Assessing flow response using combined stimulation and ablation for guidance in renal denervation

Abstract

A system and method for denervation of nerves of a blood vessel including a therapeutic device configured for navigation within a blood vessel of a patient, stimulation elements formed on the therapeutic device, a stimulation source in communication with the stimulation elements, a therapy source in communication with the therapeutic device; and a computing device to cause the stimulation source to generate a stimulations signal for application to a blood vessel wall via at least one of the plurality of stimulation elements, detect changes in blood flow through the blood vessel, cause the therapy source to generate a therapy for application the blood vessel wall, and compare a change in blood flow through the blood vessel to a threshold to determine whether the therapy has denervated nerves.

Description

ASSESSING FLOW RESPONSE USING COMBINED STIMULATION AND ABLATION FOR GUIDANCE IN RENAL DENERVATION

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 555,781, filed February 20, 2024, the entire content of which is incorporated herein by reference.Technical Field

[0002] This disclosure relates to systems and methods enabling positioning a therapeutic device within luminal tissues to enhance ablation during a therapeutic procedure. In particular aspects, the present disclosure is directed to methods and systems for denervating nerves in or around vascular tissue.Background

[0003] Catheters have been proposed for use with various medical procedures. For example, a catheter can be configured to deliver neuromodulation (e.g., denervation) therapy to a target tissue site to modify the activity of nerves at or near the target tissue site. The nerves can be, for example, sympathetic or parasympathetic nerves. The sympathetic nervous system (SNS) is a primarily involuntary bodily control system typically associated with stress responses. Chronic over-activation of the SNS is a maladaptive response that can drive the progression of many disease states. For example, excessive activation of the renal SNS has been identified experimentally and in humans as a contributor to the complex pathophysiology of arrhythmias, hypertension, states of volume overload (e.g., heart failure), and progressive renal disease.

[0004] Percutaneous renal denervation is a minimally invasive procedure that can be used to treat hypertension and other diseases caused by over-activation of the SNS. During for example, a renal denervation procedure, a clinician delivers energy, such as radiofrequency, ultrasound, cooling, or other energy to a treatment site within the renal vessels to reduce, and / or permanently stop the activity of nerves surrounding a blood vessel. The energy delivered to the treatment site may provide various therapeutic effects through alteration of sympathetic nerve activity.SUMMARY

[0005] One aspect of the disclosure is directed system for denervation of nerves of a blood vessel. The system includes a therapeutic device configured for navigation within ablood vessel of a patient; a plurality of stimulation elements formed on a distal portion of the therapeutic device; a stimulation source in communication with the plurality of stimulation elements; a therapy source in communication with the therapeutic device; and a computing device including a processor and a memory storing thereon instructions that, when executed, cause the processor to: cause the stimulation source to generate a first stimulation signal for application to a blood vessel wall via at least one of the plurality of stimulation elements; detect a first change in blood flow through the blood vessel as a result of the application of the first stimulation signal; cause the therapy source to generate a therapy for application the blood vessel wall via the therapeutic device; cause the stimulation source to generate a second stimulation signal for application to the blood vessel wall via the at least one of the plurality of stimulation element; detect a second change in blood flow through the blood vessel as result of the application of the second stimulation signal; compare the second change in blood flow through the blood vessel to a threshold; determine whether the application of the therapy has denervated nerves proximate the at least one of the plurality of stimulation elements based on the comparison of the second change in blood flow through the blood vessel to the threshold; and output an indicator related to success of the application of the therapy. Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods.

[0006] Implementations may include one or more of the following features. The system where the memory stores thereon instructions that when executed cause the processor to detect a baseline blood flow and determine whether the first detected change in blood flow from the baseline blood flow is indicative of a presence of a nerves proximate the at least one of the plurality of stimulation elements. The first stimulation signal or the second stimulation signal and the therapy are a combined signal. Detection of the first change in blood flow occurs after an initial period of time from an onset of application of therapy to the blood vessel wall and the detection of the second change in blood flow occurs after a second period of time from the onset of application of therapy to the blood vessel wall. The threshold is a magnitude of the first change in blood flow. The instructions, when executed, cause the processor to present an indicator on a user interface associated with the computing device including one or more of a presence of a nerve proximate the at least one of the plurality of stimulation elements, or an indicator of a successful denervation, or an indicator of an unsuccessful denervation. The instructions, when executed, cause the processor to stop the generation of therapy, adjust parameters of the first stimulation signal, and apply anadjusted stimulation signal for a first period of time. The instructions when executed by the processor sense a third change in blood flow from a baseline blood flow as a result of the application of the adjusted stimulation signal; determine whether the sensed third change in blood flow is indicative of a presence of a nerve proximate the at least one of the plurality of stimulation elements; and output an indicator of the presence of a nerve proximate the at least one of the plurality of stimulation elements. The instructions when executed by the processor determine that the nerves are deep and require additional time or increased therapy power to complete the therapy. The system may include a sensor configured to measure blood flow through the blood vessel. Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium.

[0007] Another aspect of the disclosure is directed to a method of performing a therapeutic procedure. The method includes applying a first stimulation signal from stimulation elements of a therapeutic device to a blood vessel wall; observing a first change in blood flow in a blood vessel in response to the first stimulation signal, applying a therapy to the blood vessel wall, applying a second stimulation signal from the stimulation elements to the blood vessel wall, observing second change in blood flow in the blood vessel in response to the second stimulation signal, and outputting an indicator of related to success of the therapy when the second change in blood flow is less than a threshold. Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods.

[0008] Implementations may include one or more of the following features. The method may include detecting a baseline blood flow and determining whether the first change blood flow from the baseline blood flow is indicative of a presence of nerves proximate the stimulation elements. The first stimulation signal or the second stimulation signal and the therapy are a combined signal. The method may include observing the first change in blood flow after an initial period of time from an onset of application of therapy to the blood vessel wall and observing the second change in blood flow occurs after a second period of time from the onset of application of therapy to the blood vessel wall. The threshold is a magnitude of the first change in blood flow. The method may include presenting an indicator on a user interface associated with a computing device including one or more of a presence of a nerve proximate the stimulation elements, an indicator of a successful denervation, or an indicator of an unsuccessful denervation. The method may include stopping applicationof therapy, adjusting parameters of the first stimulation signal, and applying an adjusted stimulation signal for a first period of time. The method may include: detecting a baseline blood flow; sensing a third change in blood flow from the baseline blood flow as a result of the application of the adjusted stimulation signal; determining whether the third sensed change in blood flow is indicative of a presence of a nerve proximate the at least one of the plurality of stimulation elements; and outputting an indicator of the presence of a nerve proximate the stimulation elements. The method may include determining that nerves are deep and require additional time or increased therapy power to complete the therapy. The method of one may include receiving an output from a sensor configured to measure blood flow through the blood vessel. Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium.

[0009] A further aspect of the disclosure is directed to a system for denervation of nerves of a blood vessel. The system includes a therapeutic device configured for navigation within a blood vessel of a patient; a plurality of stimulation elements formed on a distal portion of the therapeutic device; a stimulation source in communication with the plurality of stimulation elements; a therapy source in communication with the therapeutic device; and a computing device including a processor and a memory storing thereon instructions that, when executed, cause the processor to: detect a baseline blood flow through the blood vessel; cause the stimulation source to generate a first stimulation signal for application to a blood vessel wall via at least one of the plurality of stimulation elements; detect a first change in blood flow through the blood vessel as a result of the application of the first stimulation signal, where the first change is relative to the baseline blood flow through the vessel; determine whether the first detected change in blood flow is indicative of a presence of a nerves proximate the at least one of the plurality of stimulation elements; and in response to determining that the first detected change in blood flow is indicative of the presence of nerves, output via a user interface an indication related to the presence of nerves to a user. Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods.

[0010] A further aspect of the disclosure is directed to a system for denervation of nerves of a blood vessel. The system includes a therapeutic device configured for navigation within a blood vessel of a patient; a plurality of stimulation elements formed on a distal portion of the therapeutic device; a stimulation source in communication with the plurality of stimulation elements; a therapy source in communication with the therapeutic device; and acomputing device including a processor and a memory storing thereon instructions that, when executed, cause the processor to: cause the therapy source to deliver a denervation therapy via the therapeutic device; after delivery of the denervation therapy, detect a baseline blood flow through the blood vessel; cause the stimulation source to generate a first stimulation signal for application to a blood vessel wall via at least one of the plurality of stimulation elements; detect a first change in blood flow through the blood vessel as a result of the application of the first stimulation signal, where the first change is relative to the baseline blood flow through the vessel; determine whether the first detected change in blood flow indicates that the denervation therapy has denervated nerves proximate the blood vessel; and output an indicator related to success of the application of the denervation therapy. Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods.

[0011] Further disclosed herein is a system and method for denervation of nerves of a blood vessel including a therapeutic device configured for navigation within a blood vessel of a patient, stimulation elements formed on the therapeutic device, a stimulation source in communication with the stimulation elements, a therapy source in communication with the therapeutic device; and a computing device to cause the stimulation source to generate a stimulations signal for application to a blood vessel wall via at least one of the plurality of stimulation elements, detect changes in blood flow through the blood vessel, cause the therapy source to generate a therapy for application the blood vessel wall, and compare a change in blood flow through the blood vessel to a threshold to determine whether the therapy has denervated nerves.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Various aspects and embodiments of the disclosure are described hereinbelow with references to the drawings, wherein:

[0013] FIG. 1 is a schematic diagram of a therapy system provided in accordance with the disclosure;

[0014] FIG. 2 is a schematic view of a workstation of the therapy system of FIG. 1;

[0015] FIG. 3 is a perspective view of a therapeutic device of the therapy system ofFIG. 1 advanced within a portion of the patient’s anatomy and in a deployed condition in accordance with the disclosure;

[0016] FIG. 4A is a graphical representation of two methods of performing a diagnostic and therapeutic procedure in accordance with the disclosure;

[0017] FIG. 4B is a graphical representation of a combined stimulation signal and therapy in accordance with the disclosure;

[0018] FIG. 5 is a method of applying stimulation and therapy in accordance with the disclosure;

[0019] FIG. 6A is a method of applying stimulation and therapy in accordance with the disclosure;

[0020] FIG. 6B is a representation of the detected change in blood flow in a blood vessel in accordance with aspects of the disclosure;

[0021] FIG. 7 is a method of applying stimulation and therapy in accordance with the disclosure; and

[0022] FIG. 8 is a representation of a portion of a therapeutic device in accordance with aspects of the disclosure.DETAILED DESCRIPTION

[0023] This disclosure is directed to therapeutic systems and methods and particularly ablation systems and methods for denervation or neuromodulation of nerves such as the sympathetic, or parasympathetic, nerves. Some aspects of the disclosure are directed to ablation and denervation of unmyelinated nerve fibers in and around blood vessels and other luminal tissues. In particular, this disclosure is directed to systems and methods that provide intra-procedure and / or post-procedure feedback on the progress of the therapy.

[0024] For ease of description, much of the following description focuses on implementations of radiofrequency (RF) ablation and denervation. Those having skill in the art will recognize that T|the methods and systems described herein may employ any of the therapy modalities described herein including without limitation monopolar or bipolar RF, microwave, ultrasound, chemical, cryogenic and other already developed or yet to be developed therapy modalities. Further, combinations of these therapies may be applied without departing from the scope of the disclosure. Similarly, the following description focuses on navigation to and application of therapy to the renal artery to denervate sympathetic or, in certain embodiments, parasympathetic, nerves in, around, and proximate the renal arteries. However, the present disclosure is not so limited. In general, the devices, systems, and techniques described herein may be used in conjunction with neuromodulation (e.g., denervation) performed from within any suitable anatomical lumen that has nervesadjacent to the anatomical lumen. Example anatomical lumens include the celiac trunk and its branches (including the common hepatic artery and its branches (including the gastroduodenal artery and its branches, the right gastric artery and its branches, and the proper hepatic artery and its branches), the left gastric artery and its branches, and the splenic artery and its branches), the superior mesenteric artery and its branches, the gonadal artery and its branches, the inferior mesenteric artery and its branches, and the like. Further, although the disclosure primarily describes neuromodulation (e.g., denervation) from within one or more arteries, the devices, systems, and techniques of the disclosure also may be applied to neuromodulation from within one or more veins, such as a renal vein and its branches, a hepatic vein and its branches, an intercostal vein and its branches, or the like. In some implementations the devices, systems, and techniques described herein may be used to perform neuromodulation (e g., denervation) from within two or more anatomical lumens, e.g., in the renal arteries and the common hepatic artery, or any other combination of two or more anatomical lumens, either simultaneously or sequentially. In addition, the systems, devices, and methods described herein may be useful in conjunction with neuromodulation (e.g., denervation) within a body lumen other than a vessel, for extravascular neuromodulation and / or for use in conjunction with therapies other than neuromodulation. Still further while generally contemplated that the locations described above are to be navigated to percutaneously, for example via the femoral artery, the therapeutic devices described herein may also be placed laparoscopically placed in or near one or more of the above-identified blood vessels, or another luminal tissue without departing from the scope of the present disclosure.

[0025] Turning now to the drawings, FIG. 1 illustrates a therapy system provided in accordance with the present disclosure and generally identified by reference numeral 10. As shown in FIG. 1, therapy system 10 may be used in connection with a C-arm imaging system or other imaging station, which may facilitate navigation of a therapeutic device 50 to a desired location within the patient’s anatomy (e.g., the patient’s renal artery), application of denervation therapy to the tissue proximate the renal artery to denervate sympathetic nerves within the tissue, and monitoring of one or more parameter, such as impedance, for use in evaluating the denervation therapy.

[0026] The therapy system 10 includes a workstation 20 and a therapeutic device 50 operably coupled to the workstation 20. The therapy system may be used with an imaging device 70, which may be operably coupled to a display 72. The patient “P” is shown lying on an operating table 12 with the therapeutic device 50 inserted through a portion of thepatient’s femoral artery, although it is contemplated that the therapeutic device 50 may be inserted into any suitable portion of the patient’s vascular network that is in fluid communication with a desired blood vessel for therapy. Although generally described as having one therapeutic device 50, it is envisioned that the therapy system 10 may employ any suitable number of therapeutic devices 50. The therapeutic devices 50 may employ the same or different therapy modalities and be operably coupled to the workstation 20. Further, the therapeutic device 50 may employ a guidewire (now shown) or a guide catheter 58 (FIG. 3) without departing from the scope of the disclosure.

[0027] Continuing with FIG. 1 and with additional reference to FIG. 2, the workstation 20 includes a computer 22, a therapy source 24 (e.g., one or more of an RF generator, a microwave generator, an ultrasound generator, a cryogenic medium source, a chemical source, etc ) operably coupled to the computer 22, and a stimulation source 24a (configured for generation of stimulation signals, e.g., ultrasound, electrical, RF, etc.). In some examples, the computer 22, therapy source 24, and / or stimulation source 24a are integrated in a single component and may be referred to as a generator, controller, or console.

[0028] The computer 22 is coupled to a display 26 that is configured to display one or more user interfaces 28. The computer 22 may be a desktop computer or a tower configuration with display 26 or may include a laptop computer or other computing device. The computer 22 includes a processor 30 which executes software stored in a memory 32. The memory 32 may store one or more applications 34 and / or algorithms 44 to be executed by the processor 30. A network interface 36 enables the workstation 20 to communicate with a variety of other devices and systems via the internet. The network interface 36 may connect the workstation 20 to the Internet via a wired or wireless connection. Additionally, or alternatively, the communication may be via an ad hoc Bluetooth® or wireless network enabling communication with a wide-area network (WAN) and / or a local area network (LAN). The network interface 36 may connect to the Internet via one or more gateways, routers, and network address translation (NAT) devices. The network interface 36 may communicate with a cloud storage system 38, in which further data, image data, and / or videos may be stored. The cloud storage system 38 may be remote from or on the premises of the hospital such as in a control or hospital information technology room. It is envisioned that the cloud storage system 38 could also serve as a host for more robust analysis of acquired images (e.g., fluoroscopic, computed tomography (CT), magnetic resonance imaging (MRI), cone-beam computed tomography (CBCT), etc.), data, etc. (e.g, additional or reinforcement data for analysis and / or comparison). An input module 40 receives inputsfrom an input device such as a keyboard, a mouse, voice commands, an energy source controller (e.g., a foot pedal or handheld remote-control device) that enables the clinician to initiate, terminate, and optionally, adjust various operational characteristics of the therapy source 24 and / or stimulation source 24a, including, but not limited to, therapy or stimulation delivery, amongst others. An output module 42 connects the processor 30 and the memory 32 to a variety of output devices such as the display 26. In embodiments, the display 26 may be a touchscreen display.

[0029] The therapy source 24 may be configured to generate and output one or more of RF energy (monopolar or bipolar), microwave energy, ultrasound energy, cryogenic energy, or chemical ablation medium via semi-automated or automated control algorithm 44 stored on the memory 32 and / or under the control of a clinician. As can be appreciated, many of the therapies listed above change the temperature of the tissue (e.g., increase or decrease the temperature) to achieve the desired denervation of the nerves. The therapy source 24 may be configured to produce a selected modality and magnitude of energy and / or therapy for delivery to the treatment site via the therapeutic device 50, as will be described in further detail hereinbelow. The therapy source 24 may be configured to sense voltage and current (e.g., in the case of RF or other electrical energy) applied to target tissue via the therapeutic device 50. In addition, one or more sensors on the therapeutic device 50 may monitor the temperature of the target tissue or tissue proximate the target tissue, and / or a portion of the therapeutic device 50. Utilizing the sensed voltage and current applied to the tissue, an application 34 on the computer 22 may be configured to calculate an impedance of the tissue through which therapeutic energy is transmitted to provide an indication of the status of the tissue. The computer 22 may be configured to output the status to the display 26 on one or more user interfaces 28 to provide a clinician with both intraprocedural and post-procedural feedback regarding the therapy.

[0030] The stimulation source 24a generates a stimulation signal, for example a biphasic waveform at an energy level that is less the therapeutic (i.e., denervation energy) generated by the therapy source 24 such that the stimulation generated by the stimulation source 24a does not denervate the target tissue. Rather, the stimulation source 24a generates a stimulation signal capable of effectuating a response from the nerves indicative of tissue that would be a candidate for denervation. Responses may include an increase in blood pressure, an increase in vessel stiffness, changes in pulse wave velocity, augmentation pressure, heart rate variability, etc., and combinations of these.

[0031] In one example, the stimulation source 24a generates a biphasic waveform where a leading phase of each successive pulse of the biphasic waveform is switched or otherwise inverted. In this manner, a biphasic waveform having an initial pulse with an anodal leading phase and a cathodal trailing phase is followed by a second pulse with a cathodal leading phase and an anodal trailing phase which will be followed by a third pulse returning to an anodal leading phase and a cathodal trailing phase, and so on. Alternatively, a biphasic waveform having an initial pulse with a cathodal leading phase and an anodal trailing phase may be followed by a second pulse with an anodal leading phase and a cathodal trailing phase which will be followed by a third pulse returning to a cathodal leading phase and an anodal trailing phase. As can be appreciated, the leading phase of each pulse of the biphasic waveform may be alternated for the duration of the application of neurostimulation to the target tissue.

[0032] As noted above, the amplitude, frequency, pulse width, and / or duration of the stimulation can be selected and / or modified to ensure neurostimulation of the sympathetic nerves of the luminal tissue without damaging the luminal tissue or the nerves within or surrounding the luminal tissue or causing excess vasoconstriction about the therapeutic device (e.g., inhibiting the movement of the therapeutic device within the luminal tissue). A pulse duration (pulse width) may be modified to ensure that anodic stimulation of the tissue is maintained as at certain pulse durations regions of anodic stimulation may dissipate or otherwise disappear resulting in reduced stimulation effect. In one non-limiting embodiment, the stimulation source 24a generates biphasic waveforms having a frequency of between approximately 10 - 30Hz, a voltage of between approximately 5 - 30 V, a current of between approximately 2 - 500 mA, and a pulse width of between approximately 2 - 10 ms. It is envisioned that in embodiments where unmyelinated nerve fibers are targeted, the pulse width of the biphasic waveform may be between approximately 2-120 ms. In a further example, the stimulation parameters are a constant current of 20mA for a blood vessel branches and 30 mA for main blood vessels, a pulse width of 5 mS, a frequency of approximately 20 Hz and a duration of between 10 and 60 seconds.

[0033] While a biphasic stimulation signal has been described above, the disclosure is not so limited, and the stimulation signal may be monophasic or biphasic. The stimulation signal may be a current injection signal where a voltage is monitored for safety or a voltage injection signal. The stimulation signal may for example have a frequency of between about 5 Hz and about 1 kHz, optionally between about 10 Hz and 700Hz, between about 50Hz and 500 Hz, between about 100 Hz and 500 Hz, or between about 200 and 400 Hz. Thesignal has a pulse width of between about 3 and about 10 ms, optionally between about 5 and 8 ms, or about 7 ms. The signal has a current of between about 15 and about 50 mA, optionally between about 20 and 40 mA, or about 30 mA. The signal has a voltage of between 1 and 100 V, optionally between about 10 and 50 V, between about 20 and 40V, or about 30V or between about 25 and 75 V, between about 35 and 60 V, or about 50V.The stimulation source 24a may also be an ultrasound stimulation source, whereby the stimulation source 24a provides signals to ultrasound transducer, causing mechanical oscillation of the transducers. The oscillations apply mechanical stimulation to the blood vessel wall and trigger nervous responses (both efferent and afferent) from the nerves within the smooth muscle of the blood vessel and nerves running along or near an exterior surface of the blood vessel.

[0034] FIG. 3 depicts one embodiment of a therapeutic device 50 in accordance with the disclosure. The therapeutic device 50 includes an elongated shaft 52 having a handle (not shown) disposed on a proximal end portion of the elongated shaft 52. The therapeutic device 50 includes an energy delivery assembly 54 on a distal portion of the elongate shaft 52 at which electrodes 56 are located. The elongated shaft 52 of the therapeutic device 50 is configured to be advanced over a guide wire (not shown) within a portion of the patient’s vasculature, such as a femoral artery or other suitable portion of patient’s vascular network that is in fluid communication with the patient’s renal artery. In embodiments, the energy delivery assembly 54 is configured to be transformed from an initial, undeployed configuration having a generally linear profile, to a second, deployed or expanded configuration, where the energy delivery assembly 54 forms a generally spiral and / or helical configuration for delivering energy to a site for application of therapeutic energy or application of stimulation signals at the treatment site. In this manner, when in the second, expanded configuration, the energy delivery assembly 54, and in particular the individual electrodes 56, is pressed against or otherwise contacts the walls of the patient’s vasculature tissue. Although generally described as transitioning to a spiral and / or helical configuration, it is envisioned that the energy delivery assembly 54 may be deployed in other configurations without departing from the scope of the present disclosure. Further, the therapeutic device 50 may be configurable, for example, using one or more pull wires (not shown) to adjust the configuration to promote contact between the electrodes 56 and the wall of the renal artery. As such, the therapeutic device 50 may be capable of being placed in one, two, three, four, or more different configurations depending upon the design needs of the therapeutic device 50 or the location at which therapy is to be applied. Still further,and without departing from the scope of the disclosure, the energy delivery assembly 54 and electrodes 56 may be formed on an exterior of an inflatable balloon, and expandable basket, a lasso, or a pigtail catheter to achieve the placement of the electrodes 56 in contact with the blood vessel wall without departing from the scope of the disclosure. In addition, though generally described as being achieved using a single therapeutic device 50, multiple therapeutic devices 50 may be employed (e.g., with a separate therapeutic device 50 applying the blocking signal the block neural response).

[0035] As depicted in FIG. 3, the elongated shaft 52 may be configured to be received within a portion of a guide catheter or guide sheath (such as a 6F guide catheter) 58 that is utilized to navigate the therapeutic device 50 to a desired location. In practice, the guide catheter 58 is inserted into an access point such as the femoral artery to gain access to the vascular system. The guide catheter 58 is advanced to the desired location, for example to cannulate a renal artery. A guide wire (not shown) is advanced through the guide catheter 58 and to a location where therapy is to be applied (i.e., beyond a distal end of the guide catheter 58) and into the desired blood vessel (e g., the renal artery). The therapeutic device 50 is then advanced over the guide wire beyond the end of the guide catheter 58 exposing the electrodes 56 at the location where the therapy is to be applied. The guide wire is then retracted within the therapeutic device 50 and the guide catheter 58. Retraction of the guide wire within the therapeutic device 50 causes the energy delivery assembly 54 of the therapeutic device 50 to transition from the first, undeployed configuration, to the second, deployed or expanded configuration (as shown in FIG. 3) with the electrodes 56 contacting the wall of the blood vessel. Though described herein as advancing the therapeutic device 50 beyond the guide catheter 58, in some configurations, the guide catheter 58 may be retracted relative to the therapeutic device 50 to achieve a desired placement of the electrodes 56 in contact with the blood vessel wall. Further, though described herein in connection with the use of a guide wire, the guide wire is not required, and the placement described herein above may be achieved without the use of the guide wire (e.g., with only a guide catheter). The elongated shaft 52 of the therapeutic device 50 may include an aperture (not shown) at a distal end thereof and configured to slidably receive the guidewire over which the therapeutic device 50, either alone or in combination with the guide catheter 58, are advanced. In this manner, the guidewire is utilized to guide the therapeutic device 50 to the target tissue using over-the-wire (OTW) or rapid exchange (RX) techniques, at which point the guide wire may be partially or fully removed from the therapeutic device 50, enabling the therapeutic device 50 to transition from the first, undeployed configuration, tothe second, deployed or expanded configuration (FIG. 3). As noted elsewhere herein, the therapeutic device 50 may transition from the first, undeployed configuration to the second, deployed configuration automatically (e.g., via a shape memory alloy, etc.) or manually (e.g, via pull wires, guide wire manipulation, etc. that is controlled by the clinician).

[0036] In some embodiments, a pressure sensor 60 may be incorporated into the guide catheter 58 or the elongated shaft 52 for detection of physiological parameters of the patient. In one example the physiological parameter is blood pressure though other parameters may be detected without departing from the scope of the disclosure.

[0037] As illustrated in the figures, the electrodes 56 are disposed in spaced relation to one another along a length of the therapeutic device 50 forming the energy delivery assembly 54. As will be appreciated, these electrodes 56 are in communication with the therapy source 24 and the stimulation source 24a. The electrodes 56 may deliver therapy and / or stimulation independently of one another, simultaneously, selectively, or sequentially. The electrodes 56 may be in electrical communication with a ground pad (not shown) placed on the patient’s skin and electrically connected to the generator and / or stimulator to enable the application of monopolar RF energy for therapy. Additionally or alternatively, therapy and / or stimulation energy may be applied between any desired combination of the electrodes 56, without requiring the use of a ground pad (e g., bipolar stimulation or therapy).

[0038] In at least one embodiment of the disclosure, the therapy source 24 is also the stimulation source 24a operates in both a stimulation mode, where the therapy source 24 generates a stimulation signal having, for example, a biphasic waveform, and a denervation mode, where the therapy source 24 generates RF energy to denervate the nerves of the relevant blood vessel. It is contemplated that the therapy source 24 may be manually switched from a stimulation mode to a denervation mode and vice versa or may be automatically switched by an algorithm 44 stored on the memory 32 of the computing device. Alternatively, the electrodes 56 are in communication with a stand-alone stimulation source 24a to deliver a stimulation signal to the blood vessel in question. The stimulation signal (e.g., the biphasic waveform), is generated by the stimulation source 24a and communicated to the electrodes 56 causing stimulation of the nerves as described herein.

[0039] According to aspects of the disclosure, during the anodal phase of the biphasic pulse, the stimulation signal is applied to the target tissue via a first of the electrodes 56 and received by a second of the electrodes 56 in a bipolar manner and during the cathodal phaseof the biphasic pulse the neurostimulation is applied to the target tissue via the second of the electrodes 56 and received by the first of the electrodes 56 in a bipolar manner. It is envisioned that during the anodal phase or the cathodal phase of the bipolar pulse, the stimulation signal is applied by two or more of the electrodes 56 or received by two or more of the electrodes 56 in any suitable configuration, such as a proximal most electrode 56 and a distal most electrode 56, a proximal most electrode 56 and a next proximal most electrode 56 a proximal most electrode 56 and an electrode 56 disposed just proximal of the distal most electrode 56, etc.

[0040] Further, one or more algorithms 44 may be employed for the stimulation of the multiple electrodes 56. Where for example, if there are four electrodes, there may be a firing order for the electrodes 56 to apply the neurostimulation. In such an example the electrodes 56 may connect in a bipolar fashion as follows. In a first anodal phase between a first electrode and a fourth, first cathodal phase between the fourth electrode and the first electrode. This may be followed by a second cathodal phase between the fourth electrode and the first electrode and a second anodal phase between the first electrode and the fourth electrode. This may be followed in a similar manner by different pairs of electrodes 56, for example between the first and third electrodes 56, the first and second electrodes 56. A similar pattern may be followed between second and fourth electrodes and the second and third electrodes. Still further, an anodal and cathodal phase need not be between the same pairs of electrodes. For example, a first anodal phase may be between a first and a fourth electrode and be followed by a cathodal phase between the fourth and the second electrode. Alternatively, the first anodal phase may be between a first and a fourth electrode and followed by a cathodal phase between the fourth and first electrodes 56, as in the first example, however the second anodal phase may be between the second and the fourth electrodes followed by a second cathodal phase between the fourth and second electrodes. The firing order of the electrodes 56 is limited only by the number of electrodes 56 and the biphasic waveform.

[0041] During the application of the stimulation signal to the target tissue, alternating the leading phase of each successive pulse of the biphasic waveform stimulates a greater number of nerves within the target tissue as compared to traditional bipolar or monopolar stimulation. By stimulating a greater number of nerves within the target tissue, an optimal placement of the electrodes 56 within the target tissue for denervation can be more readily identified to ensure effective renal denervation and an optimal outcome. The location and / or orientation of the electrodes 56 relative to the tissue wall can be altered between theapplication of stimulation signals to map or otherwise identify optimal nerve candidates for denervation.

[0042] Though described herein above as employing electrodes 56 for the application of stimulation signals, where the stimulation source 24a is an ultrasonic stimulation source instead of employing electrodes 56 to apply a stimulation source to the blood vessel wall, one or more ultrasound transducers 57 can be deployed on a distal portion of the elongated shaft 52 (e.g., between electrodes 56) can be connected to the stimulation source 24a. A signal from the stimulation source 24a causes the transducers to oscillate and apply mechanical stimulation to nerves located within the smooth muscle of the blood vessel or along or near an outer surface of the blood vessel and elicit a nervous response. Accordingly, electrodes 56 and ultrasound transducers 57 can be generally referred to as stimulation elements.

[0043] During current denervation procedures, it is not possible for a clinician to visualize the locations of the nerves prior to application of the therapy. Instead, denervation catheters are positioned to the best of the clinician’s abilities, e g , based on fluoroscopic imaging of the catheter within the blood vessel, and several ablations may be performed. As a result, the clinicians have no indication the ablations they are performing are actually ablating any nerves Further, there is no indication during the procedure that the ablation was successful. Accordingly, this disclosure is directed to systems and methods of addressing these shortcomings of the current technologies.

[0044] Stimulation of efferent nerves, for example renal sympathetic nerves, can result in a change blood flow through the blood vessel to which the stimulation has been applied such as the renal artery and its branches. Assessing a change in response to stimulation, for example comparing a pre-therapy response to a post therapy response to stimulation can be employed to assess the efficacy of the therapy. In addition, the differences in response can be utilized to determine whether therapy can stop or whether further application of therapy is needed. However, the addition of and assessment of multiple stimulations of the nerves of the blood vessel increases the procedural time. In addition, there is no real guidance on when the application of therapy has reached a procedure end point. Instead the only determination being made is whether sufficient or insufficient therapy has been applied. But this can lead to the application of unneeded therapy, extending the procedure time. This increased procedural time can be reduced or eliminated by incorporating the stimulation signal with the ablation and monitoring changes in blood flow as a result of the stimulation. When stimulation results in a change in blood flow that satisfies a criteria (e.g., is below athreshold change value), the procedure is complete. This method may start with an initial stimulation signal being applied to a wall of the blood vessel, this provides an initial assessment of the placement of the therapeutic device 40 and the electrodes 56. If necessary, the therapeutic device 50 may be moved if insufficient response is detected (change in blood flow). Following the initial stimulation a combined therapy and stimulation signal until a change in blood flow following stimulation below a threshold is observed. This provides the end point for the application of the therapy and may optionally be followed by a stimulation signal to confirm the lack of response or response below a threshold, which is indicative of successful denervation.

[0045] In accordance with one aspect of the disclosure, the combined therapy and stimulation signal may be comprised of two components. The therapy signal may be for example a monopolar RF signal operating at about 466 kHz and the stimulation signal may be a DC pulse of between 10 and 50 Hz. The therapy may be applied for a duration of for example 90 ms followed by a stimulation pulse for 10 ms. Those of skill in the art will recognize that other parameters for the combined stimulation and therapy signal can be employed without departing from the scope of the disclosure.

[0046] In accordance with a further aspect of the disclosure the stimulation signal may be variable and may be controlled (e.g., caused to increase) through the procedure. The locations of nerves relative to a blood vessel may vary depending on where a therapy is being applied. In addition, there is inherent variability from person to person. To address this challenge, the initial stimulation signal may be relatively low magnitude and low pulse width stimulation signal, but sufficient to elicit a response from nerves located near the electrodes 56. Subsequent stimulation signals (e.g., following every 90 ms therapy signal) may have an increasing pulse width or magnitude. As will be appreciated, not every stimulation pulse need be greater in magnitude or pulse width than its predecessor, and one or both of magnitude or pulse width may be increased from time to time (e.g., at a predefined intervals, such as every 5thstimulation). The application of therapy and the increasing amplitude or pulse width stimulation signals can continue until a decrease in blood flow as a result of the stimulation satisfies a criteria (e.g., the blood flow change is less than a threshold change value).

[0047] Additionally or alternatively, the magnitude of the therapy (e.g., the RF signal power) may also be controlled (e g., increased) during the procedure. This enables the delivery of therapy to target nerves at the correct depth, as therapy at a higher RF signal power may ablate nerves further from the RF electrode(s). Where all the nerves are locatedcloser to the electrodes less therapy and / or lower power therapy is sufficient to ensure complete denervation. However, where the nerves are deeper, and stimulated only by the increased stimulation signal, the power of the therapy signal may be increased to ensure application of therapy and denervation of these deeper lying nerves (e.g., further away from the blood vessel wall where the electrodes 56 apply the therapy signal to tissue).

[0048] FIG. 4A schematically depicts the application of stimulation and therapy in accordance with two aspects of the disclosure. As will be appreciated, to assess a change in blood flow as a result of stimulation, a baseline blood flow value may be optionally determined prior to application of any stimulation or therapy. An initial stimulation signal 202 may be applied to target tissue for a period T and a change in a physiological parameter (here blood flow) is observed, as shown in the graph 204. If no response or insufficient response to stimulation is observed the therapeutic device 50 may be moved within the blood vessel, as described elsewhere herein. Once sufficient change in the physiological parameter is observed, therapy may be applied for a predetermined period of time. In some instances, the application of therapy may be manually controlled. It is contemplated that in such instances of manual control the computing device 22 may present a user interface 28 on the display 26 indicating that nerves have been adequately detected at the location within the blood vessel at which the therapeutic device 50 is located. The UI may also indicate that therapy may be delivered (e.g., by selection of a button displayed in the user interface). Alternatively, an application 34 stored in the memory 32 and executed by the processor, following the determination that nerves a located at the position of the therapeutic device 50 and may as part of the application 34 cause the therapy source 24 to output a therapy signal. In FIG. 4A the therapy may be for example a monopolar RF ablation energy 206. Following the application of the therapy 206, there are at least two alternatives, in a first alternative, a second stimulation signal 208 may be applied and if it is determined that the change in physiological parameter (e.g., blood flow) is below a threshold, the procedure may end. The change in physiological parameter as a result of the stimulation 208 in excess of the threshold is indicative of an unsuccessful or incomplete denervation and further therapy 210 is applied. This process of stimulation 208 and therapy 210 may be repeated until the change in a physiological parameter (e g., blood flow) caused by the stimulation 208 falls below a threshold as depicted in graph 212. Alternatively, the change is physiological parameter as shown in graph 204 as a result of stimulation and may be compared to a threshold and if the difference is greater than a threshold the denervation can be determined to be successful, and therapy ended. Still further, a rate of change of thephysiological parameter (e.g., blood flow) can be used as the threshold, and when the rate of change flattens or has a slowed rate of change as compared to prior applications of therapy. As a further component of this aspect of the disclosure, the magnitude of the therapy power (e.g., alteration of one or more of current, voltage, and duration) may be changed at each successive application of therapy 210. Further, a ramp rate may be employed such that at specific intervals of application of therapy 210 a greater therapeutic power that the preceding interval may be employed until a desired outcome is achieved (e.g., a change in blood flow response to stimulus below a desired threshold).

[0049] Alternatively, following the initial therapy a combination signal 214 including both therapy and stimulation signals may be applied by the therapeutic device 50. This combination signal 214 may be applied for predetermined period of time and / or until a change in physiological parameter (e g., decreased blood flow) during the stimulation signal portion of the combination signal is observed. The observed decrease in the physiological parameter, may be recorded as shown in graph 216 and a termination point for the application of the combination signals 214 may be for example an absolute change (e.g., pressure delta from that observed in 204) or alternatively, the observed rate of change between successive stimulation signal portions of the combination signal 214 as depicted in 216. Though described generally with respect to blood flow, other physiological parameters may also be observed and employed including pulse wave velocity, arterial stiffness, heart rate, mean arterial blood pressure and any combination of these parameters or other parameters without departing from the scope of the disclosure.

[0050] FIG. 4B depicts a graphical representation of the combined signal 214. As can be seen, there is a train of alternative times of application of stimulation and therapy. As will be described herein below, the combined signal can be applied for a period T1 after which initial assessments can be made on the efficacy of the ablation based on changes in physiological parameters (e.g., blood flow). The combined signal can then be applied for a second period T2, and confirmation of therapy can be undertaken by comparison of a change in blood flow observed as a result of stimulation to a threshold as described in greater detail below.

[0051] As will be appreciated from the forgoing description, the processes described herein can generally be separated into two separate processes. The first process is the identification of the presence of nerves and the application of therapy to those nerves. The second process is the application of therapy and the assessment or evaluation of that therapy.These processes are generally described as happening serially, however, as will be appreciated, they may be separately and independently performed.

[0052] FIG. 5 depicts a flow chart showing a method 500 in accordance with the disclosure. At step 502, the therapeutic device 50 is placed at a desired location within the patient (e.g., in a renal or hepatic artery). As part of the placement, the therapeutic device 50 may be advanced from the catheter 58 and the therapeutic device 50 allowed to expand such that the electrodes 56 are in contact with an inner wall of the artery. At step 503, an initial assessment of blood flow may be determined. At step 504 a stimulation is applied, for example a biphasic stimulation signal may be transmitted between any two of the electrodes 56. The stimulation signal may alternate the leading phase of the stimulation signal. Further, the stimulation signal may alternate between pairs of the electrodes 56 to stimulate the nerves of the blood vessel At step 506 a determination is made whether a change in physiological parameter, for example a change in blood flow observed in the blood vessel, is greater than a predetermined threshold. This may be done through the use of angiographic imaging, through the use of a separate flow meter (e g., a flow wire) via a sensor incorporated on the therapeutic device 40 of the catheter 58. If yes, the stimulation parameters are maintained at the nominal max current and duration settings at step 508 and the therapy is commenced at step 510

[0053] If, however, no change in blood pressure, or an insufficient change in blood pressure is observed at step 506, there are multiple options. In a first option, the current and duration parameters for the stimulation may be adjusted (e.g., increased) at step 512 and the method may proceed to the commencement of the application of therapy at step 510, an indicator may be generated alerting the user of the change, the indicator may be audible, tactile, visual (e g., on the user interface 28 and presented in the display 26) or combinations of these. This may be an option where a change blood flow is observed, but it is less than the threshold, indicating that the nerves being stimulated are further from the electrodes or surrounded by tissue that is mitigating the stimulation effect. Alternatively, rather than proceed to the commencement of the therapy at step 510, the method may return to step 504 to determine, for application of an adjusted stimulation signal, after which the change in blood flow is again compared to a threshold at step 506. Still further, the method may return to step 502 where the position of the therapeutic device 50 is adjusted before applying stimulation at step 504. These processes can be repeated as needed until the clinician is satisfied that the position and energy levels being applied at that position in the blood vessel of the patient achieves sufficient change in physiological parameter being monitored.

[0054] Following application of therapy at step 510, a stimulation may be applied at step 514 and the physiological parameter is again measured at step 516. If the change in the physiological parameter (e.g., blood flow in the blood vessel) is greater than a threshold, the method moves to step 518, where the power or duration of the ablation energy are adjusted, and the method returns to step 510, an indicator may be generated alerting the user of the change, the indicator may be audible, tactile, visual (e.g., on the user interface) or combinations of these, for example via a user interface 28 on the display 26. This may be repeated as necessary until the measured change in the physiological parameter is less than a threshold. This indicates that the ablation was successful in denervating the nerves in the blood vessel at that location of the therapeutic device 50. At this point, the method may optionally end or return to step 502 for re-positioning of the therapeutic device 50 for denervation at another location following the same method 500. An indicator of a successful denervation may be generated to alert the user to the success and displayed on the user interface.

[0055] FIG. 6A depicts an alternative method 600 employing the combined stimulation and therapy signal, as noted above. Method 600 is focused on providing guidance regarding placement and efficacy of the application of therapy at the placed location of the therapeutic device 50. As with method 500, method 600 starts with positioning of the therapeutic device 50 at a desired location within the patient (e.g., in a renal or hepatic artery) as step 602. As part of the placement, the therapeutic device 50 may be advanced from the catheter 58 and the therapeutic device 50 allowed to expand such that the electrodes 56 are in contact with an inner wall of the artery. At step 603, which may be optional, a baseline blood flow value may be determined. At step 604 a combined stimulation signal and therapy (e.g., signal 214 in FIG. 4A) may be applied to the blood vessel wall. As described above, during the application of the combined stimulation signal and therapy, at regular intervals the stimulation signal is switched to a therapy and then back to a stimulation signal. This repeated switching allows for the generation of a series of datapoints related to the physiological parameter being observed (e.g., change in blood flow).

[0056] At step 606, following application of combined stimulation signal and therapy 214 for a duration Tl, a determination is made whether change in a physiological parameter (e.g., change in blood flow from the baseline) is greater than a pre-determined threshold. If the determination is yes at step 608 the application of the combined stimulation signal and therapy 214 is continued until expiration of a second duration T2. At step 610 a determination is made whether the measured physiological parameter (e.g., change in bloodflow) as measured at time T2 is less than when measured at time T1. The assessment at step 610 is to determine whether the nervous response to stimulation has largely been eliminated indicating that nerves have been substantially ablated and rendered largely incapable of effecting changes in blood flow as a result of stimulation. If the answer at step 610 is yes, a green light or other indicator may be displayed on a UI 28 and displayed to the user signaling a successful ablation has been achieved. The process may then optionally end or return to step 602 where the therapeutic device 50 may be repositioned to apply therapy to another location within the same blood vessel or another blood vessel.

[0057] Returning to step 606, if the change in physiological parameter is less than a threshold at time Tl, then a further assessment is made at step 615 to determine whether the change in physiological parameter is less than a second threshold Y after time Tl. The determination at step 615 is whether the combined stimulation and ablation applied at step 604 has effectively denervated the nerves of the blood vessel resulting in a difference between the baseline blood flow from step 603 and that at time Tl being blow a threshold valve, Y. If the determination is made at step 615 that the change in physiological parameter (e.g., blood flow) as a result of the combined stimulation and ablation is greater than the threshold Y at time Tl, then the therapy and stimulation is stopped at step 616 and the stimulation signal parameters are adjusted. An indicator of the lack of stimulation may be generated alerting the user of the change, the indicator may be audible, tactile, visual (e.g., on the user interface) or combinations of these. At step 617, the adjusted stimulation signal is applied for a duration Tl. At step 618 a determination is made whether the change in physiological parameter (e.g., change in blood flow) is greater than a threshold. If the change in the physiological parameter is less than the threshold then method 600 proceeds to step 620 where an indicator is displayed in the UI 28, for example a red light, indicating that no nerves have been located at that location. The method then returns to step 602 where the therapeutic device 50 is moved to another location and the process is started again.

[0058] However, if at step 618 there was a change in physiological parameter greater than the threshold when stimulated with the adjusted stimulation signal, is an indicator that the nerves at that location are further from the blood vessel wall (e.g., deep within the tissue) at step 622. As such, to achieve the desired effects of the ablation on the nerve tissue, the procedure requires more additional application of energy by either increasing power, increasing ablation duration, changing frequency, or pulse duration, adding additional electrodes to the array or combinations thereof. An indicator may be generated, and for example displayed on the UI 28 regarding the required adjustment. The parameter may beadjusted at step 624 and the method returns to step 604, where the process repeats as described above.

[0059] If at time T 1 at step 615 a determination is made that the change in physiological parameters (e.g., blood flow) is less than the threshold value Y, the method proceeds to step 626 where stimulation having an increased amplitude or pulse width is applied to the blood vessel. Following the application of the stimulation, an assessment is made at step 628 to determine whether the change in the physiological parameter is still less than the threshold Y despite the application at step 626 of stimulation with an increased amplitude or pulse width. If the change in the physiological parameter remains less than the threshold Y, this indicates that the nerves in that portion of the blood vessel are substantially ablated, and the method proceeds to step 614. However, where the change in physiological parameters is greater than the threshold Y, this indicates that nerves deeper with the smooth muscle or running along or near the exterior wall of the blood vessel have been triggered and the method returns to step 622, as described above.

[0060] FIG. 6B depicts a plot of the change in blood flow in a blood vessel from stimulation during a combined stimulation and therapy signal (FIG. 4B) during a procedure. As can be observed, upon the initial application of stimulation the blood flow decreases sharply. As therapy is applied, the change in blood from each application of stimulation eventually begins to decrease until reaching Tl. This is indicative of the therapy ablating the stimulated nerves and the impact of the stimulation no longer results in a blood flow reduction. In fact the blood flow may return to a level above that pre ablation. The change in blood flow during the period from T1-T2 is minimal and in the plot of FIG. 6B depicts a scenario where increased stimulation parameters do not result in a change in blood flow. This can be interpreted that there are no deeper nerves and that ablation at this location has impacted on all nerves. If a change in flow between the period T1-T2 was observed this would indicate that there may be nerves beyond the original ablation zone that should be ablated. As outlined previously the ablation energy would be increased and the combined stimulation and ablation process would be repeated. .

[0061] FIG. 7 depicts a further method 700 utilizing a combined stimulation signal and therapy. Method 700 starts like method 500 and 600 with the positioning of the therapeutic device 50 within a blood vessel in need of therapy (e.g., ablation, denervation) at step 702. At step 703 a baseline blood flow value can be determined. At step 704 the combined stimulation signal and therapy 214, for example as shown in FIG. 4A, is applied to the blood vessel wall. At step 706 a determination is made whether a change in a physiologicalparameter (e.g., change in blood flow from baseline) in excess of a threshold after a duration of time T1 is observed. If the determination at step 706 is that the change in physiological parameter is in excess of the threshold, the method continues to step 708 where the application of the combined stimulation signal and therapy is continued until the expiration of time T2. At the conclusion of time T2 a determination is made at step 710 whether the measured physiological parameter (e.g., change in blood flow) at time T2 is less than when it was measured at time Tl. If the answer at step 710 is yes, the method proceeds to step 712 and a signal, such as a green light may be displayed on the UI 28 signaling a successful ablation at that location. The assessment at step 710 is to determine whether the nervous response to stimulation has largely been eliminated indicating that nerves have been substantially ablated and rendered largely incapable of effecting changes in blood flow as a result of stimulation. Optionally the method 700 may then end or may return to step 702 where the therapeutic device 50 may be repositioned for a further ablation / denervation procedure.

[0062] If, however, at step 710 the physiological parameter (e.g., change in blood flow) is not less than as measured at time Tl the method proceeds to step 714 where a determination is made whether a power limit has been reached. If the power limit has been reached, then the method may proceed to step 718 where an indicator such as a red light is displayed on UI 28 signaling to the user that insufficient therapy has been received at that location within the blood vessel. The method may then optionally end or return to step 702 for repositioning of the therapeutic device 50 and further therapy.

[0063] If at step 714 the power limit has not been reached, the method proceeds to step 716 where the power to be applied during the therapy portion of the combined stimulation signal and therapy is increased. In the case of, for example, and RF therapy the power can be adjusted by increasing the pulse width, the voltage, the amperage, the frequency, or combinations of these factors of the therapy signal. The method then returns to step 708 where the increased power combined stimulation signal and therapy is applied to the blood vessel all until the expiration of time T2. The method continues as described herein above until either a successful ablation is achieved, or an unsuccessful ablation is achieved, and the power limit has been reached.

[0064] Returning back to step 706, if following the application of the combined stimulation signal and therapy for time Tl has not resulted in a change in a physiological parameter (e.g., a change in blood flow) greater than a threshold, then a further assessment is made at step 719 to determine whether the change in physiological parameter is less thana second threshold Y after time T1. The determination at step 719 is whether the combined stimulation and ablation applied at step 704 has effectively denervated the nerves of the blood vessel resulting in a difference between the baseline blood flow from step 703 and that at time Tl being blow a threshold valve, Y. If the determination is made at step 615 that the change in physiological parameter (e.g., blood flow), as a result of the combined stimulation and ablation is greater than the threshold Y at time Tl, the method proceeds to step 720 where the application combined stimulation signal and therapy is stopped. At step 722 the stimulation signal is adjusted (e.g., frequency, current, voltage, pulse width, etc.) and the combined stimulation signal and therapy is again applied by the therapeutic device 50 to the blood vessel wall for duration Tl . At step 724 a determination is made whether a change in physiological parameter (e.g., a change in blood flow) is greater than a threshold. In some instances, this may be the same threshold as used at step 706, though another threshold may be used without departing from the scope of the disclosure. If the determination of step 724 is yes, the method proceeds to step 716 where the power of the therapy is increased. Once increased, a combined stimulation signal and therapy having both the adjusted stimulation and the increased therapy power is applied to the blood vessel of the patient at step 708. The method proceeds as described herein above until either a successful ablation / denervation is achieved, or the power limit is reached.

[0065] Where the answer to the inquiry at step 724 is no, meaning that the both the original stimulation and the adjusted stimulation signal failed to cause a change in the physiological parameter greater than the threshold, the method proceeds to step 726. In step 726 an indicator, such as a blue indicator may be displayed on the UI 28 alerting the user that there are no detectable nerves at that location and the method returns to step 702 for repositioning of the therapeutic device 50.

[0066] If at time Tl at step 719 a determination is made that the change in physiological parameters (e.g., blood flow) is less than the threshold value Y, the method proceeds to step 728 where stimulation having an increased amplitude or pulse width is applied to the blood vessel. Following the application of the stimulation, an assessment is made at step 730 to determine whether the change in the physiological parameter is still less than the threshold Y despite the application at step 626 of stimulation with an increased amplitude or pulse width. If the change in the physiological parameter remains less than the threshold Y, this indicates that the nerves in that portion of the blood vessel are substantially ablated, and the method proceeds to step 712. However, where the change in physiological parameters is greater than the threshold Y, this indicates that nerves deeper with the smooth muscle orrunning along or near the exterior wall of the blood vessel have been triggered and the method progress to step 716 where the ablation power is increased.

[0067] The described methods 500-700 are exemplary and steps of the methods may be performed in different orders or eliminated without departing from the scope of the disclosure. Further, as is known to those of skill in the art other methods may be employed to determine the locations of nerves for therapy, measure the physiological parameters, and apply the therapy to the nerves of the patient.

[0068] FIG. 8 depicts a schematic representation of a distal portion of a therapeutic device 50 showing the electrodes 56. These electrodes 56 are individually labeled El through E4. Further aspects of the disclosure are described herein with respect to this arrangement of the electrodes 56. As noted above, methods 600 and 700 describe application of a combined stimulation signal and therapy. While FIG. 4A includes one depiction of this signal, through the use of multiple electrodes 56, multiplexed signals may employ the electrodes 56 in different pairings and timings to provide more accurate determination of where nerves are located, more complete ablation or denervation of the nerves, and a more accurate determination of success of the procedures.

[0069] In accordance with one aspect of the disclosures two pairs of electrodes 56 are established. A first pair (e g., El and E2) may be used in a first phase as the stimulation electrodes and the stimulation signal passes between the two electrodes for a set duration. During that same duration, a second pair (e.g., E3 and E4) are used for application of the therapy for the set duration. In one example, the therapy is monopolar RF, wherein the energy passes from the electrodes E3 and E4 to a pad placed on the patient. The duration may be, for example, 10 seconds. At the end of the duration, the pairs are switched and El and E2 become the therapy electrodes and E3 and E4 become the stimulation electrodes. This switching back and forth between which pairs are applying therapy and which are applying stimulation may be continued (e.g., switching every 10 seconds) until the end of a longer duration (e.g., 50 seconds). In this manner, all of the electrodes 56 of the therapeutic device 50 are employed in both the stimulation and application of therapy to the nerves of the patient, enabling a larger area to receive therapy and, when the therapeutic device 50 is formed as depicted in FIG. 3, a substantially circumferential ablation about the diameter of the blood vessel may be formed substantially reducing the likelihood that nerves ( e g., sympathetic nerves) remain after application of the therapy.

[0070] In the multiplexing arrangement above, the pairs of electrodes 56 remains constant and the form of the energy or signal is switched. However, in another form ofmultiplexing the pairs themselves may be continually changed. In this example, in a first phase El and E2 may apply stimulation and E3 and E4 may apply the therapy. In the second phase, E2 and E3 apply stimulation and El and E4 apply therapy. The third phase may see E3 and E4 apply the stimulation and El and E2 the therapy. Further in a fourth phase E2 and E4 apply the stimulation and El and E3 apply the therapy. These pairings may be made until all potential pairs of electrodes have been achieved. Each phase may last from 50 msec to 5 seconds. The pattern may then be repeated until an overall therapy duration is reached (e.g., 50 seconds). In this manner every pair of electrode applies stimulation providing greater insight into the effect of that stimulation between each pair. Further a clearer picture of the effect of the therapy can be developed. Indeed, using the data generated and the methods 600 and 700, a more granular determination of the effect of the ablation achieved by each electrode 56 can be assessed allowing for the indicators (e g., red, green, blue lights) on the UI to be displayed not just for the overall procedure but for individual electrodes 56, providing greater insight into the efficacy of the procedure.

[0071] Another example of a stimulation and therapy pattern includes the reversal of the polarity of electrodes 56 for the stimulation. Again, pairs of electrodes may be employed (e.g., E 1 and E2 may be a stimulation pair). In accordance with this aspect, the combined stimulation signal and therapy (similar to 214 of FIG. 5) may be employed. During a first stimulation phase stimulation signals are passed from El to E2. Then following stimulation all four electrodes 56 are used for application of therapy for a duration (e.g., 10 seconds). A second stimulation phase may again pass stimulation signals from El to E2, and again be followed by application of therapy from all electrodes 56. In a subsequent phase the polarity of the stimulation signals may be reversed passing from E2 to El. Therapy may be applied following this reversed stimulation signal and then be followed by another cycle of stimulation and ablation. The changing of the polarity of the stimulation signal has been observed to increase the likelihood of response to stimulation and therewith the determination of success or failure of the procedure.

[0072] The switching of polarities of the stimulation is not limited to just electrodes El and E2 but can be between any two pairs of electrodes. Thus, the stimulation pairs may be switched between El and E2, E3 and E4, E2 and E3, E2 and E4, El and E3, El and E4, and each pairing may include the application of a first polarity stimulation and a reverse polarity stimulation. Between each stimulation all of the electrodes may be used for application of the therapy. This process may repeat until a set duration of stimulation and therapy has been reached as described in connection with methods 500, 600, and 700.

[0073] In a further implementation of the devices and systems of the disclosure, and particularly with reference to method 800, the stimulation signal 208 (FIG. 4A) when applied in a non-combined stimulation signal and therapy may utilize a reversing electrode pairs polarity scheme. In one example, the stimulation signal may be applied from electrode E1-E4 for a first duration, and then applied in a reverse polarity fashion from E-4 to El for a second duration. As noted elsewhere reversing the polarity enhances the nervous response to the stimulation.

[0074] Still a further implementation employs combination stimulations where two pairs of electrodes are employed simultaneously. In this example, E1-E2 apply a stimulation signal during a first period. Simultaneously electrodes E3 and E4 are also used to apply stimulation during this same period. During a second period stimulation is applied between electrodes El and E4 while simultaneously being applied between electrodes E2 and E3. In a third period stimulation may be applied between electrodes E2 and E4 while simultaneously being applied between El and E3. Each of these periods may be very short for example 1 to 25 msec, and the switching between electrode pairs may be undertaken until a duration of stimulation is reached. In some embodiments, this process may be supplemented with the application of reverse polarity stimulation as described in other aspects herein.

[0075] Those of skill in the art will recognize that the stimulation signals employed in embodiments herein may have a multiphasic-pulsed waveform (e.g., biphasic, triphasic, etc.). In one non-limiting embodiment, the neurostimulation includes a biphasic waveform, with each pulse of the biphasic waveform having an anodal leading phase and a cathodal trailing phase or vice versa. The therapy system may be configured to alternate the leading phase of each pulse of the biphasic waveform during the application of the neurostimulation such that, for example, a first pulse includes an anodal leading phase and a cathodal trailing phase, a subsequent, second pulse includes a cathodal leading phase and an anodal trailing phase, and a subsequent, third pulse returns to an anodal leading phase and a cathodal trailing phase. The leading phase of each pulse of the biphasic waveform is alternated for the duration of the application of the neurostimulation. As a result, a neural response to the neurostimulation is enhanced as compared to continuous first phase biphasic waveforms and monophasic waveforms as is known in the art. This in turn increases the likelihood of stimulating neural tissue and decreases the amount of time required to identify suitable neural tissue for denervation therapy. Further application of neurostimulation promotesaccurate determinations of the suitability of a location for receiving therapy since a greater amount of neural tissue is stimulated by the alternating biphasic waveform described herein.

[0076] As described hereinabove, it is envisioned that the physiological responses to the application of neurostimulation can be monitored by a control algorithm 44 stored on the computer 22, with the location and results of the application of neurostimulation stored in the memory 32. As noted, the observed post therapy and intra-procedural physiological responses can be compared to the pre-procedural responses to assess the efficacy of the therapy, determine if more therapy is required, and when sufficient therapy has been applied to achieve the desired ablation / denervation.

[0077] Heretofore, the therapeutic device 50 has been primarily described in connection with a shape memory construction where exit from a guide catheter 58 frees the shape memory alloy to achieve a desired spiral shape of the and place the electrodes 56 against the blood vessel walls. However, the present disclosure is not so limited and the therapeutic device 50 may be formed such that the electrodes are placed on a balloon or other mechanism to achieve the desired contact with the blood vessel walls without departing from the scope of the disclosure.

[0078] Although described generally hereinabove, it is envisioned that the memory 32 may include any non-transitory computer-readable storage media for storing data and / or software including instructions that are executable by the processor 30 and which control the operation of the workstation 20 and, in some embodiments, may also control the operation of the therapeutic device 50. In an embodiment, memory 32 may include one or more storage devices such as solid-state storage devices, e g., flash memory chips. Alternatively, or in addition to the one or more solid-state storage devices, the memory 32 may include one or more mass storage devices connected to the processor 30 through a mass storage controller (not shown) and a communications bus (not shown).

[0079] Although the description of computer-readable media contained herein refers to solid-state storage, it should be appreciated by those skilled in the art that computer-readable storage media can be any available media that can be accessed by the processor 30. That is, computer readable storage media may include non-transitory, volatile, and non-volatile, removable, and non-removable media implemented in any method or technology for storage of information such as computer-readable instructions, data structures, program modules or other data. For example, computer-readable storage media may include RAM, ROM, EPROM, EEPROM, flash memory or other solid-state memory technology, CD-ROM, DVD, Blu-Ray or other optical storage, magnetic cassettes, magnetic tape, magnetic diskstorage or other magnetic storage devices, or any other medium which may be used to store the desired information, and which may be accessed by the workstation 20.Examples

[0080] The disclosure is further described in connection with the following examples in which:

[0081] Example 1 - is a system for denervation of nerves of a blood vessel including a therapeutic device configured for navigation within a blood vessel of a patient, a plurality of stimulation elements formed on a distal portion of the therapeutic device, a stimulation source in communication with the plurality of stimulation elements, a therapy source in communication with the therapeutic device, and a computing device including a processor and a memory storing thereon instructions that, when executed, cause the processor to cause the stimulation source to generate a first stimulation signal for application to a blood vessel wall via at least one of the plurality of stimulation elements, detect a first change in blood flow through the blood vessel as a result of the application of the first stimulation signal, cause the therapy source to generate a therapy for application the blood vessel wall via the therapeutic device, cause the stimulation source to generate a second stimulation signal for application to the blood vessel wall via the at least one of the plurality of stimulation element, detect a second change in blood flow through the blood vessel as result of the application of the second stimulation signal, compare the second change in blood flow through the blood vessel to a threshold, determine whether the application of the therapy has denervated nerves proximate the at least one of the plurality of stimulation elements based on the comparison of the second change in blood flow through the blood vessel to the threshold, and output an indicator related to success of the application of the therapy.

[0082] Example 2 - is the system of example 1, wherein the memory stores thereon instructions that when executed cause the processor to detect a baseline blood flow and determine whether the first detected change in blood flow from the baseline blood flow is indicative of a presence of a nerves proximate the at least one of the plurality of stimulation elements.

[0083] Example 3 - is the system of one of the preceding examples, wherein the first stimulation signal or the second stimulation signal and the therapy are a combined signal.

[0084] Example 4 - is the system of one of the preceding examples, wherein detection of the first change in blood flow occurs after an initial period of time from an onset of application of therapy to the blood vessel wall and the detection of the second change inblood flow occurs after a second period of time from the onset of application of therapy to the blood vessel wall.

[0085] Example 5 - is the system of one of the preceding examples, wherein the threshold is a magnitude of the first change in blood flow.

[0086] Example 6 - is the system of one of the preceding examples, wherein the instructions, when executed, cause the processor to present an indicator on a user interface associated with the computing device including one or more of a presence of a nerve proximate the at least one of the plurality of stimulation elements, or an indicator of a successful denervation, or an indicator of an unsuccessful denervation.

[0087] Example 7 - is the system of one of the preceding examples, wherein the instructions, when executed, cause the processor to stop the generation of therapy, adjust parameters of the first stimulation signal, and apply an adjusted stimulation signal for a first period of time.

[0088] Example 8 - is the system of example 7, wherein the instructions when executed by the processor sense a third change in blood flow from the baseline blood flow as a result of the application of the adjusted stimulation signal, determine whether the sensed third change in blood flow is indicative of a presence of a nerve proximate the at least one of the plurality of stimulation elements; and output an indicator of the presence of a nerve proximate the at least one of the plurality of stimulation elements.

[0089] Example 9 - is the system of example 7, wherein the instructions when executed by the processor determine that the nerves are deep and require additional time or increased therapy power to complete the therapy.

[0090] Example 10 - is the system of one of the preceding examples further including a sensor configured to measure blood flow through the blood vessel.

[0091] Example 11 - is a method of performing a therapeutic procedure, including applying a first stimulation signal from stimulation elements of a therapeutic device to a blood vessel wall;, observing a first change in blood flow in a blood vessel in response to the first stimulation signal, applying a therapy to the blood vessel wall, applying a second stimulation signal from the stimulation elements to the blood vessel wall, observing second change in blood flow in the blood vessel in response to the second stimulation signal; and outputting an indicator of related to success of the therapy when the second change in blood flow is less than a threshold.

[0092] Example 12 - is the method of example 11, further including, detecting a baseline blood flow and determining whether the first change blood flow from the baseline blood flow is indicative of a presence of a nerves proximate the stimulation elements.

[0093] Example 13 - is the method of examples 11-12, wherein the first stimulation signal or the second stimulation signal and the therapy are a combined signal.

[0094] Example 14 - is the method of examples 11-13, further including observing the first change in blood flow after an initial period of time from an onset of application of therapy to the blood vessel wall and observing the second change in blood flow occurs after a second period of time from the onset of application of therapy to the blood vessel wall.

[0095] Example 15 - is the method of examples 11-14, wherein the threshold is a magnitude of the first change in blood flow.

[0096] Example 16 - is the method of examples 11-15, further including presenting an indicator on a user interface associated with a computing device including one or more of a presence of a nerve proximate the stimulation elements, an indicator of a successful denervation, or an indicator of an unsuccessful denervation.

[0097] Example 17 - is the method of examples 11-16, further including stopping application of therapy, adjusting parameters of the first stimulation signal, and applying an adjusted stimulation signal for a first period of time.

[0098] Examples 18 - is the method of example 17, further including sensing a third change in blood flow from the baseline blood flow as a result of the application of the adjusted stimulation signal, determining whether the third sensed change in blood flow is indicative of a presence of a nerve proximate the at least one of the plurality of stimulation elements, and outputting an indicator of the presence of a nerve proximate the stimulation elements.

[0099] Example 19 - is the method of example 17, further including determining that nerves are deep and require additional time or increased therapy power to complete the therapy.

[0100] Example 20 - is the method of one of examples 11-18, further including receiving an output from a sensor configured to measure blood flow through the blood vessel.

[0101] Example 21 - is a system for denervation of nerves of a blood vessel including a therapeutic device configured for navigation within a blood vessel of a patient, a plurality of stimulation elements formed on a distal portion of the therapeutic device, a stimulation source in communication with the plurality of stimulation elements, a therapy source incommunication with the therapeutic device, and a computing device including a processor and a memory storing thereon instructions that, when executed, cause the processor to, detect a baseline blood flow through the blood vessel cause the stimulation source to generate a first stimulation signal for application to a blood vessel wall via at least one of the plurality of stimulation elements, detect a first change in blood flow through the blood vessel as a result of the application of the first stimulation signal, wherein the first change is relative to the baseline blood flow through the vessel, determine whether the first detected change in blood flow is indicative of a presence of a nerves proximate the at least one of the plurality of stimulation elements, and in response to determining that the first detected change in blood flow is indicative of the presence of nerves, output via a user interface an indication related to the presence of nerves to a user.

[0102] Example 22 - is a system for denervation of nerves of a blood vessel including, a therapeutic device configured for navigation within a blood vessel of a patient, a plurality of stimulation elements formed on a distal portion of the therapeutic device, a stimulation source in communication with the plurality of stimulation elements, a therapy source in communication with the therapeutic device, and a computing device including a processor and a memory storing thereon instructions that, when executed, cause the processor to, cause the therapy source to deliver a denervation therapy via the therapeutic device, after delivery of the denervation therapy, detect a baseline blood flow through the blood vessel, cause the stimulation source to generate a first stimulation signal for application to a blood vessel wall via at least one of the plurality of stimulation elements, detect a first change in blood flow through the blood vessel as a result of the application of the first stimulation signal, wherein the first change is relative to the baseline blood flow through the vessel, determine whether the first detected change in blood flow indicates that the denervation therapy has denervated nerves proximate the blood vessel, and output an indicator related to success of the application of the denervation therapy.

[0103] While several embodiments of the disclosure have been shown in the drawings, it is not intended that the disclosure be limited thereto, as it is intended that the disclosure be as broad in scope as the art will allow and that the specification be read likewise. Therefore, the above description should not be construed as limiting, but merely as exemplifications of embodiments. Those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.

Claims

CLAIMS1. A system for denervation of nerves of a blood vessel comprising: a therapeutic device configured for navigation within a blood vessel of a patient; a plurality of stimulation elements formed on a distal portion of the therapeutic device; a stimulation source in communication with the plurality of stimulation elements; a therapy source in communication with the therapeutic device; and a computing device including a processor and a memory storing thereon instructions that, when executed, cause the processor to: cause the stimulation source to generate a first stimulation signal for application to a blood vessel wall via at least one of the plurality of stimulation elements; detect a first change in blood flow through the blood vessel as a result of the application of the first stimulation signal; cause the therapy source to generate a therapy for application the blood vessel wall via the therapeutic device; cause the stimulation source to generate a second stimulation signal for application to the blood vessel wall via the at least one of the plurality of stimulation element; detect a second change in blood flow through the blood vessel as result of the application of the second stimulation signal; compare the second change in blood flow through the blood vessel to a threshold; determine whether the application of the therapy has denervated nerves proximate the at least one of the plurality of stimulation elements based on the comparison of the second change in blood flow through the blood vessel to the threshold; and output an indicator related to success of the application of the therapy.

2. The system of claim 1, wherein the memory stores thereon instructions that when executed cause the processor to detect a baseline blood flow and determine whether the first detected change in blood flow from the baseline blood flow is indicative of a presence of a nerves proximate the at least one of the plurality of stimulation elements.

3. The system of any of the preceding claims, wherein the first stimulation signal or the second stimulation signal and the therapy are a combined signal.

4. The system of any of the preceding claims, wherein detection of the first change in blood flow occurs after an initial period of time from an onset of application of therapy to the blood vessel wall and the detection of the second change in blood flow occurs after a second period of time from the onset of application of therapy to the blood vessel wall.

5. The system of any of the preceding claims, wherein the threshold is a magnitude of the first change in blood flow.

6. The system of any of the preceding claims, wherein the instructions, when executed, cause the processor to present an indicator on a user interface associated with the computing device including one or more of a presence of a nerve proximate the at least one of the plurality of stimulation elements, or an indicator of a successful denervation, or an indicator of an unsuccessful denervation.

7. The system any of the preceding claims, wherein the instructions, when executed, cause the processor to stop the generation of therapy, adjust parameters of the first stimulation signal, and apply an adjusted stimulation signal for a first period of time.

8. The system of claim 7, wherein the instructions when executed by the processor sense a third change in blood flow from a baseline blood flow as a result of the application of the adjusted stimulation signal;determine whether the sensed third change in blood flow is indicative of a presence of a nerve proximate the at least one of the plurality of stimulation elements; and output an indicator of the presence of a nerve proximate the at least one of the plurality of stimulation elements.

9. The system of claim 7, wherein the instructions when executed by the processor determine that the nerves are deep and require additional time or increased therapy power to complete the therapy.

10. The system of any of the preceding claims, further comprising a sensor configured to measure blood flow through the blood vessel.

11. A method of performing a therapeutic procedure, comprising: applying a first stimulation signal from stimulation elements of a therapeutic device to a blood vessel wall; observing a first change in blood flow in a blood vessel in response to the first stimulation signal; applying a therapy to the blood vessel wall; applying a second stimulation signal from the stimulation elements to the blood vessel wall; observing second change in blood flow in the blood vessel in response to the second stimulation signal; and outputting an indicator of related to success of the therapy when the second change in blood flow is less than a threshold.

12. The method of claim 11, further comprising detecting a baseline blood flow and determining whether the first change blood flow from the baseline blood flow is indicative of a presence of nerves proximate the stimulation elements.

13. The method of claim 11 or 12, wherein the first stimulation signal or the second stimulation signal and the therapy are a combined signal.

14. The method of any of claims 11-13, further comprising observing the first change in blood flow after an initial period of time from an onset of application of therapy to the blood vessel wall and observing the second change in blood flow occurs after a second period of time from the onset of application of therapy to the blood vessel wall.

15. The method of any of claims 11-14, wherein the threshold is a magnitude of the first change in blood flow.

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