Exercise cardiac magnetic resonance imaging with lower body negative pressure

Abstract

A system for performing a cardiac magnetic resonance imaging (MRI) is disclosed. The system includes a magnetic resonance imaging (MRI) device, an MRI-compatible exercise ergometer, and a lower body negative pressure (LBNP) suit. The LBNP suit can include a garment defining a pair of pant legs configured to receive legs of a patient and a negative pressure port. The garment can be configured to, when connected to a vacuum source at the negative pressure port, form a sufficient seal with the patient to establish a pressure differential between an interior of the garment and an exterior of the garment.

Description

Attorney Docket No. 38357.0004P1EXERCISE CARDIAC MAGNETIC RESONANCE IMAGING WITH LOWER BODY NEGATIVE PRESSURE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No.63 / 748,166, filed January 22, 2025, the entirety of which is incorporated by reference herein.FIELD

[0002] This disclosure relates to magnetic resonance imaging (MRI) systems and, in particular, to MRI systems for cardiac magnetic resonance imaging (cMRI).BACKGROUND

[0003] Exercise cardiac magnetic resonance imaging (cMRI) offers several major advantages, including improved spatial resolution in the absence of ionizing radiation.However, exercise cMRI is limited by the physical constraints of the scanner itself, forcing subjects to exercise while laying supine. Such postural positioning causes a major hemodynamic shift toward the central circulation, minimizing the overall cardiac response to exercise.SUMMARY

[0004] Disclosed herein is a system comprising a magnetic resonance imaging (MRI) device, an MRI-compatible exercise ergometer, and a lower body negative pressure (LBNP) suit. The LBNP suit can comprise a garment defining a pair of pant legs configured to receive legs of a patient and a negative pressure port. The garment can be configured to, when connected to a vacuum source in communication with (optionally, at) the negative pressure port, form a sufficient seal with the patient to establish a pressure differential between an interior of the garment and an exterior of the garment.

[0005] In another aspect, a method comprises collecting cardiac MRI data from a patient at least partially disposed within an MRI device and wearing a lower body negative pressure suit. Collecting cardiac MRI data can include initiating operation of the MRI device to generate the cardiac MRI data; and receiving, by a computing device, the cardiac MRI data generated by the MRI device.Attorney Docket No. 38357.0004P1BRIEF DESCRIPTION OF THE DRAWINGS

[0006] The accompanying draw ings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the disclosed apparatus, system, and method and together with the description, serve to explain the principles of the disclosed apparatus, system, and method.

[0007] FIG. 1 is a perspective view of a system as disclosed herein.

[0008] FIG. 2 is a front view of an exemplary LBNP suit.

[0009] FIG. 3 is a front view of an exemplary LBNP suit, the suit including struts betw een adjacent rings to inhibit axial collapse.

[0010] FIGS. 4A-4E illustrate volumetric response to exercise cardiac magnetic resonance imaging with / without lower body negative pressure (LBNP). In particular, FIGS. 4A-4E show cardiac hemodynamic response to dynamic leg exercise with (open triangle) and without (open circle) LBNP. Specifically, FIG. 4A shows left ventricular end-diastolic volume index (LVEDV); FIG. 4B shows left ventricular end-systolic volume index (LVESV); FIG. 4C show's left ventricular stroke volume index (LVSVi); FIG. 4D shows heart rate (HR); and FIG. 4E show s cardiac index (CI). Data is presented as mean + standard error for n=9 healthy male participants.

[0011] FIG. 5 is a block diagram of a computing system comprising a computing device as disclosed herein.DETAILED DESCRIPTION

[0012] The disclosed system and method may be understood more readily by reference to the following detailed description of particular embodiments and the examples included therein and to the Figures and their previous and following description.

[0013] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

[0014] As used herein the singular forms “a,” ”an.‘‘ and Nhe” can optionally include plural referents unless the context clearly dictates otherwise. For example, unless the context dictates otherwise, use of the term “a strut” can represent disclosure of embodiments in w hich only a single such strut is provided, as w ell as embodiments in which a plurality of such struts are provided, and so forth.Attorney Docket No. 38357.0004P1

[0015] “Optional” or “optionally” means that the subsequently described event, circumstance, or material may or may not occur or be present, and that the description includes instances where the event, circumstance, or material occurs or is present and instances where it does not occur or is not present.

[0016] Ranges may be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, also specifically contemplated and considered disclosed is the range from the one particular value and / or to the other particular value unless the context specifically indicates otherwise. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another, specifically contemplated embodiment that should be considered disclosed unless the context specifically indicates otherwise. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint unless the context specifically indicates otherwise. Finally, it should be understood that all of the individual values and subranges of values contained within an explicitly disclosed range are also specifically contemplated and should be considered disclosed unless the context specifically indicates otherwise. The foregoing applies regardless of whether in particular cases some or all of these embodiments are explicitly disclosed.

[0017] Optionally, in some aspects, when values or characteristics are approximated by use of the antecedents “about,” “substantially,” or “generally,” it is contemplated that values within up to 15%, up to 10%, up to 5%, or up to 1% (above or below) of the particularly stated value or characteristic can be included within the scope of those aspects.

[0018] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed apparatus, system, and method belong. Although any apparatus, systems, and methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present apparatus, system, and method, the particularly useful methods, devices, systems, and materials are as described.

[0019] Throughout the description and claims of this specification, the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps. In particular, in methods stated as comprising one or more steps or operations it isAttorney Docket No. 38357.0004P1specifically contemplated that each step comprises what is listed (unless that step includes a limiting term such as "consisting of’), meaning that each step is not intended to exclude, for example, other additives, components, integers or steps that are not listed in the step.

[0020] Disclosed herein, and with reference to FIGS. 1-3. is a system 10 comprising a magnetic resonance imaging (MRI) device 20, an MRI-compatible exercise ergometer 30, and a lower body negative pressure (LBNP) suit 40. Referring to FIGS. 2-3, the LBNP suit 40 can comprise a garment 42 defining a pair of pant legs 44 configured to receive legs of a patient. In some aspects, the pant legs 44 can be configured to cover at least an upper portion of each thigh of the patient. In further aspects, the pant legs 44 can be configured to cover a majority of the thighs of the patient (e.g., extending to within 5 inches, or 4 inches, or 3 inches, or 2 inches, or 1 inch of each knee of the patient). Thus, in some aspects, the pant legs 44 can be sized such that the garment 42 functions as shorts. In other aspects, the pant legs 44 can be configured to extend below the knees of the patient. For example, the pant legs 44 can be configured to extend at least 1 inch or at least 2 inches or at least 3 inches or at least 4 inches or at least 5 inches below the knee. In additional aspects, the pant legs 44 can be configured to cover at least half of a calf or lower leg of the patient. Optionally, the pant legs 44 can be sized to serve as substantially full-length pant legs that substantially cover the entire leg of the patient. The LBNP suit 40 can further comprise a negative pressure port 46. The garment 42 can be configured to, when connected to a vacuum source in communication with (optionally, at) the negative pressure port 46, form a sufficient seal with the patient to establish a pressure differential between an interior of the garment and an exterior of the garment. This pressure differential can cause the LBNP suit 40 to apply a pressure against the lower body of the patient. The garment 42 can be configured to simulate upright posture during exercise cMRI. In this way, cMRI data can more accurately reflect certain health metrics of the patient.

[0021] The LBNP suit 40 can further comprise the vacuum source. For example, the vacuum source can be a pump. In some aspects, the vacuum source can be configured to maintain the pressure differential at a predetermined pressure (e.g., from about -20 mmHg to about -50 mmHg, or about -35 mmHg, or about -40 mmHg, or from -35 to -45 mmHg).

[0022] The LBNP suit 40 can further comprise a support structure 50. The support structure 50 can prevent collapse of the garment 42 when negative pressure is applied. In this way, negative pressure can be effectively and uniformly applied to desired areas of the patient. In some aspects, the support structure 50 can be positioned exterior to the garment 42. TheAttorney Docket No. 38357.0004P1support structure 50 can be, for example, an exoskeleton. In this way, the garment 42, rather than the support structure 50 can be in contact with the patient, thereby applying a more uniform pressure to the patient. Accordingly, the support structure can 50 be formed from materials of sufficient rigidity to resist deformation when negative pressure is applied to the suit.

[0023] In some aspects, the support structure 50 of the LBNP suit 40 can comprise at least one ring (optionally, a first plurality of rings 52a) surrounding a first leg 44a of the pair of pant legs 44 and at least one ring (optionally, a second plurality of rings 52b) surrounding a second leg 44b of the pair of pant legs. In one embodiment, each ring can comprise a plastic structure, such as, for example and without limitation, cross-linked polyethylene (PEX) tubing (e.g., ! inch diameter PEX tubing). For example, the tubing can be received within fabric folds that are sewn to an outer surface of the garment 42. In other aspects, each ring can be 3D printed. It is contemplated that the use of 3D-printed ring structures can allow for use of larger, more durable rings that are less susceptible to collapse under negative pressure. The support structure 50 of the LBNP suit can further comprise one or a plurality of axial struts 54 extending between adjacent rings 52 of the first plurality of rings 52a. Similarly, one or a plurality of axial struts 54 can extend between adjacent rings 52 of the second plurality of rings 52. Optionally, a pair of adjacent rings 52 of the first plurality of rings 52a can be free of an axial strut extending therebetween. In this way, the pair of adjacent rings can be configured to permit flexion of the LBNP suit at a joint of the patient. For example, uncoupled rings can be positioned on the garment 42 where the patient’s knees, hips, and / or ankles are to be received.

[0024] The garment 42 of the LBNP suit 40 can further comprise a waist portion 48 that is configured to receive at least a portion of a torso of the patient. The pair of pant legs 44 can couple to the waist portion 48. In some aspects, for example, the waist portion 48 can be configured to extend at least 6 inches, at least 12 inches, or at least 18 inches above the medial crest of the patient. The LBNP suit can further comprise at least one ring 56 surrounding the waist portion 48. For example, optionally, the LBNP suit can comprise a plurality of rings 56 surrounding the waist portion 48. Optionally, one or more struts 54 can extend between adjacent rings 56. In one embodiment, the ring(s) 56 can comprise crosslinked polyethylene (PEX) tubing (e.g., 3 / 8 inch diameter PEX tubing). For example, the tubing can be received within fabric folds that are sewn to an outer surface of the garment 42.Attorney Docket No. 38357.0004P1

[0025] More generally, the support structure 50 can comprise a plurality of members that support the garment 42. For example, the support structure 50 can comprise a lattice formed from straight and / or curved members. In further aspects, the support structure can comprise a plurality of lattices, wherein each lattice is configured to support a portion of the body of the patient between joints. For example, a first lattice can support the garment 42 around a first thigh, and a second lattice can support the garment 42 around a second thigh. In further aspects, a third lattice can support the garment 42 above the waist of the patient. The first, second, and third lattices can be hingedly coupled or coupled only by mutual attachment to the garment 42. In some aspects, fourth and fifth lattices can be configured to support the garment 42 below the knees of the patient. In some aspects, the support structure 50 can be 3D printed or can comprise 3D-printed components. It is contemplated that the use of 3D-printed members or lattices to form the support structure can allow for use of larger, more durable structures that are less susceptible to collapse under negative pressure. Accordingly, the LBNP suit 40 can be formed from MRI-compatible materials. For example, the LBNP suit 40 can be free of magnetic metal. Optionally, the LBNP suit 40 can be free of metal. For example, the LBNP suit 40 can comprise the garment 42 and the support structure 50 (e g., exoskeleton) coupled to the garment 42 by textile (e.g., cloth) stitched to the garment and surrounding at least a portion of the support structure 50.

[0026] In some aspects, the LBNP 40 suit can comprise an upper seal that is configured to seal the garment 42 above the waist of the patient. For example, the upper seal can be configured to seal against the torso of the patient. The seal can comprise, for example, at least one strap that is configured to compress the garment against the patient. In some aspects, the seal can comprise elastic that is configured to stretch to receive a patient within the garment. The seal can further comprise a material that is configured to contact skin of the patient to inhibit passage of air therebetween. Optionally, a separate garment, such as a neoprene shirt or waistbelt can be worn by the patient, and the separate garment can form a seal between the LBNP suit and the patient. The LBNP suit can comprise a closure or fastening system that is configured to tighten the LBNP suit against the patient after the patient is positioned within the suit. The fastening system can include, for example, a zipper, hook-and-loop fastener, elastic bands, a strap and buckle, combinations thereof, or other conventional securing means. In some aspects, the fastening system can comprise a first closure that is configured to tighten the LBNP suit 40 against a torso of the patient. The first closure can comprise a zipper, hook and loop material, combinations thereof, or the like. TheAttorney Docket No. 38357.0004P1first closure (or a plurality of first closures) can be positioned on the front of the suit, the rear of the suit, or on one or both sides of the suit. In additional, optional aspects, the LBNP suit 40 can comprise a respective closure at a lower end of each pant leg 44. Optionally, in some aspects, the LBNP suit 40 can comprise foot portions that are configured to surround feet of the user. In some aspects, the foot portions and the pant legs can be integrally formed. In other aspects, the garment 42 can comprise leg cuffs that are configured to seal against legs of the patient. The seal can comprise elastic and / or at least one strap that is configured to compress the garment against the patient. In further aspects, the seal of each pant leg can further comprise a material that is configured to contact skin of the patient, or a garment worn by the patient (e.g., a neoprene sock) to inhibit passage of air therebetween. In some aspects, the LBNP suit 40 does not include foot portions, and the feet of the patient are not enclosed.

[0027] In some aspects, the MRI-compatible exercise ergometer 30 can comprise at least one platform 32 that is axially movable (e.g., along a stage 34). The MRI-compatible exercise ergometer 30 can be configured to apply a resistance to axial movement of the at least one platform 32. For example, the at least one platform 32 can comprise a pair of platforms, wherein each platform is configured to contact a respective foot of a patient. Accordingly, the MRI-compatible exercise ergometer 30 can be configured to permit the patient to move her feet independently (e.g., in a stepping motion). In additional or alternative aspects, the MRI-compatible exercise ergometer can comprise pedals that permit the patient to perform a cycling-motion. Optionally, the MRI-compatible exercise ergometer 30 can be a commercially-available ergometer, such as those provided by ERGOSPECT of Innsbruck, Austria.

[0028] A method can comprise collecting cardiac MRI data from a patient at least partially disposed within an MRI device 20 and wearing a lower body negative pressure suit 40. In these aspects, collecting cardiac MRI data can comprise initiating operation of the MRI device to generate the cardiac MRI data; and receiving, by a computing device 1001 (FIG. 5), the cardiac MRI data generated by the MRI device. The cardiac MRI data can be collected while the patient is operating an MRI-compatible exercise ergometer 30.

[0029] It will be understood by those of ordinary skill in the art that the length of the lower-body negative pressure (LBNP) pants described herein may be readily modified (e.g., adjusting from lengths associated with long pants to lengths associated with shorts) without departing from the scope of the present disclosure. Such modifications do not require undue experimentation because the principles governing the functionality of the LBNP pants remainAttorney Docket No. 38357.0004P1consistent regardless of length adjustments. In particular, the practitioner need only adjust the longitudinal dimension of the pant legs to achieve the desired coverage of the patient's lower extremities. In doing so, the practitioner can ensure that the distal cuff or sealing interface is appropriately positioned and dimensioned to maintain an airtight seal. The determination of an effective seal is well within the routine skill set of those in the field, as it involves standard measurement and fitting techniques commonly employed in the design and manufacture of pressure garments.

[0030] One of ordinary skill in the art will further appreciate that the overall size of the LBNP pants may be varied to accommodate patients of differing body sizes, including pediatric patients, small adults, and larger adults. Such modifications may include, but are not limited to, adjustments in waist circumference, thigh and calf diameters, and overall garment length. These variations are considered routine and may be implemented using conventional garment-sizing methodologies without undue experimentation. The underlying principles of operation, namely the creation and maintenance of a negative pressure environment around the lower body, remain unaffected by such dimensional changes provided that the sealing interfaces are properly adapted to the modified garment dimensions.

[0031] The ability to modify these dimensions without departing from the inventive concept is a matter of routine design choice and does not require inventive skill. The selection of appropriate lengths and circumferences is considered a predictable result based on well-established garment fitting practices. Furthermore, the dimensions of the pants are not critical to the operability of the invention, provided that the pants substantially enclose the low er body and maintain a seal sufficient to sustain the desired negative pressure. Accordingly, variations in length, width, and overall size are expressly contemplated and fall within the scope of the present disclosure.

[0032] It is also contemplated that equivalent or otherwise suitable materials, sealing mechanisms, and fastening systems may be employed to achieve the same functional result. For example, the cuff may be constructed from any flexible, resilient material capable of forming an airtight seal against the skin, and the fastening system may include zippers, hook-and-loop fasteners, elastic bands, or other conventional securing means. The selection of such materials and mechanisms is considered routine and does not require undue experimentation because these alternatives are well known in the art and provide predictable results.Attorney Docket No. 38357.0004P1

[0033] In view of the foregoing, the embodiments described herein encompass LBNP suit having pant legs 44 of varying lengths, widths, and overall sizes, as well as equivalent sealing and fastening configurations. The present disclosure should not be construed as limited to any particular length, size, or material except as expressly recited in the appended claims. All such modifications and variations are intended to be included within the scope of the invention as defined by the claims.Computing System

[0034] FIG. 5 shows an exemplary' computing system 1000 that can be configured to control operation of various aspects of the system 10, such as, for example, operation of the MRI, data collection therefrom, and data analysis.

[0035] Computing system 1000 can include a computing device 1001 (or a plurality' of computing devices) and a display 1011 in electronic communication with the computing device, which can be any’ conventional computing device, such as, for example and without limitation, a personal computer, computing station (e.g., workstation), portable computer (e.g., laptop, mobile phone, tablet device), smart device (e.g., smartphone, smart watch, activity tracker, smart apparel, smart accessory ), security and / or monitoring device, a server, a router, a network computer, a peer device, edge device or other common network node, and so on. In some optional embodiments, a smart phone, tablet, or computer (i.e., a laptop or desktop computer) can comprise both the computing device 1001 and the display 1011. Alternatively, it is contemplated that the display 1011 can be provided as a separate component from the computing device 1001. For example, it is contemplated that the display 1011 can be in wireless communication with the computing device 1001. thereby allowing usage of the display 1011 in a manner consistent with that of the display of the smartphone as disclosed herein. In various aspects, the computing system 1000 can comprise a single computing device 1001 or a plurality' of computing devices 1001 that cooperate to perform the various processes disclosed herein.

[0036] The computing device 1001 may comprise one or more processors 1003, a system memory 1012, and a bus 1013 that couples various components of the computing device 1001 including the one or more processors 1003 to the system memory 1012. In the case of multiple processors 1003, the computing device 1001 may utilize parallel computing.Attorney Docket No. 38357.0004P1

[0037] The bus 1013 may comprise one or more of several possible ty pes of bus structures, such as a memory bus. memory controller, a peripheral bus, an accelerated graphics port, and a processor or local bus using any of a variety of bus architectures.

[0038] The computing device 1001 may operate on and / or comprise a variety’ of computer readable media (e g., non-transitory). Computer readable media may be any available media that is accessible by the computing device 1001 and comprises, non-transitory, volatile and / or non-volatile media, removable and non-removable media. The system memory' 1012 has computer readable media in the form of volatile memory, such as random access memory (RAM), and / or non-volatile memory’, such as read only memory (ROM). The system memory 1012 may’ store data such as MRI data 1007 and / or program modules such as operating system 1005 and MRI control software 1006 that are accessible to and / or are operated on by the one or more processors 1003.

[0039] The computing device 1001 may also comprise other removable / non-removable, volatile / non-volatile computer storage media. A mass storage device 1004 may provide nonvolatile storage of computer code, computer readable instructions, data structures, program modules, and other data for the computing device 1001. The mass storage device 1004 may be a hard disk, a removable magnetic disk, a removable optical disk, magnetic cassettes or other magnetic storage devices, flash memory cards, CD-ROM, digital versatile disks (DVD) or other optical storage, random access memories (RAM), read only memories (ROM), electrically^ erasable programmable read-only memory' (EEPROM), and the like.

[0040] Any number of program modules may be stored on the mass storage device 1004. An operating system 1005 and the MRI control software 1006 may be stored on the mass storage device 1004. One or more of the operating system 1005 and the MRI control software 1006 (or some combination thereof) may comprise program modules and the MRI control software 1006. The MRI data 1007 may also be stored on the mass storage device 1004. The MRI data 1007 may be stored in any of one or more databases known in the art. The databases may be centralized or distributed across multiple locations within the network 1015.

[0041] A user may enter commands and information into the computing device 1001 via an input device (not shown). Such input devices comprise, but are not limited to, a keyboard, pointing device (e.g., a computer mouse, remote control), a microphone, a joystick, a scanner, tactile input devices such as gloves, and other body coverings, motion sensor, and the like These and other input devices may be connected to the one or more processors 1003 via aAttorney Docket No. 38357.0004P1human machine interface 1002 that is coupled to the bus 1013, but may be connected by other interface and bus structures, such as a parallel port, game port, an IEEE 1394 Port (also known as a Firewire port), a serial port, network adapter 1008, and / or a universal serial bus (USB).

[0042] A display 1011 may also be connected to the bus 1013 via an interface, such as a display adapter 1009. It is contemplated that the computing device 1001 may have more than one display adapter 1009 and the computing device 1001 may have more than one display 1011. A display 1011 may be a monitor, an LCD (Liquid Crystal Display), light emitting diode (LED) display, television, smart lens, smart glass, and / or a projector. In addition to the display 1011, other output peripheral devices may comprise components such as speakers (not shown) and a printer (not shown) which may be connected to the computing device 1001 via Input / Output Interface 1010. Any step and / or result of the methods may be output (or caused to be output) in any form to an output device. Such output may be any form of visual representation, including, but not limited to, textual, graphical, animation, audio, tactile, and the like. The display 1011 and computing device 1001 may be part of one device, or separate devices.

[0043] The computing device 1001 may operate in a netw orked environment using logical connections to one or more remote computing devices 1014a.b,c. A remote computing device 1014a, b,c may be a personal computer, computing station (e.g., workstation), portable computer (e g., laptop, mobile phone, tablet device), smart device (e g., smartphone, smart watch, activity tracker, smart apparel, smart accessory), security and / or monitoring device, a server, a router, a network computer, a peer device, edge device or other common netw ork node, and so on. Logical connections between the computing device 1001 and a remote computing device 1014a,b,c may be made via anetwork 1015, such as a local area network (LAN) and / or a general wide area network (WAN). Such netw ork connections may be through a network adapter 1008. A network adapter 1008 may be implemented in both wired and wireless environments. Such networking environments are conventional and commonplace in dwellings, offices, enterprise-wide computer networks, intranets, and the Internet. In further exemplary aspects, it is contemplated that the computing device 1001 can be in communication with the remote computing devices 1014a,b,c through a Cloud-based network.

[0044] Application programs and other executable program components such as the operating system 1005 are shown herein as discrete blocks, although it is recognized that suchAttorney Docket No. 38357.0004P1programs and components may reside at various times in different storage components of the computing device 1001, and are executed by the one or more processors 1003 of the computing device 1001. An implementation of the MRI control software 1006 may be stored on or sent across some form of computer readable media. Any of the disclosed methods may be performed by processor-executable instructions embodied on computer readable media.

[0045] The following paragraphs describe non-limiting examples of various aspects of the disclosure.Example 1: Exercise cardiac magnetic resonance imaging with lower body negative pressure: First in-man proof-of-concept study

[0046] Background: Exercise cardiac magnetic resonance imaging (cMRI) offers several major advantages, including improved spatial resolution in the absence of ionizing radiation. However, exercise cMRI is limited by the physical constraints of the scanner itself, forcing subjects to exercise while laying supine. Such postural positioning causes a major hemodynamic shift toward the central circulation, minimizing the overall cardiac response to exercise.

[0047] Objective: Simulate upright posture during exercise cMRI.

[0048] Methods: Lower body negative pressure (LBNP) pants were constructed to simulate normal orthostatic stress caused by gravity during upright posture while allowing for dynamic leg motion during exercise. Exercise cMRI was performed using an MR compatible ergometer with and without LBNP (targeting -35 mmHg). Volumetric data were measured from a stack of short axis cine images spanning the left ventricle.

[0049] Results: In the absence of LBNP, only modest changes in left ventricular end-diastolic volume (EDV) and end-systolic volume (ESV) were observed, contributing to a 9+14 rnL / m2increase in stroke index with exercise. With LBNP at rest, EDV and ESV decreased by 18+22 mL / m2and 7+9 mL / m2, respectively. Exercise-LBNP returned EDV close to baseline values (88+14 vs. 87+13 ml / m2, p = 0.575), while ESV continued to decrease with exercise, resulting in a 18+13 mL / m2increase in stroke index.

[0050] Conclusions: These first in-man proof-of-concept data highlight the exercise cMRI hemodynamic response during simulated upright posture. That the dynamic range for stroke volume was doubled under orthostatic stress emphasizes the importance of performing exercise cMRI under conditions that best simulate normal activities of daily living.Attorney Docket No. 38357.0004P1

[0051] Introduction Exercise cardiac magnetic resonance imaging (cMRI) offers several major advantages over contemporary stress imaging approaches, including improved spatial resolution in the absence of ionizing radiation. A major limitation of exercise cMRI however, is the physical constraint of the scanner itself, forcing subjects to exercise while laying supine. Not only is this body position incongruent with typical activity patterns of daily living, but being supine causes a major hemodynamic shift toward the central circulation, minimizing the overall cardiac response to exercise. Indeed, results from several published exercise cMRI studies over the past decade show minimal changes in left ventricular end-diastolic volume (LVEDV), and only modest reductions in end-systolic volume (LVESV), regardless of age, fitness or cardiovascular disease status.1'10

[0052] To overcome this limitation, we constructed lower body negative pressure (LBNP) pants, based on the mobile LBNP suit for spaceflight,11to simulate normal orthostatic stress caused by gravity in the upright posture, while allowing for dynamic leg motion during exercise within the MRI bore. We hypothesized that exercise cMRI with LBNP would augment the dynamic range of cardiac hemodynamics during exercise.

[0053] Methods

[0054] Healthy volunteers were recruited from the local university campus. Ethical approval was obtained from the University of Texas Southwestern Medical Center Institutional Review Ethics Board. All participants provided informed written consent prior to participating in study procedures.

[0055] MRI-compatible LBNP Pants

[0056] Briefly, commercially available chest waders (White River Fly Shop, Riseform Chest Waders) comprised of waterproof and airtight fabric formed the foundation of the pants (FIG. 2). To ensure appropriate sealing and maintenance of negative pressure, a neoprene kayak skirt (Seals Sprayskirts, Pro Shocker Kayak Spray Skirt) was sewn to the waist of the chest waders at a level above the iliac crest. To prevent the collapse of the fabric during LBNP, an exoskeleton was created from uniformly spaced rings of PEX tubing sewn to the outside of the waders; consisting of doubled 1 / 4-inch PEX tubing rings from the inguinal fold to the ankles, and 3 / 8-inch PEX tubing rings from the inguinal fold to just below the iliac crest. To prevent axial collapse, vertical stabilizers of PEX tubing w ere added in all areas except those experiencing dynamic motion (i.e. knee and hip joints). A PVC inlet port was fitted to the umbilical region of the pants to allow for connection of a vacuum hose, with theAttorney Docket No. 38357.0004P1vacuum itself housed outside of the MRI room, attached to the vacuum hose through a wave guide. Vacuum power was regulated using a variable transformer (Vevor, 2KVA Transformer 20 Amp).

[0057] Cardiac MRI

[0058] Cardiac MRI was performed using a 3T MRI (Philips Achieva). with a six-channel cardiac transmit-receive surface coil for signal detection. Images were gated using a pulse oximeter, during an end-expiratory pause (~2 sec). Each stage included a short-axis stack of balanced steady-state free precession cine images, covering the entire heart from base to apex. Typical parameters include: a spatial resolution of 1.5x1.5 mm in-plane and 10 mm through-plane, flip angle 40°, repetition time 3.0 ms, and echo time 1.5 ms with 25 cardiac phases at rest and ~22 cardiac phases during exercise.

[0059] Imaging was performed at rest and during exercise at 30W and 60 W, using an MRI compatible exercise ergometer (Ergospect, Innsbruck, Austria), while wearing the MRI-compatible LBNP pants. Rest and exercise images were acquired first without LBNP and then repeated after an approximate five-minute break with LBNP (targeting -35 mmHg; as measured by digital manometer). Each stage of the imaging protocol took approximately five minutes to complete.

[0060] Left ventricular end-diastolic and end-systolic volume were measured using commercially available software (CVI42, v5.13.5, Circle Cardiovascular Imaging). Briefly, the endocardial borders of the LV were manually delineated at end-diastole (end-diastolic volume, EDV) and end-systole (end-systolic volume, ESV), respectively. Stroke volume, ejection fraction and cardiac output were then calculated according to standard equations, and all hemodynamic variables were indexed to body surface area.

[0061] Statistical analysis

[0062] Data were analyzed using SPSS v29.0. To evaluate the effect of LBNP on cardiac hemodynamics with exercise, a two-way repeated measures ANOVA was performed, with pairwise comparisons of estimated marginal means comparing conditions (LBNP vs. no LBNP). Values are reported as mean ± standard deviation (unless otherwise reported), with a p-value of < 0.05 considered statistically significant.

[0063] ResultsAttorney Docket No. 38357.0004P1

[0064] Nine healthy male participants (age 27+9 years, height 183+6 cm, weight 92+13 kg) completed the current proof-of-concept study. All performed regular recreational exercise, were not taking any cardiovascular medications, nor had any history of heart disease.

[0065] As illustrated in Figure 4 — and consistent with prior investigations — in the absence of LBNP, only modest changes in EDV and ESV were observed, contributing to a 9+14 mL / m2increase in stroke index with exercise.

[0066] Exercise cMRI-LBNP was successfully completed in all participants without incident, reaching 94% of the target LBNP (-33+6 mmHg). With LBNP at rest, EDV and ESV decreased by 18+22 mL / m2and 7+9 mL / m2, respectively. Exercise-LBNP restored EDV to baseline values (88+14 vs. 87+13 ml / m2, p = 0.575), while ESV continued to decrease with exercise, resulting in a 18+13 mL / m2increase in stroke index (doubling the hemodynamic response to exercise).

[0067] Discussion

[0068] Herein, we show the first in-man proof-of-concept of the exercise cMRI hemodynamic response during LBNP using novel MRI-compatible LBNP pants. The major novel findings are threefold: (1) whereas exercise MRI without LBNP shows little-to-no change in LVEDV, LBNP facilitates the physiologic response expected during upright exercise, (2) the healthy heart compensates for the aforementioned reduction in cardiac preload during LBNP by reducing LVESV at rest, along with further reductions with exercise (broadening end-systolic reserve), and (3) exercise LBNP doubles the dynamic range of stroke volume.

[0069] As highlighted in FIG. 4. exercise cMRI rarely elicits a change in LVEDV from baseline. This is opposite of what is expected during upright exercise, where gravity causes a reduction in preload that is countered by the skeletal muscle pump and respiratory pump during dynamic exercise. Indeed, the data herein, confirm and extend this observation, highlighting minimal changes in LVEDV when LBNP was not applied, while eliciting a marked decline in LVEDV when upright posture was simulated with LBNP (that was reversed during dynamic exercise). We interpret the lack of change in LVEDV without LBNP to reflect a near maximal loading of the central circulation during the initial transition from upright to supine (i.e. laying on the exam table). Mimicking the hemodynamic response to upright posture therefore provides additional insight not currently appreciated with conventional exercise cMRI approaches. Indeed, the magnitude of change in cardiac preloadAttorney Docket No. 38357.0004P1with LBNP may itself serve as an additional pathophysiologic end-point,12’13with changes in cardiac preload contributing significantly to the overall stroke volume response during exercise.

[0070] Multiple prior reports, across a wide range of individuals, support a reduction in LVESV during exercise cMRI (FIG. 4). The present results confirm and extend these reports, showing a measurable reduction in LVESV with exercise without LBNP, but eliciting a greater compensatory' LVESV response with LBNP, not readily achieved through conventional approaches. Indeed, LVESV was reduced with LBNP at rest in the healthy young subjects studied herein, and further reduced during exercise with LBNP. Failure to mount either of these compensatory responses would impair stroke volume reserve. Including LBNP should therefore help to differentiate between health and disease (establishing greater precision for detecting pathophysiologic differences within and between individuals).

[0071] Strengths and Limitations

[0072] A major strength of this investigation is the use of novel MRI-compatible LBNP pants that allowed for dynamic exercise to be completed inside the bore of the MRI, while simulating normal upright exercise. Moreover, the exercise workloads performed herein were specifically chosen to simulate the metabolic cost associated with common activities of daily living. In this example, LBNP was performed at a pressure of -35 mmHg. An LBNP of -40 mmHg is indeed typically cited as the pressure needed to recapitulate the orthostatic stress associated with upright posture.14We therefore cannot extrapolate the hemodynamic response to higher pressures, nor do we know the response to lower pressures. Future studies can be performed to define the hemodynamic response across multiple negative pressures. In this example, only male participants were included, mainly due to the size requirements of the MRI-compatible LBNP pants constructed. While sex is unexpected to play a significant role in the present results, inclusion of female participants in future studies is warranted. Lastly, this study was designed to provide the first in-man proof-of-concept data in support of exercise cMRI LBNP. With these proof-of-concept data now in place, future studies are needed to assess whether this approach better differentiates between health and disease.

[0073] Conclusion

[0074] Taken together, the data herein provide the first in-man proof-of-concept data highlighting the exercise cMRI hemodynamic response during simulated upright posture. That the dynamic range for stroke volume was doubled under orthostatic stress, highlights theAttorney Docket No. 38357.0004P1importance of performing exercise cMRI under conditions that best simulate normal activities of daily living. More work is needed to extend these early results to clinical populations. ReferencesThe following references are incorporated by reference herein in their respective entireties: 1. Claessen G, Schnell F, Bogaert J. el al . Exercise cardiac magnetic resonance to differentiate athlete's heart from structural heart disease. Eur Heart J Cardiovasc Imaging.2018; 19(9): 1062-1070. doi: 10.1093 / ehjci / jey0502. Santens B, Van De Bruaene A, De Meester P, et al. Decreased cardiac reserve in asymptomatic patients after arterial switch operation for transposition of the great arteries. Int J Cardiol. 2023;388:131153. doi: 10.1016 / j.ijcard.2023.1311533. Kirkham AA, Haykowsky MJ, Beaudry RI, et al. Cardiac and skeletal muscle predictors of impaired cardiorespiratory fitness post-anthracycline chemotherapy for breast cancer. Sci Rep. 2021;ll(l):14005. Published 2021 Jul 7. doi:10.1038 / s41598-021-93241-54. Claessen G, La Gerche A, Van De Bruaene A, et al. Heart Rate Reserve in Fontan Patients:Chronotropic Incompetence or Hemodynamic Limitation?. J Am Heart Assoc.2019 8(9):e012008. doi: 10.1161 / JAHA.119.0120085. Claeys M, Petit T, Bogaert J, et al. Dynamic aspects of ventricular interaction during exercise in HFpEF and in pre-capillary pulmonary hypertension. ESC Heart Fail.2023: 10(l):650-660. doi: 10.1002 / ehf2.142166. Gorecka M, Craven TP, Jex N, et al. Mitral regurgitation assessment by cardiovascular magnetic resonance imaging during continuous in-scanner exercise: a feasibility study. Int J Cardiovasc Imaging. 2024;40(7): 1543-1553. doi:10.1007 / sl0554-024-03141-87. Chew PG, Swoboda PP, Ferguson C, et al. Feasibility and reproducibility of a cardiovascular magnetic resonance free-breathing, multi-shot, navigated image acquisition technique for ventricular volume quantification during continuous exercise. Quant Imaging MedSurg. 2020;10(9):1837-1851. doi: 10.21037 / qims-20-l 178. Jaijee S, Quinlan M, Tokarczuk P, et al. Exercise cardiac MRI unmasks right ventricular dysfunction in acute hypoxia and chronic pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol. 2018;315(4):H950-H957. doi:10.1152 / ajpheart.00146.20189. Santens B, Helsen F, Van De Bruaene A, et al. Adverse functional remodelling of the subpulmonary left ventricle in patients with a systemic right ventricle is associated with clinical outcome. Eur Heart J Cardiovasc Imaging. 2022;23(5):680-688. doi : 10.1093 / ehj ci / j eab086Attorney Docket No. 38357.0004P110. Craven TP, Jex N, Chew PG, et al. Exercise cardiovascular magnetic resonance: feasibility and development of biventricular function and great vessel flow assessment, during continuous exercise accelerated by Compressed SENSE: preliminary results in healthy volunteers. Int J Cardiovasc Imaging. 2021;37(2):685-698. doi: 10.1007 / sl0554-020- 02044-811. Ashari N, Hargens AR. The Mobile Lower Body Negative Pressure Gravity Suit for Long- Duration Spaceflight. Front Physiol. 2020:11:977. Published 2020 Aug 5. doi: 10.3389 / fphys.2020.0097712. John JM, Haykowsky M, Brubaker P, Stewart K, Kitzman DW. Decreased left ventricular distensibility in response to postural change in older patients with heart failure and preserved ejection fraction. Am J Physiol Heart Circ Physiol. 2010;299(3):H883-H889. doi: 10.1152 / ajpheart.00332.201013. Arbab-Zadeh A, Dijk E, Prasad A, et al. Effect of aging and physical activity on left ventricular compliance. CzrcMto / on.2004;110(13):1799-1805. doi: 10.1161 / OLCIR.0000142863.71285. 7414. Goswami N, Blaber AP, Hinghofer-Szalkay H, Convertino VA. Lower Body Negative Pressure: Physiological Effects, Applications, and Implementation. Physiol Rev.2019;99(l):807-851. doi:10.1152 / physrev.00006.2018EXEMPLARY ASPECTS

[0075] In view of the described products, systems, and methods and variations thereof, herein below are described certain more particularly described aspects of the invention. These particularly recited aspects should not however be interpreted to have any limiting effect on any different claims containing different or more general teachings described herein, or that the ■■particular” aspects are somehow limited in some way other than the inherent meanings of the language literally used therein.

[0076] Aspect 1: A system comprising:a magnetic resonance imaging (MRI) device;an MRI-compatible exercise ergometer; anda lower body negative pressure (LBNP) suit.

[0077] Aspect 2: The system of aspect 1, wherein the LBNP suit comprises:a garment defining a pair of pant legs configured to receive legs of a patient; and a negative pressure port;Attorney Docket No. 38357.0004P1wherein the garment is configured to, when connected to a vacuum source in communication with (e.g., at) the negative pressure port, form a sufficient seal with the patient to establish a pressure differential between an interior of the garment and an exterior of the garment.

[0078] Aspect 3: The system of aspect 2, wherein the LBNP suit further comprises the vacuum source.

[0079] Aspect 4: The system of aspect 2, wherein the LBNP suit further comprises a support structure positioned exterior to the garment.

[0080] Aspect 5: The system of aspect 4, wherein the support structure of the LBNP suit comprises a first plurality of rings surrounding a first leg of the pair of pant legs and a second plurality of rings surrounding a second leg of the pair of pant legs.

[0081] Aspect 6: The system of aspect 5, wherein the support structure of the LBNP suit further comprises a plurality of axial struts extending between adjacent rings of the first plurality of rings.

[0082] Aspect 7: The system of aspect 6, further comprising a pair of adjacent rings of the first plurality of rings that are free of an axial stmt extending therebetween, wherein said pair of adjacent rings are configured to permit flexion of the LBNP suit at a joint of the patient.

[0083] Aspect 8: The system of any one of aspects 2-7, wherein the garment of the LBNP suit further comprises a waist portion that is configured to receive at least a portion of a torso of the patient, wherein the pair of pant legs couple to the waist portion, wherein the LBNP suit further comprises at least one ring surrounding the waist portion.

[0084] Aspect 9: The system of any one of the preceding aspects, wherein the MRI-compatible exercise ergometer comprises at least one platform that is axially movable, wherein the MRI-compatible exercise ergometer is configured to apply a resistance to axial movement of the at least one platform.

[0085] Aspect 10: The system of aspect 9. wherein the at least one platform comprises a pair of platforms, wherein each platform is configured to contact a respective foot of a patient.

[0086] Aspect IL A method comprising:collecting cardiac MRI data from a patient at least partially disposed within an MRI device and wearing a lower body negative pressure suit.

[0087] Aspect 12: The method of aspect 11, wherein collecting cardiac MRI data comprises:Attorney Docket No. 38357.0004P1initiating operation of the MRI device to generate the cardiac MRI data; and receiving, by a computing device, the cardiac MRI data generated by the MRI device.

[0088] Aspect 13: The method of aspect 11, wherein the LBNP suit comprises:a garment defining a pair of pant legs configured to receive legs of a patient; and a negative pressure port;wherein upon applying vacuum through the negative pressure port, the garment forms a sufficient seal with the patient to establish a pressure differential between an interior of the garment and an exterior of the garment.

[0089] Aspect 14: The method of aspect 13, wherein the LBNP suit further comprises the vacuum source.

[0090] Aspect 15: The method of aspect 13, wherein the LBNP suit further comprises a support structure positioned exterior to the garment.

[0091] Aspect 16: The method of aspect 15, wherein the support structure of the LBNP suit comprises a first plurality of rings surrounding a first leg of the pair of pant legs and a second plurality of rings surrounding a second leg of the pair of pant legs.

[0092] Aspect 17: The method of aspect 16, wherein the support structure of the LBNP suit further comprises a plurality of axial struts extending between adjacent rings of the first plurality of rings.

[0093] Aspect 18: The method of aspect 17. further comprising a pair of adjacent rings of the first plurality of rings that are free of an axial strut extending therebetween, wherein said pair of adjacent rings are configured to permit flexion of the LBNP suit at a joint of the patient.

[0094] Aspect 19: The method of any one of aspects 13-17, wherein the garment of the LBNP suit further comprises a waist portion that is configured to receive at least a portion of a torso of the patient, wherein the pair of pant legs couple to the waist portion, wherein the LBNP suit further comprises at least one ring surrounding the waist portion.

[0095] Aspect 20: The system of any one of aspects 11-19, wherein the MRI-compatible exercise ergometer comprises at least one platform that is axially movable, wherein the MRI-compatible exercise ergometer is configured to apply a resistance to axial movement of the at least one platform.

[0096] Aspect 21 : The method of any one of aspects 11-20, wherein the method is performed using the system as in any one of aspects 1-10.Attorney Docket No. 38357.0004P1

[0097] Aspect 22: A lower body negative pressure (LBNP) suit that is compatible with an MRI.

[0098] Aspect 23: The LBNP suit of aspect 22, wherein the suit is free of magnetic metal.

[0099] Aspect 24: The LBNP suit of aspect 22, wherein the LBNP suit comprises:a garment defining a pair of pant legs configured to receive legs of a patient; and a negative pressure port;wherein the garment is configured to, when connected to a vacuum source in communication with the negative pressure port, form a sufficient seal with the patient to establish a pressure differential between an interior of the garment and an exterior of the garment.

[0100] Aspect 25: The LBNP suit of aspect 22, further comprising a support structure positioned exterior to the garment.

Claims

Attorney Docket No. 38357.0004P1What is claimed is:

1. A system comprising:a magnetic resonance imaging (MRI) device;an MRI-compatible exercise ergometer; anda lower body negative pressure (LBNP) suit.

2. The system of claim 1, wherein the LBNP suit comprises:a garment defining a pair of pant legs configured to receive legs of a patient; and a negative pressure port;wherein the garment is configured to, when connected to a vacuum source in communication with the negative pressure port, form a sufficient seal with the patient to establish a pressure differential between an interior of the garment and an exterior of the garment.

3. The system of claim 2. wherein the LBNP suit further comprises the vacuum source.

4. The system of claim 2, wherein the LBNP suit further comprises a support structure positioned exterior to the garment.

5. The system of claim 4. wherein the support structure of the LBNP suit comprises a first plurality of rings surrounding a first leg of the pair of pant legs and a second plurality of rings surrounding a second leg of the pair of pant legs.

6. The system of claim 5, wherein the support structure of the LBNP suit further comprises a plurality of axial struts extending between adjacent rings of the first plurality of rings.

7. The system of claim 6, further comprising a pair of adjacent rings of the first plurality' of rings that are free of an axial strut extending therebetween, wherein said pair of adjacent rings are configured to permit flexion of the LBNP suit at ajoint of the patient.

8. The system of claim 2. wherein the garment of the LBNP suit further comprises a waist portion that is configured to receive at least a portion of a torso of the patient, wherein the pair of pant legs couple to the waist portion, wherein the LBNP suit further comprises at least one ring surrounding the waist portion.

9. The system of claim 1, wherein the MRI-compatible exercise ergometer comprises at least one platform that is axially movable, wherein the MRI-compatible exercise ergometer is configured to apply a resistance to axial movement of the at least one platform.Attorney Docket No. 38357.0004P110. The system of claim 9, wherein the at least one platform comprises a pair of platforms, wherein each platform is configured to contact a respective foot of a patient.

11. A method comprising:collecting cardiac MRI data from a patient at least partially disposed within an MRI device and wearing a lower body negative pressure suit.

12. The method of claim 11, wherein collecting cardiac MRI data comprises:initiating operation of the MRI device to generate the cardiac MRI data; and receiving, by a computing device, the cardiac MRI data generated by the MRI device.

13. The method of claim 11, wherein the LBNP suit comprises:a garment defining a pair of pant legs configured to receive legs of a patient; and a negative pressure port;wherein, upon applying vacuum through the negative pressure port, the garment forms a sufficient seal with the patient to establish a pressure differential between an interior of the garment and an exterior of the garment.

14. The method of claim 13, wherein the LBNP suit further comprises the vacuum source.

15. The method of claim 13, wherein the LBNP suit further comprises a support structure positioned exterior to the garment.

16. The method of claim 15, wherein the support structure of the LBNP suit comprises a first plurality of rings surrounding a first leg of the pair of pant legs and a second plurality of rings surrounding a second leg of the pair of pant legs.

17. The method of claim 16, wherein the support structure of the LBNP suit further comprises a plurality of axial struts extending between adjacent rings of the first plurality of rings.

18. The method of claim 17, further comprising a pair of adjacent rings of the first plurality of rings that are free of an axial strut extending therebetween, wherein said pair of adjacent rings are configured to permit flexion of the LBNP suit at a joint of the patient.

19. The method of claim 13, wherein the garment of the LBNP suit further comprises a waist portion that is configured to receive at least a portion of a torso of the patient, wherein the pair of pant legs couple to the waist portion, wherein the LBNP suit further comprises at least one ring surrounding the waist portion.Attorney Docket No. 38357.0004P120. The system of claim 11, wherein the MRI-compatible exercise ergometer comprises at least one platform that is axially movable, wherein the MRI-compatible exercise ergometer is configured to apply a resistance to axial movement of the at least one platform.

21. A lower body negative pressure (LBNP) suit that is compatible with an MRI.

22. The LBNP suit of claim 21, wherein the suit is free of magnetic metal.

23. The LBNP suit of claim 21, wherein the LBNP suit comprises:a garment defining a pair of pant legs configured to receive legs of a patient; and a negative pressure port;wherein the garment is configured to, when connected to a vacuum source in communication with the negative pressure port, form a sufficient seal with the patient to establish a pressure differential between an interior of the garment and an exterior of the garment.

24. The LBNP suit of claim 21, further comprising a support structure positioned exterior to the garment.

Images