Detection of microvascular constriction

Abstract

In some examples, an example technique for detecting microvascular constriction includes, determining, by processing circuitry, a pressure drop between a pair of locations in vasculature of a patient. The example technique may further include comparing, by the processing circuitry, the pressure drop with a reference pressure drop. The example technique may further include determining, by the processing circuitry, based on the comparison, presence of microvascular constriction in the vasculature. The example technique may further include generating, by processing circuitry, in response to determining the presence of microvascular constriction, an output indicative of the presence of microvascular constriction.

Description

DETECTION OF MICROVASCULAR CONSTRICTION

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 601,950, filed November 2023, 2023, the entire content of which is incorporated herein by reference.TECHNICAL FIELD

[0002] The present disclosure generally relates to microvascular constriction.BACKGROUND

[0003] Renal stimulation may be used to monitor and guide a renal denervation procedure. For example, the effect of electrical stimulation on a physiological parameter (e.g., blood pressure) may be compared before and after a denervation session to determine whether further ablation is needed.

[0004] Vasculature of a patient may be affected by a disease. For example, coronary disease may cause constriction of blood vessels.SUMMARY

[0005] In general, the present disclosure describes devices, systems, and techniques for detecting microvascular constriction.

[0006] It may be difficult to detect constriction in the microvasculature (also referred to as microvascular constriction) using imaging. For example, relatively narrow vessel diameters in the microvasculature, and diffusion of contrast agents in view of relatively slow flow through microvasculature may diminish spatial and / or temporal resolution in images. Thus, microvascular constriction may not be discernible solely using imaging.

[0007] In some examples, devices, systems, and techniques according to the present disclosure detect microvascular constriction based on pressure drop along microvasculature. For example, a pressure drop between two or more anatomical locations may be compared with a reference pressure drop. In some examples, the reference pressure drop may be determined based on patient cohort data, patient historical data, or anatomical computational models. Thus, microvascular constriction may be detected without requiring imaging.

[0008] In some examples, an example system includes a pressure mapping apparatus and a computing device. The pressure mapping apparatus is configured to determine a pressure drop between multiple locations (e.g., a pair of locations) in vasculature of a patient. The computing device may be configured to compare the pressure drop with a reference pressure drop. The computing device may be further configured to determine based on the comparison, presence of microvascular constriction in the vasculature. The computing device may be further configured to generate, in response to determining the presence of microvascular constriction, an output indicative of the presence of microvascular constriction.

[0009] In some examples, an example technique for detecting microvascular constriction includes, determining, by processing circuitry, a pressure drop between a pair of locations in vasculature of a patient. The example technique may further include comparing, by the processing circuitry, the pressure drop with a reference pressure drop. The example technique may further include determining, by the processing circuitry, based on the comparison, presence of microvascular constriction in the vasculature. The example technique may further include generating, by processing circuitry, in response to determining the presence of microvascular constriction, an output indicative of the presence of microvascular constriction.

[0010] In some examples, an example technique for detecting microvascular constriction includes, determining, by processing circuitry, a microvascular pressure map for a patient. The example technique may further include comparing, by the processing circuitry, the microvascular pressure map with a reference microvascular pressure map. The example technique may further include determining, by the processing circuitry, based on the comparison, presence of microvascular constriction.

[0011] In some examples, an example technique for detecting microvascular disease includes determining an occurrence of microvascular disease in response to determining a presence of microvascular constriction.

[0012] In some examples, an example technique for monitoring a denervation procedure includes determining an effectiveness of the denervation procedure in response to determining a presence of microvascular constriction.

[0013] In some examples, an example technique for neuromodulation includes delivering stimulation to a target site in a patient. The example technique may further include determining microvascular constriction of a blood vessel in response to the stimulation. The example technique may further include delivering, in response to determining the presence ofmicrovascular constriction after the stimulation, neuromodulation therapy via a device in the blood vessel. The example technique may further include determining, after delivering the neuromodulation therapy, microvascular constriction of the blood vessel. The example technique may further include delivering, in response to determining the presence of microvascular constriction after the neuromodulation therapy, further neuromodulation therapy via the device in the blood vessel.

[0014] In some examples, an example technique for neuromodulation includes delivering stimulation to a first target site in a patient. The example technique may further include determining microvascular constriction of a blood vessel in response to the stimulation. The example technique may further include determining, in response to determining the presence of microvascular constriction of the blood vessel, a second target site for neuromodulation.

[0015] In some examples, an example technique for neuromodulation includes delivering stimulation to a target site in a patient. The example technique may further include determining microvascular constriction of a blood vessel in response to the stimulation. The example technique may further include generating, by processing circuitry, in response to determining the presence of microvascular constriction of the blood vessel, an output indicating that the patient is a candidate for denervation therapy.

[0016] In some examples, a non-transitory computer readable storage medium includes program instructions configured to cause processing circuitry to determine a pressure drop between a pair of locations in vasculature of a patient. The program instructions device may be further configured to cause the processing circuitry to compare the pressure drop with a reference pressure drop. The program instructions device may be further configured to cause the processing circuitry to determine based on the comparison, presence of microvascular constriction in the vasculature. The program instructions device may be further configured to cause the processing circuitry to generate, in response to determining the presence of microvascular constriction, an output indicative of the presence of microvascular constriction.

[0017] The details of one or more examples of the techniques of this disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the techniques will be apparent from the description and drawings, and from the claims.BRIEF DESCRIPTION OF DRAWINGS

[0018] FIG. l is a block diagram illustrating an example system including a pressure mapping apparatus and a computing device configured to detect microvascular constriction.

[0019] FIG. 2 is a schematic diagram illustrating an example output generated by the computing device of FIG. 1 including an indication of microvascular constriction overlaid on a graphical representation of vasculature of a patient.

[0020] FIG. 3 is a block diagram illustrating an example configuration of the computing device of FIG. 1.

[0021] FIG. 4 is a schematic diagram illustrating an example configuration of a neuromodulation system.

[0022] FIG. 5 is a flow diagram illustrating an example technique for detecting microvascular constriction.

[0023] FIG. 6 is a flow diagram illustrating an example technique for detecting microvascular constriction.

[0024] FIG. 7 is a flow diagram illustrating an example technique for detecting microvascular disease.

[0025] FIG. 8 is a flow diagram illustrating an example technique for neuromodulation.

[0026] FIG. 9 is a flow diagram illustrating an example technique for neuromodulation.

[0027] FIG. 10 is a flow diagram illustrating an example technique for neuromodulation.

[0028] FIG. 11 illustrates an example technique for accessing a renal artery and modulating renal nerves with the system of FIG. 1 in accordance with some examples of the present disclosure.

[0029] FIG. 12 is a conceptual illustration of an example sympathetic nervous system (SNS) illustrating how the brain communicated with the body via the SNS.

[0030] FIG. 13 is an enlarged anatomic view of nerves innervating a left kidney to form the renal plexus surrounding the left renal artery.

[0031] FIG. 14 is an anatomic view of a human body depicting neural efferent and afferent communication between the brain and kidneys.

[0032] FIG. 15 is a conceptual view of a human body depicting neural efferent and afferent communication between the brain and kidneys.

[0033] FIG. 16 is an anatomic view of the arterial vasculature of a human.

[0034] FIG. 17 is an anatomic view of the venous vasculature of a human.DETAILED DESCRIPTION

[0035] The present disclosure describes devices, systems, and techniques for detecting microvascular constriction.

[0036] As used herein, the terms “distal” and “proximal” define a position or direction with respect to the treating clinician or clinician’s control device (e.g., a handle assembly). “Distal” or “distally” can refer to a position distant from or in a direction away from the clinician or clinician’s control device. “Proximal” and “proximally” can refer to a position near or in a direction towards the clinician or clinician’s control device.

[0037] Certain diseases, such as microvascular disease, may result in microvascular constriction. For example, symptoms of coronary disease with an absence of lesions in major vasculature (larger blood vessels) may indicate constriction or obstruction in the distal coronary vasculature (microvasculature). Nerve stimulation (for example, in course of monitoring a denervation procedure) may also result in microvascular constriction.

[0038] Such microvascular constriction may not be detectable by standard diagnostic techniques. For example, dimensional changes in the affected vasculature may be smaller than the minimum resolution of imaging techniques. Further, vascular constriction may cause a blood flow reduction, in turn causing diffusion of contrast agents and affecting the quality of imaging.

[0039] Pressure drop along a flow path is sensitive to flow rate, vessel diameter, and distance along the vessel at which the pressure drop is measured. Pressure drop is measured at two points in the vasculature of a patient, for example, in the aorta and the point of interest in a vessel, or alternatively, at two points within a vessel, for example, at points that are distal and proximal of a coronary lesion of interest.

[0040] In examples described herein, processing circuitry compares a determined pressure drop for a patient to a reference pressure drop, which can also be referred to as a characteristic pressure drop or a threshold pressure drop in some examples. In some examples, the reference pressure drop is any suitable pressure drop that indicates an absence of microvasculature constriction or an absence of a particular amount of microvascular constriction. For example, a reference pressure drop map may be associated with healthy vasculature and blood flow. The reference pressure drop can be a predetermined value (e.g., determined in advance of evaluating a patient for microvascular constriction) or an otherwisestored value. Pressure mapping can be performed with a device, for example, fractional flow reserve (FFR) with a pressure wire, or using virtual FFR or virtual computed tomography angiography. While pressure mapping can be performed in large caliber vessels, knowing the pressure drop in the larger vessels allows the pressure drop in the microvasculature to be estimated as the difference in pressure drop in microvasculature alone to the pressure drop from aorta to vena cava. Thus a reference microvasculature pressure drop may be established.

[0041] In some examples, the pressure drop data is categorized by patient anatomy as a whole (anatomy classified by commonalities in the patient-to-patient arterial structure). Alternatively, a model may be developed based on, for example, blood vessel segment length and diameter such that the expected normal pressure drop could be estimated in any healthy anatomy based on segmenting the anatomy, calculating pressure drop in each segment and adding up the individual segment pressure drop to get the whole.

[0042] Coronary disease may be diagnosed using the microvascular pressure map. For example, a patient cardiac anatomy may be classified as a whole and correlated with a cohort of healthy patients with similar anatomy. A deviation relative to the cohort would indicate microvascular constriction. Alternatively, a predicted pressure drop may be calculated for example by vessel segmentation. The predicted pressure drop map may then be compared to actual pressure drop map. A measured pressure drop in the arterial macrovasculature that is less than the predicted pressure drop is indicative of microvascular constriction, or microvascular disease, because microvascular constriction contributes to the residual pressure drop. Detection of microvascular constriction may assist with diagnosis and further treatment, for example, selection of pharmaceuticals or dosages. For example, if a potential treatment of microvasculature disease can be delivered locally (for example, a pharmaceutical agent via a microcatheter), then determining local levels of microvasculature may facilitate the treatment.

[0043] The microvascular pressure drop map may also be used to monitor denervation and stimulation, for example, for a renal denervation procedure and / or a hepatic denervation procedure. Neuromodulation, such as renal or hepatic denervation, may be accomplished using one or more of a variety of treatment modalities, including delivery of radiofrequency (RF) energy, microwave energy, ultrasound energy, thermal energy (e.g., direct thermal energy), optical energy, cryogenic cooling, a chemical agent, or the like. To perform intravascular neuromodulation, a neuromodulation catheter may be delivered to a bloodvessel, such as a renal artery, of a patient. In some examples, a neuromodulation catheter includes an elongate body and at least one therapy delivery element disposed on a radially expandable portion of the elongate body. The at least one therapy delivery element may include, for example, an electrode, an ultrasound transducer, a needle configured to deliver a chemical agent, a balloon configured to deliver cryo-therapy or heat-based therapy, or a fluid injection port. While the at least one therapy delivery element may be disposed on a distal portion of the elongate body of the neuromodulation catheter, in other examples, other portions of the elongate body may include the at least one therapy delivery element.

[0044] In some examples of monitoring or evaluating a denervation procedure, a presession (pre-denervation or pre-stimulation) pressure drop may be compared with a postsession (post-denervation or post-stimulation) pressure drop. The post-session pressure drop being greater than that predicted by the pre-session pressure drop is indicative of microvascular constriction. Occurrence of microvascular constriction in a patient in response to stimulation (e.g., electrical stimulation) may indicate that the patient is likely to respond to denervation (for example, renal denervation) because nerves are influenced. A clinician may refine denervation therapy based on the presence or extent of microvascular constriction. For example, absence of microvascular constriction after renal denervation may indicate that sufficient renal denervation therapy was delivered. Presence of microvascular constriction in a region may indicate parts of artery that may need further denervation due to the detected activity of nerves (e.g., indicated by microvascular constriction in response to stimulation) in the region.

[0045] Determining local levels of microvasculature constriction may facilitate denervation therapy. For example, some parts of the kidney may exhibit greater or lesser microvascular constriction than other parts of the kidney. Determining differences in microvascular constriction may provide more specific information as to the success of RDN or stim based on specific electrode locations. A distal end of the arterial macrovasculature includes a number of different small arteries delivering blood to the microvasculature. As a pressure drop for the microvasculature as a whole can be determined, a pressure drop can be calculated for each sub-branch (a sub-branch being fed by a single vessel of the macrovasculature at which a local pressure drop to the aorta can be determined). In this way, areas of increased or decreased microvascular constriction can be identified, and a clinician may be guided as to which aspects of the might preferentially be treated or left untreated.

[0046] FIG. 1 is a block diagram illustrating an example system 10 including a pressure mapping apparatus 12 and a computing device 14 configured to detect microvascular constriction. FIG. 1 provides a conceptual representation of patient vasculature 16; a microvascular constriction may be present in a vessel (e.g., a vein or an artery) of vasculature 16. In some examples, the microvascular constriction may be present along a path between pair of locations Li and L2, where Li is a first location in a major vessel, while L2is a second location in a minor vessel. For example, a major vessel may be a vessel connected to the heart or an organ, for example, an aorta or arteries. A minor vessel may be a vessel in a branch or a sub-branch of a major vessel. Alternatively, or in addition, the microvascular constriction may be present along a path between pair of locations L2and L3;L2being distal to the microvascular constriction and L3being proximal to the microvascular constriction.While the present disclosure refers to a pair of locations, in some examples, the pressure drop may be determined between multiple locations. For example, pressure drop may be determined based on two or more locations. In some examples, the microvascular constriction may be associated with a lesion, a plaque, or some condition associated with disease. In other examples, the microvascular constriction may arise from (e.g., be evoked by) stimulation, for example, electrical nerve stimulation associated with a neuromodulation treatment. In some examples, system 10 further includes a neuromodulation system 20, as described with reference to FIG. 3. Neuromodulation system 20 is configured to deliver neuromodulation therapy to the patient. In other examples, system 10 does not include neuromodulation system 20.

[0047] Pressure mapping apparatus 12 is configured to determine a pressure drop between a plurality of locations (for example, a pair of locations, such as Li and L2, or L3and L2) in vasculature 16 of the patient. For example, pressure mapping apparatus 12 may be configured to generate at least one of a fractional flow reserve (FFR) pressure map, a virtual FFR pressure map, an angiographic pressure map, a computerized tomography (CT) angiographic pressure map, or a virtual CT angiographic pressure map. In some examples, pressure mapping apparatus 12 includes one or more of a catheter, a pressure wire, or a guide wire, which can be used to sense the pressure in vasculature 16 at each location of the plurality of locations. The sensed pressure can then be used to determine the pressure drop.

[0048] In some examples, computing device 14 is configured to compare the pressure drop with a reference pressure drop. Computing device 14 may be further configured todetermine based on the comparison, presence of microvascular constriction in vasculature 16. Because a constriction reduces flow in a vessel, presence of the constriction would cause pressure at a location upstream of the constriction to be relatively higher, and thus, cause the pressure drop along the vessel and across the constriction to be relatively higher, compared to a vessel in which a constriction is absent. Accordingly, the reference pressure drop may be a pressure drop associated with healthy vasculature, or otherwise with an absence of a constriction or absence of a significant constriction associated with disease or a constricted state evoked by stimulation. If the pressure drop determined by computing device 14 is greater than the reference pressure drop, then computing device 14 may determine that a constriction is present. If the pressure determined by computing device 14 is lower than or equal to the reference pressure drop, computing device 14 may determine that a constriction is absent.

[0049] In some examples, computing device 14 is configured to determine the microvascular constriction by at least determining a presence or absence of microvascular constriction along a predetermined vessel of vasculature 16. For example, the pair of locations may straddle the predetermined vessel, and a pressure drop between the pair of locations may be indicative of presence or absence of microvascular construction between the pair of locations, and thus, along the predetermined vessel. Similarly, computing device 14 may be configured to determine microvascular constriction along any path between the pair of locations of vasculature 16. In some examples, one location of the pair of locations is in a major vessel. For example, the major vessel may be an aorta. In some examples, the pair of locations is across a suspected constriction site in the vasculature.

[0050] Computing device 14 may be further configured to generate, in response to determining the presence of microvascular constriction, an output indicative of the presence of microvascular constriction via a user interface of computing device 14. The output may include alphanumeric indicia, graphical indicia, iconography, or any other indicia suitable for indicating the presence (or an absence) of microvascular constriction. In some examples, the output includes a binary signal indicative of the presence or absence of microvascular constriction. For example, a clinician may select an anatomical path along vasculature 16, and the output may be a binary output (for example, “Yes” or “No,” or “Present” or “Absent”) indicating whether microvascular constriction is present or absent along that path. In other examples, a clinician may select a general anatomical region, or a portion of vasculature 16,and the output may indicate whether microvascular constriction is present or absent in anatomical region or portion of vasculature 16. In some examples, computing device 14 is configured to present other information via the user interface, such as, but not limited to, a determined pressure drop between two or more locations in vasculature 16 or a pressure map. In addition, as described in further detail below, in some examples, computing device 14 is configured to present information related to a neuromodulation (e.g., denervation) procedure, such as whether the patient is a candidate for neuromodulation therapy due to the presence of active nerves in vasculature of interest (e.g., the patient is expected to respond well to the neuromodulation therapy), whether a neuromodulation procedure was successful, or locations exhibiting microvasculature constriction, which indicate suitable locations for delivery of neuromodulation therapy.

[0051] In some examples, computing device 14 is configured to determine a microvascular constriction metric. For example, the magnitude of the microvascular constriction metric may be indicative of the extent of constriction. In some examples, a microvascular constriction metric having a magnitude “0” is indicative of absence of constriction, while a magnitude progressively greater than 0 may indicate a correspondingly greater extent of constriction. In some examples, the microvascular constriction metric may range from 0 to 1, with 1 indicating substantial constriction, and intermediate values indicating intermediate constriction. Thus, the microvascular constriction metric may be indicative of a level of microvascular constriction. In some examples, the microvascular constriction metric is proportional to a difference between the pressure drop and the reference pressure drop. In some examples, the microvascular constriction metric is proportional to a ratio of the pressure drop and the reference pressure drop.

[0052] In some examples, computing device 14 may determine the reference pressure drop by at least comparing pressures at a reference pair of locations in a reference pressure map corresponding to the pair of locations in vasculature 16. For example, the reference pressure map may include pressure values associated with a plurality of locations, and / or pressure drop values associated with a plurality of pairs of locations, and computing device 14 may select the reference pair closes to the pair of locations Li and L2(or L3and L2). In some examples, the reference pressure map includes at least one of a fractional flow reserve (FFR) pressure map, a virtual FFR pressure map, an angiographic pressure map, a computerized tomography (CT) angiographic pressure map, or a virtual CT angiographic pressure map.

[0053] FIG. 2 is a schematic diagram illustrating an example output 30 generated by computing device 14 of FIG. 1, which can be presented via a display device of computing device 14 or another device. Output 30 includes an indication of microvascular constriction 32 overlaid on a graphical representation 36 of vasculature 16 of the patient. In some examples, graphical representation 36 includes a three-dimensional view substantially corresponding to the anatomical arrangement of vasculature 16. In other examples, graphical representation 36 includes a two-dimensional or three-dimensional view that may or may not be anatomically accurate, but may symbolically, logically, or otherwise provide an indication of a location and / or presence or absence of microvascular constriction at that location. In some examples, graphical representation 36 includes a table or column of text, identifying the number, size, orientation, or location of one or more microvascular constrictions. Thus, computing device 14 may be configured to output a graphical or text representation of the pressure map.

[0054] FIG. 3 is a block diagram illustrating an example configuration of computing device 14 of FIG. 1. In some examples, computing device 14 may include a smart watch, a smart phone, a tablet computer, a laptop computer, a personal digital assistant (PDA), a desktop computer, a smart speaker, a sleep monitor, a wearable computing device, a smart home appliance, or any Internet-of-Things (loT) device. In some examples, computing device 14 and pressure mapping apparatus 12 are part of the same device or part of different devices.

[0055] As shown in the example of FIG. 3, computing device 14 includes processing circuitry 70, storage device 72, communication circuitry 74, and a user interface 76. While computing device 14 may be a stand-alone device as shown in FIG. 3, in other examples, computing device 14 may be any component or system that includes processing circuitry or other suitable computing environment for executing software instructions and, for example, need not necessarily include one or more elements shown in FIG. 3 (e.g., in some examples components such as storage device 72 may not be co-located or in the same housing or structure as other components).

[0056] Processing circuitry 70, in some examples, is configured to implement functionality and / or process instructions for execution within at least one computing device 14. For example, processing circuitry 70 may be capable of processing instructions, including at least one application 80, stored in storage device 72. Examples of processing circuitry 70, as well as other processors, processing circuitry, controllers, control circuitry, and the like,described herein, may include any combination of integrated circuitry, discrete logic circuitry, analog circuitry, such as one or more microprocessors, digital signal processors (DSPs), application specific integrated circuits (ASICs), or field-programmable gate arrays (FPGAs). In some examples, processing circuitry 70 includes multiple components, such as any combination of one or more microprocessors, one or more DSPs, one or more ASICs, or one or more FPGAs, as well as other discrete or integrated logic circuitry, and / or analog circuitry.

[0057] Storage device 72 (which can also be referred to as a memory) may be configured to store information within computing device 14, including at least one application 80 and data 90. Storage device 72, in some examples, is a computer-readable storage medium. In some examples, storage device 72 includes a temporary memory or a volatile memory. Storage device 72, in one example, is used by at least one application 80 running on computing device 14 to temporarily store information during program execution. Storage device 72, in some examples, also includes one or more memories configured for long-term storage of information, e.g., including non-volatile storage elements. Examples of such nonvolatile storage elements include any volatile, non-volatile, magnetic, optical, or electrical media, such as a random access memory (RAM), read-only memory (ROM), non-volatile RAM (NVRAM), electrically-erasable programmable ROM (EEPROM), flash memory, or any other digital media.

[0058] Computing device 14 utilizes communication circuitry 74 to communicate with other devices, such as pressure mapping apparatus 12, other computing devices, and neuromodulation system 20 of FIG. 1. Communication circuitry 74 may include a network interface card, such as an Ethernet card, an optical transceiver, a radio frequency transceiver, or any other type of device that can send and receive information. Other examples of such network interfaces may include 3G, 4G, 5G, and WiFi radios.

[0059] Computing device 14 may include a user interface 76. User interface 76 may be configured to provide output to a user using tactile, audio, or video stimuli and receive input from a user through tactile, audio, or video feedback. User interface 76 may include, as examples, a presence-sensitive display, a mouse, a keyboard, a voice responsive system, video camera, microphone, or any other type of device for detecting a command from a user, a sound card, a video graphics adapter card, or any other type of device for converting a signal into an appropriate form understandable to humans or machines, a speaker, a display device, such as, but not limited to, cathode ray tube (CRT) monitor, a liquid crystal display (LCD), orany other type of device that can generate intelligible output to a user. In some examples, a presence-sensitive display includes a touch-sensitive screen.

[0060] At least one application 80 executable by processing circuitry 70 of computing device 14 may include a pressure interface application 82 and a monitoring system 84 that may utilize pressure data obtained from pressure mapping apparatus 12 via pressure interface application 82. For example, monitoring system 84 may provide the pressure data to pressure comparison module 88. Pressure comparison module 88 may compare pressure data with reference pressure date (for example, stored as pressure data 92), to determine whether the pressure drop between a pair of locations measured by pressure mapping apparatus 12 is greater than a reference pressure drop associated with the pair of locations. A measured pressure being greater than the reference pressure drop is indicative of microvascular constriction.

[0061] Execution of pressure interface 82 by processing circuitry 70 configures computing device 14 to interface with pressure mapping apparatus 12. For example, pressure interface 82 configures computing device 14 to communicate with pressure mapping apparatus 12 via communication circuitry 84. Processing circuitry 70 may receive a pressure signal from pressure mapping apparatus 12, and store the pressure data 92 in storage device 72. Pressure interface 82 also configures user interface 76 for a user to interact with pressure mapping apparatus 12 and / or pressure data 92.

[0062] Processing circuitry 70 may execute monitoring system 84 to facilitate monitoring the health or the condition of the patient, e.g., based on pressure data 92 received from pressure mapping apparatus 12 and / or computing device data 94 collected by computing device 14. Monitoring system 84 may cause processing circuity 70 and computing device 14 to perform any of the techniques described herein related to detection of microvascular constriction by system 10.

[0063] In some examples, computing device 14 includes or is configured to communicate with at least one sensor configured to sense one or more physiological parameters of the patient. Processing circuitry 70 may store physiological data from the sensors as computing device data 94 in storage device 72. For example computing device data 94 may include one or more of activity levels, body mass, body mass index, heart rate, low, high, and / or irregular heart rate events, heart rate variability, electrocardiogram (ECG), blood oxygen saturation, blood pressure (systolic and / or diastolic), and respiratory rate.

[0064] In some examples, computing device 14 is configured to determine pressure drop between a pair of locations by at least segmenting paths between the pair of locations, and determining a series of pressure drops along the segments. For example, computing device 14 may be configured to determine a plurality of anatomical segments between the reference locations. Computing device 14 may be further configured to determine a respective segment pressure drop for each anatomical segment of the plurality of segments. Computing device 14 may be further configured to determine the reference pressure drop as a sum of each respective segment pressure drop.

[0065] In some examples, computing device 14 is configured to compare a patient arterial model with a plurality of candidate arterial models. Based on the comparison, computing device 14 may select a reference arterial model from the plurality of candidate arterial models that is substantially similar to the patient arterial model. Computing device 14 may be further configured to determine the reference pressure drop based on the reference arterial model.

[0066] In some examples, a plurality of measurement location pairs includes the pair of locations. In some such examples, computing device 14 is further configured to determine microvascular constriction for each measurement location pair of the plurality of measurement location pairs. In some examples, computing device 14 is further configured to determine a pressure map indicative of a respective pressure drop for each measurement location pair of the plurality of location pairs.

[0067] In some examples, computing device 14 is configured to detect microvascular constriction based on microvascular pressure maps. For example, computing device 14 may be configured to determine a microvascular pressure map for a patient. In some examples, computing device 14 is configured to select a microvascular pressure map for the patient from storage device 72, receive the microvascular pressure map from another device, or generate the microvascular pressure map based on measured or sensed pressures, or based on FFR measurements. Computing device 14 may be further configured to compare the microvascular pressure map with a reference microvascular pressure map. Computing device 14 may be further configured to determine, based on the comparison, presence of microvascular constriction. For example, computing device 14 may determine that a measured pressure drop between a pair of locations in vasculature 16 of the patient is higher than a reference pressure drop between at least one pair of locations along a path. Such an increase in measured pressure drop is indicative of constriction between the pair of locationsalong the path. Thus, computing device 14 may, based on the comparison, determine an increase in a microvascular pressure drop relative to a reference microvascular pressure drop across a pair of locations in vasculature.

[0068] In some examples, computing device 14 is configured to determine the presence of microvascular constriction by at least determining microvascular pressure drop based on pressure drop in major vessels. For example, computing device 14 may determine a global pressure drop accounting for all vessel types, and subtract the pressure drop associated with major vessels from the global pressure drop, to determine the pressure drop associated with the remaining vessels, i.e, the pressure drop associated with the microvasculature.

[0069] In some examples, computing device 14 is configured to generate the output with a further indication that the patient is a candidate for neuromodulation, based on the presence of microvascular constriction. For example, patients that exhibit microvascular constriction, for example, in response to stimulation, may be suitable candidates for neuromodulation therapy. That is, the patients that exhibit microvascular constriction in response to microvascular constriction may experience therapeutic benefits from the neuromodulation therapy. For example, the microvascular constriction in response to the stimulation may indicate the patient has active nerves in the location of interest in vasculature 16, such as delivery of neuromodulation therapy is expected to attenuate neural traffic along the nerves (such as by ablation of the nerves). In some examples, the neuromodulation includes renal denervation, hepatic denervation, or both renal and hepatic denervation.

[0070] FIG. 4 is a schematic diagram illustrating an example configuration of a neuromodulation system 20. System 20 may be used with system 10 of FIG. 1 or any other system according to the present disclosure. System 20 includes a neuromodulation catheter 112 including at least one therapy delivery element 114. Catheter 112 further includes a handle 118 and an elongate body 120 attached to handle 118. That is, handle 118 is positioned at a proximal portion of elongate body 120. Elongate body 120 may have any suitable outer diameter, and the diameter can be constant along the length of elongate body 120 or may vary along the length of elongate body 120. In some examples, elongate body 120 may be 2, 3, 4, 5, 6, or 7 French or another suitable size. Elongate body 120 extends along a central longitudinal axis L, and includes a distal portion 120A and a proximal portion 120B. Distal portion 120A includes an expandable portion 122. Expandable portion 122 is configured to transform from a relatively low-profile configuration (shown in FIG. 4) to aradially expanded deployed configuration (not shown in FIG. 4), such as a spiral or helical configuration, or an expanded balloon configuration.

[0071] In the example shown in FIG. 4, at least one therapy delivery element 114 is disposed on expandable portion 122 of elongate body 120. At least one therapy delivery element 114 is configured to deliver therapy to tissue of a patient, for example, to modulate a target nerve of the patient. At least one therapy delivery element 114 may include, but is not limited to, one or more electrodes, one or more ultrasound transducers, one or more needles configured to deliver a therapeutic agent directly or indirectly, one or more heat or cryotherapy delivery devices (for example, balloons configured to receive a thermal fluid), one or more injection ports configured to deliver a therapeutic agent, or any combination thereof. In some examples, each therapy delivery element of at least one therapy delivery element 114 is an electrode. In some examples, at least one therapy delivery element 114 includes a ring electrode surrounding a portion of elongate body 120. At least one therapy delivery element 114 may be connected to a therapy delivery device, which includes control circuitry and therapy source (for example, an electrical signal generator, a source of a therapeutic agent, a cryogenic therapeutics source, or the like; not shown in FIG. 4) via at least one electrical conductor and / or at least one lumen defined by elongate body 120 and / or handle 118. Although FIG. 4 illustrates catheter 112 as having four therapy delivery elements 114, other example catheters may include one, two, three, five, or more therapy delivery elements 114. In some examples, as shown in FIG. 4, at least one therapy delivery element 114 includes four electrodes, for example, four ring electrodes.

[0072] In some examples, at least one therapy delivery element 114, or another element of catheter 112 or a different device, may be used to deliver stimulation to a target site, for example, before or after delivering denervation therapy. In some examples, the neural response to the stimulation, or the differences in neural responses to the stimulation before and after denervation may be indicative of effectiveness of denervation. Thus, a clinician may alternate delivery of stimulation with one or more sessions of delivery of denervation therapy, to gauge the progress and effectiveness of the denervation therapy. For example, the presence of microvascular constriction in response to stimulation may indicate the nerves are still active in that particular location, such that further neuromodulation therapy is desirable to further attenuate neural traffic. An absence of microvascular constriction in response tostimulation may indicate the nerves are no longer active, such that further neuromodulation therapy is not required.

[0073] Distal portion 120A of elongate body 120 is configured to be advanced within an anatomical lumen of a human patient to locate at least one therapy delivery element 114 at a target tissue site within or otherwise proximate to the anatomical lumen. For example, elongate body 120 may be configured to position distal portion 120A within a blood vessel, a ureter, a urethra, a duct, an airway, or another naturally occurring lumen within the human body. The examples described herein focus on the anatomical lumen being a blood vessel, such as a renal vessel, but it will be understood that similar techniques may be used with other anatomical lumens.

[0074] Neuromodulation catheter 112 can be configured for delivery to a target tissue site within vasculature of a patient via a guide member, which can include, for example, one or more of a guidewire or an outer sheath. In certain examples, intravascular delivery of distal portion 120 A includes percutaneously inserting a guidewire (not shown in FIG. 4) into a vessel of a patient and moving elongate body 120 (for example, at least expandable portion 22) along the guidewire until expandable portion 122 reaches a target tissue site (for example, a renal artery). For example, distal portion 120A of elongate body 120 may define a lumen configured to receive a guidewire for delivery of expandable portion 120 to a target tissue site using over-the-wire (OTW) or rapid exchange (RX) techniques. In other examples, neuromodulation catheter 112 can be a steerable or non-steerable device configured for use without a guidewire. In still other examples, neuromodulation catheter 112 can be configured for delivery via an inner lumen of a guide member, for example, a guide catheter, an outer sheath (not shown in FIG. 4), or other guide device.

[0075] A distal end of elongate body 120 defines distal tip 126. Distal tip 126 is configured to facilitate navigation of distal portion 120A within the vasculature of the patient to a blood vessel. In some examples, distal tip 126 may be atraumatic, for example, to resist or avoid puncturing a vessel of a blood vessel during navigation of distal portion 120A within the blood vessel.

[0076] In the example illustrated in FIG. 4, catheter 112 is in a relatively low-profile delivery configuration, in which distal portion 120A defines a relatively smaller radial extent (a relatively low-profile, such as a relatively linear configuration) relative to an expanded (also referred to as a radially expanded and / or deployed) configuration in which expandableportion 122 of distal portion 120A defines a relatively larger radial extent. In some examples, the radial extent is measured in a direction orthogonal to central longitudinal axis L. Distal portion 120A may be delivered through vasculature of the patient to the target tissue site in the low-profile configuration. In some examples, expandable portion 122 is configured to self-expand within a blood vessel of a patient, e.g., via a shape-memory element (e.g., a shape memory tube or a hollow helical strand) of elongate body 120. In some examples, expandable portion extends along a straight line aligned with longitudinal axis L in the relatively low- profile configuration shown in FIG. 4. Expandable portion 122 may be constrained or restrained in the low-profile configuration by a guide member. The clinician may retract the guide member proximally relative to expandable portion 122 to unconstrain expandable portion 122 and cause or allow expandable portion 122 to transform from the low-profile configuration to an expanded configuration. Thus, expandable portion 122 may be configured to radially expand away from the straight line to the expanded configuration.

[0077] In some examples, in an expanded configuration, expandable portion 122 defines a loop, a helix, or a spiral shape, or a basket, or a stent-like configuration. In the expanded configuration, expandable portion 122 is configured to position one or more therapy delivery elements of at least one therapy delivery element 114 near a vessel wall, for example, in apposition with the vessel wall.

[0078] In some examples, expandable portion 122 may be expanded or may self-expand as a result of proximal retraction of a guide member from distal portion 120A. The clinician may retract the guide member to a location along distal portion 120A proximal to expandable portion 122 to cause or allow expandable portion 122 to expand. In the expanded configuration, expandable portion 122 may place at least one therapy delivery elements 114 at a first location relative to the vessel wall, for example, corresponding to a first rotational location. A clinician may control a therapy delivery device to deliver, provide, or facilitate neuromodulation therapy at the target tissue site, for example, through the vessel wall at the target tissue site to target tissue adjacent to the blood vessel. The neuromodulation therapy may include, but is not limited to, radiofrequency (RF) energy, microwave energy, ultrasound energy, a therapeutic agent (e.g., a chemical ablation agent), cryogenic energy, heat-based energy, or the like.

[0079] The clinician may rotate handle 118, or otherwise proximal portion 20B, to apply a torque to distal portion 120A and cause expandable portion 122 to rotate about centrallongitudinal axis L from the first rotational location to a second rotational location. For example, the application of torque from handle 118 or proximal portion 120B to expandable portion 122 may cause expandable portion 122 to rotate about longitudinal axis L, for example, in a same direction as the torque. The clinician may control system 20 to delivery therapy at the second rotational location, or after further successive rotational locations of expandable portion 122.

[0080] System 20 may be used to deliver neuromodulation, as described with reference to example techniques according to the present disclosure. System 20 may be controlled by computing device 14, or by a controller.

[0081] FIG. 5 is a flow diagram illustrating an example technique for detecting microvascular constriction. The example technique of FIG. 5 is described with reference to processing circuitry 70 of computing device 14 and system 10 of FIG. 1. However, the example technique may be implemented by any suitable computing device or system alone or in combination with processing circuitry 70. In some examples, the example technique for detecting microvascular constriction includes, determining, by processing circuitry 70, a pressure drop between a pair of locations (for example, Li and L2, or L3and L2) in vasculature 16 of a patient (200). For example, pressure mapping apparatus 12 (FIG. 1) may determine the pressure drop, and send a signal to computing device 14 indicative of the pressure drop. As another example, processing circuitry 70 can determine the pressure drop based on the pressures indicated at the locations in a pressure map stored by storage device 72 and / or received from another device, e.g., a pressure map generated by pressure mapping apparatus 12.

[0082] The example technique may further include comparing, by processing circuitry 70, the pressure drop with a reference pressure drop (202). The reference pressure drop can be, for example, stored by storage device 72 of computing device 14 or a memory of another device. For example, processing circuitry 70 may compare the respective magnitudes of the pressure drop and the reference pressure drop, and determine whether the pressure drop is greater than the reference pressure drop. The example technique may further include determining, by processing circuitry 70, based on the comparison, presence of microvascular constriction in vasculature 16 (204). For example, in some examples, if the pressure drop is greater than the reference pressure drop, then processing circuitry 70 determines that microvascular constriction is present. As another example, in some examples, if the pressuredrop is less than or equal to the reference pressure drop, then processing circuitry 70 determines that microvascular constriction is not present.

[0083] The example technique may further include generating, by processing circuitry 70, in response to determining the presence of microvascular constriction, an output indicative of the presence of microvascular constriction (208). For example, processing circuitry 70 generate the output indicative of the presence of microvascular constriction at the “YES” branch of block 206. At the “NO” branch, processing circuitry 70 may generate no output, or may generate a second output indicative of an absence of microvascular constriction between the pair of locations. Processing circuitry 70 can present the output via user interface 76 (e.g., a display device) or by transmitting a signal to another device, which can then present the information to a user.

[0084] Processing circuitry 70 may repeatedly perform the example technique of FIG. 5 for the same pair of locations, for example, at different time periods, or before and after therapy (for example, neuromodulation therapy). In some examples, processing circuitry 70 repeatedly performs the example technique of FIG. 5 for a plurality of pairs of locations, for example, corresponding to different vessels or paths in vasculature 16. Thus, processing circuitry 70 may determine that constriction is present somewhere in vasculature 16, or in a region of vasculature 16 including the plurality of pairs of locations, or in a specific pair of locations of the plurality of pairs of locations.

[0085] FIG. 6 is a flow diagram illustrating another example technique for detecting microvascular constriction. The example technique of FIG. 6 is described with reference to processing circuitry 70 of computing device 14 and system 10 of FIG. 1. However, the example technique may be implemented by any suitable computing device or system alone or in combination with processing circuitry 70. In some examples, the example technique for detecting microvascular constriction includes determining, by processing circuitry 70, a microvascular pressure map for a patient (300). For example, pressure mapping apparatus 12 may generate the microvascular pressure map, or processing circuitry 70 may generate the microvascular pressure map based on one or more signals or data received from pressure mapping apparatus 12.

[0086] The example technique may further include comparing, by processing circuitry 70, the microvascular pressure map with a reference microvascular pressure map (302). The example technique may further include determining, by processing circuitry 70, based on thecomparison, presence of microvascular constriction (304). For example, processing circuitry 70 may determine the presence of microvascular constriction in response to determining that the microvascular pressure drop is greater than the reference pressure drop. As another example, in some examples, if the pressure drop is less than or equal to the reference pressure drop, then processing circuitry 70 determines that microvascular constriction is not present.

[0087] The example technique may further include generating, by processing circuitry 70, in response to determining the presence of microvascular constriction, an output indicative of the presence of microvascular constriction (308). For example, processing circuitry 70 generate the output indicative of the presence of microvascular constriction at the “YES” branch of block 306. At the “NO” branch, processing circuitry 70 may generate no output, or may generate a second output indicative of an absence of microvascular constriction.

[0088] Processing circuitry 70 may repeatedly perform the example technique of FIG. 6, for example, at different time periods, or before and after therapy (for example, neuromodulation therapy). Thus, processing circuitry 70 may determine that constriction is present somewhere in vasculature 16, or in a region of vasculature 16.

[0089] In some examples, determining the presence of microvascular constriction (204, 304) includes based on the comparison, determining an increase in a microvascular pressure drop relative to a reference microvascular pressure drop across a pair of locations in vasculature. For example, processing circuitry 70 may determine initially that a constriction is present somewhere in vasculature 16 based on a comparison of global pressure drop, and subsequently compare regional pressure drop with a reference pressure drop for a plurality of regions to determine a region exhibiting an increased pressure drop compared to a corresponding reference region. Similarly, processing circuitry 70 may compare measured pressure drop with reference pressure drops for different pairs of locations to determine a particular pair of locations (or a path between the pair of locations) associated with a constriction. In some examples, processing circuitry 70 may determine the presence of microvascular constriction (204, 304) by at least determining microvascular pressure drop based on pressure drop in major vessels. For example, processing circuitry 70 may determine a global pressure drop for a substantial entirety of vasculature 16 (or a predetermined region of vasculature 16), and subtract a pressure drop associated with pressure drop in major vessels, to determine the residual pressure drop associated with microvasculature.

[0090] Processing circuitry 70 may further determine patient conditions or therapy in association with detecting microvascular constriction, as described with reference to FIGS. 7 to 9.

[0091] FIG. 7 is a flow diagram illustrating an example technique for detecting microvascular disease. The example technique of FIG. 7 is described with reference to processing circuitry 70 of computing device 14 and system 10 of FIG. 1. However, the example technique may be implemented by any suitable computing device or system alone or in combination with processing circuitry 70. In some examples, the example technique includes determining an occurrence of microvascular disease in response to determining a presence of microvascular constriction. For example, a patient may present symptoms consistent with cardiac disease. If an imaging-based diagnostic (for example, CT angiography or interventional angiography) reveals apparent disease (YES branch of block 400), the technique may be terminated, and the clinician may take appropriate action.However, imaging may not reveal apparent disease in the macrovasculature (NO branch of block 400).

[0092] In that case, processing circuitry 70 may determine the presence of microvascular constriction based on a determined pressure drop (404). For example, the patient cardiac anatomy may be classified as a whole and correlated with a group of healthy patients with a similar anatomy. Alternatively, processing circuitry 70 or another device determines the measured pressure drop along a region of vasculature or series of vessels, for example, by vessel segmentation (summing pressure drop along segments). Processing circuitry 70 compares the measured (or calculated) pressure drop to a reference pressure drop (for example associated with healthy patient data). A measured pressure drop being greater than the reference pressure drop is indicative of microvascular disease.

[0093] In some examples, processing circuitry 70 determines the degree of disease based on the magnitude of difference compared to the reference pressure drop. For example, greater the deviation of the measured pressure from the reference pressure drop, greater the extent or progression of microvascular disease. If the difference in measured and reference pressure drops is indicative of microvascular constriction (YES branch of block 406), then processing circuitry 70 generates an output indicative of presence of microvascular disease (408). If microvascular constriction is not determined, processing circuitry 70 may generate a secondoutput indicative of absence of microvascular disease or a need for further investigation (NO branch of block 406).

[0094] In some examples, a patient that presents with symptoms of cardiac disease may be identified as having non-culprit lesions in major vessels. That is, although lesions are observed (for example, via FFR) the lesions may be considered to not be flow-limiting. Nonetheless, the presence of such lesions may influence flow and pressure measurements in the macrovasculature (in major vessels), and leading to errors when calculating the microvascular pressure drop. In some such examples, processing circuitry 70 may “remove” the lesions using virtual FFR (for example, by modifying a site associated with the lesions in a model generated using virtual FFR), and calculating the pressure difference based on the modified model with the lesion being removed.

[0095] In some examples, an example technique for monitoring a denervation procedure includes determining an effectiveness of the denervation procedure in response to determining a presence of microvascular constriction.

[0096] FIG. 8 is a flow diagram illustrating an example technique for neuromodulation. The example technique of FIG. 8 is described with reference to processing circuitry 70 of computing device 14 and system 10 of FIG. 1, and neuromodulation system 20 of FIG. 4. However, any suitable computing device or system may be used to perform the technique of FIG. 8, alone or in combination with processing circuitry 70.

[0097] The technique of FIG. 8 includes delivering stimulation (e.g., an electrical stimulation delivered via a catheter intravascularly positioned in a blood vessel of interest) to a target site in a patient (500). For example, processing circuitry 70 can automatically control a medical device to deliver the stimulation or generate a prompt (e.g., presented via user interface 76) to cause a clinician or other device to deliver the stimulation via a medical device. The example technique further includes determining, by processing circuitry 70, microvascular constriction of a blood vessel in response to the stimulation (506). For example, the technique of FIGS. 5 or 6, or any other suitable technique, may be used to determine microvascular constriction. If microvascular constriction is absent (NO branch of block 506), then a clinician may terminate the neuromodulation, or select another target site, and the technique may be repeated. An absence of microvascular constriction in response to the stimulation can indicate, for example, that any nerves at the target site have ben ablated or otherwise attenuated, such that further neuromodulation (e.g., denervation) therapy may notbe necessary or otherwise provide further therapeutic benefits. Alternatively, or in addition, the clinician may repeat the test for microvascular constriction after a period of rest, for example, a refractory period.

[0098] The presence of microvascular constriction in response to stimulation may indicate that a target nerve has not been sufficiently denervated, while the absence of microvascular constriction may indicate that the target nerve has been sufficiently denervated. In some examples, processing circuitry 70 generates an output indicative of the presence of microvascular constriction (508) (YES branch of block 506). The clinician may accordingly proceed with delivering neuromodulation treatment. For example, the example technique may further include delivering, in response to determining the presence of microvascular constriction after the stimulation (YES branch of block 506), neuromodulation therapy via a device in the blood vessel (510). For example, the device may include neuromodulation system 20 of FIG. 3.

[0099] The example technique may further include determining, after delivering the neuromodulation therapy, microvascular constriction of the blood vessel. For example, the technique may be repeated at block 500 after block 510. The example technique may further include delivering, in response to determining the presence of microvascular constriction after the neuromodulation therapy, further neuromodulation therapy via the device in the blood vessel. For example, block 510 may be repeated as long as constriction is exhibited in response to stimulation, and the technique may be termination when constriction is no longer exhibited in response to stimulation.

[0100] FIG. 9 is a flow diagram illustrating an example technique for neuromodulation. The example technique of FIG. 9 is described with reference to processing circuitry 70 of computing device 14 and system 10 of FIG. 1, and neuromodulation system 20 of FIG. 4. However, any suitable computing device or system may be used to perform the technique of FIG. 9 alone or in combination with processing circuitry 70.

[0101] The technique may include delivering stimulation to a first target site in a patient (600). The example technique further includes determining microvascular constriction of a blood vessel in response to the stimulation (606). The example technique further includes determining, in response to determining the presence of microvascular constriction of the blood vessel (YES branch of block 606), a second target site for neuromodulation (610). The technique may be repeated for a plurality of target sites. When a suitable site is found,neuromodulation may be delivered, and the technique repeated to confirm sufficient neuromodulation or terminated. For example, the suitable site may include a site with active nerves, as indicated by presence of microvascular constriction in response to stimulation.

[0102] FIG. 10 is a flow diagram illustrating an example technique for neuromodulation. The example technique of FIG. 10 is described with reference to processing circuitry 70 of computing device 14 and system 10 of FIG. 1, and neuromodulation system 20 of FIG. 4. However, any suitable computing device or system may be used to perform the technique of FIG. 10.

[0103] The example technique includes delivering stimulation to a target site in a patient (700). The example technique may further include determining microvascular constriction of a blood vessel in response to the stimulation (706). The example technique may further include generating, by processing circuitry, in response to determining the presence of microvascular constriction of the blood vessel (YES branch of block 706), an output indicating that the patient is a candidate for denervation therapy (708). For example, the presence of microvascular constriction indicates that denervation will be effective to attenuate neural traffic. The clinician may deliver neuromodulation to the patient (710) in response to the presence of microvascular constriction. The technique may be repeated at block 700 for other target sites. In some examples, if no microvascular constriction is determined for a plurality of sites, the technique is terminated, and no neuromodulation is delivered. For example, an absence of microvascular constriction may indicate that no nerve activity is present, and that denervation is not required.

[0104] Thus, example systems and techniques according to the present disclosure may be used to detect microvascular constriction, and to determine microvascular disease, and to monitor or control neuromodulation therapy.

[0105] FIG. 11 illustrates an example technique for accessing a renal artery and modulating renal nerves with system 10 of FIG. 1 in accordance with some examples of the present disclosure. While FIG. 11 illustrates the use of catheter 112 for renal neuromodulation, catheter 112 may be used for other therapies and treatments within another blood vessel or other hollow anatomical body within the human body. Catheter 112 is configured to delivery energy (e.g., RF energy, ultrasound energy, electrical stimulation energy, or the like) to one or more target tissue sites within a renal vessel. Catheter 112 provides access to the renal plexus (RP) through an intravascular path (P), such as apercutaneous access site in the femoral (illustrated), brachial, radial, or axillary artery to the target tissue sites within a respective renal artery (RA). By manipulating proximal portion 120B or elongate body 120 from outside the intravascular path (P), a clinician may advance distal portion 120A of elongate body 120 through the sometimes-tortuous intravascular path (P) and remotely manipulate distal portion 120A (FIG. 4) of elongate body 120. Distal portion 120A may be remotely manipulated by the clinician using handle 118.

[0106] In the example illustrated in FIG. 11, distal portion 120A is delivered intravascularly to the treatment site using an inner member 123 in an over-the-wire (OTW) technique. Inner member 123 may be internal to catheter 112 (e.g., a guide wire, inner catheter, or the like) or external to catheter 112 (e.g., an outer sheath or the like). In some examples, inner member 123 is a navigation wire. Catheter 112 may define a passageway for receiving inner member 23 for delivery of catheter 112 using either an OTW or an RX technique. At the treatment site, inner member 123 can be at least partially withdrawn or removed relative to catheter 12 and distal portion 120A can transform into an expanded configuration (for example, a helical configuration, a spiral configuration, or the like) for delivering ultrasound energy. In other examples, elongate body 120 may be self-steerable such that at least one therapy delivery element 114 may be delivered to the target tissue site without the aid of inner member 123.

[0107] Renal modulation is the partial or complete incapacitation or other effective disruption of nerves of the kidneys (e.g., nerves terminating in the kidneys or in structures closely associated with the kidneys). In particular, renal neuromodulation can include inhibiting, reducing, or blocking neural communication along neural fibers (e.g., efferent or afferent neural fibers) of the kidneys. Such incapacitation can be long-term (e.g., permanent or for a period of months, years, or decades) or short-term (e.g., for periods of minutes, hours, days, or weeks). Renal neuromodulation is expected to contribute to the systemic reduction of sympathetic tone or drive or benefit at least some specific organs or other bodily structures innervated by sympathetic nerves. Accordingly, renal neuromodulation is expected to be useful in treating clinical conditions associated with central sympathetic overstimulation. For example, renal neuromodulation is expected to efficaciously treat hypertension, heart failure, acute myocardial infarction, metabolic syndrome, insulin resistance, diabetes, left ventricular hypertrophy, chronic and end state renal disease, inappropriate fluid retention in heart failure,cardio-renal syndrome, polycystic kidney disease, polycystic ovary syndrome, osteoporosis, erectile dysfunction, and sudden death, among other conditions.

[0108] Renal neuromodulation can be electrically induced or induced in another suitable manner through the delivery of energy (RF energy, ultrasound energy, microwave energy, or the like). The target tissue site can be within or otherwise proximate to a renal lumen (e.g., a renal artery, a ureter, a renal pelvis, a major renal calyx, a minor renal calyx, or another suitable structure), and the target tissue site can include tissue at least proximate to a wall of the renal lumen. For example, with regard to a renal artery, a treatment procedure can include modulating nerves in the renal plexus, which lay intimately within or adjacent to the adventitia of the renal artery. The following discussion provides further details regarding patient anatomy and physiology as it may relate to renal denervation therapy. This section is intended to supplement and expand upon the previous discussion regarding the relevant anatomy and physiology, and to provide additional context regarding the disclosed technology and the therapeutic benefits associated with renal denervation. For example, several properties of the renal vasculature may inform the design of the target tissue devices and associated methods for achieving renal neuromodulation via intravascular access and impose specific design requirements for such devices. Specific design requirements may include accessing the renal artery, positioning distal portion 16a within the renal artery, delivering the therapy to targeted tissue, or effectively modulating the renal nerves with the therapy delivery device.

[0109] As noted previously, the sympathetic nervous system (SNS) is a branch of the autonomic nervous system along with the enteric nervous system and parasympathetic nervous system. It is always active at a basal level (called sympathetic tone) and becomes more active during times of stress. Like other parts of the nervous system, the sympathetic nervous system operated through a series of interconnected neurons. Sympathetic neurons are frequently considered part of the peripheral nervous system (PNS), although many lie within the central nervous system (CNS). Sympathetic neurons of the spinal cord (which is part of the CNS) communicate with peripheral sympathetic neurons via a series of sympathetic ganglia. Within the ganglia, spinal cord sympathetic neurons are therefore called presynaptic (or preganglionic) neurons, while peripheral sympathetic neurons are called postsynaptic (or postganglionic neurons).

[0110] At synapses within the sympathetic ganglia, preganglionic sympathetic neurons release acetylcholine, a chemical messenger that binds and activates nicotinic acetylcholine receptors on postganglionic neurons. In response to this stimulus, postganglionic neurons principally release noradrenaline (norepinephrine). Prolonged activation may elicit the release of adrenaline from the adrenal medulla.[OHl] Once released, norepinephrine and epinephrine bind adrenergic receptors on peripheral tissues. Binding to adrenergic receptors causes a neuronal and hormonal response. The physiologic manifestations include pupil dilation, increased heart rate, occasional vomiting, and increased blood pressure. Increased sweating is also seen due to binding of cholinergic receptors of the sweat glands.

[0112] The sympathetic nervous system is responsible for up- and down-regulating many homeostatic mechanisms in living organisms. Fibers from the SNS innervate tissues in almost every organ system, providing at least some regulatory function to physiological features as diverse as pupil diameter, gut motility, and urinary output. This response is also known as sympatho-adrenal response of the body, as the preganglionic sympathetic fibers that end in the adrenal medulla (but also all other sympathetic fibers) secrete acetylcholine, which activates the secretion of adrenaline (epinephrine) and to a lesser extent noradrenaline (norepinephrine). Therefore, this response that acts primarily on the cardiovascular system is mediated directly via impulses transmitted through the sympathetic nervous system and indirectly via catecholamines secreted from the adrenal medulla.

[0113] FIG. 12 is a conceptual illustration of an example sympathetic nervous system (SNS) illustrating how the brain communicated with the body via the SNS. As shown in FIG. 12, the SNS provides a network of nerves that allows the brain to communicate with the body. Sympathetic nerves originate inside the vertebral column, e.g., toward the middle of the spinal cord in the intermediolateral cell column (or lateral horn), beginning at the first thoracic segment of the spinal cord and are thought to extend to the second or third lumbar segments. Because SNS cells begin in the thoracic and lumbar regions of the spinal cord, the SNS is said to have a thoracolumbar outflow. Axons of sympathetic nerves leave the spinal cord through the anterior rootlet / root. The axons pass near the spinal (sensory) ganglion, where the axons enter the anterior rami of the spinal nerves. However, unlike somatic innervation, the axons separate out through white rami connectors which connect to either the paravertebral (whichlie near the vertebral column) or prevertebral (which lie near the aortic bifurcation) ganglia extending alongside the spinal column.

[0114] To reach the target organs and glands, the axons should travel long distances in the body, and, to accomplish this, many axons relay their message to a second cell through synaptic transmission. The ends of the axons link across a space, the synapse, to the dendrites of the second cell. The first cell (the presynaptic cell) sends a neurotransmitter across the synaptic cleft where it activates the second cell (the postsynaptic cell). The message is then carried to the final destination.

[0115] In the SNS and other component of the peripheral nervous system, these synapses are made at sites called ganglia, discussed above. The cell that sends its fiber to the ganglion is called a preganglionic cell, while the cell whose fiber leaves the ganglion is called a postganglionic cell. As mentioned previously, the preganglionic cell of the SNS is located between the first thoracic (Tl) segment and third lumbar (L3) segments of the spinal cord. Postganglionic cells have their cell bodies in the ganglia and send their axons to target organs or glands.

[0116] The ganglia include not just the sympathetic trunks but also the cervical ganglia (superior, middle, and inferior), which send sympathetic nerve fibers to the head and thorax organs, and the celiac and mesenteric ganglia, which send sympathetic fibers to the gut.

[0117] FIG. 13 is an enlarged anatomic view of nerves innervating a left kidney to form the renal plexus surrounding the left renal artery. As FIG. 13 shows, the kidney is innervated by the renal plexus (RP), which is intimately associated with the renal artery. The renal plexus (RP) is an autonomic plexus that surrounds the renal artery and is embedded within the adventitia of the renal artery. The renal plexus (RP) extends along the renal artery and is embedded within the adventitia of the renal artery. Fibers contributing to the renal plexus (RP) arise from the celiac ganglion, the superior mesenteric ganglion, the aorticorenal ganglion and the aortic plexus. The renal plexus (RP), also referred to as the renal nerve, is predominantly comprised of sympathetic components. There is no (or at least very minimal) parasympathetic innervation of the kidney.

[0118] Preganglionic neuronal cell bodies are located in the intermediolateral cell column of the spinal cord. Preganglionic axons pass through the paravertebral ganglia to become the lesser splanchnic nerve, the least splanchnic nerve, the first lumbar splanchnic nerve, the second lumbar splanchnic nerve, and travel to the celiac ganglion, the superior mesentericganglion, and the aorticorenal ganglion. Postganglionic neuronal cell bodies exit the celiac ganglion, the superior mesenteric ganglion, and the aorticorenal ganglion to the renal plexus (RP) and are distributed to the renal vasculature.

[0119] Messages travel through the SNS in a bi-directional flow. Efferent messages may trigger changes in different parts of the body simultaneously. For example, the sympathetic nervous system may accelerate heart rate, widen bronchial passages, decrease motility (movement) of the large intestine, constrict blood vessels, increase peristalsis in the esophagus, cause pupil dilation, piloerection (goose bumps) and perspiration (sweating), or raise blood pressure. Afferent messages carry signals from various organs and sensory receptors in the body to other organs and, particularly, the brain.

[0120] Hypertension, heart failure, and chronic kidney disease are a few of the many disease states that result from chronic activation of the SNS, especially the renal sympathetic nervous system. Chronic activation of the SNS is a maladaptive response that drives the progression of theses disease states. Pharmaceutical management of the renin-angiotensin- aldosterone system (RAAS) has been a longstanding, but somewhat ineffective, approach for reducing over-activity of the SNS.

[0121] As mentioned above, the renal sympathetic nervous system has been identified as a major contributor to the complex pathophysiology of hypertension, states of volume overload (such as heart failure) and progressive renal disease, both experimentally and in humans. Studies employing radiotracer dilution methodology to measure overflow of norepinephrine from the kidneys to plasma revealed increased renal norepinephrine (NE) spillover rates in patients with essential hypertension, particularly so in young hypertensive subjects, which in concert with increased NE spillover from the heart, is consistent with the hemodynamic profile typically seen in early hypertension and characterized by an increased heart rate, cardiac output, and renovascular resistance. It is now known that essential hypertension is commonly neurogenic, often accompanied by pronounced sympathetic nervous system overactivity.

[0122] Activation of cardiorenal sympathetic nerve activity is even more pronounced in heart failure, as demonstrated by an exaggerated increase of NE overflow from the heart and the kidneys to plasma in this patient group. In line with this notion is the recent demonstration of a strong negative predictive value of renal sympathetic activation on allcause mortality and heart transplantation in patients with congestive heart failure, which isindependent of overall sympathetic activity, glomerular filtration late, and left ventricular ejection fraction. These findings support the notion that treatment regimens that are designed to reduce renal sympathetic stimulation have the potential to improve survival in patients with heart failure.

[0123] Both chronic and end state renal disease in some patients are characterized by heightened sympathetic nervous activation. In patients with end state renal disease, plasma levels of norepinephrine above the media have been demonstrated to be predictive for both all-cause death and death from cardiovascular disease. This can also be true for patients suffering from diabetic or contrast nephropathy. There is compelling evidence suggesting that sensory afferent signals originating from the diseased kidneys are major contributors to initiating and sustaining elevated central sympathetic outflow in this patient group; this facilitates the occurrence of the well-known adverse consequences of chronic sympathetic over activity, such as hypertension, left ventricular hypertrophy, ventricular arrhythmias, sudden cardiac death, insulin resistance, diabetes, and metabolic syndrome.

[0124] Sympathetic nerves to the kidneys terminate in the blood vessels, the juxtaglomerular apparatus, and the renal tubules. Stimulation of the renal sympathetic nerves cause increased renin release, increased sodium (Na+) reabsorption, and a reduction of renal blood flow. These components of the neural regulation of renal function are considerably stimulated in disease states characterized by heightened sympathetic tone and clearly contribute to the rise in blood pressure in hypertensive patients. The reduction of renal blood flow and glomerular filtration rate as a result of renal sympathetic efferent stimulation may be a cornerstone of the loss of renal function in cardio-renal syndrome, which is renal dysfunction as a progressive complication of chronic heart failure, with a clinical course that typically fluctuates with the patient’s clinical status and treatment. Pharmacologic strategies to thwart the consequences of renal efferent sympathetic stimulation include centrally acting sympatholytic drugs, beta blockers (intended to reduce renin release), angiotensin converting enzyme inhibitors and receptor blockers (intended to block the action of angiotensin II and aldosterone activation consequent to renin release), and diuretics (intended to counter the renal sympathetic mediated sodium and water retention). However, the current pharmacologic strategies can have significant limitations including limited efficacy, compliance issues, side effects, and others.

[0125] The kidneys communicate with integral structures in the central nervous system via renal sensory afferent nerves. Several forms of “renal injury” may induce activation of sensory afferent signals. For example, renal ischemia, reduction in stroke volume or renal blood flow, or an abundance of adenosine enzyme may trigger activation of afferent neural communication.

[0126] FIG. 14 is an anatomic view of a human body depicting neural efferent and afferent communication between the brain and kidneys. FIG. 15 is a conceptual view of a human body depicting neural efferent and afferent communication between the brain and kidneys. As shown in FIGS. 14 and 15, the afferent communication might be from kidney to the brain or might be from one kidney to the other kidney (via the central nervous system). These afferent signals are centrally integrated and may result in increased sympathetic outflow. This sympathetic drive is directed towards the kidneys, thereby activating the RAAS and inducing increased renin secretion, sodium retention, volume retention, and vasoconstriction. Central sympathetic over activity also impacts other organs and bodily structures innervated by sympathetic nerves such as the heart and the peripheral vasculature, resulting in the described adverse effects of sympathetic activation, several aspects of which also contribute to the rise in blood pressure.

[0127] The physiology therefore suggests that (i) modulation of tissue with efferent sympathetic nerves will reduce inappropriate renin release, salt retention, and reduction of renal blood flow, and that (ii) modulation of tissue with afferent sensory nerves will reduce the systemic contribution to hypertension and other disease states associated with increased central sympathetic tone through its direct effect on the posterior hypothalamus as well as the contralateral kidney. In addition to the central hypotensive effects of afferent renal denervation, a desirable reduction of central sympathetic outflow to various other sympathetically innervated organs such as the heart and the vasculature is anticipated.

[0128] As provided above, renal denervation is likely to be valuable in the treatment of several clinical conditions characterized by increased overall and particularly renal sympathetic activity such as hypertension, metabolic syndrome, insulin resistance, diabetes, left ventricular hypertrophy, chronic end state renal disease, inappropriate fluid retention in heart failure, cardio-renal syndrome and sudden death. Since the reduction of afferent neural signals contributing to the systemic reduction of sympathetic tone / drive, renal denervation might also be useful in treating other conditions associate with systemic sympathetichyperactivity. Accordingly, renal denervation may also benefit other organs and bodily structures innervated by sympathetic nerves, including those identified in FIG. 14. For example, as previously discussed, a reduction in central sympathetic drive may reduce the insulin resistance that afflicts people with metabolic syndrome and Type II diabetics. Additionally, patients with osteoporosis may also be sympathetically activated and might also benefit from the down regulation of sympathetic drive that accompanies renal denervation.

[0129] In accordance with the present technology neuromodulation of a left or right renal plexus (RP), which is intimately associated with a left or right renal artery, may be achieved through intravascular access. FIG. 16 is an anatomic view of the arterial vasculature of a human. As FIG. 16 shows, blood moved by contractions of the heart is conveyed from the left ventricle of the heart by the aorta. The aorta descends through the thorax and branches into the left and right renal arteries. Below the renal arteries, the aorta bifurcates at the left and right iliac arteries. The left and right iliac arteries descend, respectively, through the left and right legs and join the left and right femoral arteries.

[0130] FIG. 17 is an anatomic view of the venous vasculature of a human. As FIG. 17 shows, the blood collects in veins and returns to the heart, through the femoral veins into the iliac veins and into the inferior vena cava. The inferior vena cava branches into the left and right renal veins. Above the renal veins, the inferior vena cava ascends to convey blood into the right atrium of the heart. From the right atrium, the blood is pumped through the right ventricle into the lungs, where it is oxygenated. From the lungs, the oxygenated blood is conveyed into the left atrium. From the left atrium, the oxygenated blood is conveyed by the left ventricle back to the aorta.

[0131] The femoral artery may be accessed and cannulated at the base on the femoral triangle just inferior to the midpoint of the inguinal ligament. A catheter may be inserted percutaneously into the femoral artery through this access site, passed through the iliac artery and aorta, and placed into either the left or right renal artery. This comprises an intravascular path that offers minimally invasive access to a respective renal artery or other renal blood vessels.

[0132] The wrist, upper arm, and shoulder region provide other locations for introduction of catheters into the arterial system. For example, catheterization of either the radial, brachial, or axillary artery may be utilized in select cases. Catheters (e.g., catheter 12) introduced via these access points may be passed through the subclavian artery on the left side (or via thesubclavian and brachiocephalic arteries on the right side), through the aortic arch, down the descending aorta and into the renal arteries using standard angiographic techniques. Other access sites can also be used to access the arterial system.

[0133] Since neuromodulation of a left or right renal plexus (RP) may be achieved in accordance with the present technology through intravascular access, properties and characteristics of the renal vasculature may impose constraints upon or inform the design of apparatus, systems, and methods for achieving such renal neuromodulation. Some of these properties and characteristics may vary across the patient population or within a specific patient across time, as well as in response to disease states, such as hypertension, chronic kidney disease, vascular disease, end-stage renal disease, insulin resistance, diabetes, metabolic syndrome, and the like. These properties and characteristics, as explained herein, may have bearing on the efficacy of the procedure and the specific design of the intravascular device. Properties of interest may include, for example, material / mechanical, spatial, fluid dynamic / hemodynamic or thermodynamic properties.

[0134] As discussed previously, a catheter may be advanced percutaneously into either the left or right renal artery via a minimally invasive intravascular path. However, minimally invasive renal arterial access may be challenging, for example, because as compared to some other arteries that are routinely accessed using catheters, the renal arteries are often extremely tortuous, may be of relatively small diameter, or may be of relatively short length. Furthermore, renal arterial atherosclerosis is common in many patients, particularly those with cardiovascular disease. Renal arterial anatomy also may vary significantly from patient to patient, which further complicates minimally invasive access. Significant inter-patient variation may be seen, for example, in relative tortuosity, diameter, length, or atherosclerotic plaque burden, as well as in the take-off angle at which a renal artery branches from the aorta. Further, some patients include multiple left renal arteries or right renal arteries. Apparatus, systems, and methods for achieving renal neuromodulation via intravascular access should account for these and other aspects of renal arterial anatomy and its variation across the patient population when minimally invasively accessing a renal artery.

[0135] In addition to complicating renal arterial access, specifics of the renal anatomy also complicate establishment of stable contact between neuromodulatory apparatus and a luminal surface or wall of a renal artery. For example, navigation can be impeded by the tight space within a renal artery, as well as tortuosity of the artery. Furthermore, establishingconsistent contact is complicated by patient movement, respiration, or the cardiac cycle because these factors may cause significant movement of the renal artery relative to the aorta, and the cardiac cycle may transiently distend the renal artery (i.e., cause the wall of the artery to pulse).

[0136] The neuromodulation system may also be configured to allow for adjustable positioning and repositioning of distal portion 120A and at least one therapy delivery element 114 (FIG. 4) within the renal artery since location of treatment may also impact clinical efficacy. Additionally, variable positioning and repositioning of the neuromodulatory apparatus may prove to be useful in circumstances where the renal artery is particularly tortuous or where there are proximal branch vessels off the renal artery main vessel, making treatment in certain locations challenging.

[0137] As noted above, an apparatus positioned within a renal artery may be configured so that distal portion 120A of catheter 112 may intimately contact the vessel wall or extend at least partially through the vessel wall. Renal artery vessel diameter, DRA, typically is in a range of about 2-10 mm, with most of the patient population having a DRA of about 4 mm to about 8 mm and an average of about 6 mm. Renal artery vessel length, LRA, between its ostium at the aorta / renal artery juncture and its distal branchings, generally is in a range of about 5-70 mm, and a significant portion of the patient population is in a range of about 20-50 mm. Since the target renal plexus is embedded within the adventitia of the renal artery, the composite Intima-Media Thickness, IMT, (i.e., the radial outward distance from the artery's luminal surface to the adventitia containing target neural structures) also is notable and generally is in a range of about 0.5-2.5 mm, with an average of about 1.5 mm. Although a certain depth of treatment is important to reach the target neural fibers, the treatment should not be too deep (e.g., > 10 mm from inner wall of the artery) to avoid non-target tissue and anatomical structures such as anatomical structures of the digestive system of psoas muscle.

[0138] An additional property of the renal artery that may be of interest is the degree of renal motion relative to the aorta induced by respiration or blood flow pulsatility. A patient’s kidney, which is located at the distal end of the renal artery, may move as much as 10 centimeters cranially with respiratory excursion. This may impart significant motion to the renal artery connecting the aorta and the kidney, thereby requiring from the neuromodulatory apparatus a unique balance of stiffness and flexibility to maintain contact between the energy delivery element and the vessel wall during cycles of respiration. Furthermore, the take-offangle between the renal artery and aorta may vary significantly between patients, and also may vary dynamically within a patient, e.g., due to kidney motion. The take-off angle generally may be in a range of about 30°-135°.

[0139] Certain aspects of the present disclosure described in the context of particular examples may be combined or eliminated in other examples. Further, while advantages associated with certain examples have been described in the context of those examples, other examples may also exhibit such advantages, and not all examples need necessarily exhibit such advantages to fall within the scope of the present disclosure. Accordingly, the present disclosure and associated technology can encompass other examples not expressly shown or described herein.

[0140] Moreover, unless the word “or” is expressly limited to mean only a single term exclusive from the other items in reference to a list of two or more items, then the use of “or” in such a list is to be interpreted as including (a) any single item in list, (b) all of the items in the list, or (c) any combination of the items in the list. Additionally, the term “comprising” is used throughout to mean including at least the recited feature(s) such that any greater number of the same feature and / or additional types of other features are not precluded.

[0141] It should be understood that various aspects disclosed herein may be combined in different combinations than the combinations specifically presented in the description and accompanying drawings. It should also be understood that, depending on the example, certain acts or events of any of the processes or methods described herein may be performed in a different sequence, may be added, merged, or left out altogether (e.g., all described acts or events may not be necessary to carry out the techniques). In addition, while certain aspects of this disclosure are described as being performed by a single module, unit, or circuit for purposes of clarity, it should be understood that the techniques of this disclosure may be performed by a combination of units, modules, or circuitry associated with, for example, a medical device.

[0142] In one or more examples, the described techniques may be implemented in hardware, software, firmware, or any combination thereof. If implemented in software, the functions may be stored as one or more instructions or code on a computer-readable medium and executed by a hardware-based processing unit. Computer-readable media may include non-transitory computer-readable media, which corresponds to a tangible medium such as data storage media (e.g., RAM, ROM, EEPROM, flash memory, or any other medium thatcan be used to store desired program code in the form of instructions or data structures and that can be accessed by a computer).

[0143] Instructions may be executed by one or more processors that include processing circuitry, such as one or more digital signal processors (DSPs), general purpose microprocessors, application specific integrated circuits (ASICs), field programmable logic arrays (FPGAs), or other equivalent integrated or discrete logic circuitry. Accordingly, the term “processor” or “processing circuitry” as used herein may refer to any of the foregoing structure or any other physical structure suitable for implementation of the described techniques. Also, the techniques could be fully implemented in one or more circuits or logic elements.

[0144] The above detailed descriptions of examples of the technology are not intended to be exhaustive or to limit the technology to the precise form disclosed above. Although specific examples of the technology are described above for illustrative purposes, various equivalent modifications are possible within the scope of the technology, as those skilled in the relevant art will recognize. For example, while steps are presented in a given order, alternative examples may perform steps in a different order. The various examples described herein may also be combined to provide further examples. All references cited herein are incorporated by reference as if fully set forth herein.

[0145] From the foregoing, it will be appreciated that specific examples of the present disclosure have been described herein for purposes of illustration, but that various modifications may be made without deviating from the present disclosure

[0146] Various examples have been described. These and other examples are within the scope of the following claims

[0147] Example 1. A method for detecting microvascular constriction, the method comprising, by processing circuitry: determining a pressure drop between a pair of locations in vasculature of a patient; comparing the pressure drop with a reference pressure drop; determining, based on the comparison, presence of microvascular constriction in the vasculature; and generating, in response to determining the presence of microvascular constriction, an output indicative of the presence of microvascular constriction.

[0148] Example 2. The method of Example 1, wherein determining the microvascular constriction comprises determining, by the processing circuitry, a presence or absence of microvascular constriction along a predetermined vessel of the vasculature.

[0149] Example 3. The method of Examples 1 or 2, further comprising, by the processing circuitry: determining microvascular constriction in response to determining that the pressure drop is greater than the reference pressure drop.

[0150] Example 4. The method of any of Examples 1 to 3, wherein the output comprises a binary signal indicative of the presence or absence of microvascular constriction.’

[0151] Example 5. The method of any of Examples 1 to 4, wherein determining the microvascular constriction comprises determining, by the processing circuitry, a microvascular constriction metric.

[0152] Example 6. The method of Example 5, wherein a magnitude of the microvascular constriction metric is indicative of a level of microvascular constriction.

[0153] Example 7. The method of Examples 5 or 6, wherein the microvascular constriction metric is proportional to a difference between the pressure drop and the reference pressure drop.

[0154] Example 8. The method of Examples 5 or 6, wherein the microvascular constriction metric is proportional to a ratio of the pressure drop and the reference pressure drop.

[0155] Example 9. The method of any of Examples 1 to 8, further comprising, by the processing circuitry, determining the reference pressure drop by at least comparing pressures at a reference pair of locations in a reference pressure map corresponding to the pair of locations in the vasculature.

[0156] Example 10. The method of Example 9, wherein the reference pressure map comprises at least one of a fractional flow reserve (FFR) pressure map, a virtual FFR pressure map, an angiographic pressure map, a computerized tomography (CT) angiographic pressure map, or a virtual CT angiographic pressure map.

[0157] Example 11. The method of Examples 9 or 10, further comprising, by the processing circuitry: determining a plurality of anatomical segments between the reference locations; determining a respective segment pressure drop for each anatomical segment of the plurality of segments; and determining the reference pressure drop as a sum of each respective segment pressure drop.

[0158] Example 12. The method of any of Examples 1 to 11, wherein the reference pressure drop is associated with healthy vasculature.

[0159] Example 13. The method of Example 12, further comprising, by the processing circuitry: comparing a patient arterial model with a plurality of candidate arterial models; based on the comparison, selecting a reference arterial model from the plurality of candidate arterial models that is substantially similar to the patient arterial model; and determining the reference pressure drop based on the reference arterial model.

[0160] Example 14. The method of any of Examples 1 to 13, wherein one location of the pair of locations is in a major vessel.

[0161] Example 15. The method of Example 14, wherein the major vessel is an aorta.

[0162] Example 16. The method of any of Examples 1 to 15, wherein the pair of locations is across a suspected constriction site in the vasculature.

[0163] Example 17. The method of any of Examples 1 to 16, wherein a plurality of measurement location pairs comprises the pair of locations, the method further comprising determining microvascular constriction for each measurement location pair of the plurality of measurement location pairs.

[0164] Example 18. The method of Example 17, further comprising, by the processing circuitry, determining a pressure map indicative of a respective pressure drop for each measurement location pair of the plurality of location pairs.

[0165] Example 19. The method of Example 18, further comprising, by the processing circuitry, outputting a graphical representation of the pressure map.

[0166] Example 20. The method of Example 19, wherein the graphical representation is overlaid on a representation of the vasculature of the patient.

[0167] Example 21. A method for detecting microvascular constriction, the method comprising, by processing circuitry: determining a microvascular pressure map for a patient; comparing the microvascular pressure map with a reference microvascular pressure map; and determining, based on the comparison, presence of microvascular constriction.

[0168] Example 22. The method of Example 21, further comprising, by the processing circuitry, based on the comparison, determining an increase in a microvascular pressure drop relative to a reference microvascular pressure drop across a pair of locations in vasculature.

[0169] Example 23. The method of Examples 21 or 22, further comprising, by the processing circuitry, determining the presence of microvascular constriction by at least determining microvascular pressure drop based on pressure drop in a major vessel.

[0170] Example 24. The method of any of Examples 1 to 23, wherein the output further comprises an indication that the patient is a candidate for neuromodulation, based on the presence of microvascular constriction.

[0171] Example 25. The method of Example 24, wherein the neuromodulation comprises at least one of renal denervation or hepatic denervation.

[0172] Example 26. A method for detecting microvascular disease comprising the method of any of claims 1 to 25, further comprising determining an occurrence of microvascular disease in response to determining the presence of microvascular constriction.

[0173] Example 27. The method of Example 26, wherein the microvascular disease comprises microvascular coronary disease.

[0174] Example 28. A method for monitoring a denervation procedure comprising the method of any of Examples 1 to 27, further comprising determining an effectiveness of the denervation procedure in response to determining the presence of microvascular constriction.

[0175] Example 29. The method of Example 28, wherein the reference pressure drop is a pre-procedure pressure drop, and wherein the pressure drop is a post-procedure pressure drop.

[0176] Example 30. The method of Examples 28 or 29, wherein the denervation procedure comprises denervation of a nerve and delivering stimulation to the nerve, and wherein the reference pressure drop is a pre-denervation pressure drop or a pre-stimulation pressure drop.

[0177] Example 31. The method of Example 30, wherein the pressure drop is a postdenervation pressure drop or a post-stimulation pressure drop.

[0178] Example 32. The method of any of Examples 28 to 31, wherein the denervation procedure comprises renal denervation or hepatic denervation.

[0179] Example 33. A method for neuromodulation, the method comprising: delivering stimulation to a target site in a patient; determining, by the method of any of Examples 1 to 32, microvascular constriction of a blood vessel in response to the stimulation; delivering, in response to determining the presence of microvascular constriction after thestimulation, neuromodulation therapy via a device in the blood vessel; determining, after delivering the neuromodulation therapy, by the method of any of Examples 1 to 32, microvascular constriction of the blood vessel; and delivering, in response to determining the presence of microvascular constriction after the neuromodulation therapy, further neuromodulation therapy via the device in the blood vessel.

[0180] Example 34. The method of Example 33, further comprising, in response to determining an absence of microvascular constriction after the neuromodulation therapy, terminating neuromodulation.

[0181] Example 35. A method for neuromodulation, the method comprising: delivering stimulation to a first target site in a patient; determining, by the method of any of Examples 1 to 32, microvascular constriction of a blood vessel in response to the stimulation; and determining, in response to determining the presence of microvascular constriction of the blood vessel, a second target site for neuromodulation.

[0182] Example 36. A method for neuromodulation, the method comprising: delivering stimulation to a target site in a patient; determining, by the method of any of Examples 1 to 32, microvascular constriction of a blood vessel in response to the stimulation; generating, in response to determining the presence of microvascular constriction of the blood vessel, an output indicating that the patient is a candidate for denervation therapy.

[0183] Example 37. The method of Example 36, wherein the denervation therapy comprises at least one of renal denervation therapy or hepatic denervation therapy.

[0184] Example 38. A system comprising: a pressure mapping apparatus configured to determine a pressure drop between a pair of locations in vasculature of a patient; and processing circuitry configured to perform the method of any of Examples 1 to 32.

[0185] Example 39. The system of Example 38, wherein the pressure mapping apparatus is configured to generate at least one of a fractional flow reserve (FFR) pressure map, a virtual FFR pressure map, an angiographic pressure map, a computerized tomography (CT) angiographic pressure map, or a virtual CT angiographic pressure map.

[0186] Example 40. The system of Examples 38 or 39, further comprising an output device configured to generate an output based on the signal indicative of the presence of microvascular constriction

[0187] Example 41. A system comprising: a memory configured to store pressure information, the pressure information comprising at least one of the reference pressure drop ora pressure map indicating a pressure at a plurality of locations in vasculature of a patient; and processing circuitry configured to perform the method of any of claims 1 to 32 based on the pressure information.

[0188] Example 42. A system comprising: a memory; and processing circuitry configured to perform the method of any of Examples 1 to 32, wherein the processing circuitry is configured to store at least one of the determined pressure drop, the determined presence of microvascular constriction, the pressure map, or the output in the memory.

[0189] Example 43. A system comprising: a display device; and processing circuitry configured to perform the method of any of Examples 1 to 32 based on the pressure map, wherein the processing circuitry is configured to present at least one of the determined pressure drop, the determined presence of microvascular constriction, the pressure map, or the output via the display device.

[0190] Example 44. A non-transitory computer readable storage medium comprising program instructions configured to cause processing circuitry to perform the method of any of Examples 1 to 32.

Claims

CLAIMS1. A system comprising: a memory configured to store pressure information, the pressure information comprising at least one of a reference pressure drop or a pressure map indicating a pressure at a plurality of locations in vasculature of a patient; processing circuitry configured to: determine a pressure drop between a pair of locations in vasculature of a patient; compare the pressure drop with the reference pressure drop; determine, based on the comparison, presence of microvascular constriction in the vasculature; and generate, in response to determining the presence of microvascular constriction, an output indicative of the presence of microvascular constriction.

2. The system of claim 1, wherein the processing circuity is configured to determine the presence of microvascular constriction by at least determining a presence or absence of microvascular constriction along a predetermined vessel of the vasculature.

3. The system of claims 1 or 2, wherein the processing circuitry is configured to determine the presence of microvascular constriction in response to determining that the pressure drop is greater than the reference pressure drop.

4. The system of any one of claims 1 to 3, wherein the output comprises a binary signal indicative of the presence or absence of microvascular constriction.

5. The system of any one of claims 1 to 4, wherein the processing circuitry is configured to determine the microvascular constriction by at least determining, by the processing circuitry, a microvascular constriction metric.

6. The system of claim 5, wherein a magnitude of the microvascular constriction metric is indicative of a level of microvascular constriction.

7. The system of claims 5 or 6, wherein the microvascular constriction metric is proportional to a difference between the pressure drop and the reference pressure drop.

8. The system of claims 5 or 6, wherein the microvascular constriction metric is proportional to a ratio of the pressure drop and the reference pressure drop.

9. The system of any one of claims 1 to 8, wherein the processing circuitry is further configured to determine the reference pressure drop by at least comparing pressures at a reference pair of locations in a reference pressure map corresponding to the pair of locations in the vasculature.

10. The system of claim 9, wherein the reference pressure map comprises at least one of a fractional flow reserve (FFR) pressure map, a virtual FFR pressure map, an angiographic pressure map, a computerized tomography (CT) angiographic pressure map, or a virtual CT angiographic pressure map.

11. The system of claim 9 or 10, wherein the processing circuitry is configured to determine the reference pressure drop by at least: determining a plurality of anatomical segments between the reference locations; determining a respective segment pressure drop for each anatomical segment of the plurality of segments; and determining the reference pressure drop as a sum of each respective segment pressure drop.

12. The system of any of claims 1 to 11, wherein the reference pressure drop is associated with healthy vasculature.

13. The system of claim 12, wherein the processing circuitry is further configured to determine the reference pressure drop by at least: comparing a patient arterial model with a plurality of candidate arterial models;based on the comparison, selecting a reference arterial model from the plurality of candidate arterial models that is substantially similar to the patient arterial model; and determining the reference pressure drop based on the reference arterial model.

14. The system of claim 13, wherein the major vessel is an aorta.

15. The system of any one of claims 1 to 14, wherein the pair of locations is across a suspected constriction site in the vasculature.

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