WO2005079274A2 - Magnetic resonance imaging of atherosclerotic plaque - Google Patents

Abstract

Contrast-enhanced MR using a Gadofluorine contrast agent enables plaque in blood vessels to be imaged. An inversion recovery T1-weighted pulse sequence includes a diffusion flow nulling sequence that enables image acquisition within one hour of contrast injection by suppressing intravascular blood signals so that plaque can be detected.

Description

MAGNETIC RESONANCE IMAGING OF ATHEROSCLEROTIC PLAQUE

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is based on U.S. Provisional Patent Application Serial No.

60/543,968 filed on February 12, 2004, and entitled " Magnetic Resonance Imaging Of Atherosclerotic Plaque ".

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH [0002] This invention was made with government support under Grant No. H/NHLBI RO1 HL 71021 awarded by the National Institute of Health. The United States Government has certain rights in this invention.

BACKGROUND OF THE INVENTION

[0003] The field of the invention is nuclear magnetic resonance imaging methods and systems. More particularly, the invention relates to contrast enhanced imaging of atherosclerotic plaques.

[0004] When a substance such as human tissue is subjected to a uniform magnetic field (polarizing field Bo), the individual magnetic moments of the spins in the tissue attempt to align with this polarizing field, but precess about it in random order at their characteristic

Larmor frequency. If the substance, or tissue, is subjected to a magnetic field (excitation field

Bi) which is in the x-y plane and which is near the Larmor frequency, the net aligned moment, M_z, may be rotated, or "tipped", into the x-y plane to produce a net transverse magnetic moment M_t. A signal is emitted by the excited spins after the excitation signal Bi is terminated, this signal may be received and processed to form an image.

[0005] When utilizing these signals to produce images, magnetic field gradients (G_x

G_y and G_z) are employed. Typically, the region to be imaged is scanned by a sequence of measurement cycles in which these gradients vary according to the particular localization method being used. The resulting set of received MR signals are digitized and processed to reconstruct the image using one of many well known reconstruction techniques.

[0006] Atherosclerosis is a chronic systemic disease that affects the arterial wall of medium and large arteries. With its thrombotic complications, the resultant plaque may grow to obstruct the lumen or to disseminate material into the blood stream and may cause myocardial infarction, stroke, and peripheral vascular disease. These distinct clinical manifestations depend on the affected circulatory bed and the characteristics of the individual lesions. In early states, atherosclerotic plaques may not be seen by conventional x-ray angiography or other standard imaging techniques, because they develop without narrowing the arterial lumen. Despite this so called: "positive arterial remodeling", such lesions may be clinically significant even though no significant arterial lumen stenosis is detected, because complications may develop suddenly.

[0007] Non-invasive high-spatial resolution in vivo MR imaging is capable of detecting and characterizing atherosclerotic plaques. However, complete characterization and detection of high-risk plaques still remains difficult. Contrast-enhanced MR has been used for plaque imaging because it has the potential to improve the contrast-to-noise ratio (CNR) between the lumen and the vessel wall. Contrast-enhanced MR facilitates the rapid assessment of overall atherosclerotic plaque burden, particularly in deep structures such as coronary arteries, with inherent poor signal-to-noise ratio (SNR). [0008] Gadofluorine contrast agent has been shown to improve plaque detection compared to conventional contrast-enhanced MRI. Since Gadofluorine has a higher relaxivity (Rl) compared to the standard contrast agent, Gd-DTPA, the spin lattice relaxation time (Tl) of the blood immediately after injection is very short. This leads to a high signal in the arterial lumen that obscures the vessel wall and plaque visualization. This strong signal cannot be suppressed using known inversion recovery preparatory pulses, and as a result, when Gadofluorine contrast agent is used to shorten the Tl of the target tissues, a waiting period of up to 24 hours is imposed after contrast injection to allow the Tl of blood to recover. The contrast agent remains in the target tissues for a longer time period and hence the desired Tl shortening in those tissues is still present after the waiting period. [0009] The need for a long waiting period when using contrast agents such as

Gadofluorine is a significant factor in limiting their use. The long waiting period means the patient must have two appointments, one to acquire a pre-contrast image and administer the contrast agent injection, and a second appointment the next day to acquire the post-contrast image. In addition, the registration of the two acquired images so that they may be subtracted is more complicated by the removal of the patient from the scanner between image acquisitions.

SUMMARY OF THE INVENTION

[0010] The present invention is a method for acquiring contrast enhanced magnetic resonance images immediately following contrast injection, and particularly, a method for acquiring MR image data in which MR signals from moving blood, which otherwise might obscure depiction of the tissues of interest, are suppressed using a diffusion flow nulling sequence in the image acquisition pulse sequence.

[0011] A general object of the invention is to suppress the signal from moving spins after injection of a contrast agent which otherwise enhances the signal from such spins. The diffusion flow nulling sequence is performed as a preparatory pulse sequence prior to the image acquisition pulse sequence and it suppresses MR signals from moving spins regardless of the enhancement otherwise provided by a previously injected contrast agent. The diffusion flow nulling sequence requires less time to perform than other methods for suppressing such signals.

[0012] Another object of the invention is to enable MR images to be acquired promptly after injection of contrast agents that shorten the Tl relaxation time of spins in target tissues. Although the contrast agent also shortens the Tl of blood to enhance its contrast along with the target tissues, the diffusion flow nulling sequence suppresses the MR signals from moving blood. As a result, blood appears black in the reconstructed image and the target tissues, such as atherosclerotic plaques, are bright.

[0013] A more specific object of the invention is to enable the acquisition of MR images shortly after injecting contrast agents into the subject. The image may be acquired at a time in which the contrast agent has enhanced the contrast of target tissues such as arterial plaque. The bright signal otherwise produced by contrast enhanced moving spins such as blood is suppressed, however, so that clinically useful images are acquired without the need for a long delay period after contrast injection.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Fig. 1 is a block diagram of an MRI system which employs the present invention;

[0015] Fig. 2 is a graphic representation of a preferred pulse sequence for practicing the present invention on the MRI system of Fig. 1 ; and

[0016] Fig. 3 is a flow chart of the method in which the pulse sequence of Fig. 2 is employed.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT [0017] Referring first to Fig. 1, there is shown the major components of a preferred

MRI system which incorporates the present invention. The operation of the system is controlled from an operator console 100 which includes a keyboard and control panel 102 and a display 104. The console 100 communicates through a link 116 with a separate computer system 107 that enables an operator to control the production and display of images on the screen 104. The computer system 107 includes a number of modules which communicate with each other through a backplane. These include an image processor module 106, a CPU module 108 and a memory module 113, known in the art as a frame buffer for storing image data arrays. The computer system 107 is linked to a disk storage 111 and a tape drive 112 for storage of image data and programs, and it communicates with a separate system control 122 through a high speed serial link 115.

[0018] The system control 122 includes a set of modules connected together by a backplane. These include a CPU module 119 and a pulse generator module 121 which connects to the operator console 100 through a serial link 125. It is through this link 125 that the system control 122 receives commands from the operator which indicate the scan sequence that is to be performed. The pulse generator module 121 operates the system components to carry out the desired scan sequence. It produces data which indicates the timing, strength and shape of the RF pulses which are to be produced, and the timing of and length of the data acquisition window. The pulse generator module 121 connects to a set of gradient amplifiers 127, to indicate the timing and shape of the gradient pulses to be produced during the scan. The pulse generator module 121 also receives patient data from a physiological acquisition controller 129 that receives signals from a number of different sensors connected to the patient, such as ECG signals from electrodes or respiratory signals from a bellows. And finally, the pulse generator module 121 connects to a scan room interface circuit 133 which receives signals from various sensors associated with the condition of the patient and the magnet system. It is also through the scan room interface circuit 133 that a patient positioning system 134 receives commands to move the patient to the desired position for the scan.

[0019] The gradient waveforms produced by the pulse generator module 121 are applied to a gradient amplifier system 127 comprised of G_x, G_y and G_z amplifiers. Each gradient amplifier excites a corresponding gradient coil in an assembly generally designated 139 to produce the magnetic field gradients used for position encoding acquired signals. The gradient coil assembly 139 forms part of a magnet assembly 141 which includes a polarizing magnet 140 and a whole-body RF coil 152. A transceiver module 150 in the system control 122 produces pulses which are amplified by an RF amplifier 151 and coupled to the RF coil 152 by a transmit/receive switch 154. The resulting signals radiated by the excited nuclei in the patient may be sensed by the same RF coil 152 and coupled through the transmit/receive switch 154 to a preamplifier 153. The amplified MR signals are demodulated, filtered, and digitized in the receiver section of the transceiver 150. The transmit/receive switch 154 is controlled by a signal from the pulse generator module 121 to electrically connect the RF amplifier 151 to the coil 152 during the transmit mode and to connect the preamplifier 153 during the receive mode. The transmit/receive switch 154 also enables a separate RF coil (for example, a head coil or surface coil) to be used in either the transmit or receive mode. [0020] The MR signals picked up by the RF coil 152 are digitized by the transceiver module 150 and transferred to a memory module 160 in the system control 122. When the scan is completed and an entire array of data has been acquired in the memory module 160, an array processor 161 operates to Fourier transform the data into an array of image data. This image data is conveyed through the serial link 115 to the computer system 107 where it is stored in the disk memory 111. In response to commands received from the operator console 100, this image data may be archived on the tape drive 112, or it may be further processed by the image processor 106 and conveyed to the operator console 100 and presented on the display 104.

[0021] The present invention is practiced using the MRI system of Fig. 1 under the direction of a pulse sequence depicted in Fig. 2. This preferred pulse sequence is designed to image atherosclerotic plaque in blood vessels using conventional imaging pulse sequences depicted at 100. These may be fast gradient-recalled echo pulse sequences, fast spin echo pulse sequences or other known imaging pulse sequences suitable for acquiring MR data from the tissues of interest. Either a multi-slice 2D pulse sequence may be used or a 3D pulse sequence. Cardiac or respiratory gating may be used, and when cardiac gating is used the image data may be acquired in segments at specific cardiac cycle phases. Typically the chosen imaging pulse sequence is repeated n times to acquire a corresponding number of views that sample k-space in the prescribed manner, where n typically is from 1 to 15. The pulse sequence of Fig. 2 includes three separate spin preparation sequences, or modules, 102, 104 and 106 that preceed the image acquisition module 100. The pulse sequence of Fig. 2 is repeated as necessary to sample k-space sufficiently to provide data from which an image is reconstructed. [0022] The first preparatory module 102 includes an adiabatic, hyperbolic secant,

180° flip angle, RF inversion pulse 108 that inverts the spin magnetization throughout the volume of interest. The inversion pulse 108 is produced such that the subsequent inversion time Tl allows recovery of the longitudinal spin magnetization which has been Tl shortened by the contrast agent by the time the image acquisition module 100 is played out. As a result, signals from tissues with longer Tl relaxation such as muscle and other tissues outside blood vessel walls will be suppressed in the MR image data acquired during the image acquisition module 100. The inversion time Tl in the preferred embodiment ranges from 180 to 220 milliseconds, and the transmit repeat time (TR) of the entire pulse sequence is 300 milliseconds.

[0023] The second preparatory module 104 is a diffusion flow nulling sequence which dephases MR signals produced by moving spins such as blood. The diffusion module 104 includes non-selective RF pulses 110, 112 and 114 having respective flip angles of 90°, 180°, 90°. A dephasing gradient 116, 118 and 120 is applied along the respective readout, phase encoding and slice select gradient axes after the first 90° pulse 110. This dephases the spin magnetization tipped into the transverse plane by the RF pulse 110. After the 180° RF refocusing pulse 112, a dephasing gradient 122, 124 and 126 is applied along the respective readout, phase encoding and slice select gradient axes. The dephasing gradients 122, 124 and 126 have the same size (i.e., area) as the dephasing gradients 116, 118 and 120 such that the transverse magnetization of stationary spins are rephased prior to being flipped back to the longitudinal axis by the following 90° RF pulse 114. On the other hand, moving spins do not "see" the same field before and after the 180° RF pulse 112 and their transverse magnetization remains dephased when the second 90° RF pulse is applied. As a result, the net longitudinal magnetization produced by moving spins is substantially suppressed by the diffusion flow nulling sequence 104 and minimal signal will be produced by moving spins during the subsequent image acquisition module 100. This has been found to suppress intravascular signal regardless of the Tl of blood.

[0024] In the preferred embodiment the diffusion flow nulling sequence 104 is played out in 7 milliseconds with a typical ratio of RF pulse duration to gradient pulse duration of 0.5. The strength of the flow suppression is a function of the first moment of the respective dephasing and dephasing gradient lobes, where the first moment is the product of the size of the gradient lobes and the time interval between them. Thus, the amount of flow suppression in any clinical application can be changed by altering the prescribed size of gradient lobes 116-120 and 122-126 or the time interval between them. The dephasing and dephasing gradient lobes have a duration of 1.3 ms and an amplitude of 28 mT/m to produce an area of 375.2 mT.sec.m^"1 in the preferred embodiment.

[0025] The third preparatory module 106 is a fat suppression sequence comprised of an RF pulse 128 and bipolar gradient pulses 130, 132 and 134 played out along respective readout, phase encoding and slice select gradient axes. As is well known in the art, there are many different methods for suppressing the signals produced by fat spins. In this clinical application a standard CHESS fat suppression module 106 is used to null signal from peri- adventitial fat which can obscure vessel walls due to chemical shift. In contrast to such fat signals, the relativity immobile lipid protons in plaque only contribute about 10% of the signal from plaque, and thus the fat suppression has negligible effect on the reconstructed plaque image. Of course, if signal from fat is not a problem, this module 106 can be eliminated from the pulse sequence.

[0026] Referring particularly to Fig. 3, a procedure for operating the MRI system according to a preferred embodiment of the present invention includes acquiring one or more pre-contrast images as indicated at process block 200. The selected imaging pulse sequences 100 are used in this initial acquisition and the fat suppression module 106 may also be used to suppress bright signal from fat in or near the volume of interest.

[0027] As indicated at process block 202, the next step is to inject the subject with a

Gadofluorine contrast agent. Gadofluorine is a lipophilic macrocyclic water-soluble, gadolinium chelate complex (Gd-DO3A-derivative) with a perfluorinated side chain. It is commercially available from Schering AG. Gadofluorine forms 5 nm diameter micelles or aggregates in aqueous solution. Gadofluorine elicits an Rl relaxivity (at 37°C and 1.5T) of 17.4

in blood. The majority of Gadofluorine is eliminated by hepatobiliary (66%) and renal route (34%) within seven days. Due to the higher relaxivity of Gadofluorine compared to conventional Gd-chelates we inject 50 μmol Gd/kg body weight. [0028] As indicated at process block 204, a post-contrast image is then acquired using the pulse sequence described above and shown in Fig. 2. A 2D fast gradient-recalled echo pulse sequence is employed in the preferred embodiment with an excitation flip angle of 20°; receiver bandwidth ±230 Hz/pixel; slice thickness 2.5 mm; field-of-view 12 cm and acquisition matrix of 256x256 k-space samples. This acquisition may be performed within one hour after contrast injection, thus eliminating the need for a second appointment on the day after injection.

[0029] As indicated by process block 206, the pre and post-contrast images are then reconstructed. This is a conventional complex, two-dimensional Fourier transformation followed by signal magnitude computation. If a 3D imaging pulse sequence is used during the acquisition steps, this reconstruction employs a three-dimensional Fourier transformation. As indicated by process block 208 the images are then displayed. If 2D slice images are acquired, each is displayed to view a cross-section through the subject blood vessel and associated plaque. If a 3D image is acquired, 2D slice images may be taken at any location and angle through the imaged volume of interest, or a 2D projection image can be produced from any viewing angle around the acquired volume.

[0030] The present invention is particularly useful in imaging plaques using a

Gadofluorine contrast agent. Gadofluorine is a macrocyclic gadolinium based contrast agent, with high relaxivity, long-plasma half-life, water solubility, and Hpophilicity compared to Gd- DTPA. Gadofluorine enhances atherosclerotic plaque and improves plaque detection compared with non-contrast enhanced MRI. The exact mechanism of Gadofluorine uptake and accumulation into the atherosclerotic plaque detection is still unknown. The contrast agent might leak out of the lumen into plaques because of enhanced endothelial permeability in atherosclerotic plaques. Conventional contrast-enhanced MR using Gd-chelates (e.g., Gd- DTPA) do not penetrate phospholipid-cellular membranes because of their highly hydrophilic properties. These agents are confined in the extra-cellular space after intravenous administration, do not bind to plasma proteins, and are eliminated unmetabolized by the kidneys. Gadofluorine forms aggregates or micelles in aqueous solution, and because of its lipophilic properties, the compound has the ability to penetrate and accumulate within the plaque after intravenous injection.

[0031] We found a strong correlation between lipid-rich areas in histological sections of plaque and the high CNR in the MR images, suggesting a high affinity of Gadofluorine for lipid-rich plaques. Furthermore, plaques with poor content in lipids, such as fibrocellular plaques, had a weaker signal enhancement compared to the lipid-rich area. The fibrocellular plaques are usually considered as less vulnerable plaques than plaques with rich-lipid core and/or with thin fibrous cap. This affinity to the lipid-rich areas may facilitate imaging and characterization of atherosclerotic plaques. [0032] Due to the high Tl-relaxivity (Rl) of Gadofluorine compared to Gd-chelate contrast agents, the use of conventional Tl -weighted imaging is not adequate for the detection of wall enhancement immediately post-injection. Atherosclerotic plaque detection in images acquired as early as 1-hour post-injection is achieved by suppressing signal from moving spins. The use of the diffusion flow nulling sequence is an efficient way of suppressing flow spins. Flow suppression depends on vessel size, and is more efficient in large-sized arteries (e.g., aorta), where the flow is laminar. The inversion recovery preparatory sequence is used to suppress the signal from the perivascular tissues (fat and muscle), and the diffusion module 104 is used to suppress intravascular blood signal by a mechanism independent of longitudinal relaxation. This is needed due to the relatively long Gadofluorine plasma half-life, high relaxivity, and short Tl in the lumen during the 24-hours following injection. Fat suppression is used to null signals from peri-adventitial fat, which can obscure the vessel wall due to chemical shift.

[0033] While a preferred embodiment of the invention has been described, it should be apparent to those skilled in the art that variations are possible without departing from the spirit of the invention. For example, Gadofluorine is the preferred contrast agent for the arterial plaque clinical application, but other contrast agents such as EP 2104, MS-325 and P792 may be used. The present invention is particularly applicable when using contrast agents having a relaxivity over 4.0 L. mol^.sec^"1 at 1.5 Tesla. Other suppression methods such as inversion recovery and double inversion recovery work with relaxivities less than this amount, but the present invention will suppress signal with contrast agents up to 48 L.mol^.sec^"1 at 1.5 Tesla and even higher relaxivity levels at higher Bo field strengths.

Claims

CLA S 1. A method for acquiring an image with a magnetic resonance imaging (MRI) system, the steps comprising: a) producing an inversion recovery preparatory pulse; b) producing a diffusion flow nulling preparatory sequence; c) performing an image acquisition pulse sequence to acquire MR data, the image acquisition pulse sequence being performed after step b) such that MR signals from moving spins are suppressed by the diffusion flow nulling preparatory sequence, and being performed at an interval Tl after step a) such that MR signals from selected tissues are suppressed; and d) repeating steps a), b) and c) until sufficient MR data is acquired to reconstruct an image.

2. The method as recited in claim 1 in which step a) includes producing a 180° pulse.

3. The method as recited in claim 1 in which step b) includes: b)i) producing a first RF pulse; b)ii) producing a gradient; and b)iii) producing a second RF pulse.

4. The method as recited in claim 3 in which said first and second RF pulses have a flip angle of substantially 90°.

5. The method as recited in claim 3 in which step b)ii) includes producing a dephasing gradient pulse; producing a 180° RF refocusing pulse; and producing a dephasing gradient pulse.

6. The method as recited in claim 5 in which the dephasing and dephasing gradient pulses have substantially the same size.

7. The method as recited in claim 1 which includes: e) producing a fat suppression preparatory sequence prior to performing the image acquisition pulse sequence in step c), and step d) includes repeating step d).

8. A method for acquiring an image of target tissues in a subject using a magnetic resonance imaging (MRI) system, the steps comprising: a) injecting the subject with a contrast agent that shortens the Tl relaxation time of spins in said target tissues; and b) acquiring MR image data from which an image of the target tissues can be reconstructed by repeating a pulse sequence with the MRI system that includes; i) producing a diffusion flow nulling preparatory sequence that suppresses MR signals from moving intravascular blood spins; and ii) performing an image acquisition pulse sequence to acquire MR data after performing step i).

9. The method as recited in claim 8 in which the pulse sequence includes: b)iii) producing an inversion recovery preparation pulse sequence at a time interval (Tl) prior to performing step b)ii) such that MR signals produced by stationary spins which are not Tl relaxation time shortened by said contrast agent are suppressed.

10. The method as recited in claim 8 in which the contrast agent is Gadofluorine.

11. The method as recited in claim 10 in which in which the target tissue is intravascular plaques.

12. The method as recited in claim 11 in which step b) is performed in substantially less than 24 hours after step a).

13. The method as recited in claim 11 in which step b) is performed in less than one hour after step a).

14. The method as recited in claim 8 in which the contrast agent has a relaxivity constant greater than 4.0 L.mor¹.sec^"1 at a MRI system field strength of 1.5 Tesla.