WO2006028379A1 - Mri method for assessment of myocardial function and viability - Google Patents

Mri method for assessment of myocardial function and viability Download PDF

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Publication number
WO2006028379A1
WO2006028379A1 PCT/NO2005/000319 NO2005000319W WO2006028379A1 WO 2006028379 A1 WO2006028379 A1 WO 2006028379A1 NO 2005000319 W NO2005000319 W NO 2005000319W WO 2006028379 A1 WO2006028379 A1 WO 2006028379A1
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water
method
t2
intracellular
tl
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PCT/NO2005/000319
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French (fr)
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Jostein Krane
Per Jynge
Heidi Brurok
Morten Bruvold
John G. Seland
Henrik W. Anthonsen
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Jostein Krane
Per Jynge
Heidi Brurok
Morten Bruvold
Seland John G
Anthonsen Henrik W
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Application filed by Jostein Krane, Per Jynge, Heidi Brurok, Morten Bruvold, Seland John G, Anthonsen Henrik W filed Critical Jostein Krane
Publication of WO2006028379A1 publication Critical patent/WO2006028379A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/48Other medical applications
    • A61B5/4869Determining body composition
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/05Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radiowaves
    • A61B5/055Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radiowaves involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01RMEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00Arrangements or instruments for measuring magnetic variables
    • G01R33/20Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48NMR imaging systems
    • G01R33/483NMR imaging systems with selection of signals or spectra from particular regions of the volume, e.g. in vivo spectroscopy
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01RMEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00Arrangements or instruments for measuring magnetic variables
    • G01R33/20Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/28Details of apparatus provided for in groups G01R33/44 - G01R33/64
    • G01R33/281Means for the use of in vitro contrast agents

Abstract

The present invention describes a new MRI method for separately measuring the signals from intra- and extra cellular water compartments in tissue. The desired contrast (T1 contrast) in the images is obtained by adding an intracellular contrast agent, while the water compartments is identified using T1 weighted or combined T1 and T2 weighted imaging sequences.

Description

TITLE: MRI method for assessment of myocardial function and viability

FIELD OF THE INVENTION

The present invention describes a new MRI method for generating images of intracellular water in myocardium.

BACKGROUND

In ischemic heart disease (IHD) myocardial blood flow falls gradually or abruptly. The associated regional ischemia may be moderate for a long time and become symptomatic as angina pectoris. Another manifestation is hibernating myocardium where cardiac work is reduced to match reduced perfusion. If ischemia becomes severe due to rapid closure of a coronary artery, myocardial infarction and necrosis ensue accompanied by arrhythmias.

Cell death can be prevented if blood flow is restored before or early during development of severe ischemia. When therapeutic attempts at reperfusion are successful, tissue and cardiomyocyte repair may still require some time before a recovery to normal contractile function is obtained, and myocardium appears as stunned. If reperfusion is unsuccessful, the entire left ventricular myocardium may, in parallel with regional loss of viable cells, undergo unfavourable remodelling processes. The end result is heart failure with high mortality.

Within an ageing population IHD and secondary heart failure represent major challenges underlining a demand for diagnostic imaging to identify IHD in its different stages and forms. Also there is a need to diagnose heart failure developing after myocardial infarction, to identify other forms of heart failure, and to monitor the efficacy of drug treatment.

Diagnostic imaging has developed greatly in the last decades but no technical modality can yet cover the whole spectrum of diagnostic needs. Magnetic resonance (MR) imaging (MRI) is most promising with its overall versatility in free choice of image sections and in signalling techniques. MR angiography and perfusion techniques are in development, whereas analysis of contractile function is well established. An important task is to characterize cellular viability in IHD and heart failure. At present identification of necrotic myocardium and postinfarct scarring in IHD makes use of extracellular (EC) gadolinium (Gd) containing contrast media, looking for late contrast enhancement (US patent 6205349).

However, a more graded and less crude assessment of ischemic syndromes and of cell function and viability is necessary for differentiated diagnosis and for follow-up of therapy. There is thus a need in the field for a method for obtaining essentially new information derived from the intracellular (IC) space with its biochemical and physiological machinery.

The main problem with MRI of myocardium is that the involved procedures do not take into account that tissue water is heterogeneous with differences in relaxation and diffusion between IC and EC compartments. Effects from tissue inter-compartmental equilibrium water exchange can be quite significant in the quantitative analysis of various in vivo MRI data. Unfortunately, water signals from different tissue compartments as detected by MRI have the same resonance frequency, and can thus not be resolved spectroscopically

(chemical shift). However, water in different tissue compartments may have sufficiently differences in relaxation and/or diffusion properties making it possible to separate the signals. The information harvested from such a procedure depends strongly on how rapid water exchanges between the IC compartments and the EC compartments, the latter including both the interstitial and vascular compartments. If exchange is rapid, the excited water protons in one particular compartment will exchange fully with the other compartment within the time needed to obtain the desired contrast in the MR image. In such a case tissue will appear as a homogenous non-separable entity. If the exchange is sufficiently slow compared to the difference in individual relaxivities and/or diffusivities in each compartment, a separation of water signals from IC and EC compartments is possible.

SUMMARY OF THE INVENTION

The present invention thus describes a MRI method for assessment of myocardial function and viability, said method comprising detecting separately Tl and T2 relaxivities and water diffusion for differentiating intracellular water compartments from extracellular water compartments in the myocardium.

The MRI method according to the present invention thus comprises detecting separately Tl and T2 relaxivities and water diffusion in order to differentiate IC water compartments from EC water compartments in the myocardium.

Further, it is described a MRI method as claimed in claim 1 for differentiating the signals from intra- and extra cellular water in myocardial using T2- and Tl -weighted and/or diffusion weighted images in the presence of an intracellular contrast agent. Said method thus enables tracking of intracellular and extracellular water separately.

The present invention further describes a method which is based on combining inversion recovery (inversion pulse preceding the acquisition of the image) with T2-weighted imaging (T2 map), where the inversion pulse creates the necessary imaging contrast, and where the T2-map makes the separation of EC and EC water signals possible. The method according to the present invention is thus based on selection of optimal imaging parameters generated from water relaxation and relaxation-diffusion measurements and on the use of contrast media.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows results from MR measurements in rat myocardium from control hearts (a) and in rat myocardium following infusion of 25 μM MnCl2 and subsequent washout (b). The Tl distribution is obtained by Saturation Recovery measurement followed by an Inverse Laplace Transformation of the obtained data.

In control hearts (Figure 1 a) there is a main broad tissue component located around 800 ms assigned to tissue water. After moderate IC elevation of Mn (Figure 1 b) there is a significant shift in the Tl values indicating increased Tl relaxivity for IC water and two Tl components for the tissue representing IC and EC water appears, but they cannot yet be fully separated from each other. Figure 2 shows D-T2 correlation maps in control hearts obtained by a combined PGSE/CPMG measurement. The data were analyzed using Inverse Laplace Transformations in two dimensions.

Figure 2 thus shows that the T2 components can be separated in two groups, where the two shortest components have the lowest diffusion coefficient, and are thus assigned to IC water. The longest component is assigned to extra-tissue water, and is correlated to the longest component in the Tl measurements (Fig 1 a-b). These measurements also show that IC and EC water can be separated with respect to T2 in control hearts without elevation of intracellular Mn.

Figure 3 a-c shows Tl measurement (a), and Tl-weighted T2 measurements (b-c), in rat myocardium following infusion of 150 μM MnCl2 and subsequent washout. The Tl- and T2 distributions are obtained by an Inverse Laplace Transformation of the obtained data.

Figure 3a thus reveals that with enhancement of intracellular manganese, the tissue component can be clearly divided in two Tl components. Figure 3 b-c shows that in the presence of a sufficient amount of intracellular contrast agent, and using an inversion pulse with a corresponding optimized inversion time (TI), it is possible to separate IC and EC water signals. This can be directly applied in an imaging setting, where an MR image is acquired instead of the T2 measurement

DETAILED DESCRIPTION OF THE INVENTION

In MRI the tissue signal intensity depends on the density, the longitudinal (Tl) and transversal (T2) relaxation properties and also the diffusion (D) of water. Differentiated imaging of water compartments using an intracellular contrast agent depends on three main premises: 1) the possibility to separate IC from EC water within the time course of an imaging sequence through existence of large enough differences in relaxation rates and/or diffusivities, 2) a restricted exchange of water across the cell membrane compared to the differences in relaxation rates or diffusivities between the compartments, and 3) the safe use of effective and non-toxic contrast agents. The present invention shows for the first time that these three premises can be fulfilled. Thus it describes water relaxation times (Tl and T2) in tissue and cell compartments in the presence of an intracellular contrast agent, and how the differences in these relaxation times can be used in a detection of water compartments.

The present invention thus relates to a MRI method for assessment of myocardial function, said method comprising detecting separately Tl and T2 relaxivities and water diffusion for differentiating IC water compartments from EC water compartments in the myocardium.

The present invention includes selection of optimized MR parameters for the respective water compartments. Also, the invention includes optimized use of intracellular contrast agents to increase the imaging contrast and to aid in the separation of these compartments. The method according to the present invention is based on inversion recovery, saturation recovery, magnetization transfer (MT) or relaxation in the rotating frame reference (Tip) techniques.

The preferable intracellular contrast agent is a Manganese (Mn) complex releasing paramagnetic Mn ions in a slow or rapid manner after intravenous infusion, more preferably slow Mn ion releasers like Mn complexed to N,N'-dipyridoxyl-diethylene- diamine-N,N' diacetic acid (MnPLED) and derivatives thereof. Further, said intracellular contrast agent may be a chelate or particle or macromolecule containing gadolinium or iron.

According to the present invention IC and EC compartments may be differentiated with MRI. MRI makes use of strong magnetic fields (0.5 - 7.0 Tesla) and radiofrequency (rf) pulses that excite mainly water protons. The information harvested from such a procedure depends strongly on how rapid water exchanges between the IC compartments and the EC compartments, the latter including both the interstitial and vascular compartments. If exchange is rapid, the excited water protons in one particular compartment will exchange fully with the other compartment within the time needed to acquire the individual MR resonance. In such a case tissue will appear as a homogenous non-separable entity.

It has generally been assumed that water exchange across cell membranes is so rapid that what is seen with EC contrast enhanced MRI represents both the EC and the IC compartments (Donahue et al., J. Magn. Res. Imag. 1997;7: 102-111). However, results presented according to the present invention show that water exchange is slower than assumed, and that by introducing an intracellular contrast agent (manganese), the relaxivity in this water compartment can be altered to a degree where separation of the intra- and extracellular water signals is possible if the MRI parameters are adjusted accordingly.

Relaxation processes of spin bearing molecules in liquid saturated porous materials are influenced by physical and chemical surroundings. For some time it has been possible to separate fluid phases of oil and water in oil-bearing porous sediment rocks by applying the diffusion-T2 (D-T2) correlation measurement (Seland et al. Appl.. Magn.Reson 2003; 24: 41- 53). The obtained diffusion- and relaxation attenuations have been analysed by a Two Dimensional Inverse Laplace Transform (2D-DLT) procedure based on the algorithm by Venkataramanan et al (Venkataramanan et al. lee. Trans. Sign. Proc. 2002; 50: 1017- 1026). Animal and human tissues can also be regarded as heterogeneous porous systems where water is confined in different compartments and where there is exchange of water molecules between these compartments. In analogy with results obtained from geological porous media with respect to petrophysical properties using diffusion-relaxation and relaxation-relaxation correlation measurements, the present invention is based on applying these methods in MRI of myocardium, in the presence of an intracellular contrast agent. Surprisingly, the present invention now teaches that treatment in rat myocardium with intracellular manganese (Mn) results in Tl shortening and the parallel appearance of two Tl components. This is shown in Figure la-b and presents support to the present invention of differential behaviour of IC and EC water.

In the measurements of T2 relaxation we found three main tissue components as shown in Figure 2. D-T2 correlation measurements confirm that the two shortest T2 components (-30 ms and 100 ms) correspond to IC water, while the long T2 component (-300 ms) corresponds to EC water. When Mn is accumulated in the IC compartment, reduction in both T2 components is observed, but the effect of Mn is not so pronounced as found in the Tl data as seen in figure 3a and 3b. However, there is still the possibility of applying T2 weighting for differentiating between MR signals from IC and EC compartments. Hence knowing the correlation between Tl and T2 and the use of combined Tl and T2 weighted images will result in an image where a separation of IC and EC water signals is obtained, and with an increased Tl contrast derived from the IC water only.

Evidence has been reported for rapid exchange of water across liver mitochondrial membranes (Lopez-Beltran et al. J. Biol. Chemistry. 1996; 271: 10648-10653). Likewise, similar findings for heart mitochondrial membranes are reported (Ward et al. Magn. Reson. Med. 2003; 50: 1312-1316). Since mitochondria constitute about 35% of the IC space of cardiomyocytes, mitochondrial water contributes greatly to the overall IC water signal in MRI. In spite of the existence of rapid water exchange across the mitochondrial membrane the contribution from water inside mitochondria can still be differentiated from the total IC water compartment through techniques such as magnetization transfer (MT) (Ward et al. Magn. Reson. Med. 2003; 50: 1312-1316). Since Mn accumulates in mitochondria, a combination of MR techniques and Mn releasing contrast agents as described in the present application may enable novel methods for assessment of mitochondrial function.

Whether water exchange is rapid or restricted is of great importance for MRI and MR measurements. With the typically long pulse-to-acquisition intervals (>200 ms) in conventional use, if water exchange is rapid, the information derives from the whole tissue, including both the EC and IC compartments. However, water exchange is slower between the EC and the IC compartments as shown herein. Accordingly, the possibility to extract maximal Tl and T2 based information from both IC and EC environments has not yet been used in an optimal way. Since the IC compartments occupies more than 60 % of the space in most tissues, the present findings of restricted water exchange lead to serious flaws when using current techniques for MRI and tissue characterisation.

In essence, the present invention is based on the use of an intracellular contrast agent combined with specific approaches when adjusting the MRI parameters. These approaches are made possible according to the present invention from the discoveries on water relaxation and diffusion behaviour in myocardium and are based on Tl relaxation and inversion times (TI). Concerning TI, this parameter should be chosen so that it is possible to separate the magnetization from IC and EC water. For an intracellular contrast agent (Mn ions) added to the IC compartment in an amount sufficient to directly separate the IC and EC water signals based on their differences in longitudinal relaxation, TI should be chosen so that the magnetization from IC water is at a maximum, while EC magnetization is close to zero.

In the case of lower concentrations of intracellular contrast agent, where the EC and IC signals cannot easily be separated by their differences in Tl, the signals can be separated based on their differences in diffusion. Furthermore, EC and IC water signals can be separated based on their differences in T2, which combined with Tl -weighting results in a mapping of the changed Tl relaxivity of the IC signal. This can be done by applying an inversion pulse in front of the measurement of a T2-map. For every pixel in the MR image a T2 distribution like the one shown in Figure 3 (b) is obtained, making it possible to separate the IC and EC water signals, while the inversion pulse will lead to a Tl contrast for the IC signal, as observed in Figure 3 (c). -

Intravenously administered Mn ions are mainly taken up by the normal myocardium -through so-called slow calcium (Ca) channels in the cell membrane, and are thereafter retained in the IC space for many hours. As shown according to the present invention, intracellular Mn ions have a particularly high Tl relaxivity, T1 = 60 (s mM)"1, due to favourable interactions with proteins. In injured or dysfunctioning myocardium the cellular uptake is retarded or absent and hence signal intensity and contrast in MRI is reduced. Due to cell retention of Mn ions imaging can be delayed for a considerable time. This is different from current MRI methods which make use of extracellular gadolinium (Gd3+) based contrast media and which do not provide the same level of information on cellular function.

However, up till now Mn enhanced MRI has only been possible to show with the use of relatively high doses of rapidly dissociating Mn compounds, e.g. Mn/Ca gluconate. The doses used have typically been around 20 μmol/kg (Storey et al., Invest. Radiol. 2003;38:642). Taking in consideration that the LD50 value is about 10 times that dose as described in US5980863 and that administration has to be rather rapid, this approach most probably represents an unacceptable high risk to cardiac patients. However, the invention described herein enables one to lower the Mn doses considerably. IC Mn will increase differences in relaxation rates between IC and EC water and hence increase contrast between the two compartments. This can be achieved according to the present invention by optimizing imaging parameters.

Another aspect of the invention relates to Mn enhanced function and viability assessment of the myocardium. Here much more stable and hence less toxic Mn ion releasing compounds, like Mn-dipyridoxyl-diphosphate (MnDPDP), with 10 time higher LD50 values could be used, as described in WO 99/01162. However, even for this application doses could be considerably lowered. For delineation of infarcts in rats with conventional spin echo technique 15 μmol/kg MnDPDP was used. (Bremerich et al., Radiology 2000;216:524). However, it was recently described that slow infusion of 5 μmol/kg MnDPDP in healthy human volunteers causes contrast enhancement in Tl weighted images of the myocardium (Skjold A. et al. Eur. J. Radiol. 2003; 13: H). However, according to the present invention the dose of MnDPDP can be considerably decreased. Although 10-20 μmol/kg MnDPDP as a single dose does not represent any serious risk for the patient, repeated doses may induce unwanted side effects. It is well known that parenteral nutrition with essential Mn ions over time may cause serious neurotoxic symptoms (e.g. Fell et al., Lancet 1996;84:295). Although the corresponding tolerable dose of a relatively stable Mn compound is higher, repeated doses may over time represent an increased risk of unwanted side effects. Further, as described in US6258828 MnDPDP and its metabolite MnPLED possess profound cardioprotective properties. Cardioprotective effects were seen in pigs as reduction in infarct size, attenuation of ventricular fibrillation and haemodynamic improvements after myocardial ischaemia-reperfusion at doses below 10 μmol/kg (Karlsson et al., Acta Radiol 2001 ;42:540).

As the present invention shows that water exchange over the cardiac cell membrane is slower than generally believed, it opens up for harvesting selective information about IC water. Mn is taken up and retained IC in the healthy myocardium, but to a much lesser extent in dysfunctioning myocardium. As this paramagnetic metal shortens the IC Tl and T2 with subsequent effects on EC Tl and T2, Mn ions represent an ideal MRI marker of myocardial function. This is supported by the possibilities of using Mn and specific imaging techniques to obtain information about mitochondrial water and function.

The following examples are for illustrative purposes only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications can be made without violating the spirit or scope of the invention.

EXAMPLES

Isolated rat hearts perfused with Krebs buffer was used in the examples. In all examples with Mn loading of hearts the time course included: control perfusion 10 minutes; and infusion Of MnCl2 for 5 minutes (wash-in). The experiment was then continued with perfusion with buffer for 15 minutes for wash-out of all residual EC Mn ions. Control hearts followed the same time course but did not receive MnCl2. Ventricular myocardium was then rapidly removed and located in a MR tube within a 20 MHz relaxometer supplied with field gradients. The MR examinations were then performed at 370C.

Example 1

Measurement of longitudinal relaxation in myocardium.

Tl relaxation was measured using a standard Saturation Recovery pulse sequence, with 25 different delay times varying from a few milliseconds (ms) up to several seconds (s). The results from control hearts and heart perfused with buffer containing 25 μM MnCl2 are shown in Figure 1 a-b. The component in Figure 1 a with longest Tl value (~ 2000 ms) is assigned to signal from extra-tissue water, while the shortest one (-350 ms) vary in intensity and position, and can thus not be clearly assigned. In control hearts there is thus one broad tissue component located around 800 ms. When the heart is perfused with buffer containing 25 μM MnCl2 as seen in Figure 1 b, there is a significant shift in the Tl value for the tissue, indicating the increased Tl relaxivity for the IC water compartment. The results in Figure 1 (b) also indicate the appearance of two Tl components for the tissue representing IC and EC water but they cannot yet be fully separated from each other.

Example 2

Measurement of correlations between diffusion (D) and transversal relaxation (D-T2) in myocardium from control hearts.

An example from a D-T2 correlation measurement is shown in Figure 2. The data were obtained using a combined PGSE-CPMG pulse sequence, with the following crucial parameters: gradient pulse length = 2 ms; diffusion time = 8.5 ms; strength of gradient puls varied from 0-400 Gauss/cm in 16 steps; echo time in CPMG part of pulse sequence = 1 ms, with 8000 echoes collected. It reveals that the T2 components can be separated in two groups, where the two shortest components have the lowest diffusion coefficient, and are thus assigned to IC water. The longest component is assigned to extra-tissue water, and is correlated to the longest component in the Tl measurements. These measurements also show that IC and EC water can be separated with respect to T2, even in control hearts without enhancement of intracellular manganese. The results presented in Figure 2 show that using T2 weighting it is possible to separate signals from IC and EC water, and that by combining Tl and T2 weighting in an MRI setting it is possible to obtain an image where the Tl contrast is created by an intracellular contrast agent, while the compartments are separated by their differences in T2.

Example 3:

Measurement of longitudinal relaxation and Tl-weighted transverse relaxation in hearts perfused with manganese.

With enhancement of intracellular manganese, the tissue component can be clearly divided in two components. This is shown in Figure 3 a, where the Tl distribution in excised hearts after perfusion withl50 μM MnCl2 is presented. Two tissue components with Tl values of 100 and 300 ms are identified.

Tl-weighted T2 relaxation was measured using a combined Inversion Recovery - CPMG pulse sequence, where the echo time in CPMG part of pulse sequence = 1 ms, and with 8000 echoes collected. This leads to Tl weighted (Tl filtered) T2 distributions. The result from a T2 measurement in myocardium perfused with 150 μM MnCl2, and with no Tl weighting (TI=O) is shown in Figure 3 b. There are four T2 components, where the one having longest T2 is assigned to extra-tissue water. The three other can be assigned to tissue water. As shown in Figure 2, the Tl values for the IC and EC water components are 100 and 300 ms, respectively. By choosing an inversion time so that the signal from EC and extra-tissue water is equal to zero (nulled), the signal from two longest T2 components can be suppressed, while the two shortest remains. A result from such a measurement with TI= 200 ms is shown in Figure 3 c.

The results presented in Figure 3 b-c shows that in the presence of a sufficient amount of intracellular contrast agent, and using an inversion pulse with a corresponding optimized inversion time (TI), it is possible to separate IC and EC water signals. This can be directly applied in an imaging setting, where an MR image is acquired instead of the T2 measurement.

Claims

1. A MRI method for assessment of myocardial function and viability, said method comprising detecting separately Tl and T2 relaxivities and water diffusion for differentiating intracellular water compartments from extracellular water compartments in the myocardium.
2. A MRI method as claimed in claim 1 for differentiating the signals from intra- and extra cellular water in myocardium using T2- and Tl -weighted and/or diffusion weighted images in the presence of an intracellular contrast agent.
3. A method as claimed in claims 1-2, wherein said method enables tracking of intracellular and extracellular water separately.
4. A method as claimed in any preceding claim, wherein said method is based on inversion recovery in the presence of an intracellular contrast agent.
5. A method as claimed in any preceding claim, wherein said method is based on combining inversion recovery (inversion pulse preceding the acquisition of the image) with T2-weighted imaging (T2 map), where the inversion pulse creates the necessary imaging contrast, and where the T2-map makes the separation of EC and EC water signals possible.
6. A method as claimed in claims 1-4, wherein the preferable intracellular contrast agent is a Manganese (Mn) complex releasing Mn ions in a slow or rapid manner after intravenous infusion, more preferably a slow Mn ion releasing complex; and most preferably Mn complexed to N,N'-dipyridoxyl-diethylene-diamine-N,N' diacetic acid (MnPLED) and derivatives thereof.
7. A method as claimed in claims 1-4, wherein said intracellular contrast agent is a chelate or particle or macromolecule containing gadolinium or iron.
8. A method, as claimed in any preceding claim, wherein said method is capable of differentiating normal myocardium from injured or failing myocardium.
PCT/NO2005/000319 2004-09-07 2005-09-05 Mri method for assessment of myocardial function and viability WO2006028379A1 (en)

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US5869023A (en) * 1993-07-12 1999-02-09 Nycomed Imaging As Composition for MRI comprising both a positive and a negative contrast agent
WO2001087155A1 (en) * 2000-05-18 2001-11-22 Yeda Research And Development Co., Ltd. Method and apparatus for the detection and diagnosis of cancer, specifically breast cancer using diffusion mri
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