Systems and methods for monitoring and assessing neuromodulation therapy

Abstract

Systems and methods for informing and evaluating neuromodulation therapy are disclosed herein. A system configured in accordance with embodiments of the present technology can 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 can be a pressure sensing element, a flow sensing element, an impedance sensing element, and / or a temperature sensing element. The system can 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 measurements, the controller can determine the physiological parameter and compare the parameter to a predetermined threshold. Based on the comparison, the controller and / or an operator can evaluate the likelihood that the patient would benefit from neuromodulation therapy.

Description

[0001] This application is a divisional application of the invention patent application entitled “Systems and Methods for Monitoring and Evaluating Neuromodulation Therapy”, with an international application date of January 31, 2017, 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 February 1, 2016, and U.S. Provisional Patent Application No. 62 / 346,710, filed June 7, 2016, both of which are incorporated herein by reference in their entireties. 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 therapies and / or assessing the efficacy of neuromodulation therapies. Background Art

[0005] Sympathetic nervous system (SNS) is the mainly non-autonomous body control system that is usually associated with stress response.The fiber of SNS extends through the tissue in almost each organ system of human body and can affect the characteristic such as pupil diameter, intestinal motility and urine output.Such regulation can maintain homeostasis or make health ready to have adaptive utility aspect environmental factors being carried out rapid response.But the chronic overactivation of SNS is a kind of common maladaptive reaction, and it can drive the progress of many disease states.Especially, for mankind, by experiment, the overactivation of the SNS of kidney is identified as the complex pathophysiology factor that may cause arrhythmia, hypertension, volume overload state (for example, heart failure) and progressive nephropathy.

[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] Figure 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] Figure 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. Figure 1A

[0010] Figure 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] Figure 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] Figure 4 is a block diagram illustrating a method for evaluating a neuromodulation therapy according to an embodiment of the technology.

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

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

[0015] Figure 7 The embodiment according to the present technology is shown Figure 6 systems to modulate renal nerves and / or evaluate neuromodulation therapies.

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

[0017] Figure 9 is an enlarged anatomical illustration of the nerves innervating the left kidney to form the renal plexus surrounding the left renal artery.

[0018] Figure 10 and 11 Anatomical and conceptual diagrams of the human body depicting efferent and afferent neural communication between the brain and kidneys, respectively.

[0019] Figure 12 and 13 These are anatomical diagrams of the human arterial and venous vascular systems, 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 a neuromodulation therapy. This information can be used to (1) predict the likelihood that a particular patient will receive a therapeutic benefit ("responsiveness") from a neuromodulation therapy, and / or (2) assess the efficacy of a given neuromodulation therapy. Figure 1A-13 Specific details of several embodiments of the present technology are described. Although many embodiments have been described for devices, systems, and methods for intravascular renal neuromodulation, other applications and other embodiments in addition to those described herein are also within the scope of the present technology. For example, at least some embodiments of the present technology may be effective for intravascular neuromodulation, extravascular neuromodulation, non-renal neuromodulation, and / or therapies other than neuromodulation. It should be noted that other embodiments in addition to those disclosed herein are also within the scope of the present technology. In addition, embodiments of the present technology may have configurations, components, and / or procedures that are different from those illustrated or described herein. Moreover, it should be understood by those of ordinary skill in the art that embodiments of the present technology may have configurations, components, and / or procedures in addition to those illustrated or described herein, and various embodiments may 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 evaluating neuromodulation therapies and related methods

[0023] Figures 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 Figure 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 Figure 1A, the guidewire 101 includes a slender member 103 having a distal portion 103a configured to be positioned at a target site within a blood vessel V and a proximal portion (not visible) extending outside the patient's body 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 the lumen of the neuromodulation catheter 102. For example, in some embodiments, the elongated member 103 can have an outer diameter less than or equal to 0.014 inches. One or more portions of the elongated member 103 can include solid wire and / or wire loops. For example, in some embodiments, the proximal portion 103b of the elongated member 103 includes a solid wire and the distal portion 103a includes a wire loop. In other embodiments, the elongated member 103 includes only a solid wire or only a wire loop, and in other embodiments, the elongated member 103 includes other suitable components and / or configurations. Additionally, the elongated member 103 may have a uniform stiffness along its length, or may 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 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. The measurements obtained by the sensing element 105 and / or the physiological parameters derived based on one or more measurements obtained by the sensing element 105 include, for example: heart rate, temperature, blood pressure (e.g., systolic, diastolic, mean blood pressure), blood flow rate, blood flow velocity, vessel diameter, vessel segment volume, vessel cross-sectional area, vascular distensibility, renal pulse wave velocity, arterial (e.g., renal artery) input impedance (frequency domain), total renal artery resistance, renal artery capacitance, reflected pressure wave amplitude, augmentation index, blood flow reserve, resistance reserve, resistance index, capacitance reserve, hematocrit, and / or any related values ​​and / or derived values ​​(e.g., raw data values, including voltage and / or other direct measurements) of the aforementioned measurements and parameters. It should be appreciated that the foregoing list is provided by way of example only, and in other embodiments, the sensing element 105 may 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 may include one, two, or more than three sensing elements 105. Additionally, in certain embodiments, the guidewire 101 may be Doppler guidewire (Volcano Corporation, San Diego, CA) or Combo XT guidewire (Volcano Corporation, San Diego, CA).

[0026] like Figure 1B As best shown in FIG, the neuromodulation catheter 102 includes an elongated shaft 106 configured to be slidably delivered over a guidewire 101. The elongated shaft 106 has a distal portion 106a configured to be positioned intravascularly at a target site within a blood vessel V and a proximal portion 106b extending outside the patient's body to a handle (not shown) or other feature that allows an operator to manipulate the distal portion 106a of the shaft 106. Figure 1B and 1C As shown, the neuromodulation catheter 102 can be in a first state or arrangement ( Figure 1B ) and a second state or arrangement ( Figure 1C ), in which the distal portion of the neuromodulation catheter 102 is at least substantially straight, and in which the distal portion of the neuromodulation catheter 102 is converted or otherwise expanded into a spiral / helical shape.

[0027] For reference Figure 1B and 1C , the neuromodulation catheter 102 includes a plurality of energy delivery elements, such as electrodes 110 (individually identified as first to fourth electrodes 110a-110d) spaced apart along the distal portion 106a of the shaft 106. In the illustrated embodiment, the neuromodulation catheter 102 includes four electrodes 110. However, in other embodiments, the neuromodulation catheter 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 described below with reference to Figure 5 As described in more detail, the electrodes 110 and / or other features at the distal portion 106a of the shaft 106 can also be configured to apply stimulation at and / or near a target site before and / or after neuromodulation and detect a response (e.g., a hemodynamic response) resulting from the stimulation.

[0028] In other embodiments, the neuromodulation catheter 102 may include electrodes, transducers, or other elements to deliver energy to modulate nerves using other suitable neuromodulation modalities, such as pulsed electrical energy, microwave energy, light energy, ultrasound energy (e.g., intravascular 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 may be configured for cryotherapy, and cryogenic cooling may be applied to the blood vessel V using a refrigerant (e.g., via a balloon catheter circulating a refrigerant). In still other embodiments, the neuromodulation catheter 102 may be configured for chemical-based therapy (e.g., drug infusion), and the neuromodulation catheter 102 may apply one or more chemicals to the treatment site to achieve neuromodulation. Such chemicals may include neurotoxins, antagonists (e.g., citrulline), and / or tissue necrosis-inducing agents (e.g., ethanol). In such embodiments, the mode of neuromodulation (e.g., RF, ultrasound, chemical ablation, cryoablation) may be different from the mode of stimulation (e.g., electrical stimulation or chemical stimulation).

[0029] The dimensions (e.g., outer diameter and length) of the spiral / helical portion of the shaft 106 can be selected to accommodate the blood vessel or other body cavity in which the distal portion 106a of the neuromodulation catheter 102 is designed to be delivered. For example, the axial length of the spiral / helical portion of the shaft 106 can be selected to be no longer than the patient's renal artery (e.g., typically less than 7 cm) and have a diameter that accommodates the inner diameter of a typical renal artery (e.g., approximately 2-10 mm). In other embodiments, the spiral / helical portion of the shaft 106 can have other dimensions depending on the body cavity in which the shaft is configured to be deployed. In other embodiments, the distal portion 106a of the shaft 106 can have other suitable shapes (e.g., semicircular, 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 be substantially the same when expanded to the spiral / helical deployment state (e.g., in FIG. 1 ). Figure 1C ) when applying a desired outward radial force to the blood vessel to position the one or more electrodes 110 into contact with the vessel wall.

[0030] like Figure 1B and 1CAs shown, the distal portion 106a of the neuromodulation catheter 102 can optionally include an outlet 112 configured to provide an acute infusion of an agent suitable for stimulating the blood vessel V or adjacent nerves to cause a hemodynamic or hyperemic response (e.g., vasodilation). In the illustrated embodiment, for example, the outlet 112 is positioned near the electrode 110 so that the agent can flow distally through the blood vessel toward the electrode 110 after injection, but in other embodiments, the outlet 112 can be positioned elsewhere along the neuromodulation catheter 102 (e.g., between or distal to the electrodes 110). 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) for the agent. Suitable agents can include vasodilators such as adenosine, bradykinin, dipyridamole, papaverine, and / or sympathetic agonists such as epinephrine, norepinephrine, angiotensin II, and the like. In the case of sympathetic agonists, a lack of an immediate hemodynamic response in 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 bulb, applying neuropsychological stress to the patient (e.g., the Stroop color test), etc. As described above, outlet 112 is an optional component that may not be included in some embodiments.

[0031] The neuromodulation catheter 102 may 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 before, 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 the one or more measurements obtained by the sensing element 114 can be the same or similar to any of the measurements and / or physiological parameters described above with respect to the guidewire 101 and the sensing element 105.

[0032] although Figures 1A-1CThe illustrated embodiment of the neuromodulation catheter 102 has a spiral / helical 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 the following: 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 / 281,360, filed October 25, 2011; U.S. Patent Application No. 13 / 281,360, filed October 25, 2011; No. 81,361, filed on October 25, 2011; PCT Application No. PCT / US11 / 57754, filed on October 25, 2011; U.S. Provisional Patent Application No. 61 / 646,218, filed on May 5, 2012; U.S. Patent Application No. 13 / 793,647, filed on March 11, 2013; U.S. Provisional Patent Application No. 61 / 961,874, filed on October 24, 2013; and U.S. Patent Application No. 13 / 670,452, filed on November 6, 2012. All of the above applications are incorporated herein by reference in their entirety. Non-limiting examples of devices and systems include 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 may include independent access ports for receiving wired connections for the guidewire 101 and the neuromodulation catheter 102. In other embodiments, the console may include a single access port that can be used with both the guidewire 101 and the neuromodulation catheter 102 simultaneously or with one of them at a time. In other embodiments, the system 100 may 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 for 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] Figure 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: Figures 1A-1C Figure 2 Figure 1A Figure 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 therapeutically 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 value can be automatically performed by the controller 104 and / or another feature of the system 100. Based on the comparison, the controller 104 can provide an indication to the operator whether the patient is a responder or a non-responder. For example, in an embodiment where the controller 104 calculates renal wave velocity, if the renal wave velocity is above a predetermined threshold value or outside a predetermined threshold value, the controller 104 can indicate that the patient is likely a non-responder (block 212) or has a low likelihood of benefiting from neuromodulation therapy. Additionally, in some embodiments, the controller 104 can also recommend not continuing with neuromodulation therapy. However, if the renal wave velocity is below a predetermined threshold value or within a predetermined threshold value, the controller 104 can indicate that the patient is likely a responder (block 210), and in some embodiments, can recommend continuing with neuromodulation therapy. In certain embodiments, for example, the 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 baseline measurements indicate that the patient is likely a responder and the operator elects to proceed with neuromodulation therapy, the operator may then advance the neuromodulation catheter 102 over the guidewire 101 to the target site, e.g. Figure 1B The operator can then withdraw the guidewire 101 to a position proximal to the distal portion 106a of the neuromodulation catheter 102 to deploy the neuromodulation catheter 102 (e.g. Figure 1C ) and begins delivering neuromodulatory energy at the target site.

[0042] In some embodiments, it may be advantageous to leave a portion of the guidewire 101 distal to the distal end of the neuromodulation catheter 102 when the neuromodulation catheter 102 is deployed so that the one or more sensing elements 105 remain positioned in the vessel lumen and are able to sense one or more physiological parameters. For example, Figure 3One embodiment of a system 300 configured in accordance with the present technology is shown in a deployed configuration comprising 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 within the lumen of the elongated shaft 106 at the distal portion 106a. To deploy the neuromodulation catheter 102, an operator may advance the neuromodulation catheter 102 over the guidewire 301 until the distal portion 106a of the neuromodulation catheter 102 is aligned with the flexible region and allowed to assume its preset shape. Figure 3 As shown, even when the neuromodulation catheter 102 is in its deployed configuration, the distal region 309 of the guidewire 301 remains distal to the neuromodulation catheter 102, as does the sensing element 305 positioned along the exposed distal region 309. Thus, while the neuromodulation catheter 102 is administering neuromodulation therapy, at least the exposed sensing element 305 can continue to detect one or more physiological parameters.

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

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

[0045] In certain embodiments, the sensing element 114 of the neuromodulation catheter 102 may 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 should be appreciated that although the guidewire 101 / 301 and neuromodulation catheter 102 described above are configured for "over-the-wire" delivery of the neuromodulation catheter 102, other configurations are also 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 "quick 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 accommodate the neuromodulation catheter 102 and / or guidewire 101 / 301 during delivery.

[0047] B. Methods for Assessing the Efficacy of Neuromodulation Therapies

[0048] It is expected that successful or effective neuromodulation therapy (i.e., when nerves are ablated to a desired extent) will result in a hemodynamic response, which can be reflected by local and / or global changes in hemodynamic physiological parameters (e.g., blood flow, blood pressure, and 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] Figure 4 is a block diagram illustrating a method 400 for evaluating the efficacy of neuromodulation therapy according to an embodiment of the present technology. Figures 1A-1C 、 Figure 3The method 400 may be implemented using the system 100 described above and / or other suitable systems for evaluating the efficacy of neuromodulation therapy. For example, the guidewire 101, the neuromodulation catheter 102, and / or the controller 104 may be used to perform the various steps of the method 400. Figure 4 As shown, method 400 includes positioning a guidewire 101 at a target site (refer to FIG. 1 ) along a portion of a blood vessel V of a human patient prior to delivering neuromodulation energy. Figure 1A ), and obtaining a baseline measurement via a sensing element 105 positioned (or otherwise incorporated) along the guidewire 101 (box 402). The method 400 also includes transmitting the obtained measurement to the controller 104, and determining one or more baseline physiological parameters based on the obtained measurement (box 404). In some embodiments, the obtained baseline measurement 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 measurement, the method 400 optionally includes determining one or more physiological parameters using the baseline measurement and comparing the determined physiological parameters to a predetermined threshold to predict whether the patient is a responder or a non-responder, as described above with reference to Figure 2 Details.

[0050] If the operator elects to proceed with neuromodulation therapy, the method 400 includes advancing the neuromodulation catheter 102 over the guidewire 101 to the target site (see Figure 1B ), and then the guidewire 101 is withdrawn through the lumen of the neuromodulation catheter to a position at least within the lumen adjacent 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 Figure 1C ). As shown in block 406, the neuromodulation catheter 102 can then perform neuromodulation at the target site to ablate nerves adjacent to the vessel wall. For example, the method 400 can include applying RF energy (e.g., via electrodes), pulsed electrical energy, microwave energy, light 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 neuromodulation therapy is performed, the guidewire 101 can be advanced distally within the lumen of the elongated shaft 106, thereby converting the distal portion 106a to a generally straight, low-profile configuration (see FIG. Figure 1B The neuromodulation catheter 102 can then be withdrawn from the target site to expose the distal portion 103a of the guidewire 101 (see Figure 1A). The method 400 also includes obtaining, via the exposed sensing element 105, measurements related to one or more physiological parameters following neuromodulation therapy (block 408), and transmitting the obtained measurements to the controller 104. As shown in block 410, the obtained measurements can then be used to determine the one or more physiological parameters. In some embodiments, the obtained post-neuromodulation measurements and / or the determined post-neuromodulation physiological parameters can be stored by a memory of the controller and / or another feature of the system 100.

[0052] The post-neuromodulation and pre-neuromodulation physiological parameters (e.g., vascular impedance, vascular diameter, etc.) can then be compared to detect changes, if any, in the corresponding parameters as a result of the neuromodulation therapy (block 412). 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 and pre-neuromodulation parameters can be compared to a threshold value (block 414). For example, the threshold value can be equal to a percentage reduction (e.g., a 15% reduction, a 20% reduction, a 50% reduction, a 100% reduction, etc.) in one or more parameters (e.g., impedance or vascular diameter, 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 discontinue the neuromodulation therapy (block 416). 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 monitor the hemodynamic response (e.g., change in vascular impedance or diameter), as described above. Alternatively or additionally, the operator may 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 (eg, vessel impedance or diameter) at the new treatment site.

[0053] Although many hemodynamic parameters can be measured without applying stimulation, in certain procedures it may be beneficial to additionally or alternatively stimulate the nerve at or near the neuromodulation site before and after the neuromodulation therapy and measure the changes in the hemodynamic response resulting from each stimulation. Figure 5In detail, the system 100 can be configured to apply or deliver electrical and / or drug stimulation to a blood vessel to stimulate nerves at or near a target site. As used herein, stimulation refers to stimulation that is sufficient to cause a neural response in nerves (e.g., renal nerves) near a blood vessel V, but not so great that they permanently affect neural function. The stimulation can be applied proximal to the neuromodulation site, distal to the neuromodulation site, and / or on either side of the neuromodulation site. For example, in some embodiments, the stimulation is applied at a blood vessel orifice (e.g., a renal artery orifice). However, in other embodiments, the stimulation can be applied at other suitable locations.

[0054] When a nerve is active (i.e., conducting a signal), the afferent nerve will respond to the stimulus and result in a hemodynamic response. This hemodynamic response can be measured by detecting changes in vessel size (e.g., diameter, cross-sectional area, and segment volume), pressure within the vessel, blood flow through the vessel, heart rate, and / or other parameters indicative of the hemodynamic response. It is expected that after the nerves have been effectively ablated to the desired extent, the hemodynamic response to the stimulus will be eliminated or at least mitigated because the afferent nerves have been ablated or modulated. Therefore, it is envisioned to compare the hemodynamic response to the stimulus before and after neuromodulation to indicate whether the neuromodulation therapy is successful.

[0055] Figure 5 is a block diagram illustrating a method 500 for evaluating the efficacy of neuromodulation therapy according to an embodiment of the present technology. Figures 1A-1C 、 Figure 3 The system 100 described above and / or other suitable systems for evaluating the efficacy of neuromodulation therapy can be implemented. For example, the guidewire 101, the neuromodulation catheter 102, and / or the controller 104 can be used to perform the various steps of the method 500. Figure 5 As shown, method 500 includes positioning a guidewire 101 at a target site along a portion of a blood vessel V of a human patient prior to delivering neuromodulation energy (see Figure 1A ), and obtaining a baseline measurement via a sensing element 105 positioned (or otherwise incorporated) along a guidewire 101 (block 502). Alternatively or additionally, the method 500 may include advancing the neuromodulation catheter 102 over the guidewire 101 to a target site, and positioning the neuromodulation catheter 102 in a substantially straight configuration along a portion of the blood vessel V (block 503). Figure 1B Prior to delivering neuromodulation energy, the sensing element 114 of the neuromodulation catheter 102 can be used to obtain baseline measurements.

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

[0057] At any time prior to applying neuromodulation energy, method 500 optionally includes determining one or more physiological parameters using baseline measurements 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 Figure 2 As detailed.

[0058] If the operator elects to continue with neuromodulation therapy, the method 500 includes withdrawing the guidewire 101 through the lumen of the neuromodulation catheter 102 to at least a position within the lumen adjacent 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. Figure 1C ). As shown in block 510, the neuromodulation catheter 102 can then perform neuromodulation at the target site to ablate nerves adjacent to the vessel wall. For example, the method 500 can include applying RF energy (e.g., via electrodes), pulsed electrical energy, microwave energy, light 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 neuromodulation is performed, the guidewire 101 can be advanced distally within the lumen of the elongated shaft 106, thereby converting the distal portion 106a to a generally straight, low-profile configuration (see FIG. Figure 1B Method 500 also includes obtaining measurements related to one or more physiological parameters following neuromodulation therapy via sensing element 105, sensing element 114, and / or electrode 110 of guidewire 101 (block 512). (A portion of guidewire 101 may be exposed distal to neuromodulation catheter 102 and / or neuromodulation catheter 102 may be at least partially withdrawn from the target site along 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 substantially straight configuration, Figure 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 evaluating 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 on October 1, 2015 and U.S. patent application No. 13 / 670,452 filed on November 6, 2012, both of which are incorporated herein by reference in their entirety.

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

[0064] Figure 6 is a partial schematic diagram of a treatment system 600 ("system 600") configured in accordance with yet another embodiment of the present technology. System 600 may include the same Figures 1A-1C 3 and 400, and can be used to implement the various methods 200 and 400 described above. Figure 6 As shown, system 600 includes a neuromodulation catheter 602, a console 604, and a cable 606 extending therebetween. Neuromodulation catheter 602 may include an elongated shaft 608 having a proximal portion 608b, a distal portion 608a, a handle 610 operably connected to shaft 608 at proximal portion 608b, and a neuromodulation assembly 620 operably connected to shaft 608 at distal portion 608a. Shaft 608 and neuromodulation assembly 620 may be 2, 3, 4, 5, 6, or 7 French or another suitable size. Figure 6 As shown, the neuromodulation assembly 620 may include a support structure 622 carrying an array of two or more electrodes 624. The electrodes 624 may be configured to apply electrical stimulation (e.g., RF energy) to a target site in or near a patient's body, temporarily induce neurological sedation, deliver neuromodulation energy to a target site, and / or detect vascular impedance. In various embodiments, certain electrodes 624 may be dedicated to applying stimulation and / or detecting impedance, and the neuromodulation assembly 620 may include other types of therapeutic elements that provide neuromodulation therapy using various modalities (e.g., cryotherapeutic 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 of a selected form and / or magnitude 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 therapy, 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, light energy, ultrasound 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 cryotherapy, the console 604 can include a cryogen container (not shown) and can be configured to supply cryogen to the neuromodulation catheter 602. Similarly, when the neuromodulation catheter 602 is configured for chemical-based therapy (eg, drug infusion), the console 604 may include a chemical reservoir (not shown) and may 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 a unipolar electric field via one or more electrodes 624. In such embodiments, a neutral or dispersive electrode 630 can be electrically connected to the console 604 and attached to the patient's body. In embodiments including multiple electrodes 624, the electrodes 624 can independently deliver power simultaneously, selectively, or sequentially (i.e., capable of being used in a unipolar manner), and / or power can be delivered between any desired combination of electrodes 624 (i.e., capable of being used in a bipolar manner). Additionally, the operator can optionally be allowed to select which electrodes 624 are used 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 near, 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, the system 600 may further include a controller 614 communicatively coupled to the neuromodulation catheter 602. The controller 614 may be configured to initiate, terminate, and / or regulate the operation of one or more components (e.g., electrodes 624) of the neuromodulation catheter 602, directly and / or via the console 604. In other embodiments, the controller 614 may be omitted or have other suitable locations (e.g., within the handle 610, along the cable 606, etc.). The controller 614 may be configured to execute automatic control algorithms and / or receive control instructions from an operator. In addition, the console 604 may be configured to provide feedback to the operator before, during, and / or after the treatment procedure via an evaluation / feedback algorithm 616.

[0070] Figure 7 (See also Figure 6 ) shows modulation of renal nerves according to an embodiment of a system 600. A neuromodulation catheter 602 provides access to the renal plexus RP via an intravascular pathway P, such as a percutaneous access site 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 the shaft 608 from outside the intravascular pathway P, the clinician can advance the shaft 608 through the sometimes tortuous intravascular pathway P and remotely manipulate the distal portion 608a of the shaft 608 ( Figure 6 ).exist Figure 7 In the illustrated embodiment, the neuromodulation assembly 620 is intravascularly delivered to the treatment site using a guidewire 636 in an over-the-air (OTW) technique. As previously described, the distal end of the neuromodulation assembly 620 can define a channel for receiving the guidewire 636 for delivery of the neuromodulation catheter 602 using either an over-the-air (OTW) or RX technique. At the treatment site, the guidewire 636 can be at least partially withdrawn or removed, and the neuromodulation assembly 620 can be converted or otherwise moved to a deployed configuration for recording neural activity and / or delivering energy at the treatment site. In other embodiments, the neuromodulation assembly 620 can be delivered to the treatment site within a guide sheath (not shown) with or without the use of the guidewire 636. Once the neuromodulation assembly 620 is at the target site, the guide sheath can be at least partially withdrawn or retracted, and the neuromodulation assembly 620 can be converted to a deployed configuration. In still other embodiments, the shaft 608 itself can be steerable, such that the neuromodulation assembly 620 can be delivered to the treatment site without the aid of the guidewire 636 and / or 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 that can associate the target treatment site with an identifiable anatomical structure (e.g., a spinal feature) and / or a radiopaque ruler (e.g., positioned beneath or above the patient). Furthermore, in some embodiments, an image guidance component (e.g., IVUS, OCT) can be integrated with the neuromodulation catheter 602 and / or extend parallel to the neuromodulation catheter 602 to provide image guidance during positioning of the neuromodulation assembly 620. For example, an image guidance component (eg, IVUS or OCT) can be coupled to the neuromodulation assembly 620 to provide a three-dimensional image of the vasculature adjacent to the target site to facilitate positioning or deployment of the multi-electrode assembly within the target renal vessel.

[0072] Then the light from electrode 624 ( Figure 6 ) and / or other energy delivery elements are applied to target tissue to induce one or more desired neuromodulatory effects on a localized area of ​​the renal artery RA and on an adjacent area of ​​the renal plexus RP that is closely located within the adventitia of the renal artery RA, close to the adventitia of the renal artery RA, or in close proximity to the adventitia of the renal artery RA. The purposeful application of energy can achieve neuromodulation along all or at least a portion of the renal plexus RP. The neuromodulatory effect generally depends at least in part on power, time, contact between the energy delivery element and the vessel wall, and blood flow through the vessel. The neuromodulatory effect can include denervation, thermal ablation, and / or non-ablative thermal change or injury (e.g., by continuous heating and / or resistive heating). The desired thermal heating effect can include raising the temperature of the target nerve fibers above a desired threshold to achieve non-ablative thermal change, or above a higher temperature to achieve non-ablative thermal change. For example, for non-ablative thermal change, the target temperature can be higher than body temperature (e.g., about 37°C) but lower than about 45°C, or for ablative thermal change, the target temperature can be about 45°C or higher. Desirable non-thermal neuromodulatory effects may include altering electrical signals transmitted in nerves.

[0073] The cryogenic effect can also provide neuromodulation. For example, a cryotherapy applicator can be used to cool tissue at a target site to provide therapeutically effective direct cell injury (e.g., necrosis), vascular injury (e.g., by depriving cells of nutrients by destroying the supply vessels), and sublethal hypothermia with subsequent apoptosis. Exposure to cryotherapy cooling can result in acute cell death (e.g., death immediately upon exposure) and / or delayed cell death (e.g., during tissue thawing and subsequent hyperperfusion). Embodiments of the present technology can include cooling structures at or near the inner surface of the renal artery wall such that adjacent (e.g., adjacent) tissue is effectively cooled to a depth where the sympathetic renal nerves are located. For example, the cooling structure is cooled to an extent that causes therapeutically effective cryogenic renal neuromodulation. Sufficient cooling of at least a portion of the sympathetic renal nerves is expected to slow or potentially block the 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 intravascularly apply stimulation to the renal artery RA and detect the hemodynamic response to the stimulation 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 ( Figure 6 ) can process the detected hemodynamic responses before and after neuromodulation, and compare the changes in the hemodynamic responses with predetermined thresholds to evaluate whether the neuromodulation therapy is effective at the treatment site or a specific ablation site.

[0075] II. Renal neuromodulation

[0076] Renal neuromodulation is the partial or complete incapacitation or other effective disruption of the nerves of the kidney (e.g., nerves terminating in the kidney or in structures closely associated with the kidney). In particular, renal neuromodulation can include inhibiting, reducing, and / or blocking neural communication in renal nerve fibers (e.g., efferent and / or afferent nerve fibers). This incapacitation 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). It is expected that renal neuromodulation will contribute to a systemic reduction in sympathetic tone or drive and / or benefit at least some specific organs and / or other body structures innervated by the sympathetic nerves. Thus, it is expected that renal neuromodulation can be effective in treating clinical conditions associated with systemic sympathetic overactivity or hyperactivity, particularly conditions associated with overstimulation of the central sympathetic nerves. 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.

[0077] During the treatment procedure, renal neuromodulation can be induced at one or more suitable target sites electrically, thermally, chemically, or in other suitable ways or combinations of ways. The target site can be located within or otherwise adjacent to the renal cavity (e.g., the renal artery, ureter, renal pelvis, major renal calyx, minor renal calyx, or another suitable structure), and the tissue treated can include tissue at least adjacent to the renal cavity wall. For example, with respect to the renal artery, the treatment procedure can include modulating nerves in the renal plexus, which are located closely within or near the adventitia of the renal artery.

[0078] Renal neuromodulation can include a cryotherapeutic modality alone or in combination with another therapeutic modality. Cryotherapy can include cooling tissue at a target site in a manner that modulates neural function. For example, sufficient cooling of at least a portion of the sympathetic renal nerves can slow or potentially block the conduction of nerve signals to produce a prolonged or permanent reduction in renal sympathetic nerve activity. This effect can occur due to cryotherapeutic tissue damage, which can include, for example, direct cell damage (e.g., necrosis), vascular or luminal damage (e.g., by depriving cells of nutrients by destroying the supply vessels), and / or sublethal hypothermia with subsequent apoptosis. Exposure to cryotherapeutic cooling can result in acute cell death (e.g., immediate death upon exposure) and / or delayed cell death (e.g., during tissue thawing and subsequent hyperperfusion). Neuromodulation using cryotherapeutic methods according to embodiments of the present technology can include cooling structures adjacent to the inner surface of a body cavity wall so that the tissue is effectively cooled to the depth at which the sympathetic renal nerves are located. For example, in some embodiments, the cooling component of the cryotherapeutic device can be cooled to the extent that it causes therapeutically effective low-temperature renal neuromodulation. In other embodiments, the cryotherapeutic modality can include cooling that is not configured to cause neuromodulation. For example, cooling may be at or above cryogenic temperatures and may be used to control neuromodulation via another therapeutic modality (eg, to protect tissue from neuromodulatory energy).

[0079] Renal neuromodulation can include a separate electrode-based or transducer-based treatment modality or in combination with another treatment modality. Electrode-based or transducer-based treatment can include delivering electricity and / or other forms of energy to the tissue at the treatment location to stimulate and / or heat the tissue in a manner that regulates neural function. For example, fully stimulating and / or heating at least a portion of the sympathetic renal nerves can slow down or potentially block the conduction of nerve 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 the tissue at the treatment site. For example, neuromodulation according to an embodiment of the present technology can include delivering RF energy, pulsed electrical energy, microwave energy, light energy, focused ultrasound energy (e.g., high-intensity focused ultrasound energy) or another suitable type of energy, alone or in combination. The electrodes or transducers used to deliver this energy can be used alone or in combination with other electrodes or transducers in a multi-electrode or multi-transducer array. In addition, energy can be applied from within the body (e.g., within the vascular system or other body cavity in a catheter-based approach) and / or from outside the body (e.g., via an applicator located outside the body). Furthermore, when target tissue adjacent to non-target tissue is subjected to neuromodulatory cooling, the energy can be used to reduce damage to the non-target tissue.

[0080] Neuromodulation using focused ultrasound energy (e.g., high-intensity focused ultrasound energy) can be beneficial relative to neuromodulation using other therapeutic modalities. Focused ultrasound is an example of a transducer-based therapeutic modality that can be delivered from outside the body. Focused ultrasound therapy can be performed in close association with imaging (e.g., magnetic resonance imaging, computed tomography, fluoroscopy, ultrasound (e.g., intravascular or intraluminal), optical coherence tomography, or other suitable imaging modalities). For example, imaging can be used to identify the anatomical location of the 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 the power, angle, phase, or other suitable parameters to generate an ultrasound focal zone at a location corresponding to the coordinates. The focal zone can be small enough to localize therapeutically effective heating at the treatment site while partially or completely avoiding potentially harmful damage to nearby structures. To create the focal zone, the ultrasound device can be configured to pass the ultrasound energy through a lens, and / or the ultrasound energy can be generated by a curved transducer or by multiple transducers in a phased array (curved or straight).

[0081] The heating effects of electrode-based or transducer-based treatments can include ablative and / or non-ablative changes or damage (e.g., by continuous heating and / or resistive heating). For example, a treatment procedure can include raising the temperature of a target nerve fiber to a target temperature above a first threshold to achieve non-ablative changes, or above a second, higher threshold to achieve ablation. For non-ablative changes, 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, heating the tissue to a temperature between about body temperature and about 45°C can result in non-ablative changes by moderately heating the target nerve fiber or the vascular or luminal structure that perfuses the target nerve fiber. In cases where the vascular structure is affected, perfusion of the target nerve fiber can be denied, resulting in necrosis of the neural tissue. For example, heating the tissue to a target temperature above about 45°C (e.g., above about 60°C) can result in ablation by massively heating the target nerve fiber or the vascular or luminal structure that perfuses the target fiber. In some patients, it may be desirable to heat tissue to a temperature sufficient to ablate target neural fibers or vascular or luminal structures, 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 single chemical-based treatment modality or in combination with another treatment modality. Neuromodulation using chemical-based treatments can include delivering one or more chemicals (e.g., drugs or other agents) to the tissue at the treatment site in a manner that modulates neural function. For example, the chemical can be selected to generally affect the treatment site or selectively affect some structures at the treatment site rather than other structures. For example, the chemical can be guanethidine, ethanol, phenol, neurotoxin, or another suitable agent selected to change, damage, or destroy nerves. Various suitable techniques can be used to deliver the chemical to the tissue at the treatment site. For example, the chemical can be delivered via one or more needles from outside the body or within the vascular system or other body cavities. In an intravascular example, a catheter can be used to position a treatment element comprising multiple needles (e.g., microneedles) within the blood vessel, which can be retracted or otherwise blocked prior to deployment. In other embodiments, the chemical can be introduced into the tissue at the treatment site via simple diffusion through the body cavity wall, electrophoresis, or other suitable mechanisms. Similar techniques can be used to introduce chemicals that are not configured to cause neuromodulation but instead promote neuromodulation through another treatment modality.

[0083] III. Related anatomy and physiology

[0084] As previously mentioned, the sympathetic nervous system (SNS) is a branch of the autonomic nervous system and the enteric nervous system and parasympathetic nervous system. It is always active at the basal level (called sympathetic tone) and becomes more active during stress. Like other parts of the nervous system, the sympathetic nervous system works by a series of interconnected neurons. Sympathetic neurons are generally considered to be a part of the peripheral nervous system (PNS), but many are located in the central nervous system (CNS). The sympathetic neurons of the spinal cord (which are a part of the CNS) communicate with peripheral sympathetic neurons via a series of sympathetic ganglia. In the ganglion, spinal sympathetic neurons connect with peripheral sympathetic neurons by synapses. Therefore, spinal sympathetic neurons are referred to as presynaptic (or preganglionic) neurons, and peripheral sympathetic neurons are referred to as postsynaptic (or postganglionic) neurons.

[0085] At the synapses within the sympathetic ganglia, preganglionic sympathetic neurons release acetylcholine, a chemical messenger that binds to and activates the nicotinic acetylcholine receptors on postganglionic neurons. In response to this stimulation, postganglionic neurons primarily release norepinephrine (norepinephrine). Prolonged activation may 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 triggers 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 to cholinergic receptors on sweat glands.

[0087] Sympathetic nervous system is responsible for many homeostatic mechanisms in up-regulation and down-regulation or organism. Fiber from SNS dominates tissue in almost every organ system, for physiological characteristics such as pupil diameter, intestinal motility and urine output provide at least some regulatory functions. This reaction is also referred to as the sympathetic nerve-adrenal response of health, and reason is that the preganglionic sympathetic nerve fibers (and all other sympathetic nerve fibers) that end in the adrenal medulla secrete acetylcholine, and acetylcholine activates the secretion of epinephrine (adrenal hormone), and activates the secretion of norepinephrine (norepinephrine) to a lesser extent. Therefore, this reaction that mainly acts on cardiovascular system is directly mediated by the impulse that sympathetic nervous system transmits, and is indirectly mediated by the catecholamines secreted by adrenal medulla.

[0088] The SNS is generally considered an autoregulatory system in science, meaning it operates without conscious thought. Some evolutionary theorists believe that the sympathetic nervous system functioned in early organisms to maintain survival because it is responsible for initiating bodily action. An example of this initiation is the moment before waking, when sympathetic nervous system outflow spontaneously increases in preparation for action.

[0089] A. Sympathetic chain

[0090] like Figure 8 As shown, SNS provides a neural network that allows the brain to communicate with the body. The sympathetic nerve originates from the inside of the spine, towards the middle of the spinal cord in the intermediolateral cell column (or lateral horn), starting from the first thoracic segment of the spinal cord and being considered to extend to the second or third lumbar segment. Because its cells begin in the thoracic and lumbar regions of the spinal cord, the SNS is said to have a thoracolumbar outflow. The axons of these nerves make the spinal cord pass through the anterior rootlet / root. They pass near the spinal (sensory) ganglion, where they enter the anterior rami of the spinal nerves. However, different from somatic innervation, they are rapidly separated by white branch connectors, which are connected to the paravertebral (it is located near the spine) or prevertebral (it is located near the aortic bifurcation) ganglia extending beside the spine.

[0091] To reach their target organs and glands, axons must travel long distances within the body. To achieve this, many axons transmit their message to a second cell via synaptic transmission. The end of the axon connects across space (i.e., a synapse) to the dendrites of the second cell. The first cell (the presynaptic cell) sends a neurotransmitter across the synaptic cleft, where it activates the second cell (the postsynaptic cell). The message is then transmitted to its final destination.

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

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

[0094] 1. Renal innervation

[0095] like Figure 9 As shown in Figure 1, the kidney is innervated by the renal plexus (RP), which is closely related to the renal artery. The renal plexus (RP) is an autonomic nerve plexus that surrounds the renal artery 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 cause the renal plexus (RP) originate from the celiac ganglion, superior mesenteric ganglion, aortic ganglion and aortic plexus. The renal plexus (RP), also known as the renal nerve, is mainly composed of sympathetic components. The kidney does not have (or at least has only very small) parasympathetic innervation.

[0096] The preganglionic neuron cell body is located in the intermediolateral cell column of the spinal cord. The preganglionic nerve axons pass through the paravertebral ganglia (they do not synapse) to become the small splanchnic nerve, the smallest splanchnic nerve, the first lumbar splanchnic nerve, the second lumbar splanchnic nerve, and proceed to the celiac ganglion, the superior mesenteric ganglion and the aortic renal ganglion. The postganglionic neuron cell body leaves the celiac ganglion, the superior mesenteric ganglion and the aortic renal ganglion and enters the renal plexus (RP) and is distributed to the renal vasculature.

[0097] 2. Renal sympathetic nerve activity

[0098] Messages flow through social media in a bidirectional stream. Outgoing messages can trigger changes in different parts of the body simultaneously. For example, the sympathetic nervous system may accelerate heart rate; dilate bronchial passages; reduce bowel movements (movement); constrict blood vessels; increase esophageal motility; cause pupil dilation, piloerection (goose bumps), and perspiration (sweating); and increase blood pressure. Afferent messages carry signals from various organs and sensory receptors in 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 an adverse adaptation that drives the progression of these disease states. Drug management of the renin-angiotensin-aldosterone system (RAAS) has been a long-standing but somewhat ineffective method for reducing SNS overactivity.

[0100] As mentioned above, the renal sympathetic nervous system has been identified as a major factor in the complex pathophysiology of hypertension, states of volume overload (e.g., heart failure), and progressive renal disease, both experimentally and in humans. Studies using radiotracer dilution to measure norepinephrine overflow from the kidney to plasma have shown that the rate of renal norepinephrine (NE) overflow is increased in patients with essential hypertension, particularly in young hypertensive patients, consistent with increased NE overflow from the heart, 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 with significant 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 nerve 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 entire central nervous system through renal sensory afferent nerves. Several forms of "kidney injury" can induce activation of sensory afferent signals. For example, renal ischemia, decreased stroke volume or renal blood flow, or adenosine enzyme abundance may trigger activation of afferent nerve communication. Figure 10 and 11 As shown in Figure 2, this incoming communication may be from the kidney to the brain, or may be from one kidney to another kidney (via the central nervous system). These incoming signals are centrally integrated and may result in increased sympathetic outflow. This sympathetic drive targets the kidney, thereby activating the RAAS and inducing increased renin secretion, sodium retention, volume retention, and vasoconstriction. Central sympathetic nerve activity also affects other organs and body structures (such as the heart and peripheral vascular system) innervated by the sympathetic nerves, resulting in the adverse effects of the sympathetic activation, several aspects of which also contribute to elevated blood pressure.

[0107] Physiology therefore suggests that (i) modulation of tissue with efferent sympathetic nerves will reduce inappropriate renin release, salt retention, and decreased renal blood flow, and (ii) modulation of tissue with afferent sensory nerves will reduce systemic contributions to hypertension and other disease states associated with increased central sympathetic tone through its direct effects on the posterior hypothalamus and contralateral kidney. In addition to the central 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, such as the heart and vasculature.

[0108] B. Other clinical benefits of renal denervation

[0109] As described above, renal denervation may be valuable in treating several clinical conditions characterized by increased renal sympathetic nerve activity in general and specifically, 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 nerve signals contributes to a systemic reduction in sympathetic tone / drive, renal denervation may also be used to treat other conditions associated with systemic sympathetic overactivity. Thus, renal denervation may also benefit other organs and body structures innervated by the sympathetic nerves, including Figure 8 For example, as previously mentioned, reduction of central sympathetic drive can reduce insulin resistance in patients with metabolic syndrome and type 2 diabetes. Additionally, patients with osteoporosis are also sympathetically activated and may also benefit from downregulation of sympathetic drive that accompanies renal denervation.

[0110] C. Achieving intravascular access to the renal arteries

[0111] According to the present technology, neuromodulation of the left and / or right renal plexus (RP) closely associated with the left and / or right renal arteries can be achieved through intravascular access. Figure 12 As shown, blood moved by the heart's contractions is carried from the heart's left ventricle via the aorta. The aorta descends through the chest cavity and branches into the left and right renal arteries. Below the renal arteries, the aorta bifurcates into the left and right iliac arteries. The left and right iliac arteries descend through the left and right legs, respectively, and connect to the left and right femoral arteries.

[0112] like Figure 13 As shown, blood collects in the veins and returns to the heart, passing through the femoral vein into the iliac veins and into the inferior vena cava. The inferior vena cava branches into the left and right renal veins. Above the renal veins, the inferior vena cava ascends to carry blood to the right atrium of the heart. From the right atrium, blood is pumped through the right ventricle to the lungs, where it is oxygenated. From the lungs, oxygenated blood is transported to the left atrium. From the left atrium, oxygenated blood is returned to the aorta by the left ventricle.

[0113] As will be described in more 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 inserted percutaneously through this access site into the femoral artery, through the iliac arteries and aorta, and placed into the left or right renal artery. This includes an intravascular route that provides minimally invasive access to the respective renal artery and / or other renal blood vessels.

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

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

[0116] Because neuromodulation of the left and / or right renal plexus (RP) can be achieved through intravascular access in accordance with the present technology, the properties and characteristics of the renal vasculature can constrain and / or inform the design of devices, systems and methods for achieving such renal neuromodulation. Some of these properties and characteristics may vary in patient populations and / or specific patients 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.). As explained herein, these properties and characteristics may be related to the efficacy of the procedure and the specific design of the intravascular device. Properties of interest may include, for example, material / mechanical, spatial, fluid dynamic / hemodynamic and / or thermodynamic properties.

[0117] As previously mentioned, a catheter can be percutaneously accessed into the left or right renal artery via a minimally invasive intravascular route. However, minimally invasive renal artery access can be challenging, for example, because the renal artery is typically extremely tortuous, may have a relatively small diameter, and / or may have a relatively short length compared to some other arteries that are conventionally approached using a catheter. In addition, renal artery atherosclerosis is common in many patients, particularly those with cardiovascular disease. The renal artery anatomy may also vary significantly between patients, which further complicates minimally invasive access. For example, significant inter-patient variation can be seen in relative tortuosity, diameter, length, and / or atherosclerotic plaque load, as well as the angle of deviation of the renal artery from the aorta. Devices, systems, and methods for achieving renal neuromodulation via intravascular access when minimally invasively accessing the renal artery should take into account these and other aspects of the renal artery anatomy and its variation in patient populations.

[0118] In addition to complicating renal artery access, the details of the renal anatomy also complicate establishing stable contact between the neuromodulator and the luminal surface or wall of the renal artery. For example, the catheter may be hindered by the narrow space within the renal artery and the curvature of the artery. Furthermore, establishing consistent contact is complicated by the patient's movement, breathing, and / or cardiac cycle, because these factors may cause significant movement of the renal artery relative to the aorta, and the cardiac cycle may temporarily dilate 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 neuromodulatory device and the arterial luminal surface, the nerves in and around the arterial adventitia should be safely modulated by the neuromodulatory device. In view of the potential clinical complications associated with such treatment, it is very important to effectively apply thermal treatment from within the renal artery. For example, the intima and media of the renal artery are very susceptible to thermal damage. As discussed in more detail below, the thickness of the intima and media separating the vessel lumen from its adventitia means that the target renal nerves can be many millimeters away from the luminal surface of the artery. Sufficient energy should be delivered to or thermally removed from the target renal nerves to modulate the target renal nerves without excessively cooling or heating the vessel wall to the extent that the wall is frozen, dried out, or otherwise potentially affected to an undesirable extent. A potential clinical complication associated with excessive heating is thrombosis caused by the flow of coagulated blood through the artery. In view of the fact that such thrombosis may lead to renal infarction, thereby causing irreversible damage to the kidney, thermal treatment within the renal artery should be applied with caution. Therefore, the complex fluid dynamics and thermodynamic conditions that exist in the renal artery during treatment, particularly those that may affect the heat transfer dynamics at the treatment site, may be important when applying energy (e.g., heating thermal energy) and / or removing heat from tissue within the renal artery (e.g., cooling thermal conditions).

[0120] Neuromodulation devices should also be configured to allow for adjustable positioning and repositioning of the energy delivery element within the renal artery, as the location of treatment may also impact clinical efficacy. For example, given that renal nerves may be spaced circumferentially around the renal artery, it may be tempting to apply full circumferential treatment from within the renal artery. In some cases, the full-circumferential lesions that could result from continuous circumferential treatment may be associated with renal artery stenosis. Therefore, it may be desirable to create more complex lesions along the longitudinal dimension of the renal artery and / or reposition the neuromodulation device to multiple treatment locations. However, it should be noted that the benefits of creating circumferential ablations may outweigh the potential for renal artery stenosis, or the risks can be mitigated with certain embodiments or in certain patients, and creating circumferential ablations may be the goal. Additionally, variable positioning and repositioning of the neuromodulation device may prove useful in cases where the renal artery is particularly tortuous or where proximal branch vessels exit the main renal artery, making treatment in certain locations challenging. Manipulation of the device within the renal artery should also consider the mechanical trauma the device inflicts on the renal artery. For example, movement of the device within the artery due to insertion, manipulation, bending, etc., may cause incisions, perforations, denudation of the intima, 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, prolonged occlusion should be avoided to prevent renal damage such as ischemia. It may 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 aforementioned challenges of (1) renal artery access, (2) consistent and stable placement of the treatment element against the vessel wall, (3) effective application of treatment to the vessel wall, (4) positioning and potentially repositioning the treatment device to allow for multiple treatment locations, and (5) avoiding or limiting the duration of blood flow occlusion, various independent and dependent properties of the renal vasculature that may be of interest include, for example: (a) vessel diameter, vessel length, intima-media thickness, friction coefficient, and tortuosity; (b) distensibility, stiffness, and elastic modulus of the vessel wall; (c) peak systolic, end-diastolic, and mean systolic-diastolic peak blood flow velocities, and mean / maximal volumetric blood flow rates; (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 blood through the vessel wall treatment site; (e) motion of the renal artery relative to the aorta caused by respiration, patient movement, and / or blood flow pulsatility; and (f) the deviation angle of the renal artery relative to the aorta. These properties will be discussed in more detail with respect to the renal artery. However, depending on the devices, systems, and methods used to achieve renal neuromodulation, such properties of the renal arteries may also guide and / or constrain design characteristics.

[0123] As mentioned above, the device in the renal artery should conform to the geometry of the artery. Renal artery vessel diameter DRA is typically in the range of about 2-10mm, and most patient populations have a DRA of about 4mm to about 8mm and a mean value of about 6mm. The renal artery vessel length LRA between the mouth of the aorta / renal artery junction and its distal branches is generally in the range of about 5-70mm, and the major part of the patient population is in the range of about 20-50mm. Because the target renal plexus is embedded in the adventitia of the renal artery, the composite intima-media thickness IMT (i.e., the radially outward distance from the adventitia of the arterial cavity surface to the target neural structure) is also significant, and generally in the range of about 0.5-2.5mm, is on average about 1.5mm. Although a certain depth of treatment is important for arriving at the target neural fibers, treatment should not be too deep (e.g., apart from the inner wall of the renal artery>5mm), to avoid non-target tissues and anatomical structures such as the renal vein.

[0124] An additional property of the renal artery that may be of interest is the degree of renal motion relative to the aorta caused by respiration and / or blood flow pulsations. A patient's kidneys, located distal to the renal arteries, can move 4" cephalad with respiratory excursions. This can impose significant motion on the renal arteries connecting the aorta and kidneys, thereby requiring a unique balance of rigidity and flexibility from the neuromodulatory device to maintain contact between the energy delivery elements and the vessel wall during the respiratory cycle. Furthermore, the deviation angle between the renal artery and the aorta can vary significantly between patients and may also vary dynamically within a patient, for example, due to renal motion. The deviation angle can generally be in the range of approximately 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 blood 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 a target site; and

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

[0130] obtaining physiological measurements via the sensing element;

[0131] determining physiological parameters based on physiological measurements;

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

[0133] Based on the comparison, an indication is provided to the operator as to whether the patient has physiological characteristics indicative of a therapeutic response to renal neuromodulation 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. A neuromodulation / assessment system according to example 1 or 2, wherein the sensing element is configured to detect a physiological measurement indicative of renal artery wave velocity, and wherein the controller is configured to determine the renal artery wave velocity based on the physiological measurement.

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

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

[0138] The controller is configured to:

[0139] determining a first physiological parameter based on the physiological measurement values ​​obtained from the first branch,

[0140] determining a second physiological parameter based on the physiological measurements obtained from the second branch, comparing the first physiological parameter to the second physiological parameter, and

[0141] Based on the comparison, it is determined whether the first branch or the second branch is more amenable to renal neuromodulation therapy.

[0142] 5. The neuromodulation / assessment system of any one 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] determining a first physiological parameter based on physiological measurements obtained from the branch blood vessel,

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

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

[0148] Based on the comparison, it is determined whether the branch vessel or the renal artery is more amenable to 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] obtaining, via a sensing element, one or more measurements related to a physiological parameter of the patient;

[0153] determining physiological parameters based on the measured values;

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

[0155] Based on the comparison, an indication is provided to the operator regarding the likelihood that the patient will have a therapeutic response to renal neuromodulation therapy at the target site.

[0156] 7. A system according to Example 6, wherein the sensing element is one of a plurality of sensing elements positioned along a distal portion of the guidewire.

[0157] 8. A system according to example 6 or example 7, wherein the physiological parameter is renal wave velocity, and wherein the sensing element is configured to obtain measurements for determining renal wave velocity.

[0158] 9. A system according to example 6 or example 7, wherein the physiological parameter is renal resistance, and wherein the sensing element is configured to obtain a measurement value for determining renal resistance.

[0159] 10. A system according to example 6 or example 7, wherein the physiological parameter is mean blood pressure, and wherein the sensing element is configured to obtain measurements for determining mean blood pressure.

[0160] 11. A system according to example 6 or example 7, wherein the physiological parameter is mean blood flow velocity, and wherein the sensing element is configured to obtain a measurement value for determining the mean blood flow velocity.

[0161] 12. A system according to any of Examples 6-11, wherein the sensing element is configured to obtain 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.

[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] Physiological parameters compared included:

[0194] comparing the first physiological parameter to the second physiological parameter; and

[0195] Instructions include:

[0196] Determine whether branch vessels or renal vessels are more amenable to renal neuromodulation therapy.

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

[0198] Obtaining baseline measurements includes:

[0199] Obtain physiological measurements from the first branch of the renal vessels,

[0200] Physiological measurements were obtained from secondary branch vessels of the renal vasculature;

[0201] Physiological parameters determined include:

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

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

[0204] Physiological parameters compared included:

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

[0206] Instructions include:

[0207] A determination is made as to whether the first branch vessel or the second branch vessel is more amenable to renal neuromodulation therapy.

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

[0209] Obtaining baseline measurements includes measuring pressure and velocity within the renal blood vessels; and

[0210] Determination of physiological parameters includes determination of renal wave velocity using the following formula:

[0211]

[0212] Where P is the pressure, U is the velocity, and ρ 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 administered using the neuromodulation catheter.

[0216] V. in conclusion

[0217] The present disclosure is not intended to be exhaustive or to limit the present technology to the precise form disclosed herein. Although specific embodiments are disclosed herein for illustrative purposes, various equivalent modifications may be made without departing from the present technology, as will be appreciated by those skilled in the relevant art. In some cases, well-known structures and functions are not shown and / or described in detail to avoid unnecessarily obscuring the description of the embodiments of the present technology. Although the steps of the method may be presented in a particular order herein, in alternative embodiments, these steps may have another suitable order. Similarly, certain aspects of the present technology disclosed in the context of a particular embodiment may be combined or eliminated in other embodiments. In addition, although advantages associated with those embodiments may be disclosed in the context of certain embodiments, other embodiments may also exhibit such advantages, and not all embodiments must exhibit the various advantages disclosed herein to fall within the scope of the present technology. Therefore, the present disclosure and related art may encompass other embodiments that are not explicitly shown and / or described herein.

[0218] In the present disclosure, the singular terms "one", "an" and "the" always include multiple referents unless the context clearly indicates otherwise. Similarly, unless the word "or" is clearly limited to a single item in a list of two or more items in addition to other items, the use of "or" in such a list will be interpreted as including any single item in (a) the list, (b) all items in the list, or (c) any combination of items in the list. In addition, the use of the term "including" or similar terms in the present disclosure is always used to indicate that at least the (one or more) features are included, thereby not excluding any greater number of (one or more) identical features and / or one or more additional types of features. Directional terms such as "upper", "lower", "front", "back", "vertical" and "horizontal" can be used herein to express and clarify the relationship between various elements. It should be understood that such terms do not represent absolute orientation. Reference to "one embodiment", "an embodiment" or similar expressions herein means that the specific features, structures, operations or characteristics described in conjunction with the embodiment can be included in at least one embodiment of the present technology. Therefore, the appearance of such phrases or expressions herein does not necessarily refer to the same embodiment. Furthermore, the various particular features, structures, operations, or characteristics may be combined in any suitable manner in one or more embodiments.

Claims

1. A neuromodulation and assessment system comprising: 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 blood vessel of a human patient; 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 of the guidewire, wherein the sensing element is configured to detect a physiological measurement at a target site; as well as a controller configured to be communicatively coupled to the sensing element, wherein the controller is further configured to: obtaining physiological measurements via the sensing element; determining physiological parameters based on physiological measurements; comparing physiological parameters to predetermined thresholds; as well as Based on said comparison of the physiological parameter with the predetermined threshold, an indication is provided to an operator as to whether the patient has a physiological characteristic indicative of a therapeutic response to renal neuromodulation therapy at the target site, and wherein: The sensing element is configured to detect a physiological measurement at a first branch of the renal artery and a physiological measurement at a second branch of the renal artery or at the renal artery; and The controller is configured to: determining a first physiological parameter based on the physiological measurement values ​​obtained from the first branch, determining a second physiological parameter based on a physiological measurement value obtained from the second branch or a physiological measurement value obtained from the renal artery, comparing the first physiological parameter to the second physiological parameter, and Based on the comparison of the first physiological parameter and the second physiological parameter, it is determined whether the first branch or the second branch is more susceptible to renal neuromodulation therapy, or whether the first branch or the renal artery is more susceptible to renal neuromodulation therapy.

2. The neuromodulation and assessment system according to claim 1, wherein the sensing element comprises a pressure sensing element, a flow sensing element, an impedance sensing element, and / or a temperature sensing element.

3. The neuromodulation and assessment system according to claim 1 or 2, wherein the sensing element is a pressure sensing element, a flow sensing element, an impedance sensing element, and / or a temperature sensing element; The controller is further configured to: obtaining, via the sensing element, one or more measurements related to a physiological parameter of the patient; determining physiological parameters based on the measured values; comparing physiological parameters to predetermined thresholds; as well as Based on the comparison of the physiological parameter to the predetermined threshold, an indication is provided to the operator regarding the likelihood that the patient will have a therapeutic response to renal neuromodulation therapy at the target site.

4. The neuromodulation and assessment system of claim 3, wherein the sensing element is one of a plurality of sensing elements positioned along a distal portion of the guidewire.

5. The neuromodulation and assessment system of claim 3, wherein the physiological parameter is renal resistance, and the sensing element is configured to obtain measurements for determining renal resistance.

6. The neuromodulation and assessment system of claim 3, wherein the controller is further configured to indicate which portions of the blood vessels are more sensitive to neuromodulation therapy based on physiological parameters.

7. The neuromodulation and assessment system of claim 3, wherein the controller is further configured to indicate which portions of the blood vessels are less susceptible to neuromodulation therapy based on physiological parameters.

8. The neuromodulation and assessment system of claim 3, wherein the neuromodulation catheter comprises a plurality of electrodes spaced apart along a distal portion of the elongated shaft.

9. The neuromodulation and assessment system of claim 8, wherein: The controller is configured to be communicatively coupled to the plurality of electrodes, wherein the controller is further configured to: applying a first stimulus at and / or near a target site within the blood vessel; detecting, via at least one electrode of the plurality of electrodes, vascular impedance resulting from the first stimulation to determine a baseline impedance; delivering neuromodulatory energy to a target site within a blood vessel of a human patient via the distal portion of the elongated shaft; applying a second stimulus at and / or near the target site within the vessel after delivering the neuromodulatory energy; detecting, via at least one electrode of the plurality of electrodes, a vascular impedance obtained by the second stimulation to determine an impedance after nerve modulation; as well as Efficacy of neuromodulation is assessed based at least in part on a comparison of the baseline impedance and the impedance after neuromodulation.

10. A neuromodulation and assessment system according to claim 9, wherein the lumen is a first lumen, and wherein the neuromodulation catheter further comprises a second lumen extending along the elongated axis and configured to deliver an agent at and / or near a target site to provide the first stimulation and the second stimulation.

11. The neuromodulation and assessment system of claim 8, wherein the distal portion of the elongated shaft is configured to convert into a spiral shape so 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.

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