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(Circulation. 2006;113:e720-e721.)
© 2006 American Heart Association, Inc.

Images in Cardiovascular Medicine

Transition From Left Ventricular Hypertrophy to Massive Fibrosis in the Cardiac Variant of Fabry Disease

Hiroshi Hasegawa, MD, PhD; Hiroyuki Takano, MD, PhD; Satoshi Shindo, MD, PhD; Shinichi Takeda, MD, PhD; Nobusada Funabashi, MD, PhD; Keiichi Nakagawa, MD, PhD; Tetsuya Toyozaki, MD, PhD; Yoichi Kuwabara, MD, PhD; Issei Komuro, MD, PhD

From the Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.

Correspondence to Issei Komuro, MD, PhD, Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail komuro-tky{at}umin.ac.jp

A 43-year-old male patient with cardiac Fabry disease was followed up by single-photon emission computed tomography (SPECT) and ¹⁸F-deoxyglucose (FDG) positron emission tomography (PET) examinations from 1992 onward. At first, he was thought to have concentric left ventricular (LV) hypertrophy, as determined by echocardiography (LV apex wall thickness, 21 mm; diastolic interventricular septum wall thickness, 25 mm; diastolic LV posterior wall thickness, 29 mm; ejection fraction, 76%); however, a diagnosis of cardiac Fabry disease was defined by endomyocardial biopsy and decreased -galactosidase A activity of the peripheral lymphocyte in 1996. Extracardiac signs of Fabry disease were not detected at that time.

In 1992, a PET study after overnight fasting showed increased uptakes of FDG at the apical and lateral walls, whereas PET scanning after oral glucose loading showed a mildly reduced uptake of FDG. The uptakes of FDG were reduced in the apical and lateral walls of the LV on glucose loading images (Figure 1A, lower panel), whereas the uptakes of FDG were increased in the same regions on the fasting images (Figure 1A, upper panel). This mirror-image pattern of uptakes suggested myocardial ischemia at the apical and lateral walls. In 1996, SPECT and PET studies showed that no perfusion was evident in the apical region of the LV, suggesting that the myocardial tissue of the apex had been replaced by fibrous tissue (Figure 1B and Figure 2A). However, coronary angiography revealed no lesions in the coronary arteries. In 2004, echocardiography showed a moderate reduction in LV contractility (ejection fraction, 42%). Although the interventricular septum and LV posterior wall were hypertrophic (wall thicknesses, 24 and 28 mm, respectively), the apical and lateral wall thicknesses of the LV were remarkably decreased (wall thickness, 9 mm), and dyskinetic motion was recognized at the apex. SPECT and PET scans revealed that the size of the fibrotic region had expanded from 1996 to 2004 (Figures 1C and 2B). Coronary angiography revealed no obstructive lesions, and the extent of the fibrotic region did not coincide with segments of the coronary arteries (Figure 2C). These findings indicated that the hypertrophied myocardium in the apical and lateral regions of the LV had been replaced by massive fibrosis.

View larger version (47K): [in this window] [in a new window]   Figure 1. PET images of the heart in 1992, 1996, and 2004. PET scanning was performed with a whole-body scanner (Shimadzu Headtome III [Kyoto, Japan] in 1992 and 1996 and GE Advance Nxi [Milwaukee, Wis] in 2004). A transmission scan with an external source of germanium-68 and an emission scan with &370 MBq of FDG were obtained during each PET study, and attenuation was corrected. PET studies in 1992 were performed after both overnight fasting and oral loading with 75 g glucose. In 1996 and 2004, a PET study after oral glucose loading only was performed. In 1992, the PET study after overnight fasting showed increased uptakes of FDG at the apical and lateral LV walls, whereas PET images after oral glucose loading showed a mildly reduced uptake of FDG. Uptakes of FDG were reduced in the apical and lateral walls of the LV on the glucose loading images (A, lower panel), whereas uptakes of FDG were increased in the same regions on the fasting images (A, upper panel). In 1996, the size and degree of reduction of the FDG uptakes at the apical and lateral walls of the LV after oral glucose loading were larger and more severe than those in 1992, suggesting progression of myocardial ischemia (B). In 2004, a follow-up PET study after oral glucose loading showed that the reductions of FDG uptakes were larger and more severe in the same regions, suggesting the gradual loss of cardiomyocytes (C).

View larger version (78K): [in this window] [in a new window]   Figure 2. 99mTc-sestamibi SPECT images of the heart in 1996 and 2004. SPECT images were acquired 40 minutes after injection of 740 MBq 99mTc-sestamibi on a triple-head gamma camera with a high-resolution, parallel-hole collimator and computer system (PRISM 3000XP; Philips Medical Systems, Cleveland, Ohio). The SPECT studies were performed by using a circular 360° acquisition scheme for 60 projections (20x3) at 60 seconds per projection with a 64x64 matrix size. A polar map image was constructed by using short-axis slices, and the fibrotic segment was determined by noting the pixels with tracer uptake <2 SDs of normal controls. An extent score was defined as the proportion of the fibrotic segments in the polar map. Longitudinal long-axis and horizontal long-axis images in 1996 (A) and in 2004 (B) and the polar map images with 99mTc-sestamibi (C) are shown. In the images taken in 1996, increased uptake attributable to hypertrophy was seen on the basal side of the anteroseptal and lateral myocardial segments, and obviously reduced uptake of 99mTc-sestamibi was observed at the apical and lateral walls, which became prominent by 2004. Because there was no stenosis in the coronary arteries, myocardial infarction was though to be unlikely. Quantitative analysis showed that the proportion of the defect size had increased, from 36% in 1996% to 56% in 2004 (C).

Although myocardial fibrosis associated with Fabry disease has been recently reported,^1–3 the extent of fibrosis was mild and restricted to the interstitium. In our patient, replacement of hypertrophied myocardium by massive fibrosis gradually progressed during a long follow-up period. Although vascular changes due to vascular accumulation of globotriaosylceramide cause thrombotic events,⁴ the extent of the fibrotic region did not coincide with the segments of coronary arteries in our case. Because globotriaosylceramide accumulates in endothelial cells and vascular smooth cells in Fabry disease, the microcirculation of the heart might be impaired in the cardiac variant of Fabry disease. Therefore, there is a possibility that massive fibrosis was induced by cardiomyocyte death through a decrease in myocardial perfusion at the microcirculatory level. To our knowledge, this is the first report of the progressive replacement of hypertrophied myocardium by massive fibrosis as a manifestation of Fabry disease. Because massive fibrosis induces cardiac dysfunction and heart failure, early diagnosis of Fabry disease and early initiation of enzyme replacement therapy are warranted.⁵

	Disclosures

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	References

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3. Weidemann F, Breunig F, Beer M, Sandstede J, Stork S, Voelker W, Ertl G, Knoll A, Wanner C, Strotmann JM. The variation of morphological and functional 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]

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