Case 2 -
The Heart in Fabry's Disease
Royal Brompton Heart Hospital
Click on each slide thumbnail image for an enlarged view
- DOB: 09-02-1949.
- Patient aged 53 originally presented from a family screening program. His
mother presented with hypertrophic cardiomyopathy (aged 65 years) and he was subsequently also found to
have the condition. At the time his only cardiac symptom was that of palpitations. Echocardiography
demonstrated concentric left ventricular hypertrophy (maximal wall thickness 20mm). He was also found to
have asthma and was treated with inhalers and intermittent courses of oral steroids. He progressed over
5 years to heart failure and presented to hospital with severe chest pain and difficulty breathing. He
suffered cardiac arrest shortly after admission from which he was not able to be resuscitated.
- The weight of the heart is 879g. On
examination, there is left ventricular hypertrophy particularly noted in the anteroseptal and
posteroseptal wall of the left ventricle. The thickness of the postero-septal wall is 21mm whereas the
anterior and posterior appear to be 16mm. The lateral free wall of the left ventricle appears of normal
thickness at 15mm. There is hypertrophy of the trabeculae which appear quite prominent in the left
- In the postero-lateral wall of
the left ventricle there is a slightly sunken area in the inner one third of the subendocardium.
Elsewhere, the muscle appears prominent with some swirling but no other macroscopic areas of fibrosis.
- The right ventricle appears normal in the
anterior and lateral wall with overlying epicardial fat, but there is hypertrophy of the posterior wall
which is approximately 6mm.
- There is nodular
calcification of the aortic valve leaflets which extends onto the anterior mitral leaflet with
calcification extending onto the chordae of the mitral valve. The aortic leaflets are slightly thickened
but there is no significant stenosis of the valve leaflets which move freely. There is extensive nodular
calcification of the anterior leaflet of the mitral valve which involves both the annulus and the body of
the mitral leaflet. At the edge of the anterior leaflet, there is slight ballooning and thickening
between the chordae. The tricuspid valve also appears slightly thickened and ballooned between the
chordae. Pulmonary valve appears macroscopically normal. There are no congenital defects seen in the
heart. The coronary arteries appear normal with no narrowing macroscopically.
Case 2 - Figure 1 -
Shows a transverse short axis view of the heart with left ventricular hypertrophy. Note slight thinning of the posterolateral wall. There is also mild right ventricular hypertrophy in the posterobasal area.
Case 2 - Figure 2 -
Mitral valve shows extensive annular calcification with mild thickening of valve leaflets
Case 2 - Figure 3 -
Aortic valve and anterior leaflet of mitral valve shows extensive annular calcification extending onto the aortic valve. Note the mild thickening of the aortic valve leaflets.
Case 2 - Figure 4 -
Tricuspid valve shows thickening and ballooning between the chordae.
Case 2 - Figure 5 -
Transverse sections of the coronary arteries showing eccentric intimal proliferation and vacuolization of medial smooth muscle cells. Haematoxylin and Eosin stain.
Case 2 - Figure 6 -
Sections of the myocardium showing myocyte hypertrophy, vacuolization of the cytoplasm and interstitial fibrosis. Haematoxylin and Eosin stain.
Case 2 - Figure 7 -
Sections of the myocardium showing myocyte hypertrophy, vacuolization of the cytoplasm and interstitial fibrosis. Note also the foamy macrophages surrounding degenerating myocytes . Haematoxylin and Eosin stain.
Case 2 - Figure 8 -
Electron microscopic section of myocyte showing the typical lamellar bodies within the cytoplasm.
Case 2 - Figure 9 -
Shows fibrosis ( red stain) replacing myocardium and surrounding individual myocytes (yellow). Picro Sirius red staining.
Fabry disease (FD) is a genetic disorder caused by the deficiency of α-galactosidase A, resulting
in the lysosomal accumulation of glycosphingolipids. Symptoms of Fabry disease include cardiac, cerebral
and renal complications. Cardiac abnormalities in patients with Fabry's disease were first described in
the 1960s. In the 1990s a form of Fabry disease confined to the heart was reported; however, this
variant is extremely rare and a more appropriate concept is a cardiac predominance of the disease in some
patients. Up to 60% of males with classic Fabry disease have cardiac abnormalities, including left
ventricular hypertrophy (LVH) valvular dysfunction and conduction abnormalities. Cardiac manifestations
of Fabry's disease were described over 30 years ago
yet their significance
in the natural history of this disease is still the subject of much research. The increased awareness of
the condition amongst cardiologists has resulted in the emergence of new data on the prevalence and
spectrum of disease in the heart. There is an improved understanding of the disorder, but uncertainty
about some of the long-accepted truths concerning cardiovascular involvement in Fabry disease. The
prospect of enzyme replacement therapy (ERT) has opened up new therapeutic options in this condition.
Recent data suggest that left ventricular mass and systolic function in patients with Fabry disease
improve after 12 months of enzyme replacement therapy (ERT).
Case 2 - Figure 10 -
Shows mitral valve with diffuse thickening and calcification . Haematoxylin and Eosin stain.
Case 2 - Figure 11 -
Shows aorta with vacuoles within the smooth muscle cells highlighted by the van Gieson Trichrome staining.
Case 2 - Figure 12 -
Shows aorta with vacuoles within the smooth muscle cells (Haematoxylin and Eosin stain)
Key words: Cardiovascular disease, enzyme replacement
therapy, Fabry disease, left ventricular hypertrophy, conduction abnormalities, valve abnormalities,
Epidemiology of Fabry disease
Published estimates for the prevalence of Fabry disease range from 0.02 to 0.09 per 10 000 of the
However, these values are extrapolations from data obtained
from reference laboratories around the world and, as a result, do not take into account asymptomatic
heterozygotes or misdiagnosed cases. Patients with Fabry disease can present with non-specific symptoms,
resulting in a delay in diagnosis. Recent data from FOS – the Fabry Outcome Survey – suggest that there
is a delay of 13.7 years for males and 16.3 years for females from the onset of symptoms to
diagnosis . Overall, 25% of patients in FOS have reported a previous misdiagnosis.
Recent screening programs of patients with end-stage renal disease receiving haemodialysis suggest
that the prevalence of Fabry disease in this cohort ranges from 1.2 to 3.5%
Similarly, the prevalence of Fabry disease in adult males with unexplained left ventricular hypertrophy
(LVH) has been reported to be 3% or more
FD has been recognized as the
cause of left ventricular hypertrophy in 6% of men with clinical late-onset hypertrophic cardiomyopathy
FD may account for up to 12% of females with late-onset LVH . Together , these data
suggest that Fabry disease is much more common than previously thought
Frequency of cardiac disease in Fabry disease
Up to 60% of males with classic Fabry disease have cardiac abnormalities, including left ventricular
hypertrophy , valvular dysfunction and conduction abnormalities
Females are also affected, but generally present at a later age than men. In the FOS
registry, over 60% of patients have reported angina, dyspnoea or palpitations, with no gender difference
in the prevalence of these symptoms. Kampmann et al.  reported
that all female patients over the age of 45 years had evidence of LVH
The 'cardiac variant' of Fabry disease
In the early 1990s there were several reports of a form of Fabry disease confined to the heart.
Patients with this 'cardiac variant' had residual enzyme activity (approximately 1–5% of normal values)
and presented in the fifth and sixth decades of life with LVH and conduction disease without classic
manifestations such as angiokeratoma, acroparaesthesia, hypohidrosis and characteristic ophthalmological
changes. These patients occasionally had proteinuria, but did not progress to end-stage renal
Histologically, patients with the cardiac variant
were said to differ from those with classic Fabry disease in that there was an absence of vascular
endothelial glycosphingolipid deposits
In clinical practice,
this cardiac variant seems to be extremely rare, as detailed evaluation usually identifies some
manifestations of the classic form of the disease. A more appropriate concept therefore may be that
there is a cardiac predominance of the disease in some patients, rather than a purely cardiac variant.
The prevalence of Fabry disease with predominantly cardiac features was thought to be low, until a
Japanese study of 1603 males undergoing routine echocardiography found that seven (3%) of 230 patients
with LVH had Fabry disease that had not been suspected clinically . Another study performed
in a referral clinic for patients with hypertrophic cardiomyopathy in the UK reported a prevalence of
Fabry disease of 4% in men with otherwise unexplained hypertrophy. This value increased to 6% in those
first diagnosed over 40 years of age .
Cardiac Fabry disease
The dominant cardiac manifestations include myocardial hypertrophy of the left ventricle, which
mimics hypertrophic cardiomypathy. Left ventricular systolic function is usually preserved, while mild
to moderate diastolic dysfunction is regularly detected. Valvular abnormalities are frequently noted but
hemodynamically significant lesions are rare. Conduction system involvement leads initially to the
shortening of atrioventricular conduction, in later stages, with a progression of the disease,
antrioventricular blocks and various forms of supraventricular and ventricular arrhythmias appear.
Myocardial ischemia in Fabry disease has in most cases a functional origin due to endothelial dysfunction
of coronary arteries and also due to the increase oxygen demand of hypertrophied myocardium .
In females there is a strong correlation between age and the severity of LVH and all patients older
than 45 years had LVH. With increasing LVM, there was a significant age-independent decrease in systolic
and diastolic LV function. Mild thickening of the aortic valve leaflets is present in 25.5% of patients,
with the same percentage demonstrating mild thickening of the mitral valve leaflets. Mild mitral valve
prolapse was documented in 10.9% of patients . RV involvement is common in Fabry disease
and ultimately progresses to severe systolic and diastolic RV dysfunction .
Pathology of Cardiac involvement in Fabry's Disease
Pathological case reports of cardiac involvement describe cardiomegaly, left ventricular hypertrophy
and mitral and aortic regurgitation.. Valvular structural abnormalities are frequent due to valvular
infiltration. Hypertrophy of papillary muscles and/or systolic anterior motion of the mitral leaflets
associated with LV outflow obstruction may aggravate the mitral valve dysfunction. Valvular
regurgitation is usually non-significant .
Sudden death in heterozygous elderly females have been described
As well as hypertrophy localized thinning of the basal posterior wall of the left ventricle has been
described in those who die of heart failure .
The most prominent feature of cardiac disease in patients with Fabry disease is the presence of lipid
storage. This is seen in all cell types within the heart, including myocytes, specialized conduction
tissues, valves and endothelium . Endomyocardial biopsy shows myocytes cytoplasmic
vacuolization by light microscopy, and electron-dense deposits consisting of parallel or concentric
lamellae with periodic spacing . These deposits are thought to be the pathological basis
for cardiac disease in this condition; however, glycosphingolipid accumulation accounts only for
approximately 1% of the myocardial mass in patients with Fabry disease cardiomyopathy. This suggests
that other histological features, such as hypertrophy and fibrosis, are also important .
Patients develop progressive systolic dysfunction and myocardial fibrosis. which could be secondary to
coronary microvascular dysfunction . Histologically there is vacuolar cytoplasmic change in
myocytes with lamellar bodies on electron microscopic examination. A definite biochemical diagnosis of
Fabry's disease will demonstrates a large amount of trihexosylceramide in the myocardium, kidney, and
The arterial wall in large muscular arteries (coronary, renal and intrarenal) show arteriopathy with
pronounced involvement of the smooth muscle cells in the media. Arteriopathy starts with storage,
followed by cell degeneration and breakdown, extracellular matrix deposition and, often, calcification
(confined to the muscular layer). Smooth muscle cells occasionally exhibited shrinkage-type necrosis,
with dispersion of the stored lipid into the dense cytoplasmic mass. Intimal and mitral valve
fibroblasts exhibited variable storage, which was associated with cell loss and necrosis .
Progression to Heart failure
Although there are isolated case reports of heart failure in Fabry disease, its importance in the
natural history of Fabry disease is unknown. In a recent retrospective analysis of a cohort of patients
with Fabry disease cardiomyopathy followed for at least 1 year, there is a progressive deterioration in
fractional shortening (an echocardiographic measure of left ventricular contractile function) of
approximately 2.6% per year  This change in left ventricular contractile function may be due
to progressive glycosphingolipid accumulation, but recent studies by us using magnetic resonance imaging
of the heart have identified a unique pattern of myocardial gadolinium hyperenhancement 
This hyperenhancement is thought to represent fibrosis and scarring, and may be a marker of end-stage
Role of ERT in the treatment of Fabry cardiomyopathy
Until recently, Fabry's disease management consisted of symptomatic and palliative treatment, but
this has changed with the availability of the recombinant human alpha-Gal A enzyme, agalsidase. Two
different agalsidase formulations have been obtained: one from human fibroblast (agalsidase alpha), and
one from Chinese hamster ovary (CHO) cells (agalsidase beta). Both preparations have undergone clinical
trials that documented the feasibility, efficacy and safety of the treatment. Several clinical
observations have proved that agalsidase reduces the storage of the substrate from several organs and
tissues and, consequently, improves signs and symptoms of Fabry's disease . There is
improvement in renal function , but its role in improving and attenuating the progression
of cardiac symptoms is still under investigation.
Improvements in cardiac function were suggested during clinical trials with a significant improvement
in cardiac conduction being reported in patients treated with ERT for 6 months . It is also
interesting to note that administration of galactose (1g/kg, given over a 4-hour period every other day),
which enhances residual α -galactosidase A activity, results in improvement in cardiac
contractility, a moderate reduction in ventricular wall thickness and a 20% decrease in cardiac mass
after 3 months in a single patient 
More recent studies have specifically investigated the effects of ERT on cardiac structure and
function An improvement in left ventricular mass has been observed and reduction in QRS duration
 in patients as early as 6 months after the initiation of ERT .Other studies show a modest
reduction in left ventricular mass and stiffness
months of ERT. Results of 2 years of treatment with alpha-Gal A in nine patients with Fabry disease
showed that the mean slope of left ventricular mass index progression decreased .
Agalsidase alfa (Replagal) administered to male patients with Fabry disease showed significant decrease
in left ventricular mass and a significant reduction in QRS durations .
The results of these randomized, double-blind, placebo-controlled clinical trials and open-label
extensions have shown that replacement of the deficient enzyme stabilizes renal function and produces
significant improvements in myocardial mass and function . However, many of the patients
studied are relatively young and have mild cardiac abnormalities, and more research into the efficacy of
ERT in older patients is necessary. There are several critical features of ERT that require attention .
Among these are the development of severity-score indices that can be used to explicitly quantify the
benefit of ERT. Detection of early cardiac disease and the role of ERT in prevention or progression /
development of disease also needs exploring. Postmortem findings in a 47-year-old man with Fabry
disease, on enzyme replacement therapy for more than 2 years showedwidespread atherosclerotic coronary
artery disease and Fabry cardiomyopathy. With the exception of vascular endothelial cells, extensive
glycolipid storage deposits were seen in all vascular and nonvascular cells and organ systems. ERT over
a prolonged period did not appreciably clear storage material in cells other than vascular endothelial
cells . Thus the role and timing of ERT is still under investigation in dealing with the
prevention and amelioration of the cardiac complications of Fabry's disease.
In conclusion, cardiac manifestations of Fabry disease are common and much more frequent than
previously thought. Enzyme replacement therapy offers an exciting new and expensive treatment option but
more ongoing studies are needed to determine the efficacy of ERT for improving and preventing cardiac
symptoms in patients with Fabry's disease.
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