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WO2011088513A1 - Procédé de mesure du volume interstitiel dans des organes et des tissus - Google Patents

Procédé de mesure du volume interstitiel dans des organes et des tissus Download PDF

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Publication number
WO2011088513A1
WO2011088513A1 PCT/AU2011/000062 AU2011000062W WO2011088513A1 WO 2011088513 A1 WO2011088513 A1 WO 2011088513A1 AU 2011000062 W AU2011000062 W AU 2011000062W WO 2011088513 A1 WO2011088513 A1 WO 2011088513A1
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image signal
signal intensity
contrast agent
blood
organs
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James Charles Moon
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Resonance Health Analysis Services Pty Ltd
EQUILIBRIUM IMAGING Ltd
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Resonance Health Analysis Services Pty Ltd
EQUILIBRIUM IMAGING Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves
    • A61B5/055—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/41—Detecting, measuring or recording for evaluating the immune or lymphatic systems
    • A61B5/414—Evaluating particular organs or parts of the immune or lymphatic systems
    • A61B5/415—Evaluating particular organs or parts of the immune or lymphatic systems the glands, e.g. tonsils, adenoids or thymus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/41—Detecting, measuring or recording for evaluating the immune or lymphatic systems
    • A61B5/414—Evaluating particular organs or parts of the immune or lymphatic systems
    • A61B5/418—Evaluating particular organs or parts of the immune or lymphatic systems lymph vessels, ducts or nodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/48—Diagnostic techniques
    • A61B6/481—Diagnostic techniques involving the use of contrast agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
    • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
    • G01R33/5601—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording for evaluating the cardiovascular system, e.g. pulse, heart rate, blood pressure or blood flow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/42—Detecting, measuring or recording for evaluating the gastrointestinal, the endocrine or the exocrine systems
    • A61B5/4222—Evaluating particular parts, e.g. particular organs
    • A61B5/4244—Evaluating particular parts, e.g. particular organs liver
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4869—Determining body composition
    • A61B5/4875—Hydration status, fluid retention of the body
    • A61B5/4878—Evaluating oedema
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/02—Arrangements for diagnosis sequentially in different planes; Stereoscopic radiation diagnosis
    • A61B6/03—Computed tomography [CT]

Definitions

  • the present invention relates to a method for measuring an interstitial volume, such as that associated with fibrosis in organs or tissues.
  • Fibrosis is a final common endpoint in virtually all
  • cardiomyopathies and valve disease leading to heart failure and death.
  • diffuse fibrotic liver disease is the clinical result of chronic hepatitis and alcohol abuse.
  • Fibrosis may be assessed in vivo by magnetic resonance imaging (MRI) using the late gadolinium enhancement (LGE) contrast technique.
  • MRI magnetic resonance imaging
  • LGE late gadolinium enhancement
  • the fibrosis leads to an increased volume of distribution . for gadolinium and there is late enhancement of the fibrosis by MRI.
  • this technique is only
  • Embodiments of the present invention relate to a non- invasive method of measuring interstitial volume and may be used to measure a level of fibrosis in an organ, including diffuse fibrosis, amyloidosis and cell volume.
  • the present invention provides a method of measuring interstitial volume, the method
  • determining the interstitial volume by determining a volume of distribution of the contrast agent for at least the portion of the one on more organs compared to the blood using the first and second image signal intensity values.
  • the interstitial volume may be indicative of a level of amyloidosis or fibrosis, such as diffuse or focal fibrosis or oedema.
  • the step of administering to the subject an extracellular contrast agent comprises administering a bolus of a contrast agent followed by a continuous infusion of a contrast agent.
  • the continuous infusion of the contrast agent typically is conducted such that the equilibrium condition is substantially maintained during the continuous infusion of the contrast agent.
  • the continuous infusion may be an infusion that is separate to the bolus infusion.
  • the continuous infusion may be an extension of the bolus infusion.
  • the second image intensity values typically are obtained during the continuous infusion.
  • the equilibrium will be reached and typically maintained during the continuous infusion of. the contrast agent. A period of time within which the equilibrium is achieved depends on a size of the bolus, its rate of delivery, the dose rate of the
  • extracellular contrast agent may comprise administering a bolus of contrast agent (without further infusion) and imaging at the equilibrium point - the point where concentrations of contrast in tissue are at an inflection point and cease rising and start to fall.
  • the transient equilibrium point may be extended for a period of time that is sufficiently long for the obtaining second image signal intensity values, by altering the bolus injection rate and bolus profile. This alteration in bolus delivery is also designed to smooth out recirculation blood effects. Consequently, the second image signal intensity values are in this case typically obtained at transient
  • the second image signal intensity. values are typically obtained at a first maximum of a signal associated with organ tissue after
  • the step of administering to the subject an extracellular contrast typically comprises administering the contrast agent in vivo.
  • the step of determining the interstitial volume may comprise obtaining a blood sample from the subject and determining the haematocrit level.
  • the step of using the first and second image signal intensity values to determine the volume comprises calculating the volume using the following equation (or a derivative thereof) :
  • OV d (1 - haematocrit) x (OSIV2-OSIV1) / (BSIV2-BSIV1)
  • OV d is the volume of distribution of contrast agent for an organ
  • OSTV2 is an organ image signal intensity value
  • OSIV1 is an organ image signal intensity value associated with the first image signal intensity values
  • BSIVl is a blood image signal intensity value associated with the first image signal intensity values
  • BSIV2 is a blood image signal intensity value associated with the second image signal intensity values.
  • the first and second image signal intensity values for blood and one or more organs typically are derived from an image, such as from an image obtained by magnetic resonance imaging (MRI) .
  • Each image intensity value may be related to an imaging signal strength either at a region or pixel of an image or signals integrated over a region of interest or portion thereof .
  • the volume of distribution is converted to and expressed as the amount of fibrosis, amyloid or oedema (expressed as a percentage of the organ or tissue) , based on prior biopsy data in the disease in question.
  • the cell volume may be derived - the reciprocal of these percentages (1 minus percentage of fibrosis, for example)
  • the step of obtaining first and second image signal intensity values may comprise MRI.
  • the contrast agent may comprise a gadolinium chelated by an agent such as Diethylenetriaminepentaacetate (DTPA) or variants of DTPA.
  • DTPA Diethylenetriaminepentaacetate
  • the image signal intensity value may be associated with an MRI rate constant for longitudinal spin relaxation after excitation referred to as "Tl" .
  • the method typically also comprises correcting image signal intensity values or an image for fluctuations associated with the heart rate of the subject.
  • the step of obtaining first and second image signal intensity values for blood and one or more organs in a subject comprises computerised tomography.
  • the step of obtaining first and second image signal intensity values for blood and one or more organs in a subject typically comprises administering an iodine based contrast agent .
  • the present invention provides a method of diagnosing a disease, the method comprising the steps of:
  • determining an interstitial volume by determining a volume of distribution of the contrast agent for at least the portion of the one or more organs using the first and second image signal intensity values;
  • the present invention provides a method of monitoring progression of a disease, the method comprising the steps of:
  • determining an interstitial volume by determining a volume of distribution of the contrast agent for at least the portion of the one or more organs using the first and second image signal intensity values;
  • the disease is a disease associated with fibrosis or amyloidosis.
  • the method in accordance with any one of the preceding aspects may comprise analysing the volume of distribution of the contrast agent to provide information concerning a percentage of fibrosis or amyloidosis - in a specific organ and wherein providing that information comprises calibration with
  • the calibration with information obtained from human biopsies may comprise a curve fitting procedure.
  • the present invention provides a method of determining cell volume, the method comprising the steps of: obtaining first image signal intensity values for blood and at least a portion of one or more organs in a subject at an area of interest; thereafter
  • determining an interstitial volume by determining a volume of distribution of the contrast agent for at least the portion of the one or more organs using the first and second image signal intensity values;
  • the method in accordance with the fourth aspect of the present invention may comprise steps in accordance with embodiments of first, second and third aspects of the invention.
  • Figure 1 (a) shows a graph of measured Tl values for RR intervals illustrating effects of mathematical heart rate correction
  • Figure 1(b) shows a graph of volume of distribution Vd(m) as detected using cardiovascular magnetic resonance (CMR) with and without heart rate correction set out against collagen volume fraction (CVF) ;
  • Figure 2 (a) shows a schematic of a cardiovascular magnetic resonance (CMR) protocol;
  • Figure 2 (b) shows a graph illustrating a measurement of a volume of distribution Vd(m) using cardiovascular magnetic resonance (CMR) .
  • CMR cardiovascular magnetic resonance
  • Figure 3 shows a graph illustrating blood and myocardial magnetic resonance (TI) measurements after a contrast agent bolus infusion only;
  • Figure 3 (b) shows a graph illustrating blood and myocardial magnetic resonance (TI) measurements after a contrast agent bolus infusion and subsequently steady state achieved by continuous contrast agent infusion;
  • Figure 4 shows histology images for three biopsies from aortic stenosis patients illustrating the range of fibrosis present
  • Figure 5 shows a plot illustrating examples of achieved equilibrium contrasts for equilibrium MRI scanning
  • Figure 8 represents blood equilibrium contrast obtained using a bolus plus infusion of CT iodine contrast agent, in this case iodohexol ;
  • CT Computer Tomography
  • Figure 10 - 13 show graph illustrating examples of monitoring and predictin diseases (fibrosis, cell volumes and focal fibrosis quantification) using methods in accordance with embodiments of the present invention
  • Embodiments of the present invention are directed towards a method of measuring interstitial volume.
  • interstitial space refers to the space between cells in a tissue or organ. Accordingly, “interstitial volume” refers to the amount of interstitial space within a tissue or organ.
  • amyloidosis refers to an excess of amyloid proteins deposited in tissue and organs.
  • Amyloid proteins are insoluble fibrilar proteins
  • amyloidosis There are several different types of amyloidosis including Primary Amyloidosis (AL) , Secondary Amyloidosis (AA) , Familial Amyloidosis, Cutaneous Amyloidosis, Cerebral/Central Nervous System Amyloid Diseases, Heavy Light Chain Amyloidosis (AH) , Beta- 2 -Microglobulin Amyloidosis (B2M - Dialysis Related) , and Localized Amyloidosis.
  • A Primary Amyloidosis
  • AA Secondary Amyloidosis
  • Familial Amyloidosis Cutaneous Amyloidosis
  • Cerebral/Central Nervous System Amyloid Diseases Cerebral/Central Nervous System Amyloid Diseases
  • Heavy Light Chain Amyloidosis AH
  • Beta- 2 -Microglobulin Amyloidosis B2M - Dialysis Related
  • fibrosis refers to an excess or thickening of connective tissue within a tissue or organ.
  • fibrosis refers to an excess or thickening of connective tissue within a tissue or organ.
  • the immune system When cells within an organ are injured or die due to viral infection, toxins, trauma, or other factors, such as senescence, the immune system is activated and the repair process is initiated.
  • the injury or death of cells stimulates inflammatory immune cells to release cytokines, growth factors, and other chemicals. These chemical messengers direct support cells in the organ to activate and produce collagen, glycoproteins (such as
  • fibronectin a substance that is deposited in the organ and form connective tissue. At the same time, the process of breaking down or degrading collagen may be impaired. In a healthy organ, the synthesis (fibrogenesis) and breakdown . (fibrolysis) of
  • connective tissue are in balance. Accordingly, -fibrosis occurs when excessive connective tissue is synthesised faster than it can be broken down and removed from the organ.
  • Fibrosis may be defined as either “focal fibrosis” or “diffuse fibrosis”.
  • the term “focal fibrosis” refers to fibrosis that results in connective tissue build-up in a discrete area and is commonly referred to as “scarring” .
  • causes of focal fibrosis include, for example, myocardial infarction in the heart and irritants such as silica and coal dust in the lungs.
  • diffuse fibrosis refers to fibrosis that is disseminated throughout an organ or tissue.
  • Diffuse fibrosis occurs as a result of the normal aging process and may also be caused, for example, by chronic hepatitis in the liver and diabetes mellitus in the kidneys. While the methods of the some embodiments of the present invention may be used to measure both focal and diffuse fibrosis ("total fibrosis") in an organ, the present methods are especially useful in
  • organs refers to a group of tissues that perform a specific function or group of functions .
  • animal organs may include, but are not limited to the heart, lungs, brain, eve, stomach, spleen, bones, muscles, pancreas, kidneys, liver, intestines, skin, lymph nodes, urinary bladder and sex organs (for example ovary and prostate).
  • extracellular contras agent refers to an extracellular substance used to enhance the contrast of structures or fluids within the body in medical imaging.
  • extracellular refers to substances that leave the vascular compartment, do not bind tissues and are not actively transported into cells.
  • Gadolinium-based contrast agents are suitable for use iri the present invention with magnetic resonance imaging and include Gadolinium-Diethylenetriaminepentaacetate (GD-DTPA) ,
  • Gadolinium-tetraazacyclododecanetetraacetic acid Gd-DOTA
  • Gadolinium 1,4, 7-triscarboxymethyl-l, 4 , 7, 10- tetraazacyclododecane Gd-HP-D03A
  • 4RS - [4 -carboxy-5 , 8, 11- tris (carboxymethyl) -l-phenyl-2-oxa-5, 8, ll-triazatridecan-13- oato(5-)] gadolinate (2-) dihydrogen compound with 1-deoxy-l- (methylamino) -D-glucitol (1:2) (Gd-BOPTA) , Gadolinium
  • Gd-DTPA-BMA diethylenetriaminepentaacetate-bis (methylamide)
  • Gadolinium 8 , 11-bis (carboxymethyl) -14- [2- [ (2- methoxyethyl) amno] -2-oxoethyl] -6-oxo-2-oxa-5, 8 , 11, 14- tetraazahexadecan-16-oato(3-) ]
  • the contrast agent used is GD-DTPA.
  • Iodinated contrast agents are also suitable for use in the present invention with X-ray imaging or computed tomography (CT) and include Diatrizoate (Hypaque 50), Metrizoate (Isopaque Coronar 370) , Ioxaglate (Hexabrix) , Iopamidol (Isovue 370) , Ioxilan (Oxilan) , Iohexol (Omnipaque 350) and Iopromide
  • CT computed tomography
  • Iodixanol (Visipaque 320) .
  • the contrast agent used is Iohexol, (see example 11 discussed below) .
  • the extracellular contrast agent When. the extracellular contrast agent is injected intravenously into a subject as a bolus the blood/plasma concentration rises and the contrast agent leaks into the interstitium. As discussed above, extracellular contrast agents do leave the blood but cannot enter the functional cells of organs or become bound to these cells. At a time point shortly after the bolus is administered (approximately 1 to 2 minutes) , the rising interstitial concentration and the falling plasma concentration are transiently equal i.e. there is no net exchange between the two compartments (".the equilibrium point") . After this point the plasma concentration falls due to renal excretion and the gradient reverses, with the contrast agent passing out of the interstitium back into the plasma and then out of the body.
  • first and second "image signal intensity values" from regions of interest in the body of the subject are obtained using a medical imaging device.
  • the image signal intensity value may be related to signal strength either at a region of an image or integrated over an image .
  • the image signal intensity values will vary with the contrast agent and medical imaging device used. For example, if magnetic
  • MRI magnetic resonance imaging
  • gadolinium-based contrast agent is administered.
  • MRI are associated with "Tl”, which is the MRI rate constant for longitudinal spin relaxation after excitation.
  • the image signal intensity values obtained are associated with Tl.
  • CT computer tomography
  • the contrast agent used is iodine-based.
  • the image signal intensity values for CT are associated with a "Hounsfield Unit” (HU) , which is the
  • the image signal intensity value or values for a particular organ usually is directly dependent on the concentration of contrast agent in the interstitium within the organ, which in turn is directly related to the level of fibrosis in the organ.
  • the difference in the image signal intensity value or values from the blood/plasma and from an organ of interest is a direct reflection of differences in the volume of distribution of the contrast agent.
  • embodiments of the present invention obtain image signal intensity values when the diffusion of the contrast agent between the blood and organs is substantially at an equilibrium condition.
  • substantially an equilibrium condition may be established either by administering a bolus of contrast media followed by a continuous infusion of contrast media (at a dose lower than the bolus) or by imaging at or around the transient 'equilibrium point' (see above) without a continuous infusion.
  • Administration of the continuous infusion may be started at any time after the bolus is administered and continued until the second image signal intensity value is obtained.
  • the continuous infusion is started about 15 minutes after the bolus, sometimes termed a 'primed
  • infusion' and the second image signal intensity value is obtained between about 45 and about 80 minutes after the bolus was administered.
  • the continuous infusion may be started immediately after or contemporaneously with a smaller and slower bolus delivery for equilibrium in as little as 5 to 10 minutes using either iodine contrast and CT or gadolinium contrast and MRI (this will be illustrated below with reference to Figure 5, 8 and 9) .
  • Imaging may also occur without continuous infusion after the bolus infusion.
  • a bolus injection may be shaped to create a smooth peak for measurement at this transient
  • Embodiments of the present invention comprise obtaining a image value (or values) for the blood and an image .
  • signal intensity value (or values) for one or more organs of a subject before a contrast agent is administered to the subject and after diffusion of the contrast agent between the blood and organs at substantially an equilibrium condition has been established.
  • these image signal intensity values may be used to determine the contrast agent volume of distribution for an organ, which correlates with the amount of fibrosis in the organ.
  • the contrast agent volume of distribution for an organ (“organ V d " ) is calculated using the following equation:
  • OVd (1 - haematocrit) x (0SIV2-0SIV1) / (BSIV2 - BSIV1)
  • OV d is the volume of distribution of contrast agent for an organ
  • OSIV2 refers to the image signal intensity value
  • OSIV1 refers to the image signal intensity value obtained prior to the administration of any contrast agent.
  • BSIV2 refers to the image signal intensity value obtained for blood while diffusion of the contrast agent between the blood and organs approaches or is at an equilibrium condition
  • BSIV1 refers to the image signal intensity value obtained for blood prior to the administration of any contrast agent.
  • a sample of blood is taken from the subject and the haematocrit level (1 -haematocrit) determined.
  • Tests for determining the haematocrit ' level in a blood sample are well known to those skilled in the art, for example, a Complete Blood Count test may be used.
  • a late gadolinium enhancement (LGE) image is obtained after a bolus of gadolinium-based contrast agent ⁇ is ' administered.
  • LGE gadolinium enhancement
  • embodiments of the present invention also provide methods of diagnosing and monitoring the progression of diseases associated with interstitial expansion. Examples are shown in Figure 10 and 11.
  • Disease associated with interstitial expansion refers to any one of the diseases associated with interstitial expansion.
  • diagnosis of a disease may be achieved by determining the interstitial volume in an organ of a healthy individual and comparing that to the interstitial volume in the same- organ of an individual
  • FIG. 12 shows very high VDm levels in cardiac amyloidosis compared to aortic stenosis, for example, and massive
  • disease progression may be monitored by periodically assessing the interstitial volume of an organ of an individual diagnosed with a disease associated with interstitial
  • Interstitial expansion may be associated with diffuse fibrosis, amyloidosis, focal scar or oedema. Examples of diffuse fibrosis, amylodosis and focal scar imaging are shown in Figure 12.
  • Diseases associated with an expansion of interstitial volume include, for example, hypertension, cardiomyopathies, valve disease,, acute and chronic infarction, myocarditis, cirrhosis, hepatitis, atherosclerosis, asthma, scleroderma, pulmonary.
  • fibrosis diabetes mellitus, Alzheimer syndrome, Down syndrome, hereditary cerebral hemorrhage with amyloidosis, Medullary thyroid carcinoma, isolated atrial amyloidosis, pituitary amyloid and cutaneous amyloidosis.
  • the method may also comprise obtaining a measure for an age of an organ.
  • fibroses such as diffuse fibrosis, may be characterised in the above-described manner and the
  • resulting data may be compared with those of a library of age specific corresponding data previously obtained so that an effective age of the organ may be determined.
  • the fibrosis may be characterised in a plurality of organs of a subject and data analysis can provide information concerning effective relative organ ages. This is also illustrated in Example 13 for the heart.
  • a method of determining a cell volume comprises determining the distribution volume of contrast agent in the above-described manner and subtracting that volume from the total volume associated with an area of interest to obtain a measure for the volume that is substantially free of contrast agent and corresponds to the cell volume. Changes in the ratio of cell/interstitial volume may therefore be tracked over time, a example being shown in Figure 11 (described below in the context of example 12) , where organ changes are shown to be due to cell volume reduction rather than fibrosis reduction.
  • Gd-DTPA is an MRI extracellular contrast agent that potently shortens Tl.
  • phantom samples were manufactured using agar jelly (10 g/1) and pipetted drops of Gd-DTPA and MnC12 to produce phantoms with varying Tl and T2 properties. These were imaged using the standard IR FLASH (Slice thickness 8.0 mm, TR 950 ms, TE 5.17 ms) with varying heart rates, segmentation and repeat times with the gold standard being Tl relaxometry (single line readout, TR>5x Tl) .
  • Vd(b) is known (1-haematocrit) so Vd(m) is :
  • Vd(m) (l-haematocrit) x (1/Tl) myo. post - (1/Tl) myo. pre
  • FIG. 1 shows a graph illustrating the effects of mathematical heart rate correction.
  • the heart rate at the time of the Tl measurement sequence heavily influences the measured.
  • Tl. A spoiled gradient echo inversion recovery technique was used and the derived Tl for incomplete longitudinal recovery was corrected using the following method:
  • M 2 longitudinal magnetisation
  • Tl can be isolated from the above equation:
  • Tl Tl' / ln(l+f)
  • the CMR protocol is outlined in Figures 2 (a) and (b) .
  • CMR was performed using a 1.5-T magnet (Avanto, Siemens Medical
  • the Tl measurement used a standard late gadolinium enhancement (LGE) sequence.
  • LGE latitude-to-live
  • Tl measurement was performed pre- and post-equilibrium contrast using inversion times (Tl) of 140 milliseconds, then 200 to 800 milliseconds in 100 millisecond increments (see Figure 3 (a) and (b) ) .
  • Regions of interest were drawn in the blood and septum at the biopsy site. Mean signal intensities were plotted and a curve fitting technique used to find the null point Tl' .
  • a heart rate correction algorithm corrected for incomplete longitudinal recovery, and phantom work demonstrated that the combination of low flip angle, short read-out, and no parallel imaging minimally altered the derived Tl compared to Tl relaxometry.
  • null points which are coil location and scanner image scaling independent
  • pre and post scanning with a single change - equilibrium contrast post contrast scan used with repeat heart rate recording, (mean RR interval 875ms ⁇ 220ms vs. 901ms ⁇ 198ms) , meticulous iso-centering and re-importing of the pre-scan sequence
  • myocardial ratio such that any systematic changes affecting both tissue signals may affect their signal ratio less.
  • Example 4 Achieving contrast equilibrium conditions for MRI measurements
  • Figure 3 illustrates blood and myocardial magnetic resonance measurements (a) after bolus infusion only and (b) after a subsequent steady has been achieved by continuous contrast agent infusion. Contrast equilibrium was achieved by primed infusion (loading bolus followed by slow continuous infusion) . The induction of an early steady state was optimized by
  • imaging may also be conducted without requiring a further infusion after the bolus infusion.
  • bolus concentrations illustrates bolus concentrations.
  • a transient equilibrium is present when organ concentration levels cease to rise and start to fall.
  • blood and organ concentrations are basically the same. However, this occurs at a time of blood contrast recirculation, seen best in 6(a), top left.
  • the input function is altered, here being slowed until 6 (c) (bottom left) where recirculation effects are substantially reduced (the transient equilibrium is achieved after approximately 75 seconds where the myocardium' signal is peaked) . If this is over done (6d, bottom right) , no early organ inflection point is obtained.
  • the in vivo measurements were validated against human operative myocardial biopsy in patients with aortic stenosis.
  • Inter-study repeatability for the CMR measurement and fibrosis measurement of Tl was assessed by calculating the coefficient of variation (equal to the SD of the difference between two measurements over the mean of the two measurements, expressed as a percentage) . Correlation was assessed using Pearson's test (SPSS) .
  • Embodiments of the "equilibrium contrast cardiovascular magnetic resonance" (EQ-CMR) technique are. based on three elements: a bolus of the extra-cellular contrast agent
  • Figure 8 illustrates a blood equilibrium contrast obtained using a bolus plus infusion of iodohexol (CT contrast agent) .
  • CT contrast agent iodohexol
  • HPLC High performance liquid chromatography
  • Figure 9 shows examples of Equilibrium Contrast images obtained using CT.
  • Blood, liver and heart equilibrium contrast CT scanning analyses were performed using the above -described rapid iodohexol infusion (see also Figure 8) . Regions of interest have been drawn in the heart, liver and blood (with exclusion of vessels in the liver) .
  • a modified infusion protocol was tested for 10 patients (of differing body mass index, already undergoing single-phase contrast enhanced CT for clinical indications) using CT.
  • a 4cm pre-contrast spiral through the top of the liver to include the cardiac apex (120kV, 200mAs) was performed.
  • the subsequent iodine infusion was given and the 4cm spiral repeated through the cardiac apex and liver at our derived time for steady state and then at two further 10 minutes intervals (radiation dose is approximately 18 times less than a standard liver CT (5.3mSv) .
  • Regions of interest were drawn in the liver, myocardium and aortic blood,
  • Example 12 Disease monitoring and predicting
  • Figure 11 represents an example of disease monitoring and the detection of cell volume changes after intervention.
  • 60 Aortic stenosis patients have been re- scanned after 6 months and a percentage fibrosis and cells volume quantified.
  • the graphs represented in Figure 11 show, for the first time non-invasively, that LVH regression at 6 months post aortic valve replacement is cellular regression rather than fibrosis regression.
  • Figure 12 represents volume of distribution measurement in different forms of extracellular expansion: Diffuse fibrosis (conditions: aortic stenosis or hypertrophic cardiomyopathy) ; diffuse infiltration with amyloid (condition: TTR and AL systemic amyloidosis) ; and focal fibrosis (scar)
  • Diffuse fibrosis conditions: aortic stenosis or hypertrophic cardiomyopathy
  • amyloid condition: TTR and AL systemic amyloidosis
  • scar focal fibrosis
  • Figure 13 shows data illustrating a relationship between the results of equilibrium CMR measurements and age. Even though the age range of the subjects was limited, a trend may be recognizable .

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Abstract

La présente invention concerne un procédé de mesure du volume interstitiel réfléchissant une fibrose diffuse, un œdème ou une amyloïdose et sa réciproque, le volume cellulaire, dans des organes corporels. Le procédé comprend l'obtention de premières valeurs d'intensité de signal d'image (par tomodensitométrie ou imagerie par résonance magnétique) pour le sang et au moins une partie d'un ou de plusieurs organes chez un sujet au niveau d'une zone d'intérêt. Après ceci, un agent de contraste extracellulaire (à base de gadolinium ou d'iode) est administré au sujet de manière à ce que la diffusion de l'agent de contraste entre le sang et au moins la partie de l'organe ou des organes soit, au niveau de la zone d'intérêt, sensiblement à une condition d'équilibre. Après ceci, des secondes valeurs d'intensité de signal pour le sang et un ou plusieurs organes du sujet au niveau de la zone d'intérêt sont obtenues. Le procédé comprend en outre l'étape consistant à déterminer le volume interstitiel par détermination d'un volume de distribution et de sa réciproque, le volume cellulaire de l'agent de contraste au moins pour la partie de l'organe ou des organes par comparaison du volume de distribution sanguin en utilisant les premières et secondes valeurs d'intensité de signal d'image.
PCT/AU2011/000062 2010-01-20 2011-01-20 Procédé de mesure du volume interstitiel dans des organes et des tissus Ceased WO2011088513A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118021265A (zh) * 2024-01-11 2024-05-14 首都医科大学附属北京朝阳医院 一种血容量评估方法、装置、存储介质及终端

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050215883A1 (en) * 2004-02-06 2005-09-29 Hundley William G Non-invasive imaging for determination of global tissue characteristics
WO2006021096A1 (fr) * 2004-08-23 2006-03-02 Robarts Research Institute Determination de parametres hemodynamiques
WO2008029407A2 (fr) * 2006-09-06 2008-03-13 Yeda Research And Development Co. Ltd. Dispositif de surveillance de la pression d'un système dans l'espace et le temps et procédé d'évaluation de l'administration de médicaments et de la résistance à une thérapie et à un produit
WO2008128033A1 (fr) * 2007-04-11 2008-10-23 Oregon Health & Science University Procédé et appareil de détection quantitative non invasive de fibrose dans le cœur

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050215883A1 (en) * 2004-02-06 2005-09-29 Hundley William G Non-invasive imaging for determination of global tissue characteristics
WO2006021096A1 (fr) * 2004-08-23 2006-03-02 Robarts Research Institute Determination de parametres hemodynamiques
WO2008029407A2 (fr) * 2006-09-06 2008-03-13 Yeda Research And Development Co. Ltd. Dispositif de surveillance de la pression d'un système dans l'espace et le temps et procédé d'évaluation de l'administration de médicaments et de la résistance à une thérapie et à un produit
WO2008128033A1 (fr) * 2007-04-11 2008-10-23 Oregon Health & Science University Procédé et appareil de détection quantitative non invasive de fibrose dans le cœur

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118021265A (zh) * 2024-01-11 2024-05-14 首都医科大学附属北京朝阳医院 一种血容量评估方法、装置、存储介质及终端

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