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WO2025176672A1 - Vasoconstriction rénale et réponse de flux sanguin rénal à une stimulation en tant que guide de dénervation rénale - Google Patents

Vasoconstriction rénale et réponse de flux sanguin rénal à une stimulation en tant que guide de dénervation rénale

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Publication number
WO2025176672A1
WO2025176672A1 PCT/EP2025/054347 EP2025054347W WO2025176672A1 WO 2025176672 A1 WO2025176672 A1 WO 2025176672A1 EP 2025054347 W EP2025054347 W EP 2025054347W WO 2025176672 A1 WO2025176672 A1 WO 2025176672A1
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WIPO (PCT)
Prior art keywords
target tissue
blood vessel
flow parameter
therapy
nerves
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/054347
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English (en)
Inventor
Gerry O. Mccaffrey
Binit PANDA
Naryan Francis MURTHY
Shelby A. ANGEL
Sabrina Hua
Paul J. Coates
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Medtronic Ireland Manufacturing ULC
Original Assignee
Medtronic Ireland Manufacturing ULC
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Publication of WO2025176672A1 publication Critical patent/WO2025176672A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A61B18/1206—Generators therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A61B18/14—Probes or electrodes therefor
    • A61B18/1492—Probes or electrodes therefor having a flexible, catheter-like structure, e.g. for heart ablation
    • A—HUMAN NECESSITIES
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    • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
    • A61B5/026—Measuring blood flow
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    • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
    • A61B5/026—Measuring blood flow
    • A61B5/0261—Measuring blood flow using optical means, e.g. infrared light
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
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    • A61B5/4035—Evaluating the autonomic nervous system
    • A—HUMAN NECESSITIES
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    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4836—Diagnosis combined with treatment in closed-loop systems or methods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36014—External stimulators, e.g. with patch electrodes
    • A61N1/36017—External stimulators, e.g. with patch electrodes with leads or electrodes penetrating the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N7/02—Localised ultrasound hyperthermia
    • A61N7/022—Localised ultrasound hyperthermia intracavitary
    • A—HUMAN NECESSITIES
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    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/06—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating caused by chemical reaction, e.g. moxaburners
    • A—HUMAN NECESSITIES
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    • A61B18/08—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by means of electrically-heated probes
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    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/08—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by means of electrically-heated probes
    • A61B18/10—Power sources therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00345—Vascular system
    • A61B2018/00404—Blood vessels other than those in or around the heart
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    • A61B2018/00434—Neural system
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    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00505—Urinary tract
    • A61B2018/00511—Kidney
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
    • A61B2018/00577—Ablation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00636—Sensing and controlling the application of energy
    • A61B2018/00773—Sensed parameters
    • A61B2018/00863—Fluid flow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/02—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by cooling, e.g. cryogenic techniques
    • A61B2018/0212—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by cooling, e.g. cryogenic techniques using an instrument inserted into a body lumen, e.g. catheter

Definitions

  • This disclosure relates to systems and methods enabling positioning a therapeutic device within luminal tissues to enhance ablation during a therapeutic procedure.
  • Catheters 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.
  • 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.
  • a clinician delivers stimuli or energy, such as radiofrequency, ultrasound, cooling, or other energy to a treatment site to reduce activity of nerves surrounding a blood vessel.
  • the stimuli or energy delivered to the treatment site may provide various therapeutic effects through alteration of sympathetic nerve activity.
  • a method of performing a therapeutic procedure includes navigating a therapeutic device to a location within a blood vessel adj acent to target tissue, determining a first flow parameter within a portion of a blood vessel adjacent to the target tissue, applying neurostimulation to the target tissue and obtaining first images of blood vessels distal of the target tissue, applying therapy to the target tissue, applying neurostimulation to the target tissue, determining a second flow parameter within the portion of the blood vessel adjacent to the target tissue, comparing the second flow parameter to a flow parameter criteria, applying neurostimulation to the target tissue and obtaining second images of the blood vessels distal of the target tissue, comparing the first images to the second images to determine a vasoconstriction metric based on a change in at least one dimension of the blood vessels distal of the target tissue, and applying therapy to the target tissue if it is determined that the vasoconstriction metric satisfies a vasoconstriction criteria.
  • a method of performing a therapeutic procedure includes injecting a fluid into a blood vessel adjacent to target tissue, imaging blood vessels distal of the target tissue, identifying a first landmark adjacent to the target tissue, identifying a second landmark adjacent to the target tissue, identifying a first point in time at which the injected fluid flows past the first landmark, identifying a second point in time at which the injected fluid flows past the second landmark, determining a flow parameter of the injected fluid based on the identified first point in time and the identified second point in time, comparing the determined flow parameter to a flow parameter criteria, and applying therapy to the target tissue if the determined flow parameter satisfies the flow parameter criteria.
  • a system for performing a diagnostic and therapeutic procedure includes a workstation, the workstation including a processor and a memory, the memory storing instructions thereon, which when executed cause the processor to determine a first flow parameter within a portion of a blood vessel adjacent to target tissue, cause a stimulation source to output a neurostimulation signal via at least one stimulation element to the target tissue and obtain first images of blood vessels distal of the target tissue, cause a therapy source to output a therapy signal via at least one therapy element to the target tissue, apply neurostimulation to the target tissue, determine a second flow parameter within the portion of the blood vessel adjacent to the target tissue, compare the second flow parameter to a flow parameter criteria, apply neurostimulation to the target tissue and obtain second images of the blood vessels distal of the target tissue, compare the first images to the second images to determine a vasoconstriction metric based on a change in at least one dimension of the blood vessels distal of the target tissue, and apply therapy to the target tissue if it
  • a method includes causing, by a computing device, a stimulation source to output a first stimulation signal to at least one stimulation element positioned at a location within a target vessel, wherein the at least one stimulation element is coupled to a therapeutic device, causing, by the computing device, a sensor to measure a blood flow rate of within the target vessel, in response to a flow rate metric based on the blood flow rate satisfying a predetermined criteria, causing, by the computing device, the stimulation source to output a second stimulation signal to the at least one stimulation element positioned at the location within the target vessel, determining, by the computing device, based on at least one image of the target vessel collected after delivery of the second stimulation signal, at least one dimension of the target vessel distal of the location, determining, by the computing device, based on the at least one dimension of the target vessel, a vasoconstriction metric, and in response to the vasoconstriction metric satisfying a vasoconstriction criteria, outputting,
  • a method includes, after a denervation procedure has been performed at a location of a target vessel, causing, by a computing device, a stimulation source to output a first stimulation signal to at least one stimulation element positioned proximate the location, wherein the at least one stimulation element is coupled to a therapeutic device, causing, by the computing device, a sensor to measure a blood flow rate of within the target vessel, in response to a flow rate metric based on the blood flow rate satisfying a predetermined criteria, causing, by the computing device, the stimulation source to output a second stimulation signal to the at least one stimulation element positioned at the location within the target vessel, determining, by the computing device, based on at least one image of the target vessel collected after delivery of the second stimulation signal, at least one dimension of the target vessel distal of the location, determining, by the computing device, based on the at least one dimension of the target vessel, a vasoconstriction metric, and in response to the vas
  • a method may include applying neurostimulation to target tissue in and/or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall; in response to applying neurostimulation: obtaining a first flow parameter related to blood flow within the blood vessel; and obtaining first images of the blood vessel downstream of the target tissue; applying a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; after applying the neuromodulation therapy to the target tissue, applying neurostimulation to the target tissue; obtaining a second flow parameter related to blood flow within the blood vessel; determining, based on a flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue; and in response to an indication of inadequate ablation of the nerves, obtaining second images of the blood vessel downstream of the target tissue.
  • a method may include applying neurostimulation to target tissue in and/or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall; in response to applying neurostimulation: obtaining a first flow parameter related to blood flow within the blood vessel; and obtaining first images of the blood vessel downstream of the target tissue; applying a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; while applying the neuromodulation therapy to the target tissue: applying neurostimulation to the target tissue; obtaining a second flow parameter related to blood flow within the blood vessel; and iteratively determining, based on a flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue; and in response to an indication of inadequate ablation of the nerves, obtaining second images of the blood vessel downstream of the target tissue.
  • a system may include a workstation comprising a one or more processors and a memory, the memory storing instructions thereon, which when executed by the one or more processors, cause the one or more processors to: cause a neurostimulator to apply neurostimulation to target tissue in and/or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in and/or adjacent to the blood vessel wall; in response to the neurostimulator applying neurostimulation: obtain a first flow parameter related to blood flow within the blood vessel; and obtain first images of the blood vessel downstream of the target tissue; cause a therapy device to apply a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; after the neuromodulation therapy is applied to the target tissue, cause the neurostimulator to apply neurostimulation to the target tissue; obtain a second flow parameter related to blood flow within the blood vessel; determine, based on a flow parameter criteria and the second flow parameter, whether the denerv
  • a system may include a workstation comprising a one or more processors and a memory, the memory storing instructions thereon, which when executed by the one or more processors, cause the one or more processors to: cause a neurostimulator to apply neurostimulation to target tissue in and/or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall; in response to the neurostimulator applying neurostimulation: obtain a first flow parameter related to blood flow within the blood vessel; and obtain first images of the blood vessel downstream of the target tissue; cause a therapy device to apply a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; while the neuromodulation therapy is being applied to the target tissue: cause the neurostimulator to apply neurostimulation to the target tissue; obtain a second flow parameter related to blood flow within the blood vessel; and determine, based on a flow parameter criteria and the second flow parameter, whether the denervation therapy
  • a method of performing a therapeutic procedure includes navigating a therapeutic device to a location adjacent to target tissue, determining a first flow parameter within a blood vessel adjacent to the target tissue, applying neurostimulation to the target tissue and obtaining first images of blood vessels distal of the target tissue, applying therapy to the target tissue, applying neurostimulation to the target tissue, determining a second flow parameter within the blood vessel adjacent to the target tissue, comparing the second flow parameter to a flow parameter criteria, applying neurostimulation to the target tissue and obtaining second images of the blood vessels distal of the target tissue, comparing the first images to the second images to determine a vasoconstriction metric , and applying therapy to the target tissue if it is determined that the vasoconstriction metric satisfies a vasoconstriction criteria.
  • FIG. l is a schematic diagram of a therapy system in accordance with the disclosure.
  • FIG. 4 is a representation of an external stimulation energy transducer in accordance with the disclosure.
  • FIG. 6A is a graphical representation of changes in physiological parameters experienced by a patient as a result of a pre-therapy application of stimulation in accordance with the disclosure
  • FIG. 6B is a graphical representation of changes in physiological parameters experienced by a patient as a result of post-therapy application of stimulation in accordance with the disclosure
  • the flow parameters within the blood vessels may be measured or otherwise identified using flow sensors (disposed on or coupled to the therapeutic device), imaging blood vessels, or combinations thereof. It is envisioned that the flow sensor may be disposed on a guidewire.
  • imaging blood vessels reveals landmarks or other structures within the patient’s anatomy, in addition to radiopaque surgical devices, that can be used to determine distances along the length of the blood vessels.
  • a contrast agent can be injected into the blood stream of the patient and the blood vessels can be imaged during or immediately after injection. The system identifies points in time at which the contrast agent flows past the identified landmarks, which can be used to determine the flow parameters within the blood vessels.
  • a room temperature fluid may be injected into the blood stream of the patient and a temperature of fluid surrounding the therapeutic device may be monitored to identify changes in temperature.
  • a change in temperature is indicative of the room temperature fluid flowing past the therapeutic device.
  • the system identifies points in time at which temperature changes occur at various locations along the length of the blood vessel. These points in time and identified distances between these locations can be used to identify or otherwise determine the flow parameters within the blood vessels.
  • FIG. 1 illustrates a guidance and therapy system provided in accordance with the disclosure and generally identified by reference numeral 10.
  • the guidance and therapy system 10 enables navigation of a therapeutic device 50 to a desired location within the patient’s anatomy (e.g., for example, the patient’s renal artery), delivery of neurostimulation to tissue within the renal artery, observing and/or measuring a physiological response to the application of neurostimulation to the tissue, if necessary, adjustment of a position of the therapeutic device within the renal artery based upon the physiological response, reapplication of the neurostimulation to the tissue at the adjusted position, application of denervation therapy to the tissue within the renal artery to denervate sympathetic nerves within the tissue, and delivery of neurostimulation to the denervated tissue to observe and/or measure the physiological response to the neurostimulation and assess the efficacy of the denervation therapy.
  • 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 in embodiments, 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.
  • the therapy system 10 may employ any suitable number of therapeutic devices 50. It is envisioned that the therapeutic devices 50 may employ the same or different therapy modalities.
  • the therapeutic device 50 may employ a guidewire 64 and/or a guide catheter 58 (FIG. 3) without departing from the scope of the disclosure.
  • the workstation 20 includes a computer 22, a therapy source 24 e.g., for example, an ultrasound (US) generator, a Radio Frequency (RF) generator, a microwave generator, a heating and/or cooling source (e.g., for example, electrical energy and cryotherapy), a chemical source, and combinations thereof) operably coupled to the computer, and a neurostimulation source 24a operably coupled to the computer 22.
  • a therapy source 24 e.g., for example, an ultrasound (US) generator, a Radio Frequency (RF) generator, a microwave generator, a heating and/or cooling source (e.g., for example, electrical energy and cryotherapy), a chemical source, and combinations thereof) operably coupled to the computer
  • a neurostimulation source 24a operably coupled to the computer 22.
  • the stimulation source 24a may be integrated within the therapy source 24, as described hereinabove, and the therapy source 24 may generate both therapy and neurostimulation modalities.
  • 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 the display 26 or may include a laptop computer or other computing device.
  • the computer 22 includes a processor 30 which executed 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).
  • WAN wide-area network
  • LAN local area network
  • 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., for example, fluoroscopic, computed tomography (CT), magnetic resonance imaging (MRI), cone-beam computed tomography (CBCT), ultrasound, and angiography) and data (e.g., for example, additional or reinforcement data for analysis and/or comparison).
  • CT computed tomography
  • MRI magnetic resonance imaging
  • CBCT cone-beam computed tomography
  • ultrasound and angiography
  • An input module 40 receives inputs from an input device such as a keyboard, a mouse, voice commands, an energy source controller (e.g., for example, 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 neurostimulation source 24a, including, but not limited to, power delivery).
  • An output module 42 connects the processor 30 and the memory 32 to a variety of output devices such as the display 26, which in embodiments, may be a touchscreen display.
  • the therapy source 24 generates and outputs one or more of US energy, RF energy (monopolar or bipolar), microwave energy, cryogenic medium, and/or chemical ablation medium via an automated control algorithm 44 stored on the memory 32 and/or under the control of a clinician.
  • the therapy generated or output by the therapy source 24 changes a temperature of the tissue (e.g, for example, increases or decreases 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.
  • the therapy source may monitor voltage and current applied to target tissue via 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 therapy 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.
  • the stimulation source 24a In contrast with the therapy source 24, the stimulation source 24a generates and outputs a non-therapeutic stimulation signal, for example a biphasic waveform, at an energy level that is less than the therapy signal (e.g., for example, denervation signal) generated by the therapy source 24 such that the stimulation generated by the stimulation source 24a does not denervate the target tissue.
  • a non-therapeutic stimulation signal for example a biphasic waveform
  • 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, such as, for example, a change in blood pressure, an increase in vessel stiffness, pulse wave velocity, augmentation pressure, heart rate variability, fluid flow through the vessel, a velocity of fluid flowing through the vessel, vasoconstriction, and combinations thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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., for example, inhibiting the movement of the therapeutic device 50 within the luminal tissue).
  • a pulse duration e.g., for example, a pulse width
  • the stimulation 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.
  • the stimulation source 24a generates biphasic waveforms having a frequency of between approximately 10 - 30 Hz, 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.
  • the stimulation parameters may be a constant current of 20 mA for 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.
  • the stimulation source 24a may generate and output a Focused Ultrasound signal (FUS) and/or a High Intensity Focused Ultrasound signal (HIFU).
  • FUS Focused Ultrasound signal
  • HIFU High Intensity Focused Ultrasound signal
  • the stimulation source 24a may be connected to a HIFU transducer 102 (FIG. 4) to produce a FUS at a frequency of between approximately 250 KHz and 700 KHz, though certain applications employing an external HIFU transducer can require up to 4 MHz, for example about 3.57 MHz.
  • the duty cycle may range from about 5-about 10 % depending on the vessel wall composition.
  • a therapy session may have a duration of between 30 and 120 seconds.
  • the HIFU transducer 102 is acoustically coupled to a patient via a coupling medium (e.g., for example, saline) in a coupling chamber 104 that is placed on the skin of the patient.
  • a coupling medium e.g., for example, saline
  • a gel material acoustically coupling the HIFU transducer 102 with the patient may be employed without departing from the scope of the disclosure.
  • the HIFU transducer 102 can be disposed external to the patient and may be employed to both image portions of the patient, apply FUS neurostimulation, and to apply US therapy signals to the sympathetic nerves of an identified artery.
  • a neurostimulation catheter 110 may be employed having one or more HIFU transducers 112 configured to apply FUS stimulation to the nerves surrounding the blood vessel in accordance with aspects of the disclosure.
  • a third possibility is a laparoscopic approach where the HIFU transducer, (e.g., for example, similar to that shown in FIG. 5) is placed substantially non-invasively proximate the nerves to be stimulated or denervated (e.g., for example, the nerves surrounding the renal or hepatic nerves).
  • a separate therapy device for application of therapy to the nerves may be required for the application of US or RF therapy to perform the denervation.
  • the one or more HIFU transducers 112 of the neurostimulation catheter 110 can be employed to both image portions of the blood vessels from an internal perspective, apply FUS neurostimulation, and apply FUS neuromodulation.
  • the imaging device 70 may be an angiography system suitable for capturing images of renal vessels with sufficient resolution to segment and/or determine dimensions of the renal vessels.
  • the imaging device 70 may be a three-dimensional (3D) angiography system configured to capture, compare, and analyze angiographic images before and after stimulating treated nerves.
  • the imaging device 70 is a 3D rotational angiography (3DRA) system.
  • 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 therapy delivery assembly 54 at which one or more therapy elements 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 the patient’s vascular network that is in fluid communication with the patient’s renal artery.
  • the therapy 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 therapy delivery assembly forms a radially expanded configuration, such as for example, a generally spiral and/or helical configuration, for delivering therapy to a site for either or both application of stimulation or therapy at the treatment site.
  • the elongated shaft 52 may be configured to be received within a portion of a guide catheter or guide sheath e.g., for example, a 6F guide catheter) 58 that is utilized to navigate the therapeutic device 50 to a desired location.
  • a guide catheter or guide sheath e.g., for example, a 6F guide catheter
  • the guide catheter 58 may be retracted to uncover the therapy delivery assembly 54 of the therapeutic device 50.
  • retraction of the guide catheter 58 may enable the therapy delivery assembly 54 to transition from the first, undeployed configuration to the second, deployed or expanded configuration.
  • the therapy delivery assembly 54 when in the second, expanded configuration, the therapy delivery assembly 54, and in particular, the individual therapy elements 56, is pressed against or otherwise contacts the walls of the patient’s vasculature tissue.
  • the elongated shaft 52 of the therapeutic device 50 may include an aperture (not shown) that is configured to slidably receive a guidewire 64 over which the therapeutic device 50, either alone or in combination with the guide catheter 58, are advanced.
  • the guidewire 64 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 guidewire 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.
  • OW over-the-wire
  • RX rapid exchange
  • the therapy delivery assembly 54 may be deployed in other configurations (such as for example, an expanded frame or basket and a balloon) without departing from the scope of the disclosure.
  • 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.
  • the therapeutic device 50 may be configurable, for example, using one or more pull wires or other control mechanisms (not shown) to adjust the configuration to promote contact between the therapy elements 56 and the wall of the vascular tissue, may be formed from a shape memory alloy or other similar material configured to automatically transition from the first, undeployed configuration, to the second, deployed or expanded configuration, or combinations thereof when the guide catheter 58 and/or guidewire 64 are partially or fully removed.
  • the therapy elements 56 are disposed on an outer surface of the elongated shaft 52 and configured to contact a portion of the patient’s vascular tissue when the therapeutic device 50 is placed in the second, expanded configuration.
  • the therapeutic device 50 may have more or fewer therapy elements 56 without departing from the scope of the disclosure.
  • the therapy elements 56 may be one or more of ultrasound transducers, RF electrodes, 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 disclosure.
  • the therapy elements 56 may be combined mode therapy elements enabling the same therapy elements 56 to apply FUS stimulation and also US, RF, microwave, or other therapy to the blood vessel wall.
  • FUS stimulation and also US, RF, microwave, or other therapy to the blood vessel wall.
  • US, RF, microwave, or other therapy to the blood vessel wall may be combined mode therapy elements enabling the same therapy elements 56 to apply FUS stimulation and also US, RF, microwave, or other therapy to the blood vessel wall.
  • the therapy elements 56 may not be in direct contact with the patient’s vascular tissue and in embodiments, may be disposed within an expanded frame or basket and a balloon (not shown).
  • the therapy elements 56 may be disposed in spaced relation to one another along a length of the therapeutic device 50 forming the therapy delivery assembly 54.
  • the therapy elements 56 may be in communication with one or both the therapy source 24 and the stimulation source 24a, and in embodiments, the therapy source 24 may also be the stimulation source 24a and may include a diagnostic mode, where the therapy source 24 generates a stimulation signal, and a denervation mode, where the therapy source 24 generates therapy signals 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 computer 22.
  • the therapy elements 56 are in communication with a stand-alone stimulation source 24a to deliver a stimulation signal to the blood vessel in question.
  • the stimulation is generated by the stimulation source 24a and communicated to the therapy elements 56 causing stimulation of the sympathetic nerves as described herein.
  • the application of stimulation to target tissue may effectuate myriad physiological changes.
  • a change in heart rate, a change in arterial pressure, and/or a change in vessel size can be measured and/or observed.
  • the duration of the stimulation signal 120 is depicted by trace 122.
  • an increase in heart rate, depicted by trace 124, and a mean arterial pressure, depicted by trace 126 can be observed.
  • the heart rate begins to return to normal.
  • the mean arterial pressure, both during and following the application of the stimulation signal 120 elevates and remains elevated compared to the pre-stimulation mean arterial pressure.
  • This change in either or both heart rate and mean arterial blood pressure is indicative of stimulation of the afferent nerves of the blood vessel in which the therapeutic device 50 is positioned (e.g., for example, the renal and/or hepatic arteries).
  • the clinician may determine that the location of the therapy delivery assembly 54 is appropriate for the application of therapy to achieve denervation, and therapy may be applied to the target tissue at that location within the blood vessel.
  • vasoconstriction resulting from the application of the stimulation signal 120 may be observed.
  • vasoconstriction in which the application of the stimulation signal 120 effectuates a change in dimension of the blood vessels distal of the target tissue, such as for example, a reduction in blood vessel diameter and a reduction in cross-sectional area, at and around the target tissue, may be visually identified using external or internal imaging modalities.
  • the change in dimension of the blood vessels may be identified as a vasoconstriction metric.
  • identifying vasoconstriction within the blood vessels distal of the primary bifurcation can be utilized to assess the efficacy of denervation therapy applied to the afferent and efferent nerves.
  • the blood vessels 130 adjacent to or distal of the location where neurostimulation is to be applied are imaged from within the blood vessels or external to the blood vessels using any suitable imaging modality, such as, for example, ultrasound, CT, CBCT, fluoroscopy, and angiography. Thereafter, neurostimulation is applied to the target sympathetic nerves and the target blood vessels are once again imaged (FIG. 7B).
  • the images captured during or after the application of neurostimulation are compared to the images captured before neurostimulation to identify constricted blood vessels 132 at and/or distal of the location where neurostimulation was applied.
  • the images captured before or after the application of neurostimulation may be compared to a vasoconstriction criteria, such as for example, a predetermined threshold value, which may be based on a percentage of initial vessel diameter, a predetermined vessel diameter, a percentage of an initial vessel cross-sectional area, and a predetermined vessel cross-sectional area. .
  • the application of neurostimulation and ultrasound imaging may be performed as many times as necessary at the same or different locations to identify sympathetic nerves that are candidates for denervation or to identify an efficacy of the therapy applied to the target tissue.
  • therapy is applied to the candidate tissue to denervate the nerves, and thereafter, the target blood vessels 130 are imaged again (FIG. 7C).
  • neurostimulation is again applied to the target sympathetic nerves and the target blood vessels 130 are once again imaged and compared to the images captured before neurostimulation but after therapy, or in embodiments, to the images captured during or after the application of neurostimulation but before therapy, to identify the presence, or absence, of vasoconstriction (FIG. 7D).
  • the above-described process may require multiple applications of neurostimulation and/or therapy at many locations within the blood vessels, which can take a substantial amount of time and energy.
  • a reduction in the amount of neurostimulation and/or therapy required to complete a denervation procedure would not only reduce procedure time but also reduce costs.
  • vasoconstriction in the renal arteries is predicated by a change in flow parameters or flow metrics within the renal vascular system. These changes in flow parameters resulting from stimulation of the sympathetic nerves can be measured and/or observed using external or internal imaging modalities, flow instrumentation, changes in temperature response, and combinations thereof.
  • identifying a change in flow parameters resulting from stimulation of the blood vessel, occurring even before vasoconstriction can be observed can reduce the length of time stimulation must be applied in order to identify whether the target blood vessel is a candidate for denervation or to determine the efficacy of therapy applied to the target blood vessel.
  • identified changes in flow parameters may be combined with other modalities for identifying candidate tissue as an additional data point.
  • any parameter indicative of movement of fluid within a blood vessel may be used, such as for example, velocity.
  • the guidewire 64 may be a doppler flow wire or may generally include one or more flow sensors 66 (FIG. 3) operably coupled thereto and in embodiments, operably coupled to the workstation 20 using any suitable means, such as for example, wirelessly, hardwired, and combinations thereof.
  • any suitable means such as for example, wirelessly, hardwired, and combinations thereof.
  • the one or more flow sensors 66 may be disposed at any location along the length of the guidewire, or in embodiments, may be disposed on the therapeutic device 50, the elongate shaft 52, or combinations thereof without departing from the scope of the disclosure.
  • the flow sensors 66 are configured to measure or otherwise determine a flow parameter or flowrate of a fluid through the blood vessels.
  • the blood vessels constrict and effectuate a corresponding reduction of flow through the blood vessels.
  • the flow parameter within the blood vessel adjacent to target tissue may be determined before neurostimulation to determine a baseline or initial flow parameter to which subsequent flow parameter determinations can be compared. In this manner, after neurostimulation, the flow parameter is determined again and compared to a predetermined threshold value, which may be a predetermined percentage of the baseline flow parameter.
  • a flow parameter that satisfies a flow parameter criteria such as for example, a flow parameter that is less than the predetermined threshold value, is indicative of candidate tissue whereas a flow parameter that is not less than the predetermined threshold value indicates that the target tissue is not a candidate for denervation. It is contemplated that the flow parameter may be measured after the application of therapy to the target tissue to determine the efficacy of therapy.
  • first threshold value 144 there may be a first threshold value 144 and a second threshold value 146.
  • Each of the first and second threshold values 144 and 146 may be determined as a corresponding predetermined percentage of the baseline flow parameter or a flow parameter obtained pre-neuromodulation but post-neurostimulation.
  • the predetermined percentage for the first threshold value 144 may be greater than the predetermined percentage for the second threshold value 146.
  • a flow parameter 140 that is greater than the first threshold value 144 may indicate that all nerves within the target tissue are sufficiently ablated and no further ablation need be performed at the target tissue location.
  • a flow parameter 142 that is less than the second threshold value 146 may indicate that ablation is incomplete and either (1) further neuromodulation therapy should be delivered to the target tissue and/or (2) images should be obtained to ascertain which downstream blood vessels/blood vessel branches are still exhibiting vasoconstriction.
  • a flow parameter that is less than the first threshold value 144 and greater than the second threshold value 146 may indicate that ablation is partially complete images should be obtained to ascertain which downstream blood vessels/blood vessel branches are still exhibiting vasoconstriction.
  • the location of vasoconstriction may be used as a guide for where additional neuromodulation may be delivered. For instance, neuromodulation may be delivered to blood vessel branches that continue to exhibit vasoconstriction after the previous neuromodulation therapy has been delivered.
  • the flow through target blood vessels can be visualized and/or measured using the imaging device 70.
  • a contrast agent or other similar fluid is injected into the patient’s blood stream at a substantially constant flowrate using any suitable means, such as for example, intravenous, via the therapeutic device 50, via a separate surgical device in fluid communication with the target blood vessels, and combinations thereof.
  • the contrast agent is administered using a power injector.
  • the imaging device 70 captures images, either individually or as a video, of the contrast agent flowing through the target blood vessels.
  • the flow parameter, flow metric, or flowrate of the contrast agent through the target blood vessels can be estimated or determined using one or more natural, synthetic, or virtual landmarks, such as for example, structures within the blood vessels, markers (e.g., for example, radiopaque markers, fiducials, and combinations thereof) deposited within tissue surrounding the blood vessels, markers superimposed on the images captured by the imaging device 70, the therapy elements 56 of the therapeutic device 50 (FIG. 9), and combinations thereof.
  • the one or more landmarks will be described as being the therapy elements 56.
  • the therapy elements 56 are disposed in spaced relation to one another (e.g., for example, a linear distance) along the length of the target tissue.
  • the distance between each of the one or more therapy elements 56 may be calculated or known during the manufacturing process, it is contemplated that the distance between each of the therapy elements 56 may be identified and/or confirmed using the imaging device 70.
  • the flow of the contrast agent through the blood vessels is monitored and a timepoint at which the contrast agent flows past each therapy element 56 is identified.
  • the flow parameter of the contrast agent can be determined using the relationship between the distance between each therapy element 56 and the point in time the contrast agent flows past each corresponding therapy element 56, and in embodiments, a determined vessel size.
  • this process can be repeated as many times as necessary before, during, and after neurostimulation and before, during, and after therapy is applied to candidate nerves, as described in detail hereinabove.
  • visualizing and analyzing the flow of contrast agent through candidate blood vessels may be completed on a branch-based approach (e.g., for example, a first branch of the renal artery, a second branch of the renal artery, and so forth).
  • the flow of a fluid through the target blood vessels may be measured or otherwise determined by identifying a change in temperature along a length of the blood vessel over a period of time.
  • the therapeutic device 50 may include one or more temperature sensors 80 disposed thereon or in operably coupled thereto, that are operably coupled to the workstation 20.
  • one or more of the therapy elements 56 of the therapeutic device 50 may be associated with, or coupled to, a corresponding temperature sensor 80 such that the temperature sensors 80 measure a temperature of the respective therapy elements 56, the tissue in contact with the therapy elements 56, and/or the fluid flowing within the blood vessel.
  • the temperature sensor 80 may be any suitable temperature sensing device, such as for example, a thermocouple and a thermistor, and may be disposed proximate to, on, or within a portion of a respective therapy element 56.
  • two or more temperature sensors 80 are coupled to the therapeutic portion 54 of the therapeutic device 50 and disposed in spaced relation a predetermined distance from one another.
  • the distance between each of the temperature sensors 80 may be calculated or known during the manufacturing process or identified or confirmed using the imaging device 70.
  • the distance between the two or more temperature sensors 80 causes each temperature sensor 80 to measure a temperature of a fluid flowing through the blood vessel at independent times.
  • a fluid at substantially room temperature is injected into the patient’s blood stream at a substantially fixed flowrate using any suitable means, such as for example, those described hereinabove.
  • the room temperature fluid flows over the temperature sensors 80 and causes the temperature sensors 80 to sequentially measure a lower temperature as compared to ambient.
  • the measured temperature of each of the temperature sensors 80 may be compared to one or more predetermined temperature metrics or criteria, which in embodiments, may be threshold values, where the point in time at which the measured temperature at each of the temperature sensors 80 satisfies a temperature criteria, such as for example, is less than a predetermined threshold value is identified.
  • the identified points in time are compared to the identified distance between each of the temperature sensors 80 to determine or otherwise measure the flow parameter of the room temperature fluid within the blood vessel.
  • the fluid injected into the patient’s blood stream may be at any temperature that can be differentiated from a temperature of the patient’s blood flowing through the target blood vessel.
  • the flow parameter may be determined or otherwise calculating manually (e.g., for example, data displayed on the user interface 28) or via one or more algorithms 44 or software applications stored on the memory 32 of the workstation 20.
  • the algorithm 44 may be applied to the data captured during the determination of the flow parameter within the target blood vessel, may be applied simultaneously during the determination of the flow parameter, may be a set of parameters or other input variables that are manually (e.g., for example, by the clinician) or automatically (e.g., for example, using the algorithm 44 or the computer 22), or combinations thereof.
  • the determined flow parameters may be approximate values due to volume and/or pathway assumptions (e.g., disregard 3D distances and instead utilize linear distances), tolerances, or other variables.
  • the determined flow parameters may be utilized as a diagnostic tool or indication that further analysis should be conducted on certain locations within the blood vessel.
  • a flow parameter that satisfies a flow criteria such as for example, is less than a predetermined threshold value, may indicate that vasoconstriction or other physiological responses should be considered when making a determination if the target blood vessel is a candidate for denervation. It is envisioned that short durations of neurostimulation may be applied to various locations within the renal artery and the flow parameter monitored at each location.
  • the flow parameter occurs substantially simultaneously with the application of neurostimulation, and may occur before the onset of vasoconstriction, tissue that is not a candidate for denervation can quickly be distinguished from candidate tissue or tissue requiring further analysis. Further, vasoconstriction may persist for a period of time after applying neurostimulation, requiring a break or downtime before applying neurostimulation to another location of the target blood vessels.
  • Using the flow parameter as an indication of candidate tissue can reduce downtime and provide more accurate determinations of candidate tissue as compared to relying on other physiological responses.
  • FIGS. 11 A and 1 IB a method of performing a therapeutic procedure is illustrated and generally identified by reference numeral 200.
  • the therapeutic assembly of the therapeutic device is navigated to a location adjacent to target tissue.
  • a flow parameter within the blood vessel adjacent to the target tissue is determined in step 204.
  • the therapeutic portion of the therapeutic device is navigated to another location adjacent to the target tissue at step 208 and the method returns to step 204. If it is determined that the flow parameter satisfies the flow parameter criteria, or in embodiments, is less than the first predetermined threshold value, at step 210, stimulation is applied to the target tissue for a predetermined amount of time and first images of the blood vessels are obtained to identify vasoconstriction. At step 212, therapy is applied to the target tissue. At step 214, stimulation is again applied to the target tissue, and at step 216, a new flow parameter within the blood vessel adjacent to the target tissue is determined.
  • step 218 it is determined if the new flow parameter satisfies a flow parameter criteria, or in embodiments, is less than a second predetermined threshold value, which in embodiments, may be the first predetermined threshold value. If it is determined that the new flow parameter does not satisfy the flow parameter criteria, or in embodiments, is not less than the second predetermined threshold value, the method ends at step 220. If it is determined that the new flow parameter satisfies the flow parameter criteria, or in embodiments, is less than the second predetermined threshold value, at step 222, stimulation is applied to the target tissue for a predetermined period of time and second images of the blood vessels are obtained to identify vasoconstriction.
  • the second images are compared to the first images to determine a vasoconstriction metric based on a change in at least one dimension of the blood vessels distal of the target tissue, which in embodiments may be a change in blood vessel size.
  • a vasoconstriction criterion which in embodiments, may be an identified change in blood vessel size that is less than a predetermined threshold value. If it is determined that the vasoconstriction metric does not satisfy the vasoconstriction criteria, or in embodiments, the identified change in blood vessel size is not less than the predetermined threshold value, therapy is applied to the target tissue and the method returns to step 216.
  • step 230 it is determined if there are additional locations requiring treatment. If there are no additional locations requiring treatment, the method ends at step 220. If it is determined that additional location require treatment, the method returns to step 208. As can be appreciated, the above method may be repeated as many times as necessary and in any order without departing from the scope of the disclosure.
  • FIGS. 12A and 12B another embodiment of a method of performing a therapeutic procedure is illustrated and generally identified by reference numeral 300.
  • the therapeutic assembly of the therapeutic device is navigated to a location adjacent to target tissue.
  • an initial, or baseline flow parameter, or flow parameter metric, within the blood vessel adjacent to the target tissue is determined at step 304.
  • neurostimulation is applied to the target tissue, and thereafter, at step 308, the flow parameter is again determined.
  • the therapeutic portion of the therapeutic device is navigated to another location adjacent to the target tissue at step 312 and the method returns to step 304. If the determined flow parameter satisfies the flow parameter criteria, or in embodiments, is less than the predetermined threshold value, at step 314, it is determined if the determined flow parameter falls between a first predetermined threshold value and a second predetermined threshold value. If the determined flow parameter falls between the first predetermined threshold value and the second predetermined threshold value, at step 316, the therapeutic portion of the therapeutic device is navigated within a branch of the target tissue and the method returns to step 304.
  • the target tissue is imaged to identify vasoconstriction of the target tissue adjacent to and distal of the location where neurostimulation was applied.
  • a vasoconstriction metric based on at least one dimension of blood vessels distal of the target tissue, such as for example, a diameter of the target tissue, satisfies a vasoconstriction criterion, which in embodiments, may be is less than a predetermined value.
  • the therapeutic device is navigated to a new location at step 412 and the method returns to step 404. If it is determined that the flow parameter satisfies the first flow parameter criteria, at step 414, stimulation is applied to the target tissue for a predetermined period of time and first images of blood vessels distal of the target tissue are captured to identify vasoconstriction. At step 416, therapy is applied to the first location and at step 418, stimulation is applied to the target tissue. At step 420, during stimulation of the target tissue, a flow parameter within the blood vessels adjacent to the target tissue is monitored. At step 422, it is determined if the flow parameter satisfies a second flow parameter criteria.
  • the therapeutic device is navigated to the identified vessels and therapy is applied to each identified vessel.
  • the therapeutic device is navigated to the first location.
  • stimulation is applied to the target tissue, and at step 438, as the target tissue is stimulated, a flow parameter within the blood vessels adjacent to the target tissue is monitored.
  • the above method may be repeated as many times as necessary and in any order without departing from the scope of the disclosure.
  • the technique may include obtaining a flow parameter and/or images prior to delivering neurostimulation.
  • the flow parameter and images obtained prior to delivering neurostimulation may serve as baselines for subsequent analysis.
  • the flow parameter and images obtained prior to delivering neurostimulation may be obtained using any of the techniques described herein.
  • the technique may include applying a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue.
  • the neuromodulation therapy may be applied using any of the devices and techniques described herein.
  • the technique may include applying neurostimulation to the target tissue and, in response to applying the neurostimulation to the target tissue, obtaining a second flow parameter related to blood flow within the blood vessel.
  • the second flow parameter may be obtained using any of the devices and/or techniques described herein, including flow sensors, angiography, or the like.
  • neurostimulation may be applied to the target tissue which neuromodulation therapy is being applied to the target tissue.
  • neuromodulation and neurostimulation may be applied in an interleaved fashion (e.g., neuromodulation for a time, followed by neurostimulation for a time, in a repeated manner).
  • the second flow parameter may be obtained in response to each application of neurostimulation.
  • the technique also may include determining, based on a flow parameter criterion and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue.
  • the flow parameter criteria may include a criterion related to blood flow before and after neuromodulation therapy.
  • the flow parameter criterion may be a threshold flow rate based on the first flow rate or a combination of the first flow rate and the pre-stimulation, pre-neuromodulation flow rate.
  • the flow parameter criterion may be as shown in FIG. 8 and may include multiple flow parameter criteria.
  • the technique may include iteratively determining, based on a flow parameter criterion and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue. For instance, the determination may be made periodically at a set time interval based on the most recently obtained second flow parameter and the flow parameter criterion.
  • the technique also may include, in response to an indication of inadequate ablation of the nerves, e.g., a second flow parameter that is less than the first threshold value 144 shown in FIG. 8, obtaining second images of the blood vessel downstream of the target tissue.
  • the images may be used to determine whether and/or where blood vessels and/or blood vessel branches downstream of the target tissue continue to exhibit vasoconstriction after the neuromodulation therapy has been delivered. Portions of the blood vessels and/or blood vessel branches that continue to exhibit vasoconstriction after the neuromodulation therapy has been delivered may be candidates to be sites for further neuromodulation therapy.
  • the technique may include comparing the first (pre-neuromodulation) images and the second (post-neuromodulation) images to determine a vasoconstriction metric based on a change in at least one dimension of the blood vessels downstream of the target tissue.
  • the technique also may include, in response to the vasoconstriction metric satisfying a vasoconstriction criterion (e.g., showing a similar level of vasoconstriction), applying neuromodulation therapy to at least a second target tissue (e.g., associated with the similar level of vasoconstriction.
  • the second flow parameter and the flow parameter criterion indicate sufficient ablation (e.g., the flow parameter criterion is greater than the first threshold value 144 shown in FIG. 8), this may indicate that no further neuromodulation therapy is necessary.
  • 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, imaging device 70, and/or ECG machine.
  • memory 32 may include one or more storage devices such as solid-state storage devices, e.g., flash memory chips.
  • 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).
  • computer-readable 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.
  • 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 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 energy source 20.
  • Example 1 A method of performing a therapeutic procedure, comprising: navigating a therapeutic device to a location within a blood vessel adjacent to target tissue; determining a first flow parameter within a portion of a blood vessel adjacent to the target tissue; applying neurostimulation to the target tissue and obtaining first images of blood vessels distal of the target tissue; applying therapy to the target tissue; applying neurostimulation to the target tissue; determining a second flow parameter within the portion of the blood vessel adjacent to the target tissue; comparing the second flow parameter to a flow parameter criteria; applying neurostimulation to the target tissue and obtaining second images of the blood vessels distal of the target tissue; comparing the first images to the second images to determine a vasoconstriction metric based on a change in at least one dimension of the blood vessels distal of the target tissue; and applying therapy to the target tissue if it is determined that the vasoconstriction metric satisfies a vasoconstriction criteria.
  • Example 2 The method according to Example 1 , wherein
  • Example 3 The method according to Example 1 , wherein determining the first flow parameter includes: identifying a first point in time at which a contrast agent flowing through the blood vessel adjacent to the target tissue flows past a first landmark; and identifying a second point in time at which the contrast agent flowing through the blood vessel adjacent to the target tissue flows past a second landmark, the second landmark disposed distal of the first landmark.
  • Example 4 The method according to Example 1 , wherein determining the first flow parameter includes: identifying a first point in time at which a contrast agent flowing through the blood vessel adjacent to the target tissue flows past a first therapy element of the therapeutic device; and identifying a second point in time at which the contrast agent flowing through the blood vessel adjacent to the target tissue flows past a second therapy element of the therapeutic device, wherein the second therapy element is disposed distal of the first therapy element.
  • Example 5 The method according to Examples 3 or 4, wherein determining the first flow parameter includes imaging the target tissue to identify the contrast agent flowing through the blood vessel adjacent to the target tissue.
  • Example 6 The method according to any of the preceding Examples, further comprising injecting a fluid into the blood vessel adjacent to the target tissue.
  • Example 7 The method according to Example 6, wherein injecting the fluid into the blood vessel adjacent to the target tissue includes injecting a contrast agent into the blood vessel adjacent to the target tissue.
  • Example 8 The method according to Example 6, wherein injecting the fluid into the blood vessel adjacent to the target tissue includes injecting a room temperature fluid into the blood vessel adjacent to the target tissue.
  • Example 9 The method according to Example 8, wherein determining the first flow parameter includes: identifying a first point in time at which a change in temperature is measured at a first location within the target tissue as the room temperature fluid is flowing through the blood vessel adjacent to the target tissue; and identifying a second point in time at which a change in temperature is measured at a second location within the target tissue as the room temperature fluid is flowing through the blood vessel adjacent to the target tissue.
  • Example 14 The method according to any of the preceding Examples, further comprising: comparing at least one dimension of the blood vessels distal of the target tissue to a vasoconstriction metric, the vasoconstriction metric based on at least one dimension of the blood vessels distal of the target tissue; and reapplying therapy to the target tissue if the vasoconstriction metric satisfies a vasoconstriction criteria.
  • Example 15 The method according to Example 11 , wherein identifying the first point in time at which the injected fluid flows past the first landmark includes identifying a change in temperature of fluid flowing past the first landmark, wherein identifying the second point in time at which the injected fluid flows past the second landmark includes identifying a change in temperature of fluid flowing past the second landmark.
  • Example 16 A system for performing a diagnostic and therapeutic procedure, comprising: a workstation, the workstation including a processor and a memory, the memory storing instructions thereon, which when executed cause the processor to: determine a first flow parameter within a portion of a blood vessel adjacent to the target tissue; cause a stimulation source to output a neurostimulation signal via at least one stimulation element to the target tissue and obtain first images of blood vessels distal of the target tissue; cause a therapy source to output a therapy signal via at least one therapy element to the target tissue; apply neurostimulation to the target tissue; determine a second flow parameter within the portion of the blood vessel adjacent to the target tissue; compare the second flow parameter to a flow parameter criteria; apply neurostimulation to the target tissue and obtain second images of the blood vessels distal of the target tissue; compare the first images to the second images to determine a vasoconstriction metric based on a change in at least one dimension of the blood vessels distal of the target tissue; and apply therapy to the target tissue if it is determined that the
  • Example 23 A method comprising: after a denervation procedure has been performed at a location of a target vessel, causing, by a computing device, a stimulation source to output a first stimulation signal to at least one stimulation element positioned proximate the location, wherein the at least one stimulation element is coupled to a therapeutic device; causing, by the computing device, a sensor to measure a blood flow rate of within the target vessel; in response to a flow rate metric based on the blood flow rate satisfying a predetermined criteria, causing, by the computing device, the stimulation source to output a second stimulation signal to the at least one stimulation element positioned at the location within the target vessel; determining, by the computing device, based on at least one image of the target vessel collected after delivery of the second stimulation signal, at least one dimension of the target vessel distal of the location; determining, by the computing device, based on the at least one dimension of the target vessel, a vasoconstriction metric; and in response to the vasoconstriction metric satisfying
  • a method comprising: applying neurostimulation to target tissue in and/or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall; in response to applying neurostimulation: obtaining a first flow parameter related to blood flow within the blood vessel; and obtaining first images of the blood vessel downstream of the target tissue; applying a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; after applying the neuromodulation therapy to the target tissue, applying neurostimulation to the target tissue; obtaining a second flow parameter related to blood flow within the blood vessel; determining, based on a flow parameter criterion and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue; and in response to an indication of inadequate ablation of the nerves, obtaining second images of the blood vessel downstream of the target tissue.
  • a method comprising: applying neurostimulation to target tissue in and/or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall; in response to applying neurostimulation: obtaining a first flow parameter related to blood flow within the blood vessel; and obtaining first images of the blood vessel downstream of the target tissue; applying a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; while applying the neuromodulation therapy to the target tissue: applying neurostimulation to the target tissue; obtaining a second flow parameter related to blood flow within the blood vessel; and iteratively determining, based on a flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the nerves within the target tissue; and in response to an indication of inadequate ablation of the nerves, obtaining second images of the blood vessel downstream of the target tissue.
  • Clause 3 The method of clause 1 or 2, further comprising: prior to applying neurostimulation to target tissue in and/or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall: obtaining a third flow parameter related to blood flow within the blood vessel; and obtaining third images of the blood vessel downstream of the target tissue.
  • Clause 4 The method of clause 3, wherein determining, based on a flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the target nerves comprises determining, based on the first, second, and third flow parameters, whether the denervation therapy adequately ablated the target nerves.
  • Clause 5 The method of any one of clauses 1 to 4, further comprising: comparing the first images and the second images to determine a vasoconstriction metric based on a change in at least one dimension of the blood vessels downstream of the target tissue; and in response to the vasoconstriction metric satisfying a vasoconstriction criteria, applying neuromodulation therapy to at least a second target tissue.
  • Clause 6 The method of clause 5, wherein the second target tissue is in or adjacent to a blood vessel wall of a branch vessel of the blood vessel.
  • Clause 7 The method of clause 5 or 6, wherein the vasoconstriction metric satisfying the vasoconstriction criteria indicates that the second target tissue should be treated with the neuromodulation therapy.
  • Clause 8 The method of any one of clauses 1 to 7, wherein determining, based on the flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the target nerves comprises determining whether a change in flow between the first flow parameter and the second flow parameter is greater than a threshold change value.
  • a system comprising: a workstation comprising a one or more processors and a memory, the memory storing instructions thereon, which when executed by the one or more processors, cause the one or more processors to: cause a neurostimulator to apply neurostimulation to target tissue in and/or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in and/or adjacent to the blood vessel wall; in response to the neurostimulator applying neurostimulation: obtain a first flow parameter related to blood flow within the blood vessel; and obtain first images of the blood vessel downstream of the target tissue; cause a therapy device to apply a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; after the neuromodulation therapy is applied to the target tissue, cause the neurostimulator to apply neurostimulation to the target tissue; obtain a second flow parameter related to blood flow within the blood vessel; determine, based on a flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the nerve
  • Example 10 A system comprising: a workstation comprising a one or more processors and a memory, the memory storing instructions thereon, which when executed by the one or more processors, cause the one or more processors to: cause a neurostimulator to apply neurostimulation to target tissue in and/or adjacent to a blood vessel wall of a blood vessel to stimulate nerves in or adjacent to the blood vessel wall; in response to the neurostimulator applying neurostimulation: obtain a first flow parameter related to blood flow within the blood vessel; and obtain first images of the blood vessel downstream of the target tissue; cause a therapy device to apply a neuromodulation therapy to the target tissue to ablate at least some of the nerves within the target tissue; while the neuromodulation therapy is being applied to the target tissue: cause the neurostimulator to apply neurostimulation to the target tissue; obtain a second flow parameter related to blood flow within the blood vessel; and determine, based on a flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the nerves
  • Clause 11 The system of clause 9 or 10, wherein the memory further stores instructions thereon, which when executed by the one or more processors, cause the one or more processors to: prior to causing the neurostimulator to apply neurostimulation to target tissue in and/or adjacent to the blood vessel wall of the blood vessel to stimulate nerves in or adjacent to the blood vessel wall to: obtain a third flow parameter related to blood flow within the blood vessel; and obtain third images of the blood vessel downstream of the target tissue.
  • Clause 12 The system of clause 11, wherein the instructions that cause the one or more processors to determine, based on the flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the target nerves comprise instructions which, when executed by the one or more processors, cause the one or more processors to determine, based on the first, second, and third flow parameters, whether the denervation therapy adequately ablated the target nerves.
  • Clause 16 The system of any one of clauses 9 to 15, wherein the instructions that cause the one or more processors to determine, based on the flow parameter criteria and the second flow parameter, whether the denervation therapy adequately ablated the target nerves comprise instructions which, when executed by the one or more processors, cause the one or more processors to determining whether a change in flow between the first flow parameter and the second flow parameter is greater than a threshold change value.

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Abstract

Une méthode de réalisation d'une intervention thérapeutique selon l'invention comprend les étapes de navigation d'un dispositif thérapeutique vers un emplacement adjacent au tissu cible, détermination d'un premier paramètre de flux à l'intérieur d'un vaisseau sanguin adjacent au tissu cible, application d'une neurostimulation au tissu cible et obtention de premières images de vaisseaux sanguins distaux du tissu cible, application d'une thérapie au tissu cible, application d'une neurostimulation au tissu cible, détermination d'un deuxième paramètre de flux à l'intérieur du vaisseau sanguin adjacent au tissu cible, comparaison du deuxième paramètre de flux à un critère de paramètre de flux, application d'une neurostimulation au tissu cible et obtention de deuxièmes images des vaisseaux sanguins distaux du tissu cible, comparaison des premières images aux deuxièmes images pour déterminer une mesure de vasoconstriction, et application d'une thérapie au tissu cible s'il est déterminé que la mesure de vasoconstriction satisfait un critère de vasoconstriction.
PCT/EP2025/054347 2024-02-20 2025-02-18 Vasoconstriction rénale et réponse de flux sanguin rénal à une stimulation en tant que guide de dénervation rénale Pending WO2025176672A1 (fr)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
EP2517755A1 (fr) * 2004-10-05 2012-10-31 Medtronic Ardian Luxembourg S.à.r.l. Procédés et appareil pour la neuromodulation rénale
US20200179045A1 (en) * 2016-07-29 2020-06-11 Axon Therapies, Inc. Devices, systems, and methods for treatment of heart failure by splanchnic nerve ablation
US20220240807A1 (en) * 2014-10-01 2022-08-04 Medtronic Ardian Luxembourg S.A.R.L. Systems and methods for evaluating neuromodulation therapy via hemodynamic responses
US20230071511A1 (en) * 2013-10-25 2023-03-09 Ablative Solutions, Inc. Apparatus for effective ablation and nerve sensing associated with denervation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2517755A1 (fr) * 2004-10-05 2012-10-31 Medtronic Ardian Luxembourg S.à.r.l. Procédés et appareil pour la neuromodulation rénale
US20230071511A1 (en) * 2013-10-25 2023-03-09 Ablative Solutions, Inc. Apparatus for effective ablation and nerve sensing associated with denervation
US20220240807A1 (en) * 2014-10-01 2022-08-04 Medtronic Ardian Luxembourg S.A.R.L. Systems and methods for evaluating neuromodulation therapy via hemodynamic responses
US20200179045A1 (en) * 2016-07-29 2020-06-11 Axon Therapies, Inc. Devices, systems, and methods for treatment of heart failure by splanchnic nerve ablation

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