CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 5, June 2013
e6
AFRICA
traditionally defined time of onset of PPCM).
14,15
These studies
were weakened by their exclusion of patients who recovered LV
function within the first year, thereby cutting out 25–50% of the
spectrum of PPCM patients and favouring the possibility that
only FDCM phenotypes were retained, as the latter rarely recover
LV function.
Nonetheless, these findings raise two pertinent questions.
First, other than postulations of late-pregnancy oxidative stress
triggering the PPCM phenotype, how did these putative familial
DCM cases surpass the expected time of presentation for
pre-existing heart disease in the second trimester? Second, could
the genetic polymorphisms or mutations identified so far in
PPCM cases with familial disease be a co-incidental finding,
while the real culprits for PPCM phenotypes lie in other genetic
mutations inadequately sought for beyond those known to cause
familial DCM?
Familial DCM manifests in an age-dependent manner with
incomplete disease penetrance.
9
Therefore, in the absence of
long-term, population-based studies, answering our second
question will remain a challenge. As heterogeneous as familial
DCM is, over 40 defective genes have been associated with
inherited DCM, although they account for a minority of familial
DCM cases.
16
Genome-wide association studies (GWAS) may succeed in
identifying pathogenic mutations for PPCM. The only known
attempt at GWAS in PPCM patients was done in Utah,
17
and revealed 10 single-nucleotide polymorphisms (SNPs) that
may play a role in the pathogenesis of PPCM.
17
Of these,
one SNP (located on chromosome 12) demonstrated genome-
wide significance for PPCM, likely triggering disease through
abnormal immune modulation.
17
The strength of the study
lies in its efforts to exclude patients with co-morbidities that
would confound the diagnosis of PPCM, and for screening
a variety of controls, including post-menopausal controls,
17
to enable discovery of PPCM-associated loci relevant to the
at-risk population of pregnant/potentially pregnant females.
17
Furthermore, the authors went as far as to describe 30 other SNPs
which appeared to predict the absence of PPCM,
17
suggesting a
route for the exploration of protective mechanisms to PPCM.
Recent advances favouring PPCM as an independent disease
shows
in vitro
and
in vivo
evidence of an abnormal 16-kDa
prolactin pathway intertwined with oxidative stress.
18
However,
given that oxidative stress, together with signal transducer
and activation of transcription factor-3 (STAT-3) depletion,
as implicated in this model may be common to most forms
of severe heart failure, including idiopathic DCM,
19
the only
component to this pathway that might remain unique to PPCM
is that fuelling production of the 16-kDa fragment of prolactin.
However, linking this abnormal prolactin pathway exclusively to
PPCM would require proof of its absence in women with familial
DCM, including relatives who subsequently fall pregnant and
deteriorate.
Despite the GWAS described above
17
having failed to find
any SNP or other variation on the STAT-3 gene to account
for PPCM, it introduced the possibility of an association
between polymorphic variations (SNPs) on the STAT-5 gene and
PPCM. This is important because STAT-5 is a known culprit in
idiopathic DCM,
19
making the thought of it playing a role in the
development of PPCM an interesting possibility.
Novel data further suggest that imbalances between cardiac
pro-angiogenic factors PGC-1
α
and vascular endothelial growth
factor (VEGF), and anti-angiogenic factors such as the VEGF
inhibitor soluble Flt1may result in PPCM, and that this association
is more profound in the presence of gestational hypertension
and multiple pregnancy.
20
If indeed these mechanisms become
validated, it would be essential to establish any genetic bases for
these abnormalities.
Conclusion
There are several lessons to be learned from this detailed family
study of two cases with PPCM. First, we emphasise the need
for family screening of PPCM and idiopathic DCM patients,
10
with long-term follow up of screened persons, particularly of
females of child-bearing age. There is a need for well-structured
incidence studies of PPCM and idiopathic DCM, with baseline
echocardiograms of primary relatives (irrespective of symptoms),
pre-pregnancy echocardiography of all women being followed up
(irrespective of underlying co-morbidities), and follow up with
echocardiography every two to five years.
21
This exercise could
mould routine practice, given the high prevalence of familial
DCM, its lethal course, and the suggested benefits of treating
asymptomatic relatives with LV dysfunction.
11
Aside from the GWAS reported several years ago,
17
the search
for genetic abnormalities in PPCM has remained narrowed
towards screening for mutations (or SNPs) associated with
familial DCM. It would be recommended to expand on the
reported GWAS by testing the clinical impact of the SNPs
already suspected to be associated with PPCM.
17
Furthermore,
in the hope of identifying new SNPs accountable for PPCM
through target-gene search or GWAS, it may be logical to start
comparing genotypes of extreme phenotypic presentations of
both PPCM and idiopathic DCM (i.e. mild versus severe) within
and across their respective diagnostic groups.
In addition, in the search for PPCM-specific genetic
abnormalities, the co-existence of the abnormal 16-kDa prolactin
cascade would need to be evaluated in familial DCM patients
who deteriorate in pregnancy, and the genetic abnormalities
programming this abnormal pathway further explored. Lastly,
next-generation sequencing (NGS) is a recently developed,
massively parallel, large-scale sequencing technology that has
been used for rapid gene cloning and mutation detection. Taking
advantage of the larger size of families in Africa, NGS with
exome selection could be used to identify the causative genes
and to improve both genetic and clinical delineation of DCM
and PPCM.
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