Relationship between peripheral arterial disease, carotid intima-media thickness and C-reactive protein in elderly diabetic patients

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Vol.2, No.4, 115-120 (2013) Advances in Aging Research
http://dx.doi.org/10.4236/aar.2013.24017
Copyright © 2013 SciRes. OPEN ACCESS
Relationship between peripheral arterial disease,
carotid intima-media thickness and C-reactive
protein in elderly diabetic patients
Moatassem Salah Amer
1
, Samia Ahmed Abdul-Rahman
1*
, Wafaa Mostafa Abd-El Gawad
1
,
Ibrahim Ahmad Abdel Aal
2
, Ahmad Abdel Khalek Abdel Razek Mohamed
3
,
Wessam El-Huseiny Moustafa Abdel Wahab
4
1
Geriatrics and Gerontology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt;
*
Corresponding Author: sa1382001@hotmail.com
2
Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
3
Radiodiagnosis Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
4
Geriatrics and Gerontology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
Received 23 June 2013; revised 23 July 2013; accepted 30 July 2013
Copyright © 2013 Moatassem Salah Amer et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Purpose: To study the association between ca-
rotid intima media thickness (CIMT) and high
sensitivity CRP (hs-CRP) level as markers for
PAD in elderly patients with DM. Subjects: A
case-control study on 90 participants aged 60
years and older divided into 60 cases (30 pa-
tients with DM alone and 30 patients with DM
and comorbidities) and 30 healthy controls. All
were assessed by measuring CIMT, ankle bra-
chial index (AB), and markers for cardiovascular
disease such as high-sensitivity CRP (hs-CRP),
total cholesterol (TC), triglycerides (TG), high
density lipoprotein (HDL), and low density lipo-
protein (LDL). Results: hs-CRP levels showed
statistically significant difference being highest
among patients with DM and comorbidities and
lowest among controls (P < 0.001). Also, symp-
toms of PAD were significantly higher among
cases than controls. ABI was able to detect PAD
in many asymptomatic patients. Color changes
were present in only 43.30% (n = 26) of positive
PAD cases while delayed wound healing, clau-
dication pain, rest pain, cold extremities, and
trophic changes were present in 23.30% (n = 14),
16.71% (n = 10), 16.71% (n = 10), 45.00% (n = 27),
and 21.7% (n = 13). Using logistic regression
analysis revealed that DM, CIMT, and hs-CRP
were independent predictors for PAD (OR =
4.194, 7.236, 1.003; P value = 0.044, 0.25, 0.031)
after adjustment of other coronary risk factors
such as sex, smoking, hypertension, TC, and TG.
Conclusion: Diabetic elderly have higher preva-
lence of asymptomatic PAD thannon-diabetics
using solely ABI. DM, CIMT, and hs-CRP are in-
dependent predictors for the occurrence of PAD.
Hs-CRP levels are highest among diabetics with
comorbidities.
Keywords:
Peripheral Arterial Disease; Carotid
Intima-Media Thickness; Ankle Brachial Index;
C-Reactive Protein; Elderly
1. INTRODUCTION
Diabetes mellitus (DM) is a prevalent disease espe-
cially among elderly. Egypt was ranked the 10th world-
wide for the number of people with DM in 2003 (3.9
million) and this number is expected to reach 7.8 million
in 2025 [1].
Persons with DM are at an increased risk for athero-
sclerosis which is responsible for cardiovascular diseases
(CVD) (coronary heart disease, peripheral arterial dis-
ease, or cerebrovascular disease) [2]. Atherosclerosis
starts by preclinical increase in the thickness of the in-
ternal and medial membrane of the arterial wall (in-
tima-media thickness—IMT) [3] together with inflam-
mation of the wall of the artery [4]. Several studies ad-
dressed the correlation of C-reactive protein (CRP) as a
marker of inflammation to the preclinical increase in
IMT [5] and now CRP level has emerged as an interest-
ing novel and clinically useful marker for increased car-
diovascular risk [6].

M. S. Amer et al. / Advances in Aging Research 2 (2013) 115-120
Copyright © 2013 SciRes. OPEN ACCESS
116
Peripheral arterial disease (PAD) is considered an in-
dependent risk factor for vascular diseases in other arter-
ies and its prevalence increases with age, resulting in
increased rate of cardiovascular events and mortality. On
top of that, it adversely affects the functional status of the
elderly [7]. In epidemiological reports, PAD prevalence
among diabetic patients varies widely among countries,
ranging from 6.3% to 36.1% but generally; PAD is more
frequent among diabetic patients than non-diabetic ones
[8,9].
The most objective practical mean of documenting the
presence and severity of PAD is the measurement of an-
kle brachial index (ABI) [10]. It is non-invasive, simple,
and at the same time it can be correlated with coronary
artery disease [11].
Identifying markers of early PAD—in such a large
population at risk (diabetic patients)—can facilitate ap-
propriate and early intervention. For this reason, the aim
of this work was to study the association between carotid
IMT (CIMT) and high sensitivity CRP (hs-CRP) level as
markers for PAD in elderly patients with DM.
2. PATIENTS AND METHODS
2.1. Study Design and Setting
A case-control study was conducted on 90 participants
aged 60 years and older attending outpatient clinic of
Specialized Medical Hospital of Mansoura University,
Mansoura, Egypt.
Sixty cases were recruited and subdivided into group
(1) that included 30 participants suffering from DM with
other co morbidities and group (2) including 30 partici-
pants suffering from DM alone. Another 30 healthy eld-
erly represented the controls and referred to as group (3).
For purpose of the study, exclusion criteria included
any causes of altered CRP level (e.g. current infection,
rheumatological disease…etc.).
2.2. Data Collection
All participants were subjected to comprehensive ge-
riatric assessment that includes detailed personal and
medical history and physical examination. Detailed me-
dical history included common comorbidities in elderly
with special focus on PAD, hypertension, cardiovascular
diseases as coronary heart disease, and cerebrovascular
disease.
2.3. Laboratory Investigations
Markers for cardiovascular disease such as high-sen-
sitivity CRP (hs-CRP), total cholesterol (TC), triglyc-
erides (TG), high density lipoprotein (HDL), and low
density lipoprotein (LDL) levels were measured.
2.4. Radiological Assessments
2.4.1. Carotid Duplex
Bilateral B mode-Doppler with color imaging carotid
artery duplex was done to evaluate the carotid arteries.
Measurement of CIMT was made at a point on the far
wall of the common carotid artery, 2 cm proximal to the
bifurcation, from a longitudinal scan plane that showed
the intima-media boundaries most clearly. On the screen
displaying the frozen magnified image of the far wall of
the common carotid artery, two cursors were positioned
on the boundaries of the intima-media. The distance be-
tween these cursors was recorded to the nearest 0.1 mm
(maximum axial resolution of the scanner) as the IMT.
The procedure was repeated for each side of the neck.
CIMT is a simple non-invasive way and with high pre-
dictive value for cardiovascular complications [12].
2.4.2. Hand-Held Doppler Ultrasound
Bilateral measuring of ABI was done. The ABI is the
ratio of the highest systolic blood pressure (SBP) in the
dorsalis pedis or posterior tibial arteries of each leg to
that of the highest SBP in the brachial artery of each arm
[13]. During the inflation of a pneumatic cuff, the onset
of flow was detected with a hand-held continuous wave
Doppler ultrasound device probe placed over the dorsalis
pedis and posterior tibial arteries and thus denoting ankle
SBP while brachial artery SBP was assessed by the rou-
tine method using stethoscope. Decrease in the ABI is
consistent with PAD. Mild-to moderate PAD usually pro-
duces ABI in the range of 0.41 to 0.90. A reading below
0.40 suggests the presence of severe PAD [14].
2.5. Statistical Analysis
Data collected was revised, coded, tabulated, and in-
troduced into a personal computer. Statistical analysis
was performed using the 16th version of Statistical Pack-
age of Social Science (SPSS). Quantitative variables
were presented in the form of means and standard devia-
tion. Qualitative variables were presented in form of fre-
quency tables (number and percent). Comparison be-
tween quantitative variables was done using t-test to
compare two groups and ANOVA to compare more than
two groups. Control for overall type I error was per-
formed using the Bonferroni post hoc comparison test.
Comparison between qualitative variables was done us-
ing Pearson’s Chi square test or Fisher’s exact. Correla-
tion between two quantitative variables was done using
Pearson’s correlation co-efficient. Odds Ratio (OR) was
also calculated for PAD symptoms between cases and
controls. Logistic regression analysis was done to iden-
tify the predictor of PAD. P value is considered signifi-
cant if equal to or less than 0.05.

M. S. Amer et al. / Advances in Aging Research 2 (2013) 115-120
Copyright © 2013 SciRes. OPEN ACCESS
117
3. RESULTS
Ninety patients aged 60 years and more were recruited.
Mean age among group (1) was 67.30 ± 6.82 yr, group (2)
was 65.83 ± 5.96 yr and among group (3) was 67.10 ±
9.40 years. Males represented 37.8% (n = 34) while
females represented 62.2% (n = 56) of the study sam-
ple (Table 1). As for comorbidities in group (1), 40% (n
= 12) had ischemic heart disease and 16.6% (n = 5)
had cerebrovascular disease and all of them had hy-
pertension.
Systolic and diastolic blood pressures, weight and hs-
CRP levels showed statistically significant difference be-
tween group (1), (2) and (3) (P value ≤ 0.001, < 0.001,
0.030, < 0.001 respectively) being all highest among
group (1) and lowest among group (3) (Table 1). Post
hoc Bonferroni test revealed that the significant differ-
ences in systolic and diastolic blood pressures and
weight were only between those of group (1) and group
(3), while the significant differences in hs-CRP levels
were between groups (1) and (3) (P value < 0.001), (2)
and (3) (P value < 0.001), and (1) and (2) (P value <
0.021). Hs-CRP levels were highest in group (1)
(1266.67 ± 392.96 mg/dl) followed by group (2) (991.6 ±
448.12 mg/dl) then group (3) (420.43 ± 303.11 mg/dl)
(Table 1).
There is no statistical significant difference regarding
other cardiovascular risk factors (male sex, smoking, age,
Table 1. Comparison between the three studied groups as regard qualitative and quantitative variables.
DM with co-morbidity group (1) DM alone group (2) Controls group (3) P value
Sex
 Males
10(33.3%) 12(40.0%) 12(40.0%) 0.828
 Females
20(66.7%) 18(60.0%) 18(60.0%)
Age
65.83 ± 5.69 67.30 ± 6.82 67.10 ± 9.40 0.713
Smoking
 Current
0(0%) 3(10.0%) 3(10.0%) 0.391
 Non-Smoker
24(80.0%) 22(73.3%) 24(80.0%)
 Ex-Smoker
6(20.0%) 5(16.7%) 3(10.0%)
Marital status
 Single
1(3.3%) 1(3.3%) 0(0%) 0.911
 Married
17(56.7%) 16(53.3%) 16(53.3%)
 Widow
12(40.0%) 12(40.0%) 13(43.3%)
 Divorced
0(0%) 1(3.3%) 1(3.3%)
Weight 87.60 ± 9.88 82.45 ± 8.80 80.67 ± 12.07 0.030
*
Height 165.03 ± 8.18 166.60 ± 9.14 163.73 ± 8.45 0.445
BMI 32.54 ± 5.37 29.98 ± 4.34 30.26 ± 5.58 0.102
SBP 131.16 ± 18.55 115.33 ± 10.49 114.26 ± 12.83 0.000
*
DBP 81.66 ± 8.23 73.66 ± 9.27 72.83 ± 7.6 0.000
*
PAD 22(73.3%) 18(60.00%) 10 (33.3%) 0.549
Laboratory investigation
 FBS
162.50 ± 56.96 153.27 ± 63.43 93.93 ± 10.64 0.000
*
 2hPP
259.77 ± 95.01 247.03 ± 85.11 131.30 ± 24.74 0.000
*
 Hs.CRP
1266.67 ± 392.68 991.6 ± 448.12 420.43 ± 303.11 0.000
*
 TC
233.97 ± 45.91 235.70 ± 43.40 218.27 ± 46.43 0.265
 TG
162.27 ± 59.12 132.07 ± 65.81 135.33 ± 59.21 0.119
 HDL
52.57 ± 13.58 47.60 ± 18.07 50.50 ± 13.59 0.450
 LDL
150.20 ± 47.37 160.30 ± 43.74 140.47 ± 46.23 0.251
CIMT (mm)
1.082 ± 0.445 1.0791 ± 0.223 0.952 ± 0.232 0.198
ABI
0.883 ± 0.145 0.916 ± 0.159 0.915 ± 0.105 0.578
BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; PAD: peripheral arterial disease; FBS: fasting blood sugar; 2hPP: 2 hours
postprandial; Hs-CRP: high sensitivity C-reactive protein; TC: Total cholesterol; TG: triglycerides; HDL: high density lipoprotein; LDL: low density lipoprotein,
CIMT: carotid intima media thickness; ABI: ankle brachial index.
*
Statistically significant.

M. S. Amer et al. / Advances in Aging Research 2 (2013) 115-120
Copyright © 2013 SciRes. OPEN ACCESS
118
BMI, TC, TG, HDL-C, LDL-C, CIMT, and ABI) between
group (1), (2) and (3) (P value = 0.828, 0.391, 0.713,
0.102, 0.265, 0.119, 0.450, 0.251, 0.198, 0.578 respec-
tively) (Table 1).
Although not reaching statistical significance, percentage
of PAD was higher in group (1) (73.3%, n = 22) and group
(2) (60.00%, n = 18) than group (3) (33.3%, n = 10).
As regard the correlation between diabetes control and
complications, group (1) had statistically significant
higher use of insulin (100% vs 73.3%), symptoms of
poor control (96.7% vs 70%), cataract (40% vs 13.3%),
diabetic neuropathy (93.3% vs 53.3), diabetic retinopathy
(43.3% vs 6.7%), diabetic nephropathy (20% vs 0%) and
longer duration in month (170.40 ± 80.98 vs 85.87 ±
72.14) than group (2) (P value = 0.002, 0.006, 0.020, <
0.001, < 0.001, 0.010, < 0.001 respectively) (Table 2).
Generally, symptoms of PAD as color changes, de-
layed wound healing, claudication pain, resting pain,
trophic changes, cold extremities were statistically sig-
nificantly higher among cases than controls (P value ≤
0.001, 0.025, 0.035, 0.034, 0.011, 0.001). Their Odds
Ratios were higher for cases than controls. For color
changes, delayed wound healing, claudication pain, rest-
ing pain, trophic changes, cold extremities, OR were
10.286, 5.091, 7.250, 7.250, 9.667, and 6.111 respec-
tively (Table 3).
Table 2. Comparison between group (1) and group (2) as re-
gard Diabetes Control and Complications.
DM with
co-morbidity
Group (1)
DM alone
group (2)
P value
Type of treatment:
 Insulin
30(100%) 22(73.3%) 0.002
*
 Oral hypoglycemic
drugs
0 8(26.7%)
Symptoms of poor control 29(96.7%) 21(70%) 0.006
*
Recurrent infection 15(50%) 9(30%) 0.114
Diabetic foot 6(20%) 5(16.7%) 0.739
Cataract 12(40%) 4(13.3%) 0.020
*
Diabetic neuropathy 28(93.3%) 16(53.3%) 0.000
*
Hyperglycemic coma 10(33.3%) 9(30%) 0.781
Hypoglycemic attack 7(23.3%) 5(16.7%) 0.519
Diabetic retinopathy 13(43.3%) 2(6.7%) 0.001
*
Diabetic nephropathy 6(20.0%) 0(0%) 0.010
*
Duration of diabetes in
months (Mean ± SD)
170.400 ± 80.98 85.866 ± 72.14 0.000
*
*
Statistically significant.
Table 3. Comparison between cases (groups (1) & (2)) and
controls (group (3)) regarding symptoms of peripheral arterial
disease.
Cases Controls OR P value
Color changes 32(53.3%) 3(10%) 10.286 0.000
Delayed wound healing 16(26.7%) 2(6.7%) 5.091 0.025
Claudication pain 12(20%) 1(3.3%) 7.250 0.034
Resting pain 12(20%) 1(3.3%) 7.250 0.034
Cold extremities 33(55%) 5(16.7%) 9.667 0.001
Trophic changes 15(25%) 1(3.3%) 6.111 0.011
OR: odds ratio.
ABI was able to detect PAD in many asymptomatic
patients. Color changes were present in only 50.20% (n =
26) of positive PAD cases and delayed wound healing,
claudication pain, rest pain, cold extremities, and trophic
changes were present in 28.00% (n = 14), 20.00% (n =
10), 20.00% (n = 10), 54.00% (n = 27), and 26.00% (n =
13) (Table 4).
Using logistic regression analysis revealed that DM,
CIMT, and hs-CRP were independent predictors for PAD
(OR = 4.194, 7.236, 1.003; P value = 0.044, 0.25, 0.031)
after adjustment of other coronary risk factors such as
sex, smoking, hypertension, TC, and TG (Table 5).
4. DISCUSSION
DM and its complications represent a major burden to
public health. Early diagnosis and management of PVD
in the elderly especially in diabetics is very crucial be-
cause it is an independent risk factor for vascular dis-
eases in other regions, resulting in increased rate of car-
diovascular events and mortality in addition to its impact
on physical function [7,15,16].
So a case-control study was performed on 90 elderly
to identify the predictors of PAD in elderly diabetic pa-
tients. Sixty cases were divided into group (1) that in-
cluded 30 participants suffering from DM with co-mor-
bidities and group (2) including 30 participants suffering
from DM alone. Another 30 healthy elderly represented
the controls group (3).
In this study, despite finding no significant difference
in the prevalence of PAD between DM cases and controls
groups, the symptoms of PAD were statistically signifi-
cantly more in DM cases than controls.
This study like many other studies found that most
elderly men and women with PAD did not suffer symp-
toms [7,17] as more than half of the PAD cases diag-
nosed by ABI which were asymptomatic by history and
physical examination. In fact a recent database popula-
tion based study found that age was the strongest risk

M. S. Amer et al. / Advances in Aging Research 2 (2013) 115-120
Copyright © 2013 SciRes. OPEN ACCESS
119
Table 4. Relationship between symptomatic and asymptomatic
cases of peripheral arterial disease (PAD).
PAD
*
Symptomatic Asymptomatic
Color changes 26(50.20%) 24(49.807%)
Delayed wound healing 14(28.00%) 36(72.00%)
Claudication pain 10(20.00%) 40(80.00%)
Rest pain 10(20.00%) 40(80.00%)
Cold extremities 27(54.00%) 23(46.00%)
Trophic changes 13(26.00%) 37(74.00%)
*
Diagnosed by Ankle Brachial index and the presence of symptoms of
PAD.
Table 5. Logistic regression analysis for predictors of periph-
eral arterial disease.
95% Confidence
interval
OR SE P value
Lower Upper
Gender
(male)
0.433 0.766 0.274 0.096 1.941
Current
smoking
1.417 1.120 0.756 0.135 5.545
X-smoker 0.866 0.947 0.879 0.997 1.000
Hs-CRP 1.003 0.001 0.031
*
0.992 1.015
TC 0.999 0.006 0.565 0.997 1.014
TG 1.005 0.004 0.188 1.290 40.607
CIMT 7.236 0.880 0.025
*
0.141 1.573
HTN 0.471 0.616 0.221 1.042 16.887
DM 4.194 0.711 0.044
*
0.096 1.941
Constant 0.050 1.776 0.091 0.158 12.737
OR: odds ratio; PAD: peripheral arterial disease; Hs-CRP: high sensitivity C
reactive protein; TC: total cholesterol; TG: triglycerides; CIMT: carotid
intima media thickness; HTN: hypertension; DM: diabetes mellitus.
*
Statis-
tically significant.
factor for the development of asymptomatic PAD [18].
So, poorer outcomes are expected in asymptomatic eld-
erly patients with concomitant PAD and DM due to de-
layed diagnosis.
We found that DM, CIMT, and hs-CRP levels were
independent predictors for PAD after adjustment for
other coronary risk factors as sex, smoking, hypertension,
TC, and TG. So, PAD should be suspected in any elderly
patient when one or more of these risk factors is present
putting in mind that CIMT had the highest odds ratio
(7.136) followed by DM (odds ratio = 4.194) and lastly
hs-CRP (odds ratio = 1.003).
With age, there were increased IMT and inflammation
in the arterial wall due to exposure to advanced glycation
end products, which, in turn, stimulate systemic inflam-
mation, oxidative stress, fibrosis, and lipid deposition in
the arterial wall especially in DM. An increased CIMT is
considered as a sign of early atherosclerosis and as a
window for coronary and lower limb arteries [19,20].
DM patients are more likely to present late due to
impaired pain perception resulting from associated pe-
ripheral neuropathy in those patients. In fact, the pre-
sence of concomitant DM in patients with PAD was
associated with a 15-fold increased risk of lower extrem-
ity amputation [21,22].
It is also reported that CRP is present in the core of
atheromatus plaques in subjects who experienced sudden
death [23]. High CRP causes direct reduction in the nitric
oxide production and induces monocyte chemotaxis, cy-
tokine release, and tissue factor secretion (110) which
eventually predicts adverse vascular events as coronary
heart disease and PAD [24-27].
So, we concluded that DM in elderly is associated
with higher prevalence of asymptomatic PAD using
solely ABI. DM, CIMT, and hs-CRP are independent
predictors for the occurrence of PAD. Hs-CRP levels are
highest among diabetic group with comorbidities.
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