Systems and methods for monitoring and assessing neuromodulation therapy

Abstract

Systems and methods for notifying and evaluating neuromodulation therapy are disclosed herein. Systems configured in accordance with embodiments of the present technology may include, for example, a guidewire having a proximal portion, a distal portion configured to be positioned at a target site in a blood vessel of a human patient, and a sensing element positioned along the distal portion. The sensing element may be a pressure sensing element, a flow sensing element, an impedance sensing element, and / or a temperature sensing element. The system may also include a controller configured to obtain one or more measurements related to a physiological parameter of the patient via the sensing element. Based on the measurement, the controller may determine a physiological parameter and compare the parameter to a predetermined threshold. Based on the comparison, the controller and / or operator may assess the likelihood that the patient benefits from neuromodulation therapy.

Description

[0001] This application is a divisional application. The direct parent of this application is the invention patent application entitled "Systems and Methods for Monitoring and Evaluating Neuromodulation Therapy", filed on January 31, 2017, with a national application number of 202111489207.6. The original parent of this application is the invention patent application entitled "Systems and Methods for Monitoring and Evaluating Neuromodulation Therapy", filed on January 31, 2017, with an international application number of PCT / US2017 / 015887, and a national application number of 201780009142.6.

[0002] Cross Reference to Related Applications

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 289,739, filed on February 1, 2016, and U.S. Provisional Patent Application No. 62 / 346,710, filed on June 7, 2016, both of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0004] The present technology relates to neuromodulation. In particular, various embodiments of the present technology relate to systems and methods for identifying responders to neuromodulation therapy and / or evaluating the efficacy of neuromodulation therapy. BACKGROUND

[0005] The sympathetic nervous system (SNS) is a primarily involuntary bodily control system that is often associated with stress responses. Fibers of the SNS extend through tissues in nearly every organ system of the human body and can influence properties such as pupil diameter, intestinal motility, and urinary output. Such regulation can have adaptive utility in maintaining homeostasis or preparing the body for rapid reactions to environmental factors. However, chronic over-activation of the SNS is a common maladaptive response that can drive the progression of many disease states. In particular, over-activation of the SNS of the kidney has been identified experimentally in humans as a complex pathophysiological factor that can lead to cardiac arrhythmias, hypertension, volume overload states (e.g., heart failure), and progressive kidney disease.

[0006] The renal sympathetic nerves terminate in structures such as the renal blood vessels, juxtaglomerular apparatus, and renal tubules. Stimulation of the renal sympathetic nerves can result in, for example, increased renin release, increased sodium reabsorption, and decreased renal blood flow. The various neuroregulatory components of renal function are considerably stimulated in disease states characterized by elevated sympathetic tone. For example, the reduction in renal blood flow and glomerular filtration rate resulting from renal sympathetic efferent stimulation can be a major contributor to the loss of kidney function in cardiorenal syndrome (i.e., renal dysfunction becomes a progressive complication of chronic heart failure). Pharmacological strategies to counteract the consequences of renal sympathetic stimulation include centrally acting sympatholytic drugs, beta blockers (e.g., to reduce renin release), angiotensin-converting enzyme inhibitors and receptor blockers (e.g., to block the effects of angiotensin II and aldosterone activation resulting from renin release), and diuretics (e.g., to counteract renal sympathetic-mediated sodium and water retention). However, these pharmacological strategies have significant limitations, including limited efficacy, compliance issues, side effects, etc. BRIEF DESCRIPTION OF DRAWINGS

[0007] Many aspects of the technology can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale. Instead, emphasis is placed on clearly illustrating the principles of the technology. For ease of reference, in this disclosure, the same reference numbers can be used throughout the figures to identify the same, or at least substantially similar or analogous, components or features.

[0008] FIG. 1A is a partial schematic side view of a neuromodulation / evaluation system according to an embodiment of the technology, with a distal portion of a guidewire positioned within a blood vessel of a human patient.

[0009] FIG. 1B and 1C is a partial schematic side view of a neuromodulation / evaluation system according to an embodiment of the technology, with a distal portion of a neuromodulation catheter in a first state and a second state, respectively, positioned within a blood vessel of a human patient. FIG. 1A

[0010] FIG. 2 is a block diagram illustrating a method for predicting a patient’s responsiveness to a neuromodulation therapy according to an embodiment of the technology.

[0011] FIG. 3 is a partial schematic side view of another embodiment of a neuromodulation / evaluation system according to an embodiment of the technology, with a distal portion of a guidewire and a neuromodulation catheter positioned within a blood vessel of a human patient.

[0012] FIG. 4 is a block diagram illustrating a method for evaluating a neuromodulation therapy according to an embodiment of the technology.

[0013] ​FIG. 5 is a block diagram illustrating a method of assessing neuromodulation therapy according to another embodiment of the present technology.

[0014] FIG. 6 is a partial schematic diagram of a neuromodulation system configured according to another embodiment of the present technology.

[0015] FIG. 7 is shown modulating renal nerves and / or assessing neuromodulation therapy with a system according to an embodiment of the present technology. FIG. 6

[0016] FIG. 8 is a conceptual diagram of the sympathetic nervous system (SNS) and how the brain communicates with the body via the SNS.

[0017] FIG. 9 is a magnified anatomical view of nerves that innervate the left kidney to form a renal plexus around the left renal artery.

[0018] FIG. 10 and 11 are an anatomical view and a conceptual diagram of a human body depicting neural efferent and afferent communication between the brain and the kidney, respectively.

[0019] FIG. 12 and 13 are anatomical views of the arterial vasculature and venous vasculature of a human, respectively. DETAILED DESCRIPTION

[0020] Systems and methods according to embodiments of the present technology can be configured to detect physiological parameters before, during, and / or after neuromodulation therapy. This information can be used to (1) predict the likelihood that a particular patient will derive therapeutic benefit from neuromodulation therapy (“responsiveness”), and / or (2) assess the efficacy of a given neuromodulation therapy. Reference is made to FIGS. 1A-13 Specific details of several embodiments of the present technology are described with reference to devices, systems, and methods for endovascular renal neuromodulation. However, other applications and other embodiments are within the scope of the present technology beyond those described herein. For example, at least some embodiments of the present technology can be useful for endoluminal neuromodulation, extravascular neuromodulation, non-renal neuromodulation, and / or therapies other than neuromodulation. It should be noted that other embodiments beyond those disclosed herein are within the scope of the present technology. Moreover, embodiments of the present technology can have different configurations, components, and / or procedures than those illustrated or described herein. Also, a person of ordinary skill in the art will appreciate that embodiments of the present technology can have configurations, components, and / or procedures other than those illustrated or described herein, and that various embodiments can not have several of the configurations, components, and / or procedures illustrated or described herein without departing from the present technology.

[0021] ​As used herein, the terms "distal" and "proximal" define a position or direction relative to a clinician or a clinician's control device (e.g., a handle of a neuromodulation catheter). The terms "distal" and "distally" refer to a position along a length of a device away from or in a direction away from a clinician or a clinician's control device. The terms "proximal" and "proximally" refer to a position along a length of a device toward or in a direction toward a clinician or a clinician's control device. The headings provided herein are for convenience only and should not be construed as limiting the disclosed subject matter.

[0022] I. Selected embodiments of catheters and systems for informing and / or assessing neuromodulation therapy and related methods

[0023] FIGS. 1A-1C is a partial schematic side view of a neuromodulation / assessment system 100 ("system 100") configured in accordance with embodiments of the present technology and shown in different arrangements when positioned at a target site within a blood vessel V (e.g., a renal artery) of a human patient. The system 100 includes a guidewire 101 (visible only in FIG. 1A and a neuromodulation catheter 102 configured to perform neuromodulation at the target site to ablate nerves near the blood vessel wall. The system 100 also includes one or more controllers 104 communicatively coupled to the guidewire 101 and / or the neuromodulation catheter 102 via a wired or wireless communication link. As discussed in more detail below, the guidewire 101 and / or the neuromodulation catheter 102 are configured to sense one or more physiological parameters before, during, and / or after a neuromodulation therapy in order to: (1) predict a likelihood of a particular patient responding to the neuromodulation therapy, and / or (2) assess the efficacy of a specified neuromodulation therapy.

[0024] Reference is made to FIG. 1AThe guidewire 101 includes an elongated member 103 having a distal portion 103a configured to be positioned at a target site within the blood vessel V and a proximal portion (not visible) extending outside the patient to a handle (not shown) or other feature that allows an operator to manipulate the distal portion 103a. The guidewire 101 and / or the elongated member 103 can be sized to be slidably positioned within a lumen of the neuromodulation catheter 102. For example, in some embodiments, the elongated member 103 can have an outer diameter of less than or equal to 0.014 inches. One or more portions of the elongated member 103 can include a solid wire and / or a coil. For example, in some embodiments, a proximal portion 103b of the elongated member 103 includes a solid wire and a distal portion 103a includes a coil. In other embodiments, the elongated member 103 includes only a solid wire or only a coil, and in still other embodiments, the elongated member 103 includes other suitable components and / or configurations. Additionally, the elongated member 103 can have a uniform stiffness along its length, or can have a stiffness that varies along its length.

[0025] The guidewire 101 also includes one or more sensing elements 105 (shown schematically and individually identified as 105a-105c) positioned along the distal portion 103a and configured to obtain one or more measurements related to one or more physiological parameters (e.g., hemodynamic parameters) of the patient. Representative sensing elements 105 include one or more of the following: an electrocardiogram ("ECG") unit, a pressure sensor, a temperature sensor, a flow sensor (e.g., a Doppler velocity sensor or an ultrasonic flow meter), an impedance sensor, a flow rate sensor, a chemical sensor, a biological sensing element, an electrochemical sensor, a hemodynamic sensor, an optical sensor, and / or other suitable sensing devices. Measurements obtained by the sensing elements 105 and / or physiological parameters derived from one or more measurements obtained by the sensing elements 105 include, for example: heart rate, temperature, blood pressure (e.g., systolic, diastolic, mean), blood flow rate, blood flow velocity, blood vessel diameter, blood vessel segment volume, blood vessel cross-sectional area, blood vessel distensibility, renal pulse wave velocity, arterial (e.g., renal arterial) input impedance (frequency domain), total renal arterial resistance, renal arterial capacitance, reflected pressure wave amplitude, augmentation index, flow reserve, resistance reserve, resistance index, capacitance reserve, hematocrit, and / or any related and / or derived values of the foregoing measurements and parameters (e.g., raw data values, including voltage and / or other direct measurements). It should be appreciated that the foregoing list is provided by way of example only, and that in other embodiments, the sensing elements 105 can be adapted to obtain additional / different parameters. In the illustrated embodiment, the guidewire 101 includes three sensing elements 105. However, in other embodiments, the guidewire 101 can include one, two, or more than three sensing elements 105. Additionally, in certain embodiments, the guidewire 101 can be a Doppler guidewire (Volcano Corporation, San Diego, CA) or XT guidewire (Volcano Corporation, San Diego, CA).

[0026] like FIG. 1B As clearly shown, the neuromodulation catheter 102 includes an elongated shaft 106 configured for slidable delivery on a guidewire 101. The elongated shaft 106 has a distal portion 106a configured to be positioned intravascularly at a target site within a vessel V, and a proximal portion 106b extending externally to the patient's body to allow an operator to manipulate the distal portion 106a of the shaft 106. FIG. 1B and 1C As shown, the neural modulation conduit 102 can be positioned in the first state or arranged ( FIG. 1B ) and second state or arrangement ( FIG. 1C The neural modulation conduit 102 can be switched between states, in which the distal portion is at least generally straight and in the second state or arrangement, the distal portion is converted or otherwise expanded into a spiral / helical shape.

[0027] Please refer to the above. FIG. 1B and 1C The neuromodulation conduit 102 includes multiple energy delivery elements, such as electrodes 110 spaced apart along the distal portion 106a of axis 106 (each individually identified as first to fourth electrodes 110a-110d). In the illustrated embodiment, the neuromodulation conduit 102 includes four electrodes 110. However, in other embodiments, the neuromodulation conduit 102 may include one, two, three, or more than four electrodes 110, and / or may include different energy delivery elements. The electrodes 110 are configured to deliver neuromodulation energy to a target site to modulate or ablate nerves near the target site (e.g., renal nerves). As referenced below... FIG. 5 As described in more detail, the electrode 110 and / or other features at the distal portion 106a of the axis 106 may also be configured to apply stimulation at and / or near the target site before and / or after neural modulation, and to detect the response (e.g., hemodynamic response) caused by the stimulation.

[0028] In other embodiments, the neuromodulation catheter 102 can include electrodes, transducers, or other elements to deliver energy to modulate nerves using other suitable neuromodulation modalities, such as pulsed electrical energy, microwave energy, optical energy, ultrasound energy (e.g., intravascularly delivered ultrasound, extracorporeal ultrasound, and / or high intensity focused ultrasound (HIFU)), direct thermal energy, radiation (e.g., infrared radiation, visible radiation, and / or gamma radiation), and / or other suitable types of energy. In certain embodiments, the neuromodulation catheter 102 can be configured for cryotherapeutic treatment, and can apply cryogenic cooling to the blood vessel V with a refrigerant (e.g., via a balloon catheter circulating a refrigerant). In still other embodiments, the neuromodulation catheter 102 is configured for chemical-based treatment (e.g., drug infusion), and the neuromodulation catheter 102 can apply one or more chemicals to the treatment site to effect neuromodulation. Such chemicals can include neurotoxins, antagonists (e.g., citrulline), and / or tissue necrosis-inducing agents (e.g., ethanol). In such embodiments, the modality of neuromodulation (e.g., RF, ultrasound, chemical ablation, cryoablation) can be different from the modality of stimulation (e.g., electrical or chemical stimulation).

[0029] The dimensions (e.g., outer diameter and length) of the coiled / spiral portion of the shaft 106 can be selected to accommodate the blood vessel or other body lumen in which the distal portion 106a of the neuromodulation catheter 102 is designed to be delivered. For example, the axial length of the coiled / spiral portion of the shaft 106 can be selected to be no longer than a patient's renal artery (e.g., typically less than 7 cm), and to have a diameter that accommodates the inner diameter of a typical renal artery (e.g., about 2-10 mm). In other embodiments, the coiled / spiral portion of the shaft 106 can have other dimensions depending on the body lumen in which the shaft is configured to be deployed. In still other embodiments, the distal portion 106a of the shaft 106 can have other suitable shapes (e.g., semi-circular, curved, straight, etc.), and / or the neuromodulation catheter 102 can include multiple support members configured to carry one or more electrodes 110. The distal portion 106a of the shaft 106 can also be designed to exert a desired outward radial force on the blood vessel when expanded to the coiled / spiral deployed state (shown in FIG. 1) to seat the one or more electrodes 110 in contact with the blood vessel wall. FIG. 1C

[0030] As FIG. 1B and 1C ​As shown, the distal portion 106a of the neuromodulation catheter 102 can optionally include an outlet 112 configured to provide acute infusion of a medicament adapted to stimulate the blood vessel V or an adjacent nerve to cause a hemodynamic or hyperemic response (e.g., vasodilation). In the illustrated embodiment, for example, the outlet 112 is positioned proximate to the electrode 110 such that the medicament can flow distally through the blood vessel toward the electrode 110 upon infusion, although in other embodiments the outlet 112 can be positioned elsewhere along the neuromodulation catheter 102 (e.g., between electrodes 110 or distal of the electrodes). The outlet 112 can be in fluid communication with a lumen (not visible) that extends through the neuromodulation catheter 102 and is connected to a reservoir (not shown) of the medicament. Suitable medicaments can include vasodilators such as adenosine, bradykinin, dipyridamole, papaverine, and / or sympathetic agonists such as epinephrine, norepinephrine, angiotensin II, etc. In the case of sympathetic agonists, a lack of immediate hemodynamic response by the patient can indicate effective ablation. In addition to or in lieu of direct pharmacological stimulation, the sympathetic nervous system ("SNS") can be stimulated by external non-pharmacological methods such as cold pressor stimulation (e.g., immersing the patient's hand in ice water), the patient squeezing a rubber ball, administering a psychometric stress to the patient (e.g., the Stroop color test), etc. As noted above, the outlet 112 is an optional component that can not be included in some embodiments.

[0031] The neuromodulation catheter 102 can also include at least one sensing element 114 (shown schematically) and / or other devices configured to detect one or more physiological parameters of the patient prior to, during, and / or after energy delivery. The sensing element 114 can be similar to any of the sensing elements 105 described above for use with the guidewire 101. Similarly, the measurements obtained by the sensing element 114 and / or the physiological parameters derived from one or more measurements obtained by the sensing element 114 can be the same as or similar to any of the measurements and / or physiological parameters described above with respect to the guidewire 101 and the sensing elements 105.

[0032] Although FIGS. 1A-1CThe illustrated embodiment of the neuromodulation catheter 102 has a coiled / spiral configuration, but in other embodiments, the neuromodulation catheter can have other suitable shapes, sizes, and / or configurations. Other suitable devices and techniques are described, for example, in U.S. Patent Application No. 12 / 910,631, filed October 22, 2010; U.S. Patent Application No. 13 / 279,205, filed October 21, 2011; U.S. Patent Application No. 13 / 279,330, filed October 23, 2011; U.S. Patent Application No. 13 / 281,360, filed October 25, 2011; U.S. Patent Application No. 13 / 281,361, filed October 25, 2011; PCT Application No. PCT / US11 / 57754, filed October 25, 2011; U.S. Provisional Patent Application No. 61 / 646,218, filed May 5, 2012; U.S. Patent Application No. 13 / 793,647, filed March 11, 2013; U.S. Provisional Patent Application No. 61 / 961,874, filed October 24, 2013; and U.S. Patent Application No. 13 / 670,452, filed November 6, 2012. All of the above-identified applications are incorporated by reference herein in their entireties. Non-limiting examples of devices and systems include the Symplicity Flex TM Catheter, Symplicity Spyral TM Multi-electrode RF ablation catheter, and Arctic Front Advance TM Cardiac cryoablation system.

[0033] In some embodiments, the system 100 includes a console (not shown), and the controller 104 is integrated with the console. In such embodiments, the console can be configured to communicate with both the sensor 105 of the guidewire 101 and the neuromodulation catheter 102 via wireless and / or wired communication links. For example, in some embodiments, the console can include separate access ports for receiving wired connections to the guidewire 101 and the neuromodulation catheter 102. In other embodiments, the console can include a single access port that can be used with both the guidewire 101 and the neuromodulation catheter 102 at the same time or with one at a time. In other embodiments, the system 100 can include two consoles; a first console configured to communicate with the guidewire 101 and a second console configured to communicate with the neuromodulation catheter 102.

[0034] A. Selected methods of predicting patient responsiveness to neuromodulation therapy

[0035] It can be advantageous for a medical practitioner to determine one or more physiological parameters of a patient prior to delivering neuromodulation energy. Such baseline parameters are not only beneficial for assessing the efficacy of a neuromodulation therapy, but also for identifying whether a particular patient will benefit from a neuromodulation therapy in terms of treatment. For example, certain physiological parameters related to hemodynamics can be particularly informative regarding the likelihood that a patient will benefit from a neuromodulation therapy applied at a particular anatomical location. For example, it is believed that renal artery wave velocity can be a predictive marker for selecting responders to renal artery neuromodulation. In particular, recent studies have found that higher baseline renal artery wave velocity is associated with a 6-month reduction in systolic blood pressure. Accordingly, the system 100 of the present technology is configured to detect and analyze one or more physiological parameters of a patient to inform a medical practitioner’s decision to proceed with a neuromodulation therapy.

[0036] FIG. 2 is a block diagram illustrating a method 200 for predicting a patient’s response to a neuromodulation therapy in accordance with the present technology. The method 200 can be implemented using the system 100 described above with reference to FIGS. 1-3 and / or other suitable systems for identifying patient responders to a neuromodulation therapy. As shown, the method 200 includes advancing a guidewire 101 (e.g., a renal artery guidewire) into a target site within a blood vessel V (e.g., a renal artery) of a human patient and positioning a distal portion 103a of the guidewire 101 in a generally straight configuration along a portion of the blood vessel V at the target site (block 202). When the guidewire 101 is positioned at the target site, the method 200 includes obtaining one or more measurements related to one or more physiological parameters of the patient via the sensing element 105 (block 204) and, in some embodiments, transmitting the obtained measurements to the controller 104 and / or another feature of the system 100. The obtained measurements can then be used to determine a physiological parameter indicative of the patient’s response to a neuromodulation therapy, such as wave velocity at the target site (block 206). Wave velocity c can be calculated by one or more established formulas, such as the “sum of squares” equation: FIGS. 1A-1C FIG. 2 FIG. 1A FIG. 1A

[0037]

[0038] where P = pressure; U = velocity, p = density of blood. Wave velocity c can also be estimated from pressure waveform morphology alone (without considering velocity). It should be appreciated that other methods for determining wave velocity are within the scope of the present disclosure.

[0039] ​​​​Method 200 also includes comparing the physiological parameter to a predetermined threshold (block 208) to determine whether the patient is likely to benefit from the neuromodulation therapy (i.e., whether the patient is a "responder" or a "non-responder"). As used herein, the term "threshold" is used to refer to a standardized or patient-specific metric, which can be a single value or a range of values.

[0040] In various embodiments, comparing the determined physiological parameter to a predetermined threshold can be performed automatically by controller 104 and / or another feature of system 100. Based on the comparison, controller 104 can provide an indication to the operator whether the patient is a responder or a non-responder. For example, in embodiments where controller 104 calculates a renal wave velocity, if the renal wave velocity is above or outside of a predetermined threshold, controller 104 can indicate that the patient is likely to be a non-responder (block 212) or have a low likelihood of benefiting from the neuromodulation therapy. Additionally, in some embodiments, controller 104 can also recommend not proceeding with the neuromodulation therapy. However, if the renal wave velocity is below or within the predetermined threshold, controller 104 can indicate that the patient is likely to be a responder (block 210) and, in some embodiments, can recommend proceeding with the neuromodulation therapy. In particular embodiments, for example, controller 104 can have a display that visually indicates whether the patient is a responder, such as a text display, an indicator light, and / or other suitable indicator.

[0041] In those procedures where the baseline measurement indicates that the patient is likely to be a responder and the operator elects to proceed with the neuromodulation therapy, the operator can then advance neuromodulation catheter 102 over guidewire 101 to the target site, as shown in FIG. 3. The operator can then withdraw guidewire 101 to a position proximal of distal portion 106a of neuromodulation catheter 102 to deploy neuromodulation catheter 102, as shown in FIG. 4, and begin delivering neuromodulation energy at the target site. FIG. 1B FIG. 1C

[0042] In some embodiments, it can be advantageous to leave a portion of guidewire 101 distal of the distal end of neuromodulation catheter 102 when deploying neuromodulation catheter 102 such that one or more sensing elements 105 remain positioned in the vessel lumen and are able to sense one or more physiological parameters. For example, as shown in FIG. 5, a portion of guidewire 101 can be left distal of the distal end of neuromodulation catheter 102 such that one or more sensing elements 105 remain positioned in the vessel lumen and are able to sense one or more physiological parameters. FIG. 3 ​​One embodiment of a system 300 configured in accordance with the present technology is shown in a deployed configuration, which includes a guidewire 301 (only the distal portion is visible) having a flexible region along its distal portion that allows the distal portion 106a of the neuromodulation catheter 102 to assume its deployed configuration while the guidewire 301 remains positioned in the lumen of the elongated shaft 106 at the distal portion 106a. To deploy the neuromodulation catheter 102, the operator can advance the neuromodulation catheter 102 over the guidewire 301 until the distal portion 106a of the neuromodulation catheter 102 aligns with the flexible region and allows it to assume its preset shape. As shown in FIG. 3

[0043] In some cases, it can be advantageous for the medical practitioner to identify one or more locations in the blood vessel that are more suitable for effective ablation (i.e., that increase renal nerve injury and have fewer lesions). To identify such locations, the medical practitioner can utilize one or more physiological measurements and / or parameters related to hemodynamics. For example, regions of the blood vessel that exhibit abnormal hemodynamics (e.g., turbulent flow and secondary flow) can not be particularly suitable for neuromodulation therapy, and the medical practitioner can use such information to avoid administering neuromodulation therapy in those regions. Also, a comparison of hemodynamic physiological measurements and / or parameters between two or more regions of the blood vessel can inform the medical practitioner whether and / or which particular portion of the blood vessel to treat. For example, in some cases a low ratio of branch to main blood vessel flow rate can indicate that branch treatment is less (or more) desirable.

[0044] ​In certain embodiments, physiological measurements or parameters can be determined at a branch of a blood vessel (e.g., two branch blood vessels extending after a renal artery bifurcation) and / or at a main blood vessel (e.g., a renal artery), and the measurements or parameters can be compared to one another to select a location for application of neuromodulation therapy. For example, hemodynamic properties (e.g., pulse wave velocity, distensibility, etc.) can be acquired at two or more different regions of a blood vessel (e.g., a branch vessel and a main vessel, a first branch vessel and a second branch vessel, etc.) either under steady state or transiently in response to a stimulus (described in further detail below). These two properties can be compared to one another, and if the two values are heterogeneous, a practitioner can elect not to apply therapeutic neuromodulation to the less responsive blood vessel or blood vessel region. Thus, even if the main blood vessel, branch blood vessels, or blood vessel regions individually satisfy the hemodynamic criteria for therapy, treating the relatively less responsive blood vessel or branch blood vessel can be less beneficial.

[0045] In certain embodiments, the sensing element 114 of the neuromodulation catheter 102 can also be used to automatically detect one or more physiological parameters of the patient and transmit the measurements to the controller 104 for processing.

[0046] It will be appreciated that while the above described guidewire 101 / 301 and neuromodulation catheter 102 are configured for "over-the-wire" delivery of the neuromodulation catheter 102, other configurations are within the scope of the present disclosure. For example, in some embodiments, the neuromodulation catheter 102 and guidewire 101 / 301 can be configured as a "rapid exchange" system. In other embodiments, the neuromodulation catheter 102 and guidewire 101 / 301 can be configured for parallel delivery. In further embodiments, the neuromodulation catheter 102 and guidewire 101 / 301 can be delivered sequentially. Additionally, in some embodiments, the system 100 can include a delivery sheath (not shown) configured to house the neuromodulation catheter 102 and / or guidewire 101 / 301 during delivery.

[0047] B. Methods of assessing neuromodulation therapy efficacy

[0048] A successful or effective neuromodulation therapy (i.e., when a nerve is ablated to a desired extent) is expected to result in a hemodynamic response that can be reflected by local and / or global changes in hemodynamic physiological parameters such as blood flow, blood pressure, and blood vessel diameter. As described below, the system 100 of the present technology is configured to detect and assess such changes in hemodynamic parameters before, during, and / or after neuromodulation therapy.

[0049] FIG. 4 is a block diagram illustrating a method 400 for assessing efficacy of neuromodulation therapy according to embodiments of the present technology. The method 400 can be used with the system 100 described above with reference to FIG. 1. FIGS. 1A-1C 、 FIG. 3The system 100 described and / or other suitable systems for assessing the efficacy of neuromodulation therapy can implement the method 400. For example, the guidewire 101, the neuromodulation catheter 102, and / or the controller 104 can be used to perform various steps of the method 400. As FIG. 4 shown, the method 400 includes positioning the guidewire 101 at a target site along a portion of a blood vessel V of a human patient prior to delivering neuromodulation energy (see FIG. 1A ), and obtaining baseline measurements via the sensing element 105 positioned along (or otherwise incorporated with) the guidewire 101 (block 402). The method 400 also includes communicating the obtained measurements to the controller 104, and determining one or more baseline physiological parameters based on the obtained measurements (block 404). In some embodiments, the obtained baseline measurements and / or the determined baseline physiological parameters can be stored in a memory of the controller and / or another feature of the system 100. After obtaining the baseline measurements, the method 400 optionally includes utilizing the baseline measurements to determine one or more physiological parameters and comparing the determined physiological parameters to predetermined thresholds to predict whether the patient is a responder or a non-responder, as described above with reference to FIG. 2 .

[0050] If the operator elects to proceed with the neuromodulation therapy, the method 400 includes advancing the neuromodulation catheter 102 over the guidewire 101 to the target site (see FIG. 1B ), and then withdrawing the guidewire 101 through a lumen of the neuromodulation catheter to a position within the lumen proximal to the distal portion 106a of the elongated shaft 106. With the guidewire 101 withdrawn, the distal portion 106a transitions to its deployed configuration such that the electrode 110 contacts the blood vessel wall (see FIG. 1C ). As shown in block 406, the neuromodulation catheter 102 can then perform neuromodulation at the target site to ablate nerves proximal to the blood vessel wall. For example, the method 400 can include applying RF energy (e.g., via the electrode), pulsed electrical energy, microwave energy, optical energy, ultrasound energy (e.g., intravascularly delivered ultrasound, extracorporeal ultrasound, and / or HIFU), direct thermal energy, radiation, cryogenic cooling, chemical-based treatments, and / or other suitable types of neuromodulation energy.

[0051] After performing the neuromodulation therapy, the guidewire 101 can be advanced distally within the lumen of the elongated shaft 106, thereby transitioning the distal portion 106a to a generally straight, low-profile configuration (see FIG. 1B ). The neuromodulation catheter 102 can then be withdrawn from the target site to expose the distal portion 103a of the guidewire 101 (see FIG. 1AMethod 400 further includes acquiring measurements related to one or more physiological parameters following neuromodulation therapy via exposed sensing element 105 (block 408), and transmitting the acquired measurements to controller 104. As shown in block 410, the acquired measurements can then be used to determine one or more physiological parameters. In some embodiments, the acquired post-neuromodulation measurements and / or the determined post-neuromodulation physiological parameters may be stored in the controller's memory and / or another feature of system 100.

[0052] Physiological parameters (e.g., vascular impedance, vessel diameter, etc.) after and before neuromodulation can then be compared to detect changes in the corresponding parameters (if any) as a result of neuromodulation therapy (box 412). In various embodiments, this comparison can be performed automatically by controller 104 and / or another feature of system 100. In some embodiments, the difference between the parameters after and before neuromodulation can be compared to a threshold (box 414). For example, the threshold can be equal to a percentage reduction (e.g., 15%, 20%, 50%, 100%, etc.) in one or more parameters (e.g., a 15%, 20%, 50%, 100%, etc.), a predetermined impedance or diameter value associated with effective neuromodulation, and / or a value based on other factors associated with successful neuromodulation. If the difference is greater than or equal to the predetermined threshold, the operator can choose to stop the neuromodulation therapy (box 416). If the difference is less than the threshold, the operator can choose to apply one or more rounds of additional neuromodulation energy to the treatment site using the same or higher energy levels and subsequently detect hemodynamic responses (e.g., changes in vascular impedance or diameter), as described above. Alternatively or additionally, the operator may reposition the distal portion 106a of the vascular V axis 106 to apply neuromodulation energy to different treatment sites and measure hemodynamic responses (e.g., vascular impedance or diameter) at the new treatment sites.

[0053] Although many hemodynamic parameters can be measured without stimulation, in some procedures it may be beneficial to additionally or alternatively stimulate nerves at or near the neuromodulation site before and after neuromodulation therapy, and to detect changes in the hemodynamic response induced by each stimulation. See below for reference. FIG. 5In detail, system 100 can be configured to apply or deliver electrical and / or pharmacological stimulation to a blood vessel to stimulate nerves at or near a target site. As used herein, stimulation is defined as sufficient to elicit a neural response in nerves near the blood vessel (e.g., renal nerves), but not so large as to permanently affect neural function. Stimulation can be applied proximal to, distal to, and / or to either side of the site of nerve modulation. For example, in some embodiments, stimulation is applied at the orifice of the blood vessel (e.g., renal artery orifice). However, in other embodiments, stimulation can be applied at other suitable locations.

[0054] When a nerve functions (i.e., conducts signals), the afferent nerve responds to the stimulus and causes a hemodynamic response. This hemodynamic response can be measured by detecting changes in vessel size (e.g., diameter, cross-sectional area, and segmental volume), intravascular pressure, blood flow through the vessel, heart rate, and / or other parameters indicative of the hemodynamic response. It is expected that after the nerve has been effectively ablated to the desired extent, the hemodynamic response to the stimulus will be eliminated or at least mitigated, as the afferent nerve has been ablated or modulated. Therefore, it is envisioned to compare the hemodynamic response to the stimulus before and after neural modulation to indicate the success of the neuromodulation therapy.

[0055] FIG. 5 This is a block diagram illustrating a method 500 for evaluating the efficacy of neuromodulation therapy according to an embodiment of the present technology. Method 500 can be described using the above reference. FIGS. 1A-1C , FIG. 3 The described system 100 and / or other suitable systems for evaluating the efficacy of neuromodulation therapy are implemented. For example, guidewire 101, neuromodulation catheter 102, and / or controller 104 can be used to perform various steps of method 500. FIG. 5 As shown, method 500 includes positioning guidewire 101 along a portion of a blood vessel V in a human patient at a target site before delivering neuromodulation energy (see [link to relevant documentation]). FIG. 1A The baseline measurement is obtained via a sensing element 105 positioned (or otherwise integrated) along the guidewire 101 (box 502). Alternatively or additionally, method 500 may include advancing the neuromodulation catheter 102 over the guidewire 101 to the target site and positioning the neuromodulation catheter 102 in a generally straight configuration along a portion of the vessel V. FIG. 1B Before delivering neuromodulation energy, the sensing element 114 of the neuromodulation conduit 102 can be used to obtain baseline measurements.

[0056] After baseline measurements are obtained but before the application of neuromodulation energy via electrodes, and when the neuromodulation conduit 102 is positioned at the target site in a generally straight configuration ( FIG. 1B), the electrode 110 can apply electrical stimulation at the target site and / or the neuromodulation catheter 102 can release pharmacological stimulation at the treatment site via the outlet 112 (block 504). In some embodiments, stimulation can additionally or alternatively be applied by one or more electrodes disposed at a distal portion of the guidewire 101, one or more electrodes associated with a separate catheter (e.g., positioned at or near the target site), external acoustic wave stimulation devices, and other suitable stimulation devices and methods. The electrode 110, the sensing element 114, and / or one or more sensing elements 105 in conjunction with the guidewire 101 can then obtain measurements related to the physiological parameter after stimulation (block 506). As shown in block 508, the method 500 further includes determining a baseline metric (ΔΡ b ), which is the difference between the corresponding measurements obtained before and after stimulation.

[0057] At any time prior to applying neuromodulation energy, the method 500 optionally includes utilizing baseline measurements to determine one or more physiological parameters and comparing the determined physiological parameters to predetermined thresholds to predict whether the patient is a responder or non-responder, as described in detail above with reference to FIG. 2 .

[0058] If the operator elects to proceed with the neuromodulation therapy, the method 500 includes withdrawing the guidewire 101 through the lumen of the neuromodulation catheter 102 to a position at least proximal to the distal portion 106a of the elongated shaft 106. With the guidewire 101 withdrawn, the distal portion 106a transitions to its deployed configuration such that the electrode 110 contacts the vessel wall (see FIG. 1C ). As shown in block 510, the neuromodulation catheter 102 can then perform neuromodulation at the target site to ablate nerves proximal to the vessel wall. For example, the method 500 can include applying RF energy (e.g., via the electrode), pulsed electrical energy, microwave energy, optical energy, ultrasound energy (e.g., intravascularly delivered ultrasound, extracorporeal ultrasound, and / or HIFU), direct thermal energy, radiation, cryogenic cooling, chemical-based treatments, and / or other suitable types of neuromodulation energy.

[0059] After performing the neuromodulation, the guidewire 101 can be advanced distally within the lumen of the elongated shaft 106, thereby transitioning the distal portion 106a to the generally straight, low-profile configuration (see FIG. 1B ). The method 500 further includes obtaining measurements related to one or more physiological parameters after the neuromodulation therapy via the sensing elements 105 of the guidewire 101, the sensing element 114, and / or the electrode 110 (block 512). (A portion of the guidewire 101 can be exposed distal to the neuromodulation catheter 102 and / or the neuromodulation catheter 102 can be at least partially withdrawn from the target site along the guidewire 101 to expose one or more sensing elements 105.)

[0060] After obtaining the post-neuromodulation measurements, and while the neuromodulation catheter 102 is positioned at the target site in a generally straight configuration, FIG. 1B ), the electrodes 110 can apply electrical stimulation at the target site and / or the neuromodulation catheter 102 can release pharmacological stimulation at the treatment site via the outlet 112 (block 514). In some embodiments, stimulation can additionally or alternatively be applied by one or more electrodes disposed at a distal portion of the guidewire 101, one or more electrodes associated with a separate catheter (e.g., positioned at or near the target site), external acoustic wave stimulation devices, and other suitable stimulation devices and methods. The electrodes 110, the sensing element 114, and / or one or more sensing elements 105 coupled with the guidewire 101 can then obtain measurements related to the post-neuromodulation, post-stimulation physiological parameters (block 516). As shown in block 518, the method 500 further includes determining a post-neuromodulation metric (ΔΡ p ), which is the difference between the corresponding measurements obtained pre-neuromodulation, pre-stimulation and post-neuromodulation, post-stimulation.

[0061] The difference (ΔΡ) between the baseline metric (ΔΡ b ) and the post-neuromodulation metric (ΔΡ p ) can then be compared to detect a change in the respective metric (representation of the physiological parameter) as a result of the neuromodulation therapy (block 520). In various embodiments, this comparison can be performed automatically by the controller 104 and / or another feature of the system 100. In certain embodiments, the difference between the post-neuromodulation parameter and the pre-neuromodulation parameter can be compared to a threshold value (block 520). For example, the threshold value can equal a percentage reduction in one or more parameters (e.g., impedance or vessel diameter, etc.) (e.g., a 15% reduction, a 20% reduction, a 50% reduction, a 100% reduction, etc., a predetermined impedance or diameter value associated with effective neuromodulation, and / or a value based on other factors associated with successful neuromodulation. If the difference is greater than or equal to the predetermined threshold value, the operator can elect to stop the neuromodulation therapy (block 522). If the difference is less than the threshold value, the operator can elect to apply one or more additional rounds of neuromodulation energy to the treatment site using the same energy level or a higher energy level and subsequently detect the hemodynamic response (e.g., change in vessel impedance or diameter), as described above. Alternatively or additionally, the operator can reposition the distal portion 106a of the shaft 106 along the vessel V to apply neuromodulation energy to a different treatment site and measure the hemodynamic response (e.g., vessel impedance or diameter) at the new treatment site.

[0062] Other devices, systems, and methods for assessing the efficacy of neuromodulation therapy applicable to the system 100 and / or guidewire 101 of the present technology are described in PCT Application No. PCT / US15 / 53499, filed October 1, 2015, and U.S. Patent Application No. 13 / 670,452, filed November 6, 2012, both of which are incorporated herein by reference in their entirety.

[0063] Accordingly, it is contemplated that the system 100 provides a clinician with a real-time indication of nerve damage to determine whether successful neuromodulation therapy has occurred. Thus, the clinician does not need to wait until after the procedure to determine whether the treatment was effective. Any additional energy application needed to achieve neuromodulation can be performed while the neuromodulation catheter 102 is still within the blood vessel V. Accordingly, the system 100 can facilitate the implementation of efficient and effective neuromodulation therapy.

[0064] FIG. 6 is a partial schematic view of a treatment system 600 ("system 600") configured in accordance with yet another embodiment of the present technology. The system 600 can include various features similar to the systems 100 and 300 described above with respect to FIGS. 1A-1C and 3, and can be used to implement the various methods 200 and 400 described above. As FIG. 6 shown, the system 600 includes a neuromodulation catheter 602, a control console 604, and a cable 606 extending therebetween. The neuromodulation catheter 602 can include an elongate shaft 608 having a proximal portion 608b, a distal portion 608a, a handle 610 operably connected to the shaft 608 at the proximal portion 608b, and a neuromodulation assembly 620 operably connected to the shaft 608 at the distal portion 608a. The shaft 608 and the neuromodulation assembly 620 can be 2, 3, 4, 5, 6, or 7 French or another suitable size. As FIG. 6 shown, the neuromodulation assembly 620 can include a support structure 622 carrying an array of two or more electrodes 624. The electrodes 624 can be configured to apply electrical stimulation (e.g., RF energy) to a target site within or adjacent to a patient, temporarily stun a nerve, deliver neuromodulation energy to the target site, and / or detect blood vessel impedance. In various embodiments, certain electrodes 624 can be dedicated to applying stimulation and / or detecting impedance, and the neuromodulation assembly 620 can include other types of treatment elements that provide neuromodulation therapy using various modalities (e.g., cryotherapy cooling, ultrasound energy, etc.).

[0065] The distal portion 608a of the shaft 608 is configured to move within a lumen of a human patient and position the neuromodulation assembly 620 within or otherwise proximate to a target site of the lumen. For example, the shaft 608 can be configured to position the neuromodulation assembly 620 within a blood vessel, duct, airway, or another naturally occurring lumen within the human body. In certain embodiments, intravascular delivery of the neuromodulation assembly 620 includes percutaneously inserting a guidewire (not shown) into a body lumen of the patient and moving the shaft 608 and / or the neuromodulation assembly 620 along the guidewire until the neuromodulation assembly 620 reaches the target site (e.g., a renal artery). For example, the distal end of the neuromodulation assembly 620 can define a channel for engaging the guidewire in order to deliver the neuromodulation assembly 620 using over-the-wire (OTW) or rapid-exchange (RX) techniques. In other embodiments, the neuromodulation catheter 602 can be a steerable or non-steerable device configured for use without a guidewire. In still other embodiments, the neuromodulation catheter 602 can be configured for delivery via a guide catheter or sheath (not shown).

[0066] Once at the target site, the neuromodulation assembly 620 can be configured to apply stimulation, detect resulting hemodynamic responses, and provide or facilitate a neuromodulation therapy at the target site (e.g., using the electrodes 624 and / or other energy delivery elements). For example, the neuromodulation assembly 620 can detect a vascular impedance via the electrodes 624, a blood flow via a flow sensing element (e.g., a Doppler velocity sensing element), a local blood pressure within the blood vessel via a pressure transducer or other pressure sensing element, and / or other hemodynamic parameters. The detected hemodynamic responses can be transmitted to the console 604 and / or another device external to the patient. The console 604 can be configured to receive and store the recorded hemodynamic responses for further use by a clinician or operator. For example, the clinician can use the hemodynamic responses received by the console 604 to determine whether the application of neuromodulation energy effectively modulated the nerves to a desired extent.

[0067] The console 604 can be configured to control, monitor, supply, and / or otherwise support the operation of the neuromodulation catheter 602. The console 604 can also be configured to generate energy in a selected form and / or size for delivery to tissue at a target site via the neuromodulation assembly 620, and thus the console 604 can have different configurations depending on the treatment modality of the neuromodulation catheter 602. For example, when the neuromodulation catheter 602 is configured for electrode-based, heating element-based, or transducer-based treatment, the console 604 can include an energy generator (not shown) configured to generate RF energy (e.g., monopolar and / or bipolar RF energy), pulsed electrical energy, microwave energy, optical energy, ultrasonic energy (e.g., intravascularly-delivered ultrasound, extracorporeal ultrasound, and / or HIFU), direct thermal energy, radiation (e.g., infrared, visible, and / or gamma radiation), and / or other suitable types of energy. When the neuromodulation catheter 602 is configured for cryogenic treatment, the console 604 can include a refrigerant container (not shown) and can be configured to supply refrigerant to the neuromodulation catheter 602. Similarly, when the neuromodulation catheter 602 is configured for chemical-based treatment (e.g., drug infusion), the console 604 can include a chemical container (not shown) and can be configured to supply one or more chemicals to the neuromodulation catheter 602.

[0068] In selected embodiments, the system 600 can be configured to deliver monopolar electrical fields via one or more of the electrodes 624. In such embodiments, a neutral or dispersive electrode 630 can be electrically connected to the console 604 and attached to the outside of the patient's body. In embodiments including multiple electrodes 624, the electrodes 624 can be capable of delivering electrical power independently, simultaneously, selectively, or sequentially (i.e., capable of being used in a monopolar fashion), and / or can be capable of delivering electrical power between any desired combination of the electrodes 624 (i.e., capable of being used in a bipolar fashion). Additionally, an operator can optionally be permitted to select which electrodes 624 to use for power delivery in order to create a highly customized lesion(s) within the renal artery as desired. One or more sensing elements (not shown), such as one or more temperature sensing elements (e.g., thermocouples, thermistors, etc.), pressure sensing elements, optical sensing elements, flow sensing elements, chemical sensing elements, and / or other sensing elements can be located proximate to, within, or integral with the electrodes 624. The sensing element(s) and the electrodes 624 can be connected to one or more supply lines (not shown) that transmit signals from the sensing element(s) and / or deliver energy to the electrodes 624.

[0069] In various embodiments, system 600 may further include a controller 614 communicatively coupled to neuromodulation conduit 602. Controller 614 may be configured to initiate, terminate, and / or modulate the operation of one or more components of neuromodulation conduit 602 (e.g., electrode 624) directly and / or via console 604. In other embodiments, controller 614 may be omitted or have other suitable locations (e.g., within handle 610, along cable 606, etc.). Controller 614 may be configured to execute automated control algorithms and / or receive control commands from the operator. Furthermore, console 604 may be configured to provide feedback to the operator before, during, and / or after the treatment procedure via evaluation / feedback algorithm 616.

[0070] FIG. 7 (See also the following) FIG. 6 The diagram illustrates the modulation of renal nerves according to an embodiment of system 600. The neuromodulation catheter 602 provides access via an intravascular pathway P to the renal plexus RP, such as a percutaneous entry point in the femoral artery (not shown), brachial artery, radial artery, or axillary artery to a target treatment site within the corresponding renal artery RA. By manipulating the proximal portion 608b of axis 608 from outside the intravascular pathway P, the clinician can advance axis 608 through the sometimes tortuous intravascular pathway P and remotely manipulate the distal portion 608a of axis 608. FIG. 6 ).exist FIG. 7 In the illustrated embodiment, a guidewire 636 is used in OTW technology to deliver the neuromodulation component 620 intravascularly to the treatment site. As previously described, the distal end of the neuromodulation component 620 may define a channel for receiving the guidewire 636 for delivery of the neuromodulation catheter 602 using OTW or RX technology. At the treatment site, the guidewire 636 may be at least partially withdrawn or removed, and the neuromodulation component 620 may be converted or otherwise moved to a deployment arrangement to record neural activity and / or deliver energy at the treatment site. In other embodiments, the neuromodulation component 620 may be delivered to the treatment site within a guide sheath (not shown) with or without the guidewire 636. When the neuromodulation component 620 is located at the target site, the guide sheath may be at least partially withdrawn or retracted, and the neuromodulation component 620 may be converted to a deployment arrangement. In still other embodiments, the shaft 608 itself may be steerable, allowing the neuromodulation component 620 to be delivered to the treatment site without the aid of the guidewire 636 and / or the guide sheath.

[0071] Image guidance, such as computed tomography (CT), fluoroscopy, intravascular ultrasound (IVUS), optical coherence tomography (OCT), intracardiac echocardiography (ICE), or another suitable guidance modality, or a combination thereof, can be used to assist the clinician in positioning and manipulating the neuromodulation assembly 620. For example, a fluoroscopy system (e.g., including a flat panel detector, x-ray or c-arm) can be rotated to precisely visualize and identify the target treatment site. In other embodiments, the treatment site can be determined prior to delivery of the neuromodulation assembly 620 using IVUS, OCT, and / or other suitable image mapping modalities capable of correlating the target treatment site with identifiable anatomical structures (e.g., spinal column features) and / or radiopaque rulers (e.g., positioned beneath or above the patient). Further, in some embodiments, an image guidance component (e.g., IVUS, OCT) can be integrated with and / or extend parallel to the neuromodulation catheter 602 to provide image guidance during positioning of the neuromodulation assembly 620. For example, the image guidance component (e.g., IVUS or OCT) can be coupled to the neuromodulation assembly 620 to provide three-dimensional images of the vasculature proximate to the target site to facilitate positioning or deployment of the multi-electrode assembly within the target renal blood vessel.

[0072] Energy from the electrodes 624 FIG. 6 ) and / or other energy delivery elements can then be applied to the target tissue to induce one or more desired neuromodulatory effects on a local region of the renal artery RA and on an adjacent region of the renal plexus RP located immediately within, proximate to, or immediately adjacent to the adventitia of the renal artery RA. Purposeful application of energy can achieve neuromodulation along all or at least a portion of the renal plexus RP. The neuromodulatory effect is generally dependent at least in part on the power, time, contact between the energy delivery element and the blood vessel wall, and blood flow through the blood vessel. The neuromodulatory effect can include denervation, thermal ablation, and / or non-ablative thermal alteration or lesion (e.g., by sustained heating and / or resistive heating). The desired thermal heating effect can include elevating the temperature of the target neural fibers above a desired threshold to achieve a non-ablative thermal alteration, or above a higher temperature to achieve an ablative thermal alteration. For example, for a non-ablative thermal alteration, the target temperature can be above body temperature (e.g., about 37°C) but below about 45°C, or for an ablative thermal alteration, the target temperature can be about 45°C or higher. The desired non-thermal neuromodulatory effect can include altering the electrical signals transmitted in the nerves.

[0073] Hypothermic effects can also provide neuromodulation. For example, a cryotherapy applicator can be used to cool tissue at a target site to provide a therapeutically effective direct cellular injury (e.g., necrosis), vascular injury (e.g., by destroying supplying blood vessels to starve cells of nutrients), and sublethal hypothermia with subsequent apoptosis of cells. Exposure to cryotherapy cooling can result in acute cell death (e.g., immediately after exposure) and / or delayed cell death (e.g., during tissue thawing and subsequent hyperperfusion). Embodiments of the present technology can include structures that cool the interior surface at or near the wall of a renal artery such that the tissue proximate (e.g., adjacent) is effectively cooled to the depth at which sympathetic renal nerves reside. For example, the cooling structures are cooled to an extent that causes therapeutically effective hypothermic renal neuromodulation. Sufficient cooling of at least a portion of the sympathetic renal nerves is expected to slow or potentially block conduction of nerve signals to produce a prolonged or permanent reduction in renal sympathetic nerve activity.

[0074] The electrodes 624 and / or other features of the neuromodulation assembly 620 can apply a stimulus to the renal artery RA intravascularly and detect hemodynamic responses to the stimulus before and / or after applying neuromodulation energy to the renal artery RA. This information can then be used to determine the efficacy of the neuromodulation therapy. For example, the controller 614 FIG. 6 ) can process the detected hemodynamic responses before and after neuromodulation and compare changes in the hemodynamic responses to predetermined thresholds to assess whether the neuromodulation therapy is effective at the treatment site or particular ablation site.

[0075] II. Renal neuromodulation

[0076] Renal neuromodulation is the partial or complete disabling or otherwise effective disruption of nerves of the kidney (e.g., nerves that terminate in or are in close relation to structures of the kidney). In particular, renal neuromodulation can include inhibiting, reducing, and / or blocking nerve communication of nerve fibers (e.g., efferent and / or afferent nerve fibers) of the kidney. This disabling can be long term (e.g., permanent or for a period of months, years, or decades) or short term (e.g., for a period of minutes, hours, days, or weeks). Renal neuromodulation is expected to contribute to a systemic reduction in sympathetic tone or drive and / or to benefit at least some particular organs and / or other body structures innervated by the sympathetic nervous system. Thus, renal neuromodulation is expected to be effective in treating clinical conditions associated with systemic sympathetic nervous system overactivity or overdrive, particularly conditions associated with central sympathetic nervous system overstimulation. For example, renal neuromodulation is expected to be effective in treating conditions such as hypertension, heart failure, acute myocardial infarction, metabolic syndrome, insulin resistance, diabetes, left ventricular hypertrophy, chronic and end-stage renal disease, inappropriate fluid retention in heart failure, cardiorenal syndrome, polycystic kidney disease, polycystic ovary syndrome, osteoporosis, erectile dysfunction, and sudden death, among others.

[0077] During a treatment procedure, renal neuromodulation can be induced at one or more suitable target sites with electrical induction, thermal induction, chemical induction, or in other suitable manners or combinations of manners. The target sites can be located 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 tissue treated can include tissue at least proximate to a wall of the renal lumen. For example, with respect to a renal artery, the treatment procedure can include modulating nerves in a renal plexus that are located intimately within or proximate to an adventitia of the renal artery.

[0078] Renal neuromodulation can include a cryotherapeutic modality alone or in combination with another treatment modality. Cryotherapeutic treatment can include cooling tissue at a target site in a manner that modulates nerve function. For example, sufficiently cooling at least a portion of a sympathetic renal nerve can slow or potentially block conduction of nerve signals to produce a prolonged or permanent reduction in renal sympathetic nerve activity. This effect can occur as a result of cryotherapeutic tissue damage, which can include, for example, direct cell damage (e.g., necrosis), blood vessel or lumen damage (e.g., by destroying blood vessels to starve cells of nutrients), and / or sublethal hypothermia with subsequent apoptosis. Exposure to cryotherapeutic cooling can result in acute cell death (e.g., immediately upon exposure) and / or delayed cell death (e.g., during tissue thawing and subsequent hyperperfusion). Neuromodulation using cryotherapeutic treatment in accordance with embodiments of the present technology can include cooling structures proximate to an inner surface of a body lumen wall such that tissue is effectively cooled to a depth at which sympathetic renal nerves reside. For example, in some embodiments, a cooling assembly of a cryotherapeutic device can be cooled to an extent that it induces therapeutically effective cryogenic renal neuromodulation. In other embodiments, a cryotherapeutic modality can include cooling that is not configured to result in neuromodulation. For example, the cooling can be at or above a cryogenic temperature, and can be used to control neuromodulation via another treatment modality (e.g., to protect tissue from neuromodulation energy).

[0079] Renal neuromodulation can include a single electrode-based or transducer-based treatment modality or in combination with another treatment modality. Electrode-based or transducer-based treatment can include delivering electrical and / or other forms of energy to tissue at a treatment site to stimulate and / or heat tissue in a manner that modulates neural function. For example, sufficiently stimulating and / or heating at least a portion of a sympathetic renal nerve can slow or potentially block conduction of neural signals to produce a prolonged or permanent reduction in renal sympathetic nerve activity. Various suitable types of energy can be used to stimulate and / or heat tissue at a treatment site. For example, neuromodulation in accordance with embodiments of the present technology can include delivering RF energy, pulsed electrical energy, microwave energy, optical energy, focused ultrasound energy (e.g., high intensity focused ultrasound energy), or another suitable type of energy alone or in combination. Electrodes or transducers used to deliver the energy can be used alone or with other electrodes or transducers in a multi-electrode or multi-transducer array. Moreover, energy can be applied from within the body (e.g., within the vasculature or other body lumen in a catheter-based approach) and / or from outside the body (e.g., via an applicator located outside the body). Moreover, energy can be used to reduce damage to non-target tissue when target tissue adjacent to the non-target tissue is subjected to neuromodulation cooling.

[0080] Neuromodulation using focused ultrasound energy (e.g., high intensity focused ultrasound energy) can be beneficial relative to neuromodulation using other treatment modalities. Focused ultrasound is one example of a transducer-based treatment modality that can be delivered from outside the body. Focused ultrasound treatment can be performed in close relation to imaging (e.g., magnetic resonance, computed tomography, fluoroscopy, ultrasound (e.g., intravascular or intraluminal), optical coherence tomography, or other suitable imaging modality). For example, imaging can be used to identify an anatomical location of a treatment site (e.g., a set of coordinates relative to a reference point). The coordinates can then be input into a focused ultrasound device configured to vary power, angle, phase, or other suitable parameter to generate a region of ultrasound focus at a location corresponding to the coordinates. The focal region can be small enough to localize treatment-effective heating at the treatment site while partially or completely avoiding potentially damaging destruction of nearby structures. To produce the focal region, the ultrasound device can be configured to pass ultrasound energy through a lens, and / or the ultrasound energy can be produced by a curved transducer or by multiple transducers of a phased array (curved or straight).

[0081] The heating effect of an electrode-based or transducer-based therapy can include ablation and / or non-ablative alteration or damage (e.g., through sustained heating and / or resistive heating). For example, a therapy program can include raising the temperature of a target nerve fiber to a target temperature above a first threshold to achieve a non-ablative alteration, or above a second, higher threshold to achieve ablation. For a non-ablative alteration, the target temperature can be above about body temperature (e.g., about 37°C) but below about 45°C, and for ablation, the target temperature can be above about 45°C. For example, by modestly heating a target nerve fiber or a vascular or luminal structure that perfuses the target nerve fiber, heating the tissue to a temperature between about body temperature and about 45°C can result in a non-ablative alteration. In the case of a vascular structure being affected, perfusion of the target nerve fiber can be denied, resulting in necrosis of the neural tissue. For example, by substantially heating a target nerve fiber or a vascular or luminal structure that perfuses the target fiber, heating the tissue to a target temperature above about 45°C (e.g., above about 60°C) can result in ablation. In some patients, it can be necessary to heat the tissue to a temperature sufficient to ablate the target nerve fiber or vascular or luminal structure, but less than about 90°C (e.g., less than about 85°C, less than about 80°C, or less than about 75°C).

[0082] Renal neuromodulation can include a separate chemical-based therapy modality or in combination with another therapy modality. Neuromodulation using a chemical-based therapy can include delivery of one or more chemicals (e.g., a drug or other agent) to tissue at a therapy location in a manner that modulates neural function. For example, the chemical can be selected to affect the therapy location generally or to affect some structures on the therapy location selectively over others. For example, the chemical can be guanethidine, ethanol, phenol, a neurotoxin, or another suitable agent selected to alter, disrupt, or destroy nerves. The chemical can be delivered to tissue at the therapy site using various suitable techniques. For example, the chemical can be delivered via one or more needles from outside the body or within a vasculature or other body lumen. In an intravascular example, a catheter can be used to intravascularly position a therapy element including a plurality of needles (e.g., microneedles) that can be retracted or otherwise occluded prior to deployment. In other embodiments, the chemical can be introduced into tissue at the therapy location via simple diffusion through a body lumen wall, electrophoresis, or other suitable mechanism. Similar techniques can be used to introduce chemicals that are not configured to cause neuromodulation, but rather to facilitate neuromodulation by another therapy modality.

[0083] III. Related anatomy and physiology

[0084] As previously mentioned, the sympathetic nervous system (SNS) is a branch of the autonomic nervous system as well as the enteric nervous system and parasympathetic nervous system. It is active at a basal level, called sympathetic tone, at all times and becomes more active during stress. Like other parts of the nervous system, the sympathetic nervous system works through a series of interconnected neurons. Sympathetic neurons are generally considered part of the peripheral nervous system (PNS), but many are located 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, the spinal cord sympathetic neurons are coupled to the peripheral sympathetic neurons by synapses. The spinal cord sympathetic neurons are therefore called presynaptic (or preganglionic) neurons, while the peripheral sympathetic neurons are called postsynaptic (or postganglionic) neurons.

[0085] At the synapse within the sympathetic ganglia, the preganglionic sympathetic neuron releases acetylcholine, which is a chemical messenger that binds to and activates nicotinic acetylcholine receptors on the postsynaptic neuron. In response to this stimulus, the postsynaptic neuron primarily releases norepinephrine (noradrenaline). Prolonged activation can cause the release of epinephrine from the adrenal medulla.

[0086] Once released, norepinephrine and epinephrine bind to adrenergic receptors on peripheral tissues. Binding to adrenergic receptors causes neuronal and hormonal responses. Physiological manifestations include pupil dilation, increased heart rate, occasional vomiting, and increased blood pressure. Increased sweating is also observed due to binding of cholinergic receptors of sweat glands.

[0087] The sympathetic nervous system is responsible for upregulating and downregulating many homeostatic mechanisms in an organism. Fibers from the SNS innervate tissues in almost every organ system, providing at least some regulatory function for physiological characteristics such as pupil diameter, gut motility, and urinary output. This response is also known as the body's sympathetic-adrenal response, because the preganglionic sympathetic nerve fibers (as well as all other sympathetic nerve fibers) ending in the adrenal medulla secrete acetylcholine, which activates the secretion of epinephrine (adrenal hormone) and, to a lesser extent, norepinephrine (noradrenaline). Thus, this response, which primarily acts on the cardiovascular system, is mediated directly by impulses transmitted through the sympathetic nervous system and indirectly by catecholamines secreted by the adrenal medulla.

[0088] Scientifically, the SNS is often considered an autoregulatory system, i.e., a system that works without intervention through conscious thought. Some evolutionary theorists believe that the sympathetic nervous system played a role in early organisms to maintain survival, because the sympathetic nervous system is responsible for initiating body actions. One example of this initiation is in the instant before waking up, where sympathetic outflow is spontaneously increased in preparation for action.

[0089] A. Sympathetic chain

[0090] As FIG. 8 shown, the SNS provides a neural network that allows the brain to communicate with the body. Sympathetic nerves originate internally within the spinal column, 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 thought to extend to the second or third lumbar segments. Because their cells originate in the thoracic and lumbar regions of the spinal cord, the SNS is said to have thoracolumbar outflow. The axons of these nerves exit the spinal cord through the anterior rootlet / root. They pass near the spinal (sensory) ganglion, where they enter the anterior division of the spinal nerve. However, unlike the somatic innervation, they quickly separate out through white rami connectors, which connect to either the paravertebral (which lie next to the spinal column) or prevertebral (which lie near the aortic bifurcation) ganglia that extend alongside the spinal column.

[0091] To reach target organs and glands, axons should travel long distances within the body, and to accomplish this, many axons pass their information to a second cell through synaptic transmission. The end of the axon connects (i.e., synapses) across a space to a dendrite of a second cell. The first cell (presynaptic cell) sends a neurotransmitter across the synaptic gap, where it activates the second cell (postsynaptic cell). The message is then relayed to the final destination.

[0092] In the SNS and other components of the peripheral nervous system, these synapses are made at sites called ganglia, as described above. The cell that sends its fibers is called the preganglionic cell, while the cell whose fibers leave the ganglion is called the postganglionic cell. As previously mentioned, the preganglionic cells of the SNS are located between the first thoracic segment (T1) and the third lumbar segment (L3) of the spinal cord. The postganglionic cells have their cell bodies in the ganglia and send their axons to the target organ or gland.

[0093] The ganglia not only include the sympathetic trunk, but also the cervical ganglia (superior, middle, and inferior), which send sympathetic fibers to the head and thoracic organs, and the celiac and mesenteric ganglia, which send sympathetic fibers to the intestines.

[0094] 1. Nerve innervation of the kidney

[0095] As FIG. 9 shown, the kidney is innervated by the renal plexus (RP), which is closely associated with the renal artery. The renal plexus (RP) is a plexus of autonomic nerves that surrounds and is embedded in the adventitia of the renal artery. The renal plexus (RP) extends along the renal artery until it reaches the substance of the kidney. The fibers that result in the renal plexus (RP) originate from the celiac ganglion, the superior mesenteric ganglion, the aorticorenal ganglion, and the aortic plexus. The renal plexus (RP), also known as the renal nerves, is composed primarily of sympathetic components. The kidney has no (or at least very little) parasympathetic innervation.

[0096] The preganglionic neuron cell bodies are located in the intermediolateral cell column of the spinal cord. The preganglionic neuron axons pass through the paravertebral ganglia (they do not synapse) to become the lesser splanchnic nerves, least splanchnic nerves, first lumbar splanchnic nerves, second lumbar splanchnic nerves, and travel to the celiac ganglion, superior mesenteric ganglion, and aorticorenal ganglion. The postganglionic neuron cell bodies exit the celiac ganglion, superior mesenteric ganglion, and aorticorenal ganglion into the renal plexus (RP) and distribute to the renal vasculature.

[0097] 2. Renal sympathetic nerve activity

[0098] Messages flow through the SNS in a bidirectional stream. Outgoing messages can trigger changes in different parts of the body simultaneously. For example, the sympathetic nervous system can speed up heart rate; dilate bronchial passages; decrease movement (motility) in the large intestine; constrict blood vessels; increase esophageal motility; cause pupil dilation, hair erection (goosebumps), and sweating (perspiration); and increase blood pressure. Incoming messages relay signals from various organs and sensory receptors of the body to other organs, particularly the brain.

[0099] Hypertension, heart failure, and chronic kidney disease are some of the many disease states caused by chronic activation of the SNS, particularly the renal sympathetic nervous system. Chronic activation of the SNS is a maladaptive response that drives the progression of these disease states. Pharmacologic management of the renin-angiotensin-aldosterone system (RAAS) has been a long-standing but somewhat inefficient approach to reducing SNS overactivity.

[0100] As noted above, the renal sympathetic nervous system has been identified as a major contributor to the complex pathophysiology of hypertension, volume overload states (e.g., heart failure), and progressive kidney disease, both experimentally and in humans. Studies employing radiotracer dilution methods to measure norepinephrine spillover from the kidney to plasma have shown that renal norepinephrine (NE) spillover rates are increased in patients with essential hypertension, particularly young hypertensive patients, consistent with the hemodynamic profile typically seen in early hypertension and characterized by increased heart rate, cardiac output, and renal vascular resistance. It is now known that essential hypertension is often neurogenic, often accompanied by overt sympathetic nervous system overactivity.

[0101] Activation of cardiac and renal sympathetic nervous activity is even more pronounced in heart failure, as evidenced by the exaggerated increase in NE spillover from the heart and kidney to plasma in this patient group. In line with this, it was recently demonstrated that renal sympathetic activation has a strong negative predictive value for all-cause mortality and heart transplantation in patients with congestive heart failure, independent of overall sympathetic activity, glomerular filtration rate, and left ventricular ejection fraction. These findings support the notion that therapeutic strategies aimed at reducing renal sympathetic stimulation can potentially improve survival in patients with heart failure.

[0102] Chronic and end-stage renal disease is characterized by enhanced sympathetic activation. For patients with end-stage renal disease, it has been demonstrated that plasma norepinephrine levels above the median can predict all-cause and cardiovascular disease mortality. This is also true for patients with diabetes or contrast-induced nephropathy. There is compelling evidence that sensory afferent signals from the diseased kidney are the main cause of initiating and sustaining elevated central sympathetic outflow in this patient group; this promotes the occurrence of well-known adverse consequences of chronic sympathetic activity, such as hypertension, left ventricular hypertrophy, ventricular arrhythmias, sudden cardiac death, insulin resistance, diabetes, and metabolic syndrome.

[0103] (i) Renal sympathetic efferent activity

[0104] Sympathetic nerves to the kidney terminate in blood vessels, juxtaglomerular apparatus, and renal tubules. Stimulation of renal sympathetic nerves results in increased renin release, increased sodium (Na+) reabsorption, and decreased renal blood flow. These components of neural regulation of renal function are considerably stimulated in disease states characterized by elevated sympathetic tone and contribute significantly to the elevation of blood pressure in patients with hypertension. The decrease in renal blood flow and glomerular filtration rate resulting from renal sympathetic efferent stimulation can be a cornerstone of the loss of renal function in cardiorenal syndrome, which is renal insufficiency as a progressive complication of chronic heart failure, with a clinical course that will typically fluctuate with the patient's clinical condition and treatment. Pharmacological strategies to block the consequences of renal efferent sympathetic stimulation include centrally acting sympatholytic drugs, beta blockers (aimed at reducing renin release), angiotensin-converting enzyme inhibitors, and receptor blockers (aimed at blocking the effects of angiotensin II and aldosterone activation following renin release), and diuretics (aimed at counteracting sodium and water retention mediated by renal sympathetic nerves). However, current pharmacological strategies have significant limitations, including limited efficacy, compliance issues, side effects, etc.

[0105] (ii) Renal sensory afferent nerve activity

[0106] The kidneys communicate with the overall architecture in the central nervous system through renal sensory afferent nerves. Several forms of "renal injury" can induce activation of sensory afferent signals. For example, renal ischemia, beat-to-beat output or renal blood flow reduction, or adenosine enzyme abundance can trigger activation of afferent neural communication. As shown in FIG. 10 and 11 this afferent communication can be from the kidney to the brain, or it can be from one kidney to the other (via the central nervous system). These afferent signals are centrally integrated and can result in increased sympathetic outflow. This sympathetic drive is directed at the kidneys, thereby activating the RAAS and inducing increased renin secretion, sodium retention, volume retention, and vasoconstriction. Central sympathetic activity also affects other organs and body structures innervated by the sympathetic nervous system (e.g., the heart and peripheral vasculature), resulting in several adverse effects of the described sympathetic activation, several aspects of which also contribute to elevated blood pressure.

[0107] Physiology thus suggests that (i) modulation of the tissue with efferent sympathetic nerves will reduce inappropriate renin release, salt retention, and renal blood flow reduction, and (ii) modulation of the 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 effects on the hypothalamic posterior and contralateral kidney. In addition to the centrally mediated hypotensive effects of afferent renal denervation, it is expected that there will be a desirable reduction in central sympathetic outflow to various other sympathetically innervated organs (e.g., the heart and vasculature).

[0108] B. Other clinical benefits of renal denervation

[0109] As noted above, renal denervation can be valuable in treating several clinical conditions characterized by overall and particularly renal sympathetic activity increases, such as hypertension, metabolic syndrome, insulin resistance, diabetes, left ventricular hypertrophy, chronic end-stage renal disease, inappropriate fluid retention in heart failure, cardiorenal syndrome, and sudden death. Because the reduction in afferent neural signals contributes to a systemic reduction in sympathetic tone / drive, renal denervation can also be useful in treating other conditions associated with excess systemic sympathetic activity. Thus, renal denervation can also benefit other organs and body structures innervated by the sympathetic nervous system, including those shown in FIG. 8 For example, as noted previously, a reduction in central sympathetic drive can reduce insulin resistance that plagues patients with metabolic syndrome and type II diabetes. In addition, patients with osteoporosis are also activated by the sympathetic nervous system and can also benefit from the down-regulation of sympathetic drive that accompanies renal denervation.

[0110] C. Achieving endovascular access to the renal artery

[0111] According to the present technology, neuromodulation of the left and / or right renal plexus (RP) that is in close association with the left and / or right renal artery can be achieved through intravascular access. As shown in FIG. 1, blood that is moved by heart contractions is transported from the left ventricle of the heart through the aorta. The aorta descends through the thoracic cavity 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 through the left and right legs and connect to the left and right femoral arteries, respectively. FIG. 12 As shown in FIG. 2, blood that is moved by heart contractions is transported from the left ventricle of the heart through the aorta. The aorta descends through the thoracic cavity 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 through the left and right legs and connect to the left and right femoral arteries, respectively.

[0112] As shown in FIG. 3, blood that is moved by heart contractions is transported from the left ventricle of the heart through the aorta. The aorta descends through the thoracic cavity 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 through the left and right legs and connect to the left and right femoral arteries, respectively. FIG. 13 As shown in FIG. 4, blood that is moved by heart contractions is transported from the left ventricle of the heart through the aorta. The aorta descends through the thoracic cavity 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 through the left and right legs and connect to the left and right femoral arteries, respectively.

[0113] As will be described in greater detail later, the femoral artery can be accessed and catheterized at the base of the femoral triangle just below the midpoint of the inguinal ligament. A catheter can be percutaneously inserted through this access site into the femoral artery, through the iliac artery and the aorta, and placed in the left or right renal artery. This includes an intravascular path that provides a minimally invasive access to the respective renal artery and / or other renal vasculature.

[0114] The wrist, upper arm, and shoulder regions provide other locations for introducing catheters into the arterial system. For example, catheterization of the radial artery, brachial artery, or axillary artery can be used in selected cases. Utilizing standard angiographic techniques, catheters introduced through these access points can be passed through the left subclavian artery (or through the right subclavian artery and the brachiocephalic artery), through the aortic arch, down the descending aorta, and into the renal arteries.

[0115] D. Properties and characteristics of the renal vasculature

[0116] Because neuromodulation of the left and / or right renal plexus (RP) can be achieved through intravascular access according to the present technology, properties and characteristics of the renal vasculature can place constraints on and / or inform the design of devices, systems, and methods for achieving such renal neuromodulation. Some of these properties and characteristics can vary over time and in response to disease states (e.g., hypertension, chronic kidney disease, vascular disease, end-stage renal disease, insulin resistance, diabetes, metabolic syndrome, etc.) in a patient population and / or in a particular patient. As explained herein, these properties and characteristics can be relevant to the efficacy of the procedure and the particular design of the intravascular devices. Properties of interest can include, for example, material / mechanical, spatial, fluid dynamic / hemodynamic, and / or thermodynamic properties.

[0117] As previously mentioned, catheters can be percutaneously accessed into the left or right renal artery via a minimally invasive endovascular approach. However, minimally invasive renal artery access can be challenging, for example, because the renal artery is generally extremely tortuous, can have a relatively small diameter, and / or can have a relatively short length compared to some other arteries that are routinely accessed using catheters. In addition, renal artery atherosclerosis is common in many patients, particularly those with cardiovascular disease. Renal artery anatomy can also vary significantly between patients, which further complicates minimally invasive access. Significant patient-to-patient variation can be seen, for example, in the relative tortuosity, diameter, length, and / or atherosclerotic plaque burden of the renal artery, as well as the angle at which the renal artery branches from the aorta. Devices, systems, and methods for achieving renal neuromodulation via endovascular access when minimally invasively accessing the renal artery should account for these and other aspects of renal artery anatomy and its variation in the patient population.

[0118] In addition to complicating renal artery access, details of the renal anatomy also complicate the establishment of stable contact between neuromodulation devices and the luminal surface or wall of the renal artery. For example, catheters can be impeded by the narrow space within the renal artery, as well as the arterial tortuosity. In addition, establishing consistent contact is complicated by patient movement, respiration, and / or the cardiac cycle, as these factors can cause significant movement of the renal artery relative to the aorta, and the cardiac cycle can transiently expand the renal artery (i.e., cause the wall of the artery to pulsate).

[0119] Even after accessing the renal artery and facilitating stable contact between the neuromodulation device and the luminal surface of the artery, the nerves in and around the adventitia of the artery should be safely modulated by the neuromodulation device. Given the potential clinical complications associated with such treatment, it is important that heat treatment be effectively applied from within the renal artery. For example, the intima and media of the renal artery are very susceptible to thermal injury. As discussed in more detail below, the intima-media thickness, which separates the vessel lumen from its adventitia, means that the target renal nerves can be several millimeters away from the luminal surface of the artery. Sufficient energy should be delivered to or removed from the target renal nerves to modulate the target renal nerves without excessively cooling or heating the vessel wall such that the wall is frozen, desiccated, or otherwise potentially affected to an undesirable extent. A potential clinical complication associated with excessive heating is thrombosis caused by blood clot flow through the artery. Given that this thrombus can cause a renal infarction, thereby causing irreversible damage to the kidney, heat treatment within the renal artery should be applied with caution. Thus, the complex fluid and thermal conditions present in the renal artery during treatment, particularly those that can affect heat transfer kinetics at the treatment site, can be important when applying energy (e.g., heating thermal energy) and / or removing heat (e.g., cooling thermal conditions) from tissue within the renal artery.

[0120] The neuromodulation device should also be configured to allow adjustable positioning and repositioning of the energy delivery element within the renal artery, as the location of the treatment can also affect clinical efficacy. For example, given that renal nerves can be spaced circumferentially around the renal artery, it can be tempting to apply a full circumferential treatment from within the renal artery. In some cases, full circle lesions that can result from continuous circumferential treatment can be associated with renal artery stenosis. Therefore, creating more complex lesions along the longitudinal dimension of the renal artery and / or repositioning the neuromodulation device to multiple treatment locations can be desirable. However, it should be noted that the benefits of creating circumferential ablations can outweigh the possibility of renal artery stenosis, or the risk can be mitigated by certain embodiments or in certain patients and creating circumferential ablations can be a goal. Additionally, variable positioning and repositioning of the neuromodulation device can prove useful in cases where the renal artery is particularly tortuous or where proximal branch vessels exist off the main vessel of the renal artery, such that treatment in certain locations is challenging. Manipulation of the device in the renal artery should also take into account the mechanical damage the device imposes on the renal artery. For example, motion of the device in the artery caused by insertion, manipulation, mating bends, etc. can cause dissection, perforation, intimal dissection, or damage to the internal elastic lamina.

[0121] Blood flow through the renal artery can be temporarily occluded for short periods of time with minimal or no complications. However, long periods of occlusion should be avoided as ischemic injury to the kidney is to be prevented. It can also be beneficial to avoid occlusion altogether, or if occlusion is beneficial for an embodiment, to limit the duration of occlusion to, for example, 2-5 minutes.

[0122] Based on the above challenges of (1) renal artery intervention, (2) consistent and stable placement of the treatment element against the vessel wall, (3) effective application of treatment on the vessel wall, (4) positioning and possibly repositioning the treatment device to allow multiple treatment locations, and (5) avoiding or limiting the duration of blood flow occlusion, various independent and dependent properties of the renal vasculature that can be of interest include, for example: (a) vessel diameter, vessel length, intima-media thickness, coefficient of friction, and tortuosity; (b) distensibility, stiffness, and elastic modulus of the vessel wall; (c) peak systolic, end diastolic flow velocity, and average systolic-diastolic peak flow velocity, and average / maximal volume flow rate; (d) specific heat capacity of the blood and / or vessel wall, thermal conductivity of the blood and / or vessel wall, and / or convective and / or radiative heat transfer of the blood flow through the treatment site of the vessel wall; (e) renal artery motion relative to the aorta caused by respiration, patient movement, and / or blood flow pulsation; and (f) the angle of deviation of the renal artery relative to the aorta. These properties will be discussed in more detail with respect to the renal artery. However, such properties of the renal artery can also guide and / or constrain design characteristics depending on the devices, systems, and methods used to achieve renal neuromodulation.

[0123] As noted above, a device positioned within a renal artery should conform to the geometry of the artery. The renal artery vessel diameter DRA is typically in the range of about 2-10 mm, with a majority of the patient population having a DRA of about 4 mm to about 8 mm and an average of about 6 mm. The renal artery vessel length LRA between the ostium at the aorta / renal artery junction and its distal branch is generally in the range of about 5-70 mm, and a majority of the patient population is in the 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 radially outward distance from the arterial lumen surface to the adventitia containing the target neural structures) is also significant, and is generally in the range of about 0.5-2.5 mm, averaging about 1.5 mm. While a certain depth of treatment is important to reach the target neural fibers, the treatment should not be too deep (e.g., >5 mm from the inner wall of the renal artery) to avoid non-target tissue and anatomical structures such as the renal vein.

[0124] An additional property of the renal artery that can be of interest is the degree of renal motion relative to the aorta caused by respiration and / or blood flow pulsatility. A patient's kidney, located at the distal end of the renal artery, can move 4" toward the head with respiratory excursion. This can impose significant motion on the renal artery connecting the aorta and the kidney, thereby requiring a unique balance of rigidity and flexibility from the neuromodulation device to maintain contact between the energy delivery element and the vessel wall during the respiratory cycle. Furthermore, the angle of divergence between the renal artery and the aorta can vary significantly between patients, and can also dynamically change within a patient, e.g., due to renal motion. The angle of divergence can generally be in the range of about 30°-135°.

[0125] IV. Additional examples

[0126] 1. A neuromodulation / assessment system, comprising:

[0127] a neuromodulation catheter comprising an elongated shaft defining a lumen therethrough, a proximal portion, and a distal portion, wherein the distal portion is configured to deliver therapeutic neuromodulation at a target site in a renal vessel of a human patient;

[0128] a guidewire configured to be slidably positioned within the lumen of the elongated shaft, the guidewire having a distal portion and a sensing element positioned along the distal portion, wherein the sensing element is configured to detect a physiological measurement at the target site; and

[0129] a controller configured to be communicatively coupled to the sensing element, wherein the controller is further configured to:

[0130] obtain a physiological measurement via the sensing element;

[0131] determining a physiological parameter based on the physiological measurements;

[0132] comparing the physiological parameter to a predetermined threshold; and

[0133] based on the comparison, providing an indication to an operator as to whether the patient has a physiological characteristic indicative of a therapeutic response to a renal nerve modulation therapy at the target site.

[0134] 2. The neuromodulation / assessment system of example 1, wherein the sensing element comprises a pressure sensing element, a flow sensing element, an impedance sensing element, and / or a temperature sensing element.

[0135] 3. The neuromodulation / assessment system of example 1 or 2, wherein the sensing element is configured to detect physiological measurements indicative of a renal artery wave speed, and wherein the controller is configured to determine a renal artery wave speed based on the physiological measurements.

[0136] 4. The neuromodulation / assessment system of any of examples 1-3, wherein:

[0137] the sensing element is configured to detect physiological measurements at a first branch of the renal artery and at a second branch of the renal artery; and

[0138] the controller is configured to:

[0139] determine a first physiological parameter based on the physiological measurements taken from the first branch,

[0140] determine a second physiological parameter based on the physiological measurements taken from the second branch, compare the first physiological parameter to the second physiological parameter, and

[0141] based on the comparison, determine whether the first branch or the second branch is more likely to accept a renal nerve modulation therapy.

[0142] 5. The neuromodulation / assessment system of any of examples 1-3, wherein:

[0143] the sensing element is configured to detect physiological measurements at a branch vessel of the renal artery and at the renal artery; and

[0144] the controller is configured to:

[0145] determine a first physiological parameter based on the physiological measurements taken from the branch vessel,

[0146] determine a second physiological parameter based on the physiological measurements taken from the renal artery,

[0147] compare the first physiological parameter to the second physiological parameter, and

[0148] based on the comparison, determining whether the branch vessel or the renal artery is more likely to accept a renal neuromodulation therapy.

[0149] 6. A system comprising:

[0150] a guidewire having a proximal portion, a distal portion configured to be positioned at a target site in a renal blood vessel of a human patient, and a sensing element positioned along the distal portion, wherein the sensing element is a pressure sensing element, a flow sensing element, an impedance sensing element, and / or a temperature sensing element;

[0151] a controller configured to be communicatively coupled to the sensing element, wherein the controller is further configured to:

[0152] obtain, via the sensing element, one or more measurements related to a physiological parameter of the patient;

[0153] determine the physiological parameter based on the measurements;

[0154] compare the physiological parameter to a predetermined threshold; and

[0155] based on the comparison, provide an indication to an operator regarding a likelihood that the patient will be therapeutically responsive to a renal neuromodulation therapy at the target site.

[0156] 7. The system of example 6, wherein the sensing element is one of a plurality of sensing elements positioned along the distal portion of the guidewire.

[0157] 8. The system of example 6 or example 7, wherein the physiological parameter is a renal wave speed, and wherein the sensing element is configured to acquire measurements used to determine the renal wave speed.

[0158] 9. The system of example 6 or example 7, wherein the physiological parameter is a renal resistance, and wherein the sensing element is configured to acquire measurements used to determine the renal resistance.

[0159] 10. The system of example 6 or example 7, wherein the physiological parameter is a mean blood pressure, and wherein the sensing element is configured to acquire measurements used to determine the mean blood pressure.

[0160] 11. The system of example 6 or example 7, wherein the physiological parameter is a mean blood flow velocity, and wherein the sensing element is configured to acquire measurements used to determine the mean blood flow velocity.

[0161] 12. The system of any of examples 6-11, wherein the sensing element is configured to acquire measurements from a main renal artery vessel, a main bifurcation of the renal artery, and / or one or more renal branches distal to the main bifurcation of the renal artery.

[0162] 13. The system of any of examples 6-12, wherein the controller is further configured to indicate which portions of the blood vessel are more susceptible to neuromodulation therapy based on the physiological parameter.

[0163] 14. The system of any of examples 6-13, wherein the controller is further configured to indicate which portions of the blood vessel are less susceptible to neuromodulation therapy based on the physiological parameter.

[0164] 15. The system of any of examples 6-14, further comprising a neuromodulation catheter, and wherein the neuromodulation catheter comprises:

[0165] an elongated shaft defining a lumen therethrough, the elongated shaft having a proximal portion and a distal portion, wherein the distal portion is configured to be positioned at a target site; and

[0166] a plurality of electrodes spaced apart along the distal portion of the elongated shaft.

[0167] 16. The system of example 15, wherein:

[0168] the guidewire is configured to be slidably positioned within the lumen of the elongated shaft; and

[0169] the controller is configured to be communicatively coupled to the plurality of electrodes, wherein the controller is further configured to:

[0170] apply a first stimulus at and / or near the target site within the blood vessel;

[0171] detect a blood vessel impedance resulting from the first stimulus via at least one of the plurality of electrodes to determine a baseline impedance;

[0172] deliver neuromodulation energy to the target site within the blood vessel of the human patient via the distal portion of the elongated shaft;

[0173] apply a second stimulus at and / or near the target site within the blood vessel after delivering the neuromodulation energy;

[0174] detect a post-neuromodulation impedance resulting from the second stimulus via at least one of the plurality of electrodes; and

[0175] evaluate an efficacy of the neuromodulation based at least in part on a comparison of the baseline impedance and the post-neuromodulation impedance.

[0176] 17. The system of example 15, wherein the lumen is a first lumen, and wherein the neuromodulation catheter further comprises a second lumen extending along the elongated shaft and configured to deliver a medicament at and / or proximate to a target site to provide the first stimulation and the second stimulation.

[0177] 18. The system of example 15, wherein a distal portion of the elongated shaft is configured to transition into a helical shape such that at least one of the plurality of electrodes is configured to contact an inner wall of a blood vessel, and wherein at least one of the plurality of electrodes is configured to deliver neuromodulation energy.

[0178] 19. A method for assessing a patient for neuromodulation therapy, the method comprising:

[0179] delivering a distal portion of a guidewire to a target site within a renal blood vessel of a human patient, wherein the distal portion of the guidewire comprises a sensing element;

[0180] obtaining a baseline measurement related to a physiological parameter of the patient via the sensing element;

[0181] determining the physiological parameter based on the baseline measurement;

[0182] comparing the physiological parameter to a predetermined threshold; and

[0183] based on the comparison, indicating whether the patient will have a therapeutic response to a renal neuromodulation therapy.

[0184] 20. The method of example 19, wherein determining the physiological parameter comprises determining a renal wave velocity and / or a renal resistance.

[0185] 21. The method of example 19, wherein determining the physiological parameter comprises determining a mean blood pressure and / or a mean blood flow velocity.

[0186] 22. The method of any one of examples 19-21, wherein:

[0187] obtaining the baseline measurement comprises:

[0188] obtaining the physiological measurement from a branch vessel of the renal blood vessel,

[0189] obtaining the physiological measurement from the renal blood vessel;

[0190] determining the physiological parameter comprises:

[0191] determining a first physiological parameter based on the physiological measurement taken from the branch vessel, and

[0192] determining a second physiological parameter based on the physiological measurement taken from the renal blood vessel;

[0193] comparing the physiological parameters comprises:

[0194] comparing the physiological parameters comprises:

[0195] the indication comprises:

[0196] determining whether the first branch vessel or the second branch vessel is more likely to accept a renal neuromodulation therapy.

[0197] 23. The method of any of examples 19-21, wherein:

[0198] obtaining the baseline measurements comprises:

[0199] obtaining the physiological measurements from a first branch vessel of the renal blood vessel,

[0200] obtaining the physiological measurements from a second branch vessel of the renal blood vessel;

[0201] determining the physiological parameters comprises:

[0202] determining a first physiological parameter based on the physiological measurements obtained from the first branch vessel, and

[0203] determining a second physiological parameter based on the physiological measurements obtained from the second branch vessel;

[0204] comparing the physiological parameters comprises:

[0205] comparing the first physiological parameter to the second physiological parameter; and

[0206] the indication comprises:

[0207] determining whether the first branch vessel or the second branch vessel is more likely to accept a renal neuromodulation therapy.

[0208] 24. The method of example 19, wherein:

[0209] obtaining the baseline measurements comprises measuring pressure and velocity within the renal blood vessel; and

[0210] determining the physiological parameters comprises determining a renal wave speed using the equation:

[0211]

[0212] where P is pressure, U is velocity, and p is the density of blood.

[0213] 25. The method of any of examples 19-24, further comprising:

[0214] advancing a neuromodulation catheter over the guidewire to a target site; and

[0215] Renal neuromodulation therapy is applied using the neuromodulation catheter.

[0216] V. Conclusion

[0217] The present disclosure is not intended to be exhaustive or to limit the techniques to the precise form disclosed herein. Although specific embodiments are disclosed in detail in this document, various equivalent variations are possible as will be appreciated by those skilled in the relevant art, without departing from the techniques. In some instances, well-known structures and functions have not been shown and / or described in detail in order to avoid unnecessarily obscuring the description of the embodiments of the techniques. Although the steps of a method can be presented in a particular order, such an order can be modified in alternative embodiments. Similarly, certain aspects of the techniques disclosed in the context of a particular embodiment can be combined or eliminated in other embodiments. Further, although advantages of the techniques are highlighted in the context of certain embodiments, the techniques can also exhibit other advantages not mentioned in this document. Accordingly, the disclosure and related techniques can encompass other embodiments that perform the same or similar functions without using all of the features and / or benefits of the techniques described in this document. Accordingly, the terms “includes” and / or “containing” as used herein do not exclude the presence of additional elements or steps.

[0218] In the present disclosure, the singular terms “a,” “one,” and “the” include plural referents unless the context clearly dictates otherwise. Similarly, the term “or” as used herein encompasses either “and” or “or,” unless the context clearly dictates otherwise. In addition, the use of the term “including” or “containing” in the context of describing compositions or processes is used to mean that the compositions or processes include at least the recited feature, but not excluding others. Directional terms as used herein—such as “upper,” “lower,” “front,” “back,” “vertical,” and “horizontal”—are made only in relation to the figures, in which the terms “upper” and “lower” refer to the orientation of the figure as shown. It is understood that such terms are not intended to mean absolute orientation. References to “one embodiment,” “an embodiment,” or the like, mean that a particular feature, structure, operation, or characteristic being referred to can be included in at least one embodiment of the techniques. Thus, the appearances of such phrases in various places throughout this document are not necessarily all referring to the same embodiment. Furthermore, various specific features, structures, operations, or characteristics can be combined in any suitable manner in one or more embodiments.

Claims

1. A system for evaluating the efficacy of neuromodulation therapy, the system comprising: A guidewire, wherein the guidewire is configured such that it can be positioned at a target site along a portion of a blood vessel in a human patient; A neuromodulation catheter, wherein the neuromodulation catheter is configured to be advanced over the guidewire to the target site; as well as Controller The guidewire and / or the neuromodulation catheter have sensing elements that are positioned along the guidewire and / or the neuromodulation catheter or combined with the guidewire and / or the neuromodulation catheter. Prior to administering neuromodulation therapy, the controller is configured to: One or more baseline measurements or measurements prior to neural modulation are obtained via the sensing element; One or more baseline physiological parameters or pre-neuromodulation physiological parameters are determined based on the obtained baseline measurements or pre-neuromodulation measurements; Furthermore, after neuromodulation therapy has been administered, the controller is configured to: The neurally modulated measurement value is obtained via the sensing element; One or more neuromodulated physiological parameters are determined based on the obtained neuromodulated measurements; And the controller is further configured to: The physiological parameters before and after neural regulation are compared to detect changes in the corresponding parameters. The difference between the physiological parameters before and after neural regulation is compared with a threshold, and it is detected whether the difference is less than a predetermined threshold or whether the difference is greater than or equal to a predetermined threshold.

2. The system according to claim 1, wherein the physiological parameters before neural regulation and the physiological parameters after neural regulation are hemodynamic physiological parameters.

3. The system according to claim 1 or 2, wherein the physiological parameters before and after neural modulation are blood flow, blood pressure, vascular impedance and / or vascular diameter.

4. The system according to any one of claims 1-3, wherein the sensing element is a pressure sensing element, a flow sensing element, an impedance sensing element, and / or a temperature sensing element.

5. The system according to any one of claims 1-4, wherein the controller is configured to store the baseline measurement or the measurement before neural modulation and / or the baseline physiological parameter or the physiological parameter before neural modulation in the memory of the controller.

6. The system according to any one of claims 1-5, wherein the controller is configured to store the neurally modulated measurements and / or the neurally modulated physiological parameters in the memory of the controller.

7. The system according to any one of claims 1-6, wherein the system is further configured to apply or deliver electrical stimulation and / or pharmacological stimulation to a blood vessel to stimulate nerves at or near the target site.

8. The system of claim 7, wherein the controller is configured to obtain one or more pre-stimulation, pre-neuromodulation measurements and one or more post-stimulation, pre-neuromodulation measurements, and the controller is configured to determine a baseline metric, the baseline metric being the difference between corresponding measurements obtained before stimulation, before neural modulation, and after stimulation, before neural modulation.

9. The system of claim 7 or 8, wherein the controller is configured to obtain one or more pre-stimulation, post-neuromodulation measurements and one or more post-stimulation, post-neuromodulation measurements, and the controller is configured to determine a post-neuromodulation metric, the post-neuromodulation metric being the difference between corresponding measurements obtained before and after stimulation and after stimulation, post-neuromodulation.

10. The system according to claim 9, wherein, The controller is configured to compare the difference between the baseline metric and the neurally modulated metric to detect changes in the corresponding metric.

11. The system according to any one of claims 7-10, wherein the system is configured to apply or deliver electrical stimulation via one or more electrodes of the neuromodulation conduit, or via one or more electrodes disposed at a distal portion of the guidewire, or via one or more electrodes associated with an independent conduit capable of being positioned at or near the target site, or via an external acoustic stimulation device.

12. The system according to any one of claims 7-10, wherein the system is configured to release a pharmacological stimulus at the treatment site via an outlet located along a neuromodulation conduit.

13. The system according to any one of claims 1-12, wherein the controller is configured to determine one or more pre-neuromodulation physiological parameters using the baseline measurement or the pre-neuromodulation measurement, and to compare the determined pre-neuromodulation physiological parameters with a predetermined threshold to predict whether the patient is a responder or a non-responder.

14. A system for evaluating the efficacy of neuromodulation therapy, the system comprising: A guidewire, wherein the guidewire is configured such that it can be positioned at a target site along a portion of a blood vessel in a human patient; A neuromodulation catheter, wherein the neuromodulation catheter is configured to be advanced over the guidewire to the target site; as well as Controller The guidewire and / or the neuromodulation catheter have sensing elements that are positioned along the guidewire and / or the neuromodulation catheter or combined with the guidewire and / or the neuromodulation catheter. The system is configured to apply or deliver electrical and / or pharmacological stimulation to blood vessels to stimulate nerves at or near the target site. Prior to administering neuromodulation therapy, the controller is configured to: The sensing element is used to obtain one or more pre-stimulation and pre-neural modulation measurements, as well as one or more post-stimulation and pre-neural modulation measurements related to one or more physiological parameters. Determine a baseline metric, which is the difference between corresponding measurements obtained before stimulation and before neural modulation, and after stimulation and before neural modulation; Furthermore, after neuromodulation therapy has been administered, the controller is configured to: The sensing element is used to obtain one or more pre-stimulation and post-neuromodulation measurements, as well as one or more post-stimulation and post-neuromodulation measurements related to one or more physiological parameters. Determine the post-neuromodulation metric, which is the difference between corresponding measurements obtained before stimulation and after neural modulation, and between stimulation and after neural modulation. And the controller is further configured to: The difference between the baseline metric and the neurally modulated metric is compared to detect changes in the corresponding metric, and it is detected whether the difference is less than a predetermined threshold or whether the difference is greater than or equal to a predetermined threshold.

15. The system of claim 14, wherein the change in the corresponding metric is representative of a hemodynamic physiological parameter, such as blood flow, blood pressure, vascular impedance, and / or vessel diameter.

16. A system comprising: A guidewire having a proximal portion, a distal portion configured to be positioned at a target site in a renal vessel of a human patient, and a sensing element positioned along the distal portion, wherein the sensing element is a pressure sensing element, a flow sensing element, an impedance sensing element, and / or a temperature sensing element. A controller configured to communicatively connect to the sensing element, wherein the controller is further configured to: One or more measurements related to the patient's physiological parameters are obtained via the sensing element; Physiological parameters are determined based on the measured values; The physiological parameters are compared with predetermined thresholds; as well as Based on the comparison, the operator is given an indication of the patient's likelihood of responding to renal neuromodulation therapy at the target site.

17. The system of claim 16, wherein the sensing element is one of a plurality of sensing elements positioned along the distal portion of the guidewire.

18. The system of claim 16 or claim 17, wherein the physiological parameter is renal wave velocity, and wherein the sensing element is configured to acquire a measurement for determining the renal wave velocity.

19. The system of claim 16 or claim 17, wherein the physiological parameter is renal resistance, and wherein the sensing element is configured to acquire a measurement for determining renal resistance.

20. The system of claim 16 or claim 17, wherein the physiological parameter is average blood pressure, and wherein the sensing element is configured to acquire a measurement for determining the average blood pressure.

21. The system of claim 16 or claim 17, wherein the physiological parameter is average blood flow velocity, and wherein the sensing element is configured to acquire a measurement for determining the average blood flow velocity.

22. The system according to any one of claims 16-21, wherein the sensing element is configured to acquire measurements from the main renal artery, the main bifurcation of the renal artery, and / or one or more renal branches distal to the main bifurcation of the renal artery.

23. The system according to any one of claims 16-22, wherein the controller is further configured to indicate which parts of the blood vessel are more sensitive to neuromodulation therapy based on the physiological parameters.

24. The system according to any one of claims 16-23, wherein the controller is further configured to indicate, based on the physiological parameters, which parts of the blood vessels are less sensitive to neuromodulation therapy.

25. The system according to any one of claims 16-24, further comprising a neuromodulation conduit, wherein said neuromodulation conduit comprises: An elongated shaft defining a lumen therethrough, the elongated shaft having a proximal portion and a distal portion, wherein the distal portion is configured to be positioned at a target location; as well as Multiple electrodes spaced apart along the distal portion of the elongated axis.

26. The system according to claim 25, wherein: The guidewire is configured to be slidably positioned within the lumen of the elongated shaft; and The controller is configured to be communicatively coupled to the plurality of electrodes, wherein the controller is further configured to: Apply the first stimulus at and / or near the target site within the blood vessel; The baseline impedance is determined by detecting the vascular impedance obtained from the first stimulation via at least one of the plurality of electrodes. Neuromodulated energy is delivered to the target site within the blood vessels of the human patient via the distal portion of the elongated shaft; After delivering neuromodulation energy, a second stimulus is applied at and / or near the target site within the blood vessel; The vascular impedance obtained from the second stimulation is detected via at least one of the plurality of electrodes to determine the impedance after neural modulation. as well as The efficacy of neuromodulation is assessed at least in part based on a comparison of the baseline impedance and the neuromodulated impedance.

27. The system of claim 25, wherein the lumen is a first lumen, and wherein the neuromodulation conduit further comprises a second lumen extending along the elongated axis and configured to deliver a drug at and / or near the target site to provide the first stimulation and the second stimulation.

28. The system of claim 25, wherein the distal portion of the elongated shaft is configured to convert into a helical shape such that at least one of the plurality of electrodes is configured to contact the inner wall of the blood vessel, and wherein at least one of the plurality of electrodes is configured to deliver neuromodulation energy.

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