54
VOLUME 11 NUMBER 2 • JUNE 2014
RESEARCH ARTICLE
SA JOURNAL OF DIABETES & VASCULAR DISEASE
Correspondence to: Arshed A Quyyumi
Division of Cardiology, Department of Medicine, Emory University,
Atlanta, USA
Tel: 404 727 3655
Fax: 404 712 8785
e-mail:
Julian PJ Halcox
Cardiovascular Research Group Cymru, Swansea University, UK
Muhiddin A Ozkor
The Heart Hospital, University College of London Hospitals, London, UK
Girum Mekonnen
Division of Cardiology, Department of Medicine, Emory University,
Atlanta, USA
Originally published in
J Diabetes Metab
2014;
5
(4): 1000362
.
S Afr J Diabetes Vasc Dis
2014;
11
(2): 54–60
Coronary endothelial dysfunction, obesity and the
metabolic syndrome
JULIAN PJ HALCOX, MUHIDDIN A OZKOR, GIRUM MEKONNEN, ARSHED A QUYYUMI
Abstract
Objective:
To define the impact of the metabolic syndrome
(MetS) and obesity on coronary vascular function, with the
hypothesis that subjects with MetS will have endothelial
dysfunction.
Background:
Obesity or the metabolic syndrome is associated
with a higher risk of diabetes and coronary artery disease
(CAD). Endothelial dysfunction is a common causal pathway
in the initiation and progression of CAD.
Methods:
A total of 418 patients (165 obese, 239 MetS)
with and without angiographic evidence of CAD underwent
coronary vascular function testing by measuring coronary
blood flow (CBF) velocity in response to intracoronary
infusion of acetylcholine (ACH) and sodium nitroprusside
(SNP) and coronary flow reserve with adenosine.
Results:
Endothelium-dependent microvascular vasodilation
correlatedwith bodymss index (BMI) (
r
= –0.12,
p
= 0.02), with
ACH responses significantly lower in overweight, obese and
MetS subjects (
p
= 0.003). The number of MetS components
correlated with the response to ACH in both the coronary
microcirculation and the epicardial coronary arteries, and
with impaired coronary microcirculatory responses to
adenosine. No significant correlation was observed with
SNP. In multivariable analysis, beyond age, only the total
number of MetS components, and not BMI, emerged as an
independent predictor of impaired microvascular response
to ACH (CBF:
β
= –0.18,
p
< 0.001). Low-grade inflammation
(C-reactive protein) was higher in patients with MetS, but
was not associated with coronary vascular function.
Conclusions:
We demonstrate that the clustering of MetS
components is an important and independent determinant
of coronary endothelial dysfunction in subjects with and
without CAD.
Keywords:
atherosclerosis, metabolic syndrome, obesity,
endothelium, inflammation
Introduction
The prevalence of obesity has increased dramatically worldwide
whereby at least a third of adult Americans are obese and two-
third overweight.
1,2
Obese subjects are at high risk of multiple
morbidities, foremost among which are the development of
diabetes and cardiovascular disease (CVD).
3,4
Abdominal obesity in
particular is frequently associated with a clustering of multiple
interrelated cardiovascular risk factors associated with insulin
resistance that characterises the metabolic syndrome (MetS). In
addition to a large waist circumference, subjects with MetS have
increased blood pressure, dyslipidaemia characterised by low
high-density lipoproteins (HDL), high triglycerides and small dense
low-density lipoproteins (LDL) particles, and glucose intolerance
commonly accompanied by low-grade systemic inflammation and
a pro-thrombotic state.
3,5
The clustering of three or more of these risk factors in an individual
defines the MetS,
6
the incidence of which has progressively risen.
2,7,8
Because of its frequent association with the MetS variables, the
role of obesity as an independent risk factor for CVD remains
controversial.
2,9-11
Endothelial dysfunction, often a consequence of exposure of the
vasculature to risk factors, is predictive of adverse cardiovascular
outcomes, and appears to provide a common causal pathway
in the initiation and progression of CVD.
12-15
Peripheral arterial
endothelial dysfunction has been observed in obese children
and adults, and in those with MetS, even after adjustment for
conventional risk factors.
16-21
Although an independent association
between obesity and coronary endothelial dysfunction has been
described,
22
the incremental influence of the MetS variables and
low-grade systemic inflammation on coronary endothelial function
remains unknown.
Herein we investigated these relationships in a large, well-
characterised cohort of patients with and without angiographic
evidence of coronary artery disease (CAD) undergoing invasive
assessment of coronary vascular function. Our hypothesis was
that MetS will be associated with more profound and selective
dysfunction of the coronary vascular endothelium.
Methods
Patients
We prospectively studied 418 patients (239 males) undergoing
diagnostic cardiac catheterisation for evaluation of symptoms of
chest pain or abnormal cardiac stress test findings. CAD was defined
as angiographic evidence of plaque or more severe occlusive disease,
and normal coronary arteries (NCA) defined as angiographically
smooth appearing coronary arteries. Patients with three-vessel
disease, recent myocardial infarction, severe heart failure or
valvular heart disease were excluded. Diabetes was defined as a
fasting blood glucose level ≥ 126 mg/dl or treatment with dietary
modification, insulin, or oral hypoglycemic agents at the time of the
study. Hypercholesterolaemia was defined as a fasting serum total
cholesterol > 240 mg/dl or if the subject was being treated with
