NEUROMODULATION THERAPY INCLUDING TISSUE TEMPERATURE MODULATION
[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63/507,630, filed 12 June 2023, the entire content of which is incorporated herein by reference.
TECHNICAL FIELD
[0002] The present disclosure is related to neuromodulation therapy.
BACKGROUND
[0003] The sympathetic nervous system (SNS) is a primarily involuntary bodily control system typically associated with stress responses. Fibers of the SNS extend through tissue in almost every organ system of the human body and can affect characteristics such as pupil diameter, gut motility, and urinary output. Such regulation can have adaptive utility in maintaining homeostasis or in preparing the body for rapid response to environmental factors. Chronic over-activation of the SNS, however, is a common maladaptive response that can drive the progression of many disease states. Excessive activation of the renal SNS in particular 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.
SUMMARY
[0004] The present disclosure describes devices, systems, and methods for neuromodulation, such as renal neuromodulation. In examples described herein, a medical device system is configured to deliver, via one or more therapy delivery elements, neuromodulation therapy to target tissue of a patient. The one or more therapy delivery elements may include, but are not limited to, one or more electrodes (e.g., radiofrequency (RF) electrodes, microwave electrodes), ultrasound transducers, direct or indirect heating elements, cryogenic energy sources, or the like or combinations thereof. The one or more therapy delivery elements may deliver neuromodulation therapy to one or more target nerves near or adjacent to the target tissue site by delivering the neuromodulation therapy to an inner surface of a body lumen of the patient (e.g., a blood vessel, a portion of a gastrointestinal tract, a portion of a respiratory tract, or the like) to alter the temperature of the tissue and the target nerve at the target tissue site.
[0005] In order to sufficiently neuromodulate the target nerve, the medical device system may modulate the temperature of the target nerve or tissue surrounding the target nerve to an effective tissue temperature. The effective tissue temperature may be greater than or less than an initial tissue temperature, depending on the type of neuromodulation therapy being delivered to the tissue. In some examples, tissue adjacent to the inner surface of the body lumen may experience a change in temperature at a higher rate or magnitude than the target nerve or tissue adjacent the target nerve. The greater change in temperature of the tissue adjacent to the inner surface of the body lumen may be a result of the relative proximity of the tissue to the one or more therapy delivery elements of the medical device system. In such examples, the tissue adjacent to the inner surface may satisfy a threshold tissue temperature prior to the target tissue or tissue adjacent to the target tissue reaching the effective tissue temperature. The disparity in the temperature change experienced by the tissue may reduce efficacy of the neuromodulation therapy or increase a likelihood of unintended effects on the tissue of the patient.
[0006] The present disclosure describes devices and systems configured to modulate tissue temperature site at one or more distances from the inner surface of the body lumen prior to and/or during the delivery of the neuromodulation therapy, and corresponding methods. Based on the sensed tissue temperature, the devices, systems, and methods may initiate and/or temporarily cease the delivery of the neuromodulation therapy and modulate the tissue temperature (e.g., actively modulating and/or passively modulating) towards an initial tissue temperature. Based on the sensed tissue temperature after the modulation of the tissue temperature, the devices, systems, and methods described herein may restart delivery of neuromodulation therapy to the target tissue site. The devices, systems, and methods described herein may iteratively deliver neuromodulation therapy and modulate the tissue temperature until the tissue temperature of the target nerve or tissue surrounding the target nerve satisfies a threshold temperature or until the temperature profile of the tissue at the target tissue site satisfies a threshold temperature profile.
[0007] The devices, systems, and methods described in the present disclosure may provide one or more benefits over other neuromodulation devices, systems, and methods. Alternating between delivering the neuromodulation therapy to tissue at the target tissue site and modulating tissue temperature of the tissue and/or modulating the tissue temperature prior to the delivery of the neuromodulation therapy may cause the tissue to define a relatively even temperature profile from the inner surface of the body lumen to the target nerve. The relatively even temperature profile may indicate that the temperature of target nerve or tissue surrounding the target nerve satisfy the effective tissue temperature while other tissue at the target tissue site do not satisfy a threshold tissue temperature corresponding to an onset of or an increase in the likelihood of the onset of unintended effects of the neuromodulation therapy on the tissue at the target tissue site. In some examples, switching between the delivery of the neuromodulation therapy and the modulation of the tissue temperature based on sensed temperature data of the tissue at the target tissue site provides a clinician with more precise control of the tissue temperatures and reduce an amount of time required to complete the neuromodulation therapy. [0008] In some examples, the disclosure describes a system including: a catheter configured to be disposed within vasculature of a patient, the catheter including: an elongated body, and a therapy delivery element disposed on a distal portion of the elongated body; a temperature modulation element configured to be disposed within the vasculature; and control circuitry configured to: cause the temperature modulation element to modulate a temperature of a blood vessel wall at a target location within the blood vessel, wherein the temperature modulation element is configured to modulate the temperature of the blood vessel wall at the target location away from an initial temperature of the blood vessel wall; compare a temperature modulation time conducted by the temperature modulation element with a threshold time; cause, based on a determination that the temperature modulation time is greater than or equal to the threshold time, the temperature modulation element to terminate modulation of the temperature of the blood vessel wall at the target location; and cause the therapy delivery element to deliver neuromodulation energy to tissue adjacent to the blood vessel wall at the target location. [0009] In some examples, the disclosure describes a method including: advancing a temperature modulation element and a therapy delivery element of a catheter within a vasculature of a patient to a target location within a blood vessel, wherein the therapy delivery element is disposed on a distal portion of an elongated body of the catheter; causing, via control circuitry coupled to the temperature modulation element and to the catheter, the temperature modulation element to modulate a temperature of a blood vessel wall at the target location away from an initial temperature of the blood vessel wall; comparing, via the control circuitry, a temperature modulation time by the temperature modulation element against a threshold time; causing, based on a determination that the temperature modulation time is greater than or equal to the threshold time and via the control circuitry, the temperature modulation element to terminate modulation of the temperature of the blood vessel wall at the target location; and causing, via the control circuitry, the therapy delivery element to deliver neuromodulation energy to tissue adjacent to the blood vessel wall at the target location.
[0010] In some examples, the disclosure describes a computer-readable medium including instructions that, when executed, causes control circuitry of a medical device system to perform a method including: advancing a temperature modulation element and a therapy delivery element of a catheter within a vasculature of a patient to a target location within a blood vessel, wherein the therapy delivery element is disposed on a distal portion of an elongated body of the catheter; causing, via control circuitry coupled to the temperature modulation element and to the catheter, the temperature modulation element to modulate a temperature of a blood vessel wall at the target location away from an initial temperature of the blood vessel wall; comparing, via the control circuitry, a temperature modulation time by the temperature modulation element against a threshold time; causing, based on a determination that the temperature modulation time is greater than or equal to the threshold time and via the control circuitry, the temperature modulation element to terminate modulation of the temperature of the blood vessel wall at the target location; and causing, via the control circuitry, the therapy delivery element to deliver neuromodulation energy to tissue adjacent to the blood vessel wall at the target location.
[0011] The details of one or more examples are set forth in the accompanying drawings and the description below. Other features, objects, and advantages will be apparent from the description and drawings, and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] Reference is made to the attached drawings, wherein elements have the same reference numeral designations represent similar elements throughout. [0013] FIG. 1 is a partial schematic illustration of an example neuromodulation system.
[0014] FIG. 2 is a block diagram illustrating an example control device of FIG. 1.
[0015] FIG. 3A is a conceptual diagram illustrating a distal portion of an elongated member of the catheter of FIG. 1 positioned within a blood vessel.
[0016] FIG. 3B is a conceptual diagram illustrating another distal portion of an elongated member of the catheter of FIG. 1 positioned within a blood vessel.
[0017] FIG. 4A is a graph illustrating an example tissue temperature profile of tissue of a patient at a target tissue site in response to pre-therapy temperature neuromodulation.
[0018] FIG. 4B is a graph illustrating an example tissue temperature profile of the tissue of the patient at the target tissue site during delivery of a first neuromodulation therapy to the patient.
[0019] FIG. 4C is a graph illustrating example tissue temperature profiles of the tissue of the patient during modulation of the tissue temperature profile of FIG. 4A.
[0020] FIG. 4D is a graph illustrating example tissue temperature profiles of the tissue of the patient during delivery of a second neuromodulation therapy to the tissue of the patient after the modulation of the tissue temperature profile of FIG. 4B.
[0021] FIG. 4E is a graph illustrating example tissue temperature profiles of the tissue of the patient over time.
[0022] FIG. 4F is a graph illustrating another example tissue temperature profile of the tissue of the patient at the target tissue site in response to pre-therapy temperature neuromodulation .
[0023] FIG. 4G is a graph illustrating another example tissue temperature profile of the tissue of the patient at the target tissue site during delivery of the first neuromodulation therapy to the patient.
[0024] FIG. 4H is a graph illustrating another example tissue temperature profile of the tissue of the patient over time.
[0025] FIG. 5 is a flow diagram illustrating an example process of delivery neuromodulation therapy to a target tissue site of a patient.
[0026] FIG. 6 is a flow diagram illustrating another example process of delivering neuromodulation therapy to a target tissue site of a patient. [0027] FIG. 7 illustrates an example technique for accessing a renal artery and modulating renal nerves with the system of FIG. 1 in accordance with some examples of the present disclosure.
[0028] FIG. 8 is a conceptual illustration of an example sympathetic nervous system (SNS) illustrating how the brain communicated with the body via the SNS.
[0029] FIG. 9 is an enlarged anatomic view of nerves innervating a left kidney to form the renal plexus surrounding the left renal artery.
[0030] FIG. 10 is an anatomic view of a human body depicting neural efferent and afferent communication between the brain and kidneys.
[0031] FIG. 11 is a conceptual view of a human body depicting neural efferent and afferent communication between the brain and kidneys.
[0032] FIG. 12 is an anatomic view of the arterial vasculature of a human.
[0033] FIG. 13 is an anatomic view of the venous vasculature of a human.
DETAILED DESCRIPTION
[0034] The present disclosure describes devices, systems, and method for neuromodulation, such as renal neuromodulation. Although examples are described with reference to renal neuromodulation, devices, systems, and techniques described herein may be applied to other types of neuromodulation, such as neuromodulation performed on nerves other than the renal nerves, at sites other than within a renal vessel, or both. The devices, systems and techniques may be applied to other medical therapies such as other denervation therapies or other therapies involving changing the temperature of tissue of the patient. In general, the devices, systems, and techniques described herein may be used to perform neuromodulation from within any suitable anatomical lumen that has nerves adjacent to the anatomical lumen. In addition, the systems, devices, and methods described herein may be useful for neuromodulation within a body lumen other than a vessel, for extravascular neuromodulation or for use in therapies other than neuromodulation. The neuromodulation procedure may target one or more denervation site within the body of the patient. The denervation sites may include, but are not limited to, nerves proximate to a pulmonary artery, a hepatic artery, a celiac artery, a mesenteric artery, an artery connected to a digestive system of the patient, an artery connected to a reproductive system of the patient, or other arteries. Following neuromodulation, also referred to as denervation in some examples, there may be a reduction or event prevent of neural signal transmission along the target nerve.
[0035] As used herein, the terms “distal” and “proximal” define a position or direction with respect to the treating clinician or clinician’s control device (e.g., a handle assembly). “Distal” or “distally” can refer to a position distant from or in a direction away from the clinician or clinician’s control device. “Proximal” and “proximally” can refer to a position near or in a direction towards the clinician or clinician’s control device.
[0036] Neuromodulation, such as renal denervation, may be accomplished using one or more of a variety of treatment modalities, including radiofrequency (RF) energy, microwave energy, ultrasound energy, heat, cryogenic cooling, a chemical agent, or the like. To perform intravascular neuromodulation, a neuromodulation catheter may be delivered to a blood vessel, such as a renal artery, of a patient. In some examples, the neuromodulation catheter includes one or more expandable members, each of which includes one or more electrodes. The one or more expandable members can include, for example, a shape memory element configured to assume an expanded shape (e.g., a helical, spiral, basket, or stent-like shape), a balloon, or the like. Each expandable member is configured to position one or more electrodes in apposition to the vessel wall to transfer energy (e.g., RF energy) to or from tissue surrounding the vessel wall.
[0037] In some examples, a neuromodulation system is configured to deliver energy to the tissue surrounding the vessel wall and affect a change in the tissue temperature of a target nerve (e.g., the renal nerve) or tissue surrounding the target nerve. The neuromodulation system may indirectly change the tissue temperature of the target nerve by delivering energy to tissue surrounding the vessel wall, thereby causing the tissue to transmit the energy to tissue surrounding the target nerve. For example, the neuromodulation system may deliver thermal energy, RF energy, ultrasound energy, microwave energy, or the like to the tissue adjacent the vessel wall to increase the tissue temperature of tissue within a particular distance of the vessel wall. In another example, the neuromodulation system may deliver cryogenic energy to decrease the tissue temperature of tissue within a particular distance of the vessel wall. The target nerve may be within the particular distance of the vessel wall and cooling or heating the target nerve to a target tissue temperature may cause successful neuromodulation of the target nerve. [0038] Due to the relative proximity of tissue adjacent to the vessel wall to therapy delivery elements of the neuromodulation system, the tissue temperature of the tissue adjacent to the vessel wall may change (e.g., may increase or decrease) at a faster rate than tissue further away from the vessel wall (e.g., the target nerve, tissue surrounding the target nerve). A clinician may desire to prevent the tissue temperature of the tissue adjacent to the vessel wall from satisfying a threshold temperature (e.g., exceeding a maximum threshold temperature, below a minimum threshold temperature) to prevent the occurrence of unintended effects on the tissue or to reduce a likelihood of the occurrence of unintended effects on the tissue. A clinician may also wish to prevent the tissue temperature of the tissue adjacent to the vessel wall from satisfying the threshold temperature to maintain or increase efficacy of the neuromodulation therapy.
[0039] In some examples described herein, a medical device system configured to deliver neuromodulation therapy to the target nerve may modulate tissue temperature of tissue adjacent at the target tissue site away from an initial tissue temperature prior to any delivery of neuromodulation therapy to tissue at the target tissue site. The medical device system may actively modulate the tissue to increase or decrease the tissue temperature relative to the initial tissue temperature. The medical device system may modulate tissue temperature for at least a threshold amount of time. In some examples, the medical device system modulates tissue temperature until the medical device system determines that the tissue temperature has satisfied a threshold condition (e.g., a threshold temperature). In some examples, the neuromodulation therapy is configured to increase the tissue temperature of the tissue at the target tissue site, and the medical device system is configured to modulate the tissue temperature of the tissue to decrease the tissue temperature relative to an initial tissue temperature, e.g., for at least the threshold amount of time. In some examples, the neuromodulation therapy is configured to decrease the tissue temperature of the tissue at the target tissue site, and the medical device system is configured to modulate the tissue temperature of the tissue to increase the tissue temperature relative to an initial tissue temperature, e.g., for at least the threshold amount of time.
[0040] In some examples described herein, a medical device system configured to deliver neuromodulation therapy to the target nerve may alternate between delivery of neuromodulation therapy and modulation of the tissue temperature towards an initial tissue temperature. Alternating between the delivery of the neuromodulation therapy and modulation of the tissue temperature may cause the tissue at the target tissue site to develop a relative even temperature profile from the vessel wall to at least the target nerve. The medical device system may alternate between the delivery of the neuromodulation therapy the modulation of the tissue temperature based on sensed temperatures of the tissue at one or more locations. Each location may be at a set distance away from an inner surface of the vessel wall. Based on whether the sensed temperatures satisfy one or more threshold temperatures, the medical device system may switch from the delivery of the neuromodulation therapy to the modulation of the tissue temperature, or vice versa. The medical device system may iteratively deliver neuromodulation therapy and modulate the tissue temperature until the medical device system determines that the tissue at the target tissue site defines a threshold temperature profile or until the medical device system determines that the temperature of the target nerve satisfies a target temperature.
[0041] In some examples described herein, temporally adjacent deliveries of neuromodulation therapy may be separated by an intervening period of modulation of the tissue temperature. Each delivery of neuromodulation therapy may be a separate pulse of neuromodulation therapy, a separate neuromodulation therapy (e.g., a neuromodulation therapy having a continuous waveform), or a separate wave of a waveform of a single neuromodulation therapy. The use of the term “pulse” is intended to describe a separate delivery of neuromodulation therapy and is not intended to limit the neuromodulation therapy to a single wave of energy. Each delivery of neuromodulation therapy may occur over a corresponding therapy period. Each therapy period may have a same duration or may have different durations. Each intervening period of modulation of the tissue temperature may alternatively be referred to herein as a “recovery period.” Each recovery period may have a same duration or may have different durations.
[0042] Each delivery of neuromodulation therapy may define the same therapy parameters or different therapy parameters as another pulse of neuromodulation therapy. For example, separate pulses of neuromodulation therapy may define a same or different pulse threshold temperature, therapy amplitude, therapy frequency, or the like. For each pulse, the pulse threshold temperature may represent a threshold temperature at which the medical device system ceases delivery of the pulse to the target tissue. Similarly, each recovery period may define different modulation characteristics including, but are not limited to, a recovery threshold temperature, a duration of recovery period, a type of modulation (e.g., passive modulation, active modulation), or the like. For each recovery period, the recovery threshold temperature may represent a threshold temperature at which the medical device system proceeds to deliver the next pulse of neuromodulation therapy. The medical device system may iteratively adjust the threshold temperatures of different deliveries of neuromodulation therapy or of different recovery periods, e.g., to cause the tissue at the target tissue site to define a more even temperature profile.
[0043] Iteratively delivering separate deliveries of neuromodulation therapy between modulation of tissue temperature and/or modulating the tissue temperature prior to delivery of neuromodulation therapy may provide benefits over other neuromodulation methods. In some examples, the neuromodulation system described herein are configured to create a relatively even temperature profile from a vessel wall to a target nerve or to maintain a maximum portion of the temperature profile within a threshold deviation from an initial tissue temperature, thereby allowing the target nerve to reach a target temperature without causing other tissue between the target nerve and the vessel wall to exceed a maximum threshold temperature or be below a minimum threshold temperature, thereby increasing the efficacy of the neuromodulation therapy and reducing the likelihood or severity of any unintended effects. In some examples, switching between delivery of neuromodulation therapy and modulation of tissue temperature based on satisfactions of corresponding threshold temperatures by sensed tissue temperatures helps to reduce unnecessary neuromodulation therapy delivery or modulation of tissue temperature, thereby reduce an amount of time required to neuromodulate the target nerves or a need for follow-up procedures.
[0044] While RF energy delivered as an electrical signal is primarily referred to herein, in other examples, the description here can apply to other types of energy, such as, but not limited to, microwave energy, ultrasound energy, cryogenic energy, thermal energy, variations of the energy application such as gating or pulsing, or any combination therein.
[0045] In some examples, the devices, systems, and techniques described herein may be useful for neuromodulation within a blood vessel or a body lumen other than a blood vessel, for extravascular neuromodulation, for non-renal-nerve neuromodulation, and/or for use in therapies other than neuromodulation. [0046] FIG. 1 is a partially schematic illustration of an example neuromodulation system 100 (alternatively referred to herein as “system 100”) configured to alternate between delivery of neuromodulation therapy to a target tissue site and modulation of tissue temperature at the target tissue site. System 100 may alternative between delivery of neuromodulation therapy and modulation of the tissue temperature towards an initial temperature (i.e., a temperature of the tissue prior to the delivery of neuromodulation therapy) to develop an even temperature profile radiating away from the vessel wall and to neuromodulate a target nerve within the target tissue site. The even temperature profile may increase efficacy of the neuromodulation therapy and reduce the occurrence of unintended effects in the tissue at the target tissue site.
[0047] System 100 may deliver neuromodulation therapy to the tissue at the target tissue site to change the temperature of the tissue (i.e., increase or decrease the tissue temperature), e.g., to neuromodulate a target nerve within the target tissue site. System 100 may passively modulate (e.g., via blood flow within a blood vessel) or actively modulate (e.g., via a heating or cooling element placed in apposition with the vessel wall) the tissue temperature of the tissue adjacent the target tissue site, e.g., to create a more even temperature profile within the tissue at the target tissue site. System 100 may modulate the tissue temperature between temporary adjacent deliveries of neuromodulation therapy.
[0048] System 100 may be configured to sense tissue temperature along a vessel wall of a blood vessel at the target tissue site or at varying distances from the vessel wall. For example, system 100 may sense tissue impedance values at varying distances from the vessel wall and determine the tissue temperature value based on the sensed impedance values. Based on the sensed temperature values, system 100 may alternate between delivery of neuromodulation therapy and modulation of the tissue temperature during recovery periods. For example, system 100 may deliver a first neuromodulation energy to the target tissue site until the sensed tissue temperature (e.g., at a location a first distance away from the vessel wall) during the corresponding therapy period satisfies a corresponding pulse threshold temperature. System 100 may then modulate the tissue temperature until the sensed tissue temperature (e.g., at a location the first distance or a second distance away from the vessel wall) satisfies a corresponding recovery threshold temperature. System 100 may continue to alternate between delivery of neuromodulation modulation of the tissue temperature until system 100 determines that a threshold condition has occurred. The threshold condition may include, but are not limited, clinician input (e.g., via a control device), a determination that the temperature of the target nerve is at a target tissue temperature, or a determination that the temperature profile of the tissue satisfies a threshold temperature profile.
[0049] In the example shown in FIG. 1, system 100 includes a catheter 102 coupled to a control device 106. Catheter may include an elongated member 108 extending along a longitudinal axis 105 of catheter 102. A therapy delivery element 110 may be disposed along elongated member 108 (e.g., at a distal end of distal portion 108A or elongated member 108). Therapy delivery element 110 may be connected to control device 106 (e.g., via a plurality of electrical conductors disposed within elongated member 108 or handle 104 of catheter 102, via one or more elongated tubes disposed within elongated member 108 or handle 104 and extending along longitudinal axis 105). Control device 106 may, via therapy delivery element 110, deliver therapeutic energy (e.g., RF energy, ultrasound energy, microwave energy, thermal energy, cryogenic energy) to or sense signals from tissue of a vessel wall of a blood vessel of the patient (e.g., tissue at a target tissue site along the vessel wall of the blood vessel). Although FIG. 1 illustrates catheter 102 as having one therapy delivery element 110, other example catheters may include two or more therapy delivery elements 110 disposed at different positions along elongated member 108.
[0050] Elongated member 108 may have any suitable outer diameter, and the diameter can be constant along the length of elongated member 108 or may vary along the length of elongated member 108. In some examples, elongated member 108 can be 2, 3, 4, 5, 6, or 7 French or another suitable size.
[0051] Distal portion 108 A of elongated member 108 is configured to be advanced within an anatomical lumen of a human patient to locate therapy delivery element 110 at a target tissue site within or otherwise proximate to the anatomical lumen. For example, elongated member 108 may be configured to position therapy delivery element 110 within a blood vessel, a ureter, a duct, an airway, or another naturally occurring lumen within the human body. The examples described herein focus on the anatomical lumen being a blood vessel, such as a renal vessel, but it will be understood that similar techniques may be used with other anatomical lumens. In certain examples, intravascular delivery of therapy delivery element 110 includes percutaneously inserting a guidewire (not shown in FIG. 1) into a vessel of a patient and moving elongated member 108 or therapy delivery element 110 along the guidewire until therapy delivery element 110 reach a target tissue site (e.g., a renal artery). For example, distal portion 108 A of elongated member 108 may define a passageway for engaging the guidewire for delivery of therapy delivery element 110 using over- the- wire (OTW) or rapid exchange (RX) techniques. In other examples, neuromodulation catheter 102 can be a steerable or non- steerable device configured for use without a guidewire. In still other examples, neuromodulation catheter 102 can be configured for delivery via a guide catheter or sheath (not shown in FIG. 1), or another guide device.
[0052] Once at the target tissue site, therapy delivery element 110 can be configured to deliver therapy, such as RF energy to provide or facilitate neuromodulation therapy at the target tissue site. For ease of description, the following discussion will be primarily focused on delivering RF energy, in which example therapy delivery element 110 includes a plurality of electrodes. Therapy delivery element 110 may deliver RF energy to the tissue of the patient by delivering monopolar energy or bipolar energy (e.g., in the form of a monopolar and/or a bipolar electrical signal) to the tissue. It will be understood, however, that in other examples, therapy delivery element 110 may include elements or structures configured to deliver other types of therapy in addition to or instead of RF energy.
[0053] In the example shown in FIG. 1, therapy delivery element 110 is configured to assume a delivery configuration in which therapy delivery element 110 defines a relatively smaller radial extent (a relatively low profile), and a deployed configuration (e.g., a radially expanded configuration) in which therapy delivery element 110 defines a relatively larger radial extent. Distal portion 108A may be delivered through vasculature of the patient to the target tissue site while therapy delivery element 110 is in the delivery configuration. In some examples, in the deployed configuration, therapy delivery element 110 defines a helical, a spiral, a loop, a basket, or a stent-like configuration. In the deployed configuration, therapy delivery element 110 is configured to position one or more electrodes of the plurality of electrodes carried by therapy delivery element 110 near a vessel wall(e.g., in apposition to the vessel wall) or to center therapy delivery element 110 within the blood vessel (e.g., place therapy delivery element 110 along a centerline of the blood vessel). In other examples, therapy delivery element includes a balloon configured to expand from a relatively low profile delivery configuration to an expanded configuration in order to position one or more electrodes of the plurality of electrodes carried by therapy delivery element 110 near a vessel wall.
[0054] When therapy delivery element 110 is in the deployed configuration, therapy delivery element 110 may be spaced around an inner perimeter (e.g., circumference) of the vessel wall. In some examples, the therapy delivery element 110 includes a plurality of elements (e.g., electrodes, ultrasound transducers) positioned along therapy delivery element 110 such that, when therapy delivery element 110 is in the deployed configuration, the elements are substantially evenly spaced around an inner perimeter (e.g., circumference) of the vessel wall or centered within the lumen of the blood vessel. [0055] In some examples, catheter 102 includes one or more temperature modulating elements 112 disposed on distal portion 108A of elongated member 108. In some examples, temperature modulating elements 112 are a part of therapy delivery element 110 (e.g., may be a portion of an expandable element). In some examples, temperature modulating elements 112 are disposed along a different portion of elongated member 108. In some examples, temperature modulating elements 112 are disposed on a separate catheter coupled to control device 106 and configured to be place in apposition with the inner wall of the blood vessel. System 100 may modulate temperature of tissue at the target tissue site via one or more temperature modulating elements 112 between deliveries of neuromodulation therapy and/or prior to any deliveries of neuromodulation therapy. [0056] Control device 106 includes therapy delivery circuitry configured to deliver neuromodulation therapy (e.g., pulses of neuromodulation therapy, separate neuromodulation therapies) to the patient via therapy delivery element 110. The therapy delivery circuitry may be configured to modulate tissue temperature of tissue at a target tissue site via temperature modulating elements 112. The therapy delivery circuitry may include circuitry configured to generate and transmit an electrical signal via electrodes on therapy delivery element 110, generate and transmit thermal or cryogenic energy (e.g., via a heating or cooling fluid) via therapy delivery element 110, or the like. In some examples control device 106 (e.g., therapy delivery circuitry of control device 106) is configured to active modulate temperature of tissue at the target treatment site. Therapy delivery circuitry may cause temperature modulating element 112 to actively modulate tissue temperature during recovery periods.
[0057] Control device 106 further includes sensing circuitry configured to sense signals corresponding to one or more parameters (e.g., temperature, impedance, or the like) from the patient at or near a target tissue site via one or more electrodes or sensors. In some examples, different sensors may sense signals corresponding to different parameters affecting different tissues (e.g., target tissue, non-target tissue) within the target tissue site. In some examples, different sensors may sense signals corresponding to different parameters affecting a same tissue within the target tissue site. Based on the sensed signals, control device 106 may alternate between delivery of neuromodulation therapy and modulation of the tissue temperature. For example, control device 106 can be configured to switch from monopolar energy delivery to bipolar energy to the target tissue site in response to a determination, based on the sensed signals, that the parameters satisfy one or more threshold conditions or that a distance between the target nerve(s) and the blood vessel satisfies a threshold condition.
[0058] FIG. 2 is a block diagram illustrating an example of control device 106 of FIG. 1. In this example, control device 106 includes therapy delivery circuitry 206, sensing circuitry 208, control circuitry 210, user interface (UI) 212, communications circuitry 214, memory 216, and a power source 218 that provides operational power to the other components. The various circuitry may be, or include, programmable or fixed function circuitry configured to perform the functions attributed to the respective circuitry.
[0059] Control device 106 is electrically connected to therapy delivery element 110. For example, as illustrated in FIG. 2, control device 106 may be connected to electrodes 202A-N (also referred to collectively as “electrodes 202”) disposed on therapy delivery element 110 of catheter 102 (not pictured) via electrical conductors 204A-204N (also referred to collectively as “electrical conductors 204”). In some examples, other therapy delivery elements (e.g., ultrasound transducer, direct heating elements, expandable members configured to retain cryogenic cooling elements) are coupled to therapy delivery circuitry 206. In the example shown in FIG. 2, each electrode 202A-202N is electrically coupled to a separate electrical conductor 204A-204D such that each electrode is independently and separately activatable. [0060] Memory 216 may store computer-readable instructions that, when executed by control circuitry 210, cause control circuitry 210 and control device 106 to perform various functions described herein. Memory 216 may be a storage device or other non- transitory medium. Memory 216 may include any volatile, non-volatile, magnetic, optical, or electrical media, such as random- access memory (RAM), read-only memory (ROM), non-volatile RAM (NVRAM), electrically-erasable programmable ROM (EEPROM), flash memory, or any other digital media.
[0061] Control circuitry 210 (alternatively referred to as “processing circuitry 210”) may include any one or more of a microprocessor, a controller, a digital signal processor (DSP), an application-specific integrated circuitry (ASIC), a field-programmable gate array (FPGA), discrete logic circuitry, or any other circuitry configured to provide the functions attributed to control circuitry 210 herein and may be embodied as firmware, hardware, software, or any combination thereof.
[0062] Therapy delivery element 110 may be connected to therapy circuitry 206 of control device 106. For example, in some examples where therapy delivery element 110 includes electrodes 202, electrodes 202 are connected to therapy delivery circuitry 206 through electrical conductors 204. Electrical conductors 204 may have any suitable configuration, e.g., electrical wires, feedthrough assemblies, or the like extending inside handle 104 and elongated member 108 to therapy delivery element 110. In some examples, such as where therapy delivery element 110 includes a cryogenic energy source (e.g., an expandable member configured to retain a cooling fluid), a fluid source (e.g., a fluid reservoir) or one or more valves fluidically connected to or in fluid communication with therapy delivery element 110 is connected to therapy delivery circuitry 206.
[0063] In some examples where therapy delivery element 110 includes a plurality of electrodes 202, as illustrated in FIG. 2, each electrode of electrodes 202 of therapy delivery element 110 is separately electrically connected to therapy delivery circuitry 206 via a corresponding electrical conductor of electrical conductors 204. In other examples, electrodes 202 may be electrically connected, via electrical conductors 204, to a switching circuitry configured to selectively couple therapy delivery circuitry 206 or sensing circuitry 208 to selected combinations of electrodes 202.
[0064] Therapy delivery circuitry 206 is configured to generate and delivery energy, e.g., in the form of an electrical signal, to the target tissue. Although RF energy and signals are primarily referred to herein, in other examples, the energy can be other types of energy and signals, such as, but not limited to, microwave energy or ultrasound energy. In some examples, therapy delivery circuitry 206 is configured to introduce a neuromodulation fluid (e.g., a heating fluid, a cooling fluid) into or remove a neuromodulation fluid from therapy delivery element 110.
[0065] Therapy delivery circuitry 206 may be connected to a temperature modulating element (e.g., temperature modulating element 112 of FIG. 1) disposed on elongated member 108 or on another catheter. Therapy delivery circuitry 206 may be configured to, based on instructions from control circuitry 210, cause temperature modulating element 112 to actively modulate the tissue temperature of tissue adjacent a vessel wall of a blood vessel towards an initial tissue temperature. In some examples, therapy delivery circuitry is configured to cause a modulating fluid to be introduced into temperature modulating element 112 (e.g., into an expandable member of temperature modulating element 112) to modulate the temperature of the tissue towards the initial temperature. In some examples, therapy delivery element 110 is used by control device 106 as temperature modulating element 112. In some examples, separate circuitry connected to control circuitry 210 is configured to control temperature modulating element 112.
[0066] Sensing circuitry 208 is configured to sense signals corresponding to one or more parameters of the tissue, such as temperature or impedance. For example, sensing circuitry 208 can be configured to sense signals at or near the target tissue site and at varying distances from the vessel wall of the blood vessel. Sensing circuitry 208 may be coupled to one or more of electrodes 202 or other sensor(s). The other sensor(s) may include sensing elements disposed on catheter 102, on another catheter, or on the body of the patient. The other sensor(s) may be configured to communicate with sensing circuitry 208 (e.g., directly with sensing circuitry 208, via communications circuitry 214). Sensing circuitry 208 may have any suitable configuration and may, for example, include filters, amplifiers, analog-to-digital converters, or other circuitry configured to sense electrical signals (e.g., via electrodes 202, via sensor(s) or to convert the sensed electrical signals to one or more parameters (e.g., temperature/change in temperature of tissue sensed by sensor(s) or electrodes 202, impedance/change in impedance sensed by the selected electrodes 202 or sensor(s)). In some examples, sensing circuitry 208 includes one or more thermocouples (e.g., connected to each of electrodes 202 via a pair of corresponding wires, which may include conductors 204). In these examples, sensing circuitry 208 provides signals based on which control circuitry 210 may determine the temperature or change in temperature of the tissue at one or more distances away from the vessel wall via the one or more thermocouples. Sensing circuitry 208 may transmit the sensed signals to control circuitry 210 in the form of sets of sensor data. Each set of sensor data may correspond to sensed tissue signals at different times (e.g., during different therapy periods, during different recovery periods) and/or at different locations within the tissue (e.g., at different distances from the vessel wall). Control circuitry 210 may be configured to convert the sensed signals into parameter(s) of the tissue (e.g., impedance, temperature).
[0067] Control circuitry 210 may be configured to control therapy delivery circuitry 206 to deliver neuromodulation to tissue of a patient. In some examples control circuitry 210 is configured to control therapy delivery circuitry 206 or other circuitry to modulate the tissue temperature of the tissue. Control circuitry 210 may modulate the tissue temperature of the tissue between deliveries of neuromodulation therapy and/or prior to any delivery of neuromodulation therapy to the patient. Control circuitry 210 may determine, e.g., based on sensed signals and/or input from a clinician, distal portion 108A of catheter 102 and/or temperature modulating element 112 on distal portion 108 A are at a target tissue site within vasculature of the patient. Control circuitry 210 may, based on a determination that therapy modulating element 112 is at the target tissue site and/or in response to input from the clinician, modulate the tissue temperature of the tissue along and/or adjacent to a vessel wall at the target tissue site. Control circuitry 210 may be configured to modulate the tissue temperature for at least a threshold amount of time. The threshold amount of time may be at least 10 seconds (e.g., may be at least 30 seconds).
[0068] Control circuitry 210 may determine whether to deliver neuromodulation therapy (e.g., a pulse of neuromodulation therapy, a separate neuromodulation therapy) or to modulate the tissue temperature (e.g., passively or actively modulating the temperature) based at least in part on the sensed signals corresponding to parameters of the tissue. For example, control circuitry 210 may determine values for the one or more parameters (e.g., temperature of the tissue at varying distances from the vessel wall) and may compare the determined values against one or more threshold conditions (e.g., therapy threshold temperature(s), recovery threshold temperature(s)) to determine whether control device 106 should deliver neuromodulation therapy to the tissue or modulate the temperature of the tissue. The threshold conditions described herein, which can include, threshold values, threshold ranges or the like, can be stored, for example, in memory 216 of control device 106 or a memory of another device. In other examples, control circuitry 210 is configured to control therapy delivery circuitry 206 or other circuitry to deliver neuromodulation to the tissue of the patient or to modulate the temperature of the tissue based on user input, e.g., from a clinician.
[0069] For example, control circuitry 210 may determine, during delivery of neuromodulation therapy and based on the one or more sensed parameter values, that a temperature of the tissue at a first distance from the vessel wall satisfies a therapy threshold temperature corresponding to the neuro modulation therapy. Based on the determination, control circuitry 210 may cause therapy delivery circuitry 206 to cease delivery of the neuromodulation therapy. Control circuitry 210 may determine after the cessation of the delivery of the neuromodulation therapy of an onset of a recovery period. During the recovery period, control circuitry 210 may passively modulate (e.g., via blood flow within the blood vessel) or actively modulate (e.g., via a modulation energy delivered by temperature modulating element 112 disposed within the blood vessel) the temperature of the tissue. Control circuitry 210 may continue to sense signals corresponding to one or more parameters during the recovery period. Control circuitry 210 may determine, based on the one or more parameters, that the temperature of the tissue (e.g., at the first distance away from the vessel wall, at a second distance away from the vessel wall) satisfies a recovery threshold temperature. Control circuitry 210 may then terminate the recovery period and control therapy delivery circuitry 206 to deliver neuromodulation therapy to the tissue. The neuromodulation therapy may be the same as a previously delivered neuromodulation therapy may be a different neuro modulation therapy. Each delivered therapy and each recovery period may define therapy pulse threshold temperatures and recovery threshold temperatures, respectively.
[0070] Control circuitry 210 may alternate between delivering neuromodulation therapy and modulating the tissue temperature during recovery periods until control circuitry 210 determines the occurrence of one or more conditions. The conditions may include, but are not limited to, user input from the clinician, satisfaction of a target temperature by the target nerve, satisfaction of a threshold temperature profile, or the like. Control circuitry 210 may store the rules, algorithms, correlations, sensed parameters, the determined temperatures, conditions, threshold temperatures, and other information needed to carry out the therapies described herein in memory 216 or a memory of another device.
[0071] Communications circuitry 214 supports communication between control device 106 and one or more other computing devices, computing systems, or cloud computing environments. Control circuitry 210 of control device 106 may retrieve from the one or more other computing devices, computing systems, or cloud computing environments values for one or more threshold conditions, one or more associations between sensed parameters and vessel diameters or distances to target nerves, or the like. Control circuitry 210 may transmit, via communications circuitry 214, the sensed parameters, the parameters (e.g., amplitude or frequency of the neuromodulation energy) of each neuromodulation therapy, the parameters of each recovery period (e.g., amplitude, frequency, or duration of the modulation energy, recovery period duration), or instructions to other computing devices or computing systems, to the one or more other devices, systems, or cloud computing environments.
[0072] Communications circuitry 214 may communicate with the one or more other devices, systems, or cloud computing environments by wireless communication techniques. Wireless communication techniques may include RF communication techniques, e.g., via an antenna (not shown).
[0073] UI 212 may be configured to output information to or receive input from, e.g., a clinician or another user. The clinician may use UI 212 to input information (e.g., threshold condition values) into control device 106. In some examples, the clinician uses UI 212 to instruct control circuitry 210 or therapy delivery 206 to begin or cease delivery of neuromodulation energy to the target tissue site, begin or cease modulation of the tissue temperature at the target tissue site, or adjust the parameters of one or more neuromodulation therapies or recovery periods. The clinician may interact with UI 212 via one or more inputs including tactile, auditory, or visual input.
[0074] UI 212 may also output information to the clinician or another user. The outputted information may include, but is not limited, positions of one or more electrodes of electrodes 202 within the patient, the determined values (e.g., temperature or impedance values, such as for each of electrodes 202), vessel diameters, the type of neuromodulation delivered to the patient, or parameters of neuromodulation therapies delivered to or scheduled to be delivered to the patient (e.g., amplitude or frequency of the RF energy, microwave energy, ultrasound energy, thermal energy, or cryogenic energy). In some examples, UI 212 notifies the clinician of a satisfaction of a threshold condition. The notification displayed by UI 212 may include a type of the satisfied threshold condition, a threshold value corresponding to the satisfied threshold condition, or a determined value (e.g., determined or sensed by control circuitry 210 or sensing circuitry 208).
[0075] FIG. 3A is a conceptual diagram illustrating an example of distal portion 108A of elongated member 108 of catheter 102 of FIG. 1 positioned within a blood vessel 300. While distal portion 108A is illustrated as being disposed within blood vessel 300, distal portion 108A may be disposed within another body lumen of the patient. Blood vessel 300 may be a renal vessel (e.g., a renal artery, a renal vein) adjacent to renal nerve 304 and may include a vessel wall 302 defining a blood vessel lumen 306. Distal portion 108A of catheter 102 may be disposed within blood vessel lumen 306.
[0076] Distal portion 108A of FIG. 3A includes therapy delivery element 110 including a plurality of electrodes 202 disposed along a longitudinal length of therapy delivery element 110. When distal portion 108A is advanced to a target tissue site within blood vessel 300, a clinician may radially expand therapy delivery element 110 away from longitudinal axis 105 at place one or more of electrodes 202 in contact with an inner surface of vessel wall 302. The clinician may then deliver neuromodulation therapy 310 to nerve via electrodes 202. When therapy delivery element 110 is expanded, electrodes 202 may contact the inner surface of vessel wall 302 along a specific portion of the inner perimeter of blood vessel lumen 306 (e.g., to deliver neuromodulation therapy 310 to tissue less than 360 degrees around blood vessel 300) or around the entirety of the inner perimeter of blood vessel lumen 306 (e.g., to deliver neuromodulation therapy 310 to tissue 360 degrees around blood vessel 300).
[0077] The clinician may navigate distal portion 108A of catheter 102 from an incision site to target tissue site within blood vessel 300. In some examples, the clinician advances a guide member (e.g., a guidewire, a guide sheath) to or near the target tissue site and advance catheter 102 along the guide member. Distal end 308 of catheter 102 may include an atraumatic tip, e.g., to prevent unintended puncture of vessel wall 302. In some examples, distal end 308 includes one or more radiopaque markers. In some examples, electrodes 202 are sufficiently radiopaque to facilitate visualization of distal portion 108A. The clinician may visualize the location of the one or more radiopaque markers (e.g., within the vasculature of the patient) via fluoroscopy and may use the location of the one or more radiopaque markers to aid in the navigation of distal portion 108A to the target tissue site.
[0078] The clinician may cause therapy delivery element 110 to expand radially away from longitudinal axis 105 via removal of the guide member from distal portion 108A. In some examples, distal portion 108A includes an expandable member that, when unconstrained by the guide member, expands therapy delivery element 110 into the expanded configuration. In some examples, an expandable member is inserted into distal portion 108A to cause therapy delivery element 110 to expand into the expanded configuration. The expandable member may include a shape memory material (e.g., nitinol) configured to self-expand within blood vessel lumen 306. When expanded, therapy delivery element 110 may define a spiral, coil, helix, loops, a basket, or a stentlike shape.
[0079] Expansion of therapy delivery element 110 may place electrodes 202 in apposition with the inner surface of vessel wall 302. Each of electrodes 202 may be configured to sense parameter(s) (e.g., temperature, impedance) of the tissue surrounding blood vessel 300 at different distances along reference axis 312. Reference axis 312 extends radially away from a longitudinal axis of blood vessel 300, which may align with longitudinal axis 105 when distal portion 108A is disposed within blood vessel lumen 306. Reference axis 312 may intersect the longitudinal axis of blood vessel 300 and renal nerve 304 and may be defined along a reference plane normal to the longitudinal axis of blood vessel 300. Although FIG. 3A illustrates a single reference axis 312, therapy delivery element 110 may sense signals from and deliver neuromodulation therapy 310 to tissue surrounding blood vessel 300 along a plurality of reference axes, each of the plurality of reference axes being defined along the reference plane normal to the longitudinal axis of blood vessel 300.
[0080] Electrodes 202 may transmit neuromodulation therapy 310 (e.g., a first pulse of neuromodulation therapy 310, a first neuromodulation therapy 310) through vessel wall 302 and towards renal nerve 304 along reference axis 312. Neuromodulation therapy 310 may include, but are not limited to, RF energy, microwave energy, or thermal energy. Neuromodulation therapy 310 may change the temperature of the tissue along and/or surrounding reference axis 312. For example, RF energy, microwave energy, or thermal energy may increase the tissue temperature of tissue along reference axis 312.
[0081] System 100 may determine, based on sensed tissue temperatures, that tissue at a first distance away from vessel wall 302 satisfies a first threshold temperature (e.g., a first therapy threshold temperature). System 100 may, in response, cause electrodes 202 to cease delivery of neuromodulation therapy 310 and enter a recovery period. During the recovery period, blood vessel 300 may passively modulate the tissue temperature of tissue adjacent to blood vessel 300 towards an initial tissue temperature. For example, blood flowing within blood vessel lumen 306 may cause the tissue temperature to modulate towards the initial tissue temperature. System 100 may sense that the tissue temperature at either the first distance or a second distance (e.g., a second distance greater than or less than the first distance) from vessel wall 302 satisfies one or more criteria. The one or more criteria may include, but are not limited to, a second threshold temperature (e.g., the recovery threshold temperature) or threshold period of time for tissue temperature to modulate from the first threshold temperature to the second threshold temperature. In some examples, system 100 determines the threshold period of time based at least in part on a pre-determined time-temperature curve. The time-temperature curve may correlate duration of modulation of the tissue temperature to changes in tissue temperature (e.g., relative to the first threshold temperature). System 100 may store a plurality of different time-temperature curves and may apply different temperature profiles based on parameters of neuromodulation therapy 310 (e.g., type of neuromodulation therapy 310, first threshold temperature) and/or type of tissue temperature modulation (e.g., passive modulation, active modulation) to determine the threshold period of time. Different time-temperature curves may correspond to different types of tissue temperature modulation. System 100 may, in response to determining that one or more criteria have been satisfied, cause electrodes 202 to begin delivery of neuromodulation therapy 310 (e.g., a second pulse of neuromodulation therapy 310, a second neuromodulation therapy 310) to tissue at the target tissue site. Each of neuromodulation therapy 310 may be of a same or a different type of energy or may define same or different neuromodulation therapy parameter values as another of neuromodulation therapy 310.
[0082] In some examples, during recovery periods, system 100 actively modulates the tissue temperature of at the target tissue site. In some examples, system 100 places temperature modulating element 112 (e.g., disposed on distal portion 108A, therapy delivery element 110, or on another catheter disposed within blood vessel lumen 306) in apposition with the vessel wall and actively modulate (e.g., via an element not native to the body of the patient) the tissue of the temperature. In some examples, temperature modulating element 112 includes an expandable member (e.g., an expandable balloon) containing a temperature modulating fluid. In some examples, temperature modulating element 112 introduces a temperature modulating fluid into blood vessel lumen 306, e.g., as described in commonly owned U.S. Patent Application No. 15/959,043 (now issued as U.S. Patent No. 11,478,298) filed on April 20, 2018 and entitled “Controlled irrigation for neuromodulation systems and associated methods.” In some examples, system 100 simultaneously passively and actively modulates the temperature of the tissue towards the initial temperature during recovery periods.
[0083] Tissue closer to vessel wall 302 may experience the change in temperature at a faster rate than tissue further away from vessel wall 302 due to the relative proximity to blood vessel lumen 306. As a result, repeated cycles of the delivery of neuromodulation therapies 310 and the modulation of the temperature of the tissue during recovery periods may cause the tissue to define a relatively even temperature profile along reference axis 312.
[0084] FIG. 3B is a conceptual diagram illustrating another example of distal portion 108A of elongated member 108 of catheter 102 of FIG. 1 positioned within blood vessel 300. As illustrated in FIG. 3B, distal portion 108A includes an expandable member 314 configured to transition between a collapsed delivery state and an expanded state. When expandable member 314 is in the expanded state, an outer surface of expandable member 314 is place in apposition with the inner surface of vessel wall 302. In the expanded state, expandable member 314 may partially or entirely occlude blood vessel lumen 306. One or more sensors may be disposed on an outer surface of expandable member 314 or coupled to expandable member 314 and may sense signals corresponding to parameters of the tissue (e.g., tissue impedance, tissue temperature) along reference axis 312 when expandable member 314 is in the expanded state.
[0085] Therapy delivery element 110 may be disposed within an inner volume of expandable member 314 and may deliver neuromodulation energy 310 through expandable member 314 and into tissue adjacent to vessel wall 302 along reference axis 312. In such examples, therapy delivery element 110 may include, but is not limited to, ultrasound transducer(s) or a therapeutic fluid. Neuromodulation therapy 310 may include ultrasound energy (e.g., from ultrasound transducer(s)), thermal energy, or cryogenic energy (e.g., from the therapeutic fluid). Distal portion 108A may extend along longitudinal axis 105 within the inner volume of expandable member 314 to distal end 308. Therapy delivery elements 110 (e.g., ultrasound transducers) may be disposed on or connected to a portion of distal portion 108 A within the inner volume of expandable member 314.
[0086] In the example illustrated in FIG. 3B, system 100 may expand expandable member 314 into the expanded configuration via introduction of a fluid into the inner volume of expandable member 314. The fluid may be a therapeutic fluid and may be configured to transmit thermal energy or cryogenic energy to the tissue. In some examples, the fluid includes a cooling fluid configured to maintain a temperature of therapy delivery elements 110 disposed within the inner volume of expandable member 314, e.g., to prevent overheating of therapy delivery elements (e.g., ultrasound transducer(s)).
[0087] During each recovery period between temporally adjacent deliveries of neuromodulation therapy 310, system 100 may introduce a temperature modulating fluid into the inner volume of expandable member 314 to modulate (e.g., to actively modulate) the temperature of tissue adjacent blood vessel 300. In some examples, where therapy delivery element 110 includes a therapeutic fluid disposed within the inner volume of expandable member 314, system 100 removes the therapeutic fluid and introduce the temperature modulating fluid into the inner volume. In some examples, the therapeutic fluid is a heating fluid and the temperature modulating fluid may be a cooling fluid. In another example, the therapeutic fluid may be a cooling fluid (e.g., a cryogenic fluid) and the temperature modulating fluid may be a heating fluid. During each recovery period, expandable member 314 may be expanded to entirely occlude blood vessel lumen 306 or may be partially expanded to partially occlude blood vessel lumen 306, e.g., to neuromodulate the temperature of tissue without blocking blood flow within blood vessel lumen 306.
[0088] FIG. 4A is a graph 402 illustrating an example tissue temperature profile 408 of tissue of a patient at a target tissue site in response to pre-therapy modulation of the tissue temperature. Graph 402 illustrates temperature 406 of tissue at different distances 404 from a blood vessel (e.g., blood vessel 300 of FIGS. 3A and 3B). Distances 404 may be measured from an inner surface of a vessel wall (e.g., vessel wall 302) of the blood vessel and along reference axis 312.
[0089] As illustrated in graph 402, prior to any delivery of neuromodulation therapy and/or any modulation of temperature 406 of tissue, the tissue at a target tissue site exhibits an initial tissue temperature 408. Initial tissue temperature 408 may be uniform at different distances 404 or may vary based on distance 404. Initial tissue temperature 408 may be about an internal body temperature of the patient (e.g., about 37 degrees Celsius (°C) or about 98.6 degrees Fahrenheit (°F).
[0090] System 100 may actively modulate temperature 406 of tissue prior to delivery of a first neuromodulation therapy to the tissue. System 100 may actively modulate temperature 406 of the tissue up to a depth of at least a distance DI from blood vessel 300. Distance DI may be up to about 8 millimeters (mm). In some examples, distance DI may be up to about 2 mm. Modulation of temperature 406 of tissue may increase or decrease (e.g., as illustrated in FIG. 4A) temperature 406 of tissue relative to initial tissue temperature 408. System 100 may modulate temperature 406 of the tissue via one or more of the active modulation techniques described herein. For example, system 100 may place temperature modulating element 112 such as a cooling element, a heating element, or an expandable member (e.g., expandable member 314) containing a temperature modulating element in apposition with the inner surface of vessel wall 302.
[0091] In some examples, system 100 may continue to sense (e.g., via electrodes 202, via sensor(s) coupled to control device 106) temperature 406 of the tissue at vessel wall 302 and/or at one or more distances 404 from vessel wall 302. System 100 may continue to modulate temperature 406 of tissue over time 409 until a temperature profile 410 of the tissue satisfies a threshold temperature T(0). T(0) may correspond to a threshold starting temperature for the tissue prior to delivery of a first neuromodulation therapy. Threshold temperature T(0) may be entered into system 100 by a clinician and may be based on the location of blood vessel 300 within vasculature of the patient, types of tissue surrounding blood vessel 300, and/or a distance between a target nerve (e.g., target nerve 304) and vessel wall 302.
[0092] In some examples, system 100 may modulate temperature 406 of the tissue at or adjacent to vessel wall 302 for at least a threshold period of time. The threshold period may be at least about 10 seconds (e.g., may be at least about 30 seconds). In some examples, the clinician may determine, based on threshold temperature T(0) and a modulation rate of temperature modulation element 112, the threshold period of time. In such examples, when system 100 modulates temperature 406 of tissue for up to the threshold period of time, temperature 406 of temperature profile 410 does not satisfy threshold temperature T(0).
[0093] FIG. 4B is a graph 412 illustrating an example tissue temperature profile 414 of tissue of a patient at a target tissue site during delivery of a first neuromodulation therapy (e.g., a first pulse of neuromodulation therapy, a first neuromodulation therapy) to the patient. Graph 412 illustrated temperature 406 of tissue at different distances 404 from a blood vessel (e.g., blood vessel 300 of FIGS. 3A and 3B).
[0094] In some examples, as illustrated in graph 412, temperature 406 of tissue at vessel wall 302 may be less than a maximum temperature along temperature profile 414, e.g., due to temperature modulating effects of blood flow within blood vessel 300. In other examples, therapy delivery element 110 fully occludes tissue at vessel wall 302, and temperature 406 of tissue at vessel wall 302 may define a maximum temperature along temperature profile 414.
[0095] As illustrated in graph 412, temperatures 406 of tissue at distances 404 closer to the blood vessel may be higher than other tissue at distances 404 further away from blood vessel 300 in a same amount of time 416 (i.e., tissue closer to blood vessel 300 may experience an increase in temperature 406 at a faster rate than tissue further away from blood vessel 300). The resulting temperature profile 414 resulting from the first neuromodulation therapy may exhibit disparities in temperature 406 of tissue at different distances 404 from vessel wall 302. For example, tissue at a distance DI from blood vessel 300 may exhibit a higher temperature 406 than tissue at a distance D2 from blood vessel 300. System 100 may deliver the first neuromodulation therapy to the tissue until tissue at distance DI satisfies a threshold temperature T1 (alternatively referred to as “therapy threshold temperature Tl”). Therapy threshold temperature T1 may be greater than or equal to 50°C (e.g., greater than or equal to 60°C, greater than or equal to 70°C). For example, for each neuromodulation therapy, system 100 delivers the therapy until temperature 406 of the tissue at a corresponding distance DI from blood vessel 300 satisfies a corresponding therapy threshold temperature Tl for the delivered therapy. Once system 100 determines that temperature 406 of tissue at distance DI from blood vessel 300 satisfies (i.e., is greater than or equal to) therapy threshold temperature Tl, system 100 may terminate delivery of the neuromodulation therapy and begin modulation of temperature 406 (e.g., via passive or active modulation) towards an initial temperature of the tissue. In the example illustrated in graph 412, modulation of temperature 406 may cause a decrease in temperature 406 away from therapy threshold temperature Tl.
[0096] In some examples, system 100 delivers the first neuromodulation therapy to the tissue when the tissue is at initial tissue temperature 408. In some examples, as illustrated in FIG. 4B, system 100 delivers the first neuromodulation therapy to the tissue when the tissue exhibits tissue temperature profile 410. The temperature disparities in temperature profile 410 are in an opposite direction as the disparities in temperature profile 414. For example, disparities in temperature profile 410 indicate lowered temperatures relative to initial tissue temperature 408 and disparities in temperature profile 414 indicate increased temperatures relative to initial tissue temperature 408. When system 100 delivers neuromodulation therapy to the tissue when the tissue starts at temperature profile 410, the opposing disparities in temperature profile 410 may reduce a magnitude of disparities of portions of temperature profile 414 relative to a temperature profile 414 resulting from delivery of the first neuromodulation therapy to the tissue when tissue begins at initial tissue temperature 408. The reduction in magnitude of disparities may result in a relatively more event temperature profile 414 and/or may reduce a number or duration of neuromodulation therapies delivered to the patient to achieve a target tissue temperature profile and/or target efficacy.
[0097] FIG. 4C is a graph 418 illustrating example tissue temperature profiles 420 A- D (collectively referred to herein as tissue temperature profiles 420”) of the tissue of the patient during modulation of tissue temperature profile 414 of FIG. 4B. As illustrated in FIG. 4C, modulation of temperature 406 over tissue over time 422 causes tissue temperature profile 414 to change (e.g., decrease) towards an initial tissue temperature (e.g., initial tissue temperature profile 408 as illustrated in FIG. 4A) over time 422. Modulation of the temperature 406 may cause tissue closer to blood vessel 300 (e.g., at distance DI from blood vessel 300) to cool at a faster rate than tissue further away from blood vessel 300 (e.g., at distance D2 from blood vessel 300). As a result, modulation of the tissue may increase the evenness of temperature profiles 420 over time 422 (i.e., reduce a magnitude of disparity between a highest temperature value and a lowest temperature value along each of temperature profiles 420). As illustrated in FIG. 4C, as temperature profiles 420 change over time 422 (i.e., from temperature profile 420A to temperature profile 420D), temperature profiles 420 may increasingly define a plateau (i.e., a region along temperature profiles 420 with relatively little change in temperature 406 as distance 404 increases).
[0098] System 100 may actively or passively modulate temperature 406 of tissue to cause the changes in temperature profiles over time 422. System 100 may continue to sense temperatures 406 of tissue (e.g., at varying distances from blood vessel 300 during modulation of the tissue). In some examples, system 100 may determine a total duration of the modulation of temperature 406 over time 422. System 100 may determine that temperature 406 of tissue at one or more distances from blood vessel 300 satisfies a threshold temperature T2 (also referred to as “recovery threshold temperature T2”), i.e., that temperature 406 of tissue at the one or more distances is less than or equals to recovery threshold temperature T2. Recovery threshold temperature T2 may be the same as or different from (e.g., higher than, lower than) threshold temperature T(0). The one or more distances may be DI, D2, or any other distance from blood vessel 300. For example, system 100 may compare temperature 406 of tissue at one or more locations to therapy threshold temperature T1 (e.g., as illustrated in graph 412) and may compare temperature 406 of tissue at different locations to recovery threshold temperature T2.
[0099] Recovery threshold temperature T2 may be between therapy threshold temperature T1 of a preceding therapy of neuromodulation therapy and initial tissue temperature 408 of the tissue. For example, if therapy threshold temperature T1 is less than initial tissue temperature 408, recovery threshold temperature T2 may be greater than therapy threshold temperature T1 and less than or equals to initial tissue temperature 408. In another example, if therapy threshold temperature T1 is greater than initial tissue temperature 408, recovery threshold temperature T2 may be less than therapy threshold temperature T1 and greater than or equals to initial tissue temperature 408.
[0100] In response to determining that temperature 406 of the tissue at the one or more distances satisfies recovery threshold temperature T2, system 100 may terminate the recovery period and modulation of the tissue temperature. System 100 may then begin delivery of neuromodulation therapy (e.g., another pulse of neuromodulation therapy, another neuromodulation therapy). Due to system 100 being configured to terminate each recovery period based on a comparison between temperature 406 of tissue and recover threshold temperature T2, each recovery period may have a different duration than every other recovery period or each of a plurality of neuromodulation therapies delivered to the tissue of the patient.
[0101] In some examples, instead of or in addition to determining whether temperature 406 satisfies recovery threshold temperature T2, system 100 may terminate the recovery period based on a determination that a duration of time 422 satisfies (e.g., is greater than or equal to) a threshold period of time corresponding to recovery threshold temperature T2. System 100 may determine the threshold period of time based on therapy threshold temperature Tl, recovery threshold temperature T2, and a time-temperature curve for the tissue. The time-temperature curve may illustrate a correlation between a duration of time 422 and a temperature difference between temperature 406 and therapy threshold temperature Tl. System 100 may store a plurality of time-temperature curves, e.g., in memory 216. Each time-temperature curves may correspond to different therapy threshold temperatures Tl and/or to different modulation modalities. For example, system 100 may store, for a same neuromodulation therapy and a same therapy threshold temperature Tl, different time-temperature curves for passive modulation (e.g., temperature modulation via blood flow) and/or for different types of active modulation (e.g., temperature modulation via a heating element, via a cooling element, via a temperature modulating fluid disposed within blood vessel 300, or via a temperature modulation fluid disposed within expandable member 314). System 100 may determine the threshold amount of time for tissue temperature to transition from therapy threshold temperature Tl to recovery threshold temperature T2 and terminate the recovery period based on a determination that duration of time 422 satisfies the threshold period of time.
[0102] FIG. 4D is a graph 424 illustrating example tissue temperature profiles 426A- D (collectively referred to as “tissue temperature profiles 426”) of the tissue of the patient during delivery of a second neuromodulation therapy (e.g., a second pulse of neuromodulation therapy 310, a second neuromodulation therapy 310) to the tissue of the patient after the modulation of tissue temperature profiles 420 of FIG. 4C. At the start of the second neuromodulation therapy, temperature 406 of tissue at varying distances 404 from blood vessel 300 may define temperature profile 420D. Temperature profile 420D may correspond to a final temperature profile of a temporally preceding recovery period (e.g., the recovery period illustrated in graph 418 of FIG. 4C).
[0103] The second neuromodulation therapy may define different therapy parameters than a temporally preceding neuromodulation therapy (e.g., the first neuromodulation therapy illustrated in graph 412 of FIG. 4B). For example, the second neuromodulation therapy may define different therapy types, therapy amplitudes, therapy frequencies, therapy duration, therapy delivery location, pulse threshold temperature Tl, distance DI, or the like. Due to system 100 beginning and ending delivery of each neuromodulation therapy due to a comparison of temperature 406 of specific tissue to a corresponding pulse threshold temperature Tl, the therapy period of each neuromodulation therapy may have a different duration.
[0104] As system 100 delivers the second neuromodulation therapy over time 427, temperature profiles 426 of the tissue changes (e.g., increases, as illustrated in graph 424, decreases) towards therapy threshold temperature Tl for the second neuromodulation therapy. System 100 may sense temperature 406 of tissue at one or more distances 404 away from blood vessel 300 during delivery of the second neuromodulation therapy and compare the sensed temperature 406 against therapy threshold temperature Tl. In response to determining that temperature 406 of tissue at the one or more distances 404 (e.g., at distance DI) satisfies therapy threshold temperature Tl, system 100 may terminate delivery of the second neuromodulation therapy. System 100 may then begin the next recovery period and modulation of temperature 406 of tissue.
[0105] Compared to temperature profile 414, final temperature profile 426D for the second neuromodulation therapy may define a relatively more even temperature profile. For example, final temperature profile 426D may define a relatively larger plateau region (e.g., around distance DI) than temperature profile 414.
[0106] FIG. 4E is a graph 428 illustrating example tissue temperature profiles 430A-N (collectively referred to as “tissue temperature profiles 420”) of the tissue of the patient over time 431. Each of tissue temperature profiles 430 may correspond to a final temperature profile sensed by system 100 during delivery of each neuromodulation therapy. As illustrated in FIG. 4D, due to cycles of modulation of temperature 406 during recovery periods between deliveries of temporally adjacent neuromodulation therapies, tissue temperature profiles 430 define relatively more even profiles over time 431 (e.g., define plateaus over longer distances 404 over time 431).
[0107] System 100 may continue to alternate between deliveries of neuromodulation therapies and modulation of temperature 406 during recovery periods until a final temperature profile 430N satisfies a threshold temperature profile. System 100 may terminate the delivery of neuromodulation therapy to the tissue of the patient in response to determining that final temperature profile 430N satisfies the threshold temperature profile. In some examples, system 100 may terminate delivery of neuromodulation therapy based on a determination that temperature 406 of target tissue has exceeded therapy threshold temperature T1 (e.g., for neuromodulation therapies configured to increase tissue temperature) or is below the therapy threshold temperature (e.g., for neuromodulation therapies configured to decrease tissue temperature) for at least a threshold of time.
System 100 may further notify the clinician, e.g., via UI 212 of control device 106, that the neuromodulation therapy is complete.
[0108] System 100 may determine that final temperature profile 430N satisfies the threshold temperature profile based on a determination that a plateau 432 defined by final temperature profile 430N extends along a threshold distance (e.g., from distance DI to distance D2). Plateau 432 may encompass a target nerve (e.g., renal nerve 304). In some examples, renal nerve 304 is disposed at a distance D2 from blood vessel 300.
Temperature 406 at various distances 404 along plateau 432 may be less than or equals to a maximum therapy threshold temperature across the plurality of neuromodulation therapies. In some examples, system 100 determines that final temperature profile 430N satisfies the threshold temperature profile by determining that final temperature profile 430N matches the threshold temperature profile by a threshold percentage (e.g., 70%, 75%, 80%, 90%). In some examples, system 100 determines that final temperature profile 430N satisfies the threshold temperature profile by determining that temperature 406 of the target nerve satisfies a target temperature while temperature 406 of other tissue at one or more distances (e.g., distance DI, distance D2) from blood vessel 300 do not satisfy a maximum therapy threshold temperature for the plurality of therapies, or therapy threshold temperature T1 for a currently delivered therapy.
[0109] In some examples, system 100 iteratively adjusts one or more parameters of neuromodulation therapies or recovery periods over time 431, e.g., based on sensed temperature 406 during therapy periods of prior delivery therapies or during prior recovery periods. The iterative adjustment of the parameter(s) may further increase the evenness of temperature profiles 430 or reduce an amount of time required to achieve final temperature profile 430N. For example, system 100 may iteratively increase recovery threshold temperatures D2 of recovery periods over time 431.
[0110] In some examples, as illustrated in FIGS. 4A-4E, temperature profiles (e.g., temperature profiles 410, 414, 420, 426, 430) include localized differences in temperature 406 (e.g., a local increase in temperature 406, a local decrease in temperature 406) at varying distances 404, e.g., due to tissue characteristics of different tissues (e.g., muscle tissue, fat tissue, blood vessels, nerves). In some examples, the temperature profiles define a continuous curve from blood vessel 300 to tissue at a furthest distance 404.
[0111] While FIGS. 4A-4E illustrate tissue temperature profiles resulting from heating of the tissue via neuromodulation therapies and cooling of the tissue via tissue modulation during recovery periods, system 100 may make similar determinations with respect to cooling of the tissue via neuromodulation therapies and heating of the tissue via tissue modulation during recovery periods.
[0112] FIG. 4F is a graph 442 illustrating another example tissue temperature profile of the tissue 444 of the tissue of the patient at the target tissue site in response to pretherapy temperature neuromodulation. System 100 may modulate temperature 406 of the tissue prior to delivery of a first neuromodulation therapy over time 446 to cause the temperature profile of the tissue to transition from initial tissue temperature 408 to temperature profile 444. As illustrated in FIG. 4F, temperature profile 444 exhibit disparities in temperature 406 of tissue at various distances 404 relative to initial tissue temperature 408. The disparities in temperature 406 may be higher in temperature 406 than initial tissue temperature 408. System 100 may modulate temperature 406 of tissue until a maximum temperature of temperature profile 444 satisfies a threshold temperature (e.g., threshold temperature T3) and/or for a threshold period of time (e.g., up to 10 seconds, up to 30 seconds, at least 10 seconds, at least 30 seconds). Threshold temperature T3 may be equal to or different from threshold temperature Tl, e.g., as illustrated in FIGS. 4B-4E. System 100 may continue to sense, (e.g., via electrodes 202 or sensor(s) coupled to control device 106) temperature 406 of tissue at vessel wall 302 and/or at one or more distances 404 from vessel wall 302 and terminate modulation of the tissue based on a determination that a maximum temperature of temperature profile 444 satisfies threshold temperature T3.
[0113] FIG. 4G is a graph 442 illustrating another example tissue temperature profile 448 of the tissue of the patient at the target tissue site during delivery of the first neuromodulation therapy to the patient. In the example illustrated in FIG. 4G, the first neuromodulation therapy may be configured to lower temperature 406 of tissue (e.g., may be a cryogenic energy therapy). The first neuromodulation therapy may reduce temperature 406 from initial tissue temperature 408 or from temperature profile 444 in a similar manner as previously described herein with respect to FIG. 4B, albeit in an opposite direction relative to initial tissue temperature 408. In some examples, where system 100 begins delivery of the first neuromodulation therapy when tissue is at temperature profile 444, the disparities in temperature profile 444 (e.g., increased temperatures relative to initial tissue temperature 408) may reduce the magnitude of disparities within temperature profile 448 and/or increase the evenness of temperature profile 448.
[0114] The first neuromodulation therapy may alter temperature 406 of tissue over time 449. Time 449 may be of a same duration or of a different duration than the duration of any other neuromodulation therapies described herein. System 100 may deliver the first neuromodulation therapy until system 100 determines that a minimum temperature of temperature profile 448 satisfies a threshold temperature T1 (also referred to as “therapy threshold temperature T4”). Therapy threshold temperature T4 may greater than or equal to about -70°C (e.g., greater than or equal to about 60°C, greater than or equal to about - 50°C).
[0115] FIG. 4H is a graph 450 illustrating another example tissue temperature profile of the tissue of the patient over time 454. System 100 may alternate between cooling the tissue (e.g., via pulses of neuromodulation therapy or separate neuromodulation therapies) (e.g., as illustrated in FIG. 4G) and heating the tissue (e.g., via tissue temperature modulation during recovery periods) to cause the tissue to develop more even temperature profiles 452A-N (also referred to herein as “temperature profiles 452”) over time 454. Temperature profiles 452 may become more even over time (e.g., temperature profiles 452 with increasing plateaus) along distance 404. System 100 may terminate all neuromodulation therapy in response to determining that tissue temperature profile 452N along distance 404 satisfies a threshold temperature profile, e.g., as previously described above. The delivery of neuromodulation therapy and modulation of tissue of the patient illustrated in FIGS. 4F-4H may be substantially similar to the techniques described in FIGS. 4A-4E to deliver cooling neuromodulation therapies to the tissue at the target tissue site, e.g., as compared to the heating neuromodulation therapies illustrated in FIGS. 4A- 4E.
[0116] FIG. 5 is a flow diagram illustrating an example process of delivery neuromodulation therapy to a target tissue site of a patient. While FIG. 5 is primarily described with reference to delivery of neuromodulation therapy by catheter 102 of FIG. 1 to a target tissue site within a renal vessel of the patient, the example process described herein may be applied by another example medical device or to target tissue site within another body lumen, as described herein.
[0117] A medical device system (e.g., system 100) may deliver a first neuromodulation therapy to tissue adjacent a blood vessel wall (e.g., vessel wall 302 of blood vessel 300) (502). The clinician may advance a distal portion (e.g., distal portion 108A) of an elongated member (e.g., elongated member 108) of a catheter (e.g., catheter 102) from an incision site to blood vessel 300 through vasculature of the patient. In some examples, the clinician advances a guide member (e.g., a guidewire, a guide sheath) to the target tissue site and advance distal portion 108A of elongated member 108 of catheter 102 along the guide member to the target tissue site.
[0118] Once the clinician determines that distal portion 108A is at the target tissue site (e.g., via one or more imaging techniques such as fluoroscopy), the clinician may align a therapy delivery element (e.g., therapy delivery element 110) disposed on distal portion 108 A with the target treatment site and place therapy delivery element 110 in contact with an inner surface of vessel wall 302. In some examples, as illustrated in FIG. 3A, the clinician causes therapy delivery element 110 to radially expand away from longitudinal axis 105 of elongated member 108 and place one or more electrodes (e.g., electrodes 202) disposed along therapy delivery element 110 in apposition with the inner surface of vessel wall 302. In such examples, each of electrodes 202 may be configured to deliver RF energy, microwave energy, or thermal energy to tissue adjacent to blood vessel 300. In some examples, as illustrated in FIG. 3B, the clinician causes an expandable member (e.g., expandable member 314) disposed on distal portion 108A to radially expand away from longitudinal axis 105 and place an outer surface of expandable member 314 in apposition with the inner surface of vessel wall 302. In such examples, therapy delivery element 110 may include ultrasound transducer(s) or therapeutic fluids disposed within an inner volume of expandable member 314 and may be configured to deliver ultrasound energy, thermal energy, or cryogenic energy to the tissue adjacent to blood vessel 300.
[0119] Once the clinician determines that the therapy delivery elements 110 are placed in contact with the inner wall of vessel wall 302 at the target tissue site, the clinician may operate system 100 to cause therapy delivery element 110 to deliver the first neuromodulation therapy through the tissue adjacent to blood vessel 300 and to a target nerve at the target tissue site (e.g., renal nerve 304) during a corresponding therapy period (e.g., a first therapy period). Therapy delivery element 110 may deliver the neuromodulation therapy up to 360 degrees around the circumference of blood vessel 300. In some examples, therapy delivery element 110 transmits the neuromodulation therapy along an axis (e.g., along reference axis 312) extending radially away from blood vessel 300 and intersecting blood vessel 300 and renal nerve 304. Neuromodulation therapy may include energy including RF energy, microwave energy, ultrasound energy, thermal energy, or cryogenic energy. The first neuromodulation therapy may be defined by one or more therapy parameters including therapy amplitude, therapy frequency, therapy duration (e.g., a duration of the first therapy period), or pulse threshold temperature T1 for the pulse.
[0120] In some examples, system 100 may modulate the temperature of tissue at vessel wall 302 (e.g., along inner surface of vessel wall 302) prior to delivery of the first neuromodulation therapy or of any neuromodulation therapy. System 100 may actively modulate temperature 406 of the tissue by placing temperature modulating element 112 in apposition with the inner surface of vessel wall 302. Modulation of tissue may cause the tissue temperature to deviate away from initial tissue temperature 408, e.g., in an opposite direction from the first neuromodulation therapy. For example, if the first neuromodulation therapy is configured to increase tissue temperature, pre-therapy modulation of tissue may decrease tissue temperature, and vice versa. Pre-therapy modulation of the tissue temperature may cause the first neuromodulation therapy to form a more even temperature profile and may reduce a number and/or duration of neuromodulation therapies to achieve a threshold efficacy and/or a threshold temperature profile).
[0121] System 100 may terminate delivery of the first neuromodulation therapy in response to determining that a sensed temperature (e.g., temperature 406) of the tissue satisfies a first threshold temperature (504). The first threshold temperature may correspond to therapy threshold temperature T1 for the first neuromodulation therapy. System 100 may sense signals corresponding to parameters of the tissue (e.g., impedance, temperature 406) at varying distances 404 from blood vessel 300 (e.g., from an inner surface of vessel wall 302 of blood vessel 300) during delivery of the first neuromodulation therapy, e.g., during the first therapy period. System 100 may sense the signals from the tissue via therapy delivery element 110 (e.g., via one or more of electrodes 202 on therapy delivery element 110) or via one or more sensors disposed on therapy delivery element 110 or otherwise placed in apposition with vessel wall 302. System 100 may compare sensed temperatures 406 of the tissue (e.g., at a distance DI from blood vessel 300) against a therapy threshold temperature (e.g., therapy threshold temperature T1 or T3). Distance DI may correspond to tissue defining temperature 406 having a maximum deviation from an initial tissue temperature (e.g., tissue defining a highest temperature 406, tissue defining a lowest temperature 406). Distance DI may be predetermined or may be determined by system 100 based on the sensed parameters.
[0122] In response to determining that temperature 406 satisfies the therapy threshold temperature, system 100 may terminate the delivery of the first neuromodulation therapy. In some examples, where the first neuromodulation therapy increases temperature 406 of the tissue, system 100 determines that temperature 406 satisfies therapy threshold temperature T1 by determining that temperature 406 is greater than or equals to therapy threshold temperature Tl. In some examples, where the first neuromodulation therapy decreases temperature 406 of the tissue, system 100 determines that temperature 406 satisfies therapy threshold temperature T3 by determining that temperature 406 is less than or equals to therapy threshold temperature T3.
[0123] System 100 may modulate temperature 406 of the tissue towards an initial tissue temperature (506). System 100 may enter a recover period and modulate temperature 406 during the recovery period. System 100 may actively or passively modulate temperature 406 of the tissue. System 100 may passively modulate temperature 406 by at least powering off therapy delivery element 110 or otherwise terminate the delivery of the first neuromodulation therapy. Blood flow through blood vessel lumen 306 of blood vessel may heat or cool tissue adjacent to blood vessel 300, e.g., via convection. [0124] System 100 may actively modulate temperature 406 of the tissue by placing temperature modulating element 112 in apposition with the inner surface of vessel wall 302. In some examples, system 100 expands an expandable member (e.g., an expandable balloon) and introduce a temperature modulating fluid into the expandable member to modulate temperature 406 of tissue. In some examples, where the first pulse of neuromodulation therapy increased temperature 406 of tissue, a cooling element or an expandable member containing a cooling temperature modulating fluid reduces temperature 406 of the tissue towards an initial temperature of the tissue. In some examples, where the first pulse of neuromodulation therapy decreases temperature 406 of tissue, a heating element or an expandable member containing a heating temperature modulating fluid increases temperature 406 of the tissue towards the initial temperature of the tissue. The initial temperature of the tissue may correspond to a temperature of the tissue prior to the delivery of any neuromodulation therapy to the tissue.
[0125] In some examples, expandable member 314 is configured to retain both the therapeutic fluid and the temperature modulating fluid. In such examples, system 100 may modulate temperature 406 of the tissue by removing the therapeutic fluid from the inner volume of expandable member 314 and introducing the temperature modulating fluid into the inner volume. The therapeutic fluid and the temperature modulating fluid may be a same type of fluid or may be of different types of fluids.
[0126] System 100 may terminate modulation of temperature 406 of the tissue and deliver a second neuromodulation therapy to the tissue in response to determining that the sensed temperature 406 of the tissue satisfies a second threshold temperature (508). The second threshold temperature may correspond to a (e.g., recovery threshold temperature T2) for the recovery period. During modulation of temperature 406, system 100 may continue to sense signals from the tissue at varying distances 404 (e.g., at distance DI, at another distance D2) from blood vessel 300. System 100 may compare temperature 406 of the tissue at one or more distances 404 from blood vessel 300 (e.g., at distance DI, at distance D2). Distance D2 may correspond to a distance of renal nerve 304 from blood vessel 300. [0127] System 100 may compare sensed temperatures 406 at the one or more distances to the recovery threshold temperature and cause therapy delivery element 110 to deliver a second neuromodulation therapy based on a determination that sensed temperatures 406 satisfy the recovery threshold temperature. The recovery threshold temperature may be between a therapy threshold temperature of the first neuromodulation therapy and the initial tissue temperature 408. In some examples recovery threshold temperature is equal to the initial temperature.
[0128] System 100 may select the second neuromodulation therapy from a plurality of neuromodulation therapies or select therapy parameters for the second neuromodulation therapy based on predetermined instructions or based on sensed temperatures 406. The therapy parameters for the second neuromodulation therapy may be the same as or may be different from the therapy parameters for the first neuromodulation therapy. For example, the first neuromodulation therapy and the second neuromodulation therapy may define the same or different therapy threshold temperatures.
[0129] System 100 may terminate the delivery of the second neuromodulation therapy and modulate temperature 406 of the tissue during another recovery period in response to a determination that temperature 406 of the tissue (e.g., at distance DI) satisfies the therapy threshold temperature for the second neuromodulation therapy.
[0130] System 100 may iteratively deliver neuromodulation therapies and modulate temperature 406 of the tissue during recovery periods until the tissue reaches a desired temperature profile (510). System 100 may determine a temperature profile of the tissue (e.g., along reference axis 312) based on the sensed temperatures 406 of the tissue at varying distances 404. System 100 may determine that the temperature profile satisfy the desired temperature profile (e.g., a threshold temperature profile) by determining that the temperature profile defines a plateau (e.g., plateau 432) encompassing a threshold distance or encompassing renal nerve 304, by determining that the temperature profile matches the threshold temperature profile by a threshold percentage (e.g., an 80% match), or by determining that the temperature of renal nerve 304 satisfies a target temperature while temperatures 406 of the tissue do not satisfy one or more of the therapy threshold temperatures of the plurality of neuromodulation therapies.
[0131] In some examples, prior to the delivery of the first pulse of neuromodulation therapy, system 100 receives from the clinician, e.g., via UI 212 of control device 106 of system 100, a type of neuromodulation therapy, the location of the target treatment site, or a target location within the tissue at the target treatment site. Based on the clinician input, system 100 may determine a depth of the target location and may determine the threshold temperature profile based at least on the determined depth or the clinician input.
[0132] System 100 may adjust the parameters of neuromodulation therapies and recovery periods over time, e.g., based on prior sensed temperatures 406. For example, system 100 may alter therapy threshold temperatures and recovery threshold temperatures of upcoming neuromodulation therapies and upcoming recovery periods, e.g., based on sensed temperatures 406 during prior neuromodulation therapies and prior recovery periods.
[0133] By alternating between deliveries of neuromodulation therapy and modulations of tissue temperature 406 during recovery periods, system 100 may cause the tissue to develop an even temperature profile. Tissue closer to blood vessel 300 may change temperature 406 at faster rates, thereby resulting in an even temperature profile across a plurality of delivered neuromodulation therapies and recovery periods. The even temperature profile may define plateau 432 extending from blood vessel 300 to renal nerve 304. By developing an even temperature profile, system 100 may reduce a likelihood of an occurrence of an unintended effect on the tissue, e.g., due to the disparate rate of change of tissue temperature at varying distance 404. The even temperature profile may also increase efficacy of the neuromodulation therapy by allowing system 100 to cause renal nerve 304 to reach a target temperature without increase the risk of an unintended effect. The increased efficacy may reduce an amount of time required for the procedure or reduce a need for follow-up procedures.
[0134] FIG. 6 is a flow diagram illustrating another example process of delivering neuromodulation therapy to a target tissue site of a patient. While FIG. 6 is primarily described with reference to delivery of neuromodulation therapy by catheter 102 of FIG. 1 to a target tissue site within a renal vessel of the patient, the example process described herein may be applied by another example medical device or to target tissue site within another body lumen, as described herein.
[0135] System 100 may deliver a first neuromodulation therapy through blood vessel wall 302 to adjacent tissue (602). System 100 may place therapy delivery element 110 disposed on distal portion 108A of elongated member 108 of catheter 102 in apposition with an inner surface of vessel wall 302 of blood vessel 300 and cause therapy delivery element 110 to deliver the first neuromodulation therapy through vessel wall 302 to the adjacent tissue. In some examples, distal portion 108A, therapy delivery element 110, or an expandable member (e.g., expandable member 314) disposed on distal portion 108A radially expands away from longitudinal axis 105 of elongated member 108 to place therapy delivery element 110 in apposition with the inner surface of vessel wall 302. In some examples, therapy delivery element 110 is disposed around the inner surface such that neuromodulation therapy delivered by therapy delivery element 110 may affect tissue up to 360 degrees around blood vessel 300. In some examples, system 100 may modulate the tissue temperature of tissue along vessel wall 302 via temperature modulating element 112 prior to delivery of the first neuromodulation therapy, e.g., as previously described herein.
[0136] The first neuromodulation therapy may include energy configured to change a temperature 406 of the adjacent tissue. Therapy delivery element 110 may include electrodes, ultrasound transducer(s) direct heating elements, therapeutic fluids disposed within an expandable member, or the like. The adjacent tissue may transmit the neuromodulation therapy from the inner surface of vessel wall 302 to a target nerve (e.g., renal nerve 304). The energy may include RF energy, ultrasound energy, microwave energy, thermal energy, or cryogenic energy.
[0137] System 100 may sense tissue temperature 406 at one or more distances 404 from the blood vessel wall 302 (604). System 100 may sense temperature 406 via therapy delivery element 110 (e.g., via electrodes 202 of therapy delivery element 110), via one or more sensors disposed on distal portion 108A and placed in apposition with the inner surface of vessel wall 302, or one or more sensors disposed on another catheter of system 100 disposed within blood vessel lumen 306 of blood vessel 300. In some examples, system 100 directly senses temperature 406 from the adjacent tissue at different distances 404 from the inner surface of vessel wall 302. In some examples, system 100 senses other parameter values of the tissue (e.g., impedance of the tissue) at the different distances 404 and may determine the corresponding temperatures 406 of the tissue based on the sensed parameter values.
[0138] System 100 may determine whether the sensed temperature 406 satisfy a first threshold temperature (606). The sensed temperature 406 may correspond to temperature 406 of tissue at a first distance DI from the blood vessel 300. The tissue at distance DI may correspond to tissue having a highest temperature (e.g., when the first neuromodulation therapy is configured to increase temperature 406 of the tissue) or a lowest temperature (e.g., when the first neuromodulation therapy is configured to decrease temperature 406 of the tissue) of tissues at varying distances 404 from blood vessel 300. The first threshold temperature may correspond to therapy threshold temperature T1 for the first neuromodulation therapy. System 100 may determine therapy threshold temperature T1 for each delivered neuromodulation therapy based at least in part on the type of tissue adjacent to blood vessel 300, physiology of the patient, a type of neuromodulation therapy delivered to the patient, or a desired maximum treatment distance from blood vessel 300. System 100 may compare the sensed temperature 406 to the first threshold temperature continuously or periodically (e.g., once per several seconds or minutes).
[0139] In response to determining that the sensed temperature 406 does not satisfy the first threshold temperature (“NO” branch of 606), system 100 may continue to deliver the first neuromodulation therapy to the adjacent tissue (602). In response to determining that sensed temperature 406 satisfies the first threshold temperature (“YES” branch of 606), system 100 may determine whether a sensed temperature profile satisfies a threshold temperature profile (608).
[0140] System 100 may determine a temperature profile of the tissue along a reference axis (e.g., reference axis 312) based on the sensed temperatures 406 of tissues at varying distances 404 along reference axis 312. System 100 may determine whether threshold temperature profile is satisfied by determining whether the temperature profile defines a plateau encompassing renal nerve 304 or tissue at the desired treatment depth, whether the temperature profile matches the threshold temperature profile for a certain percentage, or whether renal nerve 304 or the tissue at the desired treatment depth achieves (e.g., exceeds) a target temperature for a threshold period of time.
[0141] In response to determining that the sensed temperature profile satisfies the threshold temperature profile (“YES” branch of 608), system 100 may complete therapy delivery (616). System 100 may notify the clinician, via UI 212 of control device 106, that system 100 has completed therapy delivery. [0142] In response to determining that the sensed temperature profile does not satisfy the threshold temperature profile (“NO” branch of 608), system 100 may terminate the delivery of the neuromodulation therapy (610) and modulate temperature 406 of the tissue towards an initial temperature (612). System 100 may modulate temperature 406 as a part of a recovery period following the delivery of the neuromodulation therapy. System 100 may passively or actively modulate temperature 406, e.g., as previously described herein. For example, system 100 may place temperature modulating element 112 (e.g., an expandable member of temperature modulating element 112 configured to retain a temperature modulating fluid) in apposition with vessel wall 302 to modulate temperature 406 of the tissue. In another example, system 100 may at least partially collapse therapy delivery element 110, distal portion 108A, or expandable member 314 radially towards longitudinal axis 105, e.g., to allow blood to flow across the inner surface of vessel wall 302 and modulate temperature 406 of the tissue, e.g., via convection.
[0143] During modulation of temperature 406 of the tissue, system 100 may continue to sense (e.g., via sensors or therapy delivery element 110) temperature 406 of the tissue at various distances 404 from blood vessel 300. System 100 may determine whether the sensed temperature satisfies a second threshold temperature (614). The second threshold temperature may correspond to recover threshold temperature T2 for a current recovery period. System 100 may compare temperature 406 of tissue at one or more distances 404 against the second threshold temperature continuously or periodically.
[0144] Based on a determination that the sensed temperature 406 does not satisfy the second threshold temperature (“NO” branch of 614), system 100 may continue to modulate temperature 406 of the tissue (612). Based on a determination that the sensed temperature 406 does satisfy the second threshold temperature (“YES” branch of 614), system 100 may deliver a subsequent neuromodulation therapy (e.g., a second neuromodulation therapy) (602). System 100 may continue to perform the process of steps 602-614 until system 100 determines that the sensed temperature profile satisfies the threshold temperature profile (“YES” branch of 608) and competes therapy delivery (616). [0145] FIG. 7 illustrates an example technique for accessing a renal artery and modulating renal nerves with the system of FIG. 1 in accordance with some examples of the present disclosure. While FIG. 7 illustrates the use of catheter 102 for renal neuromodulation, catheter 102 may be used for other therapies and treatments within another blood vessel or other hollow anatomical body within the human body. Catheter 102 is configured to delivery energy (e.g., RF energy, ultrasound energy, electrical stimulation energy, or the like) to one or more target tissue sites within a renal vessel. Catheter 102 provides access to the renal plexus (RP) through an intravascular path (P), such as a percutaneous access site in the femoral (illustrated), brachial, radial, or axillary artery to the target tissue sites within a respective renal artery (RA). By manipulating proximal portion 108B or elongated member 108 from outside the intravascular path (P), a clinician may advance at least distal portion 108A of elongated member 108 through the sometimes-tortuous intravascular path (P) and remotely manipulate distal portion 108A (FIG. 1) of elongated member 108. Distal portion 108A may be remotely manipulated by the clinician using the handle 104.
[0146] In the example illustrated in FIG. 7, distal portion 108A is delivered intravascularly to the treatment site using an inner member 136 in an over-the-wire (OTW) technique. Inner member 136 may be internal to catheter 102 (e.g., a guide wire, inner catheter, or the like) or external to catheter 102 (e.g., an outer sheath or the like). In some examples, inner member 136 is a navigation wire. Catheter 102 may define a passageway for receiving inner member 136 for delivery of catheter 102 using either an OTW or an RX technique. At the treatment site, inner member 136 can be at least partially withdrawn or removed relative to catheter 102 and distal portion 108A can transform into an expanded configuration (e.g., a helical configuration, a spiral configuration, or the like) for delivering ultrasound energy. In other examples, elongated member 108 may be selfsteerable such that therapy delivery element 110 may be delivered to the target tissue site without the aid of inner member 136.
[0147] Renal modulation is the partial or complete incapacitation or other effective disruption of nerves of the kidneys (e.g., nerves terminating in the kidneys or in structures closely associated with the kidneys). In particular, renal neuromodulation can include inhibiting, reducing, or blocking neural communication along neural fibers (e.g., efferent or afferent neural fibers) of the kidneys. Such incapacitation can be long-term (e.g., permanent or for a period of months, years, or decades) or short-term (e.g., for periods of minutes, hours, days, or weeks). Renal neuromodulation is expected to contribute to the systemic reduction of sympathetic tone or drive or benefit at least some specific organs or other bodily structures innervated by sympathetic nerves. Accordingly, renal neuromodulation is expected to be useful in treating clinical conditions associated with central sympathetic overstimulation. For example, renal neuromodulation is expected to efficaciously treat hypertension, heart failure, acute myocardial infarction, metabolic syndrome, insulin resistance, diabetes, left ventricular hypertrophy, chronic and end state renal disease, inappropriate fluid retention in heart failure, cardio-renal syndrome, polycystic kidney disease, polycystic ovary syndrome, osteoporosis, erectile dysfunction, and sudden death, among other conditions.
[0148] Renal neuromodulation can be electrically induced or induced in another suitable manner through the delivery of energy (RF energy, ultrasound energy, microwave energy, or the like). The target tissue site can be within or otherwise proximate to a renal lumen (e.g., a renal artery, a ureter, a renal pelvis, a major renal calyx, a minor renal calyx, or another suitable structure), and the target tissue site can include tissue at least proximate to a wall of the renal lumen. For example, with regard to a renal artery, a treatment procedure can include modulating nerves in the renal plexus, which lay intimately within or adjacent to the adventitia of the renal artery. The following discussion provides further details regarding patient anatomy and physiology as it may relate to renal denervation therapy. This section is intended to supplement and expand upon the previous discussion regarding the relevant anatomy and physiology, and to provide additional context regarding the disclosed technology and the therapeutic benefits associated with renal denervation. For example, several properties of the renal vasculature may inform the design of the target tissue devices and associated methods for achieving renal neuromodulation via intravascular access and impose specific design requirements for such devices. Specific design requirements may include accessing the renal artery, positioning distal portion 108A within the renal artery, delivering the therapy to targeted tissue, or effectively modulating the renal nerves with the therapy delivery device.
[0149] As noted previously, the sympathetic nervous system (SNS) is a branch of the autonomic nervous system along with the enteric nervous system and parasympathetic nervous system. It is always active at a basal level (called sympathetic tone) and becomes more active during times of stress. Like other parts of the nervous system, the sympathetic nervous system operated through a series of interconnected neurons. Sympathetic neurons are frequently considered part of the peripheral nervous system (PNS), although many lie within the central nervous system (CNS). Sympathetic neurons of the spinal cord (which is part of the CNS) communicate with peripheral sympathetic neurons via a series of sympathetic ganglia. Within the ganglia, spinal cord sympathetic neurons are therefore called presynaptic (or preganglionic) neurons, while peripheral sympathetic neurons are called postsynaptic (or postganglionic neurons).
[0150] At synapses within the sympathetic ganglia, preganglionic sympathetic neurons release acetylcholine, a chemical messenger that binds and activates nicotinic acetylcholine receptors on postganglionic neurons. In response to this stimulus, postganglionic neurons principally release noradrenaline (norepinephrine). Prolonged activation may elicit the release of adrenaline from the adrenal medulla.
[0151] Once released, norepinephrine and epinephrine bind adrenergic receptors on peripheral tissues. Binding to adrenergic receptors causes a neuronal and hormonal response. The physiologic manifestations include pupil dilation, increased heart rate, occasional vomiting, and increased blood pressure. Increased sweating is also seen due to binding of cholinergic receptors of the sweat glands.
[0152] The sympathetic nervous system is responsible for up- and down-regulating many homeostatic mechanisms in living organisms. Fibers from the SNS innervate tissues in almost every organ system, providing at least some regulatory function to physiological features as diverse as pupil diameter, gut motility, and urinary output. This response is also known as sympatho-adrenal response of the body, as the preganglionic sympathetic fibers that end in the adrenal medulla (but also all other sympathetic fibers) secrete acetylcholine, which activates the secretion of adrenaline (epinephrine) and to a lesser extent noradrenaline (norepinephrine). Therefore, this response that acts primarily on the cardiovascular system is mediated directly via impulses transmitted through the sympathetic nervous system and indirectly via catecholamines secreted from the adrenal medulla.
[0153] FIG. 8 is a conceptual illustration of an example sympathetic nervous system (SNS) illustrating how the brain communicated with the body via the SNS. As shown in FIG. 8, the SNS provides a network of nerves that allows the brain to communicate with the body. Sympathetic nerves originate inside the vertebral column, e.g., toward the middle of the spinal cord in the intermediolateral cell column (or lateral horn), beginning at the first thoracic segment of the spinal cord and are thought to extend to the second or third lumbar segments. Because SNS cells begin in the thoracic and lumbar regions of the spinal cord, the SNS is said to have a thoracolumbar outflow. Axons of sympathetic nerves leave the spinal cord through the anterior rootlet/root. The axons pass near the spinal (sensory) ganglion, where the axons enter the anterior rami of the spinal nerves. However, unlike somatic innervation, the axons separate out through white rami connectors which connect to either the paravertebral (which lie near the vertebral column) or prevertebral (which lie near the aortic bifurcation) ganglia extending alongside the spinal column.
[0154] To reach the target organs and glands, the axons should travel long distances in the body, and, to accomplish this, many axons relay their message to a second cell through synaptic transmission. The ends of the axons link across a space, the synapse, to the dendrites of the second cell. The first cell (the presynaptic cell) sends a neurotransmitter across the synaptic cleft where it activates the second cell (the postsynaptic cell). The message is then carried to the final destination.
[0155] In the SNS and other component of the peripheral nervous system, these synapses are made at sites called ganglia, discussed above. The cell that sends its fiber to the ganglion is called a preganglionic cell, while the cell whose fiber leaves the ganglion is called a postganglionic cell. As mentioned previously, the preganglionic cell of the SNS is located between the first thoracic (Tl) segment and third lumbar (L3) segments of the spinal cord. Postganglionic cells have their cell bodies in the ganglia and send their axons to target organs or glands.
[0156] The ganglia include not just the sympathetic trunks but also the cervical ganglia (superior, middle, and inferior), which send sympathetic nerve fibers to the head and thorax organs, and the celiac and mesenteric ganglia, which send sympathetic fibers to the gut.
[0157] FIG. 9 is an enlarged anatomic view of nerves innervating a left kidney to form the renal plexus surrounding the left renal artery. As FIG. 9 shows, the kidney is innervated by the renal plexus (RP), which is intimately associated with the renal artery. The renal plexus (RP) is an autonomic plexus that surrounds the renal artery and is embedded within the adventitia of the renal artery. The renal plexus (RP) extends along the renal artery and is embedded within the adventitia of the renal artery. Fibers contributing to the renal plexus (RP) arise from the celiac ganglion, the superior mesenteric ganglion, the aorticorenal ganglion and the aortic plexus. The renal plexus (RP), also referred to as the renal nerve, is predominantly comprised of sympathetic components. There is no (or at least very minimal) parasympathetic innervation of the kidney.
[0158] Preganglionic neuronal cell bodies are located in the intermediolateral cell column of the spinal cord. Preganglionic axons pass through the paravertebral ganglia to become the lesser splanchnic nerve, the least splanchnic nerve, the first lumbar splanchnic nerve, the second lumbar splanchnic nerve, and travel to the celiac ganglion, the superior mesenteric ganglion, and the aorticorenal ganglion. Postganglionic neuronal cell bodies exit the celiac ganglion, the superior mesenteric ganglion, and the aorticorenal ganglion to the renal plexus (RP) and are distributed to the renal vasculature.
[0159] Messages travel through the SNS in a bi-directional flow. Efferent messages may trigger changes in different parts of the body simultaneously. For example, the sympathetic nervous system may accelerate heart rate, widen bronchial passages, decrease motility (movement) of the large intestine, constrict blood vessels, increase peristalsis in the esophagus, cause pupil dilation, piloerection (goose bumps) and perspiration (sweating), or raise blood pressure. Afferent messages carry signals from various organs and sensory receptors in the body to other organs and, particularly, the brain.
[0160] Hypertension, heart failure, and chronic kidney disease are a few of the many disease states that result from chronic activation of the SNS, especially the renal sympathetic nervous system. Chronic activation of the SNS is a maladaptive response that drives the progression of theses disease states. Pharmaceutical management of the renin- angiotensin-aldosterone system (RAAS) has been a longstanding, but somewhat ineffective, approach for reducing over-activity of the SNS.
[0161] As mentioned above, the renal sympathetic nervous system has been identified as a major contributor to the complex pathophysiology of hypertension, states of volume overload (such as heart failure) and progressive renal disease, both experimentally and in humans. Studies employing radiotracer dilution methodology to measure overflow of norepinephrine from the kidneys to plasma revealed increased renal norepinephrine (NE) spillover rates in patients with essential hypertension, particularly so in young hypertensive subjects, which in concert with increased NE spillover from the heart, is consistent with the hemodynamic profile typically seen in early hypertension and characterized by an increased heart rate, cardiac output, and renovascular resistance. It is now known that essential hypertension is commonly neurogenic, often accompanied by pronounced sympathetic nervous system overactivity.
[0162] Activation of cardiorenal sympathetic nerve activity is even more pronounced in heart failure, as demonstrated by an exaggerated increase of NE overflow from the heart and the kidneys to plasma in this patient group. In line with this notion is the recent demonstration of a strong negative predictive value of renal sympathetic activation on allcause mortality and heart transplantation in patients with congestive heart failure, which is independent of overall sympathetic activity, glomerular filtration late, and left ventricular ejection fraction. These findings support the notion that treatment regimens that are designed to reduce renal sympathetic stimulation have the potential to improve survival in patients with heart failure.
[0163] Both chronic and end state renal disease in some patients are characterized by heightened sympathetic nervous activation. In patients with end state renal disease, plasma levels of norepinephrine above the media have been demonstrated to be predictive for both all-cause death and death from cardiovascular disease. This can also be true for patients suffering from diabetic or contrast nephropathy. There is compelling evidence suggesting that sensory afferent signals originating from the diseased kidneys are major contributors to initiating and sustaining elevated central sympathetic outflow in this patient group; this facilitates the occurrence of the well-known adverse consequences of chronic sympathetic over activity, such as hypertension, left ventricular hypertrophy, ventricular arrhythmias, sudden cardiac death, insulin resistance, diabetes, and metabolic syndrome.
[0164] Sympathetic nerves to the kidneys terminate in the blood vessels, the juxtaglomerular apparatus, and the renal tubules. Stimulation of the renal sympathetic nerves cause increased renin release, increased sodium (Na+) reabsorption, and a reduction of renal blood flow. These components of the neural regulation of renal function are considerably stimulated in disease states characterized by heightened sympathetic tone and clearly contribute to the rise in blood pressure in hypertensive patients. The reduction of renal blood flow and glomerular filtration rate as a result of renal sympathetic efferent stimulation may be a cornerstone of the loss of renal function in cardio-renal syndrome, which is renal dysfunction as a progressive complication of chronic heart failure, with a clinical course that typically fluctuates with the patient’s clinical status and treatment. Pharmacologic strategies to thwart the consequences of renal efferent sympathetic stimulation include centrally acting sympatholytic drugs, beta blockers (intended to reduce renin release), angiotensin converting enzyme inhibitors and receptor blockers (intended to block the action of angiotensin II and aldosterone activation consequent to renin release), and diuretics (intended to counter the renal sympathetic mediated sodium and water retention). However, the current pharmacologic strategies can have significant limitations including limited efficacy, compliance issues, side effects, and others.
[0165] The kidneys communicate with integral structures in the central nervous system via renal sensory afferent nerves. Several forms of “renal injury” may induce activation of sensory afferent signals. For example, renal ischemia, reduction in stroke volume or renal blood flow, or an abundance of adenosine enzyme may trigger activation of afferent neural communication.
[0166] FIG. 10 is an anatomic view of a human body depicting neural efferent and afferent communication between the brain and kidneys. FIG. 11 is a conceptual view of a human body depicting neural efferent and afferent communication between the brain and kidneys. As shown in FIGS. 10 and 11, the afferent communication might be from kidney to the brain or might be from one kidney to the other kidney (via the central nervous system). These afferent signals are centrally integrated and may result in increased sympathetic outflow. This sympathetic drive is directed towards the kidneys, thereby activating the RAAS and inducing increased renin secretion, sodium retention, volume retention, and vasoconstriction. Central sympathetic over activity also impacts other organs and bodily structures innervated by sympathetic nerves such as the heart and the peripheral vasculature, resulting in the described adverse effects of sympathetic activation, several aspects of which also contribute to the rise in blood pressure.
[0167] The physiology therefore suggests that (i) modulation of tissue with efferent sympathetic nerves will reduce inappropriate renin release, salt retention, and reduction of renal blood flow, and that (ii) modulation of tissue with afferent sensory nerves will reduce the systemic contribution to hypertension and other disease states associated with increased central sympathetic tone through its direct effect on the posterior hypothalamus as well as the contralateral kidney. In addition to the central hypotensive effects of afferent renal denervation, a desirable reduction of central sympathetic outflow to various other sympathetically innervated organs such as the heart and the vasculature is anticipated. [0168] As provided above, renal denervation is likely to be valuable in the treatment of several clinical conditions characterized by increased overall and particularly renal sympathetic activity such as hypertension, metabolic syndrome, insulin resistance, diabetes, left ventricular hypertrophy, chronic end state renal disease, inappropriate fluid retention in heart failure, cardio-renal syndrome and sudden death. Since the reduction of afferent neural signals contributing to the systemic reduction of sympathetic tone/drive, renal denervation might also be useful in treating other conditions associate with systemic sympathetic hyperactivity. Accordingly, renal denervation may also benefit other organs and bodily structures innervated by sympathetic nerves, including those identified in FIG. 10. For example, as previously discussed, a reduction in central sympathetic drive may reduce the insulin resistance that afflicts people with metabolic syndrome and Type II diabetics. Additionally, patients with osteoporosis may also be sympathetically activated and might also benefit from the down regulation of sympathetic drive that accompanies renal denervation.
[0169] In accordance with the present technology neuromodulation of a left or right renal plexus (RP), which is intimately associated with a left or right renal artery, may be achieved through intravascular access. FIG. 12 is an anatomic view of the arterial vasculature of a human. As FIG. 12 shows, blood moved by contractions of the heart is conveyed from the left ventricle of the heart by the aorta. The aorta descends through the thorax and branches into the left and right renal arteries. Below the renal arteries, the aorta bifurcates at the left and right iliac arteries. The left and right iliac arteries descend, respectively, through the left and right legs and join the left and right femoral arteries. [0170] FIG. 13 is an anatomic view of the venous vasculature of a human. As FIG. 13 shows, the blood collects in veins and returns to the heart, through the femoral veins into the iliac veins and into the inferior vena cava. The inferior vena cava branches into the left and right renal veins. Above the renal veins, the inferior vena cava ascends to convey blood into the right atrium of the heart. From the right atrium, the blood is pumped through the right ventricle into the lungs, where it is oxygenated. From the lungs, the oxygenated blood is conveyed into the left atrium. From the left atrium, the oxygenated blood is conveyed by the left ventricle back to the aorta.
[0171] The femoral artery may be accessed and cannulated at the base on the femoral triangle just inferior to the midpoint of the inguinal ligament. A catheter may be inserted percutaneously into the femoral artery through this access site, passed through the iliac artery and aorta, and placed into either the left or right renal artery. This comprises an intravascular path that offers minimally invasive access to a respective renal artery or other renal blood vessels.
[0172] The wrist, upper arm, and shoulder region provide other locations for introduction of catheters into the arterial system. For example, catheterization of either the radial, brachial, or axillary artery may be utilized in select cases. Catheters (e.g., catheter 102) introduced via these access points may be passed through the subclavian artery on the left side (or via the subclavian and brachiocephalic arteries on the right side), through the aortic arch, down the descending aorta and into the renal arteries using standard angiographic techniques. Other access sites can also be used to access the arterial system. [0173] Since neuromodulation of a left or right renal plexus (RP) may be achieved in accordance with the present technology through intravascular access, properties and characteristics of the renal vasculature may impose constraints upon or inform the design of apparatus, systems, and methods for achieving such renal neuromodulation. Some of these properties and characteristics may vary across the patient population or within a specific patient across time, as well as in response to disease states, such as hypertension, chronic kidney disease, vascular disease, end-stage renal disease, insulin resistance, diabetes, metabolic syndrome, and the like. These properties and characteristics, as explained herein, may have bearing on the efficacy of the procedure and the specific design of the intravascular device. Properties of interest may include, for example, material/mechanical, spatial, fluid dynamic/hemodynamic or thermodynamic properties.
[0174] As discussed previously, a catheter may be advanced percutaneously into either the left or right renal artery via a minimally invasive intravascular path. However, minimally invasive renal arterial access may be challenging, for example, because as compared to some other arteries that are routinely accessed using catheters, the renal arteries are often extremely tortuous, may be of relatively small diameter, or may be of relatively short length. Furthermore, renal arterial atherosclerosis is common in many patients, particularly those with cardiovascular disease. Renal arterial anatomy also may vary significantly from patient to patient, which further complicates minimally invasive access. Significant inter-patient variation may be seen, for example, in relative tortuosity, diameter, length, or atherosclerotic plaque burden, as well as in the take-off angle at which a renal artery branches from the aorta. Further, some patients include multiple left renal arteries or right renal arteries. Apparatus, systems, and methods for achieving renal neuromodulation via intravascular access should account for these and other aspects of renal arterial anatomy and its variation across the patient population when minimally invasively accessing a renal artery.
[0175] In addition to complicating renal arterial access, specifics of the renal anatomy also complicate establishment of stable contact between neuromodulatory apparatus and a luminal surface or wall of a renal artery. For example, navigation can be impeded by the tight space within a renal artery, as well as tortuosity of the artery. Furthermore, establishing consistent contact is complicated by patient movement, respiration, or the cardiac cycle because these factors may cause significant movement of the renal artery relative to the aorta, and the cardiac cycle may transiently distend the renal artery (i.e., cause the wall of the artery to pulse).
[0176] The neuromodulatory apparatus may also be configured to allow for adjustable positioning and repositioning of distal portion 108A and therapy delivery element 110 (FIG. 1) within the renal artery since location of treatment may also impact clinical efficacy. Additionally, variable positioning and repositioning of the neuromodulatory apparatus may prove to be useful in circumstances where the renal artery is particularly tortuous or where there are proximal branch vessels off the renal artery main vessel, making treatment in certain locations challenging.
[0177] As noted above, an apparatus positioned within a renal artery should be configured so that expandable distal portion 108A of catheter 102 may intimately contact the vessel wall or extend at least partially through the vessel wall. Renal artery vessel diameter, DRA, typically is in a range of about 2-10 mm, with most of the patient population having a DRA of about 4 mm to about 8 mm and an average of about 6 mm. Renal artery vessel length, LRA, between its ostium at the aorta/renal artery juncture and its distal branchings, generally is in a range of about 5-70 mm, and a significant portion of the patient population is in a range of about 20-50 mm. Since the target renal plexus is embedded within the adventitia of the renal artery, the composite Intima-Media Thickness, IMT, (i.e., the radial outward distance from the artery's luminal surface to the adventitia containing target neural structures) also is notable and generally is in a range of about 0.5- 2.5 mm, with an average of about 1.5 mm. Although a certain depth of treatment is important to reach the target neural fibers, the treatment should not be too deep (e.g., > 10 mm from inner wall of the artery) to avoid non-target tissue and anatomical structures such as anatomical structures of the digestive system of psoas muscle.
[0178] An additional property of the renal artery that may be of interest is the degree of renal motion relative to the aorta induced by respiration or blood flow pulsatility. A patient’s kidney, which is located at the distal end of the renal artery, may move as much as 10 centimeters cranially with respiratory excursion. This may impart significant motion to the renal artery connecting the aorta and the kidney, thereby requiring from the neuromodulatory apparatus a unique balance of stiffness and flexibility to maintain contact between the energy delivery element and the vessel wall during cycles of respiration. Furthermore, the take-off angle between the renal artery and aorta may vary significantly between patients, and also may vary dynamically within a patient, e.g., due to kidney motion. The take-off angle generally may be in a range of about 30°-135°.
[0179] The above detailed descriptions of examples of the technology are not intended to be exhaustive or to limit the technology to the precise form disclosed above. Although specific examples of the technology are described above for illustrative purposes, various equivalent modifications are possible within the scope of the technology, as those skilled in the relevant art will recognize. For example, while steps are presented in a given order, alternative examples may perform steps in a different order. The various examples described herein may also be combined to provide further examples. All references cited herein are incorporated by reference as if fully set forth herein.
[0180] From the foregoing, it will be appreciated that specific examples of the present disclosure have been described herein for purposes of illustration, but that various modifications may be made without deviating from the present disclosure.
[0181] Certain aspects of the present disclosure described in the context of particular examples may be combined or eliminated in other examples. Further, while advantages associated with certain examples have been described in the context of those examples, other examples may also exhibit such advantages, and not all examples need necessarily exhibit such advantages to fall within the scope of the present disclosure. Accordingly, the present disclosure and associated technology can encompass other examples not expressly shown or described herein. [0182] Further, although techniques have been described in which a neuromodulation catheter is positioned at a single location within a single renal artery, in other examples, the neuromodulation catheter may be repositioned to a second treatment site within a single renal artery (e.g., proximal or distal of the first treatment site, may be repositioned in a branch of the single artery, may be repositioned within a different renal vessel on the same side of the patient (e.g., a renal vessel associated with the same kidney of the patient), may be repositioned in a renal vessel on the other side of the patient (e.g., a renal vessel associated with the other kidney of the patient), or any combination thereof. At each location where the neuromodulation catheter is positioned, renal neuromodulation may be performed using any of the techniques described herein or any other suitable renal neuromodulation technique or any combination thereof.
Moreover, unless the word “or” is expressly limited to mean only a single term exclusive from the other items in reference to a list of two or more items, then the use of “or” in such a list is to be interpreted as including (a) any single item in list, (b) all of the items in the list, or (c) any combination of the items in the list. Additionally, the terms “about” or approximately,” when preceding a value, should be interpreted to mean plus or minus 10% of the value, unless otherwise indicated. Additionally, the term “comprising” is used throughout to mean including at least the recited feature(s) such that any greater number of the same feature and/or additional types of other features are not precluded.
[0183] The techniques of this disclosure may also be described in the following examples.
[0184] Example 1: a system including: a catheter configured to be disposed within vasculature of a patient, the catheter including: an elongated body, and a therapy delivery element disposed on a distal portion of the elongated body; a temperature modulation element configured to be disposed within the vasculature; and control circuitry configured to: cause the temperature modulation element to modulate a temperature of a blood vessel wall at a target location within the blood vessel, wherein the temperature modulation element is configured to modulate the temperature of the blood vessel wall at the target location away from an initial temperature of the blood vessel wall; compare a temperature modulation time conducted by the temperature modulation element with a threshold time; cause, based on a determination that the temperature modulation time is greater than or equal to the threshold time, the temperature modulation element to terminate modulation of the temperature of the blood vessel wall at the target location; and cause the therapy delivery element to deliver neuromodulation energy to tissue adjacent to the blood vessel wall at the target location.
[0185] Example 2 : the system of example 1, wherein the elongated body defines a longitudinal axis and includes an expandable member disposed at the distal portion of the elongated body, wherein the temperature modulation element includes an inner volume of the expandable member, wherein the inner volume of the expandable member is in fluid communication with a fluid source via an inner lumen of an elongated tube, wherein the expandable member is configured to expand radially away from the longitudinal axis in response to introduction of a temperature modulating fluid into the inner volume until an outer surface of the expandable member is in apposition with the blood vessel wall at the target location, and wherein when the outer surface of the expandable member is in apposition with the blood vessel wall at the target location, the temperature modulating fluid within the inner volume of the expandable member is configured to modulate the temperature of the blood vessel wall at the target location.
[0186] Example 3 : the system of example 2, wherein the therapy delivery element is disposed on the outer surface of the expandable member, and wherein the expandable member is configured to expand radially away from the longitudinal axis and place the therapy delivery element in apposition with the blood vessel wall.
[0187] Example 4 : the system of example 2, wherein the therapy delivery element is disposed within the inner volume of the expandable member, and wherein the expandable member is configured to expand radially away from the longitudinal axis and place the therapy delivery element along a centerline of the blood vessel at the target location. [0188] Example 5: the system of example 1, wherein the temperature modulation element includes a heating element configured to be disposed within the blood vessel and placed in apposition with the blood vessel wall.
[0189] Example 6: the system of example 1, wherein the temperature modulation element includes a cooling element configured to be disposed in the blood vessel and placed in apposition with the blood vessel wall.
[0190] Example 7: the system of any of examples 1-6, wherein the tissue includes a first tissue, and wherein the control circuitry is configured to: cause the temperature modulation element to modulate the temperature of the blood vessel wall at the target location until the control circuitry determines that temperature of a second tissue adjacent to the blood vessel wall satisfies a threshold temperature.
[0191] Example 8 : the system of example 7, wherein the control circuitry is configured to determine that the temperature of the second tissue satisfies the threshold temperature by determining that the temperature is greater than or equal to the threshold temperature.
[0192] Example 9 : the system of example 7, wherein the control circuitry is configured to determine that the temperature of the second tissue satisfies the threshold temperature by determining that the temperature is less than or equal to the threshold temperature.
[0193] Example 10: the system of any of examples 7-9, wherein the control circuitry is configured to: receive, from a sensor, sensed signals indicative of the temperature of the second tissue, and determine the temperature of the second tissue based on the received sensed signals.
[0194] Example 11: the system of example 10, wherein the sensed signals include an impedance of the second tissue.
[0195] Example 12: the system of any of examples 7-11, wherein the second tissue is along the blood vessel wall at the target location.
[0196] Example 13: the system of any of examples 1-12, wherein modulation of the temperature of the blood vessel wall increases the temperature of the tissue relative to the initial temperature, and wherein the delivery of the neuromodulation energy decreases the temperature of the tissue.
[0197] Example 14: the system of any of examples 1-12, wherein modulation of the temperature of the blood vessel wall decreases the temperature of the blood vessel wall relative to the initial temperature, and wherein the delivery of the neuromodulation energy increases the temperature of the tissue.
[0198] Example 15: the system of any of examples 1-14, wherein the threshold time is at least 10 seconds.
[0199] Example 16: the system of any of examples 1-15, wherein the threshold time is at least 30 seconds.
[0200] Example 17: a method including: advancing a temperature modulation element and a therapy delivery element of a catheter within a vasculature of a patient to a target location within a blood vessel, wherein the therapy delivery element is disposed on a distal portion of an elongated body of the catheter; causing, via control circuitry coupled to the temperature modulation element and to the catheter, the temperature modulation element to modulate a temperature of a blood vessel wall at the target location away from an initial temperature of the blood vessel wall; comparing, via the control circuitry, a temperature modulation time by the temperature modulation element against a threshold time; causing, based on a determination that the temperature modulation time is greater than or equal to the threshold time and via the control circuitry, the temperature modulation element to terminate modulation of the temperature of the blood vessel wall at the target location; and causing, via the control circuitry, the therapy delivery element to deliver neuromodulation energy to tissue adjacent to the blood vessel wall at the target location.
[0201] Example 18: the method of example 17, wherein the elongated body defines a longitudinal axis and includes an expandable member disposed at the distal portion of the elongated body, wherein the temperature modulation element includes an inner volume of the expandable member, wherein the inner volume of the expandable member is in fluid communication with a fluid source via an inner lumen of an elongated tube, and wherein causing the temperature modulation element to modulate the temperature of the blood vessel wall includes: introducing, via the control circuitry, the temperature modulating fluid into the inner volume of the expandable member to cause the expandable member to expand radially away from the longitudinal axis and place an outer surface of the expandable member in apposition with the blood vessel wall.
[0202] Example 19: the method of example 18, wherein the therapy delivery element is disposed on the outer surface of the expandable member, and wherein causing, via the control circuitry, the therapy delivery element to deliver the neuromodulation energy to the tissue adjacent to the blood vessel wall at the target location includes: introducing, via the control circuitry, the temperature modulating fluid into the inner volume of the expandable member to cause the expandable member to expand radially away from the longitudinal axis and place the therapy delivery element in apposition with the blood vessel wall; and causing, via the control circuitry, the therapy delivery element to deliver the neuromodulation energy to the tissue through the blood vessel wall.
[0203] Example 20: the method of example 18, wherein the therapy delivery element is disposed within the inner volume of the expandable member, and wherein causing, via the control circuitry, the therapy delivery element to deliver the neuromodulation energy to the tissue adjacent to the blood vessel wall at the target location includes: introducing, via the control circuitry, the temperature modulating fluid into the inner volume of the expandable member to cause the expandable member to expand radially away from the longitudinal axis and the place the therapy delivery element along a centerline of the blood vessel at the target location, and causing, via the control circuitry, the therapy delivery element to deliver the neuromodulation energy when the therapy delivery element is placed along the centerline of the blood vessel.
[0204] Example 21: the method of example 18, wherein the temperature modulation element includes a heating element configured to be disposed within the blood vessel and placed in apposition with the blood vessel wall.
[0205] Example 22: the method of example 18, wherein the temperature modulation element includes a cooling element configured to be disposed within the blood vessel and placed in apposition with the blood vessel wall.
[0206] Example 23: the method of any of examples 18-22, wherein the tissue includes a first tissue, and wherein the method further includes: causing, via the control circuitry, the temperature modulation element to modulate the temperature of the blood vessel wall at the target location until the control circuitry determines that temperature of a second tissue adjacent to the blood vessel wall satisfies a threshold temperature.
[0207] Example 24: the method of example 23, further including determining, via the control circuitry, that the temperature of the second tissue satisfies the threshold temperature by determining that the temperature is greater than or equal to the threshold temperature.
[0208] Example 25: the method of example 23, further including determining, via the control circuitry, that the temperature of the second tissue satisfies the threshold temperature by determining that the temperature is less than or equal to the threshold temperature.
[0209] Example 26: the method of any of examples 23-25, further including: sensing, via a sensor coupled to the control circuitry, signals indicative of the temperature of the second tissue; and determining, via the control circuitry, the temperature of the second tissue based on the sensed signals. [0210] Example 27: the method of example 26, wherein the sensed signals include an impedance of the second tissue.
[0211] Example 28: the method of any of examples 23-27, wherein the second tissue is along the blood vessel wall at the target location.
[0212] Example 29: the method of any of examples 17-28, wherein modulating of the temperature of the blood vessel wall increases the temperature of the tissue relative to the initial temperature, and wherein delivering the neuromodulation energy to the tissue decreases the temperature of the tissue.
[0213] Example 30: the method of any of examples 17-29, wherein modulating of the temperature of the blood vessel wall decreases the temperature of the tissue relative to the initial temperature, and wherein delivering the neuromodulation energy to the tissue increases the temperature of the tissue.
[0214] Example 31: the method of any of examples 17-30, wherein the threshold time is at least 10 seconds.
[0215] Example 32: the method of any of claims 17-31, wherein the threshold time is at least 30 seconds.
[0216] Example 33: a computer-readable medium including instructions that, when executed, causes control circuitry of a medical device system to perform the method of any of claims 17-32.
[0217] Various examples have been described. These and other examples are within the scope of the following claims.