US20100129292A1 - Method and apparatus for noninvasive quantitative detection of fibrosis in the heart - Google Patents

Method and apparatus for noninvasive quantitative detection of fibrosis in the heart Download PDF

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US20100129292A1
US20100129292A1 US12/595,567 US59556708A US2010129292A1 US 20100129292 A1 US20100129292 A1 US 20100129292A1 US 59556708 A US59556708 A US 59556708A US 2010129292 A1 US2010129292 A1 US 2010129292A1
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fibrosis
extracellular
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heart
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Michael Jerosch-Herold
Sumeet S. Chugh
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Oregon Health and Science University
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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
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    • A61B5/0033—Features or image-related aspects of imaging apparatus, e.g. for MRI, optical tomography or impedance tomography apparatus; Arrangements of imaging apparatus in a room
    • A61B5/0035—Features or image-related aspects of imaging apparatus, e.g. for MRI, optical tomography or impedance tomography apparatus; Arrangements of imaging apparatus in a room adapted for acquisition of images from more than one imaging mode, e.g. combining MRI and optical tomography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61B5/004—Features or image-related aspects of imaging apparatus, e.g. for MRI, optical tomography or impedance tomography apparatus; Arrangements of imaging apparatus in a room adapted for image acquisition of a particular organ or body part
    • A61B5/0044—Features or image-related aspects of imaging apparatus, e.g. for MRI, optical tomography or impedance tomography apparatus; Arrangements of imaging apparatus in a room adapted for image acquisition of a particular organ or body part for the heart
    • A—HUMAN NECESSITIES
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    • A61B6/03—Computed tomography [CT]
    • A—HUMAN NECESSITIES
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    • A61B5/026—Measuring blood flow
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    • A—HUMAN NECESSITIES
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    • A61B6/503—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications for diagnosis of the heart
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    • A61B6/504—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications for diagnosis of blood vessels, e.g. by angiography
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    • 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
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    • G01R33/5602—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution by filtering or weighting based on different relaxation times within the sample, e.g. T1 weighting using an inversion pulse
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    • G06T2207/30004—Biomedical image processing
    • G06T2207/30048—Heart; Cardiac

Definitions

  • Embodiments relate to the field of medical diagnostics and monitoring, and, more specifically, to a method and apparatus for noninvasive quantitative detection of both diffuse and focal fibrosis in the heart.
  • Myocardial fibrosis is a morphologic change common to multiple cardiac disease conditions.
  • replacement fibrosis
  • interstitial reactive fibrosis
  • fibrosis is quantified by histochemical analysis of tissue samples obtained by surgical biopsy. The availability of a non-invasive test to quantify replacement and interstitial fibrosis, which may be correlated with the collagen volume fraction (CVF), would be a significant advance.
  • FIG. 1 illustrates inversion recovery signal intensity curves.
  • T1 was quantified for user-defined regions of interest in the heart.
  • a software program was used to load the DICOM-format MRI images for a series of 12 to 17 inversion times, and fit inversion recovery signal intensity curves, as shown for two regions in FIG. 1 , were generated to determine T1.
  • This analysis was performed twice, first for measurements of T1 before contrast enhancement, and then after incubation of the samples in a gadolinium contrast agent solution for 24 hours.
  • the graph shows differences in regional T1 after placing the sample in the contrast agent solution, and the area with the shorter T1 (posterior lateral region) corresponds to a region with marked fibrosis.
  • FIGS. 2A and 2B illustrate heart slice images.
  • FIG. 2A shows a post-mortem T1-weighted MRI image of a heart slice (patient with cardiomegaly, and extensive atherosclerosis) after 24 hour incubation in contrast agent (gadodiamide) solution. The inversion time of 300 ms resulted in a contrast, such that tissue with higher gadodiamide distribution volume appears brighter.
  • FIG. 2B shows a histological image of the same myocardial slice stained and showing extensive fibrosis in posterior-lateral areas, matching those with increased signal intensity on the MRI image.
  • FIGS. 3A and 3B illustrate tissue samples stained and viewed under polarized light and classified as normal, or showing interstitial or replacement fibrosis, respectively.
  • the measured gadodiamide distribution volumes, and CVFs for these three classifications, are shown (boxes show 25% and 75% percentile limits).
  • the points represent the measured values, and the gadodiamide distribution volume.
  • Open circles represent the samples that remained unthawed for 60 hours. Closed circles represent samples that remained unthawed for 32 hours.
  • the two graphs show different slopes based on the time lag between thawing of the sample and the post-contrast MRI measurement. Longer lag times increase cell membrane breakdown and therefore gadodiamide distribution volume is larger for the series of measurements with longer sample incubation times.
  • the dotted lines in the graphs show the 95% confidence limits.
  • FIG. 5 is a flowchart outlining methods of measuring extracellular-volume fractions in accordance with embodiments.
  • FIGS. 6A and 6B provide output graphs of methods of performing rapid imaging before, during and after contrast agent contact to measure contrast enhancement in the sample and in blood resident in a ventricular cavity or one or more large vessels in accordance with an embodiment.
  • the description may use perspective-based descriptions such as up/down, back/front, left/right, and top/bottom. Such descriptions are merely used to facilitate the discussion and are not intended to restrict the application of the embodiments.
  • a phrase in the form “A/B” or in the form “A and/or B” means “(A), (B), or (A and B)”.
  • a phrase in the form “at least one of A, B, and C” means “(A), (B), (C), (A and B), (A and C), (B and C), or (A, B and C)”.
  • a phrase in the form “(A)B” means “(B) or (AB)” that is, A is an optional element.
  • a computing system may be endowed with one or more components of the disclosed apparatuses and/or systems and may be employed to perform one or more methods as disclosed herein.
  • Embodiments provide a noninvasive quantitative method for detecting the extent and/or types of fibrosis in the heart.
  • information pertaining to the extent and/or types of fibrosis may aid in the diagnosis of specific cardiac diseases and heart failure and/or may assist in determining suitable treatment options.
  • Embodiments provide methods and apparatuses for determining the extent of fibrosis in viable and nonviable myocardium, which may then be correlated to heart disease and failure.
  • a method of screening individuals for the purpose of heart disease or heart failure prevention may be provided using the detection methodology described herein.
  • a method allows for the detection and quantification of cardiac fibrosis using contrast enhanced magnetic resonance imaging (MRI) (or another imaging method such as computed tomography) as an alternative to histological evaluation.
  • MRI contrast enhanced magnetic resonance imaging
  • a method provides for measurement of the myocardial partition coefficient for an extracellular contrast agent, showing the relative distribution volume of the contrast agent, which may be used to quantify diffuse, reactive, interstitial, or replacement fibrosis, conditions that may be inadequately detected by current methods. All forms of fibrosis lead to an expansion of the extracellular matrix, which in turn increases the volume accessible to extracellular contrast agents, such as gadiodiamide in the case of MRI.
  • Embodiments may be applied to in-vitro and in-vivo evaluation.
  • DCE delayed contrast enhancement
  • gadodiamide-DTPA gadodiamide-DTPA
  • Embodiments disclosed herein provide a novel approach, whereby the relative distribution volume of contrast agent, and/or the myocardial partition coefficient for the contrast agent, is determined to obtain a quantitative measure of the extracellular volume fraction as a marker of fibrosis in viable or nonviable myocardium.
  • the myocardial partition coefficient is proportional to the extracellular volume fraction.
  • the extracellular volume fraction may be quantified with MRI by determining the change of R1 relaxation rate constants in tissue and blood, respectively, both before and after administration of the contrast agent.
  • one may employ a dynamic imaging method to measure signal changes observed with a heavily T1-weighted pulse sequence between the pre-contrast and post-contrast states.
  • the measurement of the myocardial partition coefficient for certain contrast agents is suitable for differentiating extent of myocardial fibrosis on a continuous scale, spanning the range from normal myocardium, through diffuse interstitial and replacement fibrosis in viable myocardium, to non-viable fibrotic scar tissue.
  • the myocardial partition coefficient for a contrast agent is defined as the ratio of the contrast agent concentrations in tissue and blood, at equilibrium. At equilibrium, the concentration of an extracellular contrast agent within the interstitial space should equal the plasma concentration.
  • the partition coefficient for an extracellular contrast agent may express the partition coefficient for an extracellular contrast agent as:
  • Hct is the blood hematocrit.
  • An MRI contrast agent is typically detected through its effect on the 1 H MR signal.
  • the signal from the blood constituents, plasma, and erythrocytes is characterized by a single relaxation rate due to fast exchange of water between plasma and erythrocytes—the intracellular lifetime of water inside erythrocytes is ⁇ 10 ms under physiological conditions.
  • the distribution volume of certain contrast agents may be elevated in myocardium with even mild interstitial fibrosis.
  • the distribution volume may be linearly related to the CVF, an established histological quantification of myocardial fibrosis.
  • a suitable contrast agent may be an extracellular contrast agent or a collagen binding agent.
  • a suitable contrast agent may be Gadolinium or a Gadolinium-based compound, such as gadodiamide.
  • an in-vitro MRI technique for comparison of contrast agent distribution volume as a measure of both replacement and interstitial myocardial fibrosis, with a histologically determined myocardial CVF, the current gold standard for quantification of myocardial fibrosis.
  • the MRI measures of fibrosis may correlate significantly with CVF supporting the suitability of the new methodology.
  • gadodiamide MRI differentiates between normal myocardium, and interstitial (reactive) fibrosis, and between normal myocardium and replacement (scar) fibrosis.
  • the contrast distribution volume and CVF also vary significantly across fibrosis categories, namely normal, interstitial and replacement fibrosis, allowing for types of fibrosis to be distinguished as well.
  • Embodiments use MRI to derive a quantitative measure of fibrosis, which correlates with CVF in myocardial tissue.
  • MRI of delayed contrast hyper-enhancement with gadodiamide-contrast reflects the breakdown of the cell-membrane, which increases the volume of distribution of gadodiamide-contrast relative to viable myocardium.
  • a dense collagen matrix leads to focal hyper-enhancement relative to areas with viable myocardium.
  • contrast hyper-enhancement was similar to the hyper-enhancement observed in acute infarcts.
  • Other causes of increased myocardial fibrosis have also been shown to lead to increased gadodiamide-contrast uptake compared to normal tissue.
  • the contrast distribution volume estimate from MRI and CVF from a photometric assay correlate well, the underlying methods have some significant differences worth noting.
  • the photometry-based determination of CVF requires the selection of small (approximately 40 mm 2 ) areas under a microscope for the pixel count, and the resulting CVF estimate may not be representative of a wall segment.
  • MRI the region of interest is user-defined, at a much lower magnification scale and signal-averages for arbitrarily-sized regions are readily calculated for each image.
  • This difference between the CVF measurement and the MRI method is analogous to a biopsy-based measurement compared to an imaging-based measurement. While the first represents an often arbitrary and restricted choice of tissue within the heart, the latter may be freely specified by an observer, assuming good image quality and spatial resolution.
  • each sample of ventricular myocardium was 1 to 2 cm in thickness, and cut at the mid-level of the ventricular septum to include left and right ventricular free walls. All samples were stored at ⁇ 80° C. until time of analysis.
  • a pre-contrast MRI was performed approximately 10-12 hours after thawing each sample.
  • the samples were brought to room temperature before each MRI measurement.
  • TR repetition time
  • TE echo-time
  • image matrix 256 by 256.
  • a beaker with the tissue sample immersed in saline was placed in a small radio-frequency coil designed for wrist imaging, and all images were acquired at 3 Tesla (Siemens Trio, Siemens Medical Solutions, Malvern, Pa.).
  • the sample was incubated at 3-4° C. in a gadodiamide-saline solution for 24 hours (initial gadodiamide concentration in saline before immersion of tissue slice was ⁇ 3 mM; saline R1 at 3 Tesla after 24 hours incubation: 3.9 ⁇ 0.3 s ⁇ 1 ).
  • the gadodiamide contrast agent (Omniscan; GE-Healthcare, Princeton, N.J.) has an osmolality at 37° C. of 789 (mOsmol/kg water).
  • a second post-contrast MRI was then performed, with identical sequence parameters as for the first measurement. The effects of duration of thawing were also evaluated.
  • tissue samples remained thawed for 60 hours before the second MRI was performed. All other tissue samples were kept in a temperature range from 3-4° C. during gadodiamide incubation and room temperature for 32 hours before the second MRI. Thawing time is potentially important because the integrity of the cell membranes degrades during the time the tissue is not frozen. Accordingly, these two sets of samples with different durations of thawing were analyzed separately.
  • FIG. 1 is an example of an MRI image of a sample.
  • the samples were preserved in formalin.
  • the formalin fixed tissue was then processed, embedded in paraffin and sections prepared of the entire surface area of the sample including septum, left ventricular free wall and right ventricular free wall.
  • the sections, 5 microns in thickness, were stained with picrosirius red and viewed under polarized light at 40 ⁇ power.
  • FIG. 2 shows a stained sample and a corresponding MRI image, with matching areas identified by arrows.
  • Areas of interest were identified histologically on the paraffin-embedded slices. Matching locations were identified on the MRI images by using anatomical landmarks such as the insertion of the right ventricle into the left ventricle, or papillary muscles. Given the differences in tissue size and shape between fresh tissue and paraffin embedded tissue, in an embodiment, locations are estimated to be matched with an accuracy of approximately ⁇ 1 cm in the circumferential direction, and approximately ⁇ 0.5 cm in the radial direction.
  • CVF is a computer assisted quantification of myocardial fibrosis in histological sections widely used for analysis of myocardial collagen content.
  • a modified version of the photometric assay was employed in this study, by using picrosirius red instead of a trichrome stain.
  • each area of interest was subdivided into quadrants. Within each quadrant, 16 digital photos were taken under 40 ⁇ magnification. Each photo represented 2.5 mm 2 ; therefore, 40 mm 2 were analyzed from each section. This allows for a representative sampling of CVF.
  • CVF Connective tissue pixel count in 16 fields/Total pixel count in 16 fields (3)
  • FIG. 4 Measured values for CVF and gadodiamide distribution volume were found to be closely correlated.
  • the two graphs in FIG. 4 represent the results for each of two batches of samples. Each batch had a different thawing time.
  • the slopes of the two are different based on the time lag between thawing of the sample and the post-contrast MRI measurement.
  • FIG. 4 A strong positive correlation between CVF and gadodiamide-MRI is shown in FIG. 4 . While the findings were consistent with either thawing time, longer times likely increased gadodiamide distribution volume due to increased cell membrane breakdown, thus increasing the slope of the regression line. A more uniform distribution of gadodiamide in the tissue samples after 60 hours may account in part for the better correlation of the apparent gadodiamide distribution volume with the CVF, compared to the samples incubated in gadodiamide-saline solution for 32 hours.
  • FIG. 5 is a flowchart outlining various methods of measuring extracellular-volume fractions in accordance with embodiments.
  • measurements may be obtained of an extracellular volume fraction in a tissue sample with an MR contrast agent.
  • multiple pre- and post-contrast injection T1 measurements may be obtained. Such an operation may be performed over an exemplary period of approximately 15-20 minutes.
  • a plurality of T1 relaxation time measurements may be performed in blood and in the sample, both before and after contact with one or more contrast agents to determine the tissue sample partition coefficient for the extracellular contrast agent.
  • a blood hematocrit may be obtained, and the sample partition coefficient and the blood hematocrit may be used to calculate the extracellular volume in the tissue sample.
  • the time course of signal enhancement in blood and tissue may be determined during a first pass. Such an operation may be performed over an exemplary period of approximately 4-5 minutes.
  • a model-based analysis of tissue contrast enhancement may be performed, and then an extracellular volume calculated from best-fit model parameters.
  • rapid imaging before, during and after contrast agent contact may be performed to measure contrast enhancement in the sample and in blood resident in a ventricular cavity or one or more large vessels.
  • the dynamics of contrast enhancement may be analyzed with a two-space model to determine the extracellular volume in the sample.
  • FIGS. 6A and 6B provide output graphs of methods of performing rapid imaging before, during and after contrast agent contact to measure contrast enhancement in the sample and in blood resident in a ventricular cavity or one or more large vessels in accordance with an embodiment.
  • images of the heart may be acquired rapidly during the first pass of an injected extracellular contrast agent, resulting in signal intensity changes in the blood pool of the left ventricular cavity (“arterial input”) and in myocardial tissue as shown in FIG. 6A .
  • An initial peak in the arterial input may be observed during the first pass of the contrast agent, followed by recirculation and approximation to a semi-equilibrium state.
  • the partition coefficient calculation one may also take a running average (the second (smooth) curve in FIG. 6B ) and estimate the partition coefficient when concentration in the blood pool is in semi-equilibrium.
  • a window representing a suitable semi-equilibrium is outlined by the small box in FIG. 6B .
  • myocardial fibrosis there are several important heart diseases/conditions for which qualitative and quantitative measurements of myocardial fibrosis would be valuable for diagnosis and/or risk assessment, including (1) the broad category of heart failure that results from a variety of conditions ranging from familial disorders to myocardial infarction, (2) patients who will suffer sudden cardiac arrest in the future, which again may result from a spectrum of heart conditions, and (3) congenital heart disease, comprising several distinct disorders eventually having a component of myocardial fibrosis. In both ischemic and non-ischemic heart diseases, fibrosis often plays an important role. Even with healthy aging, diffuse fibrosis may be the underlying cause of stiffening of the ventricles which may be an important contributor toward diastolic dysfunction.
  • biopsies Prior methods utilize biopsies to obtain an indication of fibrosis, but biopsies are simply localized samples that do not provide a reliable indication of the overall (global) fibrosis burden.
  • embodiments herein provide an imaging-based test to analyze diffuse fibrosis to determine the global fibrosis burden. Such an analysis provides important information to help in planning suitable treatment.
  • a positive correlation between the methodology presented herein and the amount(s) of myocardial fibrosis for both interstitial as well as replacement fibrosis has been shown.
  • the present methods may be helpful in risk stratification for sudden cardiac death as well as disease severity of the conditions identified above.
  • embodiments may be used to correlate a determination of the presence of, location of, or extent of fibrosis in a tissue sample or whole heart with a heart condition, disease, or associated risk of a particular heart disease or failure.
  • a determined amount and/or location of myocardial fibrosis may be correlated to the risk of heart disease or failure.
  • a risk factor such as a numeric or textual risk factor, may be assigned reflecting the extent and/or location of myocardial fibrosis (i.e., a scaled number, a percentage, a textual indicator such as high, medium, low, etc.).
  • a higher amount of fibrosis (such as represented as a percentage of fibrotic tissue to healthy tissue) may result in a higher risk factor.
  • other factors may be included in the analysis, such as age of the patient, other health conditions, etc.
  • an apparatus or system may comprise a server or other computing device, a storage medium and a plurality of programming instructions stored in the storage medium.
  • the programming instructions may be adapted to program an apparatus to enable the apparatus to perform one or more of the previously-discussed methods.
  • the programming instructions may be adapted to program an apparatus to enable the apparatus to perform image acquisition and/or analysis.

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