CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 1, January/February 2011
AFRICA
39
being 50 years in males and 70 in females,
14,15
although another
series reports mean ages of 45 and 55 years, respectively.
16
It
has been generally stated in the literature that, at least prior to
enzyme replacement therapy, men died from the consequences
of renal failure, and women succumbed to cardiac complica-
tions.
2,14-17
Cardiac involvement
Fabry’s patients with cardiac involvement may present with
dyspnoea, palpitations, syncope or angina, depending on the
cardiac tissue involved. Classic Fabry’s is associated with cardiac
manifestations including arrhythmias, valvular abnormalities
and cardiomyopathy; however, the cardiac variant of Fabry’s
presents later in life as left ventricular hypertrophy (LVH) with
residual alpha-galactosidase A activity.
7
Sixty per cent of Fabry’s
patients have some cardiac manifestation, usually arrhythmias.
16
As in other organ tissues, cardiac dysfunction is due to
glycosphingolipid accumulation in the myocytes and conduction
tissue, but probably more importantly with respect to the cardio-
myopathy is myocyte hypertrophy and fibrosis as glycosphin-
golipid deposition accounts for less than 3% of the total myocar-
dial mass.
18
Hypertrophic myocytes contain vacuoles laden
with sphingolipids, resulting in eventual fibrosis. The extent of
myocyte hypertrophy and the accumulation of glycosphingolip-
id-laden vacuoles correlates with the extent of LV wall thicken-
ing on imaging.
19
Similar cell degeneration occurs in valvular as
well as conduction tissue.
Cardiomyopathy
Although the hallmark of cardiac involvement in Fabry’s disease
(classical or the cardiac variant) is LVH, Fabry’s cardiomyopathy
is a restrictive cardiomyopathy,
20-22
as it results from the accu-
mulation of glycosphingolipids, whereas hypertrophic cardio-
myopathy, i.e. non-physiological hypertrophy, is due to abnormal
contractile proteins. However, the hallmark of restrictive cardio-
myopathy is impaired ventricular filling, and in one series of 30
patients, no patient had severe diastolic dysfunction consistent
with a restrictive pattern.
23
Mild to moderate diastolic dysfunc-
tion is often present.
24
Furthermore, most restrictive cardiomyo-
pathies do not have LVH.
Amyloidosis can present with hypertrophy but it can easily
be distinguished from Fabry’s in that the voltage is decreased on
ECG. Also unlike other infiltrative cardiomyopathies, in Fabry’s
only 1% of the myocardium contains the infiltrative material
(glycosphingolipids). Therefore, as with other cardiomyopathies
secondary to glycogen or lysosomal storage disorders,
13
Fabry’s
cardiomyopathy could be considered a ‘pseudo’-hypertrophic
cardiomyopathy in that myocyte hypertrophy and fibrosis play a
more prominent role than restrictive physiology in contributing
to the heart failure.
In the cardiac variant of Fabry’s disease, patients have some
alpha-galactosidase A activity and present later in life, often
with only cardiac manifestations, although proteinuria can also
be present.
7
The cardiac variant, first described in 1990,
25,26
may
be due to alternative splicing in the alpha-galactosidase A gene,
27
and in the first published case series, five of seven patients had
no mutations in the coding regions despite very low levels of
mRNA.
7
The aetiology of the cardio-tropism of the cardiac vari-
ant of Fabry’s has not been elucidated.
Both the classical and cardiac variant of Fabry’s can cause
global LVH or an asymmetrical septal hypertrophy similar to
hypertrophic obstructive cardiomyopathy. However, systolic
function is usually preserved, although there is a trend towards
increased LV end-diastolic volume.
28,29
Diastolic dysfunction is
often present, but usually only moderate at worst and without
a restrictive filling pattern.
23,24
In heterozygous women with
Fabry’s (mean age 40 years), 12.7% had concentric remodelling,
52.7% had concentric LV hypertrophy, and 10.9% had eccentric
LVH by echocardiogram.
30
Similar percentages were seen in
hemizygous men, with 37% having concentric hypertrophy, and
37 and 10% having asymmetric septal hypertrophy.
23
Hypertrophy is present in 51 to 55% of males with a median
age of 43 to 45 years, versus 33 to 38% of females with a
median age of 55 years.
18,31
Gender, age and renal function are
directly and independently related to the presence of LVH, but
not to blood pressure, i.e. LVH is the direct result of myocardial
infiltration and not from primary hypertension or secondary to
renal dysfunction. The presence of LVH has also been shown to
be logarithmically related to alpha-galactosidase A activity.
29
In a
relatively large case series of 1 448 Fabry’s patients, 11% of men
and 6% of women had congestive heart failure (CHF) symptoms
and 35% had evidence of cardiac hypertrophy. However, the
mean ejection fraction (EF) was preserved (63.1
±
9.1%).
32
In a case-control series using echocardiography, tissue
Doppler imaging (TDI) and cardiac MRI (CMR) to characterise
Fabry’s cardiomyopathy, a distinct pattern of progression was
seen in genetically- or biopsy-proven cases of Fabry’s disease.
33
No patient had late gadolinium enhancement (LGE) (indicative
of fibrosis, as will be discussed later) without LVH. Women
younger than 20 years had no evidence of hypertrophy, normal
radial and longitudinal function on TDI and no LGE. Women
without LVH had reduced longitudinal function isolated to the
lateral wall of the LV. Women with LVH had reduced longitudi-
nal and radial function; women with LVH and LGE had severely
reduced longitudinal and radial function.
Males without LVH had reduced longitudinal function in the
lateral wall and septum, whereas males with LVH but without
LGE also had reduced radial function. Males with LVH and LGE
had severe longitudinal and radial dysfunction. In general, global
LV function was not impaired.
33
Similarly, another series found
no evidence of either LVH or LV remodelling by echocardiogram
in patients younger than 30 years old.
23
Therefore, functional
abnormalities arise before hypertrophy, and fibrosis visible on
CMR only occurs after hypertrophy. These changes take time to
develop as the glycosphingolipids accumulate.
The disproportionate amount of fibrosis in the lateral wall
may be due to increased wall stress or a relatively oxygen-defi-
cient environment. Lastly, there is no evidence of RV regional
functional abnormalities or late-enhancement, possibly due to
decreased work load of the right heart or that enhancement is
more difficult to detect in the RV due to its smaller size and
fewer myocytes.
33
Coronary artery disease/angina
Patients with Fabry’s have been documented as having an
increased risk for coronary artery disease (CAD).
2,17
However,
in case-control series and cross-sectional studies, there is no
evidence of increased admissions for myocardial infarctions,
