Factors Associated With Atherosclerosis Expansion in Patients with Coronary Artery Disease  

Larisa N. Yakovleva , Olga E. Matuzok , Igor V. Kuznetsov , Vira I. Tseluyko
Kharkiv Medical Academy of Postgraduate Education, Ukraine
Author    Correspondence author
International Journal of Molecular Medical Science, 2014, Vol. 4, No. 3   doi: 10.5376/ijmms.2014.04.0003
Received: 08 Apr., 2014    Accepted: 10 May, 2014    Published: 17 Jun., 2014
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This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Aim of this study was investigation of possible relations of traditional risk factors and polymorphism of endothelial NO synthase (еNOs) gene, angiotensin-converting enzyme (ACE) gene and  gene of type 1 angiotensin II receptors (АT2R1) with atherosclerosis expansion in patients with coronary artery disease.
We examined 120 patients with CAD (108 male, 12 female) with stable angina pectoris of ІІ–ІІІ functional class and haemodynamically significant coronary artery stenosis confirmed by coronary angiography. Examination included: usual clinical tests; ankle-brachial pressure index measurement; doppler-ultrasound of lower limb vessels and carotid arteries with quantitative evaluation of intima-media thickness; exercise tolerance testing. Patients were divided into 2 groups: group 1 - 55 patients with signs of atherosclerosis in 2 or more vascular areas, group 2 - 65 patients with isolated coronary atherosclerosis.
Allele polymorphism of Т-786С promotor of еNOs gene, I/D polymorphism of ACE gene and А1166С polymorphism of АT2R1 gene were determined in polymerase chain reaction. We used Student’s t -Test to compare quantitative signs and Pearson Х2 criterion to compare qualitative ones, multifactorial step-by-step regression analysis to reveal cause-and-effect relations.

 

Signs of non-coronary atherosclerosis were found in 48.5% of our patients. Patients with CAD and multiple locus atherosclerosis were more likely to have mutant alleles of Т-786С polymorphism of еNOs gene and А1166С polymorphism of АT2R1 gene. We found an independent relation between multiple locus atherosclerosis and smoking, type II diabetes mellitus, family history of cardiovascular diseases with early onset, multivessel CAD and presence of С allele of Т-786С polymorphism of еNOs gene.
Keywords
Atherosclerosis; Risk factors; Gene polymorphism; Coronary artery disease

 1. Background

Atherosclerosis is the morphologic basis for most cardiovascular diseases (CVD). Epidemiologic data suggest that atherosclerosis is a systemic process which frequently involves more than one vascular area. Two thirds of patients with CAD have atherosclerotic lesions of carotid or lower limb arteries (Barabash et al., 2011).
To date, atherosclerosis is considered as multifactorial process. Its initiation and further development is determined by complex interaction of multiple environmental conditions, traditional risk factors (RF) and numerous gene mutations (Maligina et al., 2011; Arking et al., 2009) Epidemiologic studies provided strong evidence of causal relationship between atherosclerosis and dislipidemia, arterial hypertension (AH), type II diabetes mellitus (DM), smoking, low physical activity, family history of CVD etc. (Tegos et al., 2001).
It is proven that genetic factors may play an important role in pathogenesis of atherosclerosis but attempts to associate its development with mutation in unique gene or group of genes were not successful (Lieb et al., 2013). That`s why many recent studies are aimed to search so-called "candidate genes". Products of expression of such genes (ferment, receptor, structural or transport protein) may influence atherosclerosis pathogenesis and clinical features of CVD morphologically related to atherosclerosis.
Polymorphism of many genes may play a significant role in pathogenesis of atherosclerosis, but genes of renin-angiotensin-aldosterone system (RAAS) components and endothelial NOS (eNOS) gene attract special attention. Data on relation between their polymorphisms and atherosclerosis expansion are limited and controversial. Further- more, it is not known by now if these genetic factors are independent RF of atherosclerosis or they modulate effect of traditional risk factors.
The aim of the study was to investigate the possible relations of traditional risk factors and polymorphism of endothelial NO synthase (еNOs) gene, angiotensin-converting enzyme (ACE) gene and gene of type 1 angiotensin II receptors (АT2R1) with atherosclerosis expansion in patients with coronary artery disease (CAD).
2 Materials and Methods
We examined 120 patients with CAD (108 male, 12 female) aged (58.67±0.77) years. Inclusion criteria were: age over 45, stable angina pectoris of II-III functional class (Canadian Cardio- vascular Society angina classification, 1974) and haemodynamically significant coronary artery stenosis estimated with coronary angiography. Exclusion criteria included severe heart failure and other severe concomitant conditions (tumors, chronic renal failure, severe DM and so on).
Clinical characteristics of patients are shown in Table 1. The most frequent concomitant conditions were arterial hypertension (AH) – 95 (79.2%) patients, obesity with body mass index over 30 kg/m2 – 48 (40.0%), type II DM – 26 (21.7%), hyperlipidaemia – 98 (81.7%), smoking – 72 (60%) and alcohol abuse – 20 (16.7%). Myocardial infarction was present in medical history of 86 patients (71.7%).
Examination included: general clinical examination; ABI measurement; doppler-ultrasound of LLV and carotid arteries with evaluation of IMT; exercise tolerance testing (modified Bruce protocol).
Allele polymorphism of Т-786С promotor of еNOs gene, I/D polymorphism of ACE gene and А1166С polymorphism of АT2R1 gene were determined in polymerase chain reaction (PCR). Accuracy of frequencies distribution evaluated according to Hardy–Weinberg principle (pi2 +2 pipj + pj2 = 1). All patients were informed about investigation conducted and provided informed consent for gene polymorphisms identification (according to Declaration of Helsinki requirements).
Table 1 Characteristic of examined patients (n=120)
Index
Value
Mean age, years
58.67±0.77
Male, n (%)
108 (90.0)
AH, n (%)
95 (79.2)
DMtype ІІ, n (%)
26 (21.7)
Body mass index, kg/m2
28.59±0.52
Obesity (body mass index >30 kg/m2), n (%)
48 (40.0)
Abdominal obesity (waist > 102 cm for males, > 88 cm for females), n (%)
60 (50.0)
Smoking, n (%)
72 (60)
Alkohol abuse, n (%)
20 (16.7)
Hyperlipidemia (total cholesterol >5,2 mmol/l, and/or LDL  >3 mmol/l, and/orTG >1.7 mmol/l), n (%)
98 (81.7)
Family history of CAD with early onset (male < 55 years, female < 65 years), n (%)
72 (60.0)
History of MI, n (%)
86 (71.7)
History of repeated MI, n (%)
12 (10.0)
Stroke/TIA in medical history n (%)
4 (3.3)
Carotid arteries atherosclerosis, n (%)
23 (19.2)
LLV atherosclerosis, n (%)
43 (25.8)
Hemodyamically significant atherosclerosis on coronary angiography:
One vessel involved, n (%)
21 (17.5)
Two vessels involved, n (%)
39 (32.5)
Three vessels involved, n (%)
60 (50.0)
Angina pectoris functional class
Functional class ІІ, n (%)
38 (31.6)
Functional class ІІІ, n (%)
82 (68,3)
Note: data shown as absolute and relative values – n (%) or mean value and mean value error (M+m). Intables 1, 2 : AH - arterialhypertension, MImyocardialinfarction, LDLlowdensitylipoproteides, TGtriglycerides
Statistical analysis performed with «Statistica 8.0» software package (StatSoft Inc, USA), Microsoft Office Exel-2003. In case of normal distribution quantitative characters were reported as average ± standard deviation (М±m). We used Student’s t- Test to compare mean values of two samples. Distinctions of mean values were considered probable with р<0.05. Qualitative distinctions between groups were evaluated with Pearson Х2 criterion. We also used multifactorial step-by-step regression analysis to reveal cause-and-effect relations. Regression coefficients were considered statistically significant with р<0.05.
3 Results and Discussion
We revealed atherosclerotic lesions in carotid arteries in 23 (19.2%) of examined patients (IMT ≥0.9 мм and/or atherosclerotic plaques (AP)) and LLV atherosclerosis in 43 (25.8%) patients who had ABI <0.9 or AP in LLV at LLV Doppler ultrasound. In 11 (9.2%) patients we found atherosclerosis involving three vascular areas – coronary, carotid arteries and LLV. Based on extent of atherosclerotic impairment patients were divided into two groups. Group I consisted of 55 patients who had atherosclerosis in more than one vascular area (Table 2) with average ABI value (0.76±0.02), IMT - (1,01±0,02) mm. Group II included 65 persons with isolated coronary atherosclerosis.
In group I every third patient (30,9%) had type II DM, while in group II -only 13,8% patients, p< 0,05. Patients in group I were more likely to be smokers: 40 (72,7 %) and 32 (49,2 %), accordingly, p < 0,05.
Patients in group I were more likely to have CAD with early onset in their family history: 39 (70,9%) against 33 (50,7%), p < 0,05.  They had earlier onset of CAD also than patients with isolated coronary atherosclerosis: (44,67±0,38) years and (45,75±0,39) years, accordingly, p = 0,05).
Examined groups of patients had also statisticallysignificant distinctions in coronary angiography results. Haemodinamically significant athero- sclerosis of three CA was found in 33 (60,0%) patients of group I, while in group II - in 27 patients (41,5%), p < 0,05. Diffuse coronary artery involvement was somewhat more frequent in group I, but distinctions were not strictly significant (6 (10,9%) against 2 (3,1%), p = 0,08).
Evaluation of ACE gene I /D polymorphism showed that ІІ, ІDandDDgenotypes were distributed in group I as follows: 21,7%; 63,7% and 23,6 % (Table 2). In group II distribution of these genotypes was somewhat different: homozygotes ІІ – 24.6 %, heterozygotes ІD – 44.6 % and mutant homozygotes DD - 30,8 %. Distinctions between groups proved to be statistically significant only regarding ID genotype (p < 0.05). The possible cause that no significant differences of D allele frequencies was found between groups may be due to sample limitations, aswe included only patients with CAD and verified coronary atherosclerosis which has been shown to be associated with ACE gene polymorphism in many studies (particularly, in our earlier work)(Tseluyko et al., 2008, Kolaković et al., 2012).
 
Results of genotyping were shown in Table 3.
 
Table 2 Clinical, anamnestic characteristic of patients and results of additional diagnostic tests in examined groups of patients (n=120).
Index
Group І
(n=55 )
Group ІІ
(n=65)
p-level
Mean age, years
59.87±1.17
57.75±7.57
0.95
AH, n (%)
47 (84.4)
48 (73.8)
0.089
DMtype ІІ, n (%)
17 (30.9)
9 (13.8)
0.02
Body mass index, kg/m2
27.90±0.81
28.92±0.65
0.56
Obesity (body mass index >30 kg/m2), n (%)
19 (34.5)
29 (44.6)
0.26
Smoking, n (%)
40  (72.7)
32 (49.2)
0.01
Family history of CAD with early onset, n (%)
39 (70.9)
33 (50.7)
International Journal of Molecular Medical Science
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