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April2013 Vol.50 Issue:      2 Table of Contents
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Presymptomatic Atherosclerosis: Association with Cardiovascular Risk Factors and Role of Inflammatory Mediators

Asmaa M. Ebraheim1, Abdelazim M. Reda1, Marwa Farghaly1,

Rania M El-hoseiny2, Shaheera El Shafee3

Departments of Neurology1, Critical Care Unit2, Clinical Pathology3; Cairo University; Egypt



ABSTRACT

Background: During the last decade, compelling experimental and clinical evidence has demonstrated that both systemic and local inflammation might play a prominent role in the pathogenesis of atherosclerosis. Objective: Identify risk factors and possible role of inflammatory mediators in the development of asymptomatic atherosclerosis in carotid and lower extremity arteries. Methods: Thirty subjects aged above 60 years were included. Patients were evaluated clinically with special emphasis on vascular risk factors. All subjects undergone U/S imaging (Doppler for ankle brachial index, Extra- cranial color coded duplex) for calculation of ankle brachial index (ABI) and carotid intima media thickness (CIMT). Moreover, routine laboratory investigations, CRP, levels of soluble intercellular adhesive molecule (sICAM) and vascular cell adhesive molecule (sVCAM) were carried out. Subjects with medical disease that may affect the levels of ICAM and VCAM were excluded from the study. Results: Lower extremities asymptomatic atherosclerosis was associated with diabetes and hypertension (p=0.005 and 0.002 respectively). Both carotid and lower extremities asymptomatic atherosclerosis were significantly associated and correlated with age. Neither of them was associated or correlated with any of the studied inflammatory mediators. Conclusions: Age is an important factor in the development of presymptomatic carotid atherosclerosis, while diabetes and hypertension in addition to increased age are associated with increased risk of development of presymptomatic lower extremities atherosclerosis. The lack of significant association or correlation between CRP and adhesion molecules with presymptomatic atherosclerosis, raises inquiries about the exact role played by inflammatory mediators in the initiation of disease pathology, and emphasizes that this area warrants further research. [Egypt J Neurol Psychiat Neurosurg.  2013; 50(2): 149-156]

 Key Words:  Atherosclerosis, asymptomatic, adhesion molecules

Correspondence to Asmaa M. Ebraheim, Department of Neurology, Cairo University, Egypt. Tel.: +201112399993     e-mail: belalktoof@yahoo.com





INTRODUCTION

 

Atherosclerosis is a form of arterial disease that manifests in the coronary circulation as coronary artery disease (CAD), in the carotid arteries as cerebrovascular disease, and in the aorta and lower extremity arteries as peripheral arterial disease (PAD). The systemic nature of the disease is reflected in the fact that individuals with PAD or carotid artery disease are more likely to have CAD than those without1. Atherosclerosis can begin in relatively young individuals and continue to develop for many decades before clinical signs are observed2. The major established risk factors for the development of atherosclerosis include increasing age (above 40 years), cigarette smoking, diabetes mellitus (DM), hyperlipidemia, and hypertension3,4. Inflammation is becoming increasingly recognized as an important factor  in  the  pathogenesis  of atherosclerosis, with its

 

development and progression orchestrated by several molecules belonging to different families of inflammatory mediators, such as cytokines, chemokines and adhesion molecules5. This study was designed to identify risk factors and possible role of inflammatory mediators in the development of presymptomatic atherosclerosis in carotid and lower extremity arteries. Early identification of this disease, exploration of the factors that precipitated it and more aggressive medical interventions could substantially improve both morbidity and survival1.

This study was designed to identify risk factors and possible role of inflammatory mediators in the development of presymptomatic atherosclerosis in carotid and lower extremity arteries.

 

SUBJECTS AND METHODS

 

Study Design:

A cross sectional study both descriptive and analytic.

Subjects:

Thirty Egyptian subjects above sixty were included. They were volunteers selected from the general population with no history suggestive of ischemic manifestations whether cerebral, cardiac or peripheral.

 

They were divided according to carotids’ maximum intima media thickness (CIMT) 5 in to:

-        Group I: with increased CIMT (≥0.9 mm) indicating the presence of carotid atherosclerosis.

-              Group II: with normal CIMT (˂0.9 mm).

 

Moreover, subjects were divided according to ankle brachial index (ABI)6 in to:

-        Group A: with ABI˂0.9 (indicating the presence of peripheral arterial disease).

-              Group B: with ABI≥0.9.

 

Patients with medical conditions that may affect the levels of inflammatory mediators were excluded. These include; malignancy, active infection, systemic inflammatory diseases, acute cardiovascular disease (such as acute myocardial infarction, unstable angina pectoris and congestive heart failure) and intake of immunosuppressive or immunomodulatory treatment.

 

Methods:

The following batteries of assessments were carried out for all participants:

 

I.             Through clinical assessment:

It was done including careful history taking, general medical examination and neurological examination (including a neurovascular examination), with special emphasis on vascular risk factors as follows:

Obesity was assessed by measuring body mass index (BMI)7. Subjects having BMI >30.0 Kg/m2 were considered obese. Waist circumference (WC) was measured by a tape placed on the top of the hip bone evenly around the bare abdomen, a high risk waist circumference is: over 40 inches (102 cm) in males and over 35 inches (88 cm) in females.

Hypertension was defined as a history of elevated blood pressure before admission that required treatment or persistently elevated blood pressure (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg) during follow up.

Dyslipidemia was defined as abnormal lipid profile detected when total cholesterol level >220 mg/dl, HDL < 40 mg/dl, LDL cholesterol > 130 mg/dl, Triglycerides > 150 mg/dl.

Subjects were considered to be smokers if they were current smokers or had stopped less than 1 month before enrolment in the study.

Diabetes mellitus was defined as a history of current use of anti-diabetes therapy or elevated glucose fasting level > 126 mg/dl.

 

II.           Laboratory investigations:

Routine laboratory investigations that included: complete blood picture, fasting and 2-hour postprandial blood sugar, urea, creatinine, uric acid, liver function tests, lipid profile and urine analysis.

Inflammatory markers: CRP, levels of soluble intercellular adhesive molecule (sICAM) and vascular cell adhesive molecule (sVCAM) were measured. The assay of adhesion molecules used commercially available monoclonal antibodies based ELISA kits (R&D Systems, Minneapolis, MN, U.S.A.).

 

III.   Vascular Ultrasound assessment (Extracranial carotid artery duplex and peripheral Doppler studies):

This was performed at Kasr El Aini Neurology department Neurovascular laboratory using Phillips HDI 5000 ultrasound equipment.

Intima Media Thickness: longitudinal scanning and quantification of the intima media thickness (IMT) 5 at the distal far wall of common carotid artery was done. CIMT ≥ 0.9mm was considered abnormal.

Ankle Brachial Index (ABI) 6 was used to detect the presence of subclinical PAD (ABI ˂ 0.9)

 

Statistical Methods

Data was coded and entered using the statistical package (SPSS) version 12. Data was summarized using mean and standard deviation for quantitative variables and percent for qualitative variables. Comparison between groups was done using chi square test for quantitative variables and ANOVA. Multiple comparisons were done using post Hoc test for normally distributed quantitative variables and parametrical. Mann-Whitney test for not normally distributed quantitative variables. The Chi-squared test for association is the most common method used for the measurement of the strength of association between two qualitative variables

 

RESULTS

 

A.               Demographic and Clinical data

The age of the participants ranged from 60 to 74 years with a mean of 62.8±3.5 years. The females (n=20) represented a relatively larger proportion (66.66%) compared to the males (n=10) (33.33%). Five of the hypertensive individuals were on angiotensin converting enzyme inhibitors and all diabetics were receiving insulin.

 

B.               Comparative results of risk factors:

Increase in CIMT was not associated with significantly higher percentages of different risk factors among subjects (Table 1).

Preclinical lower extremities (ABI ˂ 0.9) atherosclerosis was significantly associated with higher percentage of diabetics and hypertensives. No statistically significant difference reported regarding the other risk factors (Table 2).

Regarding the values of risk factors of participants in all subgroups, there was a statistically significant difference between group I and group II regarding age (p=0.004) being higher in group I, HDL cholesterol (P=0.03) being higher in group I, BMI (p=0.02) being higher in group II. No statistically significant difference between the two groups regarding the mean values of other risk factors. There was no statistically significant difference between groups A, B regarding the mean values of studied risk factors  apart from age (p=0.041) being higher in group A (Table 3).

 

C.               Comparative results of inflammatory markers:

There was no statistically significant difference between groups I and II or groups A and B regarding inflammatory markers and adhesion molecules (Table 4).

 

D.               Correlative results

CIMT had a significant positive correlation with age and inverse correlation with BMI. ABI showed a statistically significant inverse correlation with age, FBS, PPBS. ABI and CIMT were not significantly correlated with other studied risk factors. No statistically significant correlations were found between CRP or soluble adhesion molecules and ABI or CIMT (Table 5).


 

 

Table 1. Comparison between group I and group II regarding the number and percentage of subjects with different risk factors.

 

 

Group I

(n=20)

Group II (n=10)

P-value

Hypertension

7        35%

 

3        30%

1.000

 

Diabetes

4        20%

1       10%

0.640

 

 

Smoking

4        20%

2       20%

1.000

Dyslipidemia, increased total cholesterol>220 mg/dl

6        30%

 

2       20%

0.682

Obesity, increased BMI>30 kg/m2

7        35%

6       60%

0.255

Obesity, increased WC >102cm in males, >88 cm  in females

9        45%

7       70%

0.260

ABI ˂ 0.9

8        40%

2       20%

0.419

ABI ankle brachial index, BMI body mass index, WC waist circumference.

 

Table 2. Comparison between groups A and  B regarding the number and percentage of subjects with different risk factors.

 

 

Group A

(n=10)

 

Group B

(n=20)

 

 

P-value

Hypertension

7       70%

 

3        15%

0.005*

 

Diabetes

5       50%

0         0%

0.002*

 

 

Smoking

4      40%

2       10%

0.141

Dyslipidemia, increased total cholesterol>220 mg/dl

4       40%

 

4       20%

0.384

Obesity, increased BMI>30 kg/m2

3       30%

10       50%

0.44

Obesity, increased WC >102cm in males, >88 cm  in females

3       30%

13        65%

0.12

CIMT ≥ 0.9 mm

8       80%

12        60%

0.419

BMI body mass index, CIMT carotid intima media thickness, WC waist circumference.

*Significant at P<0.01

 

Table 3. Comparison of Risk factors (mean± SD) in different groups of CIMT (I, II) and ABI (A, B).

 

 

Group I

n= 20

Group II

n=10

P value

Group A

n=10

Group B

n=20

P value

Age in years

63.75±3.86

60.8±0.92

0.004*

65.2±4.78

61.55±1.7

0.041*

Obesity

BMI, kg/m2

 

27.35±4.99

33.1±7.94

0.02*

27.2±5.9

30.3±6.8

0.23

WC, cm

104.3±17.25

108±14

0.55

106.9±22.9

104±11.9

0.75

Cholesterol, mg/dl

189.1±46.77

184.7±51.81

0.86

195.3±54.3

183.8±44.9

0.54

HDL, mg/dl

30.6±6.82

24.5±7.26

0.03*

29.2±8.07

28.2±7.3

0.74

LDL, mg/dl

70.85±31.42

67.1±40.07

0.37

75±53.8

66.9±33.5

0.56

Triglycerides, mg/dl

121.1±59.2

124.6±48.44

0.55

118.6±40.7

124.1±61.8

0.93

Hypertension duration, years

6.6±4.07

3±2

0.20

6.6±4.07

3±2

0.20

FBS, mg/dl

148.6±92.14

103.4±18.2

0.16

170.5±112.4

115.05±47.9

0.12

PPBS, mg/dl

 

168.15±107.1

110.9±19.31

0.11

202.1±131.1

122.5±49.3

0.05*

BMI body mass index, FBS fasting blood sugar, PPBS post prandial blood sugar, WC waist circumference.

*Significant at P<0.05

 

Table 4. Inflammatory markers and soluble adhesion molecules (Mean ± SD) in groups of CIMT (I, II) and ABI (A, B).

 

 

Group I

(n= 20)

Group II

(n=10)

P-value

Group A

( n=10)

Group B

(n=20)

P value

CRP,

mg/L

6.09± 5.8

6.12± 5.65

0.84

8±7.2

5.15±4.63

0.29

sVCAM, ng/ml

463.45±92.74

468.4±115.1

0.90

425.9±75.91

484.9±104.65

0.12

sICAM, ng/ml

225.65±76.43

243.27±168.1

0.75

215.6±73.11

239.4±128.87

0.59

CRP C-reactive protein, sICAM soluble intercellular adhesive molecule, sVCAM soluble vascular cell adhesive molecule.

 

Table 5. Correlations between risk factors and inflammatory mediators with CIMT and ABI.

 

 

CIMT

ABI

r

p

r

p

Age in years

0.543

0.002*

-0.496

0.005*

BMI, kg/m2

-0.367

0.04*

0.259

0.167

WC, cm

-0.091

0.634

-0.049

0.798

Hypertension duration, years

0.591

0.072

-0.413

0.236

Diabetes duration, years

0.094

0.881

0.281

0.647

FBS, mg/dl

0.241

0.199

-0.412

0.024*

PPBS, mg/dl

0.283

0.129

-0.477

0.008*

Cholesterol, mg/dl

-0.281

0.134

-0.287

0.124

CRP, mg/L

0.034

0.305

-0.185

0.327

sICAM, ng/ml

-0.096

0.615

-0.001

0.994

sVCAM, ng/ml

-0.043

0.860

0.209

0.269

BMI body mass index, FBS fasting blood sugar, PPBS post prandial blood sugar, CRP C-reactive protein, sICAM soluble intercellular adhesive molecule, sVCAM soluble vascular cell adhesive molecule, WC waist circumference.

*Significant at P<0.01

 

 


DISCUSSION

 

The long induction period of atherosclerosis makes it suitable for the study of subclinical disease for preventive purposes. The first subclinical sign of atherosclerosis is an increase in arterial intima-media thickness (IMT). Increased CIMT has been shown to predict CAD and cerebrovascular disease8. Using this non-invasive, relatively inexpensive means, we detected asymptomatic increased CIMT (≥ 0.9 mm) in two thirds of the studied subjects (n = 20). Furthermore, ABI test is noninvasive, inexpensive, reliable and has become the diagnostic test of choice for detecting PAD, having 95% sensitivity and 99% specificity9.Using this tool, we diagnosed asymptomatic PAD (ABI<0.9) in about 30% of the participants (n=10).  Prevalence of PAD in our study is in good agreement with some studies with estimated prevalence above 20%10,11. Prevalence of PAD in our study was higher than that reported by Karetova et al.12 (13.7%), as their selected population were above 50 years unlike ours (above 60 years). Age is one of the most important risk factors of atherosclerosis. The prevalence of PAD increases sharply with age by up to twofold per decade of life9. These data were supported by our results. Increased CIMT and decreased ABI were significantly correlated with age.

Regarding the studied risk factors for the development of atherosclerosis, hypertension was diagnosed in 70% of subjects with (ABI<0.9) and this was significantly different from the percentage recorded among those with (ABI≥0.9).  This finding was in accordance with previous studies12,13 Hypertension had been thought to be of greater causal importance in the development of cerebrovascular ischemic events relative to other risk factors1.However, the present study failed to find any association between hypertension and increased CIMT. This was in accordance with Tonstad et al.14, who stated that baseline systolic blood pressure was not associated with change in CIMT.

Of the participants, 16.7% were diabetics. All of them discovered to have (ABI<0.9).  We detected significant correlation between increased blood sugar and ABI. Our finding goes in accordance with a previous study which estimated the prevalence of PAD among diabetics to be three times higher than among nondiabetics15. The role of diabetes in the pathogenesis of PAD can be considered in at least two major ways. First, diabetes may accelerate the development of atherosclerotic vessel occlusion through different mechanisms; alternatively, it may negatively impact adaptive processes involved in restoring perfusion following vessel occlusion (e.g. angiogenesis)16. Moreover, there is sufficient evidence to support a significant role for genetic background in diabetic individual’s risk of developing PAD17.

In the present study, no statistically insignificant correlation was found between increased blood sugar and CIMT. This goes in accordance with Halcox et al.18, although, the majority of research shows that the increase in IMT in obese individuals is influenced by impaired glucose metabolism19 and correlated with fasting blood sugar20. The significantly lower BMI in our participants with increased CIMT may, in part, explain the difference.

In the current study BMI was significantly lower in the group of increased CIMT, in addition to documented significant inverse correlation between the two parameters. On the other hand, percentage of obese subjects was higher among participants without detectable PAD but this was not statistically significant. It could be hypothesized that poor health status or smoking might simultaneously be associated with lower BMI and increased carotid or peripheral arterial disease prevalence, thereby obscuring a positive association that might exist if adiposity itself directly or indirectly fosters the development of asymptomatic atherosclerosis21. Moreover, most large scale epidemiologic studies, had observed no association22, 29 or an inverse association24, 25 between BMI and PAD prevalence. Regarding the relationship between CIMT and obesity contradictory results were documented 26,27.

          Conflicting results were reported regarding the correlation between CIMT18,28 and ABI29,30 with different parameters in lipid profile. While elevated cholesterol levels have long been recognized as a risk factor for CAD, epidemiological correlation between plasma cholesterol and the risk of stroke is less well established1. In our participants no difference in the percentage of dyslipidemic subjects, values of total cholesterol, triglycerides and LDL, between individuals with asymptomatic carotid atherosclerosis and those without. Surprisingly, HDL profile was significantly better in those with increased CIMT. The presence of significantly higher weight among subjects with normal CIMT might explain their worse HDL values. Decreased HDL levels in obesity have been attributed to both an enhancement in the uptake of HDL2 by adipocytes and an increase in the catabolism of apolipoprotein A-I on HDL particles. In addition, there is a decrease in the conversion of the pre-beta1 subfraction, the initial acceptor of cholesterol from peripheral cells, to pre-beta2 particles31. Moreover, Shargorodsky et al.19 found that the increase in IMT was influenced by plasma lipid concentration in obese individuals. The increased BMI in subgroup without asymptomatic PAD might explain their comparable lipid profile to those with asymptomatic PAD.

A meta-analysis of 4 prospective and 13 cross-sectional studies reported that overall the prevalence of symptomatic PAD was increased 2.6 fold in current smokers and 2.3 fold in ex-smokers; smoking was one of the strongest determinants of CIMT32. Interestingly, these results were not replicated by the current study which was concerned with the presymptomatic stage of the disease.

Atherosclerotic patients with one clinical manifestation of the disease are predisposed to the development of ischemic events in other arterial circulations1. In the current study we detected concomitant asymptomatic carotid and lower extremities atherosclerosis in 8 subjects (26.7%). This represents 80% of subjects with asymptomatic lower extremities atherosclerosis and 40% of subjects with asymptomatic carotid atherosclerosis. Although the figure 80% was much higher than those reported by other studies 1, 33, it was comparable to the percentage of subjects with asymptomatic carotid atherosclerosis among those with ABI≥0.9.

In the current study, none of the studied inflammatory markers showed significant correlation with ABI or CIMT. In accordance with our results, Lakoski et al.34 found a poor correlations between IMT with CRP levels in the general population. In other studies, elevation of CRP was significantly positively correlated with CIMT 28 or associated with the presence of carotid plaques35. On the other hand, McDermott et al.36 failed to show any significant association between CRP and ABI in subjects without a history of CAD. Controversy exists whether CRP is causally related to the development of atherosclerosis37 or CAD38,39. Many previous studies reported elevated levels of C-reactive protein (CRP) in association with CAD38, 39. Discrepancies of results may be also due to differences in study populations and diagnostic criteria. Moreover, CRP could be elevated due to conditions unrelated to the disease of interest (e.g. infection) 40.

Soluble intercellular adhesive molecule (sICAM) and soluble vascular cell adhesive molecules (sVACM) are responsible for firm adhesion and subsequent infiltration of the leucocytes in the vessel wall41. Previous results suggested that sICAM is a marker that is correlated with the degree of athero­sclerosis using ABI42 and CIMT43. Similar to our findings, Hodis et al.44 found that changes in sICAM did not correlate with changes in carotid artery intima media thickness. Also for sVCAM, the findings are not consistent45,46. Furthermore, in the study of Silvestro et al.47, none of the variables examined (CRP, IL-6, sICAM-1 and sVCAM-1) in PAD differed between healthy controls and asymptomatic patients, whereas blood levels of CRP, IL-6 and sICAM-1 were higher in claudicants (symptomatic ischemia) than in controls. Therefore, the selection of our participants being in the presymptomatic stage could explain the absence of correlation and association between their inflammatory profile and CIMT or ABI. Moreover, the present study had some limitations. First, the inflammatory markers were measured only once, and intraindividual variation therefore could not be taken into account. Second, we did not adjust our analysis for medication use. Third, the small sample size and the lack of follow up data. Fourth, exclusion of asymptomatic atherosclerosis in arteries other than those of interest among the controls, during the comparative analysis, had not been done.

In conclusion, increasing age is an important factor in the development of presymptomatic carotid atherosclerosis, while diabetes and hypertension in addition to increased age are associated with increased risk of development of presymptomatic lower extremities atherosclerosis. The role of inflammatory mediators in initiating the pathogenesis of atherosclerosis in the presymptomatic stage is questionable. Their effect on the arterial wall might follow their release in response to ischemia (i.e. during the symptomatic stage).

 

[Disclosure: Authors report no conflict of interest]

 

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الملخص العربى

 

تصلب الأوعية الدموية الغير عرضى : تحديد عوامل الخطر المؤثرة ودور مؤشرات الالتهاب

 

خلفية: خلال العقد الماضي، أظهرت الأدلة التجريبية والسريرية أن الالتهاب قد يلعب دوراً بارزاً في التسبب في تصلب الشرايين.

الهدف: تحديد عوامل الخطر للتصلب في الشرايين السباتية والشرايين الطرفية السفلية ومعرفة دور جزيئات الالتصاق )كمؤشر للالتهاب(  في حدوث تصلب للشرايين ما قبل المرحلة العرضية. الطرق: لقد أجريت الدراسة على ثلاثين مريضاً يبلغون من العمر أكثر من 60 سنة، وقد تم إخضاع مرضى الدراسة للفحص السريري الكامل بما في ذلك رصد عوامل الخطر،حساب دليل تصلب الشريان السباتي (سمك بطانة الشريان السباتي 0.9 مم) أو الشرايين الطرفية السفلية (مؤشر الكاحل / العضد <0.9) باستخدام الدوبلر الملون إضافة إلي التحاليل المخبرية الروتينية، بروتين سي التفاعلي، ومستويات جزيئات الالتصاق بين الخلايا القابلة للذوبان (sICAM) وجزيئات الالتصاق لخلايا الأوعية الدموية (sVCAM). تم استبعاد المرضى الذين يعانون من أسباب طبية قد تؤثر على مستويات ICAM وVCAM من الدراسة. النتائج: أظهرت الدراسة ارتفاعاً إحصائياً في نسبة الذكور، مرض السكري، وارتفاع ضغط الدم في الأفراد ذوى مؤشر الكاحل / العضد (ABI <0.9). تم إيجاد علاقة ذات دلالة إحصائية بين بطانة الشريان السباتي ومؤشر الكاحل/العضد وارتفاع السن. لا توجد أية فروق أو علاقة ذات دلالة إحصائية فيما يتعلق بمستوى مؤشرات الالتهاب و مؤشر الكاحل / العضد أو بطانة الشريان السباتي. الاستنتاجات: لا فرق في بروتين سي التفاعلي، ومستويات جزيئات الالتصاق بين الأشخاص المصابين بتصلب الشرايين السباتية أو الطرفية الصامت والأشخاص غير المصابين.

 



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