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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:542-546.)
© 1997 American Heart Association, Inc.

Articles

Water Diffusion Properties of Human Atherosclerosis and Thrombosis Measured by Pulse Field Gradient Nuclear Magnetic Resonance

Presented at the Second Scientific Conference on the Application of NMR to the Cardiovascular System, Atlanta, Ga, December 1993.

Jean-François Toussaint; James F. Southern; Valentin Fuster; ; Howard L. Kantor

From the Service Hospitalier Frédéric Joliot, CEA, Orsay, France (J-F.T.); the NMR Center (J-F.T., H.L.K.) and Pathology Department (J.F.S.), Massachusetts General Hospital, Boston, Mass; and the Cardiovascular Institute, Mount Sinai Medical Center (V.F.), New York, NY.

Correspondence to J.F. Toussaint, MD, PhD, Service Hospitalier Frédéric Joliot, Groupe de RMN, 4 Place du Général Leclerc, 91401 Orsay, Cedex, France. E-mail toussain{at}uriens.shfj.cea.fr.

	Abstract

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Abstract Using pulsed field gradient methods combined with magnetic resonance imaging, we calculated the apparent water diffusion coefficient D in different atherosclerotic components to probe the microstructure of normal and diseased arteries by characterizing molecular motion. D was equal to 0.26±0.13x10^-5 cm²·s^-1 in plaque lipid core, 1.45±0.41x10^-5 cm²·s^-1 in collagenous cap, and 1.54±0.30x10^-5 cm²·s^-1 in normal media. Water diffuses isotropically in the atheromatous core of the plaque, suggesting the absence or destruction of confining structures. The comparable diffusion coefficients in collagenous cap and normal media are consistent with similar biophysical barriers in both components. In thrombi, D varies with the aging processes (fresh thrombus, 0.72±0.11x10^-5 cm²·s^-1; 1-week-old thrombus, 0.36±0.08x10^-5 cm²·s^-1; old occluding thrombus, 1.33±0.33x10^-5 cm²·s^-1), consistent with the cross-linking of the fibrin strands occurring in the early phase and the later thrombus organization. Defining an indirect index of arterial lipid infiltration, remodeling, and aging, diffusion imaging provides a new nuclear magnetic resonance characterization of atherothrombosis.

Key Words: diffusion • magnetic resonance imaging • fibrous cap • lipid core • thrombus

	Introduction

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Plaque characterization is the challenge of any new imaging device for studying atherosclerosis progression. The principal tool staging the disease, ie, x-ray angiography, does not describe the diseased organ but only reveals its footprint on the lumen; although it can provide long-term prognostic parameters, it does not anticipate the rupture of a susceptible plaque,¹ nor does it predict myocardial infarction.² NMR was used to characterize atheromatous lesions noninvasively: through T2 contrast, this technique can discriminate lipid-rich from fibrous regions in vitro³ as well as in vivo.⁴ By combination of T1 and T2 contrast, the components of normal and diseased arteries can be imaged: lipid-rich core, collagen, calcifications, media, adventitia, and perivascular fat.

We propose here a new NMR method for plaque characterization measuring water diffusion in atherosclerotic components with a PFG sequence. The PFG technique, initially introduced by Stejskal and Tanner,⁵ allows determination of D. This technique, which does not require dyes or foreign materials to be introduced into the studied system, has been successfully implemented in vitro as well as in vivo to measure D noninvasively in different organs, such as heart,⁶ muscle,⁷ liver,⁸ and brain.⁹ In the latter, diffusion MRI allows a very early diagnosis of interstitial water alterations, such as those seen after ischemia and stroke.¹⁰ We tested this tool to describe atheromatous plaque and hypothesized that water diffusion was hindered in the lesion core. We studied diffusion isotropy at the plaque shoulder, where a large destruction of collagenous fibers occurs.¹¹ Finally, we determined water diffusion variations in aging thrombus to fully characterize all components of atherothrombosis.

	Methods

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PFG NMR
In the PFG NMR experiment, water molecules are labeled by the Larmor precession frequencies of the proton spins at the hydrogen sites. These frequencies are made to be spatially dependent by the application of a magnetic field, which varies with position. Stejskal and Tanner⁵ first described the method and provided the mathematical analysis to measure D by implementing a pair of gradient pulses about the 180° radiofrequency refocusing pulse of a conventional spin-echo sequence. The first gradient pulse occurs in the dephasing period following the 90° radiofrequency pulse, and the second occurs in the rephasing period following the 180° pulse. The advantage of such a method is the accurate definition of the diffusion time (delay between the gradient pulses), allowing measurements of restricted diffusion and diffusion barrier spacing: when the diffusion time is accurately known, only the molecular translational motion taking place between the two diffusion gradient pulses plays a role in the experiment.

We performed all experiments on an MSL 400 spectrometer/imager (Bruker Instruments) equipped with an Oxford 8.9-cm vertical bore superconducting magnet (proton frequency at 400.13 MHz) operated with an Aspect 3000 system. We used a 20-mm probe equipped with actively shielded imaging gradient sets. All experiments were conducted at 37°C; temperature was controlled by a thermistance inserted into the probe. We used a series of six spin-echo images with two rectangular diffusion gradients applied 1 ms apart from the nonselective refocusing pulse. Imaging parameters were TR, 1 second; TE, 12 ms; slice thickness, 600 µm; field of view, 2 cm; resolution, 156x312 µm; four averages with phase cycling. We used a diffusion gradient duration =3 ms and a diffusion time of 5.1 ms, with six b values ranging from 984 to 21 430 s/cm², by varying the amplitude gradient from 1 to 30 G/cm [b values are defined by b=²·G²·²·(-/3), as shown in the equation below]. To test for isotropic water diffusion, gradients were applied in plane in the dimensions parallel and perpendicular to the luminal surface defining the diffusion coefficients D|| and D+, respectively. Diffusion maps were produced for each sample and dimension by the equation⁵ log(M/Mo)=-²·G²·²·(-/3)·D, where Mo is the initial magnetization; is the gyromagnetic ratio; G is the diffusion gradient amplitude; is the diffusion gradient duration; is the time between the two diffusion gradients start to start, the diffusion time being defined by -/3 (see Reference 12¹² ). Values of b were chosen within the constraints of the imaging sequence: a very long echo time could not be used because of the short water T2 inside the lipid core.³ We therefore incremented the gradient strength from low b values up to the maximal permitted amplitude.⁶

Sample Preparation
Five fibrofatty human lesions from iliac and femoral arteries were frozen and stored at -60°C after dissection at autopsy. Lesions were rewarmed and kept at a constant temperature of 37°C in saline for 30 minutes before NMR analysis. Previous studies have shown a full reversibility in the temperature-dependent changes of the ¹H spectrum of atheromatous plaque between 17°C and 47°C.¹³ Samples were marked according to a previously described method to guide the pathologist's work.³ Each sample was preserved in saline 0.9% with sodium azide (0.001%) and fixed in formalin just after the experiment.

Fresh human thrombi were prepared from whole-blood samples of a healthy fasting volunteer who had not taken any drug for the previous month. Venipuncture was performed in the antecubital vein with a 19-gauge needle without a tourniquet; three 15-mL samples were drawn and exposed to a Tygon tubing for 45 minutes.¹⁴ The three resulting thrombi were washed with saline, placed in sealed glass NMR tubes, and analyzed immediately and 1 week after preparation (fresh and 1-week-old in vitro thrombi). During the week between preparation and the second examination, thrombi were stored in the same sealed tube at -4°C to prevent dehydration. Two old in situ organized thrombi from occluded iliac arteries were sampled at autopsy and similarly analyzed.

Histology
Arteries and thrombi were cut at a central level corresponding to the imaging plane in the magnet and step-sectioned every 200 µm. Staining was performed according to a previously described technique³ : we used trichrome and Sudan black for two successive slices.

Statistical Analysis
Data are expressed as mean±SD. Measurements were compared by ANOVA with a significance level of 95%. A Student's two-tailed unpaired t test was used to compare media and collagen with lipid core and to compare organized with in vitro thrombus values. We used a Student's paired t test to compare fresh and 1-week-old in vitro thrombus. A value of P<.05 was considered significant.

	Results

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Determination of D is shown in the Table for measurements of five plaques (with the four components: lipid-rich core, collagenous cap, normal media, and adventitia), three in vitro prepared thrombi (two fresh and 1-week-old in vitro thrombi), and two in situ organized thrombi. To test the accuracy of our method, D was also determined three times for a test tube filled with water at room temperature: results are also given in the Table (water).

View this table: [in this window] [in a new window]   Table 1. D (Mean±SD) for Plaque Components (n=5), In Vitro Prepared Thrombi (n=3), In Situ Organized Thrombi (n=2), and Water (n=3)

Curve fits for water diffusion in the collagenous cap and lipid core of a fibrofatty plaque are shown in Fig 1.

View larger version (11K): [in this window] [in a new window]   Figure 1. Variation of the NMR signal intensity as a function of diffusion gradient amplitude in lipid core () and collagenous cap () of a fibrofatty plaque. In collagenous cap, D=1.45x10-5 cm2·s-1; in lipid core, D=0.42x10-5 cm2·s-1; r=.998 and r=.997 for linear fits, respectively.

The diffusion maps of a fatty plaque are shown along with the T1 and T2 weighted images in Fig 2. Note the decreased D value in the upper plaque corresponding to the short T2 region of this fatty plaque (T2w image, Fig 2, top). The diffusion gradients were oriented parallel (Fig 2, bottom, left) and perpendicular (Fig 2, bottom, right) to the luminal surface at the plaque site. The histology of this plaque is shown in Fig 3 (trichrome staining).

View larger version (82K): [in this window] [in a new window]   Figure 2. Top, T1 weighted (T1w, left) and T2 weighted (T2w, right) images of an atherosclerotic femoral artery. A large calcification (Ca) is seen on both T1w and T2w images, with a complete collagenous cap (black arrow). A crescent-shaped fatty plaque is revealed by T2 contrast (white arrow); no cap is seen at luminal surface (L indicates lumen). Internal tube diameter is 18 mm; this corresponds to edge-to-edge distance in each image. Bottom, Diffusion maps of same artery. Diffusion gradients were oriented parallel (D||) and perpendicular (D+) to luminal surface of upper fatty plaque. In this lipid core, D|| is 0.45x10-5 cm2·s-1 and D+ is 0.41x10-5 cm2·s-1. Detail at bottom is a magnification of box centered on fatty plaque from D+ image.

View larger version (108K): [in this window] [in a new window]   Figure 3. Histology of plaque shown in Fig 2 (trichrome staining). A large calcified plaque with complete collagenous cap is seen at bottom. At top, crescent-shaped plaque shows a loose lipid infiltration (arrow) without cap. Adventitia is stained green; internal (IEL) and external (EEL) elastic laminae are clearly distinguished.

In our experimental conditions, the data showed that the values obtained for the diffusion gradients parallel and perpendicular to the luminal surface did not differ in lipid core: D||=0.26±0.13x10^-5 cm²·s^-1, and D+=0.28±0.14x10^-5 cm²·s^-1.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Diffusion of a fluid results from random translational motions. Measuring displacements of water molecules by calculating D can probe the microstructure of the environment in which these displacements take place. Using PFG NMR, we demonstrate here that water diffusion is limited in the lipid core of atheromatous plaques: D values are much lower in that region than in the other components of normal and diseased arterial walls. We also show that water diffuses isotropically in these components.

Technical Considerations
The accuracy of our measurements is shown by the calculations we performed in water using the same imaging and temperature parameters: the D value for pure water is in excellent agreement with published data.^{5 15} The 5.6% SD obtained after three measurements demonstrates the stability of our system. The low value found in the lipid core probably does not result from the influence of the lipid peak on D calculation (lipids have a much lower self-diffusion coefficient than water ¹² : 1.5x10^-7 cm²·s^-1), because we have demonstrated that the lipid peak accounts for 10% of the ¹H signal in the atheromatous core,³ and it is therefore negligible in the D calculations based on imaging; this is further evidenced by the high correlation coefficients of the linear fits shown in the plot in Fig 1. In calculating the b values, we did not consider the cross-terms resulting from the interaction between the imaging and the diffusion gradients.¹⁶ Some authors, however, previously calculated this error and showed that it could be neglected in similar experimental designs and apparatus.⁶ Again, this can be appreciated in the correlation coefficient of the linear fits in Fig 1 and the small difference of D in water as compared with literature data.^{5 15}

Water Diffusion in Atheromatous Core
Diffusion has been studied with PFG NMR in mixtures of proteins and lipids,¹⁷ with D values approximately one sixth that of bulk water. In this type of fat/protein emulsions, water diffusion seems to be confined to a one-dimensional geometry: water is adsorbed on surfaces within the protein matrix with thin layers organized in a random walk structure and many branch points over the path of molecular displacement. In this structure, water molecules have freedom to move over distances much larger than the fat droplet radii. Such a structure might very well describe atheroma, with a mixture of lipids and proteins (breakdown products from lipoprotein denaturation) interacting with water.¹⁸ In fact, the linearity of the fits shown in Fig 1 strongly suggests that the spin displacements follow a brownian random walk over the experiment time scale (displacement proportional to the square root of time). The mechanisms for altered water diffusion in such atheromatous structures are not known, but we can hypothesize that it may result from (1) the presence of oxidized lipoproteins,^{19 20} which restrict diffusion by allowing water penetration into their micellar structure²¹ ; (2) altered water exchange; or (3) the presence of lipids in smectic (liquid crystalline) or solid phase (crystal),²² which may structure water to a higher degree than matrix proteoglycans or proteins do.²³

Whatever the mechanisms, the alteration of water diffusion in lipid cores may help to further discriminate this major component of susceptible plaques^{11 24} by NMR. Other groups have studied lipid diffusion in atheromatous plaques and showed that some of these lipids were in an oily phase at body temperature and observable in vitro by MRI in human²⁵ and in animal models.²⁶ This determination, however, faces the problem of low signal-to-noise ratio compared with water signal³ and long acquisition times: 2.5 hours for 64 averages in vitro.²⁵

Isotropy
Isotropic water diffusion was expected from structural works by Nakatake and Yamamoto²⁷ that showed destruction of the proteinic structure of arterial lesions. Using scanning electron microscopy, they demonstrated that experimental atherosclerosis severely destroyed fibrous elastin sheet–like laminae and led to changes in configuration of the successive barriers in the intima as well as in the media, with the most important transformation occurring in the perimeter of the plaque under sites of destruction of the internal elastic lamina (see Fig 6 in Reference 27²⁷ ). The alterations of elastic fibers revealed sites of proliferation in remodeling walls. These results were similar to those of Kameyama²⁸ in human coronary arteries from patients who died of acute myocardial infarction: these authors showed a destruction of elastic fibers in atheroma contributing to an unbalanced distribution of stress in the vascular wall. They proposed that the changes in the elastin configuration reflected the migration of smooth muscle cells, a crucial effector of atheroma progression.

Although we did not calculate the eigenvalues of the diffusion anisotropy tensor, we did not measure any difference in atheromata between the D values calculated along the axis tangential or perpendicular to the luminal surface: water diffusion is isotropic in the atheromatous core of the plaque. This result may theoretically be attributed to isotropically distributed confining structures, but it seems unlikely in such heterogeneous necrotic cores²⁹ ; it more likely suggests that no confining structure remains in the rubble of these cores.³⁰ Coupled studies comparing scanning electron microscope and PFG NMR may help to confirm the complete destruction of the elastic fibers. MRI with very high resolution may also image microscopic structures such as collagenous/elastinic bridges. However, because of the limits of both field strength and gradient strength, such a resolution will not be easily reached in the near future in vivo. Therefore, measuring water diffusion in vivo in these regions may provide an indirect index of arterial infiltration and remodeling.

Water Diffusion in Collagenous Cap and Media
D is similar in collagenous cap and media. Along with their similar T2s,³ this suggests biophysical similarity of these two arterial components. The entangled network of protein matrix produced by smooth muscle cells may explain this structural similarity.

Water Diffusion in Thrombus
D in a thrombus varies in parallel with the processes that occur during the successive phases of aging. An early phase occurring after 1 week in vitro shows a reduction of D. The limited water mobility during this phase is consistent with the early cross-linking and entanglement of the fibrin strands³¹ and increasing fiber thickness³² associated with thrombus reduction in experimental thrombosis.³³ The in situ organized thrombi that developed in vivo have a D value closer to that of collagenous cap and media: this similarity may result from a cellular process due to the migration of monocytes and smooth muscle cells into the thrombus³⁴ during its incorporation and organization in the injured wall.³³ The larger thrombus cellularity after recolonization may later increase water diffusion.

These results may be useful for a better discrimination of the different components of atherothrombosis. We demonstrated that in vitro MRI could differentiate lipid core from collagenous cap and disease-free media of atheromatous plaques through T2 contrast.³ However, we recently showed that short T2 regions may also correspond to intraplaque hemorrhage or thrombi through another contrast mechanism linked to the presence of hemoglobin breakdown products.⁴ D values calculated here may further enlarge our possibilities of discriminating the different characteristics of plaque rupture by MRI and their precise role in vivo.

Conclusions
Water diffusion is isotropic and decreased in the core of human atherosclerotic plaques compared with collagenous cap and media; this lower value may be explained by the physical state of atheromatous lipids. On the other hand, D varies with time in thrombus, consistent with the processes occurring during the successive phases of thrombosis. ¹H-NMR diffusion imaging of atherosclerotic plaque may improve our understanding of plaque progression and rupture.

	Selected Abbreviations and Acronyms

 

D = apparent water diffusion coefficient MRI = magnetic resonance imaging NMR = nuclear magnetic resonance PFG = pulsed field gradient

	Acknowledgments

 
We gratefully acknowledge the support of the Harold M. English Fund from the Harvard Medical School, La Bourse Accelli de la Société Française de Cardiologie, and Le Fonds d'Etudes et de Recherche du Corps Médical des Hôpitaux de Paris. We would like to thank Drs Denis Le Bihan and Leo Garrido for their invaluable aid and the staff and members of the MGH-NMR Center for the use of the NMR system. We thank Dr Erling Falk for useful discussions concerning atherosclerosis characterization. We are grateful for the photographic assistance of Michele Forrestall and Steve Conley.

Received June 19, 1996; accepted October 8, 1996.

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