Diagnostic/Ablation Steerable Catheter (Biosense Webster, Diamond Bar, Calif. 91765, USA) and a Celsius radiofrequency generator (STOCKERT 70 RF Generator, Model Stockert GmbH EP-SHUTTLE ST-3205, STOCKERT GmbH, Freiburg, Germany). Four pigs were used in the study.
(119) The energy levels used for the ablations applied were as follows: Right Renal Artery Ablation, 8 W, 120 s; Left Renal Artery Ablation 16 W, 120 s (n=3). Right Renal Artery Ablation, 16 W, 120 s; Left Renal Artery Ablation, 8 W, 120 s (n=3).
(120) The pigs were anesthetized, and 4-5 renal ablations were performed for each renal artery (right and left) separately. Renal angiography was performed before and after the ablation to examine the patency of renal arteries. Pigs were allowed to recover from the procedures. In order to determine the safety levels of ablation energy, one pig (Right renal artery, 16 W, 120 s; Left renal artery ablation, 8 W, 120 s) was terminated for assessment of acute lesions due to two different energy levels of ablation. Twelve weeks after the ablation procedure, angiography was performed on the animals for both renal arteries. Thereafter, the animals were sacrificed, and renal arteries and kidneys examined for any visible abnormalities; pictures were taken with renal arteries intact and cut open, with both kidneys cut open longitudinally. Samples from both renal arteries were collected for further histology studies according to the histology maps shown in
EXAMPLE 5
Renal Mapping Catheter Designs
(121) New catheters designed with functions of stimulation, mapping, ablation and angiography are hereby disclosed.
(122) The catheter apparatus comprises an elongated catheter having a catheter tip on the distal end which, once inserted, is intended to remain in a static position within the renal vascular architecture; a proximal end; and a plurality of ablation electrodes. In one embodiment, the ablation electrodes are evenly-spaced down the length of the elongated catheter tip. The plurality of these ablation electrodes are spaced from the proximal end and from the distal end of the elongated catheter tip by electrically nonconductive segments. In one embodiment, the first electrode on the tip side of the catheter or on the end side of the catheter can be used as a stimulation reference for any other electrodes to deliver electrical stimulation; alternatively, any one of these electrodes can be used as a reference for other electrodes.
(123) In one embodiment, the elongated catheter tip is of a helical shape.
(124) In another embodiment, one or more conducting wires are coupled with and supplying direct or alternating electrical current to the plurality of electrodes via one or more conducting wires. A controller is configured to control the electrical current to the plurality of electrodes in either an independent manner, or a simultaneous manner while the catheter tip remains in a static position in the renal artery.
(125) In another embodiment, one or more conducting wires are coupled with and supplying radiofrequency (RF) energy to the plurality of electrodes, the RF energy being either unipolar RF energy or bipolar RF energy. A radiofrequency generator supplies energy via the one or more conducting wires to the plurality of electrodes. A controller is configured to control the energy source to supply energy to the plurality of electrodes in either an independent manner, a sequential manner, or a simultaneous manner while the catheter tip remains in a static position in the renal artery
(126) The RF energy sent to the electrodes may be controlled so that only low-level electrical energy impulses are generated by the electrodes in order to merely stimulate underlying nerve tissue, and in particular, renal nerve tissue. Alternately, the RF energy sent to the electrodes may be controlled so that greater electrical energy impulses are generated by the electrodes in order to ablate underlying nerve tissue, and in particular, renal nerve tissue. The catheter tip, and in particular, the electrodes, are designed to remain in contact with the renal artery lumen, in the same place, throughout stimulation and ablation
(127) In another embodiment, the catheter is capable of being used with radiofrequency generators currently utilized in the practice of cardiac tissue ablation. These radiofrequency generators may include, but are not necessarily limited to those currently produced by Medtronic, Cordis/Johnson & Johnson, St. Jude Medical, and Biotronic.
(128) Exemplary embodiments of the invention, as described in greater detail below, provide apparatuses for renal nerve denervation
(129)
(130) In one embodiment, the catheter has an elongated tip of a helical shape. A plurality of electrodes is evenly spaced starting from their placement at the proximal end of the catheter tip through the distal end of the catheter tip by electrically nonconductive segments.
(131) In certain embodiments, the catheter tip of the ablation catheter comprises a single helix; in others, it is composed of a double helix. The coil or coils of the helix or helices of the catheter tip may be either round or flat. Electrodes may be placed evenly down the length of the coils; for example, they can be spaced either 60°, 90° or 120° apart, but may be placed in other conformations or separated by different degrees
(132) In one embodiment, the electrodes may be either flat and rectangular or square in shape, if the coil of a helix is itself flattened. Alternately, the electrodes may be round and/or built into the helix if the coil is itself round. In another embodiment, the catheter tip has a length of from 2.0 cm to 8.0 cm and a diameter of 0.5 mm to 10.0 mm; the diameters of coil may vary from 3.0 mm to 7.5 mm; the distances of each coil may vary from 4 mm to 6 mm; and the fully uncoiled lengths of the coils may vary from 31 mm to 471 mm; the catheter's total length is from 1 m to 2.0 m.
(133) In another embodiment, the catheter tip of the ablation catheter comprises a balloon catheter system. In one embodiment, electrodes are evenly spaced at intervals along a helical coil which is either round or flat in shape and wrapped around the balloon; in other embodiments, electrodes are spaced along an umbrella frame apparatus which is either round or flat in shape and wrapped down the length of the balloon. In certain embodiments, the umbrella frame apparatus has an open end and in others, a closed end. The electrodes will come into contact with the renal architecture upon inflation of the balloon apparatus. In one embodiment, the catheter tip has a length of 2.0 cm to 8.0 cm and a diameter from 0.5 mm to 10.0 mm when the balloon is not inflated; the diameters of coil may vary from 3.0 mm to 8 mm; the distances of each coil may vary from 4 mm to 6 mm; the numbers of coils may vary from 3.3 to 20; and the fully uncoiled lengths of the coils may vary from 31 mm to 471 mm. the catheter's total length is from 1 m to 2.0 m.
(134) In one embodiment, the diameter of the catheter tip when the balloon is inflated may range from 0.5 mm to 10 mm. The diameter of the coil around the balloon may range from 3 mm to 10 mm and the diameter of a fully inflated balloon is from 3 mm to 10 mm.
(135) The invention may also comprise a catheter tip which is tube-like, cylindrical, and self-expanding with adjustable sizes. The materials used for these catheter tips may, in certain embodiments, comprise nickel-titanium (nitinol) alloy.
(136) In one embodiment of this invention, there is provided a renal nerve modulation and ablation processes (on either the left side kidney, right side kidney, or both) comprising insertion of one of the catheters described above into either the left renal artery (LRA) or the right renal artery (RRA) followed by renal nerve mapping as substantially described above, followed by targeted ablation by individual electrodes.
(137) In one embodiment, nerve stimulation takes place by application of the following parameters: 0.1 ms-20 ms, 2V-30V, 5 mA-40 mA, and 100 Ohm-1000 Ohm. In one embodiment, nerve ablation takes place by application of the following parameters: below 12 watts and 30 seconds-180 seconds.
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