Renal nerve stimulation to guide RF renal denervation

Abstract

A system and method, for assessment of blood vessels, the system including a computing device, and a computer readable recording medium storing instructions that, when executed by the computing device, cause the computing device to obtain a systemic blood pressure of a patient, obtain a diameter of a blood vessel of interest, obtain a blood flow through the blood vessel of interest, and calculate a corrected blood flow value based at least in part on the obtained blood flow, the diameter of the blood vessel, and the systemic blood pressure.

Description

RENAL NERVE STIMULATION TO GUIDE RF RENAL DENERVATION

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 555,786, filed February 20, 2024, the entire content of which is incorporated herein by reference.Technical Field

[0002] This disclosure relates to systems and methods enabling positioning a therapeutic device within luminal tissues to enhance ablation during a therapeutic procedure. In particular aspects, the present disclosure is directed to methods and systems for denervating nerves in or around vascular tissue.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 including includes a computing device; and a computer readable recording medium storing instructions that,when executed by the computing device, cause the computing device to: obtain a systemic blood pressure of a patient; obtain a diameter of a blood vessel of interest; obtain a blood flow through the blood vessel of interest; and calculate a corrected blood flow value based at least in part on the obtained blood flow, the diameter of the blood vessel, and the systemic blood pressure. 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 including a catheter configured to be navigated within the blood vessel of interest of a patient, the catheter may include a plurality of stimulation elements, and the catheter being configured to apply stimulation to nerves beyond a wall of the blood vessel of interest; a therapy source configured to communicate with at least one therapy delivery element coupled to a distal portion of the catheter; and a stimulation source configured to output a stimulation signal to at least one stimulation element of the plurality of stimulation elements. The instructions further cause the computing device to: calculate a first corrected blood flow value based at least in part on a first diameter of the blood vessel of interest and a first blood flow value, both obtained prior to application of the stimulation signal to a wall of the blood vessel of interest; and calculate a second corrected blood flow value based at least in part on a second diameter of the blood vessel of interest and a second blood flow value, both obtained after application of the stimulation signal to the wall of the blood vessel of interest. The system may include a user interface configured to display an indicator of a comparison of the first corrected blood flow value and the second corrected blood flow value. The indicator signifies that movement of the catheter is appropriate or that application of therapy at a current location of catheter is appropriate. The instructions further cause the computing device to determine a third corrected blood flow value based at least in part on a third diameter of the blood vessel of interest and a third blood flow value, both obtained after application of therapy to the blood vessel. The system may include a user interface configured to display an indicator of a comparison of the second corrected blood flow value and the third corrected blood flow value. The indicator signifies that an applied therapy was efficacious or that further therapy is appropriate. The system may include a pressure sensor configured to detect the systemic blood pressure of the patient and output a signal indicative of the systemic blood pressure of the patient to the computing device. The instructionsfurther cause the computing device to obtain the blood flow from the flow sensor. The instructions further cause the computing device to obtain the image from the imaging device and determine the diameter of the blood vessel of interest based on the image. Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium.

[0007] Another aspect of the disclosure is directed to a method for denervation of nerves of a blood vessel. The method also includes detecting a systemic blood pressure of a patient; determining a diameter of the blood vessel of interest; determining a blood flow through the blood vessel of interest; and calculating a corrected blood flow value from the determined blood flow, the diameter of the blood vessel, and the systemic blood pressure. 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 including applying a stimulation signal to a blood vessel wall of a blood vessel of interest via at least one of a plurality of stimulation elements on a distal portion of a catheter located within the blood vessel of interest. The method may include calculating a first corrected blood flow value based at least in part on a first diameter of the blood vessel of interest and a blood flow value, both obtained prior to applying stimulation and calculating a second corrected blood flow value based at least in part on a second diameter of the blood vessel of interest and a second blood flow value, both obtained after applying stimulation to a wall of blood vessel of interest. A difference between the first corrected blood flow value and the second corrected blood flow value in excess of a threshold indicates the catheter is located proximate sympathetic nerves. The method may include applying therapy to the blood vessel. The method may include calculating a third corrected blood flow value based at least in part on a third diameter of the blood vessel of interest and a third blood flow value, both obtained after application of the therapy. A difference between the second corrected blood flow value and the third corrected blood flow value in excess of a threshold indicates an efficacious therapy. The therapy is one or more of monopolar radio frequency therapy, a bipolar radio frequency therapy, a microwave therapy, a cryogenic therapy, an ultrasound therapy, or a chemical therapy. The stimulation signal is a monophasic or biphasic stimulation signal. The systemic blood pressure is detected by a pressure sensor locatedwithin an aorta of the patient and configured to output a signal indicative of the systemic blood pressure of the patient and the blood flow is detected by a blood flow sensor configured to detect blood flow through the blood vessel of interest. A change in diameter of a blood vessel is determined via imaging. 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 and method, for assessment of blood vessels, the system including a computing device, and a computer readable recording medium storing instructions that, when executed by the computing device, cause the computing device to obtain a systemic blood pressure of a patient, obtain a diameter of a blood vessel of interest, obtain a blood flow through the blood vessel of interest, and calculate a corrected blood flow value based at least in part on the obtained blood flow, the diameter of the blood vessel, and the systemic blood pressure.BRIEF DESCRIPTION OF THE DRAWINGS

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

[0011] FIG. l is a schematic diagram of a therapy system provided in accordance with 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 ofFIG. 1 advanced within a portion of the patient’s anatomy and in a deployed condition in accordance with the disclosure; and

[0014] FIG. 4 is a flow chart depicting a method in accordance with the disclosure.DETAILED DESCRIPTION

[0015] 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 intra-procedure and / or post-procedure feedback on the progress of the therapy. Prior to application of therapeutic energy to nerves proximate a blood vessel or other luminal tissue,a therapy device may be used to apply a stimulation signal to the blood vessel. The stimulation signal may activate the nerves proximate the blood vessel and can result in vasoconstriction of the blood vessel. Following stimulation, changes in a variety of parameters (e.g., relative to baseline values of the parameters measured prior to stimulation) can be observed, including blood pressure, blood flow volume, and a dimension (e.g., a radius, diameter, or cross-sectional area) of the blood vessel. Two or more of these parameters can be analyzed together (e.g., combined) to provide a pre-therapy blood vessel status. The pre-therapy status can, among other things, provide an indication that stimulation captured one or more nerves adjacent the blood vessel, and therapy device is located at a location where therapy is likely to be efficacious (e.g., result in denervation of sympathetic nerves). The therapy device is then used to apply therapy to the blood vessel. Periodically or after application of therapy, the therapy device is again used to apply stimulation to the blood vessel. Again, after stimulation observation is made of the same parameters (e.g., blood pressure, blood flow volume, and / or vessel dimension) and the system determines an intra- or post-therapy blood vessel status. A comparison of the pre- therapy status to the intra- or post-therapy status yields an indication of efficacy or completeness of the therapy. Where necessary additional therapy may be applied until a threshold change is observed between the pre- and intra- or post-therapy status. These and other aspects of the disclosure are described in greater detail below.

[0016] 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 Tjthe 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 andits 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 herein may 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.

[0017] 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 (e.g., a catheter) 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 pressure, vessel dimension, or blood flow, for use in evaluating the denervation therapy.

[0018] 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 imagingdevice 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 (e.g., a radial artery) 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.

[0019] Continuing with FIG. 1 and with additional reference to FIG. 2, the workstation 20 includes a computing device 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 computing device 22, and a stimulation source 24a (configured for generation of stimulation signals, e.g., ultrasound, electrical, RF, etc.). In some examples, the computing device 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.

[0020] The computing device 22 is coupled to a display 26 that is configured to display one or more user interfaces 28. The computing device 22 may be a desktop computer or a tower configuration with display 26 or may include a laptop computer or other computing device. The computing device 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 remotefrom 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.

[0021] The therapy source 24 may be configured to generate and / or 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 therapies listed 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 computing device 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 computing device 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.

[0022] The stimulation source 24a may be configured to generate a stimulation signal, for example 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 signal generated by the stimulation source 24a does not denervate the target tissue. Rather, the stimulation source 24a generates a stimulation signal capable of eliciting a response from the nerves indicative of presence of nerves within the tissue that would be a candidate for denervation. Responses may include an increase in local or systemic blood pressure, changes in blood vessel diameter, changes in blood flow (volume or velocity), an increase in vessel stiffness, changes in pulse wave velocity, augmentation pressure, heart rate variability, etc., and combinations of any two or more of these.

[0023] In some examples, the stimulation source 24a is configured to generate a biphasic waveform where 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 an initial pulse with a cathodal leading phase and an anodal trailing phase may be followed by a second pulse with an anodal leading phase and a cathodal trailing phase which will be followed by a third pulse returning to a cathodal leading phase and an anodal trailing phase. As can be appreciated, 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.

[0024] As noted above, the amplitude, frequency, pulse width, and / or duration of the stimulation waveform can be selected and / or modified to facilitate neurostimulation of the sympathetic nerves of the luminal tissue without damaging the luminal tissue or the nerves within or surrounding the luminal tissue or causing excess vasoconstriction about the therapeutic device (e.g., inhibiting the movement of the therapeutic device within the luminal tissue). A pulse duration (pulse width) may be modified so that anodic stimulation of the tissue is maintained, as at certain pulse durations regions of anodic stimulation may dissipate or otherwise disappear, resulting in reduced stimulation effect. In one non-limiting embodiment, the stimulation source 24a generates biphasic waveforms having a frequency of between approximately 10 - 30Hz, a voltage of between approximately 5 - 30 V, a current of between approximately 2 - 500 mA, and a pulse width of between approximately 2 - 10 ms. It is envisioned that in embodiments where unmyelinated nerve fibers aretargeted, the pulse width of the biphasic waveform may be between approximately 2-120 ms. In a further example, the stimulation parameters are a constant current of 20mA for a blood vessel branches and 30 mA for main blood vessels, a pulse width of 5 mS, a frequency of approximately 20 Hz and a duration of between 10 and 60 seconds.

[0025] While a biphasic stimulation signal has been described above, the disclosure is not so limited, and the stimulation signal may be monophasic or biphasic. The stimulation signal may be a current injection signal where a voltage is monitored for safety or a voltage injection signal. The 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. The stimulation source 24a may also be an ultrasound stimulation source, whereby the stimulation source 24a provides signals to ultrasound transducer, causing mechanical oscillation of the transducers. The oscillations apply mechanical stimulation to the blood vessel wall and trigger nervous responses (both efferent and afferent) from the nerves within the smooth muscle of the blood vessel and nerves running along or near an exterior surface of the blood vessel.

[0026] FIG. 3 depicts one embodiment of a therapeutic device 50 (e.g., a catheter) 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 stimulation elements, such as electrodes 56 or ultrasound transducers 57, are located. As used herein electrodes 56 and ultrasound transducer 57 generally referred to as stimulation elements.

[0027] 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, radial artery or other suitable portion of patient’s vascular network that is in fluid communication with the patient’s blood vessel of interest (such as a renal artery). Inembodiments, 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 stimulation elements (e.g., electrodes 56), are 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. For instance, if the stimulation elements include at least one ultrasound transducer 57, in some examples, the at least one ultrasound transducer 57 may be carried by the elongated shaft 52 and may be enclosed within an expandable balloon. 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 stimulation elements (e.g., 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 stimulation elements (e.g., 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 stimulation elements (e.g., 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.

[0028] In the example 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 is utilized 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 or radial 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., beyonda 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 stimulation elements (e.g., 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 stimulation elements (e.g., 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 stimulation elements (e.g., 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).

[0029] In some embodiments, a pressure sensor 60 may be incorporated into the guide catheter 58 or the elongated shaft 52 for detection of physiological parameters of the patient. In one example, the physiological parameter includes blood pressure, though other parameters may be detected without departing from the scope of the disclosure.

[0030] As illustrated in the figures, the stimulation elements (e.g., 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 incommunication with the therapy source 24 and the stimulation source 24a. The electrodes 56 may deliver therapy and / or stimulation independently of one another (e.g., monopolar), 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).

[0031] In other examples, rather than each electrode of electrodes 56 being electrically connected to both the therapy source 24 and the stimulation source 24a, a first set of one or more of electrodes 56 may be electrically connected to the therapy source 24 (and not the stimulation source 24a), and a second set of one or more of electrodes 56 may be electrically connected to the stimulation source 24a (and not the therapy source 24). Further where ultrasound transducers 57 are employed as the stimulation elements, the ultrasound transducers may be electrically connected to the stimulation source 24a and the electrodes 56 in electrical communication with the therapy source 24.,

[0032] In at least one embodiment of the disclosure, the therapy source 24 is also the stimulation source 24a and can be configured to operate in both a stimulation mode, where the therapy source 24 generates a stimulation signal having, for example, a biphasic waveform, and a denervation mode, where the therapy source 24 generates RF energy to denervate the nerves of the relevant blood vessel. It is contemplated that the therapy source 24 may be manually switched from a stimulation mode to a denervation mode and vice versa or may be automatically switched by an algorithm 44 stored on the memory 32 of the computing device. Alternatively, the electrodes 56 are in communication with a stand-alone stimulation source 24a to deliver a stimulation signal to the blood vessel in question. The stimulation signal (e.g., the biphasic waveform), is generated by the stimulation source 24a and communicated to the electrodes 56 causing stimulation of the nerves as described herein.

[0033] The application of stimulation to the wall of a blood vessel and observation of a neural response is one method for identifying locations for application of denervation therapy and / or evaluating results of denervation therapy. For example, the therapeutic device 50 of Fig. 3 may be placed within a blood vessel of interest (e.g., a renal artery), anda stimulation signal generated by the stimulation source 24a may be applied to the blood vessel wall via the electrodes 56. If there are nerves sufficiently near the electrodes 56 (e.g., within the smooth muscle of the blood vessel or along or near an outer surface of the blood vessel), these nerves will be stimulated resulting in a stimulation response. One such response, where efferent nerves are stimulated, is a reduction in blood flow (e.g., blood flow velocity, blood flow volume, or the like). A drop in blood flow in excess of a threshold may indicate that the therapeutic device 50 is positioned sufficiently near the nerves that application of therapy (e.g., a monopolar RF signal from the therapy source 24 applied via electrodes 56) will successfully denervate the nerves at that location of the blood vessel of interest.

[0034] Blood flow may be calculated via any suitable technique. For instance. Blood flow may be calculated using angiographic imaging with contrast medium introduction. For instance, a bolus of contract medium may be introduced to the blood vessel of interest using therapeutic device 50, a guide catheter, or the like. A sequence of angiographic images may be collected by imaging device 70, and a blood flow velocity may be calculated based on a distance the contrast flows over a given time. Optionally, a volumetric flow rate may be determined using a blood flow velocity and a cross-sectional area of the blood vessel of interest as determined using the angiographic images. Alternatively, changes in blood flow velocity and / or volumetric flow may be observed using a flow wire or other blood flow detector (such as electrodes 56). As will be appreciated, other methods of determining blood flow may be employed without departing from the scope of the disclosure.

[0035] Blood flow through a blood vessel is impacted by a variety of related physiological parameters including vascular resistance, the cross-sectional area of the blood vessel (which is related to a diameter of the blood vessel), and the pressure of the blood in the aorta. Further, in the case of blood flow through renal arteries, renal resistance is another factor impacting renal blood flow. However, responses to stimulation, as described above, are not limited to just changes in blood flow. The stimulation may result in a response in efferent nerves resulting in changes in diameter (vasoconstriction) of the blood vessel to which the stimulation is applied. Further, there can be localized spasms of smooth muscle tissue of the blood vessel interacting with the stimulation signal. Further, in addition to stimulation of efferent nerves, afferent nerves will also be stimulated. The application of stimulation to these afferent nerves can trigger the central nervous systems to respond to thestimulation resulting changes such as an increase in systemic blood pressure of the patient. Thus, observing only a change in blood flow resulting from application of stimulation may provide a useful but incomplete indication of the placement of the therapeutic device 50 and the electrodes 56 located thereon with respect to the nerves targeted for denervation and / or evaluation of the results of denervation therapy. Further, application of therapy at these locations may yield less than expected efficacy.

[0036] In accordance with one aspect of the disclosure, computing device 22 may determine a corrected blood flow value. Computing device 22 may determine the corrected blood flow value using one or more algorithms 44 stored in the memory 32 of Fig. 2. The algorithm may be a standard algorithm applied to all patients or a customized algorithm taking into account such factors as sex, weight, age, comorbidities, and / or other characteristics of an individual patient. The corrected blood flow value adjusts the observed blood flow by taking into account observed changes in one or more of blood vessel dimension (e.g., diameter) or changes in systemic blood pressure (for which a mean arterial pressure (MAP) may be used in some implementations). This corrected blood flow value provides a more accurate indication of the changes in blood flow associated with the efferent nerve response to stimulation and provides improved guidance on the presence of nerves adjacent the electrodes 56 and / or efficacy of a denervation procedure.

[0037] For instance, the blood flow velocity may be affected by a volumetric flow rate, blood pressure driving flow (e.g., MAP or systemic blood pressure), and cross-sectional area of the vessel through which the blood is flowing. Thus, by considering blood flow, blood pressure, and dimensions of the blood vessel, a more accurate blood flow value may be determined compared to instances in which blood pressure and / or blood vessel dimensions (and / or changes to these factors) are not taken into account.

[0038] In some examples, the corrected blood flow value may be generated from a model simulation representative of blood flow through the vessel of interest, e.g., a renal artery tree. For instance, the model simulation may include a three-dimensional model or representation of the vessel of interest. The three-dimensional model may be based on, for example, multiple fluoroscopic, CT, or other images of the vessel of interest. In instances in which the images are two-dimensional, the three-dimensional model may be determined using reconstruction from two or more two-dimensional images captured at different angles. The three-dimensional model may thus represent the geometry (including diameter andcross-sectional area) of the vessel of interest along its length, including any branches. Flow through the three-dimensional model of the vessel of interest may be modeled using computational fluid dynamics (CFD), a reduced order model, or the like, using boundary conditions including the pressure (e.g., MAP or systemic blood pressure) and blood flow velocity. In addition, in some examples, other parameters may be employed either individually or to generate the corrected blood flow value including pulse wave velocity, augmentation pressure, and heart rate variability without departing from the scope of the disclosure.

[0039] In accordance with the disclosure, changes in blood vessel diameter at one or more locations along the vessel of interest can be calculated from angiographic imaging using contrast medium. The diameter of a blood vessel before stimulation and after stimulation are compared to determine a magnitude of blood vessel diameter change as a result of the stimulation. This may be an absolute magnitude of change (e.g., 2-3 mm) or in can be a relative change (e.g., 20% reduction in diameter). Those of skill in the art will recognize that an imaging video may be employed where a series of images are acquired both before, during, and after application of the stimulation such that average values of blood vessel diameter can be acquired and utilized to calculate the change in diameter as a result of the stimulation.

[0040] As an alternative, a similar process may be undertaken without the use of a contrast medium. With the therapeutic device 50 located within the blood vessel, images can be acquired. The electrodes 56 of the therapeutic device 50 are radiopaque, and can be seen in angiographic (e.g., X-ray images) or ultrasound images. By comparing images acquired before stimulation with images acquired during or after stimulation, changes in the spacing of the electrodes 56 can be observed. As the blood vessel constricts, the therapeutic device 50 as shown in Fig. 3 is straightened and the spacing between the electrodes 56, which are in contact with the blood vessel wall, changes. This change in spacing can be utilized to determine a change in diameter of the blood vessel as a result of the stimulation.

[0041] The pressure sensor 60 located on the guide catheter 58 or therapeutic device 50 can detect blood pressure (and changes in blood pressure). Though shown in Fig. 3 on a distal portion of the guide catheter 58, the pressure sensor 60 may be located more proximal on the guide sheath 58 to ensure that the pressure sensor 60 remains in the aorta to detectchanges in aortal (e.g., systemic) blood pressure, MAP, or the like. Alternatively, a separate device may include the pressure sensor 60.

[0042] Fig. 4 presents a method 400 incorporating the corrected blood flow value in accordance with the disclosure. Following navigation of a guide catheter 58 and therapeutic device 50 to a desired blood vessel (e.g., renal artery as shown in Fig. 3) the therapeutic device 50 may be advanced from the guide catheter 58 and the therapeutic device 50 allowed to expand such that the electrodes 56 are in contact with an inner wall of the artery. At step 402 the blood pressure in the aorta is acquired via the sensor 60. At step 404, the diameter of the blood vessel may be determined (e.g., via angiography or other imaging as described above). And at step 406 an initial blood flow may be determined (BF 1). For instance where the blood vessel to be denervated is the renal artery leading from the aorta to the kidneys, the blood flow that is calculated is the renal blood flow. At step 408 an initial corrected blood flow (CBF1) value is optionally calculated. In other examples, step 408 may be omitted, and a non-corrected blood flow value (BF1) may be used instead. At step 410 stimulation is generated in the stimulation source 24a and applied via the electrodes 56 to the blood vessel wall. At step 412 the blood pressure in the aorta after application of the stimulation is acquired via the sensor 60. At step 414, the diameter of the blood vessel is again determined and at step 416 a second blood flow is determined. At step 418 a second corrected blood flow (CBF2) value is calculated based on the second blood flow and one or both of the blood vessel dimensions or the blood pressure, as described above. At step 420, a determination is made whether the difference between the first corrected blood flow value and the second corrected blood flow value exceeds a threshold. If yes, then then an indicator may be displayed on the user interface 28 confirming that the change in corrected blood flow value exceeded a threshold at step 424 and the method progresses to step 426 where therapy is applied to the blood vessel wall (e.g., via the electrodes 56). If no at step 420, an indicator may be displayed on the user interface 28 that the change in corrected blood flow value did not exceed a threshold and that the therapeutic device 50 should be repositioned at step 422. At step 423 an inquiry may be presented on the user interface 28 as to whether the procedure should be ended, which may occur for example if after repeated attempts a positive response cannot be achieved at step 420. If the procedure is not to end, after repositioning the therapeutic device 50, the method then returns to step 402 or step 410 where stimulation is again applied to the wall of the blood vessel.

[0043] At step 426 therapy is applied to the blood vessel wall. Following application of the therapy at step 428 stimulation is again applied to the blood vessel via the electrodes 56. At step 430 pressure in the aorta is again acquired via the sensor 60. At step 432, the diameter of the blood vessel is again determined, and at step 434 the blood flow is determined. At step 436 a third corrected blood flow (CBF3) value is calculated based on the third blood flow and one or both of the blood vessel dimensions or the blood pressure, as described above. At step 438, a determination is made whether the difference between the third corrected blood flow value and the second corrected blood flow value exceeds a threshold. If yes, then an indicator may be displayed on the user interface 28 that a sufficient denervation has been achieved at step 440 and the method ends. If no at step 438, an indicator may be presented on the user interface at step 442 that a sufficient denervation has not been achieved. At step 443, an inquiry may be presented on the user interface 28 as to whether the procedure should be ended, which may occur for example if after repeated attempts a positive response cannot be achieved at step 438. If the procedure is not to end, the method returns to step 426 where further therapy is applied and the method steps 426- 438 repeat until an efficacious denervation is achieved. Alternatively, the therapeutic device 50 may be repositioned within the blood vessel (e.g., by an interventional cardiologist), and the method may return to step 402 or step 410 to determine if the new location is suitable for performing further denervation therapy.

[0044] Though described as including a variety of steps in method 400 and in a particular order, the order of the method steps may be rearranged, and steps of the method may be omitted entirely without departing from the scope of the disclosure. Further, although the method 400 includes determining a corrected blood flow value both before and after application of therapy, in other examples, a method may include only one or the other. For instance, a method may include determining a corrected blood flow value only before application of therapy to facilitate identification of locations at which to apply therapy. Conversely, a method may include determining a corrected blood flow value only after application of therapy to facilitate evaluation of denervation success.

[0045] 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 theoperation 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).

[0046] Although 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 non-removable media implemented in any method or technology for storage of information such as computer-readable instructions, data structures, program modules or other data. 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

[0047] The disclosure is further described in connection with the following examples in which:

[0048] Example l is a system including a computing device; and a computer readable recording medium storing instructions that, when executed by the computing device, cause the computing device to, obtain a systemic blood pressure of the patient, obtain a diameter of a blood vessel of interest, obtain a blood flow through the blood vessel of interest; and calculate a corrected blood flow value based at least in part on the determined blood flow, the diameter of the blood vessel, and the systemic blood pressure.

[0049] Example 2 is the system of example 1, further including a catheter configured to be navigated within the blood vessel of interest of a patient, the catheter comprising a plurality of stimulation elements, and the catheter being configured to apply stimulation to nerves beyond a wall of the blood vessel of interest, a therapy source configured to communicate with at least one therapy delivery element coupled to a distal portion of the catheter, and a stimulation source configured to output a stimulation signal to at least one stimulation element of the plurality of stimulation elements.

[0050] Example 3 is the system of examples 1 or 2, further including a pressure sensor configured to detect the systemic blood pressure of the patient and output a signal indicative of the systemic blood pressure of the patient to the computing device.

[0051] Example 3 is the system of any of the preceding examples, further including a flow sensor configured to detect blood flow through the blood vessel of interest, wherein the instructions further cause the computing device to obtain the blood flow from the flow sensor.

[0052] Example 5 is the system of any of the preceding examples, further including an imaging device configured to image of the blood vessel of interest, wherein the instructions further cause the computing device to obtain the image from the imaging device and determine the diameter of the blood vessel of interest based on the image.

[0053] Example 6 is the system of any of examples 2 to 5, wherein the instructions further cause the processor to, calculate a first corrected blood flow value based at least in part on a first diameter of the blood vessel of interest and a first blood flow value, both obtained prior to application of the stimulation signal to the wall of the blood vessel of interest, and calculate a second corrected blood flow value based at least in part on a second diameter of the blood vessel of interest and a second blood flow value, both obtained after application of the stimulation signal to the wall of the blood vessel of interest.

[0054] Example 7 is the system of example 6, further including a user interface configured to display an indicator of a comparison of the first corrected blood flow value and the second corrected blood flow value.

[0055] Example 8 is the system of example 7, wherein the indicator signifies that movement of the catheter is appropriate or that application of therapy at the current location of catheter is appropriate.

[0056] Example 9 is the system of example 6 to 8 wherein the instructions further cause the computing device to determine a third corrected blood flow value based at least in part on a third diameter of the blood vessel of interest and a third blood flow value, both obtained after application of therapy to the blood vessel.

[0057] Example 10 is the system of example 9, further including a user interface configured to display an indicator of a comparison of the second corrected blood flow value and the third corrected blood flow value.

[0058] Example 11 is the system of example 10, wherein the indicator signifies that an applied therapy was efficacious or that further therapy is appropriate.

[0059] Example 12 is a method for assessing nerves of a blood vessel including detecting a systemic blood pressure of the patient, determining a diameter of the blood vessel of interest, determining a blood flow through the blood vessel of interest and calculating a corrected blood flow value from the determined blood flow, the diameter of the blood vessel, and the systemic blood pressure.

[0060] Example 13 is the method of example 12, further including applying a stimulation signal to a blood vessel wall of a blood vessel of interest via at least one of a plurality of stimulation elements on a distal portion of a catheter located within the blood vessel of interest.

[0061] Example 14 is the method of examples 12-13, further including calculating a first corrected blood flow value based at least in part on a first diameter of the blood vessel of interest and a blood flow value, both obtained prior to applying stimulation and calculating a second corrected blood flow value based at least in part on a second diameter of the blood vessel of interest and a second blood flow value, both obtained after applying stimulation to the wall of blood vessel of interest.

[0062] Example 15 is the method of example 14, wherein a difference between the first corrected blood flow value and the second corrected blood flow value in excess of a threshold indicates the catheter is located proximate sympathetic nerves.

[0063] Example 16 is the method of examples 12-15 further comprising applying therapy to the blood vessel.

[0064] Example 17 is the method of example 16, further comprising calculating a third corrected blood flow value based at least in part on a third diameter of the blood vessel of interest and a third blood flow value, both obtained after application of the therapy.

[0065] Example 18 is the method of example 17, wherein a difference between the second corrected blood flow value and the third corrected blood flow value in excess of a threshold indicates an efficacious therapy.

[0066] Example 19 is the method of any of examples 13-18, wherein the stimulation signal is a monophasic or biphasic stimulation signal.

[0067] Example 20 is the method of any of examples 16-19, wherein the therapy is one or more of monopolar radio frequency therapy, a bipolar radio frequency therapy, a microwave therapy, a cryogenic therapy, an ultrasound therapy, or a chemical therapy.

[0068] Example 21 is the method of any of examples 12-20, wherein the systemic blood pressure is detected by a pressure sensor located within an aorta of the patient and configured to output a signal indicative of the systemic blood pressure of the patient and the blood flow is detected by a blood flow sensor configured to detect blood flow through the blood vessel.

[0069] Example 22 is the method of any of claims 12-21, wherein a change in diameter of a blood vessel is determined via imaging.

[0070] 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

CLAIMS:

1. A system comprising: a computing device; and a computer readable recording medium storing instructions that, when executed by the computing device, cause the computing device to: obtain a systemic blood pressure of the patient; obtain a diameter of a blood vessel of interest; obtain a blood flow through the blood vessel of interest; and calculate a corrected blood flow value based at least in part on the determined blood flow, the diameter of the blood vessel, and the systemic blood pressure.

2. The system of claim 1, further comprising: a catheter configured to be navigated within the blood vessel of interest of a patient, the catheter comprising a plurality of stimulation elements, and the catheter being configured to apply stimulation to nerves beyond a wall of the blood vessel of interest; a therapy source configured to communicate with at least one therapy delivery element coupled to a distal portion of the catheter; a stimulation source configured to output a stimulation signal to at least one stimulation element of the plurality of stimulation elements.

3. The system of claims 1 or 2, further comprising a pressure sensor configured to detect the systemic blood pressure of the patient and output a signal indicative of the systemic blood pressure of the patient to the computing device.

4. The system of any of the preceding claims, further comprising a flow sensor configured to detect blood flow through the blood vessel of interest, wherein the instructions further cause the computing device to obtain the blood flow from the flow sensor.

5. The system of any of the preceding claims, further comprising an imaging device configured to image of the blood vessel of interest, wherein the instructions further cause the computing device to obtain the image from the imaging device and determine the diameter of the blood vessel of interest based on the image.

6. The system of any one of claims 2 to 5, wherein the instructions further cause the processor to: calculate a first corrected blood flow value based at least in part on a first diameter of the blood vessel of interest and a first blood flow value, both obtained prior to application of the stimulation signal to the wall of the blood vessel of interest; and calculate a second corrected blood flow value based at least in part on a second diameter of the blood vessel of interest and a second blood flow value, both obtained after application of the stimulation signal to the wall of the blood vessel of interest.

7. The system of claim 6, further comprising a user interface configured to display an indicator of a comparison of the first corrected blood flow value and the second corrected blood flow value.

8. The system of claim 7, wherein the indicator signifies that movement of the catheter is appropriate or that application of therapy at the current location of catheter is appropriate.

9. The system of any of the preceding claims wherein the instructions further cause the computing device to determine a third corrected blood flow value based at least in part on a third diameter of the blood vessel of interest and a third blood flow value, both obtained after application of therapy to the blood vessel.

10. The system of claim 9, further comprising a user interface configured to display an indicator of a comparison of the second corrected blood flow value and the third corrected blood flow value.

11. The system of claim 10, wherein the indicator signifies that an applied therapy was efficacious or that further therapy is appropriate.

12. A method for denervation of nerves of a blood vessel comprising: detecting a systemic blood pressure of the patient; determining a diameter of the blood vessel of interest; determining a blood flow through the blood vessel of interest; calculating a corrected blood flow value from the determined blood flow, the diameter of the blood vessel, and the systemic blood pressure.

13. The method of claim 12, further comprising applying a stimulation signal to a blood vessel wall of a blood vessel of interest via at least one of a plurality of stimulation elements on a distal portion of a catheter located within the blood vessel of interest.

14. The method of claim 12-13, further comprising calculating a first corrected blood flow value based at least in part on a first diameter of the blood vessel of interest and a blood flow value, both obtained prior to applying stimulation and calculating a second corrected blood flow value based at least in part on a second diameter of the blood vessel of interest and a second blood flow value, both obtained after applying stimulation to the wall of blood vessel of interest.

15. The method of claim 14, wherein a difference between the first corrected blood flow value and the second corrected blood flow value in excess of a threshold indicates the catheter is located proximate sympathetic nerves.

Images