58
VOLUME 11 NUMBER 2 • JUNE 2014
RESEARCH ARTICLE
SA JOURNAL OF DIABETES & VASCULAR DISEASE
coronary endothelial dysfunction. In one of the largest cohorts to
date evaluating coronary vascular function, we found that MetS
is associated with coronary microvascular endothelial dysfunction
in those with and without atherosclerosis. In particular, a striking
relationship emerged between increasing MetS risk factor burden
and coronary endothelial dysfunction; for every additional
component of MetS, the coronary flow response to ACH was
approximately 13% lower. Although obesity appeared to be an
independent predictor of coronary microvascular responses, this
relationship was no longer apparent when the number of MetS
components was introduced into the model, suggesting that it is
the burden of metabolic risk factors in the context of obesity which
are most likely to determine the coronary pathology rather than the
body habitus per se. Notably, neither obesity nor MetS (whether
considered as a discrete entity or as number of MetS components)
was related to endothelium-independent coronary vascular
responses, indicating that the abnormal response to ACH is most
likely due to an abnormality in the endothelial layer rather than the
ability of the coronary smooth muscle to respond to exogenous
nitric oxide. Intriguingly, we also found that the microvascular flow
reserve in response to intracoronary infusion of adenosine was
depressed in subjects with MetS.
The endothelium is a fundamental regulator of vascular
homeostasis. Alteration in endothelial function is not only one of
the earliest recognisable changes in the atherosclerotic disease
process, but is also an indicator of an increased risk of later clinical
complications.
13,14,24-27
Exposure to conventional risk factors for
atherosclerosis results in endothelial dysfunction which is, in part,
explained by the risk factor burden
28-30
and is predictive of future
cardiovascular events even in vascular territories remote from the site
of testing.
14,31,32
In fact, recent studies have shown that endothelial
dysfunction predates future development of hypertension and
diabetes, and predicts more rapid progression of atherosclerosis.
33,34
While non-invasive methods assessing peripheral vascular
endothelial function appear to correlate modestly with coronary
endothelial status, and clearly have great value for assessment
of low to intermediate risk groups, invasive testing remains the
‘gold-standard’ technique for assessment of coronary vascular
physiology.
35,36
The MetS is a clustering of the risk factors characterised by
abdominal adiposity, hypertension, dyslipidaemia (low HDL, high
triglycerides and small dense LDL particles) and impaired glucose
homeostasis characteristic of insulin resistance.
7
Although under
normal conditions insulin promotes the release of NO from normal
endothelium, when individuals have developed tissue insensitivity
to insulin, there is clear evidence of reduced endothelial NO
availability.
37-39
We found a statistically independent association
between MetS and coronary microvascular endothelial dysfunction
particularly in relation to increasing MetS risk factor burden. Our
results are in agreement with findings in the peripheral circulation
where endothelial responses to pressure alterations to finger
cuff (using digital arterial tonometry), to increased flow in the
brachial artery and to ACH in the femoral microcirculation were
impaired in subjects with MetS.
16,19,20
Although we also observed
increasing epicardial endothelial dysfunction with exposure to MetS
components, this relationship did not persist after adjustment for
the presence of CAD.
The lower microcirculatory responses to both ACH and adenosine
suggest that both endothelial function and flow reserve, respectively,
are adversely affected by MetS. However, the magnitude of reduction
in flow reserve (10%) in the presence of MetS was far more modest
than the nearly 25% reduction in flow response to ACH, indicating
a proportionately greater effect on the endothelium. Vasodilation in
response to adenosine is multifactorial in nature, including a small but
significant contribution of nitric oxide (NO).
40
Therefore adenosine
responses, unlike the response to SNP, cannot be considered to
entirely represent endothelium-independent function. It is therefore
possible that the reduced response we observed with adenosine
in subjects with MetS may also reflect reduced availability of NO.
Nevertheless the reduced coronary flow reserve may contribute to
reduced vasodilation during physiologic stress such as exercise in
these patients, potentially contributing to myocardial ischaemia.
Mechanisms responsible for the development of endothelial
dysfunction in obesity include increased levels of oxidative stress
leading to reduced NO bioavailability,
41
reduced generation of
endothelium-derived hyperpolarising factor
42
and increased
production of endothelium-dependent constricting factors such
as endothelin-1.
43,44
Of the individual components of MetS, the
presence of obesity was a consistent determinant of vascular
endothelial dysfunction in the coronary microcirculation in our
study. Several investigators have previously shown both in adults
and children that obesity is independently associated with impaired
peripheral endothelial function and that this can be improved
by appropriate lifestyle interventions.
17,18,38,41,45-47
One previous study
examining coronary microvascular endothelial function confirmed
these finding in a population with minimal or no coronary artery
disease.
22
Our study extends these observations to patients with
CAD and in the context of the associated MetS risk factor burden.
The cluster of abnormalities that emerge with visceral obesity may
also have both direct and indirect adverse effects on the vascular
endothelium. When the total number of components of MetS was
introduced as a covariate, obesity was no longer a predictor of
endothelial dysfunction in our study. Therefore it appears to be the
clustering of the components of MetS that typically associate with
increasing obesity, that best predict an increased risk of endothelial
dysfunction rather than the obesity itself or any one of the other
associated individual risk factors.
Visceral adipose tissue is a rich source of pro-inflammatory
cytokines such as TNF-
α
and IL-6 which also contribute to both
insulin resistance and endothelial dysfunction.
48
Moreover, markers
of inflammation, such as elevated CRP levels, and endothelial
dysfunction have both been associated with poor long term
prognosis in subjects with and without known CAD.
25,49-51
Although
a previous study found a correlation between CRP levels and forearm
vascular endothelial function, adjustment for obesity or MetS was
not performed.
52
Others have confirmed our observations.
16,22,53
Furthermore, despite higher CRP levels in obese subjects and in
those with MetS as previously reported, the association between
endothelial dysfunction and MetS was not affected by further
adjustment for CRP levels. These observations suggest that the
degree of coronary endothelial dysfunction is best explained by
the conventional MetS risk factor burden rather than the level of
systemic inflammation as assessed by CRP levels. Indeed, during
long term follow-up of a subset of these subjects, we found
that adverse cardiovascular events were predicted by presence of
coronary endothelial dysfunction and not by CRP levels.
14
Limitations
Although BMI is a good marker for increased risk of adverse
‘cardiometabolic’ outcomes, the subjects in this study were not
