CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 1, January/February 2011
AFRICA
41
A recent larger study confirmed the usefulness of TDI in
detecting sub-clinical cardiac involvement, showing signifi-
cantly lower Ea velocities (lateral 12.00
±
3.34 cm/s, septal
5.52
±
2.12 cm/s), although Sa velocities did not differ between
Fabry’s patients and controls. Late diastolic velocities (Aa) and
isovolumic contraction times (IVCT) were also significantly
lower in Fabry’s patients without LVH compared to controls.
Isovolumic relaxation times (IVRT) were significantly longer in
all Fabry’s patients compared to controls. IVCT
≤
105 ms was
the best predictor for sub-clinical involvement with a sensitivity
of 100% and specificity of 91%. An Ea velocity of
<
15.5 cm/s
had a sensitivity of 44.4% and specificity of 93.2% while IVRT
>
60 ms had a sensitivity and specificity of 27.8 and 96.6%,
respectively, for detecting pre-clinical cardiac involvement in
Fabry’s patients.
42
Therefore TDI may be a valuable and inexpensive modal-
ity for detecting cardiac involvement in hemizygous men and
heterozygous or ‘carrier’ females.
28
Cardiac MRI
Cardiac MRI (CMR) has firmly established its usefulness in the
evaluation of left ventricular dysfunction and cardiomyopathy,
specifically in the absence of coronary artery disease on angio-
gram, i.e. non-ischaemic cardiomyopathy.
47
CMR is non-invasive
and can be used to not only assess cardiac function, but also for
tissueabnormalitiessuchasfibrosis,infiltrationandinflammation.
With respect to Fabry’s cardiomyopathy, most commonly seen
on CMR is regional or global myocardial hypertrophy; however,
one potential distinguishing feature of cardiac hypertrophy due
to Fabry’s disease is late enhancement of gadolinium, also called
delayed contrast enhancement. Gadolinium enhancement occurs
when chelated gadolinium stays in the intercellular space; in
conditions causing fibrosis, the intercellular space is increased
and distribution is slower.
48
Areas of late gadolinium enhance-
ment (LGE) in Fabry’s cardiomyopathy correspond histologi-
cally to collagen, but unlike post myocardial infarction scarring,
the collagen is not in disarray.
49
The scarring in Fabry’s is not as
well defined as fibrosis seen post myocardial infarction (MI),
with LGE being able to differentiate between the two.
47
Although LGE is not a specific finding with regard to restric-
tive or hypertrophic cardiomyopathies and can be seen in any
aetiology of LVH,
50
fibrosis may be more focal than other forms
of cardiomyopathy (e.g. versus global sub-endocardial involve-
ment in amyloidosis) and various cardiomyopathies may have
different tissue predilections (e.g. papillary muscle in cardiac
sarcoidosis).
51
Although reports are not always consistent for
various cardiomyopathies
52
and more work needs to be done to
evaluate the utility of LGE in differentiating different cardiomyo-
pathies,
53
for reasons which have not been completely elucidated,
the earliest evidence of LGE in Fabry’s disease is the basal
infero-lateral wall (also known as the postero-lateral wall).
48,54-56
A recent study comparing patients with symmetric hyper-
trophic cardiomyopathy and Fabry’s cardiomyopathy found late
gadolinium enhancement of the infero-lateral basal or mid-basal
segments sparing the sub-endocardium to be specific for Fabry’s.
57
However, LGE is only present in severe stages of Fabry’s cardio-
myopathy, reflecting the extensive fibrosis due to glycosphin-
golipid accumulation,
55,56
and LGE has been shown to correlate
with a poorer prognosis in non-ischaemic cardiomyopathy.
58
Another potential method for screening patients with Fabry’s
disease for early cardiac involvement or differentiating physi-
ologic LVH from Fabry’s cardiomyopathy using CMR is T2
relaxation time, which has been shown to be prolonged in Fabry’s
patients with and without increased myocardial wall thickness.
59
ECG
ECG findings are non-specific but may show manifestations of
conduction tissue infiltration, such as PR prolongation,
38
varying
degrees of heart block, sinus bradycardia, sick sinus syndrome,
and atrial or ventricular arrhythmias.
39
Myocardial infiltration
may present as evidence of atrial enlargement or LVH.
Screening patients with LVH for Fabry’s disease
Of patients with late-onset cardiac hypertrophy, the prevalence
of Fabry’s disease has been reported to be as high as 6% in men
(mean age 53 years)
60
and 12% in women (mean age 50 years).
61
A recent study from Spain showed the incidence to be 1% by
genotyping (mean age 58 years) (0.9% in men and 1.1% in
women), although low alpha-galactosidase activity was present
in 3%.
62
Strong consideration should be made to check alpha-
galactosidase A activity in middle-aged patients with hypertro-
phy in the absence of long-standing hypertension.
Treatment
Enzyme replacement therapy (ERT) for the treatment of Fabry’s
disease was first performed in the 1970s,
63
however, open-label
phase 2 trials were not performed until the 2000s.
63
ERT using
recombinant human alpha-galactocidase A (generic names agal-
sidase alpha and agalsidase beta) was approved for use in Europe
in 2001 and in the United States in 2003.
64
Initial randomised controlled trials (RCT) showed that 69% of
the treatment group was free of renal microvascular endothelial
deposits of globotriaosylceramide (primary endpoint) versus no
change in the placebo group after 20 weeks (
p
<
0.001). There
was also a statistically significant difference in endothelial
deposits in the heart (
p
<
0.001).
63
Although there did not appear to be a difference in quality of
life as assessed by the SF-36,
63
another RCT showed a statisti-
cally significant decrease in pain severity and improvement
in quality of life (primary outcome). This study also showed
improvement in renal architectural distortion (mesangial diam-
eter) (
p
=
0.01) and increase in creatinine clearance (
p
=
0.02).
65
In a more recent, larger RCT, 42% of placebo patients versus
27% of treated patients had clinical events (defined as renal,
cardiac or cerebrovascular event or death); the time to first clini-
cal event adjusted for baseline proteinuria favoured agalsidase
beta but included the null (hazard ratio 0.47, CI: 0.21–1.03;
p
<
0.06). Time to first cardiac event (arrhythmia, angina or MI)
was not affected. Although overall the results were less than
overwhelming, treatment effect was greater in patients with
preserved renal function.
64
There are no data currently regarding
ERT and affect on mortality.
Cardiomyopathy
Observational studies have been performed which specifically
analyse cardiac endpoints in Fabry’s patients on ERT. Several
studies have documented statistically significant improvement
