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1774 Full PDF
1774 Full PDF
O R I G I N A L
A R T I C L E
c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c
From the 1Clinical Pharmacology Unit, Queens Medical Research Institute, University of Edinburgh, Edinburgh,
U.K.; and the 2Department of Renal Medicine, Royal Inrmary of Edinburgh, Edinburgh, U.K.
Corresponding author: Jane Goddard, jane.goddard@luht.scot.nhs.uk.
Received 2 December 2011 and accepted 14 March 2012.
DOI: 10.2337/dc11-2345
This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10
.2337/dc11-2345/-/DC1.
2012 by the American Diabetes Association. Readers may use this article as long as the work is properly
cited, the use is educational and not for prot, and the work is not altered. See http://creativecommons.org/
licenses/by-nc-nd/3.0/ for details.
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of arterial stiffness (7), and endothelial dysfunction is also a common feature of CKD
(8) and a predictor of CVD (9).
Metabolic syndrome (MS) is a clustering of metabolic abnormalities and risk
factors for CVD and includes abdominal
obesity, hyperglycemia, hypertension,
hypertriglyceridemia, and reduced HDL
cholesterol (10). As MS is associated with
increased risks of diabetes and CVD
(11,12), its treatment and prevention
have become one of the major public
health challenges worldwide. The risk
factors for MS, either together or individually, are also associated with arterial stiffness and endothelial dysfunction both in
health (13,14) and disease (15,16).
MS is widely prevalent in CKD (17)
and is itself a risk factor for CKD (18).
Although a recent study has suggested
that MS and its risk factors contribute to
arterial stiffness and endothelial dysfunction in dialysis patients (19), there are no
data relating to predialysis CKD. This is
clearly important because targeting MS
risk factors in early CKD may retard
CKD progression, delaying the onset of
dialysis and its associated morbidity, as
well as reducing the overall risk of CVD.
In this current study, we investigated
the relationships of MS and its individual
components to arterial stiffness and endothelial dysfunction in CKD patients across a
wide range of renal function from early
CKD to predialysis. Importantly, we planned
to recruit patients without diabetes or cardiovascular comorbidity. We hypothesized
that the presence of MS, or its components,
would be associated with increased
arterial stiffness and endothelial dysfunction and that these relationships
would be independent of renal function
and other well-established risk factors for
CVD.
RESEARCH DESIGN AND
METHODSdThe rationale and study
design have been reported in detail elsewhere (4). In brief, subjects were recruited
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Table 1dRisk factors for MS, arterial stiffness, and endothelial function
N
Male/female (n)
Smoker/nonsmoker (n)
Age (years)
eGFR (mL/min/1.73 m2)
BMI (kg/m2)*
Risk factors for MS
Waist circumference (cm)*
SBP (mmHg)*
DBP (mmHg)*
Glucose (mmol/L)*
Triglycerides (mmol/L)*
HDL cholesterol (mmol/L)*
Arterial stiffness and endothelial
dysfunction
CF-PWV (m/s)*
cAIx (%)
FMD (%)
NTG (%)
No MS
Risk for MS
MS
83
50/33
14/69
46 6 10
73 6 34
26 6 4
27
18/9
2/25
49 6 11
65 6 33
28 6 5
26
20/6
9/17
50 6 8
59 6 36
33 6 4
90 6 11
113 6 13
72 6 10
4.8 6 0.5
1.1 6 0.4
1.4 6 0.3
96 6 13
124 6 15
76 6 8
5.1 6 0.5
1.4 6 0.8
1.2 6 0.3
111 6 12
124 6 13
76 6 8
5.4 6 0.6
2.4 6 1.2
0.9 6 0.2
6.4 6 1.0
22 6 13
4.8 6 2.9
12.4 6 5.2
7.0 6 1.4
22 6 13
3.4 6 2.8
10.6 6 4.1
7.5 6 1.7
25 6 11
3.5 6 2.8
10.2 6 4.6
No MS, subjects with zero to one risk factor for MS; risk for MS, subjects with two risk factors for MS; MS,
subjects with three or more risk factors for MS. *P , 0.05 for one-way ANOVA by MS groups.
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Figure 1dScatter and box plots showing associations between the number of the MS risk factors and CF-PWV (A and C) and FMD (B and D). No
MS (, solid tted line), subjects without MS (zero to one risk factor); risk for MS (-, long-dashed tted line), subjects at risk for developing MS
(two risk factors); MS (4, short-dashed tted line), subjects with MS (three or more risk factors). P values are for one-way ANOVA (C and D).
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Figure 2dScatter plots showing correlations between CF-PWV and waist circumference (A),
waist-to-hip ratio (B), SBP (C), and plasma glucose (D). Scatter plots showing correlations
between FMD and waist circumference (E), waist-to-hip ratio (F), SBP (G), and plasma glucose
(H). Male: -, dashed line; female: , solid line.
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Model 1
Model 2
Model 3
Model 4
eGFR
Age
Sex (male/female)
Smoking status (yes/no)
Presence of MS (yes/no)
Number of MS risk factors (05)
Waist circumference
SBP
DBP
Plasma glucose
Triglycerides
HDL cholesterol
r2
20.11
0.52*
0.18
20.09
d
d
d
d
d
d
d
d
0.28*
20.11
0.49*
0.15
20.14
0.20*
d
d
d
d
d
d
d
0.31*
20.12
0.47*
0.16
20.10
d
0.23*
d
d
d
d
d
d
0.32*
20.11
0.39*
0.01
20.03
d
d
0.24*
0.53*
20.27*
0.03
0.06
20.09
0.48*
FMD
Predictors
Model 1
Model 2
Model 3
Model 4
eGFR
Age
Sex (male/female)
Smoking status (yes/no)
Presence of MS (yes/no)
Number of MS risk factors (05)
Waist circumference
SBP
DBP
Plasma glucose
Triglycerides
HDL cholesterol
r2
0.02
20.10
20.11
20.02
d
d
d
d
d
d
d
d
0.04
0.02
20.10
20.11
20.02
20.10
d
d
d
d
d
d
d
0.04
0.18
20.07
20.11
20.01
d
20.18
d
d
d
d
d
d
0.07
0.10
20.05
20.06
20.02
d
d
20.14
20.50*
0.28
20.02
20.05
0.08
0.12*
assess vascular function of the resistance arteries, whereas FMD is a measure of conduit
artery function. Thus, it is possible that MS
is associated with a predominant dysfunction of the resistance vessels and, hence, by
using FMD, we did not detect signicant
endothelial dysfunction in our study cohort.
We also observed no association between
the number of risk factors for MS and
FMD. This is in contrast to a previous study
in subjects at risk for developing diabetes
(36), but this may in part be explained by
genetic inuences in diabetes (and insulin
resistance states) not currently considered
to be of importance in the majority of
CKD patients.
Of all the risk factors studied here,
conventional and MS related, only BP is
an independent predictor of endothelial
dysfunction (Table 2, model 4). This result both conrms and contradicts those
of previous studies. Similar to our ndings, Scuteri et al. (35) found BP (both
SBP and DBP) to be an independent predictor of endothelial dysfunction in normoglycemic rst-degree relatives of
patients with diabetes. However, Kovaite
et al. (29) found this not to be the case
when studying 186 asymptomatic subjects without overt cardiovascular disease.
Notably, one-third of subjects studied fullled criteria for MS. A study in CKD has
shown that, similar to the current data, renal function is a predictor of endothelial
dysfunction (39). However, this study
was performed in CKD patients with diabetes and this may act as a signicant confounder. Furthermore, in that study, an
invasive forearm technique measured endothelial function in a different vascular
bed compared with the technique of FMD
used in the current study.
Interestingly, we found an inverse
association between DBP and CF-PWV
(Table 2) and a positive association between DBP and FMD (Table 2). However,
these may be explained by an effect of
pulse pressure, which is positively associated with CF-PWV and inversely related
to FMD, since both SBP and DBP were
entered into the analysis.
We recognize some limitations to the
current study. There are several criteria
for the diagnosis of MS (14). As our patients were not diabetic, we cannot use the
criteria proposed by the World Health
Organization and, therefore, the evaluation
of an effect of insulin resistance to arterial
stiffness and endothelial dysfunction is limited and does not allow data comparison
with other studies using World Health Organization criteria. Also, an increased girth
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