WO2014164696A1

WO2014164696A1 - Systems and methods for diagnosing coronary microvascular disease

Info

Publication number: WO2014164696A1
Application number: PCT/US2014/023241
Authority: WO
Inventors: Donna COLLINS; Mary Lynn Gaddis; Nathaniel J. Kemp; Bernhard Sturm
Original assignee: Collins Donna; Mary Lynn Gaddis; Kemp Nathaniel J; Bernhard Sturm
Priority date: 2013-03-12
Filing date: 2014-03-11
Publication date: 2014-10-09
Also published as: EP2967391A4; CN105228518B; US20140276036A1; US10638939B2; US20200260964A1; EP2967391A1; EP3895604A1; JP2016521138A; CN105228518A

Abstract

The invention provides systems and methods for assessing the vasculature of a subject. In certain aspects, systems and methods of the invention involve receiving functional flow data of a subject via a data collector co-located with a radiopaque label, receiving imaging data of the vasculature including the radiopaque label, generating a vasculature map corresponding to the functional flow data, and displaying the vasculature map image on a monitor.

Description

SYSTEMS AND METHODS FOR DIAGNOSING CORONARY MICROVASCULAR

DISEASE

Related Application

The present application claims the benefit of and priority to U.S. provisional patent application serial number 61/776,863, filed March 12, 2013, the content of which is incorporated by reference herein in its entirety.

Technical Field

This application generally relates to systems and methods for assessing vasculature of a subject.

Background

Coronary microvascular disease, also known as small vessel disease, is a condition in which the small arteries in the heart become narrow. Typically, the walls of the small arteries are damaged or diseased. Coronary microvascular disease affects the vessels differently from traditional coronary artery disease. Coronary artery disease is an obstruction of blood flow through the coronary artery due to plaque accumulation and blood clots that form as a result of the accumulated plaque. However, the accumulation of plaque and resultant blockages are not always present in coronary microvasculature disease. Instead, coronary microvasculature disease is caused by an adverse constriction/relaxation of the small blood vessels. This adverse constriction/relation is believed to be caused by changes in the arterial cells and the surrounding muscle tissues. Coronary microvascular disease is especially problematic in women, who are more likely to experience the disease relative to men.

Diagnosing coronary microvascular disease has been a challenge. Conventional methods

(such as angiography, stress test, and cardiac MRI stress test, etc.) are designed to detect blockages in the arteries. These tests are unable to consistently diagnose coronary microvascular disease because the small diseased vessels are often unrestricted by plaque, and thus are not visible on angiograms and MRI scans. Accordingly, women and other susceptible groups, such as diabetics, experiencing unexplainable fatigue, chest pain, or overall malaise associated with heart disease may test negative for heart disease.

Summary

The invention overcomes the limitations of conventional methods for detecting coronary microvascular disease by mapping one or more functional flow measurements to an image of the vasculature. Functional flow measurements allow one to determine abnormal constriction or relaxation of blood vessels, even in the absence of a stenosis, by monitoring blood flow velocity and pressure. When functional flow measurements are mapped or co-registered to a vasculature image, one may determine the location and severity of damaged blood vessels that are otherwise not indicated in the vasculature image obtained by an external imaging modality.

Methods of the invention are accomplished by receiving functional flow data of a subject with a data collector co-located with a radiopaque label, and receiving imaging data of the vasculature including the radiopaque label. Using the received functional flow data and imaging data, a vasculature map image corresponding to the functional flow data is generated and displayed on a monitor. In certain embodiments, the vasculature map image corresponding to the functional flow data is generated by co-registering the functional flow data with the imaging data. By co-locating a radiopaque label with the data collector, it is easier to identify the exact location of the data collector and to correlate given functional flow measurements with a specific location within the vasculature. This makes possible systems that can simultaneously display functional flow measurements and pinpoint the location of those functional flow measurements on a corresponding vasculature map image.

Methods of the invention also provide for displaying a composite image including the vasculature map image and a functional flow image. The functional flow image may include the functional flow measurements specific to a certain location in the vasculature as shown on the vasculature map image. The vasculature map image may show a location of the data collector, which directly corresponds to the displayed functional flow image. In some embodiments, the location of the data collector is the real-time location of the data collector, e.g. the current location of the data collector as inserted in the vasculature.

According to certain aspects, methods of the invention further include analyzing the functional flow data for one or more parameters, and providing an alert on the vasculature map image when the one or more parameters are at or beyond a threshold level. In certain embodiments, the alert is a visual alert. The visual alert may include a color-coded indicator, a pulsating indicator, a color map of the one or more parameters, a callout marker, or a

combination thereof.

The data collector may be located on a guidewire, catheter, or other intraluminal device configured to access the vasculature. Typically, the data collector for obtaining functional flow data is a pressure sensor, flow sensor, or combination thereof. Preferably, the intraluminal device is a guidewire with both a pressure sensor and a flow sensor on a distal portion of the device. Pressure sensors are able to obtain pressure measurements and flow sensors are able to obtain velocity measurements within a blood vessel. The ability to measure and compare both the pressure and flow significantly improves the diagnostic accuracy of ischemic testing.

The imaging data may be obtained using any external imaging modality, including e.g. computed tomography, angiography, and magnetic resonance imaging. When the external imaging modality requires flow contrast, the flow contrast may not enter the all of the vessels of the vasculature (such as the small vessels associated with coronary microvasculature disease) in adequate amounts for proper imaging, which may prevent mapping of vessels without contrast. Consequently, the external imaging modality used preferably does not require a flow contrast for imaging to increase the likelihood that the small vessels associated with coronary

microvasculature disease are imaged and mapped. Brief Description of the Drawings

FIG. 1 is a schematic illustration of a system for implementing co-registration of functional flow data and external imaging data.

FIG. 2 shows depict a background vasculature image map obtained by an external imaging modality according to certain embodiments.

FIG. 3 depicts a composite image showing a vasculature map image corresponding to functional flow data and a functional flow image.

FIG. 4 depicts a simultaneous display of a functional flow image and a vasculature map image, highlighting via a box the location in which the functional flow image data was obtained.

FIG. 5 depicts an alternative simultaneous display of a functional flow image and a vasculature map image, highlighting the location in which the functional flow image data was obtained. FIG. 6 indicates alerts according to certain embodiments. An arrow indicating the location of the data collector and lines visually linking the functional flow image to that location are given a different color if one or more parameters from the functional flow data at that location are at or above a threshold level for those one or more parameters.

FIG. 7 shows a color map of the vasculature image map for a parameter.

FIG. 8 is an image that simultaneously shows the functional flow image corresponding to point X from FIG. 7.

FIGS. 9A-9B show use of callout markers on the vasculature image map to signify areas of interest of the vasculature corresponding to the functional flow data.

FIG. 10 exemplifies a guidewire suitable for use with the present invention.

FIG. 11 is block diagram of a system of the invention for locating the position of a functional flow data relative to an image of the vasculature of the subject.

FIG.12 is a block diagram of a networked system for locating the position of a functional flow data relative to an image of the vasculature of the subject.

Detailed Description

Methods and systems of the invention include functional flow and image data acquisition equipment and data/image processors that generate views on a single display that simultaneously provides positional information and functional flow data associated with a data collector (e.g., a pressure sensor, flow sensor, temperature sensor, or combination thereof). The data collector is mounted upon a flexible elongate member (e.g, a catheter, guidewire, etc.) and co-located with a radiopaque label that can be tracked with an external imaging modality.

Turning initially to FIG. 1, an exemplary system is schematically depicted for carrying out the present invention in the form of co-registration of imaging data obtained from an external imaging modality and functional flow data obtained from a data collector. The external imaging modality data and functional flow data acquisition sub- systems are generally well known in the art. With regard to the external imaging modality data, a patient 10 is positioned upon a table 12 for imaging. The table 12 is arranged to provide sufficient space for the positioning of an external imaging modality 14 in an operative position in relation to the patient 10 on the table 12. Imaging data acquired by the external imaging modality 14 passes to an external imaging modality processor 18 via transmission cable 16. The imaging modality processor 18 converts the received imaging data received via the cable 16 into vasculature image data. The vasculature image data is initially stored within the processor 18.

With regard to portions of the system associated with acquiring functional flow data, an functional flow device 20 (preferably a pressure guidewire, flow guidewire, or combined pressure/flow guidewire) is inserted within the patient 10 so that its distal portion, including a data collector 22 (e.g. a pressure sensor, flow sensor, or both), is in the vicinity of a desired region of the vasculature. While not specifically identified in FIG. 1, a radiopaque label located near the data collector 22 provides indicia of a current location of the data collector 22 in an external image. By way of example, the data collector 22 may be a crystal semiconductor material that responds to pressure gradients and converts the pressure to corresponding electrical signals. The corresponding electrical signals are transmitted along the length of the functional flow device 20 to a proximal connector 24. Data collectors may come in a variety of

configurations on the functional flow device. Regardless of the configuration, the radiopaque label should be co-located with the data collector, i.e. placed near or at the data collector. In some instances, the data collector itself may comprise a radiopaque material.

The proximal connector 24 of the functional flow device 20 is communicatively coupled to a functional flow data processor 26. The functional flow data processor 26 converts the signals received via the proximal connector 24 into, for example, pressure measurements, flow measurements, Fractional Flow Reserve measurements, Coronary Flow Reserve measurements, etc. Additionally, the functional flow processor 26 generates a functional flow image by converting the functional flow data into a displayable format. The functional flow data rendered by the functional flow processor 26 is initially stored within the processor 26.

The type of diagnostic functional flow data acquired by the data collector 22 and processed by the functional flow processor 26 varies in accordance with alternative embodiments of the invention. In accordance with a particular embodiment, the diagnostic probe 22 is equipped with one or more sensors (e.g., Doppler flow and/or pressure) for providing

hemodynamic information (e.g., blood flow velocity and pressure)— also referred to as functional flow data. It is thus noted that the term "functional flow image" is intended to be broadly interpreted to encompass a variety of ways of representing vascular information including blood pressure, blood flow velocity/volume, blood vessel cross-sectional composition, shear stress throughout the blood, shear stress at the blood/blood vessel wall interface, etc. In the case of acquiring hemodynamic data for particular portions of a blood vessel, effective diagnosis relies upon the ability to visualize a current location of the data collector 22 within a vasculature while simultaneously observing functional flow metrics indicative of cardiovascular disease. Co- registration of hemodynamic and external vasculature images facilitates precise treatment of diseased vessels. In addition, it is contemplated that the functional flow device includes one or more imaging collector to provide, for example, cross-sectional images of the vasculature along with the functional flow data. Data obtained by the imaging collectors may also be processed by the functional flow processor 26 and co-registered with the external imaging data.

A co-registration processor 30 receives functional flow data from the functional flow processor 26 via line 32 and vasculature image data from the external imaging modality processor 18 via line 34. Alternatively, the communications between the sensors and the processors are carried out via wireless media. The co-registration processor 30 renders a vasculature map image corresponding to the functional flow data. For example, a vasculature map image is provided showing a location of the data collector within the vasculature, for example, as indicated by the radiopaque label. In accordance with an embodiment of the present invention, indicia (e.g., a radiopaque marker artifact) are provided on the vasculature map images of a location corresponding to a simultaneously-displayed functional flow image. In preferred embodiments, software tagging provides other visual indicia (e.g. callout marker, box, arrow, or other computing icons) to show the radiopaque marker artifact. In one embodiment, a composite image is displayed showing the vasculature map image with the indicia and the functional flow data image specific to the location of the indicia in the vasculature map image. The vasculature map image and the functional flow image may be simultaneously displayed on a monitor, or each displayed independently on a monitor by minimizing or maximizing the vasculature map image or the functional flow image via a user interface.

The co-registration processor 30 initially buffers external imaging data received via line

34 from the external imaging modality processor 18 in a first portion 36 of image data memory 40. This provides an initial background vasculature map image, which can be updated with time-stamp vasculature map image frames. Thereafter, during the course of a catheterization procedure functional flow data and vasculature map image data received via lines 32 and 34, respectively, is stored within a second portion 38 and a third portion 42, respectively, of the image data memory 40. The individually rendered frames of stored image data are appropriately tagged (e.g., time stamp, sequence number, etc.) to correlate functional flow data frames and corresponding vasculature map (including the radiopaque marker indicia) image data frames. The stored functional flow data frames corresponding to certain vasculature image map frames can be used to track functional flow data across various locations within the vasculature. In certain embodiments, an alert is provided on the vasculature map image that indicates a level of the functional flow data obtained at various locations in the vasculature by the data collector.

In addition, additional markers can be placed on the surface of the patient or within the vicinity of the patient within the field of view of the external imaging modality device. The locations of these markers are then used to position the radiopaque label upon the angiographic image in an accurate location.

The co-registration processor 30 renders a co-registration image from the data previously stored within the first portion 36, second portion 38 and third portion 42 of the image data memory 40. By way of example, a functional flow data frame is selected from the second portion 38. The co-registration processor 30 identifies vasculature map image frame within the third portion 42 corresponding to the selected functional flow data frame from the second portion 38. Thereafter, the co-registration processor 30 superimposes the vasculature map image frame from the third portion 42 upon the initial vasculature map image retrieved from the first portion 36. In addition, the functional flow data may be processed to determine clinically relevant

measurements from the functional flow data, such as Fractional Flow reserve measurements, Coronary Flow reserve measurements, combined P-V curves, and to display those measurements along with, e.g. pressure and flow readings, in a functional flow image. Thereafter, the co- registered vasculature map image and functional flow image may be simultaneously displayed, along-side one another, upon a graphical display device 50. The co-registered image and functional flow data frames driving the display device 50 are also stored upon a long-term storage device 60 for later review in a session separate from a procedure that acquired the vasculature image data and functional flow data stored in the image data memory 40.

While not shown in FIG. 1, a pullback device may be operably associated with the functional flow device that moves the functional flow 20 from the patient at a

controlled/measured manner. Such devices are well known in the art. Incorporation of such devices facilitates calculating a current position of the data collector 22 within a field of view at points in time when the external imaging modality is not actively providing imaging data. For example, if angiography/fluoroscopy is used as an external imaging modality, the pull-back mechanism can be used to track the position of the data collector on the initial background vasculature map image when fluoroscopy is not active.

FIGS. 2-4 illustrate exemplary techniques for mapping functional flow data of the vasculature to vasculature imaging data obtained by an external imaging modality.

Turning to FIG. 2, the external imaging modality processor 18 captures an initial background vasculature map image 200 in a desired projection (patient/vessel orientation) and magnification. By way of example, the initial image 200 is initially captured by the external imaging modality prior to tracking the functional flow device to the region of interest within a patient's vasculature. Although, one may also capture a background vasculature map image during the procedure. The initial image 200 provides shows vessels 210 of the vasculature.

Turning to FIG. 3, an exemplary co-registration display 401 (including the correlated vasculature map images and function flow data image) depicts a functional flow image containing functional flow measurements and data relative to the location of the data collector. A vasculature map image 410 is simultaneously displayed along-side the functional flow image 400 on the display 50. The vasculature map image 410 includes a radiopaque label 420, generated from external imaging data rendered by a vasculature image frame, superimposed on a background image rendered from the first portion 36 of the memory 40. The vasculature image frame corresponds to the current location of the data collector 22 within a vessel under observation. Precise matching of the field of view represented in both the background vasculature image and the collected vasculature map image frame during the procedure (i.e., precise projection and magnification of the two images) allows identification of the current position of the data collector corresponding to the displayed functional flow image 400 in the right pane of the co-registered images displayed in FIG. 3.

In some embodiments, image tagging software can be used to automatically identify the location of the radiopaque label, which may appear as a small spot having a darker color than the rest of the image. The image tagging software can automatically locate a box corresponding to the position of the data collector on the vasculature map image, e.g., as shown in FIG. 4. A physician using such this system will be able to locate specific structures of interest and return to those structures with less effort. Accordingly, the procedure will take less time, and the patient and the physician will be exposed to less radiation. After functional flow data is obtained for a region of the vasculature, a physician need only click on a location within those that region on the vasculature map image to pull up the functional flow image corresponding to that location.

In addition to the embodiments described above, the devices, methods, and systems of the invention can be used to catalogue and display overlapping images of intravascular imaging and vascular structure, as is shown in FIG. 5. Again, using image tagging software, or other algorithms, it is possible to display a vasculature map image that co-displays intravascular images. FIG. 5 shows a simulated functional flow image co-located with the location of the data collection on a vasculature map image of pulmonary arteries.

The system also takes heart motion into account when generating/acquiring the external image data of the vasculature (e.g. radiological) and functional flow data. By way of example, by only acquiring the image data for the vasculature map during the peak R-wave of the EKG, heart motion is much less a factor and good overlay correlation exists between the angiogram and fluoroscope fields of view. The peak R-wave is selected because it represents end-diastole, during which the heart has the least amount of motion, and thus, a more consistent condition from which to obtain the external image data. The peak R-wave is also an easy point in the EKG for the system to detect.

With continued reference to FIG. 3 in an exemplary embodiment when the functional flow device 20 begins to collect data, the functional flow data is displayed in tandem with the enhanced vasculature map 410 including both the background vasculature map image and the superimposed vasculature map frame. The enhanced vasculature map image 410 and the functional flow data 400 are displayed close to (e.g., alongside) each other on the display 50, so that the operator can concentrate on the information in the cross-sectional image 400 while virtually simultaneously observing the status of the enhanced radiological image 410.

The simultaneous display of both the composite image with the vasculature map and the functional flow data allows instant awareness of both disease state of a vessel segment and the location of the vessel segment within a patient. Such comprehensive information is not readily discernible in conventional methods for assessing cardiovascular disease. In addition, the functional flow measurements allow one to identify defects and conditions that are not readily visible in vasculature image alone, such as symptoms of microvasculature disease. Neither flythrough nor stacked images alone allows for the simultaneous appreciation of 1) all of the information in a cross-section, 2) a feel for the shape of the vessel and 3) the location of the cross-section along the length of the vessel.

The above-described "co-registration" of a vasculature map image including the radiopaque label and functional flow images/information delivers all three of these items in a presentation that is straight forward to an operator with even average visual and spatial abilities. The co-registration display is presented, by way of example, either on a console display for the functional flow device, or the co-registration display is presented on one or more external imaging modality monitors, either in the room where the procedure is occurring or in a remote location. For example, one monitor over the table in the procedure room allows the attending physician to view the procedure, while at the same time a second consulting physician who has not scrubbed for the case is also able to view the case via a second monitor containing the co- registration display from a separate control room. Control room viewing is also possible without having to wear leaded covering.

With regard to the persistence of the background vasculature map image portion of the enhanced vasculature map image 410 (including the radiopaque label), a single initial image is, by way of example, obtained/generated and stored in the first portion 36 of the memory 40 for a given procedure/patient position. If the field of view changes or the patient's position changes, then an updated background vasculature image is generated and stored in the first portion 36. Alternatively, the background vasculature map image is live or continuously updated. The projection of the roadmap vasculature map image onto the enhanced vasculature image 410 is preferably in an orientation and magnification that best displays the entire vessel to be viewed, taking into account the foreshortening that is present in a tortuous/winding vessel. Alternatively, two background vasculature images (or even two enhanced radiological images 410) can be used/displayed in place of the one image 410.

According to certain aspects, systems and methods of the invention provide for analyzing the functional flow data for one or more parameters and providing an alert on the vasculature map image when the one or more parameters are above the threshold level. Threshold levels may be established to set forth acceptable data ranges that are indicative of stenosis, vessel constriction or other vessel damage. For example, threshold levels may be established for a parameter to categorize the parameter as normal or abnormal. In addition, a threshold level may be established for an intermediate range between normal and abnormal. In one embodiment, parameters for function flow data include levels for Coronary flow reserve, Fractional flow reserve, pressure- volume (P-V) curves/loops, or combinations thereof.

Coronary flow reserve is defined as the ratio of maximal coronary flow with hyperemia to normal flow. Coronary flow reserve signifies the ability of the myocardium to increase blood flow in response to maximal exercise. A ratio at or above 2 is considered normal. Abnormal CFR (a ratio below 2) indicates stenosis, abnormal constriction of microarteries, or both.

Coronary flow reserve measures the velocity of the flow. Fractional flow reserve measure pressure differences across a portion of a vessel to determine whether a level of constriction or stenosis of the vessel will impede oxygen delivery to the heart muscle. Specifically, Fractional flow reserve is a ratio of a level of pressure distal to a portion of a vessel under examination to a level of pressure proximal to a portion of a vessel under examination. Often a cut-off point is 0.75 to 0.80 has been used, in which high values indicate a non- significant stenosis or constriction and lower values indicate a significant stenosis and lesion.

P-V loops provide a framework for understanding cardiac mechanics. Such loops can be generated by real time measurement of pressure and volume within the left ventricle. Several physiologically relevant hemodynamic parameters such as stroke volume, cardiac output, ejection fraction, myocardial contractility, etc. can be determined from these loops.

To generate a P-V loop for the left ventricle, the LV pressure is plotted against LV volume at multiple time points during a single cardiac cycle. The presence of a stenosis or constriction can alter the curve/shape of P-V loop from a normal P-V loop.

It has been shown that distal pressure and velocity measurements, particularly regarding the pressure drop-velocity relationship such as Fractional Flow reserve (FFR), Coronary flow reserve (CFR) and combined P-V curves, reveal information about the stenosis severity. For example, in use, the functional flow device may be advanced to a location on the distal side of the stenosis. The pressure and flow velocity may then be measured at a first flow state. Then, the flow rate may be significantly increased, for example by the use of drugs such as adenosine, and the pressure and flow measured in this second, hyperemic, flow state. The pressure and flow relationships at these two flow states are then compared to assess the severity of the stenosis and provide improved guidance for any coronary interventions. The ability to take the pressure and flow measurements at the same location and same time with a combined pressure/flow guidewire, improves the accuracy of these pressure- velocity loops and therefore improves the accuracy of the diagnostic information.

Coronary flow reserve, Fractional flow reserve, and P-V loops may require

measurements taken at different locations in the artery. In order to provide measurements for these parameters, systems and methods of the invention may assess pressure and flow at a first location of the data collector against a second location of the data collector within the

vasculature. For example, a first location that is distal to a segment of a vessel under

examination and a second location that is proximal to that segment of a vessel. The obtained measurements across the two locations are then assessed against the one or more threshold levels, and an alert is provided on the vasculature image map when the one or more parameters are at or beyond a threshold level. The alert, for example, may be indicated for a single location of the data collector on the vasculature map image corresponding to one or more parameters, or may be indicated for several locations of the data collector corresponding to a plurality of parameters, or may be indicated over one or more location points of the data collector that correspond to a single parameter on the vasculature image map.

In some embodiments, the alert is a color coded indicator, a pulsating indicator, a color map of the one or more parameters, a callout marker, or a combination thereof. If functional flow data corresponding to one or more locations on the vasculature image map is above or at a threshold level, an alert is provided at those one or more locations. Any combination of alerts used to indicate areas of interest on the vasculature map image are contemplated herein. In one example, the alert is a color-coded callout marker. In another example, the alert is a color map with a call-out marker. FIGS. 6-9B indicate use of alerts according to certain embodiments.

As shown in FIG. 6, an arrow indicating the location of the data collector and lines visually linking the functional flow image to that location are given a different color if one or more parameters from the functional flow data at that location are at or above a threshold level for those one or more parameters. For example, the arrow and linking lines in FIG. 6 may be green if the functional flow data indicates, for example, that there is no abnormal vessel constriction or stenosis at that particular location in the vasculature. Alternatively, red may be used to indicate abnormal vessel constriction or stenosis at a particular location in the

vasculature. In another embodiment, instead of or in combination with the color used to indicate a level of constriction or stenosis, the arrow and/or linking lines may pulsate to indicate a level of constriction or stenosis. In other examples, the functional flow image itself may pulsate to indicate a measurement at or beyond a threshold level.

FIG. 7 shows a color map of the vasculature image map for a parameter. As show in FIG. 7, region of the vasculature are labeled A, B, and C. Those regions indicate different colors of the vasculature based on measurements of functional flow data corresponding to those regions. For the color map, regions A may be green to indicate that those regions have normal functional flow data measurements; region B may be yellow to indicate that those regions have intermediate functional flow data measurements (borderline between healthy and abnormal), and regions C may be red to indicate that those regions have abnormal flow data measurements. As a result, a physician, using systems of the invention, need only look at the vasculature map image to quickly pinpoint regions of interests in the vasculature. In addition, the physician need only click on a location within the color map region of the vasculature map to pull up functional flow image data corresponding to that location. For example, if the physician clicked on point X, FIG. 8 would appear that simultaneously shows the functional flow image corresponding to point X.

FIGS. 9A-9B show use of callout markers on the vasculature image map to signify areas of interest of the vasculature corresponding to the functional flow data. As discussed, the area of interest may be a location where a parameter of the functional flow data at that location is at or above a threshold level. Upon clicking one of the call-out markers, the functional flow image associated with that location of the vasculature will appear, such as in FIG. 9B. In certain embodiments, one may click on multiple callout markers during a session to compare functional flow images corresponding to the callout markers.

Functional flow devices suitable for use in methods and systems of the invention may be a guidewire or a catheter. Preferably, the functional flow device is a guidewire sized to fit within the interior of a microvascular vessel. Exemplary guidewires include FloWire Doppler

Guidewire and the ComboWire XT Guidewire by Volcano Corporation.

FIG. 10 depicts a guidewire 5 suitable for use in methods and systems of the invention. The guidewire 5 includes a flexible elongate member 100 having a proximal portion 102 and a distal portion 104. The guidewire 5 may have an average diameter of 0.018" and less. The flexible elongate member 100 typically includes an elongate shaft 116 and a coil segment 112. The flexible elongate shaft 116 can be formed of any suitable material such as stainless steel, nickel and titanium alloy (Nitinol, polyimide, polyetheretherketone or other metallic or polymeric materials and having a suitable wall thickness, such as, e.g., 0.001" to 0.002". This flexible elongate shaft is conventionally called a hypotube. In one embodiment, the hypotube may have a length of 130 to 170 cm. The guidewire further includes a core member 150 disposed within a lumen of the elongate member 100. The core member 150 extends from the proximal portion to the distal portion of the flexible elongate member 100 to provide the desired torsional properties to facilitate steering of the guidewire in the vessel and to provide strength to the guidewire and prevent kinking. The core member can be formed of a suitable material such as stainless steel, nickel and titanium alloy (Nitinol), polyimide, polyetheretherketone, or other metallic or polymeric materials.

A proximal end of the core member 150 may be connected to a handle. The proximal end of core member 150 can be removeably coupled to a connector housing 106. In addition to receiving the proximal end of the core member 150, the connector housing 106 may also removeably connect to and receive one or more electrical connection wires (not shown) that run the length of the elongate body 100 and connect to one or more sensors on the distal portion 102. This removable connection allows one to disconnect the guidewire from the connector housing 106 when placing a catheter over the guidewire and reconnect the guidewire thereafter to prove electrical communication to the sensors. The connector housing 106 may include one or more electrical connections that mate with the electrical conductor wires. The connector housing 106 may be connected to an output connector 72 via a cable 108. The output connector 72 may be the proximal connector 24 shown in FIG. 1, or coupled to the proximal connector 24 shown in FIG. 1. The proximal connector 24 transmits signals from one or more sensors to the functional flow data processor 26 of FIG. 1.

A sensor housing 120 may be positioned on the elongate member 100. The sensor housing 120 includes a housing body that defines a lumen. One or more cavities may be shaped into the walls of the sensor housing to form windows for sensors disposed or mounted therein. The sensor housing is preferably positioned between the coil segment 112 and the distal tip 110. The sensor housing 120 contains one or more data collectors configured to receive and transmit functional flow data to functional flow processor 26.

Data collectors suitable for use in methods and devices of the invention include, for example, a pressure sensor, flow sensor, or combination thereof. The data collectors are co- located with a radiopaque label so that the location of the functional flow data can be determined.

A pressure sensor allows one to obtain pressure measurements within a body lumen. A particular benefit of pressure sensors is that pressure sensors allow one to measure of FFR in vessel. FFR is a comparison of the pressure within a vessel at positions prior to the stenosis and after the stenosis. The level of FFR determines the significance of the stenosis, which allows physicians to more accurately identify clinically relevant stenosis. For example, an FFR measurement above 0.80 indicates normal coronary blood flow and a non-significant stenosis. Another benefit is that a physician can measure the pressure before and after an intraluminal intervention procedure to determine the impact of the procedure.

A pressure sensor can be mounted on the distal portion of a flexible elongate member. In certain embodiments, the pressure sensor is positioned distal to the compressible and bendable coil segment of the elongate member. This allows the pressure sensor to move along with the along coil segment as bended and away from the longitudinal axis. The pressure sensor can be formed of a crystal semiconductor material having a recess therein and forming a diaphragm bordered by a rim. A reinforcing member is bonded to the crystal and reinforces the rim of the crystal and has a cavity therein underlying the diaphragm and exposed to the diaphragm. A resistor having opposite ends is carried by the crystal and has a portion thereof overlying a portion of the diaphragm. Electrical conductor wires can be connected to opposite ends of the resistor and extend within the flexible elongate member to the proximal portion of the flexible elongate member. Additional details of suitable pressure sensors that may be used with devices of the invention are described in U.S. Pat. No. 6,106,476. U.S. Pat. No. 6,106,476 also describes suitable methods for mounting the pressure sensor 104 within a sensor housing.

A flow sensor can be used to measure blood flow velocity within the vessel, which can be used to assess coronary flow reserve (CFR). The flow sensor can be, for example, an ultrasound transducer, a Doppler flow sensor or any other suitable flow sensor, disposed at or in close proximity to the distal tip of the guidewire. The ultrasound transducer may be any suitable transducer, and may be mounted in the distal end using any conventional method, including the manner described in U.S. Pat. No. 5,125,137, 6,551,250 and 5,873,835.

External imaging modality devices for use in methods and devices of the invention include, for example, X-ray angiography imaging, computed tomography imaging, and magnetic resonance imaging devices. Preferably, the imaging modality is computed tomography which does not require the use of a contrast, which may not enter the small vessels of the

microvasculature or stenosis vessels in adequate amounts for proper imaging.

A system of the invention may be implemented in a number of formats. An embodiment of a system 300 of the invention is shown in FIG. 11. The core of the system 300 is a computer 360 or other computational arrangement (see FIG. 12) comprising a processor 365 and memory 367. The memory has instructions which when executed cause the processor to receive imaging data of vasculature of a subject collected with an image collector co-located with a radiopaque label. The functional flow data of vasculature will typically originate from a data collector 320, which is in electronic and/or mechanical communication with a functional flow device 325. The memory additionally has instructions which when executed cause the processor to receive an image of the subject including the radiopaque label. The image of the subject will typically be an x-ray image, such as produced during an angiogram, CT scan, MRI scan. The image of the subject will typically originate in an external imaging device 340, which is in electronic and/or mechanical communication with a radiological source 343 and a radiological image collector 347 such as a flat panel detector. Having collected the images, the processor then processes the image, and outputs an image of the subject showing the location of the data collector 320, as well as an image of the vasculature of a subject. The images are typically output to a display 380 to be viewed by a physician or technician. In some embodiments a displayed image will simultaneously include both the functional flow image and the image of the vasculature, for example as shown in FIGS. 3-5.

In advanced embodiments, system 300 may comprise an imaging engine 370 which has advanced image processing features, such as image tagging, that allow the system 300 to more efficiently process and display combined functional flow and vasculature map images. The imaging engine 370 may automatically highlight or otherwise denote areas of interest in the vasculature. The imaging engine 370 may also produce 3D renderings of the vasculature map images. In some embodiments, the imaging engine 370 may additionally include data acquisition functionalities (DAQ) 375, which allow the imaging engine 370 to receive the imaging data directly from the functional flow device 325 or collector 347 to be processed into images for display. Other advanced embodiments use the I/O functionalities 362 of computer 360 to control the intravascular imaging 320 or the external imaging modality 340. In these embodiments, computer 360 may cause the data collector of the functional flow device 325 to travel to a specific location, e.g., if the functional flow device 325 is a pull-back type. The computer 360 may also cause source 343 to irradiate the field to obtain a refreshed image of the vasculature, or to clear collector 347 of the most recent image. While not shown here, it is also possible that computer 360 may control a manipulator, e.g., a robotic manipulator, connected to functional flow device 325 to improve the placement of the functional flow device 325.

A system 400 of the invention may also be implemented across a number of independent platforms which communicate via a network 409, as shown in FIG. 12. Methods of the invention can be performed using software, hardware, firmware, hardwiring, or combinations of any of these. Features implementing functions can also be physically located at various positions, including being distributed such that portions of functions are implemented at different physical locations (e.g., imaging apparatus in one room and host workstation in another, or in separate buildings, for example, with wireless or wired connections).

As shown in FIG. 12, the functional flow data collector 320 and the external imaging modality 340 are key for obtaining the data, however the actual implementation of the steps for data collection, co-registration of the data, storage and data output, can be performed by multiple processors working in communication via the network 409, for example a local area network, a wireless network, or the internet. The components of system 400 may also be physically separated. For example, terminal 467 and display 380 may not be geographically located with the functional flow data collector 320 and the external imaging modality 340.

As shown in FIG. 12, imaging engine 859 communicates with host workstation 433 as well as optionally server (not shown) over network 409. In some embodiments, an operator uses host workstation 433, computer 360, or terminal 467 to control system 400 or to receive images and functional flow data. An image may be displayed using an I/O 362, 437, or 471, which may include a monitor. Any I/O may include a monitor, keyboard, mouse or touch screen to communicate with any of processor 365,441, or 475, for example, to cause data to be stored in any tangible, nontransitory memory 367, 445, or 479. Server generally includes an interface module to communicate over network 409 or write data to data file. Input from a user is received by a processor in an electronic device such as, for example, host workstation 433, terminal 467, or computer 360. In certain embodiments, host workstation 433 and imaging engine 855 are included in a bedside console unit to operate system 400.

In some embodiments, the system may render three dimensional imaging of the vasculature or the intravascular images. An electronic apparatus within the system (e.g., PC, dedicated hardware, or firmware) such as the host workstation 433 stores the three dimensional image in a tangible, non-transitory memory and renders an image of the 3D tissues on the display 380. In some embodiments, the 3D images will be coded, as previously-discussed, for faster viewing. In certain embodiments, systems of the invention render a GUI with elements or controls to allow an operator to interact with three dimensional data set as a three dimensional view. In other embodiments an operator may select points from within one of the images or the three dimensional data set by choosing start and stop points while a dynamic progress view is displayed in display. In other embodiments, a user may cause a functional flow device to be relocated to a new position in the body by interacting with the vasculature map image.

In some embodiments, a user interacts with a visual interface and puts in parameters or makes a selection. Input from a user (e.g., parameters or a selection) are received by a processor in an electronic device such as, for example, host workstation 433, terminal 467, or computer 360. The selection can be rendered into a visible display. In some embodiments, an operator uses host workstation 433, computer 360, or terminal 467 to control system 400 or to receive images. An image may be displayed using an I/O 362, 437, or 471, which may include a monitor. Any I/O may include a keyboard, mouse or touch screen to communicate with any of processor 365, 441, or 475, for example, to cause data to be stored in any tangible, nontransitory memory 367, 445, or 479. Server generally includes an interface module to effectuate communication over network or write data to data file. Methods of the invention can be performed using software, hardware, firmware, hardwiring, or combinations of any of these. Features implementing functions can also be physically located at various positions, including being distributed such that portions of functions are implemented at different physical locations (e.g., imaging apparatus in one room and host workstation in another, or in separate buildings, for example, with wireless or wired connections). In certain embodiments, host workstation 433 and imaging engine 855 are included in a bedside console unit to operate system 400.

Processors suitable for the execution of computer program include, by way of example, both general and special purpose microprocessors, and any one or more processor of any kind of digital computer. Generally, a processor will receive instructions and data from a read-only memory or a random access memory or both. The essential elements of computer are a processor for executing instructions and one or more memory devices for storing instructions and data. Generally, a computer will also include, or be operatively coupled to receive data from or transfer data to, or both, one or more mass storage devices for storing data, e.g., magnetic, magneto-optical disks, or optical disks. Information carriers suitable for embodying computer program instructions and data include all forms of non-volatile memory, including by way of example semiconductor memory devices, (e.g., EPROM, EEPROM, NAND-based flash memory, solid state drive (SSD), and other flash memory devices); magnetic disks, (e.g., internal hard disks or removable disks); magneto-optical disks; and optical disks (e.g., CD and DVD disks). The processor and the memory can be supplemented by, or incorporated in, special purpose logic circuitry.

To provide for interaction with a user, the subject matter described herein can be implemented on a computer having an I/O device, e.g., a CRT, LCD, LED, or projection device for displaying information to the user and an input or output device such as a keyboard and a pointing device, (e.g., a mouse or a trackball), by which the user can provide input to the computer. Other kinds of devices can be used to provide for interaction with a user as well. For example, feedback provided to the user can be any form of sensory feedback, (e.g., visual feedback, auditory feedback, or tactile feedback), and input from the user can be received in any form, including acoustic, speech, or tactile input.

The subject matter described herein can be implemented in a computing system that includes a back-end component (e.g., a data server), a middleware component (e.g., an application server), or a front-end component (e.g., a client computer 360 having a graphical user interface or a web browser through which a user can interact with an implementation of the subject matter described herein), or any combination of such back-end, middleware, and front- end components. The components of the system can be interconnected through network 409 by any form or medium of digital data communication, e.g., a communication network. Examples of communication networks include cell networks (3G, 4G), a local area network (LAN), and a wide area network (WAN), e.g., the Internet.

The subject matter described herein can be implemented as one or more computer program products, such as one or more computer programs tangibly embodied in an information carrier (e.g., in a non-transitory computer-readable medium) for execution by, or to control the operation of, data processing apparatus (e.g., a programmable processor, a computer, or multiple computers). A computer program (also known as a program, software, software application, app, macro, or code) can be written in any form of programming language, including compiled or interpreted languages (e.g., C, C++, Perl), and it can be deployed in any form, including as a stand-alone program or as a module, component, subroutine, or other unit suitable for use in a computing environment. Systems and methods of the invention can include programming language known in the art, including, without limitation, C, C++, Perl, Java, ActiveX, HTML5, Visual Basic, or JavaScript.

A computer program does not necessarily correspond to a file. A program can be stored in a portion of file that holds other programs or data, in a single file dedicated to the program in question, or in multiple coordinated files (e.g., files that store one or more modules, subprograms, or portions of code). A computer program can be deployed to be executed on one computer or on multiple computers at one site or distributed across multiple sites and

interconnected by a communication network.

A file can be a digital file, for example, stored on a hard drive, SSD, CD, or other tangible, non-transitory medium. A file can be sent from one device to another over network 409 (e.g., as packets being sent from a server to a client, for example, through a Network Interface Card, modem, wireless card, or similar).

Writing a file according to the invention involves transforming a tangible, non-transitory computer-readable medium, for example, by adding, removing, or rearranging particles (e.g., with a net charge or dipole moment) into patterns of magnetization by read/write heads, the patterns then representing new collocations of information desired by, and useful to, the user. In some embodiments, writing involves a physical transformation of material in tangible, non- transitory computer readable media with certain properties so that optical read/write devices can then read the new and useful collocation of information (e.g., burning a CD-ROM). In some embodiments, writing a file includes using flash memory such as NAND flash memory and storing information in an array of memory cells include floating-gate transistors. Methods of writing a file are well-known in the art and, for example, can be invoked automatically by a program or by a save command from software or a write command from a programming language. In certain embodiments, display 380 is rendered within a computer operating system environment, such as Windows, Mac OS, or Linux or within a display or GUI of a specialized system. Display 380 can include any standard controls associated with a display (e.g., within a windowing environment) including minimize and close buttons, scroll bars, menus, and window resizing controls. Elements of display 380 can be provided by an operating system, windows environment, application programming interface (API), web browser, program, or combination thereof (for example, in some embodiments a computer includes an operating system in which an independent program such as a web browser runs and the independent program supplies one or more of an API to render elements of a GUI). Display 380 can further include any controls or information related to viewing images (e.g., zoom, color controls, brightness/contrast) or handling files comprising three-dimensional image data (e.g., open, save, close, select, cut, delete, etc.). Further, display 380 can include controls (e.g., buttons, sliders, tabs, switches) related to operating a three dimensional image capture system (e.g., go, stop, pause, power up, power down).

In certain embodiments, display 380 includes controls related to three dimensional imaging systems that are operable with different imaging modalities. For example, display 380 may include start, stop, zoom, save, etc., buttons, and be rendered by a computer program that interoperates with functional flow device and external imaging modalities. Thus display 380 can display an image derived from a three-dimensional data set with or without regard to the imaging mode of the system.

Incorporation by Reference

References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes.

Equivalents

Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

What is claimed is:

1. A system for assessing vasculature of a subject, comprising:

a processor; and

a computer-readable storage medium having instructions that when executed cause the processor to:

receive functional flow data of the subject via a data collector co-located with a radiopaque label;

receive imaging data of the vasculature including the radiopaque label; and generate a vasculature map image corresponding to the functional flow data.

2. The system of claim 1, wherein the computer-readable storage medium has instruction that when executed cause the processor, prior to the generating step, to:

co-register the functional flow data with the imaging data of the vasculature.

3. The system of claim 1, wherein the computer-readable storage medium has instructions that when executed cause the processor to:

display the vasculature map image on a monitor; and

show a location of the data collector on the vasculature map image.

4. The system of claim 1, wherein the computer-readable storage has instructions that when executed cause the processor to:

analyze the functional flow data for one or more parameters;

provide an alert on the vasculature map image when the one or more parameters are at or beyond a threshold level.

5. The system of claim 3, wherein the computer-readable storage medium has instructions that when executed cause the processor to:

provide a functional flow image comprising the functional flow data at the location of the data collector.

6. The system of claim 5, wherein the computer-readable storage medium has instruction that when executed cause the processor to:

display, via the monitor, a composite image comprising the vasculature map image and the functional flow image.

7. The system of claim 4, wherein the alert is a visual alert.

8. The system of claim 7, wherein the visual alert is selected from the group consisting of a color-coded indicator, a pulsating indicator, a color map of the one or more parameters, a callout marker, or a combination thereof.

9. The system of claim 3, wherein the location of the data collector is a real-time location of the data collector.

10. The system of claim 1, wherein the functional flow data comprises data selected from the group consisting of pressure data, flow data, or a combination thereof.

11. A method for assessing vasculature of a subject, the method comprising

receiving functional flow data of the subject via a data collector co-located with a radiopaque label;

receiving imaging data of the vasculature including the radiopaque label; and generating a vasculature map image corresponding to the functional flow data.

12. The method of claim 11, wherein the vasculature map image shows a location of the data collector.

13. The method of claim 11, the method further comprising the steps of

analyzing the functional flow data for one or more parameters;

providing an alert on the vasculature map when the one or more parameters are at or beyond a threshold level.

14. The method of claim 12, the method further comprising the step of

providing a functional flow image comprising the functional flow data at the location of the data collector.

15. The method of claim 14, the method further comprising the step of

displaying, via the monitor, a composite image comprising the vasculature map image and the functional flow image.

16. The method of claim 13, wherein the alert is a visual alert.

17. The method of claim 16, wherein the visual alert is selected from the group consisting of a color-coded indicator, a pulsating indicator, a color map of the one or more parameters, a callout marker, or a combination thereof.

18. The method of claim 12, wherein the location of the data collector is an actual realtime location of the data collector or a previous location of the data collector.

19. The method of claim 11, wherein the functional flow data comprises data selected from the group consisting of pressure data, flow data, or a combination thereof.

20. The method of claim 11, wherein the method comprises, prior to the generating step, the step of co-registering the functional flow data and the imaging data.