Impact of Enzyme Replacement Therapy on Cardiac Morphology and Function

and Late Enhancement in Fabrys Cardiomyopathy

Meinrad Beer, MD
a,
*, Frank Weidemann, MD
b
, Frank Breunig, MD
b
, Anita Knoll, MD
b
,
Sabrina Koeppe, MD
a
, Wolfram Machann, MD
a
, Dietbert Hahn, MD
a
,
Christoph Wanner, MD
b
, Jrg Strotmann, MD
b
, and Jrn Sandstede, MD
a
The present study evaluated the evolution of cardiac morphology, function, and late
enhancement as a noninvasive marker of myocardial brosis, and their inter-relation
during enzyme replacement therapy in patients with Fabrys disease using magnetic
resonance imaging and color Doppler myocardial imaging. Late enhancement, which
was present in up to 50% of patients, was associated with increased left ventricular
mass, the failure of a signicant regression of hypertrophy during enzyme replace-
ment therapy, and worse segmental myocardial function. Late enhancement may
predict the effect of enzyme replacement therapy on left ventricular mass and cardiac
function. 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;97:15151518)
Fabrys disease is an X-linked lysosomal storage disorder
caused by a deciency of the enzyme -galactosidase and is
1 cause of unexplained left ventricular hypertrophy in mid-
dle-aged men.
1
Left ventricular hypertrophy is associated
with progressive myocardial brosis and followed by death
from heart failure.
2
Besides hypertrophy, intramural myo-
cardial contrast enhancement (late enhancement [LE]), as a
marker of increased myocardial collagen content,
3
can be
demonstrated in patients with Fabrys disease by gadolini-
um-enhanced magnetic resonance imaging (MRI).
4
Since
2001, specic enzyme replacement therapy (ERT) for -ga-
lactosidase has become available, improving clinical symp-
toms as well as the capillary clearance of globotriaosyl
ceramide.
5,6
Moreover, a decrease in left ventricular mass
and a reduction in left ventricular dysfunction have been
demonstrated.
7
Whether those with evidence of LE respond
to ERT is unknown. Therefore, we performed a prospective
study to analyze changes in LE under ERT and to determine
the impact of LE on regional myocardial function in patients
with Fabrys disease.

Thirty-ve patients (mean age 39 10 years; 20 men) with
genetically proved Fabrys disease were consecutively in-
cluded in the study. Seventeen patients were scheduled to
receive ERT (mean age 41 8 years) because of the
severity of disease (male gender; symptoms such as severe
acroparesthesia and myalgia; and/or signs of vital organ
involvement such as left ventricular hypertrophy, impaired
kidney function, central nervous system involvement; and
history of stroke).
8
-Galactosidase (agalsidase ; Fabra-
zyme, Genzyme Corporation, Cambridge, Massachusetts)
was given at a dose of 1 mg/kg body weight intravenously
every 2 weeks for 12 months in an open-labeled study. The
investigation conformed to the principles of the Declaration
of Helsinki. Written informed consent was obtained from all
patients, and the study was approved by the local ethics
committee.
MRI was performed with a 1.5-T scanner (Magnetom
VISION, Siemens Medical Systems, Erlangen, Germany).
Short- and long-axis cine MRI was performed using a seg-
mented 2-dimensional spoiled-gradient echo sequence (eld of
view 240 320 mm
2
, matrix 126 256, repetition time 9.9
ms, echo time 4.8 ms, ip angle 30, slice thickness 8 mm).
The same sequence was consistently used for baseline and
follow-up examinations. Left ventricular mass, volume, and
function were analyzed as previously described.
9
Regional
wall motion was assessed visually by 2 experienced observ-
ers using the standard 17-segment model.
10
LE was ob-
tained 10 to 15 minutes after the injection of gadopentetate
dimeglumine 0.2 mmol/kg (Magnevist, Schering AG, Ber-
lin, Germany) using an inversion recovery 2-dimensional
turbo-gradient echo sequence (eld of view 240 320
mm
2
, matrix 165 256, repetition time 7.5 ms, echo time
3.4 ms, ip angle 25, inversion time determined individu-
ally). The quantitative evaluation of contrast enhancement
was performed as previously described.
9
The mass of the
enhanced area was obtained by summing the volume for
each section and is expressed as a percentage of total left
ventricular muscle mass.
Real-time 2-dimensional color Doppler myocardial im-
aging data were recorded from the interventricular septum
and the left ventricular lateral and inferior walls using stan-
dard apical 4- and 2-chamber views to evaluate longitudinal
function (Vivid V, GE Vingmed Ultrasound AS, Horten,
a
Institut fr Rntgendiagnostik and
b
Medizinische Klinik der Univer-
sitt Wrzburg, Wrzburg, Germany. Manuscript received June 29, 2005;
revised manuscript received and accepted November 28, 2005.
Drs. Breunig, Strotmann, Wanner, and Weidemann received speakers
honoraria or grant support from Genzyme CEE GmbH, Konstanz, Ger-
many.
* Corresponding author: Tel: 49-931-201-34884; fax: 49-931-201-
34857.
E-mail address: beer@roentgen.uni-wuerzburg.de (M. Beer).
0002-9149/06/$ see front matter 2006 Elsevier Inc. All rights reserved. www.AJConline.org
doi:10.1016/j.amjcard.2005.11.087
Norway; 3.5 MHz). Color Doppler myocardial imaging data
were analyzed using dedicated software (TVI, GE Vingmed
Ultrasound AS) as described previously.
7
Briey, the region
of interest was continuously positioned within the segment
being interrogated using a semi-automatic tracking algo-
rithm to derive strain-rate proles from the at-risk seg-
ments. From the resulting strain rate and strain curves, peak
systolic strain rate and systolic strain were measured. Using
the apical 4- and 2-chamber views, myocardial function in
12 segments in every patient was assessed. After analyzing
myocardial function in these segments, every segment was
assigned to be LE positive or LE negative. Matching the
segmentation between MRI and echocardiography was done
using the standard 17-segment model.
10
All data are presented as mean SD. The Mann-Whit-
ney U test was used to determine differences between pa-
tients with and without LE. The nonparametric Wilcoxons
matched-pairs test was used to evaluate differences between
baseline and follow-up examination results. Pearsons cor-
relation coefcient was used for the comparison of MRI
data (LE vs left ventricular mass). A p value of 0.05 was
considered statistically signicant. The interpreters of the
MRI data were blinded to the echocardiographic data, and
the interpreters of the echocardiographic data were blinded
to the MRI data.
The baseline examinations of all 35 included patients
revealed LE (0.5 1.0% of left ventricular mass) in 11
patients (31%). Two of the 15 female patients displayed LE
(1.1% and 2.3% of left ventricular mass). Left ventricular
mass (mean 158 60 g) was correlated with the extent
of LE (r 0.54, p 0.0001). The baseline examinations of
the 17 patients scheduled for ERT detected LE in 47% of
patients (8 of 17), with restriction to the inferior or lateral
wall of the left ventricle in 6 patients and the anterior or
septal parts in 2 patients. Within these regions, LE was
distributed intramurally (6 of 8 patients) and subepicardially
(2 of 8 patients). No patient showed involvement of the
subendocardial layer. Quantitative analysis showed LE to
be 1.3 1.1% or 2.5 2.0 ml (range 0.5 to 3.8% or 0.8 to
6.8 ml) of total left ventricular mass. Patients with LE had
larger left ventricular masses (211 58 vs 160 23 g, p
0.046). No signicant differences were found for all other
left ventricular morphologic parameters (Table 1). Regional
function in the segments displaying LE was signicantly
less compared with the patients without LE (strain rate 1.0
0.3 vs 1.3 0.4 1/s, p 0.0001; strain 8.6 5% vs 18.3
7.8%, p 0.001). Moreover, nonenhanced segments of
patients with 1 segment positive for LE also showed
severe restriction of regional function in comparison with
the data of patients without LE (strain rate 1.1 0.5 vs 1.3
0.4 1/s, p 0.01; strain 10.5 8% vs 18.3 7.8%, p
0.001).
The follow-up examinations of patients with ERT showed
no regression of LE. In contrast, the amount of LE increased
from 1.3 1.1% to 2.6 2.1% or 2.5 2.0 to 4.9 3.1 ml
(range 0.5 to 7.1% or 0.8 to 9.6 ml, p 0.028), as outlined
for 1 patient in Figure 1. In contrast, no patients without LE
developed LE during ERT. Signicant regressions of left
ventricular mass and volume occurred during ERT (Table
1). Separating patients according to the occurrence of LE,
Figure 1. A 54-year-old man at baseline (upper panel) and after 1 year of
ERT (lower panel). The increase of LE (white arrows) is clearly seen on
3 contiguous short-axis views.
Table 1
Baseline and follow-up data from patients scheduled for enzyme replacement therapy
Parameter All Patients LE (positive) LE (negative) p Value for LE
Positive vs LE
Negative
Baseline
(n 17)
Follow-up
(n 17)
p
Value
Baseline
(n 8)
Follow-up
(n 8)
p
Value
Baseline
(n 9)
Follow-up
(n 9)
p
Value
Baseline Follow-up
Left ventricular mass (g) 184 49* 168 53 0.003 211 58 195 64 0.161 160 23 145 27 0.008 0.046 0.074
End-diastolic volume (ml) 141 29 121 47 0.039 144 27 120 50 0.123 138 31 122 47 0.214 0.481 0.888
End-systolic volume (ml) 54 18 44 19 0.028 53 13 43 15 0.123 54 23 46 22 0.110 0.743 0.815
Stroke volume (ml) 87 16 77 30 0.076 91 18 77 37 0.161 84 16 78 25 0.441 0.606 0.963
Cardiac output (l/min) 6.3 1.2 5.0 1.5 0.003 6.6 1.4 5.0 1.8 0.030 6.0 0.9 5.0 1.3 0.050 0.481 0.673
Ejection fraction (%) 63 7 64 7 0.149 63 5 65 5 0.263 62 9 63 8 0.595 0.743 0.743
LE (% left ventricular
mass)
0.6 1.0* 1.2 1.9 0.028 1.3 1.1 2.6 2.1 0.028 0.0 0.0 0.0 0.0 1.000 0.000 0.000
* Correlating r 0.55; p 0.0017.
1516 The American Journal of Cardiology (www.AJConline.org)
only patients without LE had signicant regressions of left
ventricular mass (p 0.008), whereas patients with LE
showed a tendency toward the regression of left ventricular
mass that did not reach statistical signicance (p 0.161;
Figure 2). Echocardiography revealed an improvement of
regional function in patients without LE (strain rate 1.3
0.4 to 1.5 0.5 1/s, p 0.0001; strain 18.3 7.8% to
20.5 6.8%, p 0.047). In addition, patients with LE
showed an improvement of regional function, but it was
restricted to myocardial segments without LE (strain rate
1.1 0.5 to 1.3 0.5 1/s, p 0.003; strain 10.5 8% to
14.2 8%, p 0.008). Segments with LE showed no
signicant improvement (strain rate 1.0 0.3 to 1.2 0.4
1/s, p 0.05; strain 8.6 5% to 12.5 5%, p 0.05).

The incidence and distribution resembled the pattern of LE
observed in other forms of cardiomyopathy.
1113
The greater
percentage of hyperenhanced myocardium and the better
correlation of hyperenhancement related to the left ventric-
ular mass index in a previous study of patients with Fabrys
disease
4
can be explained by the greater degree of left
ventricular hypertrophy in this previous study (left ventric-
ular mass 188 vs 100 g/m
2
[LE positive vs LE negative]
compared with 115 vs 85 g/m
2
in our study). LE did in-
crease during follow-up. Compared with the small magni-
tude of LE (percentage left ventricular mass), the follow-up
increase in LE was large, a doubling over 1 year. There are
several possible explanations. First of all, one must be
cautious to rule out artifactual reasons. However, the ap-
plied technique of manual planimetry (for the quantication
of LE) has high reproducibility, as recently shown
14,15
; all
investigators were already experienced analyzers of cardiac
magnetic resonance images including LE; and all examina-
tions were performed using the same magnetic resonance
scanner and the same acquisition protocol. Nevertheless,
one cannot rule out that ERT has a disproportionate effect
on background interstitial brosis rather than focal brosis,
so that a reduction in background paradoxically makes focal
brosis more prominent. The impaired ability of LE imag-
ing to discriminate diffuse brosis has already been dis-
cussed for subgroups of patients with dilated cardiomyop-
athy.
12
LE was associated with impaired cardiovascular im-
provement during ERT according to changes in left ventric-
ular mass and regional function, as shown for other forms of
cardiomyopathy.
13
Only patients without LE had signicant
reductions in left ventricular mass during ERT, as well as
improvements in regional myocardial function. Patients
with LE in 1 part of the left ventricle also showed restric-
tions in myocardial function in all other parts of the left
ventricle.
The limitations of this study include a lack of follow-up
examinations of equally ill patients without ERT because of
the limited number of patients with Fabrys disease and
ethical concerns about postponing ERT in patients for the
advantage of follow-up magnetic resonance examinations.
Therefore, we do not know the natural course of LE devel-
opment in Fabrys disease, and thus we do not know
whether the fact that none of the patients who did not have
LE at baseline developed LE during ERT was a success due
to ERT. Second, none of the patients had clinical histories
of coronary artery disease, elevated plasma creatine kinase
levels, or electrocardiographic signs of coronary artery dis-
ease. However, coronary angiography had not been per-
Figure 2. Changes in left ventricular mass during ERT. Only patients without LE showed signicant regressions of left ventricular mass. (A) Patients with
LE; (B) patients without LE. *p 0.01 baseline versus 12 months;
#
p 0.05 baseline, patients without LE versus patients with LE.
1517 Cardiomyopathy/Late Enhancement in Fabrys Disease
formed. Nevertheless, the preferential intramural pattern of
LE observed in our patients resembled that described for
other forms of cardiomyopathy
1113
and is completely dif-
ferent from the subendocardial or transmural pattern ob-
served in coronary artery disease.
16
Moreover, a previous
study by Moon et al
4
excluded coronary artery disease in
patients with Fabrys disease despite the presence of LE.
Acknowledgment: We thank Bettina Borst for her excel-
lent technical assistance in our MRI studies.
1. Sachdev B, Takenaka T, Teraguchi H, Tei C, Lee P, McKenna WJ,
Elliott PM. Prevalence of Anderson-Fabry disease in male patients
with late onset hypertrophic cardiomyopathy. Circulation 2002;105:
14071411.
2. Desnick RJ, Ioannou YA, Eng CM. -Galactosidase A deciency:
Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The
Metabolic and Molecular Bases of Inherited Disease, Vol. 3. 8th Ed.
New York, New York: McGraw-Hill, 2001:37333774.
3. Moon JC, Reed E, Sheppard MN, Elkington AG, Ho SY, Burke M,
Petrou M, Pennell DJ. The histologic basis of late gadolinium enhance-
ment cardiovascular magnetic resonance in hypertrophic cardiomyop-
athy. J Am Coll Cardiol 2004;43:22602264.
4. Moon JCC, Sachdev B, Elkington AG, McKenna WJ, Mehta A,
Pennell DJ, Leed PJ, Elliott PM. Gadolinium enhanced cardiovascular
magnetic resonance in Anderson-Fabry disease. Evidence for a disease
specic abnormality of the myocardial interstitium. Eur Heart J 2003;
24:21512155.
5. Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P, Waldek S,
Caplan L, Linthorst GE, Desnick RJ, International Collaborative Fabry
Disease Study Group. Safety and efcacy of recombinant human
alpha-galactosidase A-replacement therapy in Fabrys disease. N Engl
J Med 2001;345:916.
6. Schiffmann R, Kopp JB, Austin HA III, Sabnis S, Moore DF, Weibel
T, Balow JE, Brady RO. Enzyme replacement therapy in Fabry dis-
ease: a randomized controlled trial. JAMA 2001;285:27432749.
7. Weidemann F, Breunig F, Beer M, Sandstede J, Turschner O, Voelker
W, Ertl G, Knoll A, Wanner C, Strotmann JM. Improvement of cardiac
function during enzyme replacement therapy in patients with Fabry
disease: a prospective strain rate imaging study. Circulation
2003;108:12991301.
8. Desnick RJ, Brady R, Barranger J, Collins AJ, Germain DP, Goldman
M, Grabowski G, Packman S, Wilcox WR. Fabry disease, an under-
recognized multisystemic disorder: expert recommendations for diag-
nosis, management, and enzyme replacement therapy. Ann Intern Med
2003;138:338346.
9. Sandstede JJ, Pabst T, Beer M, Lipke C, Baurle K, Butter F, Harre K,
Kenn W, Voelker W, Neubauer S, Hahn D. Assessment of myocardial
infarction in humans with (23) Na MR imaging: comparison with cine
MR imaging and delayed contrast enhancement. Radiology 2001;221:
222228.
10. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey
WK, Pennell DJ, Rumberger JA, Ryan T, Verani MS, American Heart
Association Writing Group on Myocardial Segmentation and Regis-
tration for Cardiac Imaging. Standardized myocardial segmentation
and nomenclature for tomographic imaging of the heart: a statement
for healthcare professionals from the Cardiac Imaging Committee of
the Council on Clinical Cardiology of the American Heart Association.
Circulation 2002;105:539542.
11. Bogaert J, Goldstein M, Tannouri F, Golzarian J, Dymarkowski S.
Original report. Late myocardial enhancement in hypertrophic cardio-
myopathy with contrast-enhanced MR imaging. Am J Roentgenol
2003;180:981985.
12. McCrohon JA, Moon JC, Prasad SK, McKenna WJ, Lorenz CH, Coats
AJ, Pennell DJ. Differentiation of heart failure related to dilated cardio-
myopathy and coronary artery disease using gadolinium-enhanced car-
diovascular magnetic resonance. Circulation 2003;108:5459.
13. Teraoka K, Hirano M, Ookubo H, Sasaki K, Katsuyama H, Amino M,
Abe Y, Yamashina A. Delayed contrast enhancement of MRI in
hypertrophic cardiomyopathy. Mag Reson Med 2004;22:155161.
14. Bulow H, Klein C, Kuehn I, Hollweck R, Nekolla SG, Schreiber K,
Haas F, Bhm J, Schnackenburg B, Lange R, Schwaiger M. Cardiac
magnetic resonance imaging: long term reproducibility of the late
enhancement signal in patients with chronic coronary artery disease.
Heart 2005;91:11581163.
15. Mahrholdt H, Wagner A, Holly TA, Elliott MD, Bonow RO, Kim RJ,
Judd RM. Reproducibility of chronic infarct size measurement by
contrast-enhanced magnetic resonance imaging. Circulation 2002;106:
23222327.
16. Kim RJ, Wu E, Rafael A, Chen EL, Parker MA, Simonetti O, Klocke
FJ, Bonow RO, Judd RM. The use of contrast-enhanced magnetic
resonance imaging to identify reversible myocardial dysfunction.
N Engl J Med 2000;343:14451453.
1518 The American Journal of Cardiology (www.AJConline.org)