DOI:10.2214/AJR.05.0442
AJR 2007; 188:850-853
© American Roentgen Ray Society
MRI Characterization of Myocardial Tissue in Patients with Fabry's Disease
Massimo Imbriaco1,
Letizia Spinelli2,
Alberto Cuocolo1,
Simone Maurea1,
Giacomo Sica1,
Mario Quarantelli1,
Antonio Pisani3,
Raffaele Liuzzi4,
Bruno Cianciaruso3,
Massimo Sabbatini3 and
Marco Salvatore1
1 Department of Radiology, University Federico II, Via Pansini 5, Via Posillipo
196, Napoli 80123, Italy.
2 Department of Clinical Medicine and Cardiovascular Sciences, University
Federico II, Napoli, Italy.
3 Department of Nephrology, University Federico II, Napoli, Italy.
4 Institute of Biostructure and Bioimaging, University Federico II, Napoli,
Italy.
Received March 14, 2005;
accepted after revision September 23, 2005.
Address correspondence to M. Imbriaco
(mimbriaco{at}hotmail.com).
Abstract
OBJECTIVE. Fabry's disease is a multisystem X-linked disorder of
lysosomal metabolism frequently associated with left ventricular (LV)
hypertrophy. In this study, we aimed to assess whether myocardial T2
relaxation time determined by a black blood multiecho multishot MRI sequence
could be used to evaluate cardiac involvement in patients with Fabry's
disease.
CONCLUSION. Myocardial T2 relaxation time is prolonged in patients
with Fabry's disease compared with that of hypertrophic patients and healthy
control subjects. MRI may be useful for the characterization of myocardial
tissue in patients with Fabry's disease.
Keywords: cardiac imaging • cardiovascular disease • cerebrovascular disease • Fabry's disease • MRI • renal disease • T2 relaxation time
Introduction
Fabry's disease is an X-linked recessive lysosomal storage disorder
that is caused by a deficiency of lysosomal enzyme 
-galactosidase A,
also termed "ceramide trihexosidase," which is responsible for the
hydrolysis of terminal -galactosyl residues from glycolipids and
glycoproteins [1]. Undigested
glycosphingolipids with terminal -galactosyl moieties—mainly,
globotriaosylceramide—progressively accumulate in various types of
cells, including vascular endothelial cells, renal epithelial cells, and
myocardial cells. Cardiac involvement is common and is the most frequent cause
of death in such patients [2].
The accumulation of glycosphingolipids in cardiac tissue leads to increased
ventricular wall thickness and impaired left ventricular (LV) function; mitral
valve prolapse [3]; and ECG
abnormalities, including a short P-R interval, various degrees of
atrioventricular block, and ST segment and T wave abnormalities
[4].
In a previous article, Matsui et al.
[5] described a patient with
Fabry's disease in whom MRI revealed an increase in signal intensity and a
prolongation of T2 relaxation time throughout the entire LV myocardium. In
this study, we aimed to assess whether myocardial T2 relaxation time
determined by a black blood multiecho multishot MRI sequence could help to
evaluate cardiac involvement in patients with Fabry's disease.
Subjects and Methods
Patients
From October 2003 to May 2005, 12 patients with genetically confirmed
Fabry's disease (nine men, hemizygotes, and three women, heterozygotes; median
age, 33 years; age range, 22-54 years), 12 patients with LV hypertrophic
cardiomyopathy and no other metabolic disease (nine men and three women;
median age, 34 years; age range, 20-64 years), and 12 age-matched healthy
control subjects (nine men and three women; median age, 28 years; age range,
18-59 years) underwent MRI. Informed consent from all subjects included in
this study and approval from our hospital ethics committee were obtained. All
the patients available were included in the study, and all healthy control
subjects were volunteers.
The initial clinical symptoms during childhood and adolescence experienced
by the 12 patients with Fabry's disease in our study included a variety of
Fabry's disease symptoms such as acroparesthesia (n = 8),
hypohidrosis (n = 6), angiokeratoma (n = 5), and abdominal
pain (n = 3). Diagnosis of Fabry's disease in the male patients was
based on a median -galactosidase A enzymatic activity of 0.20 nmol/h/mL
(range, 0.1-1.4 nmol/h/mL; normal range, 4.0-21.9 nmol/h/mL). All female
patients were obligate carriers and showed a median -galactosidase
enzymatic activity of 2.20 nmol/h/mL. All patients underwent 12-lead ECG and
Doppler echocardiography before MRI. The clinical characteristics, genotypes,
and enzymatic activities of the patients with Fabry's disease are shown in
Table 1.
MRI Technique
MR studies were performed using a 1.5-T MRI system (Gyroscan Intera,
Philips Medical Systems) equipped with high performance gradients (maximum
gradient amplitude, 30 mT/m; maximum slew rate, 150 mT/m/ms). Images were
acquired with a five-element cardiac phased-array coil using a
vectorcardiographic method for ECG-gating and respiratory gating. After a
survey scan was obtained, a breath-holding T2-weighted black blood multiecho
multishot turbo spin-echo (TSE) sequence with four different TEs was used to
obtain images of the four-chamber horizontal long-axis plane for myocardial T2
relaxation time measurements. The following parameters were used: TR/effective
TEs, 1,500/45, 60, 75, 90; matrix, 256 x 512; field of view, 400 mm;
slice thickness, 10 mm; number of slices, 3; TSE factor, 23; flip angle,
90°; and scanning time, 22 seconds for each slice, all breath-holding, for
a total acquisition time of 66 seconds. LV long-axis and four-chamber
horizontal long-axis images were acquired using a breath-holding 3D balanced
turbo field-echo multiphase multislice sequence (TR/effective TE, 2.8/1.4;
matrix, 160 x 256; slice thickness, 10 mm; flip angle, 50°);
subsequently, biventricular short-axis images were obtained using nine or 10
slices to cover the left ventricle from the apex to the base for evaluation of
LV mass. The total acquisition time ranged between 25 and 30 minutes.
MRI Analysis
Postprocessing was performed on a dedicated workstation (Viewforum, Philips
Medical Systems). A first qualitative analysis was performed; however, changes
in signal intensity were too subtle to be qualitatively detected. Therefore, a
quantitative analysis was performed. For evaluation of myocardial T2
relaxation time, fixed regions of interest were placed along the
interventricular septum, apex, and lateral walls on the first-echo image and
reproduced on the other echo images. Myocardial T2 relaxation time was
calculated using a linear least-squares fit applied on the logarithm of
myocardial signal intensity versus TE according to the formula M(TE)
M0e-TE/T2, where M(TE) is the averaged
signal from all regions of interest of the corresponding TE image,
M0e is exponential, and TE is the TE from all regions of
interest of the corresponding TE image.
LV wall thickness was measured at the level of the mid septum. Analysis of
LV mass was performed by choosing the slice with the greatest cardiac diameter
of the 3D balanced turbo field-echo multiphase multislice acquisition in the
biventricular short axis; subsequently, the endocardial and epicardial borders
were manually traced to include the papillary muscles on each end-diastolic
and end-systolic frame for each of the nine or 10 slices, as previously
described [6]. LV mass index
was subsequently calculated by normalizing LV mass for a square meter of body
surface area. In addition, the LV ejection fraction was calculated for the
patients with Fabry's disease, the patients with LV hypertrophy, and the
healthy control subjects.
Statistical Analysis
Data are presented as median values, with the corresponding range.
Differences among patients with Fabry's disease, patients with LV hypertrophy,
and healthy control subjects were obtained using a nonparametric
analysis-of-variance Kruskal-Wallis test. A p value of less than 0.05
was considered statistically significant.
Results
In patients with Fabry's disease, the myocardial T2 relaxation time was
significantly higher (p < 0.001) in all myocardial
regions—that is, in the interventricular septum, apex, and lateral
wall—than in patients with LV hyper-trophy and healthy control subjects
(Fig. 1A,
1B,
1C). For LV functional
parameters, the maximum LV wall thickness (mm) and LV mass index
(g/m2) values were significantly higher (p < 0.001) in
patients with LV hypertrophy than in those with Fabry's disease and healthy
control subjects. Conversely, the LV ejection fraction (%) values were similar
(p = not significant) among the patients with Fabry's disease, the
patients with LV hypertrophy, and the healthy control subjects
(Table 2).
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Fig. 1A —Graphs show myocardial T2 relaxation times measured in
cardiac areas. Individual data points for myocardial T2 relaxation time (in
milliseconds) measured in septum (A), apex (B), and lateral wall
(C) in three groups of study population; numbers are median values. LV
= left ventricular.
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Fig. 1B —Graphs show myocardial T2 relaxation times measured in
cardiac areas. Individual data points for myocardial T2 relaxation time (in
milliseconds) measured in septum (A), apex (B), and lateral wall
(C) in three groups of study population; numbers are median values. LV
= left ventricular.
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Fig. 1C —Graphs show myocardial T2 relaxation times measured in
cardiac areas. Individual data points for myocardial T2 relaxation time (in
milliseconds) measured in septum (A), apex (B), and lateral wall
(C) in three groups of study population; numbers are median values. LV
= left ventricular.
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In three patients with Fabry's disease and no evidence of LV hypertrophy
(median wall thickness, 12 mm; range, 11-13 mm; median LV mass index, 75
g/m2; range, 73-91 g/m2) or cardiac involvement, a
markedly prolonged mean myocardial T2 relaxation time was observed: 81
milliseconds (range, 80-84 milliseconds) in the interventricular septum, 87
milliseconds (range, 80-94 milliseconds) in the apex, and 85 milliseconds
(range, 75-86 milliseconds) in the lateral wall. Two of these three patients
were female obligate carriers who initially presented with renal involvement,
as shown by mild proteinuria and abdominal pain, and no evidence of cardiac
manifestations, such as valvular or coronary artery disease, conduction
abnormalities, arrhythmias, or myocardial infarction.
Figure 2A,
2B,
2C shows examples of the
T2-weighted TSE black blood MR sequence in the three groups of the study
population with their corresponding myocardial T2 relaxation times.
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Fig. 2A —Four-chamber horizontal long-axis T2-weighted black blood
turbo spin-echo MR images (TR/effective TE, 1,500/75) of subjects from each of
three groups in study population. White circles outline regions of interest in
mid septum, apex, and lateral wall, and corresponding myocardial T2 relaxation
times are shown. 48-year-old man (patient 5 in
Table 1) with Fabry's disease.
Myocardial T2 relaxation times are 86 milliseconds in mid septum, 91
milliseconds in apex, and 90 milliseconds in inferior wall.
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Fig. 2B —Four-chamber horizontal long-axis T2-weighted black blood
turbo spin-echo MR images (TR/effective TE, 1,500/75) of subjects from each of
three groups in study population. White circles outline regions of interest in
mid septum, apex, and lateral wall, and corresponding myocardial T2 relaxation
times are shown. 57-year-old man with left ventricular hypertrophy. Myocardial
T2 relaxation times are 69 milliseconds in mid septum, 67 milliseconds in
apex, and 71 milliseconds in inferior wall.
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Fig. 2C —Four-chamber horizontal long-axis T2-weighted black blood
turbo spin-echo MR images (TR/effective TE, 1,500/75) of subjects from each of
three groups in study population. White circles outline regions of interest in
mid septum, apex, and lateral wall, and corresponding myocardial T2 relaxation
times are shown. Healthy 27-year-old female volunteer. Myocardial T2
relaxation times are 54 milliseconds in mid septum, 51 milliseconds in apex,
and 53 milliseconds in inferior wall.
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Discussion
The results of this study show that myocardial T2 relaxation time is
significantly prolonged in patients with Fabry's disease compared with that
calculated in patients with LV hypertrophy and healthy control subjects.
Therefore, MRI may be useful for the characterization of myocardial tissue in
patients with Fabry's disease.
Fabry's disease is a rare X-linked genetic disorder of glycosphingolipid
metabolism [1,
2]. In the classical form of
Fabry's disease, males have no or a very low level of -galactosidase A
activity that results in severe renal, cerebrovascular, and cardiac disease
manifestations. Before the advent of renal dialysis or transplantation, the
median survival of patients with Fabry's disease was approximately 50 years
[7]. Clinical manifestations,
which usually begin during childhood or adolescence, include intermittent pain
in the extremities (acroparesthesias); skin lesions (angiokeratomas);
hypohidrosis; heat, cold, and exercise intolerance; mild proteinuria; and
gastrointestinal disorders. During adulthood, the renal involvement leads to
end-stage renal disease, which requires dialysis or kidney transplantation.
Cardiac manifestations include LV hypertrophy, valvular disease, ascending
aorta dilatation, coronary artery disease, and conduction abnormalities that
lead to congestive heart failure, arrhythmias, and myocardial infarction
[3,
8]. Moreover, the heart can be
the only organ involved in male patients with specific gene mutations and in
female carriers with low enzymatic activity, the so-called "cardiac
Fabry variant." This is characterized by progressive severe LV
hypertrophy that mimics an obstructive or nonobstructive hypertrophic
cardiomyopathy [9].
In a previous article, Matsui et al.
[5] described a man with
Fabry's disease in whom MRI revealed an increase in signal intensity and a
prolongation of T2 relaxation time throughout the entire LV myocardium. In our
study, we observed similar findings in a larger series of patients, and we
compared these findings with those of patients with LV hypertrophy and healthy
control subjects. In the study of Matsui et al., MRI was performed on a 0.5-T
scanner using a gated multislice spin-echo technique. However, with
conventional spin-echo techniques, the T2 relaxation rates measured on MRI may
vary widely; this is mainly related to motion artifacts and error caused by
the flow of blood from the cavities projecting into the myocardium
[10]. The application of fast
sequences, such as inversion recovery black blood spinecho sequences, has made
it possible to obtain more reliable data. In particular, Marie et al.
[11] reported that myocardial
T2 relaxation times, as determined using a black blood MRI sequence, could be
used to identify most of the moderate acute transplant rejections documented
with biopsy performed at the same time, suggesting that routine myocardial
biopsy might be avoided in patients with a normal T2 value. In the present
study, we used a T2-weighted black blood TSE sequence that allowed the blood
signal and its confounding effect on myocardial T2 measurements to be
suppressed; in cases of misregistration due to respiratory artifacts, the
sequence was repeated.
The prolonged myocardial T2 relaxation time observed in the present study
might be related to the biophysical and biochemical characteristics of the
tissue. Researchers have shown that factors, such as myocardial water and
lipid alterations, can lead to an abnormal prolongation of the myocardial T2
relaxation time and to an increase in signal intensity
[12]. Therefore, it is
reasonable to presume that the marked deposition of glycolipid in the
myocardium might lead to a prolongation of the myocardial T2 relaxation time
and to an increase in signal intensity in patients with Fabry's disease. In
three patients in our series, the myocardial T2 relaxation time was markedly
prolonged compared with that of healthy control subjects even in the absence
of other cardiac involvement; in these three cases, there were no signs of LV
hypertrophy, the median wall thickness was 12 mm (range, 11-13 mm), and the
median LV mass index was 75 g/m2 (range, 73-91 g/m2). In
addition, two of the three patients were female obligate carriers who
presented with initial renal involvement characterized by mild proteinuria.
These findings, although observed in only three patients, suggest the
possibility of using myocardial T2 relaxation time as an early marker of
myocardial involvement in patients with Fabry's disease.
The present study has some limitations that should be considered. The
number of patients with Fabry's disease was relatively small and does not
allow us to establish a threshold value of myocardial T2 relaxation time above
which it is possible to exactly define cardiac involvement in Fabry's disease.
Another limitation is the lack of histologic correlation. Therefore, further
studies of larger patient populations are warranted to confirm our preliminary
findings.
In conclusion, a prolonged myocardial T2 relaxation time as determined
using a black blood TSE MRI sequence could provide a new means for assessing
cardiac involvement in patients with Fabry's disease. In addition, myocardial
T2 relaxation time might be used to assess early myocardial involvement even
in the absence of signs of LV hypertrophy.
Acknowledgments
We sincerely thank Graciana Diez-Roux for critically reviewing the
manuscript; and Guglielmo Caprio, Alfredo Palazzo, Ciro Varchetta, and
Francesco Varchetta, technologists, for their valuable technical assistance in
making this study possible.
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Abstract
Introduction
