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Associations of coronary artery atherosclerosis in women with blood serum lipids, apolipoproteins a-i and b, and ab0 blood groups.

作者:Arūnas Maksvytis,
畢業學校:Kaunas University of Medicine
出版單位:Network of Lithuanian Academic Libraries
核准日期:2007-04-25
類型:Dissertation
權限:unrestricted.Release the entire work immediately for access worldwide..I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of ....

英文摘要

At present, cardiovascular diseases cause ca. 30 of deaths worldwide, and are the most common cause of death and disability (The World Health Report 2002; Pearson 1999). Coronary artery disease (CAD) accounts for nearly 50 of all deaths caused by cardiovascular diseases. In 2002, 7.2 million people died of CAD worldwide, and 5.8 million new cases were diagnosed. In 2000, the number of people with CAD around the world amounted to ca. 40 millions (Mackay 2004).
The modern understanding of the pathophysiology of atherosclerosis and the concept of “cardiovascular risk factors” started forming in 1950s, when the first findings of the Framingham study were published (Wilson et al. 1998, D’Agostino et al. 2000). Information accumulated during scientific research on atherosclerosis allowed for a significant reduction of CAD-related mortality in the developed countries during the last 20 years, but a more profound analysis showed that the mortality mostly decreased in males, whereas in females it continues to grow. Nearly two-thirds of suddenly deceased women previously showed no clinical symptoms of CAD (AHA 2002). This most probably was influenced by a still predominant erroneous opinion that women, especially of younger age, very rarely have CAD and atherosclerosis of peripheral arteries. Epidemiological studies showed that cardiovascular diseases induced by atherosclerosis are equally frequent cause of death in both males and females. Of all patients who in 2000 in the U.S. died of cardiovascular diseases, 53.5 were females (AHA 2003). Cardiovascular death in young (pre-menopausal) women undoubtedly occurs less frequently, but morbidity with cardiovascular diseases is a significant and clearly related with CAD risk factors. As the Framingham study showed, with age, the incidence of cardiovascular diseases equally increases in both sexes; however, in women, clearly increasing morbidity with CAD begins 10-15 years later than in men (Castelli 1988).
It is universally accepted that older age, family history, smoking, arterial hypertension (AH), obesity, increased total and low density lipoprotein (LDL) cholesterol, decreased blood serum high density lipoprotein (HDL) cholesterol, and Type 2 diabetes mellitus (DM) are risk factors for CAD (Grundy et al. 1999), but their significance in males and females may differ (Mosca et al. 1999). This especially applies to Type 2 DM – there is a 3- to 7-fold increase in the risk for developing CAD in women, whereas in men – 2- to 3-fold increase (Barrett-Connor et al. 1991), and the causes of this phenomenon are still unclear. In addition to that, dyslipidemia as a risk factor for CAD in females is more significant than in males: increased levels of triglycerides (TG) and decreased levels of HDL cholesterol are more characteristic of females with CAD (Mosca et al. 1999). In women, there is another sex-related risk factor for CAD – the menopause; post-menopausal women more frequently develop CAD, compared to pre-menopausal women of the same age (LaRosa 1997).
The influence of lipids on the progression of atherogenesis in women is not fully investigated. There are a number of studies that in cases of CAD detected significantly increased levels of apolipoprotein (apo) B, whereas the levels of LDL cholesterol did not differ from those in healthy subjects (Genest et al. 1992; Kwiterovich et al. 1992; Caslake et al. 2000). Studies in men showed that the level of apoB is significant in determining the risk for CAD (Kwiterovich et al. 1992, Stakishaitis et al. 1991). It is thought that in determining the risk for CAD, the concentration of apoA-I may be more informative than HDL cholesterol (Garfagnini et al. 1995, Luc et al. 2002). Much new information on the importance of apolipoproteins in prognosticating the risk for CAD was obtained from the AMORIS clinical trial (175 553 patients studied) (Walldius et al. 2001). However, it is noteworthy that the majority of studies on apolipoproteins are performed in men. Only in a few apolipoprotein studies in women, CAD diagnosis was confirmed angiographically (Westerveld et al. 1998, Bahl et al. 1994).
Studies on atherosclerosis in women became more active after 1990, when the World Health Organization for the first time announced that women die of CAD as frequently as men, and the course of CAD in women is more severe (WHO 1990). Since then a lot of information has been accumulated, proving that the development and course of atherosclerosis in women differ from those in men. It is becoming obvious that the influence of Type 2 DM, obesity, dyslipidemia, and their combination is highly significant in the development of atherosclerosis in women (Mosca et al. 1999; Barrett-Connor et al. 1991), but so far this has not been sufficiently studied.
1.2. The aim of the study
To determine blood serum concentrations of total cholesterol, HDL cholesterol, triglycerides, and apoA-I and apoB in women referred for scheduled coronary angiography, to determine the associations of these concentrations with changes in coronary arteries and coronary risk factors (obesity and Type 2 DM), and to determine the distribution of AB0 system blood groups among females with established CAD.
1.3. The objectives of the study
1. To investigate the blood serum concentrations of total cholesterol, HDL cholesterol, triglycerides, apoA-I and apoB TG, as well as apoB/apoA-I ratio in women with angiographically determined CAD or with clear coronary arteries, and to compare the obtained findings with those of healthy female controls with normal weight.
2. To determine the differences in the blood serum concentrations of total cholesterol, HDL cholesterol, triglycerides, apoA-I and apoB TG, as well as apoB/apoA-I ratio in women diagnosed with CAD with different degrees of the outspread of the disease (in one sub-group, sporadic plaque was found in 1 or 2 coronary arteries, while in the other subgroup a diffuse disease involving 3 coronary arteries was detected).
3. To determine blood serum concentrations of total cholesterol, HDL cholesterol, triglycerides, apoA-I and apoB, as well as apoB/apoA-I ratio in women with CAD and Type 2 DM, and to compare the obtained findings with those of female subjects with CAD but without DM.
4. To determine blood serum concentrations of total cholesterol, HDL cholesterol, triglycerides, apoA-I and apoB, as well as apoB/apoA-I ratio in obese female subjects without CAD (clear coronary arteries group), and to compare the obtained findings with those of healthy normal weight female controls.
5. To determine the distribution of the AB0 system blood groups among women with angiographically confirmed CAD, and to compare the obtained findings with those of healthy female blood donors and healthy long-lived women.
1.4. Scientific novelty and practical significance of the study
So far in Lithuania there have been no studies on atherosclerosis in women. The novelty of our study is not limited to its object.
• The spreading of CAD in women was evaluated angiographically. In the majority of studies performed worldwide, CAD was evaluated only according to the anamnestic data – clinical manifestations of angina pectoris, previous myocardial infarction, etc. The survey of original scientific articles published in the Medline database during 1976-2005 yielded only 12 studies on atherosclerosis in women where angiographic control was applied.
• When studying CAD in women, we strived to determine the significance of lipids (total cholesterol, HDL cholesterol, and TG), apoA-I and B, and apoB/apoA-I ratio.
• We strived to determine the influence of overweight/obesity and Type 2 DM on the blood serum levels of apoA-I and B.
• For the first time in Lithuania, a possible association between the blood types of the AB0 system and CAD in women was established.
The information obtained during the study complements theoretical knowledge on the development of CAD in women, and the significance of apoA-I and B in the prognostication of CAD. The study showed that obesity and Type 2 DM in women is also associated with atherogenic changes in the concentration of lipids and apolipoproteins. The performed investigations of the blood types of the AB0 system in women with CAD revealed complex relationships between genetic determinants and atherogenesis: B blood group may have influence on the development of CAD, while blood group 0 in women may have athero-protective properties.
2. MATERIALS AND METHODS
2.1. The contingent of the study
The study was performed in Klaipėda Seamen’s Hospital in 2002-2005. The study protocol was confirmed by The Bioethical Committee of Lithuania (permission to perform a biomedical study No. 01-64/2001-11-28). All participants of the study were familiarized with the study protocol, and signed an informed consent (2 copies) to participate in the study; each participant received one copy of the signed informed consent.
The groups of subjects were formed according to the set objectives of the study (part 1); the scheme of group formation is presented in Fig. 1.
The studied women were selected according to the following criteria:
2.1.1. Inclusion criteria
• Age over 40 years (this age margin was chosen after the analysis of the findings of coronary angiographies performed during the last 5 years at Klaipėda Seamen’s Hospital, which showed that women under 40 years of age relatively rarely undergo coronary angiography, and the majority of cases when this examination was performed were acute coronary syndromes);
• Written consent to participate in the study;
• Performed scheduled coronary angiography, when non-invasive methods showed the presence of stable angina pectoris (this study was aimed at determining the treatment tactics).
2.1.2. Exclusion criteria:
• No conformity with the inclusion criteria;
• Usage of lipid-lowering medications, preparations with sex hormones, or estrogen receptor modulators;
• Pregnancy or lactation during the period of the study;
• Diseases:
- Rheumatic cardiac valve disease,
- Chronic heart failure (II or higher NYHA functional class),
- Cardiomyopathy,
- Active infection,
- Respiratory, renal or hepatic diseases with moderate or higher degree functional failure,
- Diseases of the nervous system with functional disorder,
- Oncological diseases,
- Alcoholism or drug addiction,
- Other diseases that may bring about changes in blood lipid concentration;
• History
- Acute coronary syndrome experienced less than three months before,
- Condition following percutaneous angioplasty of coronary arteries;
• The subject does not understand the point of the study;
• Suspicion that the subject may not comply with the study protocol (fasting for 12 hours before blood sampling).
2.1.3. Composition of study groups
After coronary angiography, the participants were differentiated into two groups – those with and without CAD; these groups were compared to the group of healthy volunteers (objective 1).
Women in whom stenosis >50 of the lumen in at least one coronary artery were evaluated as having CAD (“CAD” group). Women in whom coronary arteries had no visual changes or only individual insignificant irregularities of the vessel contour were detected were evaluated as having no CAD (“No-CAD” group).
In one part of the treatment, an evaluation of the associations of serum lipids and apolipoproteins with the spreading of CAD was planned (objective 2). According to the initial plan, women with CAD had to be differentiated into 3 subgroups – those with 1, 2, and 3 vessel disease. It was noticed that such differentiation of the subjects results in subgroups with 1 and 2 vessel disease being too small for statistical processing of the data, and therefore a different model was chosen. Women with CAD were differentiated into two subgroups – those with 1 or 2 vessel disease, and those with 3 vessel disease. Women in whom individual stenoses >50 of the lumen were detected in 1 or 2 coronary arteries, were attributed to the subgroup of subjects with 1 or 2 vessel disease. Women in whom all 3 coronary arteries were diffusely changed, and local stenoses in all 3 coronary arteries exceeded 50 of the lumen, were attributed to the subgroup of subjects with 3 vessel disease. This group also included women in whom CAD in 3 vessels was accompanied by the narrowing of the left main coronary artery. The findings on women whose changes in coronary arteries were difficult to attribute to either of the two subgroups were not analyzed further.
The other part of the study was aimed at the evaluation of the differences in the blood levels of lipids and apolipoproteins in subjects with CAD and Type 2 DM, compared to subjects with CAD but without DM (objective 3). In order to do this, the group of women with CAD was divided into two subgroups – “CAD with DM”, and “CAD without DM”.
The “CAD with DM” subgroup comprised women who up to the last admission to hospital were diagnosed with Type 2 DM (the case being recorded in medical documentation) and pharmaceutical treatment were administered.
The “CAD without DM” subgroup comprised women who were not diagnosed with DM prior to the study, and in whom the glucose levels in the blood sample (taken after 12 hours of fasting) did not exceed 6.1 mmol/l.
The group and the subgroups of subjects with CAD were compared to the group of subjects with no-CAD (confirmed angiographically) and the group of healthy volunteer controls.
2.2. Control group
The control group of healthy volunteers was formed according to the following criteria:
2.2.1. Inclusion criteria:
• Age over 40 years,
• Written consent to participate in the study,
• No CAD, AH, or DM,
• Body mass index (BMI) < 25 kg/m2.
2.2.2. Exclusion criteria:
• No conformity with the inclusion criteria,
• Usage of lipid-lowering medications, preparations with sex hormones, or estrogen receptor modulators,
• Smoke cigarettes or smoked before,
• Pregnancy or lactation,
• The presence of acute or chronic diseases,
• Alcoholism or addiction to drugs,
• The subject does not understand the point of the study,
• Suspicion that the subject may not comply with the study protocol (fasting for 12 hours before blood sampling).
In order to determine how the blood serum levels of lipids and apolipoproteins are related to overweight and obesity, a comparison of the subjects in whom coronary angiography did not reveal any changes in coronary arteries (no-CAD group) and healthy volunteers from control group was performed (objective 4).
2.3. The questionnaire, performed examinations, and accumulation of data
Women who agreed to participate in the study were purposefully questioned according to the inquiry. Subjects who corresponded to the inclusion criteria had questionnaires filled. The questionnaires included the date of the inquiry, running number, the subject’s name, surname, date of birth, address, phone number, anamnesis (data on CAD, AH, DM, obesity, smoking, and menopause), anthropometrical data (height, weight, and BMI), and the date of the blood sampling. The results of lipid and apolipoprotein tests were also included into the questionnaire. The data of the questionnaire, the findings of blood tests (blood serum concentrations of total cholesterol, HDL cholesterol, TG, and apoA-I and B) and data of coronary angiography were collected and stored in the MS Excel table.
2.4. Characteristics of the subjects
The study initially involved 103 women referred to scheduled coronary angiography. Following angiography, 11 subjects were excluded from the study due to difficulty in attributing them, according to the severity of damage to CA, to either CAD or no-CAD groups or certain CAD sub-groups. After exclusion, study population consisted of 92 women. The control group was formed of 30 healthy volunteers. The characteristics of the subjects are presented in Table 1.
There was no statistically significant difference in mean age between the groups (p=0.077). Mean BMI was significantly greater in the CAD and no-CAD groups, compared to the controls (p<0.0001); this difference was conditioned by statistically reliably greater weight of the studied subjects in these groups, compared to the control group (p<0.0001). The comparison of BMI between the CAD and the no-CAD groups yielded no statistically significant difference (p=0.21). The results of BMI measurements in the case and the control groups are presented in Fig. 2.
In the CAD group, 20 (32.8) patients had Type 2 DM, whereas in the no-CAD group there were no such cases. The control group did not include any subjects with DM according to the inclusion criteria. 56 (91.8%) patients in the CAD group, and 24 (77.4%) in the no-CAD group had primary arterial hypertension (p=0.09); the control group did not include any subjects with arterial hypertension according to the inclusion criteria. In the CAD group, menopause had started in 59 (96.7%) women, in the no-CAD group – in 29 (93.5%), and in the control group – in 28 (93.3%) women, p>0.05. There was no statistically significant difference in the mean duration of the menopause between the groups (p>0.05).
2.5. Laboratory studies
Laboratory studies were performed in the laboratory of Klaipėda Seamen’s Hospital. Blood serum samples were taken in the morning prior to coronary angiography, after at least 12 hours of fasting. Blood serum concentration of total cholesterol, HDL cholesterol, and TG were determined using the enzyme colorimetric method with COBAS-MIRA (Roche Diagnostics, Basel, Switzerland) analyzer and the application of Human (Human GmbH, Wiesbaden, Germany) diagnostic sets. Concentrations of ApoA-I and B in the same serum samples were determined using the imuno-turbidimetric method with COBAS-MIRA analyzer and the application of Spinreact (Spinreact S. A., Sant Esteve De Bas, Spain) diagnostic sets. Blood serum samples for apo studies were temporarily frozen - at the temperature of -40°C for not longer than 3 months. The samples were unfrozen only once before performing the tests.
2.6. Coronary angiography and its evaluation
Coronary angiography was performed at the Department of Cardiovascular Radiology of Klaipėda Seamen’s Hospital using the Philips Integris 3000 (Philips Medical Systems, Holland) angiographic equipment and plying the standard Judkins (Baim et al. 2000) technique. Indications for coronary angiography were suspected CAD and previously, using non-invasive methods, detected stable angina pectoris. Healthy volunteers included into the control group did not undergo coronary angiography.
Angiography of the left coronary artery was performed at least from 4, and that of the right coronary artery – at least from 2 standard projections. The obtained angiograms were recorded into videotapes.
Coronary angiograms were evaluated visually from the recorded image. The data on women in whom changes in coronary arteries were difficult to attribute to either of the aforementioned groups were not analyzed further.
2.7. Studies of the blood types of the AB0 system
The data on the blood types of the AB0 system in women with CAD were collected retrospectively. The surgery journals of Vilnius University Center of Cardiosurgery, Kaunas University of Medicine Clinic of Cardiosurgery, and the Department of Cardiosurgery of Klaipėda Seamen’s Hospital were used to select women who during 1994-2001 underwent surgery for pronounced CAD. Case histories of these women were used to collect data on blood types. Data on blood types of the selected healthy controls and long-lived women were taken from D. Stakišaitis’s doctoral dissertation (Stakišaitis 1992).
2.8. Statistical analysis of the data
The ANOVA model was used to evaluate statistically significant differences between the quantitative parameters of independent groups. The evaluation of statistically significant differences in mean concentrations of lipids and apolipoproteins between independent samples was performed using Student’s t test (if two samples were compared) and Newman-Keuls test (if three or more samples were compared). In the evaluation of statistical reliability, p value below 0.05 was considered to be statistically significant.
In order to determine relationships between qualitative characteristics, the methods of multiple linear and regression analysis were applied. For linear relationship between quantitative characteristics, Pearson’s coefficient r was calculated. The inter-comparison of correlation coefficients r and the evaluation of the statistical significance of the differences were performed using MedCalc 8.0.1.0 computer software package. The findings obtained during the study were analyzed using computer software packages Statistica 5.5, SPSS 11.5, and MS Excel 2002.
Genetic distances of the AB0 locus in groups were calculated according to the techniques proposed by Kazarinova-Fukshansky and Hummel (Kazarinova-Fukshansky et al. 1991); allele frequency of blood types of the AB0 system in the studied groups was compared using cluster analysis.
3. RESULTS
3.1. Results of the examination of blood serum concentration of total cholesterol, HDL cholesterol, and TG
We studied blood serum concentration of total cholesterol, HDL cholesterol, and TG in the three groups (CAD, no-CAD, and controls). The results of the investigation are presented in Table 2.
The inter-comparison of the three groups did not yield any statistically significant differences in blood serum concentration of total cholesterol (p=0.45). Blood serum concentration of HDL cholesterol was statistically significantly greater in the control group, compared to the CAD and the no-CAD groups (p < 0.0002). There was no statistically significant difference in the concentration of HDL cholesterol between the CAD and the no-CAD groups (p = 0.29). Mean concentrations of HDL cholesterol in the studied groups are presented in Fig. 3.
Comparing to the control group, blood serum concentration of TG in the CAD group was statistically significantly greater (p<0.0005). There was no statistically significant difference in blood serum concentration of TG between the no-CAD and the control groups (p=0.53). Data on the concentration of TG in the studied groups are presented in Fig. 4.
The analysis of blood serum concentration of lipids showed that total cholesterol
level did not differ statistically significantly between the studied groups, i.e. its levels were similar in women with manifested CAD, in those with risk factors but no CAD, and in healthy women. The levels of HDL cholesterol were statistically reliably greater in healthy women, whereas the comparison between the CAD and the no-CAD groups did not yield any significant differences. Statistically significantly higher levels of TG were found in the CAD group, whereas TG concentration between the no-CAD and the control groups did not differ statistically significantly.
3.2. Results of the investigations of blood serum levels of apolipoproteins A-I and B
The subjects underwent tests of blood serum concentration of apoA-I and B; in addition to that, the apoB/apoA-I ratio was calculated. The results of the examination are presented in Table 3.
The comparison of the concentration of apoA-I in the control group with that in the CAD and the no-CAD groups showed statistically significant differences (respectively, p<0.0002 and p<0.01). The highest concentration of apoA-I was found in the control group, and the lowest – in the CAD group. The data on the concentration of apoA-I in the case and the control groups are presented in Fig. 5.
The blood serum of the control group subjects was found to have statistically reliably the lowest levels of ApoB; the comparison of the CAD and the no-CAD groups did not yield any statistically significant differences (p=0.95). The findings on the levels of ApoB in the blood serum of the case and the control subjects are presented in Fig. 6.
The comparison of the control group with the CAD and the no-CAD groups showed that the ApoB/apoA-I ratio was statistically reliably lower in the control group (accordingly, p<0.0002 and p<0.001). The inter-comparison of the CAD and the no-CAD groups did not show any statistically significant difference (p=0.25). The findings of the ApoB/apoA-I studies in the case and the control groups are presented in Fig. 7.
The analysis of ApoA-I and B blood serum concentration in the case and the control groups showed that the studied CAD, no-CAD, and the control groups differed statistically reliably with respect to the levels of apoA-I; the lowest levels were found in the CAD group, and the highest – in the control group. Statistically reliably lower ApoB levels and the apoB/apoA-I ratio were characteristic of the control group.
3.3. Correlations between the levels of total cholesterol, HDL cholesterol, and apolipoproteins A-I and B in blood serum
A statistically significant correlation between blood serum concentrations of HDL cholesterol and apoA-I was detected in the CAD group (r=0.47, p<0.001, 95% CI 0.20 to 0.73), the no-CAD group (r=0.51, p<0.01, 95% CI 0.03 to 1.00), and the control group (r=0.52, p<0.01, 95% CI –0.38 to 1.41). The correlation between the concentrations of HDL cholesterol and apoA-I in blood serum of the studied groups is presented in Fig. 8.
The comparison of the correlation coefficients of HDL cholesterol and apoA-I in the studied groups did not yield any statistically significant differences (all p>0.7).
A statistically significant correlation between blood serum concentrations of total cholesterol and apoB was found in the CAD group (r=0.65, p<0.001, 95% CI 0.31 to 0.99), the no-CAD group (r=0.71, p<0.001, 95% CI –0.99 to 2.40), and the control group (r=0.53, p<0.01, 95% CI –1.76 to 2.82). The correlation between blood serum levels of total cholesterol and apoB in the studied groups is presented in Fig. 9.
The comparison of the correlation coefficients of total cholesterol and apoB in the studied groups did not yield any statistically significant differences (all p>0.2).
A statistically significant correlation between blood serum concentrations of total cholesterol and apoA-I was found in the CAD group (r=0.41, p<0.001, 95% CI 0.14 to 0.68) and the control group (r=0.49, p<0.01, 95% CI –1.86 to 2.85). Differently from the CAD group, the aforementioned correlation was not characteristic of subjects of the no-CAD group (r=0.14, p>0.05). The comparison of the correlation coefficients of total cholesterol and apoA-I in the studied groups did not yield any statistically significant differences (all p>0.1).
3.4. Blood serum concentrations of lipids and apolipoproteins in relation with the spread of coronary atherosclerosis
In order to determine whether the concentration of lipids and apolipoproteins correlates with the degree of the spread of coronary atherosclerosis, the CAD group was divided into 2 sub-groups according to the spread of disease. The 1-2 vessel disease subgroup included 30 subjects, and the 3 vessel disease subgroup – 31 subjects. These subgroups were compared to the no-CAD and the control groups. The characteristics of the studied subgroups and groups are presented in Table 4.
There was no statistically significant difference in subjects’ age between both CAD subgroups or in the no-CAD and the control groups (p=0.16). BMI, when comparing both CAD subgroups and the no-CAD group, did not differ statistically significantly (p>0.05). BMI of the subjects in the control group was statistically significantly lower than that in both CAD subgroups and the no-CAD group (p<0.0002). This difference is related to statistically significantly lower weight of the controls, compared to the subjects in both CAD subgroups and the no-CAD group (p<0.00001).
There was no statistically significant difference in the number of subjects with DM and arterial hypertension between the two CAD subgroups (accordingly, 30 and 35.5%, p=0.65; 90 and 93.5%, p=0.62). Menopause in the 1-2 vessel disease subgroup had started in 29 women (96.7%), and in the 3 vessel disease subgroup - in 30 women (96.8%); there was no statistically significant difference in the mean duration of the menopause between the subgroups (p=0.70).
The findings of the studies of blood serum lipids and apolipoproteins A-I and B in the studied subgroups formed according to the degree of CAD spread, and the no-CAD and the control groups are given in Table 5.
The comparison of the total cholesterol, HDL cholesterol and TG levels in CAD subgroups did not showed significant differences. The comparison of the apoB/apoA-I blood serum concentration ratios in CAD sub-groups and the no-CAD group did not yield any statistically significant differences (p>0.05). The ApoB/apoA-I ratio in the control group was statistically reliably lower than in the two CAD subgroups and the no-CAD group (p=0.00005).
The comparison of blood serum concentrations of lipids, apolipoproteins A-I and B, and the apoB/apoA-I ratio in the subgroups of subjects with different degrees of CAD spread did not yield any statistically significant differences.
3.5. Data of the studies of blood serum lipids and apoA-I and B in subjects with Type 2 DM and CAD
The study investigated the changes in blood serum concentrations of lipids and apolipoproteins A-I and B in women with angiographically defined CAD and Type 2 DM. The subjects of the CAD group were differentiated into two subgroups: 1) subjects with CAD and Type 2 DM formed the “CAD with DM” subgroup (n=20); 2) subjects with CAD but with no DM detected formed the “CAD without DM” subgroup (n=41). These subgroups were compared to the no-CAD and control groups. The characteristics of the groups are presented in Table 6.
Subjects in the “CAD with DM” subgroup were statistically reliably younger than those in the “CAD without DM” subgroup (p=0.038). The comparison of the ”CAD with DM” subgroup with the no-CAD and the control groups did not yield any statistically significant differences (accordingly, p=0.11 and p=0.07).
Subjects in the “CAD with DM” subgroup had greater weight, and their BMI was statistically significantly greater than that in the “CAD without DM” subgroup or the no-CAD and the control groups.
Arterial hypertension was found in 19 (95%) subjects in the “CAD with DM” subgroup, in 37 (90.2%) subjects in the “CAD without DM” subgroup, and in 24 (77.4%) subjects in the no-CAD group; there was no statistically significant difference in the prevalence of arterial hypertension between these groups (all p>0.05).
Menopause had started in 19 (95%) subjects in the “CAD with DM” subgroup, in 40 (97.6%) subjects in the “CAD without DM” subgroup, in 29 (93.5%) subjects in the no-CAD group, and in 28 (93.3%) in the control group; the differences in the incidence of menopause in the studied groups were statistically insignificant (p>0.05). mean duration of the menopause in the subjects in the “CAD with DM” subgroup was 15.7 (SD 8.1) years, in the “CAD without DM” subgroup – 17.9 (SD 8.4) years, in the no-CAD group – 14.0 (SD 8.4) years, and in the control group – 14.5 (SD 9.6) years. There was no statistically significant difference in the mean duration of the menopause between the studied subgroups or groups (p>0.05). The results of the studies of blood serum lipids and apolipoproteins A-I and B in the studied subgroups formed according to the presence of CAD and Type 2 DM, and in the no-CAD and the control groups are presented in Table 7.
The comparison of the studied subgroups and groups did not yield any statistically significant differences in blood serum levels of total cholesterol (p>0.05). The levels of HDL cholesterol were statistically reliably higher in the control group (p<0.0001); the comparison of both CAD subgroups and the no-CAD group showed that the differences in the levels of HDL cholesterol were statistically insignificant (p>0.05).
Blood serum concentrations of TG statistically reliably were the highest in the “CAD with DM” subgroup, and the lowest – in the no-CAD and the control groups. The obtained findings are presented in Fig. 10.
Blood serum concentration of apoA-I in subjects of the “CAD with DM” subgroup was lower than that in the “CAD without DM” subgroup, but the difference was statistically insignificant (p=0.29). Blood serum levels of apoA-I in subjects of the “CAD with DM” subgroup were statistically reliably lower than those in the subjects of the no-CAD (p<0.01) or the control (p<0.0002) groups. Blood serum levels of apoA-I in subjects of the “CAD without DM” subgroup were statistically reliably lower than those in the subjects of the no-CAD (p<0.039) or the control (p<0.0005) groups. The comparison of the no-CAD and the control groups showed that blood serum levels of apoA-I were statistically reliably lower in the subjects of the no-CAD group (p<0.02). The data on blood serum concentrations of apoA-I in the studied subgroups and groups are given in Fig. 11.
The highest blood serum concentration of apoB was detected in the subjects of the “CAD with DM” subgroup; a statistically significant difference was found when comparing the “CAD with DM” and the “CAD without DM” subgroups (p=0.025), and when comparing the “CAD with DM” with the control group (p<0.001); the comparison of the “CAD with DM” subgroups with the no-CAD groups showed that the difference was statistically insignificant (p=0.088). The findings on the blood serum levels of ApoB are presented in Fig. 12.
The ApoB/apoA-I ratio was statistically significantly the highest in the “CAD with DM” subgroup, and the lowest – in the control group. There was no statistically significant difference between the “CAD without DM” subgroup and the no-CAD group in this respect. The data on the ApoB/apoA-I concentration ratio in the studied subgroups and groups are given in Fig. 13.
The studies of blood serum lipids and apolipoproteins in the subjects showed that that women with CAD are characterized by clearly greater blood serum concentrations of TG and significantly lower blood serum concentrations of apoA-I; these changes are more marked in subjects with Type 2 DM. Subjects with CAD and Type 2 DM also are characterized by markedly greater blood serum levels of apoB.
3.6. Findings of the study on blood serum lipids and apolipoproteins A-I and B in women with diagnosed overweight or obesity
The study investigated the influence of overweight and obesity on blood serum levels of lipids and apoA-I and B in women. For this reason, the no-CAD and the control groups were compared. The characteristics of the groups are presented in Table 1.
The comparison of the subjects’ age in the no-CAD and the control groups did not yield any statistically significant differences (p=0.54). The studied women of the no-CAD group, compared to the control group, had statistically reliably greater BMI (p<0.0001). This difference is stipulated by markedly higher body weight of the subjects in the no-CAD group (p<0.0001), since the subjects’ height in the no-CAD and the control groups did not differ statistically significantly (p=0.3). There were no subjects with DM in the two groups. Arterial hypertension was diagnosed in 24 (77.4%) women of the no-CAD group. The control group did not have any subjects with arterial hypertension (according to the exclusion criterion). Menopause had started in 29 (93.5%) subjects in the no-CAD group, and the mean duration of the menopause was 14.0 (SD 8.4) years. In the control group, menopause had started in 28 (93.3%) women, and the mean duration of the menopause was 14.5 (SD 9.6) years. There were no statistically significant differences in the frequency of cases when the menopause had already started between the no-CAD and the control group (p>0.05). The mean duration of the menopause did not differ statistically significantly between the two groups (p<0.05).
Blood serum levels of total cholesterol, HDL cholesterol, and TG in the no-CAD and the control groups is presented in Table 2. The data on the studies of blood serum concentrations of ApoA-I and apoB, and the apoB/apoA-I ratio in the no-CAD and the control groups are presented in Table 3. Blood serum levels of total cholesterol in the no-CAD and the control groups did not differ statistically significantly (p=0.29). Blood serum concentration of HDL cholesterol was statistically reliably higher in the control group compared to no-CAD group (p<0.0005). The data on the blood serum levels of HDL cholesterol in the subjects of the no-CAD and the control groups are given in Fig. 3. The comparison of the no-CAD and the control groups showed that the difference in blood serum levels of TG was statistically insignificant (p=0.5). The data on blood serum concentration of TG in the no-CAD and the control groups are presented in Fig. 4. Blood serum concentration of ApoA-I was statistically reliably lower in the no-CAD group, compared to the control group (p=0.009). The data on the blood serum levels of apoA-I are given in Fig. 5. Mean blood serum concentration of apoB in the no-CAD group was statistically reliably higher, compared to that in the control group (p=0.04). The data on blood serum concentrations of apoB in the no-CAD and the control groups are given in Fig. 6. The ApoB/apoA-I ratio in the subjects of the no-CAD group was statistically significantly higher than that in the control group (p=0.0006). The data on the examinations of the ApoB/apoA-I ratio in the no-CAD and the control groups are given in Fig. 7.
In the control group, no statistically significant correlations between the anthropometric indicators (body mass, height, and BMI) and lipids (total cholesterol, HDL cholesterol, and TG) or apoA-I or B levels were found. In the no-CAD group, statistically significant negative correlations were found between the concentration of apoA-I and weight (r=-0.36, p<0.05, 95% CI –0.86 to 0.14), and between apoA-I concentration and BMI (r=-0.36, p<0.05, 95% CI –0.86 to 0.14).
The study showed that overweight subjects without angiographically detectable coronary atherosclerosis (the no-CAD group) are characterized by statistically significantly lower levels of HDL cholesterol and apoA-I, and statistically significantly higher apoB levels and the apoB/apoA-I ratio, compared to healthy women with normal weight.
3.7. Lipidogenic factors in the prognostication of CAD in women
The application of the stepwise logistic regression showed that in the prognostication of CAD in women, statistically significant indicators were blood serum concentrations of TG and apoA-I, and blood serum concentrations of total cholesterol, HDL cholesterol, and apoB were statistically insignificant. The data of the logistic regression analysis are presented in Table 8.
3.9. Frequency of the AB0 system blood groups in women with CAD
AB0 system blood groups were found in 441 women prior to myocardial revascularization surgery. The subjects were distributed into 2 groups according to age. I CAD group include women aged 60 years and younger; 109 subjects were attributed to this group; their mean age was 55.1 (SD 4.8) years. II CAD group included women over 60 years of age. This group consisted of 332 subjects, and their mean age was 68.1 (SD 5.0) years. The frequency of AB0 blood groups in the studied groups of subjects was calculated. For comparison, blood findings of 595 healthy female blood donors with AB0 blood group were used. In addition to that, the frequency of blood groups in subjects with CAD was compared to that of 75 long-lived women whose mean age was 94.1 (SD 3.8) years. The frequency of AB0 blood groups in the studied groups of subjects is presented in Table 9.
The data presented in Table 9 show that blood group 0 was statistically significantly more rarely found in the I CAD group than in the donor group (accordingly, 28.4% and 38.2%; p<0.04). B blood group was statistically reliably more frequent in the II CAD group than among blood donors (accordingly, 22.9% and 15.0%; p<0.04). B blood group was statistically reliably less frequent among long-living women, compared to blood donors and the I and II CAD groups (respectively, 6.7% compared to 15.0, 20.2, and 22.9%; p<0.01). The analysis of the frequency of the AB0 blood group did not yield any statistically reliable differences between the studied groups.
The relative indicator of risk for CAD according to the blood group in women was the following: in the I CAD group - A/0=1.56, B/0=1.81, and AB/0=1.03; in the II CAD group - A/0=1.06, B/0=1.69, and AB/0=0.69; in the general CAD group - A/0=1.17, B/0=1.71, and AB/0=0.77; in the group of long-living women - A/0=1.38, B/0=0.45, and AB/0=0.38.
Studies showed that the frequency of AB0 alleles differed statistically reliably: when comparing the I CAD and the donor and the long-living women groups; when comparing the II CAD and the long-living women and donor groups (P<0.05); and when comparing the frequency of AB0 alleles between the groups of donors and long-living women (P<0.05). The inter-comparison of both CAD groups did not yield any difference in the frequency of AB0 alleles. The frequency of AB0 blood group phenotypes did not correspond with the Hardy-Weinberg rule in either the studied group of long living women or the two CAD groups.
The matrix of genetic distances between the studied groups is presented in Table 10.
The differentiation of the studied groups of subjects according to AB0 blood groups was analyzed using the cluster analysis technique. The findings of the cluster analysis are presented in Fig. 14.
The cluster analysis showed that long-living women formed a separate cluster; the second cluster was formed by both CAD groups, and the third one – by blood donors.
4. CONCLUSIONS
1. The comparison of the total blood serum cholesterol concentrations in female subjects with angiographically confirmed CAD, without CAD, and in normal weight healthy controls did not yield any significant differences. There were no significant differences in blood serum concentrations of HDL cholesterol between female subjects with and without CAD, but in both groups blood serum concentrations of HDL cholesterol were statistically significantly lower than those in healthy controls. In females with CAD, blood serum concentrations of triglycerides were significantly higher than those in female subjects without CAD and healthy controls with normal weight. Females with CAD were characterized by significantly lower blood serum concentrations of apoA-I, compared to female subjects without CAD or healthy controls.
2. The inter-comparison of female CAD patients with different degrees of the outspread of the disease (in one sub-group, sporadic plaque was detected in 1 or 2 coronary arteries, and in the other a diffuse disease of 3 coronary arteries was detected) concerning blood serum concentrations of total cholesterol, HDL cholesterol, triglycerides, apoA-I and apoB did not yield any significant differences.
3. Female subjects with CAD and Type 2 DM are characterized by statistically reliably higher blood serum concentrations of triglycerides and apoB, compared to female subjects with CAD but without DM.
4. Overweight or obese females without CAD are characterized by statistically reliably lower blood serum concentrations of HDL cholesterol and apoA-I, and statistically reliably higher apoB levels and apoB/apoA-I ratios, compared to healthy female controls with normal weight.
5. Blood group B was statistically reliably more common among females with CAD, while blood group 0 – statistically reliably less frequent, compared to healthy blood donors and long-living females.
5. PRACTICAL SIGNIFICANCE OF THE STUDY
The material accumulated during the study complements theoretical knowledge on the peculiarities of the development of CAD in women.
The study showed that for the evaluation of the risk for CAD in women, blood serum concentration of HDL cholesterol is more important than the concentration of total cholesterol, and therefore practitioners should primarily pay attention to a decreased HDL cholesterol levels when evaluating the risk for CAD in women.
The determination of the concentration of TG is of high practical significance in the evaluation of the risk for CAD in women.
Investigation of apolipoproteins A-I and B may allow for a more precise evaluation of the risk for CAD, and therefore it is expedient to apply these investigations in daily practice, especially in the evaluation of the risk for CAD in obese women and those with Type 2 DM.
A decrease in apoA-I levels and an increase in TG concentrations may be evaluated as the most important lipid risk factors for CAD in women.
The study showed that obesity in women is associated with atherogenic changes in blood serum lipids and apolipoproteins. This finding may be of practical significance in the formation of the directions of primary prevention of CAD.
The findings of the study showed that in blood serum of women with Type 2 DM, atherogenic lipids and apolipoproteins predominate, which is important in treating such women for dyslipidemia – a more aggressive approach may be required in order to achieve the desired target.
The determination of blood serum concentrations of apoA-I and B may be an important determinant for the evaluation of the therapeutic effect when treating women with CAD and Type 2 DM for dyslipidemia.
The study showed that blood group B may be associated with the development of CAD, whereas blood group 0 in women may have athero-protective properties.

 

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