High frequency renal nerve stimulation intraprocedural feedback

Abstract

A system for denervation of nerves of a blood vessel including a catheter for navigation within a blood vessel of a patient, the catheter including electrodes and configured to apply a therapy to nerves beyond a wall of the blood vessel, a therapy source in communication with a distal portion of the catheter, and a stimulation source configured to output a neural block stimulation signal to at least a first of the electrodes and configured to output a first low frequency stimulation signal to at least a second of the electrodes, wherein application of the neural block stimulation signal via the electrodes to the wall of a blood vessel generates a neural block in afferent sympathetic nerves proximate the wall of the blood vessel, and application of the low frequency stimulation triggers a response in efferent sympathetic nerves proximate the wall of the blood vessel.

Description

HIGH FREQUENCY RENAL NERVE STIMULATION INTRAPROCEDURAL FEEDBACK

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 552,098, filed February 10, 2024, the entire content of which is incorporated herein by reference.Technical Field

[0002] This disclosure relates to systems and methods assessing placement of an ablation probe within a blood vessel. Further, aspects of the disclosure are directed to methods and systems for stimulating nerves proximate a blood vessel.Background

[0003] Catheters have been proposed for use with various medical procedures. For example, a catheter can be configured to deliver neuromodulation (e.g., denervation) therapy to a target tissue site to modify the activity of nerves at or near the target tissue site. The nerves can be, for example, sympathetic or parasympathetic nerves. The sympathetic nervous system (SNS) is a primarily involuntary bodily control system typically associated with stress responses. Chronic over-activation of the SNS is a maladaptive response that can drive the progression of many disease states. For example, excessive activation of the renal SNS has been identified experimentally and in humans as a contributor to the complex pathophysiology of arrhythmias, hypertension, states of volume overload (e.g., heart failure), and progressive renal disease.

[0004] Percutaneous renal denervation is a minimally invasive procedure that can be used to treat hypertension and other diseases caused by over-activation of the SNS. During for example, a renal denervation procedure, a clinician delivers energy, such as radiofrequency, ultrasound, cooling, or other energy to a treatment site within the renal vessels to reduce, and / or permanently stop the activity of nerves surrounding a blood vessel. The energy delivered to the treatment site may provide various therapeutic effects through alteration of sympathetic nerve activity.SUMMARY

[0005] One aspect of the disclosure is directed to a system for denervation of nerves of a blood vessel. The system includes a catheter configured to be navigated within a blood vessel of a patient, the catheter including a plurality of electrodes and configured to apply a therapy tonerves beyond a wall of the blood vessel; a therapy source in communication with a distal portion of the catheter; and a stimulation source configured to output a neural block stimulation signal to at least a first one of the plurality of electrodes and configured to output a first low frequency stimulation signal to at least a second one of the plurality of electrodes, where application of the neural block stimulation signal via the electrodes to the wall of a blood vessel generates a neural block in afferent sympathetic nerves proximate the wall of the blood vessel, and application of the low frequency stimulation triggers a response in efferent sympathetic nerves proximate the wall of the blood vessel. Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods.

[0006] Implementations may include one or more of the following features. The system where the triggered response in the efferent sympathetic nerves proximate the wall of the blood vessel is one or more of a change in blood pressure in the blood vessel or a change in vasoconstriction of the blood vessel. The stimulation source is configured to output the neural block stimulation signal to a proximal most pair of the plurality of electrodes. The stimulation source is configured to output the first low frequency stimulation signal to a distal most pair of the plurality of electrodes. The therapy source is configured to generate one or more of a monopolar radio frequency therapy, a bipolar radio frequency therapy, a microwave therapy, an ultrasound therapy, a cryogenic therapy, or a chemical therapy. The neural block stimulation signal may include at least one of a high frequency stimulation signal or an anodal de stimulation signal. The neural block stimulation signal is configured to block transmission of signals along afferent sympathetic nerves proximate the wall of the blood vessel. Therapy source is in electrical communication with at least one electrode of the plurality of electrodes. The memory is configured to store instructions that when executed cause the processor to output for display on a user interface an indication of whether the first low frequency stimulation triggered a response in the efferent sympathetic nerves proximate the wall of the blood vessel. The stimulation source is configured to output a second low frequency stimulation signal to all electrodes of the plurality of electrodes following application of therapy and a second low frequency stimulation signal, the computing device stores in the memory instructions that when executed cause the processor to output for display on the user interface an indication of success of the therapy. Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium.

[0007] A further aspect of the disclosure is directed to a method of performing a therapeutic procedure. The method also includes applying a neural block stimulation signal to a wall of a blood vessel via at least a first of a plurality of electrodes on a distal portion of a catheter located within the blood vessel, where the neural block stimulation signal blocks transmission of signals along afferent sympathetic nerves proximate the wall of the blood vessel; applying a first low frequency stimulation signal to the wall of the blood vessel via at least a second of the plurality of electrodes on the distal portion of the catheter, where the low frequency stimulation signal triggers a response in efferent sympathetic nerves proximate the wall of the blood vessel; detecting a change in physiological properties of the blood vessel; and applying therapy to sympathetic nerves proximate the plurality of electrodes. Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the methods.

[0008] Implementations may include one or more of the following features. The method where the triggered response in the efferent sympathetic nerves proximate the wall of the blood vessel is one or more of a change in blood pressure in the blood vessel or a change in diameter of the blood vessel. The neural block stimulation is applied to a proximal most pair of the plurality of electrodes. The first low frequency stimulation signal is applied to a distal most pair of the plurality of electrodes. A therapy source is configured to generate one or more of a monopolar radio frequency therapy, a bipolar radio frequency therapy, a microwave therapy, an ultrasound therapy, a cryogenic therapy, or a chemical therapy. The neural block stimulation signal may include at least one of a high frequency stimulation signal or an anodal de stimulation signal. The neural block stimulation signal is configured to block transmission of signals along afferent sympathetic nerves proximate the wall of the blood vessel. The method may include delivering a therapy signal to at least one of the plurality of electrodes. The method may include displaying on a user interface an indication of whether the first low frequency stimulation triggered a response in the efferent sympathetic nerves proximate the wall of the blood vessel. The method may include: applying a second low frequency stimulation signal to all of the plurality of electrodes after application of therapy, detecting a change in physiological properties of the blood vessel as a result of the second low frequency stimulation signal, and displaying on the user interface an indication of success of the therapy. Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium.

[0009] Further disclosed herein is a system for denervation of nerves of a blood vessel including a catheter for navigation within a blood vessel of a patient, the catheter including electrodes and configured to apply a therapy to nerves beyond a wall of the blood vessel, a therapy source in communication with a distal portion of the catheter, and a stimulation source configured to output a neural block stimulation signal to at least a first of the electrodes and configured to output a first low frequency stimulation signal to at least a second of the electrodes, wherein application of the neural block stimulation signal via the electrodes to the wall of a blood vessel generates a neural block in afferent sympathetic nerves proximate the wall of the blood vessel, and application of the low frequency stimulation triggers a response in efferent sympathetic nerves proximate the wall of the blood vessel.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Various aspects and embodiments of the disclosure are described hereinbelow with references to the drawings, wherein:

[0011] FIG. l is a schematic diagram of a therapy system provided in accordance with some examples of the disclosure;

[0012] FIG. 2 is a schematic view of a workstation of the therapy system of FIG. 1;

[0013] FIG. 3 is a perspective view of a therapeutic device of the therapy system of FIG.1 advanced within a portion of the patient’s anatomy and in a deployed condition in accordance with some examples of the disclosure;

[0014] FIG. 4 is a flow chart depicting a method of stimulation and therapy in accordance with some examples of the disclosure;

[0015] FIG. 5 depicts the placement of a therapeutic device in accordance with some examples of the disclosure; and

[0016] FIG. 6 is a flow chart depicting a method of stimulation and therapy in accordance with some examples of the disclosure.DETAILED DESCRIPTION

[0017] This disclosure is directed to therapeutic systems and methods and particularly ablation systems and methods for denervation or neuromodulation of nerves such as the sympathetic, or parasympathetic, nerves. Some aspects of the disclosure are directed to ablation and denervation of unmyelinated nerve fibers in and around blood vessels and other luminal tissues. In particular, this disclosure is directed to systems and methods that provide intraprocedure and / or post-procedure feedback on the progress of the therapy. Prior to applicationof therapeutic energy to nerves proximate a blood vessel or other luminal tissue, a stimulation signal may be applied to the blood vessel. The stimulation signal may be received by the nerves proximate the blood vessel and can result in vasoconstriction of the blood vessel. While this can be an effective indicator of the proximity of the therapy delivery device to the nerves, indicating that the application of the therapy at that location is likely to be effective, this stimulation can also result in an increase in blood pressure. Where the patient in question already has elevated blood pressure, such an increase may be undesirable, and can result in cessation of an ongoing procedure or at minimum delay in a procedure to allow the patient’s blood pressure to return to baseline or normal (for the patient) levels. Accordingly, improvements are needed to provide feedback to clinicians that address these shortcomings of the current technologies.

[0018] For ease of description, much of the following description focuses on implementations of radiofrequency (RF) ablation and denervation. Those having skill in the art will recognize that the methods and systems described herein may employ any of the therapy modalities described herein including without limitation monopolar or bipolar RF, microwave, ultrasound, chemical, cryogenic and other already developed or yet to be developed therapy modalities. Further, combinations of these therapies may be applied without departing from the scope of the disclosure. Similarly, the following description focuses on navigation to and application of therapy to the renal artery to denervate sympathetic or, in certain embodiments, parasympathetic, nerves in, around, and proximate the renal arteries. However, the present disclosure is not so limited. In general, the devices, systems, and techniques described herein may be used in conjunction with neuromodulation (e.g., denervation) performed from within any suitable anatomical lumen that has nerves adjacent to the anatomical lumen. Example anatomical lumens include the celiac trunk and its branches (including the common hepatic artery and its branches (including the gastroduodenal artery and its branches, the right gastric artery and its branches, and the proper hepatic artery and its branches), the left gastric artery and its branches, and the splenic artery and its branches), the superior mesenteric artery and its branches, the gonadal artery and its branches, the inferior mesenteric artery and its branches, and the like. Further, although the disclosure primarily describes neuromodulation (e.g., denervation) from within one or more arteries, the devices, systems, and techniques of the disclosure also may be applied to neuromodulation from within one or more veins, such as a renal vein and its branches, a hepatic vein and its branches, an intercostal vein and its branches, or the like. In some implementations the devices, systems, and techniques described hereinmay be used to perform neuromodulation (e.g., denervation) from within two or more anatomical lumens, e.g., in the renal arteries and the common hepatic artery, or any other combination of two or more anatomical lumens, either simultaneously or sequentially. In addition, the systems, devices, and methods described herein may be useful in conjunction with neuromodulation (e.g., denervation) within a body lumen other than a vessel, for extravascular neuromodulation and / or for use in conjunction with therapies other than neuromodulation. Still further while generally contemplated that the locations described above are to be navigated to percutaneously, for example via the femoral artery, the therapeutic devices described herein may also be placed laparoscopically placed in or near one or more of the above-identified blood vessels, or another luminal tissue without departing from the scope of the present disclosure.

[0019] Turning now to the drawings, FIG. 1 illustrates a therapy system provided in accordance with the present disclosure and generally identified by reference numeral 10. As shown in FIG. 1, therapy system 10 may be used in connection with a C-arm imaging system or other imaging station, which may facilitate navigation of a therapeutic device 50 to a desired location within the patient’ s anatomy (e.g. , the patient’ s renal artery), application of denervation therapy to the tissue proximate the renal artery to denervate sympathetic nerves within the tissue, and monitoring of one or more parameter, such as impedance, for use in evaluating the denervation therapy.

[0020] The therapy system 10 includes a workstation 20 and a therapeutic device 50 operably coupled to the workstation 20. The therapy system may be used with an imaging device 70, which may be operably coupled to a display 72. The patient “P” is shown lying on an operating table 12 with the therapeutic device 50 inserted through a portion of the patient’s femoral artery, although it is contemplated that the therapeutic device 50 may be inserted into any suitable portion of the patient’s vascular network that is in fluid communication with a desired blood vessel for therapy. Although generally described as having one therapeutic device 50, it is envisioned that the therapy system 10 may employ any suitable number of therapeutic devices 50. The therapeutic devices 50 may employ the same or different therapy modalities and be operably coupled to the workstation 20. Further, the therapeutic device 50 may employ a guidewire (now shown) or a guide catheter 58 (FIG. 3) without departing from the scope of the disclosure.

[0021] Continuing with FIG. 1 and with additional reference to FIG. 2, the workstation 20 includes a computer 22, a therapy source 24 (e.g., one or more of an RF generator, a microwave generator, an ultrasound generator, a cryogenic medium source, a chemical source, etc.)operably coupled to the computer 22, and a stimulation source 24a (configured for generation of stimulation signals, e.g., ultrasound, electrical, RF, etc.). In some examples, the computer 22, therapy source 24, and / or stimulation source 24a are integrated in a single component and may be referred to as a generator, controller, or console.

[0022] The computer 22 is coupled to a display 26 that is configured to display one or more user interfaces 28. The computer 22 may be a desktop computer or a tower configuration with display 26 or may include a laptop computer or other computing device. The computer 22 includes a processor 30 which executes software stored in a memory 32. The memory 32 may store one or more applications 34 and / or algorithms 44 to be executed by the processor 30. A network interface 36 enables the workstation 20 to communicate with a variety of other devices and systems via the internet. The network interface 36 may connect the workstation 20 to the Internet via a wired or wireless connection. Additionally, or alternatively, the communication may be via an ad hoc Bluetooth® or wireless network enabling communication with a wide- area network (WAN) and / or a local area network (LAN). The network interface 36 may connect to the Internet via one or more gateways, routers, and network address translation (NAT) devices. The network interface 36 may communicate with a cloud storage system 38, in which further data, image data, and / or videos may be stored. The cloud storage system 38 may be remote from or on the premises of the hospital such as in a control or hospital information technology room. It is envisioned that the cloud storage system 38 could also serve as a host for more robust analysis of acquired images (e.g., fluoroscopic, computed tomography (CT), magnetic resonance imaging (MRI), cone-beam computed tomography (CBCT), etc.), data, etc. (e.g., additional or reinforcement data for analysis and / or comparison). An input module 40 receives inputs from an input device such as a keyboard, a mouse, voice commands, an energy source controller (e.g., a foot pedal or handheld remote-control device) that enables the clinician to initiate, terminate, and optionally, adjust various operational characteristics of the therapy source 24 and / or stimulation source 24a, including, but not limited to, therapy or stimulation delivery, amongst others. An output module 42 connects the processor 30 and the memory 32 to a variety of output devices such as the display 26. In embodiments, the display 26 may be a touchscreen display.

[0023] The therapy source 24 may be configured to generate and output one or more of RF energy (monopolar or bipolar), microwave energy, ultrasound energy, cryogenic energy, or chemical ablation medium via semi-automated or automated control algorithm 44 stored on the memory 32 and / or under the control of a clinician. As can be appreciated, many of the therapieslisted above change the temperature of the tissue e.g., increase or decrease the temperature) to achieve the desired denervation of the nerves. The therapy source 24 may be configured to produce a selected modality and magnitude of energy and / or therapy for delivery to the treatment site via the therapeutic device 50, as will be described in further detail hereinbelow. The therapy source 24 may be configured to sense voltage and current (e.g., in the case of RF or other electrical energy) applied to target tissue via the therapeutic device 50. In addition, one or more sensors on the therapeutic device 50 may monitor the temperature of the target tissue or tissue proximate the target tissue, and / or a portion of the therapeutic device 50. Utilizing the sensed voltage and current applied to the tissue, an application 34 on the computer 22 may be configured to calculate an impedance of the tissue through which therapeutic energy is transmitted to provide an indication of the status of the tissue. The computer 22 may be configured to output the status to the display 26 on one or more user interfaces 28 to provide a clinician with both intraprocedural and post-procedural feedback regarding the therapy.

[0024] In contrast with the therapy source 24, the stimulation source 24a outputs a non- therapeutic signal to effectuate an efferent response from the nerves in or near the location of the therapeutic device 50. The stimulation signal may be a current injection signal where a voltage is monitored for safety or a voltage injection signal. In one example, the stimulation source 24a generates a low frequency stimulation signal. The low frequency stimulation signal may for example have a frequency of between about 5 Hz and about 1 kHz, optionally between about 10 Hz and 700Hz, between about 50Hz and 500 Hz, between about 100 Hz and 500 Hz, or between about 200 and 400 Hz. The signal has a pulse width of between about 3 and about 10 ms, optionally between about 5 and 8 ms, or about 7 ms. The signal has a current of between about 15 and about 50 mA, optionally between about 20 and 40 mA, or about 30 mA. The signal has a voltage of between 1 and 100 V, optionally between about 10 and 50 V, between about 20 and 40V, or about 30V or between about 25 and 75 V, between about 35 and 60 V, or about 50V.

[0025] The low frequency stimulation signal from the stimulation source 24a may be a monophasic or a biphasic waveform. In the case of a biphasic wave form a leading phase of each successive pulse of the biphasic waveform is switched or otherwise inverted. In this manner, a biphasic waveform having an initial pulse with an anodal leading phase and a cathodal trailing phase is followed by a second pulse with a cathodal leading phase and an anodal trailing phase which will be followed by a third pulse returning to an anodal leading phase and a cathodal trailing phase, and so on. Alternatively, a biphasic waveform having aninitial pulse with a cathodal leading phase and an anodal trailing phase may be followed by a second pulse with an anodal leading phase and a cathodal trailing phase which will be followed by a third pulse returning to a cathodal leading phase and an anodal trailing phase. The leading phase of each pulse of the biphasic waveform may be alternated for the duration of the application of neurostimulation to the target tissue. In this manner the stimulation source 24a generates a biphasic waveform at an energy level that is less the therapeutic (i.e., denervation energy) generated by the therapy source 24 such that the stimulation generated by the stimulation source 24a does not denervate the target tissue.

[0026] Without departing from the scope of the disclosure, the stimulating source 24a may also generate anodal or cathodal DC neural block signals. These anodal or cathodal DC signals may be employed to generate a neural block stimulation (e.g., an Anodal DC block) such that nerve signals are prevented from transmitting through the nerve. The neural block stimulation signals may be either current injection signals or voltage injections signals. The neural block stimulation signals may have a voltage of between 1 and 100 V, optionally between about 10 and 50 V, between about 20 and 40V, or about 30V, between about 25 and 75 V, between about 35 and 60 V, or about 50V. The neural bloc stimulation signals may have a current of between about 0.1 and 50 mA, optionally between about 1 and 30 mA, between about 5 and 25 mA, between about 10 and 20 mA, or about 15mA.

[0027] In addition, or in alternative, the stimulation source 24a may be configured to produce a high frequency neural block stimulation. Like the anodal or cathodal DC signals, high frequency neural block stimulation also prevents transmission of signals along the nerve. As with the other signals output by the stimulation source the high frequency neural block stimulation may be a current injection signal or a voltage injection signal. While the low frequency stimulation signals described above have a frequency of typically between 5 Hz and 1 kHz, high frequency neural block stimulation signals have a frequency of between about 1 kHz and about 40 kHz, optionally between 5 kHz and 30 kHz, between 10 kHz and 20 kHz, or about 15 kHz. The signal has a current of between about 1 and about 50 mA, optionally between about 5 and 40 mA, between about 15 and 30 mA, or about 25 mA. The signal may have a voltage of between 1 and 100 V, optionally between about 10 and 50 V, between about 20 and 40V, or about 30V, between about 25 and 75 V, between about 35 and 60 V, or about 50V. The high frequency stimulation may have a duty cycle of between about 1 and 100%, optionally between about 5 and 80%, between about 15 and 75%, between about 25 and 60%, between about 35 and 50%, or about 50%. As will be appreciated, the low frequency stimulation isintended to elicit a nervous response, while the high frequency signal, like the anodal or cathodal neural block signal, is intended to suppress the neural response.

[0028] FIG. 3 depicts one embodiment of a therapeutic device 50 in accordance with the disclosure. The therapeutic device 50 includes an elongated shaft 52 having a handle (not shown) disposed on a proximal end portion of the elongated shaft 52. The therapeutic device 50 includes an energy delivery assembly 54 on a distal portion of the elongate shaft 52 at which electrodes 56 are located. The elongated shaft 52 of the therapeutic device 50 is configured to be advanced over a guide wire (not shown) within a portion of the patient’s vasculature, such as a femoral artery or other suitable portion of patient’s vascular network that is in fluid communication with the patient’s renal artery. In embodiments, the energy delivery assembly 54 is configured to be transformed from an initial, undeployed configuration having a generally linear profile, to a second, deployed or expanded configuration, where the energy delivery assembly 54 forms a generally spiral and / or helical configuration for delivering energy to a site for application of therapeutic energy or application of stimulation signals at the treatment site. In this manner, when in the second, expanded configuration, the energy delivery assembly 54, and in particular the individual electrodes 56, is pressed against or otherwise contacts the walls of the patient’s vasculature tissue. Although generally described as transitioning to a spiral and / or helical configuration, it is envisioned that the energy delivery assembly 54 may be deployed in other configurations without departing from the scope of the present disclosure. Further, the therapeutic device 50 may be configurable, for example, using one or more pull wires (not shown) to adjust the configuration to promote contact between the electrodes 56 and the wall of the renal artery. As such, the therapeutic device 50 may be capable of being placed in one, two, three, four, or more different configurations depending upon the design needs of the therapeutic device 50 or the location at which therapy is to be applied. Still further, and without departing from the scope of the disclosure, the energy delivery assembly 54 and electrodes 56 may be formed on an exterior of an inflatable balloon, and expandable basket, a lasso, or a pigtail catheter to achieve the placement of the electrodes 56 in contact with the blood vessel wall without departing from the scope of the disclosure. In addition, though generally described as being achieved using a single therapeutic device 50, multiple therapeutic devices 50 may be employed (e.g., with a separate therapeutic device 50 applying the blocking signal the block neural response).

[0029] As depicted in FIG. 3, the elongated shaft 52 may be configured to be received within a portion of a guide catheter or guide sheath (such as a 6F guide catheter) 58 that isutilized to navigate the therapeutic device 50 to a desired location. In practice, the guide catheter 58 is inserted into an access point such as the femoral artery to gain access to the vascular system. The guide catheter 58 is advanced to the desired location, for example to cannulate a renal artery. A guide wire (not shown) is advanced through the guide catheter 58 and to a location where therapy is to be applied (i.e., beyond a distal end of the guide catheter 58) and into the desired blood vessel (e.g., the renal artery). The therapeutic device 50 is then advanced over the guide wire beyond the end of the guide catheter 58 exposing the electrodes 56 at the location where the therapy is to be applied. The guide wire is then retracted within the therapeutic device 50 and the guide catheter 58. Retraction of the guide wire within the therapeutic device 50 causes the energy delivery assembly 54 of the therapeutic device 50 to transition from the first, undeployed configuration, to the second, deployed or expanded configuration (as shown in FIG. 3) with the electrodes 56 contacting the wall of the blood vessel. Though described herein as advancing the therapeutic device 50 beyond the guide catheter 58, in some configurations, the guide catheter 58 may be retracted relative to the therapeutic device 50 to achieve a desired placement of the electrodes 56 in contact with the blood vessel wall. Further, though described herein in connection with the use of a guide wire, the guide wire is not required, and the placement described herein above may be achieved without the use of the guide wire (e.g., with only a guide catheter). The elongated shaft 52 of the therapeutic device 50 may include an aperture (not shown) at a distal end thereof and configured to slidably receive the guidewire over which the therapeutic device 50, either alone or in combination with the guide catheter 58, are advanced. In this manner, the guidewire is utilized to guide the therapeutic device 50 to the target tissue using over-the-wire (OTW) or rapid exchange (RX) techniques, at which point the guide wire may be partially or fully removed from the therapeutic device 50, enabling the therapeutic device 50 to transition from the first, undeployed configuration, to the second, deployed or expanded configuration (FIG. 3). As noted elsewhere herein, the therapeutic device 50 may transition from the first, undeployed configuration to the second, deployed configuration automatically (e.g., via a shape memory alloy, etc.) or manually (e.g., via pull wires, guide wire manipulation, etc. that is controlled by the clinician).

[0030] In some embodiments, a pressure sensor 60 may be incorporated into the guide sheath 58 or the shaft elongated 52 for detection of physiological parameters of the patient. In one example the physiological parameter is blood pressure though other parameters may be detected without departing from the scope of the disclosure.

[0031] As illustrated in the figures, the electrodes 56 are disposed in spaced relation to one another along a length of the therapeutic device 50 forming the energy delivery assembly 54. As will be appreciated, these electrodes 56 are in communication with the therapy source 24 and the stimulation source 24a. The electrodes 56 may deliver therapy and / or stimulation independently of one another, simultaneously, selectively, or sequentially. The electrodes 56 may be in electrical communication with a ground pad (not shown) placed on the patient’s skin and electrically connected to the generator and / or stimulator to enable the application of monopolar RF energy for therapy. Additionally or alternatively, therapy and / or stimulation energy may be applied between any desired combination of the electrodes 56, without requiring the use of a ground pad (e.g., bipolar stimulation or therapy).

[0032] As noted above, application of low frequency stimulations signals from the stimulation source 24a to the sympathetic nerves in and around the blood vessel elicit a nervous response resulting in physiological changes within the patient. These physiological changes may include vasoconstriction, an increase in blood pressure, an increase in vessel stiffness or rigidity, changes in pulse wave velocity, augmentation pressure, heart rate variability, etc., and combinations of these. As noted above, an increase in blood pressure can have adverse consequences on the patient ranging from a patient being excluded from undertaking a procedure due to the expected increase in blood pressure, cancellation of a therapy of a patient that experiences an increase in blood pressure that the clinician is not comfortable with during a procedure, or a delay in the procedure while the clinician waits for the blood pressure of the patient to return to baseline or normal.

[0033] In contrast, anodal or cathodal DC stimulation and high frequency stimulation signals generate a neural block preventing the transmission of signals along the nerves. The neural block prevents the transmission of both efferent and afferent nerve signals. This neural block can in one aspect of the disclosure be employed to block the efferent signals from the central nervous system from reaching portions of a blood vessel or other structures (e.g., organs) that are distal of the neural block.

[0034] In accordance with a method 400 of the application, a neural block stimulation signal (e.g., a high frequency stimulation signal or anodal DC stimulation) is applied to the wall of a blood vessel in which the therapeutic device 50 has been navigated at step 402. Specifically the neural block stimulation blocks the transmission of signals in both the afferent and efferent sympathetic nerves. By blocking the signals from traversing the efferent sympathetic nerves, the signals from the central nervous system which can result in a variety of effects on the bloodvessel (e.g., vasoconstriction, increased rigidity, etc.) is temporarily prevented from reaching portions of the blood vessel and other structures distal of neural block. In addition, by blocking the afferent sympathetic nerves, no signals are transmitted along the afferent sympathetic nerves from the blood vessel or organs (e.g., kidneys) in the direction of the central nervous system. Blocking these afferent signals prevents the central nervous system from responding and producing any undesirable additional nervous response.

[0035] At step 404 a determination is made whether a change in vascular tone of the blood vessel is observed. Vascular tone refers to the stiffness or rigidity of the blood vessel. Patient’s suffering from hypertension, at least in part as a result of the central nervous system overstimulating of the sympathetic nerves that traverse close to and through the muscle layers of the blood vessel, often also express constricted and stiff or rigid blood vessels. Accordingly, application of the neural block stimulation temporarily prevents the signals from the central nervous system from reaching the efferent sympathetic nerves (e.g., in portions of the blood vessel beyond the neural block. The result is a change in vascular tone of the blood vessel to which the neural block stimulation has been applied. If such a change in vascular tone is detected, the clinician can have confidence that the therapeutic device 50 is position within the blood vessel at a location where therapy is likely to denervate the sympathetic nerves of the blood vessel and the method progresses to step 408 where therapy is applied to the blood vessel wall to denervate the nerves in and near the blood vessel wall. If no change in vascular tone is observed, this indicates that there are no sympathetic nerves located proximate the therapeutic device 50 and the method moves to step 406, where the therapeutic device is repositioned, and the method returns to step 402.

[0036] The change in vascular tone may be directly observed or detected (e.g., via imaging such as an angiogram) to observe a change in vasodilation (e.g., a change in the diameter of the blood vessel). Alternatively, a change in vascular tone may be observed by detection of a change in blood pressure in the blood vessel or other downstream structures. The change in pressure may be detected by a detector such as a pressure sensor 60. Another indicator of a change in vascular tone is a change of pulse wave velocity of the blood traversing the blood vessel and other downstream structures. In another example, the change in vascular tone may be determined via detection of changes in volumetric blood flow through the blood vessel and other downstream structures (e.g., the arterioles of the kidneys). This observation may be made for example via angiographic imaging and periodic dosing of contrast medium and observation of the time required for the dye to traverse through the blood vessel and / or other downstreamstructures. Alternatively changes in volumetric flow may be observed using a flow wire blood flow detector. As will be appreciated, other methods of determining changes in vascular tone may be employed without departing from the scope of the disclosure.

[0037] Following application of the therapy at step 408 a neural block stimulation is applied to the blood vessel nerves via the electrodes 56 at step 410. At step 412 a determination is made whether there has again been a change in the vascular tone as a result of the neural block stimulation applied at step 410. If there is no change in vascular tone detected the method moves to step 414 where the method ends as the therapy was successful in denervating the nerves of the blood vessel. Alternatively, if a change in vascular tone is detected at step 412, the method returns to step 408 for the application of additional therapy. This process may be repeated until a successful therapy is achieved, or until a threshold application of therapy is exceeded and again the method ends. Optionally prior to reapplication of therapy the therapeutic device 50 may be repositioned at step 414.

[0038] At the determinations of steps 404 and 412, indicators may be presented on a user interface 28 on the computer 22 to provide an indicator of the outcome of each neural block stimulation. In a simple form this may be color (e.g., green) and text indicators, for example that the therapeutic device 50 is properly placed and that therapy can commence. Alternatively, a different color (e.g., red) may be displayed in connection with text indicating that the therapeutic device should be moved to a different location. Similarly, a color and text can be used to indicate a successful therapy or that additional therapy is required. Further, the change in vascular tone may be quantified and a percentage, bar graph, or other quantification of the effects of the neural block stimulation can be presented on the user interface 28 to provide more relative change or efficacy indications to the clinician.

[0039] As an alternative, in method 400 at step 410 rather than reapplying a neural block stimulation, a low frequency stimulation (e.g., one which is intended to stimulate rather than block the sympathetic nerves of the blood vessel and result in vasoconstriction or an increase in blood pressure in the blood vessel) may be applied. For example, the biphasic stimulation described above may be applied for a specified duration. Again if no change in vascular tone (e.g., vasoconstriction or change in blood pressure) is observed, the method ends at step 412, but if a change in vascular tone is observed the method returns to step 408 for the application of additional therapy as described above. As will be appreciated, rather than no change in blood pressure vascular tone, a change in blood pressure and vascular tone below a threshold may be observed and the method may end at step 412.

[0040] In accordance with a further alternative in method 400, step 404 may indicate a localized change in vascular tone. This localized change in vascular tone provides an indication of a location at which therapy is likely to be effective. Thus following step 404, at optional step 407 the therapeutic device 50 may be navigated to the location where the change in vascular tone is detected. In one example, this may be to blood vessels more distal than the location where neural block stimulation has been applied (e.g., branches of the renal artery following application of neural block stimulation in the renal artery). Further, step 407 may be appropriate where two separate catheters are employed, one for application of the stimulation signals, and a second catheter (therapeutic device 50) for application of the therapy.

[0041] A second aspect of the disclosure is directed at applying a neural block to the afferent sympathetic nerves (e.g., in the direction of the central nervous system) while simultaneously applying a low frequency stimulation signal to the efferent sympathetic nerves. An example of this may be seen in FIG. 5 where the therapeutic device 50 is placed within the blood vessel and the electrodes 56 are placed in contact with the wall of the blood vessel, as described above. Unlike method 400 where all electrodes 56 apply the same form of stimulation to the wall of the blood vessel and therewith the nerves in or near the blood vessel wall, as can be seen with reference to FIG. 5 electrodes El and E2 (the distal most electrodes 56 on the therapeutic device 50) can be used to apply the low frequency stimulation signal and the electrodes E3 and E4 (the proximal most electrodes 56) can be used to apply the neural block stimulation (e.g., a high frequency stimulation signal). As a result, the central nervous system is effectively blinded to the state of the blood vessel and other structures distal of the neural block. Simultaneously, or with a slight delay, the application of the low frequency stimulation signals triggers a response in the efferent sympathetic nerves of the blood vessel (e.g., vasoconstriction). In this way placement of the therapeutic device 50 proximate the sympathetic nerves can be confirmed. Vasoconstriction typically results in a reduction in diameter of the blood vessel and can be readily observed via imaging (e.g., ultrasound or angiography). This efferent stimulation of the blood vessel can be achieved without any indication of the stimulation or its results (e.g., vasoconstriction) being signaled to the central nervous system due to the application of the neural block stimulation to the afferent sympathetic nerves. Thus the potential triggering of undesirable effects such as increased blood pressure of the patient is reduced and / or substantially prevented.

[0042] A further aspect of the disclosure is described in connection with method 600 in FIG. 6. Following placement of a therapeutic device 50 at a desired location within a bloodvessel a first set of electrodes 56 (e.g., E3 and E4 of FIG. 5) apply neural block stimulation to the wall of the blood vessel at step 602 to achieve a neural block of the afferent sympathetic nerves of the blood vessel. Simultaneously, or after a short delay, a second set of electrodes (e.g., El and E2 of FIG. 5) apply efferent stimulation (e.g., low frequency stimulation) to the sympathetic nerves of the blood vessel. This efferent stimulation is configured to stimulate the efferent sympathetic nerves of the blood vessel to trigger a response (e.g., vasoconstriction). Those of skill in the art will recognize that the application stimulation will also stimulate afferent nerves, but the transmission of that stimulation is prevented by the applied neural block stimulation. At step 604 a determination is made whether a change in blood pressure (e.g., as detected by sensors 60) or vasoconstriction is observed (e.g., via imaging). Though described here in connection with blood pressure and vasoconstriction, other indicators of the effectiveness of the low frequency stimulation signals in eliciting a response from the efferent sympathetic nerves can be additionally or alternatively observed in connection with step 604. If the determination at step 604 is no, the method moves to step 606 where the therapeutic device 50 is repositioned and the method returns to step 602. If the determination at step 604 is yes, indicating that the electrodes are located proximate nerves to be denervated, the therapy is applied at step 608.

[0043] Following application of therapy at step 608, efferent stimulation (e.g., low frequency stimulation) is applied via all electrodes 56 (e.g., E1-E4) at step 610 to elicit a response of the efferent sympathetic nerves (e.g., vasoconstriction or a change in blood pressure). At step 612 a determination is made whether such a response is detected. If no response is detected, the method moves to step 614 where the method ends because the therapy was successful. If, however, a response is detected, the method returns to step 408 where additional therapy is applied. Optionally, the therapeutic device 50 may be repositioned at step 616. When the therapeutic device 50 is repositioned, the method returns to step 602. By returning to step 602 the method 600 ensures that the new location of the therapeutic device 50 is proximate efferent sympathetic nerves for denervation. This method may be repeated until the therapy is successful. As will be appreciated, because the initial application of therapy at step 608 is expected to be successful, there is no need to apply an afferent neural block at step 610.

[0044] As with method 400 the user interface 28 may be configured to display indicators following the determinations of steps 604 and 612, to provide an indicator of the outcome ofeach neural block stimulation and the therapy or to provide additional pre- and post-therapy feedback to the clinician.

[0045] Heretofore, the therapeutic device 50 has been primarily described in connection with a shape memory construction where exit from a guide catheter 58 frees the shape memory alloy to achieve a desired spiral and / or helical shape of the distal end and place the electrodes 56 against the blood vessel walls. However, the present disclosure is not so limited and the therapeutic device 50 may be formed such that the electrodes are placed on a balloon or other mechanism to achieve the desired contact with the blood vessel walls without departing from the scope of the disclosure.

[0046] Although described generally hereinabove, it is envisioned that the memory 32 may include any non-transitory computer-readable storage media for storing data and / or software including instructions that are executable by the processor 30 and which control the operation of the workstation 20 and, in some embodiments, may also control the operation of the therapeutic device 50. In an embodiment, memory 32 may include one or more storage devices such as solid-state storage devices, e.g., flash memory chips. Alternatively, or in addition to the one or more solid-state storage devices, the memory 32 may include one or more mass storage devices connected to the processor 30 through a mass storage controller (not shown) and a communications bus (not shown).

[0047] The description of computer-readable media contained herein refers to solid-state storage. It should be appreciated by those skilled in the art that computer-readable storage media can be any available media that can be accessed by the processor 30. That is, computer readable storage media may include non-transitory, volatile, and non-volatile, removable, and nonremovable media implemented in any method or technology for storage of information such as computer-readable instructions, data structures, program modules or other data. For example, computer-readable storage media may include RAM, ROM, EPROM, EEPROM, flash memory or other solid-state memory technology, CD-ROM, DVD, Blu-Ray or other optical storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other medium which may be used to store the desired information, and which may be accessed by the workstation 20.EXAMPLES

[0048] The disclosure is further described in connection with the following examples in which:

[0049] Example 1 A system for denervation of nerves of a blood vessel including, a catheter configured to be navigated within a blood vessel of a patient, the catheter including a plurality of electrodes and configured to apply a therapy to nerves beyond a wall of the blood vessel, a therapy source in communication with a distal portion of the catheter, and a stimulation source configured to output a neural block stimulation signal to at least a first one of the plurality of electrodes and configured to output a first low frequency stimulation signal to at least a second one of the plurality of electrodes, wherein application of the neural block stimulation signal via the electrodes to the wall of a blood vessel generates a neural block in afferent sympathetic nerves proximate the wall of the blood vessel, and application of the low frequency stimulation triggers a response in efferent sympathetic nerves proximate the wall of the blood vessel.

[0050] Example 2. The system of any of the preceding examples, wherein the triggered response in the efferent sympathetic nerves proximate the wall of the blood vessel is one or more of a change in blood pressure in the blood vessel or a change in vasoconstriction of the blood vessel.

[0051] Example 3. The system of any of the preceding examples, wherein the stimulation source is configured to output the neural block stimulation signal to a proximal most pair of the plurality of electrodes.

[0052] Example 4. The system of any of the preceding examples, wherein the stimulation source is configured to output the first low frequency stimulation signal to a distal most pair of the plurality of electrodes.

[0053] Example 5. The system of any of the preceding examples, wherein the therapy source is configured to generate one or more of a monopolar radio frequency therapy, a bipolar radio frequency therapy, a microwave therapy, an ultrasound therapy, a cryogenic therapy, or a chemical therapy.

[0054] Example 6. The system of any of the preceding examples wherein the neural block stimulation signal comprises at least one of a high frequency stimulation signal or an anodal DC stimulation signal.

[0055] Example 7. The system of any of the preceding examples, wherein the neural block stimulation signal is configured to block transmission of signals along afferent sympathetic nerves proximate the wall of the blood vessel.

[0056] Example 8. The system of any of the preceding examples, wherein therapy source is in electrical communication with at least one electrode of the plurality of electrodes.

[0057] Example 9. The system of any of the preceding examples further including, a computing device including a memory and a processor, wherein the memory is configured to store instructions that when executed cause the processor to output for display on a user interface an indication of whether the first low frequency stimulation triggered a response in the efferent sympathetic nerves proximate the wall of the blood vessel.

[0058] Example 10. The system of example 9, wherein the stimulation source is configured to output a second low frequency stimulation signal to all electrodes of the plurality of electrodes following application of therapy and a second low frequency stimulation signal, the computing device stores in the memory instructions that when executed cause the processor to output for display on the user interface an indication of success of the therapy.

[0059] Example 11. A method of performing a therapeutic procedure, including, applying a neural block stimulation signal to a wall of a blood vessel via at least a first of a plurality of electrodes on a distal portion of a catheter located within the blood vessel, wherein the neural block stimulation signal blocks transmission of signals along afferent sympathetic nerves proximate the wall of the blood vessel, applying a first low frequency stimulation signal to the wall of the blood vessel via at least a second of the plurality of electrodes on the distal portion of the catheter, wherein the low frequency stimulation signal triggers a response in efferent sympathetic nerves proximate the wall of the blood vessel, detecting a change in physiological properties of the blood vessel; and applying therapy to sympathetic nerves proximate the plurality of electrodes.

[0060] Example 12. The method of example 11, wherein the triggered response in the efferent sympathetic nerves proximate the wall of the blood vessel is one or more of a change in blood pressure in the blood vessel or a change in diameter of the blood vessel.

[0061] Example 13. The method of examples 11-12, wherein the neural block stimulation is applied to a proximal most pair of the plurality of electrodes.

[0062] Example 14. The method of any of examples 11-13, wherein the first low frequency stimulation signal is applied to a distal most pair of the plurality of electrodes.

[0063] Example 15. The method of examples 11-14, wherein a therapy source is configured to generate one or more of a monopolar radio frequency therapy, a bipolar radio frequency therapy, a microwave therapy, an ultrasound therapy, a cryogenic therapy, or a chemical therapy.

[0064] Example 16. The method of examples 11-15 wherein the neural block stimulation signal comprises at least one of a high frequency stimulation signal or an anodal DC stimulation signal.

[0065] Example 17. The method of examples 11-16, wherein the neural block stimulation signal is configured to block transmission of signals along afferent sympathetic nerves proximate the wall of the blood vessel.

[0066] Example 18. The method of examples 11-17, further comprising delivering a therapy signal to at least one of the plurality of electrodes.

[0067] Example 19. The method of examples 11-18 further comprising displaying on a user interface an indication of whether the first low frequency stimulation triggered a response in the efferent sympathetic nerves proximate the wall of the blood vessel.

[0068] Example 20. The method of examples 1-19 further including applying a second low frequency stimulation signal to all of the plurality of electrodes after application of therapy, detecting a change in physiological properties of the blood vessel as a result of the second low frequency stimulation signal, and displaying on the user interface an indication of success of the therapy.

[0069] While several embodiments of the disclosure have been shown in the drawings, it is not intended that the disclosure be limited thereto, as it is intended that the disclosure be as broad in scope as the art will allow and that the specification be read likewise. Therefore, the above description should not be construed as limiting, but merely as exemplifications of embodiments. Those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.

Claims

CLAIMS1. A system for denervation of nerves of a blood vessel comprising: a catheter configured to be navigated within a blood vessel of a patient, the catheter including a plurality of electrodes and configured to apply a therapy to nerves beyond a wall of the blood vessel; a therapy source in communication with a distal portion of the catheter; a stimulation source configured to output a neural block stimulation signal to at least a first one of the plurality of electrodes and configured to output a first low frequency stimulation signal to at least a second one of the plurality of electrodes, wherein application of the neural block stimulation signal via the electrodes to the wall of a blood vessel generates a neural block in afferent sympathetic nerves proximate the wall of the blood vessel, and application of the low frequency stimulation triggers a response in efferent sympathetic nerves proximate the wall of the blood vessel.

2. The system of claim 1, wherein the triggered response in the efferent sympathetic nerves proximate the wall of the blood vessel is one or more of a change in blood pressure in the blood vessel or a change in vasoconstriction of the blood vessel.

3. The system of claim 1 or 2, wherein the stimulation source is configured to output the neural block stimulation signal to a proximal most pair of the plurality of electrodes.

4. The system of any of the preceding claims, wherein the stimulation source is configured to output the first low frequency stimulation signal to a distal most pair of the plurality of electrodes.

5. The system of any of the preceding claims, wherein the therapy source is configured to generate one or more of a monopolar radio frequency therapy, a bipolar radio frequency therapy, a microwave therapy, an ultrasound therapy, a cryogenic therapy, or a chemical therapy.

6. The system of any of the preceding claims wherein the neural block stimulation signal comprises at least one of a high frequency stimulation signal or an anodal DC stimulation signal.

7. The system of any of the preceding claims, wherein the neural block stimulation signal is configured to block transmission of signals along afferent sympathetic nerves proximate the wall of the blood vessel.

8. The system of any of the preceding claims, wherein therapy source is in electrical communication with at least one electrode of the plurality of electrodes.

9. The system of any of the preceding claims further comprising: a computing device including a memory and a processor, wherein the memory is configured to store instructions that when executed cause the processor to output for display on a user interface an indication of whether the first low frequency stimulation triggered a response in the efferent sympathetic nerves proximate the wall of the blood vessel.

10. The system of claim 9, wherein the stimulation source is configured to output a second low frequency stimulation signal to all electrodes of the plurality of electrodes following application of therapy and a second low frequency stimulation signal, the computing device stores in the memory instructions that when executed cause the processor to output for display on the user interface an indication of success of the therapy.

11. A method of performing a therapeutic procedure, comprising: applying a neural block stimulation signal to a wall of a blood vessel via at least a first of a plurality of electrodes on a distal portion of a catheter located within the blood vessel, wherein the neural block stimulation signal blocks transmission of signals along afferent sympathetic nerves proximate the wall of the blood vessel; applying a first low frequency stimulation signal to the wall of the blood vessel via at least a second of the plurality of electrodes on the distal portion of the catheter,wherein the low frequency stimulation signal triggers a response in efferent sympathetic nerves proximate the wall of the blood vessel; detecting a change in physiological properties of the blood vessel; and applying therapy to sympathetic nerves proximate the plurality of electrodes.

12. The method of claim 11, wherein the triggered response in the efferent sympathetic nerves proximate the wall of the blood vessel is one or more of a change in blood pressure in the blood vessel or a change in diameter of the blood vessel.

13. The method of claim 11 or 12, wherein the neural block stimulation is applied to a proximal most pair of the plurality of electrodes.

14. The method of any one of claims 11 to 13, wherein the first low frequency stimulation signal is applied to a distal most pair of the plurality of electrodes.

15. The method of any one of claims 11 to 14, wherein a therapy source is configured to generate one or more of a monopolar radio frequency therapy, a bipolar radio frequency therapy, a microwave therapy, an ultrasound therapy, a cryogenic therapy, or a chemical therapy.

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