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Impact of Enzyme Replacement Therapy on Cardiac Morphology and Functionand 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 lateenhancement as a noninvasive marker of myocardial brosis, and their inter-relationduring enzyme replacement therapy in patients with Fabrys disease using magneticresonance imaging and color Doppler myocardial imaging. Late enhancement, whichwas present in up to 50% of patients, was associated with increased left ventricularmass, the failure of a signicant regression of hypertrophy during enzyme replace-ment therapy, and worse segmental myocardial function. Late enhancement maypredict the effect of enzyme replacement therapy on left ventricular mass and cardiacfunction. 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;97:15151518)

Fabrys disease is an X-linked lysosomal storage disordercaused 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 associatedwith progressive myocardial brosis and followed by deathfrom heart failure. 2 Besides hypertrophy, intramural myo-cardial contrast enhancement (late enhancement [LE]), as amarker of increased myocardial collagen content, 3 can bedemonstrated in patients with Fabrys disease by gadolini-um-enhanced magnetic resonance imaging (MRI). 4 Since2001, specic enzyme replacement therapy (ERT) for -ga-lactosidase has become available, improving clinical symp-toms as well as the capillary clearance of globotriaosylceramide. 5,6 Moreover, a decrease in left ventricular mass

and a reduction in left ventricular dysfunction have beendemonstrated. 7 Whether those with evidence of LE respondto ERT is unknown. Therefore, we performed a prospectivestudy to analyze changes in LE under ERT and to determinethe impact of LE on regional myocardial function in patientswith Fabrys disease.

Thirty-ve patients (mean age 39 10 years; 20 men) withgenetically proved Fabrys disease were consecutively in-cluded in the study. Seventeen patients were scheduled toreceive ERT (mean age 41 8 years) because of theseverity of disease (male gender; symptoms such as severeacroparesthesia and myalgia; and/or signs of vital organ

involvement such as left ventricular hypertrophy, impairedkidney 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 intravenouslyevery 2 weeks for 12 months in an open-labeled study. Theinvestigation conformed to the principles of the Declarationof Helsinki. Written informed consent was obtained from allpatients, and the study was approved by the local ethicscommittee.

MRI was performed with a 1.5-T scanner (MagnetomVISION, 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 mm2

, matrix 126 256, repetition time 9.9ms, echo time 4.8 ms, ip angle 30, slice thickness 8 mm).The same sequence was consistently used for baseline andfollow-up examinations. Left ventricular mass, volume, andfunction were analyzed as previously described. 9 Regionalwall 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 gadopentetatedimeglumine 0.2 mmol/kg (Magnevist, Schering AG, Ber-lin, Germany) using an inversion recovery 2-dimensionalturbo-gradient echo sequence (eld of view 240 320mm2 , 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 enhancementwas performed as previously described. 9 The mass of theenhanced area was obtained by summing the volume foreach section and is expressed as a percentage of total leftventricular muscle mass.

Real-time 2-dimensional color Doppler myocardial im-aging data were recorded from the interventricular septumand the left ventricular lateral and inferior walls using stan-dard apical 4- and 2-chamber views to evaluate longitudinalfunction (Vivid V, GE Vingmed Ultrasound AS, Horten,

a Institut fr Rntgendiagnostik and bMedizinische 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 speakershonoraria 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.orgdoi:10.1016/j.amjcard.2005.11.087

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Norway; 3.5 MHz). Color Doppler myocardial imaging datawere analyzed using dedicated software (TVI, GE VingmedUltrasound AS) as described previously. 7 Briey, the regionof interest was continuously positioned within the segmentbeing 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. Usingthe apical 4- and 2-chamber views, myocardial function in12 segments in every patient was assessed. After analyzingmyocardial function in these segments, every segment wasassigned to be LE positive or LE negative. Matching thesegmentation between MRI and echocardiography was doneusing 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 Wilcoxonsmatched-pairs test was used to evaluate differences betweenbaseline and follow-up examination results. Pearsons cor-relation coefcient was used for the comparison of MRIdata (LE vs left ventricular mass). A p value of 0.05 wasconsidered statistically signicant. The interpreters of theMRI data were blinded to the echocardiographic data, andthe interpreters of the echocardiographic data were blindedto the MRI data.

The baseline examinations of all 35 included patientsrevealed LE (0.5 1.0% of left ventricular mass) in 11patients (31%). Two of the 15 female patients displayed LE(1.1% and 2.3% of left ventricular mass). Left ventricularmass (mean 158 60 g) was correlated with the extentof 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 lateralwall of the left ventricle in 6 patients and the anterior orseptal parts in 2 patients. Within these regions, LE wasdistributed intramurally (6 of 8 patients) and subepicardially(2 of 8 patients). No patient showed involvement of thesubendocardial layer. Quantitative analysis showed LE tobe 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 hadlarger left ventricular masses (211 58 vs 160 23 g, p0.046). No signicant differences were found for all otherleft ventricular morphologic parameters ( Table 1 ). Regionalfunction in the segments displaying LE was signicantlyless compared with the patients without LE (strain rate 1.00.3 vs 1.3 0.4 1/s, p 0.0001; strain 8.6 5% vs 18.37.8%, p 0.001). Moreover, nonenhanced segments of patients with 1 segment positive for LE also showedsevere restriction of regional function in comparison withthe data of patients without LE (strain rate 1.1 0.5 vs 1.30.4 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 showedno regression of LE. In contrast, the amount of LE increasedfrom 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 outlinedfor 1 patient in Figure 1. In contrast, no patients without LEdeveloped LE during ERT. Signicant regressions of leftventricular mass and volume occurred during ERT ( Table1). 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 on3 contiguous short-axis views.

Table 1Baseline and follow-up data from patients scheduled for enzyme replacement therapy

Parameter All Patients LE (positive) LE (negative) p Value for LEPositive vs LE

Negative

Baseline(n 17)

Follow-up(n 17)

pValue

Baseline(n 8)

Follow-up(n 8)

pValue

Baseline(n 9)

Follow-up(n 9)

pValue

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 0.074End-diastolic volume (ml) 141 29 121 47 0.039 144 27 120 50 0.123 138 31 122 47 0.214 0.481 0.888End-systolic volume (ml) 54 18 44 19 0.028 53 13 43 15 0.123 54 23 46 22 0.110 0.743 0.815Stroke volume (ml) 87 16 77 30 0.076 91 18 77 37 0.161 84 16 78 25 0.441 0.606 0.963Cardiac 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 0.673Ejection fraction (%) 63 7 64 7 0.149 63 5 65 5 0.263 62 9 63 8 0.595 0.743 0.743LE (% 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.

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only patients without LE had signicant regressions of leftventricular mass (p 0.008), whereas patients with LEshowed a tendency toward the regression of left ventricularmass 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 LEshowed an improvement of regional function, but it wasrestricted to myocardial segments without LE (strain rate1.1 0.5 to 1.3 0.5 1/s, p 0.003; strain 10.5 8% to14.2 8%, p 0.008). Segments with LE showed nosignicant improvement (strain rate 1.0 0.3 to 1.2 0.41/s, p 0.05; strain 8.6 5% to 12.5 5%, p 0.05).

The incidence and distribution resembled the pattern of LEobserved in other forms of cardiomyopathy. 1113 The greaterpercentage of hyperenhanced myocardium and the bettercorrelation of hyperenhancement related to the left ventric-ular mass index in a previous study of patients with Fabrysdisease 4 can be explained by the greater degree of leftventricular 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-upincrease in LE was large, a doubling over 1 year. There areseveral possible explanations. First of all, one must becautious to rule out artifactual reasons. However, the ap-plied technique of manual planimetry (for the quanticationof LE) has high reproducibility, as recently shown 14,15 ; allinvestigators were already experienced analyzers of cardiac

magnetic resonance images including LE; and all examina-tions were performed using the same magnetic resonancescanner and the same acquisition protocol. Nevertheless,one cannot rule out that ERT has a disproportionate effecton background interstitial brosis rather than focal brosis,so that a reduction in background paradoxically makes focalbrosis 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 signicantreductions in left ventricular mass during ERT, as well asimprovements in regional myocardial function. Patientswith LE in 1 part of the left ventricle also showed restric-tions in myocardial function in all other parts of the leftventricle.

The limitations of this study include a lack of follow-upexaminations of equally ill patients without ERT because of the limited number of patients with Fabrys disease andethical concerns about postponing ERT in patients for theadvantage 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 knowwhether the fact that none of the patients who did not haveLE at baseline developed LE during ERT was a success dueto ERT. Second, none of the patients had clinical historiesof coronary artery disease, elevated plasma creatine kinaselevels, 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 withLE; (B) patients without LE. *p 0.01 baseline versus 12 months; # p 0.05 baseline, patients without LE versus patients with LE.

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formed. Nevertheless, the preferential intramural pattern of LE observed in our patients resembled that described forother forms of cardiomyopathy 1113 and is completely dif-ferent from the subendocardial or transmural pattern ob-served in coronary artery disease. 16 Moreover, a previousstudy 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.

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