Blood volume measurement sensors for renal stimulation response and renal denervation endpoint evaluation

Abstract

Systems and methods of performing a therapeutic procedure employing a therapeutic device including electrodes by applying a stimulation signal from the electrodes to a blood vessel wall, observing a physiological response to the stimulation signal, applying a therapy to the blood vessel wall, applying another stimulation signal from the electrodes to the blood vessel, and observing second physiological response to the second stimulation signal. When the second physiological response is different from the first physiological response by more than a threshold the therapy is successful.

Description

BLOOD VOLUME MEASUREMENT SENSORS FOR RENAL STIMULATION RESPONSE AND RENAL DENERVATION ENDPOINT EVALUATION

[0001] This application claims the benefit of U.S. Provisional Patent Application, Serial No. 63 / 498,975, filed May 25 2023, the entire content of which is incorporated herein by reference.Technical Field

[0002] This disclosure relates to systems and methods of determining changes in physiological parameters of blood vessels during or resulting from nerve stimulation or a therapeutic denervation procedure.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 likely 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 a renal denervation procedure, a clinician delivers energy, such as radiofrequency, ultrasound, cooling, or other energy to a treatment site to reduce 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.

[0005] One aspect of current systems is the limited feedback provided to the user that the application of denervation therapy has resulted in a measurable physiological change. Further the limited feedback makes therapy endpoint determination difficult. Accordingly, this disclosure is directed to systems and methods of addressing these shortcomings of the current technologies.SUMMARY

[0006] One aspect of the disclosure is directed to a method of evaluating a denervation procedure including, prior to applying a therapy at a location of a blood vessel wall outputting, by an interrogator, an interrogator signal including a frequency sweep to drive an antenna placed within a blood vessel; detecting at the interrogator a first reflected component of the signal. The method also includes while applying the therapy at the location of the blood vessel wall monitoring a subsequent reflected component of the signal; determining that a change between the subsequent reflected component and the first reflected component exceeds a threshold value; and in response to determining the change between the subsequent reflected component and the first reflected component exceeds the threshold value, performing an action. 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 and systems described herein.

[0007] Implementations of this aspect of the disclosure may include one or more of the following features. The method where performing the action includes at least one of outputting an indication that the change exceeds the threshold value or ceasing application of the therapy to the location of the blood vessel. The method further includes applying a stimulation signal from electrodes of a therapeutic device to the blood vessel wall. Monitoring the subsequent reflected component of the signal includes observing a response to the stimulation signal in the reflected component of the signal. The stimulation signal causes a reduction in volume of blood within the blood vessel by stimulation of nerves in or near the blood vessel wall causing contraction of muscle fibers in the blood vessel. Monitoring the subsequent reflected component includes continuously monitoring the subsequent reflected component, periodically monitoring the subsequent reflected component, or intermittently monitoring the subsequent reflected component. An increase in a peak magnitude or an increase in a resonant frequency associated with the subsequent reflected component relative to a peak magnitude or a resonant frequency associated with the first reflected component indicates a reduction in volume of blood within the blood vessel. The stimulation signal is part of a sequential stimulation protocol, an alternating stimulation protocol, or a continuous stimulation protocol. Monitoring the subsequent reflected component includes periodically monitoring the subsequent reflected component, where the simulation signal is part of the sequential stimulation protocol or the alternating stimulation protocol, and where periodically monitoring the subsequent reflected component is undertaken during a stimulation portion ofthe sequential stimulation protocol or the alternating stimulation protocol. The therapy includes at least one of monopolar radio frequency denervation, bipolar radio frequency denervation, ultrasound denervation, focused ultrasound denervation, cryogenic denervation, or chemical denervation. The increase in blood volume within the blood vessel is indicative of a successful denervation of nerves in or near the location of the blood vessel wall. A decrease in a magnitude or a decrease in a resonant frequency associated with the subsequent reflected component following the application the therapy is indicative of an increase in blood volume within the blood vessel. The method further including outputting by the interrogator, a second interrogator signal including a second frequency sweep to drive a second antenna within the blood vessel; detecting at the interrogator a reflected component of the second interrogator signal; and calculating a pulse wave velocity or a pulse transit time of blood within the blood vessel. The change in pulse wave velocity or the pulse transit time in excess of the threshold value is indicative of an increase in blood volume within the blood vessel. The increase in blood volume within the blood vessel is indicative of a successful denervation of nerves in or near the blood vessel. The blood vessel is one or more of a celiac trunk, a hepatic artery, splenic artery, gastric artery, superior mesenteric artery, inferior mesenteric artery, gonadal artery, splanchnic artery or branches thereof. Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium, including software, firmware, hardware, or a combination of them installed on the system that in operation causes or cause the system to perform the actions. One or more computer programs can be configured to perform particular operations or actions by virtue of including instructions that, when executed by data processing apparatus, cause the apparatus to perform the actions.

[0008] A further aspect of the disclosure is directed to a therapeutic system also including an elongate member configured to be navigated within a blood vessel, the elongate member including a proximal portion and a distal portion; a plurality of electrodes formed on a distal portion of the elongate member, the electrodes in electrical communication with a stimulation source; an antenna loop formed on at least one of the electrodes; a sensor loop formed on at least one of the electrodes; and an interrogator in electrical communication with the antenna loop and configured to initiate an interrogator signal including a frequency sweep to drive the antenna loop, where the interrogator is configured to receive a signals indicative of a reflected component of the interrogator signal from the sensor loop. Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on oneor more computer storage devices, each configured to perform the actions of the methods and systems described herein.

[0009] Implementations of this aspect of the disclosure may include one or more of the following features. The therapeutic system where the antenna loop and the sensor loop inductively couple upon the antenna loop transmitting the interrogator signal. The therapeutic system further includes a therapy source for delivery of a therapy to a location of a blood vessel wall. The therapy includes at least one of monopolar radio frequency denervation, bipolar radio frequency denervation, ultrasound denervation, focused ultrasound denervation, cryogenic denervation, or chemical denervation. The therapy source is in electrical communication with the electrodes for application of the therapy to the location of a blood vessel wall. The electrodes are configured to apply a stimulation signal to the blood vessel wall. The stimulation source is configured out output of a sequential stimulation protocol, an alternating stimulation protocol, or a continuous stimulation protocol. The therapeutic system further including a computing device including a processor and a memory, the memory storing thereon an application that when executed by the processor: receives the signals indicative of a reflected component of the interrogator signal; and detects changes in the signals indicative of the reflected component of the interrogator signal. The action includes outputting to a display device in communication with the computing device an indication that the change exceeds the threshold or ceasing application of the therapy to the location of the blood vessel wall. The application, when executed by the processor, and in response to detecting a change in the signal is indicative of the reflected component of the interrogator signal in excess of a threshold, performs an action. The interrogator is in electrical communication with the second antenna loop and configured to initiate a second interrogation signal including a second frequency sweep to drive the second antenna, where the interrogator is configured to receive a second signal indicative of a reflect component of the second interrogator signal from the second sensor loop. The therapeutic system further including a computing device including a processor and a memory, the memory storing thereon an application that when executed by the processor: receive the signals indicative of a reflected component of the interrogator signal; receives the signals indicate of a reflected component of the second interrogator signal; and calculate a pulse wave velocity or a pulse transit time of blood within the blood vessel. Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium, including software, firmware, hardware, or a combination of them installed on the system thatin operation causes or cause the system to perform the actions. One or more computer programs can be configured to perform particular operations or actions by virtue of including instructions that, when executed by data processing apparatus, cause the apparatus to perform the actions.

[0010] Yet a further aspect of the disclosure is directed to a therapeutic system including an elongate member configured for navigation within a blood vessel, the elongate member including a distal portion and a proximal portion; a plurality of electrodes formed on the distal portion of the elongate member, the electrodes configured to be in electrical communication with a stimulation source; and an ultrasonic transducer formed on the elongate member, where the ultrasonic transducer is configured to detect a signal indicative of a vascular bruit of the blood vessel. 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 and systems described herein.

[0011] Implementations of this aspect of the disclosure may include one or more of the following features. The therapeutic system further including a therapy source for delivery of a therapy to a location of a blood vessel wall. The therapy includes at least one of monopolar radio frequency denervation, bipolar radio frequency denervation, ultrasound denervation, focused ultrasound denervation, cryogenic denervation, or chemical denervation. The therapy source is in electrical communication with the electrodes for application of the therapy to the location of a blood vessel wall. The electrodes are configured to apply a stimulation signal to the blood vessel wall. The stimulation source is configured out output of a sequential stimulation protocol, an alternating stimulation protocol, or a continuous stimulation protocol. The therapeutic system further including a computing device including a processor and a memory, the memory storing thereon an application that when executed by the processor: receives from the ultrasound transducer the signal indicative of the vascular bruit of the blood vessel; calculates from the received signal indicative of a vascular bruit to spectral power; and detects changes in the spectral power. The application when executed by the processor, and in response to detecting a change in the spectral power in excess of a threshold, performs an action. The action includes outputting to a display device in communication with the computing device an indication that the change exceeds the threshold or ceasing application of the therapy to the location of the blood vessel wall. Implementations of the described techniques may include hardware, a method or process, or computer software on a computer- accessible medium, including software, firmware, hardware, or a combination of theminstalled on the system that in operation causes or cause the system to perform the actions. One or more computer programs can be configured to perform particular operations or actions by virtue of including instructions that, when executed by data processing apparatus, cause the apparatus to perform the actions.

[0012] Still a further aspect of the disclosure is directed to a method of evaluating a denervation procedure. The method also includes receiving, by a computing device, a signal indicative of a vascular bruit of a blood vessel in which an elongate member has been placed, where the vascular bruit is detected by an ultrasonic transducer carried by the elongate member; converting, by the computing device, the vascular bruit to spectral power; monitoring the spectral power over time as a therapy is applied to a blood vessel wall of the blood vessel in which the elongate member has been placed; determining a change in the spectral power over time exceeds a threshold value; and in response to determining the change in the spectral power over time exceeds the threshold value, performing an action. 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 and systems described herein.

[0013] Implementations of this aspect of the disclosure may include one or more of the following features. The method where performing the action includes at least one of outputting an indication that the change exceeds the threshold value or ceasing application of the therapy to the location of the blood vessel. The method further includes applying a stimulation signal from electrodes of a therapeutic device to the blood vessel wall. Monitoring the spectral power includes observing a response to the stimulation signal in the spectral power. An increase in the spectral power indicates a reduction in volume of blood within the blood vessel. The stimulation signal causes a reduction in volume of blood within the blood vessel by stimulation of nerves in or near the blood vessel wall causing contraction of muscle fibers in the blood vessel. The stimulation signal is part of a sequential stimulation protocol, an alternating stimulation protocol, or a continuous stimulation protocol. Monitoring the spectral power includes a continuously monitoring the spectral power, periodically monitoring the spectral power or periodically monitoring the spectral power. Monitoring the spectral power includes periodically monitoring the spectral power, where the stimulation signal is part of the sequential stimulation protocol or the alternative stimulation protocol, and where the periodically monitoring is undertaken during a stimulation portion of the sequential stimulation protocol or the alternating stimulation protocol. The therapy includes at least oneof monopolar radio frequency denervation, bipolar radio frequency denervation, ultrasound denervation, focused ultrasound denervation, and cryogenic denervation, or chemical denervation. A decrease in the spectral power following the application the therapy is indicative of an increase in blood volume within the blood vessel. The increase in blood volume within the blood vessel is indicative of a successful denervation of nerves in or near the location of the blood vessel wall. The blood vessel is one or more of a celiac trunk, a hepatic artery, splenic artery, gastric artery, superior mesenteric artery, inferior mesenteric artery, gonadal artery, splanchnic artery or branches thereof. Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium, including software, firmware, hardware, or a combination of them installed on the system that in operation causes or cause the system to perform the actions. One or more computer programs can be configured to perform particular operations or actions by virtue of including instructions that, when executed by data processing apparatus, cause the apparatus to perform the actions.

[0014] Further disclosed herein are systems and methods of performing a therapeutic procedure employing a therapeutic device including electrodes by applying a stimulation signal from the electrodes to a blood vessel wall, observing a physiological response to the stimulation signal, applying a therapy to the blood vessel wall, applying another stimulation signal from the electrodes to the blood vessel, and observing second physiological response to the second stimulation signal. When the second physiological response is different from the first physiological response by more than a threshold the therapy is successful.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Various aspects and embodiments of the disclosure are described hereinbelow with references to the drawings, wherein:

[0016] FIG. l is a schematic diagram of a therapy system provided in accordance with the disclosure;

[0017] FIG. 2 is a schematic view of a workstation of the therapy system of FIG. 1;

[0018] FIG. 3 is a perspective view of a therapeutic device of the therapy system of FIG.1 advanced within a portion of the patient’s anatomy and in a deployed condition in accordance with the disclosure;

[0019] FIG. 4A is a schematic view of an electrode in accordance with the disclosure;

[0020] FIG. 4B is a graph of a change in SI 1 in response to changes in volume of fluid;

[0021] FIG. 5A is a flow chart detailing a method in accordance with the disclosure;

[0022] FIG. 5B is a graph depicting changes in resonant frequency and SI 1 magnitude through a cardiac cycle;

[0023] FIG. 5C is a graph of a change in SI 1 over time at a given resonant frequency;

[0024] FIG. 6A is a perspective view of a therapeutic device in accordance with the disclosure;

[0025] FIG. 6B is a profile view of an ultrasonic transducer on the catheter of FIG. 6 A in accordance with the disclosure;

[0026] FIG. 7 is a flow chart of a method in accordance with the disclosure;

[0027] FIG 8A is a plot of a carotid bruit at a high blood pressure, and a plot of the conversion of that carotid bruit to spectral power; and

[0028] FIG 8B is a plot of a carotid bruit at a low blood pressure, and a plot of the conversion of that vascular bruit to spectral power.DETAILED DESCRIPTION

[0029] This disclosure is directed to therapeutic systems and methods for nerve stimulation or therapeutic denervation or neuromodulation of sympathetic or parasympathetic nerves, and in particular, unmyelinated nerve fibers in and around blood vessels and other luminal tissues. In particular, this disclosure is directed to systems and methods that provide feedback of a physiological response to the application of nerve stimulation before, during, or after therapeutic denervation.

[0030] In accordance with one aspect of the disclosure a signal generator or vector network analyzer (VNA) is employed to power an antenna formed on or carried by a catheter. The antenna transmits an RF signal that inductively couples with a passive sensor. The passive sensor is also formed on or carried by the catheter. The signal generator or VNA receives a reflected component of the signal generated for transmission by the antenna, the Si l component, via the passive sensor. The reflected component varies based on the permittivity of the medium through which the antenna is attempting to transmit. By analyzing the reflected component, the SI 1 component, a determination of the volume of the medium can be assessed. This determination of volume changes of the medium (e.g., blood passing through a blood vessel) can be assessed to determine among other things vasoconstriction, for example vasoconstriction as a result of applied stimulation which reduces the volume of blood in the blood vessel. The SI 1 component, and with it the volume of the blood vessel, can also assistin identifying therapeutic end points, such as complete denervation of nerves, which generally results in an increase of volume in the blood vessel. The SI 1 component may also be used to calculate features of blood flow including pulse wave velocity or pulse transit time, which are themselves informative of changes in volume of a blood vessel, for example as a result of denervation.

[0031] A further aspect of the disclosure is directed a catheter incorporating a piezoelectric film to detect a vascular bruit. A vascular bruit is a vascular sound caused in part by turbulent flow of the blood. The piezoelectric film acts as an internal stethoscope (a piezo-microphone) detecting the turbulent flow of blood over the piezoelectric film. As the blood flows over the piezoelectric film, a signal is generated by the piezoelectric film in response to the turbulent flow of blood impacting the piezoelectric film. That signal, the vascular bruit, varies with blood pressure and blood volume flowing through the blood vessel. Accordingly, by detecting changes in the vascular bruit, a determination can be made of the blood pressure and therewith the volume of blood flow through the blood vessel. In this way, changes in blood pressure and blood flow caused by stimulation or denervation can be assessed for a variety of purposes. These and other aspects of the disclosure are described in greater detail below.

[0032] For ease of description, much of the following description focuses on implementations of electrical stimulation and radio frequency (RF) denervation. Those having skill in the art will recognize that the methods and systems described herein may employ any of the therapy and / or neurostimulation modalities described herein including without limitation, monopolar RF, bi-polar RF, microwave, ultrasound, focused ultrasound, cryogenic, chemical, and others. 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 and can be employed for denervating nerves accessible via any blood vessel described herein (e.g., celiac trunk, hepatic, splenic, gastric, superior mesenteric, inferior mesenteric, gonadal, splanchnic, etc., and branches and / or combinations of each) or other luminal tissue (e.g., a bile duct, urinary tract, etc.).

[0033] Turning now to the drawings, FIG. 1 illustrates a guidance and therapy system provided in accordance with the present disclosure and generally identified by reference numeral 10. As will be described in further detail hereinbelow, the guidance and therapy system 10 enables navigation of a therapeutic device 50 to a desired location within the patient’s anatomy (e.g., the patient’s renal artery). The therapeutic device 50 is configured to apply neurostimulation (e.g., to the blood vessel wall) to trigger a neurological response (e.g., vasoconstriction or a temporary rise in blood pressure) and to apply of denervation therapy to denervate nerves within and around the blood vessel to treat one or more conditions. The therapeutic device is also configured to deliver an interrogation signal to assess blood flow parameters providing data on the effects of the neuro stimulation and denervation therapy, for example to determine an endpoint of and / or response of the patient to the denervation therapy.

[0034] The guidance and therapy system 10 includes a workstation 20, a therapeutic device 50 operably coupled to the workstation 20, and an imaging device 70, which may be operably coupled to the workstation 20. The patient “P” is shown lying on an operating table 12 with the therapeutic device 50 inserted through a portion of the patient’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 may be operably coupled to the workstation 20. Further, the therapeutic device 50 may employ a guidewire or a guide catheter 58 (FIG. 3) without departing from the scope of the disclosure. In some examples, therapeutic device 50 may not be coupled to the workstation 20 for example, where therapy is applied via cryogenic or chemical ablation processes. .

[0035] Continuing with FIG. 1 and with additional reference to FIG. 2, the workstation 20 includes a computer 22, a therapy source 24 (e.g., an RF generator, a microwave generator, an ultrasound generator, a cryogenic medium source, a chemical source, etc.) operably coupled to the computer 22, and an interrogation signal source 24a operably coupled to the computer 22. Although generally described as being separate from the therapy source 24, it is envisioned that the interrogation signal source 24a may be integrated within the therapy source 24, and the therapy source 24 may generate both therapy and interrogation signal modalities.

[0036] As will be appreciated, in some instances the therapy source 24 or the interrogation signal source 24a may be separate from the workstation 20 but still controlled by the workstation 20 (e.g., via wireless communication protocols including BLUETOOTH® and others). Further, in instances where, for example, the therapy device 50 is configured for application of cryotherapy or chemical ablation the workstation may have no connection or control of the therapy source 24 and the interrogation signal source 24a. In such instances, the interrogation signal source 24a may be incorporated into a handle of the therapy device 50 oras a separate device inserted into the blood vessel of the patient and utilized as described elsewhere herein.

[0037] The computer 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 inputs from 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, power 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.

[0038] The therapy source 24 generates and / or outputs one or more of RF energy (monopolar or bipolar), microwave energy, ultrasound energy, cryogenic medium, or chemical ablation medium via an automated control algorithm 44 stored on the memory 32 and / or under the control of a clinician. As can be appreciated, the therapy generated or output by the therapy source 24 may change a temperature of the tissue (e.g., increases or decreased the temperature) to achieve the desired denervation of the nerves or otherwise affect nerve tissue to inhibit orterminate nerve function. The therapy source 24 may be configured to produce and / or output 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. In examples in which the therapy source 24 outputs electrical energy, the therapy source 24 may monitor voltage and current applied to target tissue via the therapeutic device 50 and monitor the temperature of the target tissue or tissue proximate the target tissue, and / or a portion of the therapeutic device 50. The therapeutic device 50, or therapy source 24 may also measure and monitor the impedance of the tissue through which therapeutic or guidance energy is transmitted to provide an indication of the status of the tissue.

[0039] The stimulation source 24a generates a stimulation signal, for example a biphasic waveform at an energy level that is less than a therapeutic energy level (i.e., a denervation energy level) 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 adjacent to a therapeutic element of therapeutic device 50. Responses may include an increase in blood pressure, an increase in vessel stiffness, a change in blood vessel diameter (vasoconstriction), changes in pulse wave velocity, augmentation pressure, heart rate variability, etc., and combinations of these.

[0040] 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, apulse width of 5 mS, a frequency of approximately 20 Hz and a duration of between 10 and 60 seconds.

[0041] A further aspect of the disclosure, described in greater detail below, is an interrogator 64 (e.g., a vector network analyzer) which may be incorporated into the workstation 20 and utilized to detect changes in volume of a blood vessel to be treated. The signals detected by the interrogator 64 and their significance regarding volume of blood within the blood vessel, may be presented on the display 26 (e.g., vasoconstriction and endpoints for therapy application).

[0042] 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 at which one or more therapy electrodes 56 are located. The elongated shaft 52 of the therapeutic device 50 is configured to be advanced 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 either or both application of a stimulation signal or therapeutic energy at the treatment site. Those of skill in the art will recognize in the context of the instant application that application of therapeutic energy should be construed to include application of cryogenic cooling to the treatment site to achieve a thermally induced neuromodulation as well as application chemical denervation methodologies. 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.

[0043] 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 at which point if a guide catheter 58 is retracted to uncover the therapeutic device 50. As noted hereinabove, retraction of the guide catheter 58 may enable the energy delivery assembly 54 to transition from the first, undeployed configuration, to the second, deployed or expanded configuration.

[0044] The elongated shaft 52 of the therapeutic device 50 may further include an aperture (not shown) at a distal end thereof and configured to slidably receive a 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, to the second, deployed or expanded configuration (FIG. 3). As noted elsewhere herein, the therapeutic device 50 may be 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).

[0045] Continuing with FIG. 3, in embodiments where the therapeutic device 50 is an RF ablation catheter, the energy delivery assembly 54 includes one or more electrodes 56 disposed on an outer surface thereof that are configured to contact a portion of the patient’s vascular tissue when the therapeutic device 50 is placed in the second, expanded configuration. As shown herein, the therapeutic device 50 includes four electrodes 56. However, the present disclosure is not so limited and the therapeutic device 50 may have more or fewer electrodes 56 without departing from the scope of the present disclosure. One of skill in the art will recognize that one or more of the electrodes 56 may be replaced with ultrasound transducers, microwave antennae, ports for delivery of cryoablation medium or chemical medium and other implements and / or ablation and denervation modalities without departing from the scope of the present disclosure.

[0046] 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 both the therapy source 24 and the stimulation source 24a. In one example the therapy source 24 produces, monopolar RF energy to denervate the sympathetic nerves of the relevant blood vessel. The electrodes 56may deliver RF energy independently of one another (e.g., monopolar), simultaneously, selectively, sequentially, and / or between any desired combination of the electrodes 56 (e.g., bipolar). It is envisioned in one embodiment that the therapy source 24 is also the stimulation source 24a and includes a diagnostic mode, where the therapy source 24 generates a stimulation signal having, 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 sympathetic nerves as described herein. The application of stimulation may achieve one of a number of physiological responses including an increase in systolic blood pressure, increase in mean arterial blood pressure, an increase in vessel stiffness, changes in diameter of the blood vessel (e.g., vasoconstriction), an increase in pulse wave velocity, an increase in pulse duration, an increase in vessel stiffness, and combinations of these along with other responses.

[0047] Though the electrodes 56 are described herein as having both therapy and stimulation capabilities, the disclosure is not so limited. For instance, therapeutic device 50 may include one or more electrodes 56 configured to deliver therapy (and not stimulation) and one or more electrodes 56 configured to deliver stimulation (and not therapy).

[0048] In accordance with a further aspect of the disclosure as depicted in FIG. 4A, one or more of the electrodes 56 may include an antenna loop 60 and a sensor loop 62. The antenna loop 60 and sensor loop 62 may be formed of one or more electrically exposed wire traces of, for example, graphene, copper or another suitable material. The antenna loop 60 and the sensor loop 62 may be electrically isolated from the electrode 56, for example, the wire traces of the antenna loop 60 and the sensor loop 62 may be coated a one or more sides with a polymeric material or other material that does not interfere with a signal emitted by the antenna loop 60. The sensor loop 62 is entirely passive and includes no direct electrical connections to the antenna loop 60 or any other component of the therapeutic device 50. In contrast, the antenna loop 60 is connected to a signal generator or interrogator 64, such as a vector network analyzer, capable of generating a signal for inductive coupling the antenna loop 60 and the sensor loop 62.

[0049] In practice, the interrogator 64 generates a frequency sweep (e.g., from about 1-5 MHz) signal causing the antenna loop 60 to resonate and transmit an RF signal to inductively couple with the sensor loop 62. Those of skill in the art will understand that the RF signal is a non-therapeutic RF signal. However, a portion of the signal generated by the interrogator 64, will not be transmitted by the antenna 60, based in part on the permittivity of the medium through which the output of the antenna loop 60 is to pass. This portion of the signal from the interrogator 64 is reflected back to the interrogator 64 via antenna 60. This reflected component of the signal from the interrogator 64 is calculated as the Si l component of the signal. The antenna 60 may be designed to resonate and transmit an RF signal at a particular frequency at which the magnitude SI 1 component is the least, thus at that frequency substantially all of the signal generated by the interrogator 64 is transmitted by the antenna.

[0050] As will be appreciated, the magnitude and minimum amplitude frequency of the SI 1 component or the reflected signal varies based on the permittivity of the medium through which the RF signal is to be transmitted. Relatedly, when the medium fluid properties remain constant, permittivity also changes with changes in volume of the medium, and as shown in FIG. 4B, the frequency of the Si l component also changes. Thus, as the volume of the medium changes, the magnitude and frequency of the SI 1 component also changes. As a result, by analyzing the SI 1 component and the frequency at which its minimum amplitude is found, changes in volume of the medium can be detected. As described in greater detail below, these changes in volume can be analyzed for detection of vasoconstriction in response to stimulation, as well as detection of effective denervation signaling an appropriate time for cessation of therapy application.

[0051] Method 500, depicted in FIG. 5A utilizes therapeutic device 50 employing the antenna 60 and sensor 62 to detect vasoconstriction and the endpoints of therapy application. There are several protocols for stimulating the nerves of a blood vessel, e.g., the sympathetic nerves of the renal artery. These stimulation protocols include sequential stimulation where stimulation is applied for a duration, followed by therapy for a duration, and concluding application of stimulation. For example, initial stimulation may be applied to the tissue to achieve a response for between 5 and 60 seconds, in certain aspects about 10 seconds followed by application of therapy, for a duration of between 20 and 60 seconds, in certain aspects about 40 seconds, and then a further of stimulation for between 5 and 20 seconds, in certain aspects about 10 seconds.

[0052] A second stimulation protocol is an alternating stimulation protocol. In an alternating protocol a series of shorter duration of stimulation signals (e.g., between 5 and 20ms, in certain aspects about 10 ms) are applied followed by therapy of between 20 and 60 ms (in certain aspects about 40 ms). This pattern of, for example, 10 ms of stimulation followed by 40 ms of therapy is repeated for an overall duration (e.g., between 30 and 120 seconds, in certain aspects about 60 seconds).

[0053] Still a further stimulation protocol is a simultaneous protocol where stimulation is applied for a short duration (e.g., 5-20 ms up to 1-5 s) prior to application of the therapy. The stimulation and the therapy are applied until either a change in physiological parameter is detected or until an energy application threshold (e.g., duration, tissue temperature, energy quantity) is reached. In instances where a change in the measured parameter or a change in response to stimulation is not detected, the process may be repeated. During the short duration of only stimulation being applied, a determination can be made whether a response is detected, and if no response is detected, the application of the denervation energy may be stopped or prevented and one or more indicators may be presented to a user indicating either that the placement of the therapy device 50 should be adjusted, or that a preceding application of therapy has been successful.

[0054] In accordance with the disclosure, a drop in magnitude or the frequency of minimum amplitude of the SI 1 component, as shown in FIG. 4B, is associated with an increase in volume of the medium through which the antenna 60 is transmitting, for example the volume of a blood vessel. As is generally understood, persons suffering from hypertension often experience a reduced diameter of certain blood vessels (e.g., renal, hepatic, or others). The reduction of diameter, which necessarily results in a reduction in volume of blood flowing through the blood vessel, is the result of neuronal activity (overactive sympathetic nerves) causing muscular contractions within the blood vessel. Further stimulation (e.g., electrical or focused ultrasound) nonetheless typically results in further contraction and reductions in diameter of the blood vessel. Thus, by sensing the change in the Si l component, efficacy of the stimulation (e.g., proper placement of the therapeutic device) can be assessed. Denervation severs the pathway for neuronal activity through the sympathetic nerves allowing the muscles to relax and therewith increasing the diameter of the blood vessel. Accordingly, analysis of the Si l component, as described herein, can be utilized to assess the progress of a denervation procedure and identify whether the denervation has been successful and to provide an indication of an endpoint for the application of therapeutic energy.

[0055] With respect to method 500, at step 502 the therapeutic device 50 is navigated to a location in a blood vessel for denervation. Once placed within a blood vessel (e.g., a renal orhepatic artery) an interrogator 64 may initiate a frequency sweep (e.g., from about 1 to about 5 GHz to cause the antenna to resonate and transmit at step 504. With the transmission of step 504, an initial Si l value determined at step 506. At step 508 stimulation is initialized from the stimulation source 24a and applied to the tissue via the electrodes 56. Regardless of the stimulation protocol employed, at step 510 a determination is made whether any response to the stimulation is detected. In accordance with the disclosure, this response may be a detected shift in the magnitude or frequency of minimum amplitude of the S 11 component signaling a change in diameter of the blood vessel as a result of the application of stimulation, and necessarily therewith the volume of the blood in the blood vessel. If no response to the stimulation is detected at step 510, the method 500 returns to step 502 for replacement of the therapeutic device 50 within the blood vessel.

[0056] In embodiments where the SI 1 component is being detected by the interrogator 64, and in accordance with FIG. 4B, effective stimulation of the nerves within or near the blood vessel results in a change in volume of the blood vessel (vasoconstriction) that is observable based on a detected change in the magnitude of the SI 1 component and the frequency at which the Si l component is observed. Stimulation of nerves of the blood vessel to cause vasoconstriction results in an increase in both magnitude and frequency of the SI 1 component.

[0057] At step 512 therapy is initialized, as noted above, any of the stimulation protocols may be employed, thus any of the related therapies may also be employed. The therapy may be the application of an RF monopolar signal via the electrodes 56 to the tissue of the blood vessel. With therapy initialized, the Si l component may be continually, periodically, or intermittently monitored by the interrogator 64 at step 514. As an example, the periodicity may be defined by the application of stimulation (e.g., only being assessed following each stimulation). In an example, following each application of stimulation (e.g., in a the SI 1 component may be analyzed at step 514, as described herein above, and a change in Si l magnitude or frequency, as compared to step 506 in excess of a threshold can be assessed at step 516. If the threshold has not been reached, at step 518 an inquiry is made whether the therapy duration or energy application limit has been reached, if not the method returns to step 512 for additional or continued application of therapy. Alternatively, at step 514 the Si l component can be continually analyzed, including during application of therapy at step 512, and when a change of SI 1 in excess of a threshold is detected the application of the therapy is stopped at step 516. In either case, the change in SI 1 is utilized to determine the endpoint of the therapy and provide an indicator to the user that the therapy has been successful.Conversely, if the therapy duration or energy limit is reached without detecting a change greater than a threshold at step 518, the method is stopped.

[0058] Alternatively or in addition to the above systems and methods utilizing the Si l component as an indicator of vasoconstriction and as an endpoint for application of therapeutic energy for denervation, the Si l component can be monitored continuously and corelated to other blood flow parameters. Pulse wave velocity (PWV) is the speed at which a pressure pulse of blood travels through an artery such as the renal or hepatic artery. A related parameter is a pulse transit time, which refers to the time required for a pulse wave to travel between two sites along the artery. As will be appreciated, the velocity is equal to the distance between the two points divided by the time between the two points.

[0059] FIG. 5B depicts a change in resonant frequency (or frequency of minimum amplitude) of the SI 1 component through the systolic and diastolic phases of a heartbeat. This change in the resonant frequency, as noted above, is based at least in part on the changes in electric permittivity as the volume of blood in an artery changes. The frequency of minimum amplitude and magnitude of SI 1 can be tracked and analyzed throughout the cardiac cycle. As will be appreciated, once a therapy device 50 is placed within a blood vessel, absent stimulus (either from the therapy device 50 or other source) or application of therapeutic denervation energy, the changes in volume of blood within the blood vessel varies on a consistent basis throughout the cardiac cycle. Thus, the plot in FIG. 5B correlates to the pressure wave of the blood flowing through the blood vessel in question. Si l tracks systole and diastole of the pressure wave as the flow and volume changes during these diastole and systole cycles.

[0060] FIG. 5C depicts a plot of the SI 1 magnitude (measured in decibels - dB) over time at a given resonant frequency. In FIG. 5C the resonant frequency in question is about 3.21 MHz, which generally comports with the peak resonant frequency observed in FIG. 5B. However, the value of the peak resonant frequency can be determined on an individual basis for each patient. As can be seen in FIG. 5C, the magnitude of the S 11 component at the resonant frequency varies over time. The increasing plot (1) substantially corresponds to the systolic phase, with an increasing value until reaching the peak magnitude, and the decreasing plot (2) substantially corresponds to the diastolic phase.

[0061] In accordance with one aspect of the disclosure, the therapeutic device 50 includes at least two electrodes 56 each of which includes an antenna 60 and a sensor 62, each of which is connected to the interrogator 64. The distance between the electrodes 56 along the length of the vessel, on which the antennae 60 are located is known. By comparing the plots of FIG. 5C,a time between a peak magnitude for each sensor 56 can be determined (i.e., the pulse transit time). By dividing the distance between the sensors 56 by the pulse transit time, the velocity at which the blood is flowing in the blood vessel (the PWV), can be calculated. As will be appreciated, by denervating efferent sympathetic nerves in and around the blood vessel, the nerves cease stimulating the muscle fibers of the blood vessel. As a result, the muscles fibers relax, and the stiffness of the blood vessel is reduced. With the decrease in stiffness of the blood vessel, the pulse transit times increase, and the PWV through the blood vessels decreases. These changes in pulse transit time and PWV can be used either alone or in combination with the SI 1 changes (e.g., as in method 500) to determine an end point for application of therapeutic energy or to confirm a successful denervation of the blood vessel. Thus, in one aspect of the disclosure along with detecting an initial Si l component values at step 506, an initial pulse transit time or PWV can be calculated. A second pulse transit time or PWV value can be calculated after the application of the denervation therapy. A decrease of a PWV or an increase in pulse transit time in excess with a threshold can be considered in confirming the success of the denervation. This change may be an absolute value based on empirically collected data, it may be a percentage value change, or some other threshold value to confirm the efficacy of the denervation. As will be appreciated, if a change in excess of the desired threshold is not achieved, the method may return to step 512 for continued application of therapeutic energy to complete the denervation.

[0062] A further aspect of the disclosure is directed to the therapeutic device 50 depicted in FIG. 6A. As with the aspects shown in FIG. 3, the therapeutic device 50 includes a plurality of electrodes 56. In addition, the therapeutic device 50 includes one or more ultrasonic transducers 66. As shown in Fig. 6A the ultrasonic transducer 66 are located proximal of the electrodes 56. In accordance with one aspect of the disclosure as shown in FIG. 6B the ultrasonic transducers 66 are formed of a poly vinylidene fluoride (PVDF) film 68 secured to the elongate shaft 52, for example via an epoxy coating 70. A lead, not shown, can electrically connect the ultrasonic transducer 66 to the workstation 20.

[0063] A vascular bruit is a vascular sound that is typically observed with a stethoscope which is placed over the carotid artery. When there is blood flow through a stenotic area (i.e., an area of constriction), the stenotic area causes turbulent flow which is distinct and observable as distinct from normal flow in the blood vessel. The vascular bruit is a function of the patient’s blood pressure, volume of blood flow, and the area of the stenosis. A therapeutic device 50 as depicted in FIG. 6A employing the ultrasonic transducers 66 is effectively an ultrasonicstethoscope that is placed within the blood vessel and capable of listening to the flow of blood through the blood vessel.

[0064] In accordance with a method 700, depicted in FIG. 7, the therapeutic device 50 is placed or repositioned within a desired blood vessel at step 702. Once positioned, the therapeutic device 50 creates a stenosis within the blood vessel. The observed sounds caused by placement of the therapeutic device 50 may take a period of time to stabilize but will generally be consistent once properly placed. At step 704, an initial vascular bruit is detected by listening to the flow of the blood over the ultrasonic transducer 66. The impact of the flow of blood over the ultrasonic transducer 66, and particularly the impact of the systolic pressure waves, cause the ultrasonic transducers 66 to output an electrical signal that can be analyzed by an application 34 executed by the computer 22. At step 706, the application 34 can convert the electrical signals generated by the ultrasonic transducer 66 into spectral power. FIG. 8A depicts the vascular bruit (blood flow sounds) for a blood vessel under high blood pressure, for example caused by overactive sympathetic nerves stimulating the muscle fibers within the blood vessel or as a result of stimulation causing vasoconstriction. As can be seen the spectral power in FIG. 8A is highly distinct with clear sharp peaks plotted over time. A patient suffering from hypertension would expect a spectral power signal similar to FIG. 8A, though every individual will have some variations in the absolute values of spectral power.

[0065] At step 708 stimulation can be optionally applied, and where no response is detected at step 710, the method may return to step 702 for adjustment of placement of the therapeutic device 50. Alternatively, the method 700 may proceed to step 712 where therapeutic energy (e.g., monopolar RF) is applied to the wall of the blood vessel. As with method 500 either periodic or continual monitoring of the spectral power can be performed at step 714. As with method 500 this may be associated with the stimulation protocol being employed. Further both periodic or continual monitoring of spectral power may also be undertaken. At step 716 a determination is made whether a chance in spectral power greater than a threshold has been achieved. If yes at step 716, the method stops. If less than the threshold change is undertaken the method advances to step 718 to determine whether a therapy duration or energy limit has been reached, if yes, the method ends, but if not, the method returns to step 712 to continue therapy.

[0066] FIG. 8B depicts both the sounds measured by the ultrasonic transducer 66 and the spectral power of that sound for a patient with normal or low blood pressure. The absolute value of the lower spectral power may be different for each individual patient, and thecomparison or the thresholds may be a percentage change of the spectral power measurement at step 706 and the observed values at step 714 (e.g., a change of 25% may signify a successful denervation resulting in a low or normalized blood pressure). Additionally or alternatively, the methods described here can be used to detect a change in vascular bruit following application of stimulation to achieve vasoconstriction. With vasoconstriction (e.g., as a result of the application of stimulation to electrodes 56) the vascular bruit will be sharper (e.g., similar to FIG. 8A) and when vasoconstriction is eased the vascular bruit will be more relaxed (e.g., similar to FIG. 8B).

[0067] In accordance with aspects of the present disclosure, the therapeutic device50 may be navigated within the vessels or luminal tissue in one configuration e.g., a linear configuration) and once located at a desired location, deployed or otherwise actuated to achieve a second configuration. Further, though the disclosure focuses in part on Si l detection or vascular bruit, the disclosure is not so limited and one or more of changes in pulse width velocity, observed blood vessel diameter (e.g., via fluoroscopy or ultrasound imaging), and others may be employed either alone or in combination with other responses to stimulation and denervation without departing from the scope of the disclosure.

[0068] 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).

[0069] 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-Rayor other optical storage, magnetic cassettes, magnetic tape, magnetic disk storage 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.

[0070] 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.

[0071] Example 1. A method of evaluating a denervation procedure, comprising: prior to applying a therapy at a location of a blood vessel wall: outputting, by an interrogator, an interrogator signal comprising a frequency sweep to drive an antenna placed within a blood vessel; detecting at the interrogator a first reflected component of the signal; and while applying the therapy at the location of the blood vessel wall: monitoring a subsequent reflected component of the signal; determining that a change between the subsequent reflected component and the first reflected component exceeds a threshold value; and in response to determining the change between the subsequent reflected component and the first reflected component exceeds the threshold value, performing an action.

[0072] Example 2. The method of Example 1, wherein performing the action comprises at least one of outputting an indication that the change exceeds the threshold value or ceasing application of the therapy to the location of the blood vessel.

[0073] Example 3. The method of Example 1, further comprising applying a stimulation signal from electrodes of a therapeutic device to the blood vessel wall.

[0074] Example 4. The method of Example 3, wherein monitoring the subsequent reflected component of the signal comprises observing a response to the stimulation signal in the reflected component of the signal.

[0075] Example 5. The method of Example 3, wherein an increase in a peak magnitude or an increase in a resonant frequency associated with the subsequent reflected component relative to a peak magnitude or a resonant frequency associated with the first reflected component indicates a reduction in volume of blood within the blood vessel.

[0076] Example 6. The method of Example 4, wherein the stimulation signal causes a reduction in volume of blood within the blood vessel by stimulation of nerves in or near the blood vessel wall causing contraction of muscle fibers in the blood vessel.

[0077] Example 7. The method of Example 5, wherein the stimulation signal is part of a sequential stimulation protocol, an alternating stimulation protocol, or a continuous stimulation protocol.

[0078] Example 8. The method of Example 6, wherein monitoring the subsequent reflected component comprises continuously monitoring the subsequent reflected component, periodically monitoring the subsequent reflected component, or intermittently monitoring the subsequent reflected component.

[0079] Example 9. The method of Example 7, wherein monitoring the subsequent reflected component comprises periodically monitoring the subsequent reflected component, wherein the simulation signal is part of the sequential stimulation protocol or the alternating stimulation protocol, and wherein periodically monitoring the subsequent reflected component is undertaken during a stimulation portion of the sequential stimulation protocol or the alternating stimulation protocol.

[0080] Example 10. The method of Example 1, wherein the therapy comprises at least one of monopolar radio frequency denervation, bipolar radio frequency denervation, ultrasound denervation, focused ultrasound denervation, cryogenic denervation, or chemical denervation.

[0081] Example 11. The method of Example 1, wherein a decrease in a magnitude or a decrease in a resonant frequency associated with the subsequent reflected component following the application the therapy is indicative of an increase in blood volume within the blood vessel.

[0082] Example 12. The method of Example 10, wherein the increase in blood volume within the blood vessel is indicative of a successful denervation of nerves in or near the location of the blood vessel wall.

[0083] Example 13. The method of Example 1, further comprising outputting by the interrogator, a second interrogator signal comprising a second frequency sweep to drive a second antenna within the blood vessel; detecting at the interrogator a reflected component of the second interrogator signal; and calculating a pulse wave velocity or a pulse transit time of blood within the blood vessel.

[0084] Example 14. The method of Example 13, further comprising detecting a change in pulse wave velocity or pulse transit time in excess of a threshold value, wherein the change in pulse wave velocity or the pulse transit time in excess of the threshold value is indicative of an increase in blood volume within the blood vessel.

[0085] Example 15. The method of Example 14, wherein the increase in blood volume within the blood vessel is indicative of a successful denervation of nerves in or near the blood vessel.

[0086] Example 16. The method of Example 1, wherein the blood vessel is one or more of a celiac trunk, a hepatic artery, splenic artery, gastric artery, superior mesenteric artery, inferior mesenteric artery, gonadal artery, splanchnic artery or branches thereof.

[0087] Example 17. A therapeutic system comprising: an elongate member configured to be navigated within a blood vessel, the elongate member comprising a proximal portion and a distal portion; a plurality of electrodes formed on a distal portion of the elongate member, the electrodes in electrical communication with a stimulation source; an antenna loop formed on at least one of the electrodes; a sensor loop formed on at least one of the electrodes; and an interrogator in electrical communication with the antenna loop and configured to initiate an interrogator signal comprising a frequency sweep to drive the antenna loop, wherein the interrogator is configured to receive a signals indicative of a reflected component of the interrogator signal from the sensor loop.

[0088] Example 18. The therapeutic system of Example 17, wherein the antenna loop and the sensor loop inductively couple upon the antenna loop transmitting the interrogator signal.

[0089] Example 19. The therapeutic system of Example 18, further comprising a therapy source for delivery of a therapy to a location of a blood vessel wall.

[0090] Example 20. The therapeutic system of Example 19, wherein the therapy comprises at least one of monopolar radio frequency denervation, bipolar radio frequency denervation, ultrasound denervation, focused ultrasound denervation, cryogenic denervation, or chemical denervation.

[0091] Example 21. The therapeutic system of Example 19, wherein the therapy source is in electrical communication with the electrodes for application of the therapy to the location of a blood vessel wall.

[0092] Example 22. The therapeutic system of Example 21, further comprising a stimulation source in electrical communication with the electrodes, wherein the electrodes are configured to apply a stimulation signal to the blood vessel wall.

[0093] Example 23. The therapeutic system of Example 22, wherein the stimulation source is configured out output of a sequential stimulation protocol, an alternating stimulation protocol, or a continuous stimulation protocol.

[0094] Example 24. The therapeutic system of Example 23, further comprising a computing device including a processor and a memory, the memory storing thereon an application that when executed by the processor: receives the signals indicative of a reflected component of the interrogator signal; and detects changes in the signals indicative of the reflected component of the interrogator signal.

[0095] Example 25. The therapeutic system of Example 23, wherein the application, when executed by the processor, and in response to detecting a change in the signals indicative of the reflected component of the interrogator signal in excess of a threshold, performs an action.

[0096] Example 26. The therapeutic system of Example 24, wherein the action comprises outputting to a display device in communication with the computing device an indication that the change exceeds the threshold or ceasing application of the therapy to the location of the blood vessel wall.

[0097] Example 27. The therapeutic system of Example 17, further comprising: a second antenna loop formed on a second of the at least one electrodes; a second sensor loop formed on a second of the at least one electrodes; wherein the interrogator is in electrical communication with the second antenna loop and configured to initiate a second interrogation signal comprising a second frequency sweep to drive the second antenna, wherein the interrogator is configured to receive a second signal indicative of a reflect component of the second interrogator signal from the second sensor loop.

[0098] Example 28. The therapeutic system of Example 27, further comprising a computing device including a processor and a memory, the memory storing thereon an application that when executed by the processor: receive the signals indicative of a reflected component of the interrogator signal; receives the signals indicate of a reflected component of the second interrogator signal; and calculate a pulse wave velocity or a pulse transit time of blood within the blood vessel.

[0099] Example 29. A therapeutic system comprising: an elongate member configured for navigation within a blood vessel, the elongate member comprising a distal portion and a proximal portion; a plurality of electrodes formed on the distal portion of the elongate member, the electrodes configured to be in electrical communication with a stimulation source; and an ultrasonic transducer formed on the elongate member, wherein the ultrasonic transducer is configured to detect a signal indicative of a vascular bruit of the blood vessel.

[0100] Example 30. The therapeutic system of Example 29, further comprising a therapy source for delivery of a therapy to a location of a blood vessel wall.

[0101] Example 31. The therapeutic system of Example 30, wherein the therapy comprises at least one of monopolar radio frequency denervation, bipolar radio frequency denervation, ultrasound denervation, focused ultrasound denervation, cryogenic denervation, or chemical denervation.

[0102] Example 32. The therapeutic system of Example 30, wherein the therapy source is in electrical communication with the electrodes for application of the therapy to the location of a blood vessel wall.

[0103] Example 33. The therapeutic system of Example 32, further comprising a stimulation source in electrical communication with the electrodes, wherein the electrodes are configured to apply a stimulation signal to the blood vessel wall.

[0104] Example 34. The therapeutic system of Example 33, wherein the stimulation source is configured out output of a sequential stimulation protocol, an alternating stimulation protocol, or a continuous stimulation protocol.

[0105] Example 35. The therapeutic system of claim 34, further comprising a computing device including a processor and a memory, the memory storing thereon an application that when executed by the processor: receives from the ultrasound transducer the signal indicative of the vascular bruit of the blood vessel; calculates from the received signal indicative of a vascular bruit to spectral power; and detects changes in the spectral power.

[0106] Example 36. The therapeutic system of Example 35, wherein the application when executed by the processor, and in response to detecting a change in the spectral power in excess of a threshold, performs an action.

[0107] Example 37. The therapeutic system of Example 36, wherein the action comprises outputting to a display device in communication with the computing device an indication that the change exceeds the threshold or ceasing application of the therapy to the location of the blood vessel wall.

[0108] Example 38. A method of evaluating a denervation procedure, comprising: receiving, by a computing device, a signal indicative of a vascular bruit of a blood vessel in which an elongate member has been placed, wherein the vascular bruit is detected by an ultrasonic transducer carried by the elongate member; converting, by the computing device, the vascular bruit to spectral power; monitoring the spectral power over time as a therapy is applied to a blood vessel wall of the blood vessel in which the elongate member has been placed; determining a change in the spectral power over time exceeds a threshold value; and in responseto determining the change in the spectral power over time exceeds the threshold value, performing an action.

[0109] Example 39. The method of Example 38, wherein performing the action comprises at least one of outputting an indication that the change exceeds the threshold value or ceasing application of the therapy to the location of the blood vessel.

[0110] Example 40. The method of Example 39, further comprising applying a stimulation signal from electrodes of a therapeutic device to the blood vessel wall.

[0111] Example 41. The method of Example 40, wherein monitoring the spectral power comprises observing a response to the stimulation signal in the spectral power.

[0112] Example 42. The method of Example 41, wherein an increase in the spectral power indicates a reduction in volume of blood within the blood vessel.

[0113] Example 43. The method of Example 42, wherein the stimulation signal causes a reduction in volume of blood within the blood vessel by stimulation of nerves in or near the blood vessel wall causing contraction of muscle fibers in the blood vessel.

[0114] Example 44. The method of Example 43, wherein the stimulation signal is part of a sequential stimulation protocol, an alternating stimulation protocol, or a continuous stimulation protocol.

[0115] Example 45. The method of Example 44, wherein monitoring the spectral power comprises a continuously monitoring the spectral power, periodically monitoring the spectral power or periodically monitoring the spectral power.

[0116] Example 46. The method of Example 45, wherein monitoring the spectral power comprises periodically monitoring the spectral power, wherein the stimulation signal is part of the sequential stimulation protocol or the alternative stimulation protocol, and where the periodically monitoring is undertaken during a stimulation portion of the sequential stimulation protocol or the alternating stimulation protocol.

[0117] Example 47. The method of Example 46, wherein the therapy comprises at least one of monopolar radio frequency denervation, bipolar radio frequency denervation, ultrasound denervation, focused ultrasound denervation, and cryogenic denervation, or chemical denervation.

[0118] Example 48. The method of Example 38, wherein a decrease in the spectral power following the application the therapy is indicative of an increase in blood volume within the blood vessel.

[0119] Example 49. The method of Example 48, wherein the increase in blood volume within the blood vessel is indicative of a successful denervation of nerves in or near the location of the blood vessel wall.

[0120] Example 50. The method of Example 38, wherein the blood vessel is one or more of a celiac trunk, a hepatic artery, splenic artery, gastric artery, superior mesenteric artery, inferior mesenteric artery, gonadal artery, splanchnic artery or branches thereof.

[0121] Further disclosed herein is the subject-matter of the following clauses:1. A therapeutic system comprising: an elongate member configured to be navigated within a blood vessel, the elongate member comprising a proximal portion and a distal portion; a plurality of electrodes formed on a distal portion of the elongate member, the electrodes in electrical communication with a stimulation source; an antenna loop formed on at least one of the electrodes; a sensor loop formed on at least one of the electrodes; and an interrogator in electrical communication with the antenna loop and configured to initiate an interrogator signal comprising a frequency sweep to drive the antenna loop, wherein the interrogator is configured to receive a signals indicative of a reflected component of the interrogator signal from the sensor loop.2. The therapeutic system of clause 1, wherein the antenna loop and the sensor loop inductively couple upon the antenna loop transmitting the interrogator signal.3. The therapeutic system of clause 1 or 2, further comprising a therapy source for delivery of a therapy to a location of a blood vessel wall; and / or wherein the therapy comprises at least one of monopolar radio frequency denervation, bipolar radio frequency denervation, ultrasound denervation, focused ultrasound denervation,cryogenic denervation, or chemical denervation; and / or wherein the therapy source is in electrical communication with the electrodes for application of the therapy to the location of a blood vessel wall. The therapeutic system of any one of clauses 1-3, further comprising a stimulation source in electrical communication with the electrodes, wherein the electrodes are configured to apply a stimulation signal to the blood vessel wall. The therapeutic system of clause 4, wherein the stimulation source is configured out output of a sequential stimulation protocol, an alternating stimulation protocol, or a continuous stimulation protocol. The therapeutic system of any one of clauses 1-5, further comprising a computing device including a processor and a memory, the memory storing thereon an application that when executed by the processor: receives the signals indicative of a reflected component of the interrogator signal; and detects changes in the signals indicative of the reflected component of the interrogator signal. The therapeutic system of clause 6, wherein the application when executed by the processor, and in response to detecting a change in the signals indicative of the reflected component of the interrogator signal in excess of a threshold, outputs to a display device in communication with the computing device an indication that thechange exceeds the threshold or ceasing application of the therapy to the location of the blood vessel wall.8. The therapeutic system of any one of clauses 1-7, further comprising: a second antenna loop formed on a second of the at least one electrodes; a second sensor loop formed on a second of the at least one electrodes; wherein the interrogator is in electrical communication with the second antenna loop and configured to initiate a second interrogation signal comprising a second frequency sweep to drive the second antenna, wherein the interrogator is configured to receive a second signal indicative of a reflect component of the second interrogator signal from the second sensor loop.9. The therapeutic system of clause 8, further comprising a computing device including a processor and a memory, the memory storing thereon an application that when executed by the processor: receive the signals indicative of a reflected component of the interrogator signal; receives the signals indicate of a reflected component of the second interrogator signal; and calculate a pulse wave velocity or a pulse transit time of blood within the blood vessel.10. A therapeutic system comprising: an elongate member configured for navigation within a blood vessel, the elongate member comprising a distal portion and a proximal portion;a plurality of electrodes formed on the distal portion of the elongate member, the electrodes configured to be in electrical communication with a stimulation source; and an ultrasonic transducer formed on the elongate member, wherein the ultrasonic transducer is configured to detect a signal indicative of a vascular bruit of the blood vessel. The therapeutic system of clause 10, further comprising a therapy source for delivery of a therapy to a location of a blood vessel wall; and / or wherein the therapy comprises at least one of monopolar radio frequency denervation, bipolar radio frequency denervation, ultrasound denervation, focused ultrasound denervation, cryogenic denervation, or chemical denervation and / or; therapy source is in electrical communication with the electrodes for application of the therapy to the location of a blood vessel wall. The therapeutic system of clause 10 or 11, further comprising a stimulation source in electrical communication with the electrodes, wherein the electrodes are configured to apply a stimulation signal to the blood vessel wall. The therapeutic system of clause 12, wherein the stimulation source is configured out output of a sequential stimulation protocol, an alternating stimulation protocol, or a continuous stimulation protocol. The therapeutic system of any one of clauses 10-13, further comprising a computing device including a processor and a memory, the memory storing thereon an application that when executed by the processor:receives from the ultrasound transducer the signal indicative of the vascular bruit of the blood vessel; calculates from the received signal indicative of a vascular bruit to spectral power; and detects changes in the spectral power. The therapeutic system of clause 14, wherein the application when executed by the processor, and in response to detecting a change in the spectral power in excess of a threshold, outputs to a display device in communication with the computing device an indication that the change exceeds the threshold or ceasing application of the therapy to the location of the blood vessel wall.

Claims

CLAIMS:

1. A therapeutic system comprising: an elongate member configured to be navigated within a blood vessel, the elongate member comprising a proximal portion and a distal portion; a plurality of electrodes formed on a distal portion of the elongate member, the electrodes in electrical communication with a stimulation source; an antenna loop formed on at least one of the electrodes; a sensor loop formed on at least one of the electrodes; and an interrogator in electrical communication with the antenna loop and configured to initiate an interrogator signal comprising a frequency sweep to drive the antenna loop, wherein the interrogator is configured to receive a signals indicative of a reflected component of the interrogator signal from the sensor loop.

2. The therapeutic system of claim 1, wherein the antenna loop and the sensor loop inductively couple upon the antenna loop transmitting the interrogator signal.

3. The therapeutic system of claim 1 or 2, further comprising a therapy source for delivery of a therapy to a location of a blood vessel wall; and / or wherein the therapy comprises at least one of monopolar radio frequency denervation, bipolar radio frequency denervation, ultrasound denervation, focused ultrasound denervation, cryogenic denervation, or chemical denervation; and / or wherein the therapy source is in electrical communication with the electrodes for application of the therapy to the location of a blood vessel wall.

4. The therapeutic system of any one of claims 1-3, further comprising a stimulation source in electrical communication with the electrodes, wherein the electrodes are configured to apply a stimulation signal to the blood vessel wall.

5. The therapeutic system of claim 4, wherein the stimulation source is configured out output of a sequential stimulation protocol, an alternating stimulation protocol, or a continuous stimulation protocol.

6. The therapeutic system of any one of claims 1-5, further comprising a computing device including a processor and a memory, the memory storing thereon an application that when executed by the processor: receives the signals indicative of a reflected component of the interrogator signal; and detects changes in the signals indicative of the reflected component of the interrogator signal.

7. The therapeutic system of claim 6, wherein the application when executed by the processor, and in response to detecting a change in the signals indicative of the reflected component of the interrogator signal in excess of a threshold, outputs to a display device in communication with the computing device an indication that the change exceeds the threshold or ceasing application of the therapy to the location of the blood vessel wall.

8. The therapeutic system of any one of claims 1-7, further comprising: a second antenna loop formed on a second of the at least one electrodes;a second sensor loop formed on a second of the at least one electrodes; wherein the interrogator is in electrical communication with the second antenna loop and configured to initiate a second interrogation signal comprising a second frequency sweep to drive the second antenna, wherein the interrogator is configured to receive a second signal indicative of a reflect component of the second interrogator signal from the second sensor loop.

9. The therapeutic system of claim 8, further comprising a computing device including a processor and a memory, the memory storing thereon an application that when executed by the processor: receive the signals indicative of a reflected component of the interrogator signal; receives the signals indicate of a reflected component of the second interrogator signal; and calculate a pulse wave velocity or a pulse transit time of blood within the blood vessel.

10. A therapeutic system comprising: an elongate member configured for navigation within a blood vessel, the elongate member comprising a distal portion and a proximal portion; a plurality of electrodes formed on the distal portion of the elongate member, the electrodes configured to be in electrical communication with a stimulation source; and an ultrasonic transducer formed on the elongate member, wherein the ultrasonic transducer is configured to detect a signal indicative of a vascular bruit of the blood vessel.

11. The therapeutic system of claim 10, further comprising a therapy source for delivery of a therapy to a location of a blood vessel wall; and / or wherein the therapy comprises at least one of monopolar radio frequency denervation, bipolar radio frequency denervation, ultrasound denervation, focused ultrasound denervation, cryogenic denervation, or chemical denervation and / or; therapy source is in electrical communication with the electrodes for application of the therapy to the location of a blood vessel wall.

12. The therapeutic system of claim 10 or 11, further comprising a stimulation source in electrical communication with the electrodes, wherein the electrodes are configured to apply a stimulation signal to the blood vessel wall.

13. The therapeutic system of claim 12, wherein the stimulation source is configured out output of a sequential stimulation protocol, an alternating stimulation protocol, or a continuous stimulation protocol.

14. The therapeutic system of any one of claims 10-13, further comprising a computing device including a processor and a memory, the memory storing thereon an application that when executed by the processor: receives from the ultrasound transducer the signal indicative of the vascular bruit of the blood vessel; calculates from the received signal indicative of a vascular bruit to spectral power; and detects changes in the spectral power.

5. The therapeutic system of claim 14, wherein the application when executed by the processor, and in response to detecting a change in the spectral power in excess of a threshold, outputs to a display device in communication with the computing device an indication that the change exceeds the threshold or ceasing application of the therapy to the location of the blood vessel wall.

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