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DOI:10.2214/AJR.05.0442
AJR 2007; 188:850-853
© American Roentgen Ray Society


Clinical Observations

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
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Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
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
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
Fabry's disease is an X-linked recessive lysosomal storage disorder that is caused by a deficiency of lysosomal enzyme {alpha}-galactosidase A, also termed "ceramide trihexosidase," which is responsible for the hydrolysis of terminal {alpha}-galactosyl residues from glycolipids and glycoproteins [1]. Undigested glycosphingolipids with terminal {alpha}-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
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
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 {alpha}-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 {alpha}-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.


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TABLE 1: Clinical Characteristics and Genetic and Enzymatic Activities of Patients with Fabry's Disease

 

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
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Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
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).


Figure 1
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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.

 

Figure 2
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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.

 

Figure 3
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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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TABLE 2: Left Ventricular (LV) Functional Parameters Measured in the Three Study Groups

 

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.


Figure 4
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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.

 

Figure 5
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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.

 

Figure 6
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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.

 

Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
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 {alpha}-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.


References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 

  1. Brady RO, Gal AE, Bradley RM, Martensson E, Warshaw AL, Laster L. Enzymatic defect in Fabry's disease: ceramidetrihexosidase deficiency. N Engl J Med 1967;276 : 1163-1167[Medline]
  2. MacDermot KD, Holmes A, Miners AH. Natural history of Fabry disease in affected males and obligate carriers females. J Inherit Metab Dis 2001; 24:13 -14[Medline]
  3. Goldman ME, Cantor R, Schwartz MF, Baker M, Desnick RJ. Echocardiographic abnormalities and disease severity in Fabry's disease. J Am Coll Cardiol 1986;7 : 1157-1161[Abstract]
  4. Pochis WT, Litzow JT, King BG, Kenny D. Electrophysiologic findings in Fabry's disease with a short PR interval. Am J Cardiol 1994; 74:203 -204[CrossRef][Medline]
  5. Matsui S, Murakami E, Takekoshi N, Nakatou H, Enyama H, Takeda F. Myocardial tissue characterization by magnetic resonance imaging in Fabry's disease. Am Heart J 1989;117 : 472-474[CrossRef][Medline]
  6. Sandstede J, Lipke C, Beer M, et al. Age- and gender-specific differences in left and right ventricular cardiac function and mass determined by cine magnetic resonance imaging. Eur Radiol2000; 10:438 -442[CrossRef][Medline]
  7. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet 2001;38 : 750-760[Abstract/Free Full Text]
  8. Weidemann F, Breunig F, Beer M, et al. The variation of morphological and cardiac manifestation in Fabry disease: potential implications for the time course of the disease. Eur Heart J 2005; 26:1221 -1227[Abstract/Free Full Text]
  9. von Scheidt W, Eng CM, Fitzmaurice TF, et al. An atypical variant of Fabry's disease with manifestations confined to the myocardium. N Engl J Med 1991;324 : 395-399[Medline]
  10. Doornbos J, Verwey H, Essed CE, Balk AH, de Roos A. MR imaging in assessment of cardiac transplant rejections in humans. J Comput Assist Tomogr 1990; 14:77 -81[Medline]
  11. Marie PY, Angioi M, Carteaux JP, et al. Detection and prediction of acute heart transplant rejection with the myocardial T2 determination provided by a black-blood magnetic resonance imaging sequence. J Am Coll Cardiol 2001; 37:825 -831[Abstract/Free Full Text]
  12. Higgins CB, Herfkens R, Lipton MJ, et al. Nuclear magnetic resonance imaging of acute myocardial infarction in dogs: alterations in magnetic relaxation times. Am J Cardiol1983; 52:184 -188[CrossRef][Medline]

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