Magnetic resonance imaging

Abstract

A method of determining the amount of intracellular manganese in the myocardium of an individual pre-administered with a manganese contrast agent, or a pharmaceutically acceptable salt thereof, comprising subjecting, the individual to a MRI procedure to assess the signal intensity (SI) of images, or more preferably the longitudinal relaxation rate, R.sub.1 throughout the myocardium.

Claims

1. A method of diagnosing cardiac remodeling and likelihood of arrhythmias and of heart failure, by a single examination in a human individual weeks to months after said individual has suffered an acute myocardial infarction, said method consisting of four consecutive steps: (i) administering intravenously to said individual a manganese contrast agent capable of releasing manganese ions or an intact manganese contrast agent, or pharmaceutically acceptable salts thereof, for enabling uptake of manganese in cardiomyocytes of said individual; (ii) thereafter subjecting said individual to one MRI procedure measuring a longitudinal relaxation rate, R.sub.1, or its reciprocal a longitudinal relaxation time, T.sub.1, throughout sectors and layers of the myocardium and expressing the measured R.sub.1 or T.sub.1 values in maps of said myocardium; (iii) detecting the presence of a continuous gradient of R.sub.1 or T.sub.1 in the myocardium from a site of infarction to a region remote from said site, wherein the R.sub.1 values correlate positively and the T.sub.1 values correlate negatively to the function and viability of cardiomyocytes; and (iv) diagnosing the individual with cardiac remodeling and likelihood of arrhythmias and heart failure when the presence of said continuous gradient in R.sub.1 or T.sub.1 is detected; wherein the step (iii) comprises: (a) determining whether the R.sub.1 values of the sectors or layers exhibit the continuous gradient from subnormal values at a site of infarction to supernormal values at a region remote from said site, wherein the R.sub.1 values correlate positively to the function and viability of cardiomyocytes; or (b) determining whether the T.sub.1 values of the sectors or layers exhibit the continuous gradient from supernormal values at a site of infarction to subnormal values at a region remote from said site, wherein the T.sub.1 values correlate negatively to the function and viability of cardiomyocytes.

2. The method as claimed in claim 1 wherein said manganese contrast agent capable of releasing manganese ions is a manganese ion releasing chelate.

3. The method as claimed in claim 2 wherein said manganese ion releasing chelate has a Ka value in the range of 10.sup.7 to 10.sup.25.

4. The method as claimed in claim 2, wherein said manganese ion releasing chelate is a dipyridoxyl compound.

5. The method as claimed in claim 2, wherein said manganese ion releasing chelate is a compound of formula II and salts thereof, ##STR00003## wherein in formula II each R.sup.1 independently represents hydrogen or CH.sub.2COR.sup.5; R.sup.5 represents hydroxy, optionally hydroxylated alkoxy, amino or alkylamido; each R.sup.2 independently represents an alkyl group substituted by one or more groups selected from hydroxyl, COOR.sup.8, CONR.sup.8.sub.2, NR.sup.8.sub.2, OR.sup.8, NR.sup.8, O, OP(O)(OR.sup.8)R.sup.7, OP(O)(OM)R.sup.7 and OSO.sub.3M; R.sup.7 is OM, hydroxy, an optionally hydroxylated, optionally alkoxylated alkyl or aminoalkyl group; R.sup.8 is a hydrogen atom, or an optionally hydroxylated, optionally alkoxylated alkyl group; M is a hydrogen atom or one equivalent of a physiologically tolerable cation; R.sup.3 represents a C.sub.1-8 alkylene group; and each R.sup.4 independently represents hydrogen or C.sub.1-3 alkyl.

6. The method as claimed in claim 5, wherein each R.sup.2 independently represents a C.sub.1-6 alkyl group substituted by one or more groups selected from the group consisting of hydroxyl, COOR.sup.8, CONR.sup.8.sub.2, NR.sup.8.sub.2, OR.sup.8, NR.sup.8, O, OP(O)(OR.sup.8)R.sup.7, OP(O)(OM)R.sup.7 and OSO.sub.3M.

7. The method as claimed in claim 5, wherein the physiologically tolerable cation is an alkali or alkaline earth cation, an ammonium ion or an organic amine cation.

8. The method as claimed in claim 5, wherein R.sup.3 represents a C.sub.1-6 alkylene group.

9. The method as claimed in claim 5, wherein R.sup.3 represents a C.sub.2-4 alkylene group.

10. The method as claimed in claim 2, wherein said manganese ion releasing chelate has a Ka value in the range of 10.sup.9 to 10.sup.24.

11. The method as claimed in claim 2, wherein said manganese ion releasing chelate has a Ka value in the range of 10.sup.10 to 10.sup.23.

12. The method as claimed in claim 2, wherein said manganese ion releasing chelate has a Ka value in the range of 10.sup.12 to 10.sup.22.

13. The method as claimed in claim 1, wherein said manganese contrast agent capable of releasing manganese ions is selected from the group consisting of MnDPDP, MnDPMP and MnPLED.

14. The method as claimed in claim 1, wherein said manganese contrast agent capable of releasing manganese ions is selected from the group consisting of MnDPMP and MnPLED.

15. The method as claimed in claim 1, wherein said manganese contrast agent capable of releasing manganese ions is MnDPDP.

16. The method as claimed in claim 1, wherein said manganese contrast agent capable of releasing manganese ions or an intact manganese contrast agent, or pharmaceutically acceptable salts thereof is administered in a dose of 0.5 to 40 mol/kg bodyweight.

17. The method as claimed in claim 16, wherein the dose is 1 to 20 mol/kg bodyweight.

18. The method as claimed in claim 16, wherein the dose is 2 to 10 mol/kg bodyweight.

19. The method as claimed in claim 1, wherein said manganese contrast agent capable of releasing manganese ions or an intact manganese contrast agent, or pharmaceutically acceptable salts thereof is administered by intravenous infusion over 1 to 30 minutes.

20. The method as claimed in claim 19, wherein the intravenous infusion is over 2 to 20 minutes.

21. The method as claimed in claim 19, wherein the intravenous infusion is over 5 to 10 minutes.

22. The method as claimed in claim 1, wherein said administration of said manganese contrast agent capable of releasing manganese ions or an intact manganese contrast agent, or pharmaceutically acceptable salts thereof is conducted outside of the magnetic field used for said MRI procedure and MRI is carried out within 0.5 to 6 hours thereafter.

23. The method as claimed in claim 22, wherein the MRI is carried out within 1 to 4 hours thereafter.

24. The method as claimed in claim 22, wherein the MRI is carried out within 1.5 to 3 hours thereafter.

25. The method as claimed in claim 22, wherein the MRI is carried out within 30 to 60 minutes thereafter.

26. The method as claimed in claim 1, wherein said administration of said manganese contrast agent capable of releasing manganese ions or an intact manganese contrast agent, or pharmaceutically acceptable salts thereof is conducted inside of the magnetic field used for said MRI procedure and MRI is carried out intermittently before, during and/or thereafter.

27. The method as claimed in claim 1 wherein said manganese contrast agent capable of releasing manganese ions is administered to said individual.

28. The method of claim 1, wherein the number of sectors of the myocardium is 5 to 50.

29. A method of diagnosing cardiac remodeling and likelihood of arrhythmias and of heart failure, by a single examination in a human individual weeks to months after said individual has suffered an acute myocardial infarction, said method consisting of four consecutive steps: (i) administering intravenously to said individual a manganese contrast agent capable of releasing manganese ions or an intact manganese contrast agent, or pharmaceutically acceptable salts thereof, for enabling uptake of manganese in cardiomyocytes of said individual; (ii) thereafter subjecting said individual to one MRI procedure measuring a signal intensity in R.sub.1 weighted images throughout sectors and layers of the myocardium and expressing the measured signal intensity in images of said myocardium; (iii) detecting the presence of a continuous gradient of signal intensity in the myocardium from a site of infarction to a region remote from said site, wherein the signal intensity correlates positively to the function and viability of cardiomyocytes; and (iv) diagnosing the individual with cardiac remodeling and likelihood of arrhythmias and heart failure when the presence of said continuous gradient in signal intensity is detected; wherein the step (iii) comprises determining whether the signal intensity of the sectors or layers exhibit the continuous gradient from subnormal values at a site of infarction to supernormal values at a region remote from said site.

30. A method of detecting a continuous gradient of a longitudinal relaxation rate or a longitudinal relaxation time in a myocardium from a site of infarction to a region remote from said site in a human individual in a single examination, said method consisting of: (i) administering intravenously over 1 to 30 minutes a dose of 0.5 to 40 mol/kg body weight of a chelated manganese contrast agent capable of releasing manganese ions with a Ka value in the range of 10.sup.7 to 10.sup.25, or a pharmaceutically acceptable salt thereof, to said individual weeks to months after said individual has suffered an acute myocardial infarction; (ii) subjecting said individual to one MRI procedure measuring a longitudinal relaxation rate, R.sub.1, or its reciprocal the longitudinal relaxation time, T.sub.1, throughout sectors and layers of the myocardium of said individual and expressing the measured R.sub.1 or T.sub.1 values in maps of said myocardium; (iii) dividing the maps of R.sub.1 or T.sub.1 into transmural sectors or layers to create a composite distribution plot of R.sub.1 or T.sub.1; (iv) detecting the presence of the continuous gradient of the R.sub.1 or T.sub.1 values of the sectors or layers in the myocardium from a site of infarction to a region remote from said site, wherein the R.sub.1 values correlate positively or the T.sub.1 values correlate negatively to the function and viability of cardiomyocytes; and (v) diagnosing the individual with cardiac remodeling and an increased risk of arrhythmia or heart failure when the presence of said continuous gradient in R.sub.1 or T.sub.1 is detected; wherein the step (iv) comprises: (a) determining whether the R.sub.1 values of the sectors or layers exhibit the continuous gradient from subnormal values at a site of infarction to supernormal values at a region remote from said site, wherein the R.sub.1 values correlate positively to the function and viability of cardiomyocytes; or (b) determining whether the T.sub.1 values of the sectors or layers exhibit the continuous gradient from supernormal values at a site of infarction to subnormal values at a region remote from said site, wherein the T.sub.1 values correlate negatively to the function and viability of cardiomyocytes.

31. A method of assessing the risk of arrhythmias or heart failure in an individual, examined weeks to months after suffering an acute myocardial infarction, by subjecting said individual to a single diagnostic procedure to determine the presence and extent of remodeling of myocardium, said method consisting of the following four steps: (i) administering intravenously a manganese contrast agent capable of releasing manganese ions or an intact manganese chelate contrast agent for cardiomyocyte uptake, or a pharmaceutically acceptable salt thereof, to said individual; (ii) subjecting said individual to an MRI procedure to determine viability and function of cardiomyocytes by measuring a longitudinal relaxation rate, R.sub.1, or its reciprocal a longitudinal relaxation time, T.sub.1, throughout sectors and layers of the myocardium and mapping the measured R.sub.1 or T.sub.1 values throughout said myocardium; (iii) detecting remodeling of myocardium by observing a continuous gradient of R.sub.1 or T.sub.1 in the myocardium from a site of infarction to a region remote from said site wherein the R.sub.1 values correlate positively and the T.sub.1 values correlate negatively to the function and viability of cardiomyocytes; and (iv) quantifying the extent of remodeling and the risk of arrhythmias or heart failure by measuring the continuous gradient in R.sub.1 or T.sub.1; wherein the step (iii) comprises: (a) determining whether the R.sub.1 values of the sectors or layers exhibit the continuous gradient from subnormal values at a site of infarction to supernormal values at a region remote from said site, wherein the R.sub.1 values correlate positively to the function and viability of cardiomyocytes; or (b) determining whether the T.sub.1 values of the sectors or layers exhibit the continuous gradient from supernormal values at a site of infarction to subnormal values at a region remote from said site, wherein the T.sub.1 values correlate negatively to the function and viability of cardiomyocytes.

32. The method of claim 31, wherein the method assesses the risk of arrhythmias.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The method of the invention will now be illustrated further by way of examples with particular reference to certain non-limiting embodiments and to the accompanying figures wherein:

(2) FIG. 1 shows the hypothesised metabolic breakdown of MnDPDP in vivo.

(3) FIG. 2 shows the changes in signal intensity (SI) in the myocardium (black) and blood (grey) in a healthy individual following administration of Teslascan (5 mol/kg over 5 minutes (a) and over 30 minutes (b))

(4) FIG. 3 shows temporal R.sub.1 changes from blood (dotted line), suspected myocardial infarct (grey line) and the remote region (black line) in a patient with a fully developed infarct.

(5) FIG. 4 shows temporal R.sub.1 changes from blood (dotted line), suspected infarcted region (grey line) and a remote region (black line) in a patient wherein treatment by PCI at onset of infarction resulted in myocardial salvage.

(6) FIG. 5 shows R.sub.1 maps of short axis slices from a patient treated with PCI but with a fully developed infarct.

(7) FIG. 6 shows R.sub.1 maps of short axis slices from a patient wherein treatment by PCI at onset of infarction resulted in myocardial salvage

EXAMPLES

Magnetic Resonance Imaging

(8) MR-examinations were carried out in 10 patients 3-12 weeks following an acute coronary episode with onset of acute myocardial infarction (AMI). All patients were revascularized by percutaneous coronary intervention (PCI) immediately after admission to hospital for AMI.

(9) Examinations were performed on a Siemens Magnetom Symphony 1.5 Tesla scanner with Quantum gradients (Software Version: Syngo 2002B, VA21B. Gradient strength: 30 mT/m.). Recordings were done with a body phase-array surface coil. An electrocardiographic (ECG) signal was used for heart rate monitoring and sequence triggering.

(10) Steady-state free precession (true-FISP) cine short axis slices were made covering the ventricular length. Each slice was acquired during one breath-hold, with a slice thickness of 8 millimeters and slice separation of 10 millimeters. Based on examination of the short axis cine images for signs of impaired wall motion and systolic wall thickening, one slice was selected in each patient for imaging of contrast enhancement. The slice location parameters from this slice of interest (SOI) were copied and used through the remaining MRI examinations.

(11) Pre-contrast myocardial and blood R.sub.1-measurements in the SOI were performed through a series of 20 images using an inversion recovery (IR) turbo-FLASH (fast low-angle shot) sequence with subsequently increasing inversion-times (T.sub.1). The sequence used a nonselective 180 degree inversion pulse followed by an ultra fast FLASH sequence, consisting of repetitive low-angle slice selective -pulses with gradient echoes generated in between the -pulses. The inversion times used spanned from 90 to 5000 ms. The parameter settings were: bandwidth: 1000 Hz/pixel, echo spacing (TR): 1.9 ms, TE: 1.06 ms, field of view: 380 mm, slice thickness: 8 mm, -flip angle: 12 degrees and a phase partial Fourier of 6/8.

(12) After the initial R.sub.1-measurement, the MR-scanner was set to record a series of IR-images with the same parameter settings as used for the R.sub.1-measurements, but with a fixed inversion time of 400 ms.

(13) After 10 reference images, patients received 5 mol MnDPDP per kg body weight of a 0.01 mmol/ml solution (Teslascan, Amersham) as a peripheral intravenous infusion over five minutes. A total of 300-350 IR images were acquired over of 40-45 minutes. Throughout these infusion series, a time interval of 7-8 seconds was maintained between individual images.

(14) Then imaging, for the purpose of visualization of infarcted regions, was performed. Two T.sub.1 weighted ECG-gated segmented sequences were tried out: an IR turbo-FLASH sequence and an IR true-FISP sequence with the possibility of phase sensitive reconstruction. In either case, individualized inversion times were used, depending on heart rate and ability for breath holds.

(15) Finally, a second R.sub.1-measurement consisting of 20 IR turbo-FLASH images over five min was performed one hour after the start of the contrast infusion. R.sub.1 analyses

(16) R.sub.1 Analysis

(17) The images for the R.sub.1 measurements were analyzed using software written in Matlab version 6.5 (MathWorks, USA) and the inner and outer borders of the LV wall were drawn manually in each single slice. The outlined myocardium was then divided into 24 sectors. The signal intensity was extracted and analyzed separately for each sector. The signal equation was fitted to the data from the sectors to obtain an estimate of R.sub.1.

(18) $\begin{array}{cc}S=.Math.M_0\sin \left[\left(1-2e^{\left(-R_1\mathrm{TI}\right)}\right)a^{n-1}+\frac{b\left(1-a^{n-1}\right)}{\left(1-a\right)}\right].Math.& \left[1\right]\end{array}$

(19) In this equation, S is the signal intensity, is a constant dependent on receiver gain, instrumental conditions and T.sub.2* decay (which is a constant with the short TEs used), M.sub.0 is the fully relaxed longitudinal magnetization, is the angle of the RF pulse used, TI is the inversion time measured to the start of the -RF-pulse chain, n is the number of -pulses until the centre of K-space, TR is the time interval between two -pulses in the pulse chain, a=(cos exp(R.sub.1TR)) and b=(1exp(R.sub.1TR)). The fitting was performed with two variables: R.sub.1 and the product of M.sub.0. These two variables were optimized using a simplex search method and a least-squares cost function.

(20) Separate R.sub.1 values were calculated for each of the 24 sectors for both the reference R.sub.1 measurements and the measurements after one hour. A R.sub.1 value for each sector was calculated as the one-hour R.sub.1 value minus the reference value.

(21) Temporal R.sub.1 Changes

(22) Temporal R.sub.1 changes following contrast infusion were created by combining each patient's reference R.sub.1 measurements with the patient's infusion series. The images were analysed together in software written in Matlab. Based upon the R.sub.1 values, two small ROIs (5 to 8 pixels in size) were drawn centrally in the LV wall. One ROI was placed in the centre of the assumed infarct region and one in a remote region supplied by a different coronary artery. A third ROI was placed in blood in the LV cavity, and given a diameter of approximately half the inner LV diameter. Each ROI was drawn in the first image and copied through all images of the R.sub.1-measurement as well as through the infusion series. The ROIs were then manually adjusted for respiratory motions. Signal intensities were extracted and pre-contrast R.sub.1-measurements were made though Equation 1. The estimated M.sub.0 products were then, by equation 1, used to convert the changes in signal intensities following the infusions into temporal R.sub.1 changes

(23) Results

(24) Infusion and Post Infusion MRI Kinetics

(25) FIGS. 3 and 4 show the results of temporal R.sub.1 determination in two of the ten patients. FIG. 3 shows the results obtained from a patient treated with PCI but who still developed a full infarct as confirmed by previous history and now also by T.sub.1 weighted MRI. During the infusion of Teslascan (0-5 min) there is an early Mn uptake not only in the remote and viable region but also in the infarcted area, and after the infusion there is a late Mn uptake in the remote region but not in the infarcted area. The absence of late uptake in the infarct region indicates that it contains scar tissue without viable myocardial cells.

(26) In contrast, FIG. 4 shows the results obtained from a patient who received treatment by PCI much earlier after the onset of infarction. In this patient early intervention resulted in myocardial salvage as confirmed by clinical parameters and now also by T.sub.3 weighted MRI. During the infusion of Teslascan (0-5 min), similar uptake profiles with both an early and a late Mn uptake were observed both in the previous area at risk (infarcted region) as in the remote region. This indicates that all cells are viable.

(27) These observations in the two patients indicate two phases of Mn.sup.2+ ion uptake and that different manganese agents were responsible: an early uptake during the 5 min period of infusion occurred from the mother substance MnDPDP; and a late uptake occurred in the postinfusion period after conversion of MnDPDP to its two metabolites MnDPMP and MnPLED. Surprisingly, the observations show that whereas an early uptake with MnDPDP indicates viability plus perfusion of the myocardium, a late uptake specifically indicates viability. MnDPDP is therefore a viability plus perfusion marker, whilst MnDPMP and MnPLED are pure viability markers.

(28) R.sub.1 Mapping of Short Axis Slices

(29) R.sub.1 maps in short axis slices of the heart covering the previous areas of developed or suspected infarctions were prepared for the same two patients and are shown in FIGS. 5 and 6. These show that much more graded information can be obtained by the uses and methods of the invention. Prior to infusion of Teslascan hardly any differences can be observed in the R.sub.1 values between sectors, but 45 min thereafter a much more marked heterogeneity appears.

(30) In the patient with a persistent post infarction defect (FIG. 5), in the first background MR images the R.sub.1's are 0.80 s.sup.1 and 0.95 s.sup.1 in the infarcted vs the remote zones, i.e. a difference in R.sub.1 of 0.15 s.sup.1 In the manganese enhanced MR images the respective R.sub.1's are 0.95 s.sup.1 and 1.35 s.sup.1, i.e. a difference in R.sub.1 of 0.40 s.sup.1. This result may be explained by the remote regions late uptake of manganese. Surprisingly and more importantly, however, there is a gradual difference from the infarct zone (0.95 s.sup.1): to the border zone (1.10 s.sup.1); then to large intermediary zones (1.20 s.sup.1); and finally into the remote and major zone (1.35 s.sup.1).

(31) In the patient with myocardial salvage (FIG. 6), there is hardly any differences between transmural sectors before or after contrast. Thus homegeneity is maintained and there is an average elevation of R.sub.1 of 0.40 s.sup.1 as expected for normal myocardium after Mn infusion. The intersector variation is within 0.05 to 0.10 s.sup.1.

(32) These results from R.sub.1 mapping demonstrates detectable regional alterations in tissue relaxation and thus in tissue Mn uptake/retention during recovery from a fully developed AMI. This is consistent with postinfarct cardiac remodelling, here for the first time demonstrated with intracellular paramagnetic Mn ions reflecting either the overall number of live cardiac cells and/or the state of function of these cells.

(33) In the patient with the persistent infarct and scar tissue the R.sub.1 findings were consistent with a reduced LV ejection fraction (49%) and indicated a need for therapy in order to delay the development of an overt HF. In the other patient without signs of remodelling of the left ventricle and a normal LV ejection fraction (71%) there was no need for such specific therapy.