CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 4, May 2012
184
AFRICA
Editorial
Endothelial dysfunction: are we ready to heed the
vasculature’s early-warning signal?
HANS STRIJDOM
Endothelial dysfunction (ED) refers to a spectrum of
pathophysiological changes in the vascular endothelium that
ultimately results in a loss of vascular homeostasis. Traditional
cardiovascular risk factors (e.g. diabetes mellitus, smoking,
dyslipidaemia and hypertension) are all associated with the
development of ED via sustained and harmful effects, mediated
by circulating stimuli such as pro-inflammatory tumour necrosis
factor-alpha (TNF-alpha), oxidised low-density lipoprotein
(ox-LDL), asymmetrical dimethyl-arginine (ADMA),
angiotensin II and hyperglycaemia.
1
The underlying cellular mechanisms of ED are directly
or indirectly related to the development of oxidative stress
(particularly increased superoxide anion production via NADPH-
oxidase and xanthine oxidase), which reduces the bioavailability
of the main endothelial-derived vasodilator, nitric oxide (NO)
via the reaction of superoxide with NO (thereby scavenging NO)
to form peroxynitrite (ONOO
-
), a highly reactive molecule. The
latter has the ability to uncouple endothelial NO synthase (eNOS),
which further reduces NO production and simultaneously
increases superoxide anion generation.
2
As a result, vascular
endothelial function becomes compromised, manifesting as
a loss of endothelium-dependent vasorelaxation, increased
thrombosis, the development of a generalised pro-inflammatory
state (increased expression of vascular adhesion molecules) and
increased vascular permeability.
3
Ultimately, ED can develop
into atherosclerosis.
2
The importance of ED as a potential predictor of long-term
development of atherosclerosis and cardiovascular event rate
2
is evident by the high number of research articles on this topic
(PubMed search with keywords: endothelial + dysfunction
revealed 51 600 hits and approximately 3 000–4000 articles per
year on this topic since 2005). Herein, however, lies both the
greatest potential and challenge of current research into ED,
namely translating the wealth of data obtained with laboratory-
based research into scientifically validated predictive, diagnostic
and even therapeutic tools in the clinical setting.
As Mudau
et al.
explain in their comprehensive review article
on the cellular mechanisms and clinical applications of ED in the
current issue of this journal, there is no doubt that ED serves as a
crucial pathophysiological link between traditional cardiovascular
risk factors and the eventual development of atherosclerosis and
ischaemic heart disease (IHD).
4
Particularly helpful in this regard
is the fact that ED is an early, reversible event.
5
This presents
researchers and clinicians with a golden opportunity to not only
predict the development of atherosclerosis, IHD and possibly
other cardiovascular events, but also prevent the development
of these conditions by therapeutically reversing early vascular
dysfunction.
As Mudau and co-workers report, there are several
biomarkers that could be used to assess endothelial function.
However, currently elevated ADMA levels appear to be the
most promising biomarker of ED in terms of prognostic value
and positive correlation with cardiovascular risk. Promising
data have also been obtained from studies investigating
ex-vivo
functional endothelial assessment techniques (current gold
standard: flow-mediated dilatation) with regard to their ability to
predict cardiovascular risk.
Despite many promising studies showing that biomarkers
of ED and
ex-vivo
endothelial function assessment are strongly
correlated with cardiovascular risk, a consensus for their universal
clinical usefulness remains elusive.
6
Reaching consensus is
hampered by factors such as the availability of special equipment
in everyday practice, the lack of data on the predictive value of
more recent endothelial function assessment techniques, and the
lack of studies investigating which patient groups will benefit
most from
ex-vivo
endothelial function measurement.
6
Finally,
more studies demonstrating that putative anti-ED therapies
actually achieve their clinical benefit by the improvement of
endothelial function are required.
In the South African/African context, research into ED, its
underlying mechanisms and potential clinical application is
equally relevant. Indications are pointing to significant increases
in the incidence of cardiovascular disease among people of
African heritage in South Africa as a result of epidemiological
transition and chronic diseases of lifestyle.
7
Data from the Heart of Soweto (HOS) study in 2006 indicated
a high prevalence of traditional cardiovascular risk factors
such as hypertension and obesity, with almost two-thirds of
the patients in the study cohort presenting with multiple risk
factors.
7
Approximately 10% of the patients in the HOS study
were diagnosed with coronary artery disease. In addition, recent
research has drawn attention to the interaction between HIV
infection, anti-retroviral treatment and the increased rate of
coronary artery disease in HIV-infected patients.
8
Due to the
fact that HIV-infected patients on treatment live longer, they are
subjected to traditional cardiovascular risk factors similar to the
non-infected population. However, of concern is the additional
burden of non-traditional risk factors, namely the direct
vascular effects of the HI virus and the anti-retroviral drugs.
7,8
Consequently, HIV-infected patients on treatment now face the
risk of developing premature ED and accelerated atherosclerosis.
In a recent study in South Africa, significantly higher levels
of inflammatory biomarkers associated with ED were detected in
newly diagnosed, untreated HIV-infected participants of African
descent compared to non-infected participants, which was
accompanied by age-related increases in arterial stiffness.
9
In view
