Oxidative stress can be involved as both a primary event and a consequence of metabolic disorders, resulting in a malice cycle of oxidative stress, cardiovascular disease pathophysiology. It depends upon various environmental situations such as pollution, stress, food quality, lifestyle, and many psychosocial factors. The important role of oxidative stress in the etiology of atherosclerosis is marked by lipid alterations and oxidizability of lipoproteins. Oxidized LDL is considered to be a key event in the biological process that promotes inflammation causing endothelial injury leading to the progression of early atherosclerotic lesions [
Menopause, a form of reproductive aging, is marked by many hormonal variations which cause imbalance in the oxidative processes. Estrogens exert beneficial effects on endothelial dysfunction, a prerequisite of atherosclerosis by modulating lipid profile and increasing the production of nitric oxide [
Redox-status imbalance leads to oxidative stress, a condition where reactive oxygen species (ROS)/prooxidants overcome antioxidant capacity resulting in serious cell damage. Endothelial cells and vascular smooth cells are known to be the potent sources of reactive oxygen species which are thought to be involved in the onset and development of endothelial dysfunction [
An increased level of oxidative stress in the body which is marked by the reduction in estrogen also depends on the concentration and chemical structure of this hormone. Specifically, at high concentration estrogen tends to have a beneficial antioxidant effect by inhibiting the 8-hydroxylation of guanine DNA bases. However, at low concentration, especially when the structure contains a catechol it has a prooxidants-like effect such as breaks in genetic material, formation of DNA adducts, and oxidation of bases [
Oxygen radicals can modify amino acid side chains, cleave polypeptide bonds, and make proteins more susceptible to proteolytic degradation [
Many studies have investigated menopausal CVD risk by lipid levels and oxidative stress and have compared premenopausal levels with postmenopausal levels, indicating enhanced lipid levels and oxidative stress in postmenopausal women as compared to premenopausal women [
A cohort of 523 menopausal women from northern Punjabi population was recruited in the present study which comprised 265 menopausal women (mean age, 44 ± 4 years) suffering from CVD. The diagnosis of heart disease was made on the basis of clinical symptoms, supportive documented ECG findings, history of the patient, and angiography as required for the disease [
All subjects were subjected to collection of blood samples after 12 hr overnight fasting under aseptic conditions. The blood sample was then centrifuged at 3000 rpm for 15 minutes to obtain a clear serum sample. For analysis of lipid profile total serum cholesterol was estimated by the method of CHOD-PAP [
The statistical analysis was performed using Statistical Package for Social Science program (SPSS version 16.0; SPSS Inc., Chicago, IL). All values were expressed as mean ± SD. Means for both the groups were statistically evaluated by independent Student’s
Table
Frequency of risk factors in menopausal women (with and without CVD).
Risk factors | Group | |
---|---|---|
Non-CVD menopausal women |
CVD menopausal women | |
Hypertension |
0.46 | 0.69 |
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||
Dyslipidemia |
0.45 | 0.62 |
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||
Diabetes |
0.24 | 0.26 |
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||
Obesity |
0.62 | 0.53 |
Comparison of frequency of risk factors between non-CVD menopausal women and CVD menopausal women was done using chi square (
In Figure
Levels of lipid profile in normolipidemic CVD and non-CVD menopausal women. TC, total cholesterol; TG, triglycerides; HDL-C, high density lipoprotein-cholesterol; LDL-C, low density lipoprotein-cholesterol; VLDL-C, very low density lipoprotein-cholesterol; AIP [
Levels of lipid profile in hyperlipidemic CVD and non-CVD menopausal women.
Comparisons of prooxidants (MDA and LDL carbonyl content) and antioxidant (SOD) levels between normolipidemic CVD and non-CVD menopausal women and between hyperlipidemic CVD and non-CVD ones are illustrated in Figures
Levels of MDA, LDL carbonyl content, and SOD in normolipidemic CVD and non-CVD menopausal women. MDA, malondialdehyde; SOD, superoxide dismutase.
Levels of MDA, LDL carbonyl content, and SOD in hyperlipidemic CVD and non-CVD menopausal women. MDA, malondialdehyde; SOD, superoxide dismutase.
In order to ascertain any relationship between the risk factors and the LDL particle size among normolipidemic and hyperlipidemic CVD menopausal women and non-CVD ones Pearson’s correlation analysis was carried out (Table
Correlation matrix (bivariate) of various risk factors among normolipidemic and hyperlipidemic menopausal women with and without CVD.
AIP [ |
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Variables | Normolipidemic non-CVD menopausal women | Normolipidemic CVD menopausal women | Hyperlipidemic non-CVD menopausal women | Hyperlipidemic CVD menopausal women | ||||
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|
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|
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|
TC | −0.179 | <0.05 | −0.068 | NS | 0.013 | NS | 0.243 | <0.01 |
TG | 0.356 | <0.01 | 0.439 | <0.001 | 0.666 | <0.001 | 0.702 | <0.001 |
VLDL-C | 0.324 | <0.01 | 0.396 | <0.01 | 0.680 | <0.001 | 0.700 | <0.001 |
LDL-C | 0.135 |
|
0.310 |
|
0.048 |
|
0.248 |
|
HDL-C | −0.800 | <0.001 | −0.799 | <0.001 | −0.632 | <0.001 | −0.813 | <0.001 |
MDA | 0.118 |
|
0.199 |
|
0.171 |
|
0.207 |
|
LDL cbpr. | −0.024 |
|
0.650 |
|
0.046 |
|
0.385 |
|
SOD | −0.121 | NS | 0.032 | NS | 0.026 | NS | 0.031 | NS |
AIP is atherogenic index of plasma taken as an index of LDL particle size.
A significant negative correlation between HDL-C and AIP has been observed in all the four groups, that is, in normolipidemic non-CVD (−0.800), normolipidemic CVD (−0.799), hyperlipidemic non-CVD (−0.632), and hyperlipidemic CVD (−0.813). However, a significant positive correlation of TG with AIP was found in all the four groups, that is, in normolipidemic non-CVD (0.356), normolipidemic CVD (0.439), hyperlipidemic non-CVD (0.666), and hyperlipidemic CVD (0.702), whereas significant association of LDL-C with AIP was only found in normolipidemic CVD group (0.310) and in hyperlipidemic CVD group (0.248).
With regard to the association of LDL carbonyl content and AIP, positive significant correlation was observed in normolipidemic CVD group (0.650) and in hyperlipidemic CVD group (0.385). Conversely, no such significant correlation was observed in non-CVD group of both normolipidemia and hyperlipidemia.
Cardiovascular disease (CVD) and its associated unfavorable complications are the major cause of morbidity and mortality especially in women at menopausal age despite recent advances in diagnostic facilities and treatment modalities. Role of hyperlipidemia in the pathophysiology of atherosclerotic CVD as a risk factor is clear. However, there are many additional mechanisms such as acute inflammatory response [
Lipid peroxidation is believed to be involved in the peroxidative modification of low density lipoproteins (LDL). Oxidative (modified) LDLs have diverse and potent effects throughout the inflammatory response and play prominent roles in atherosclerotic changes. Increased production of these reactive oxygen species (ROS) like superoxide ion mediates various signaling pathways that underline vascular inflammation in atherogenesis [
From our investigations we observed that 37% of noteworthy population of women had normal lipid profile but still they suffered from heart disease. This reflects the weak predictive influence of the lipid levels. These women are thus at increased risk of heart disease in the absence of better risk indicators which are needed to be explored.
Accordingly, evaluation of oxidant-antioxidant profile may have an added advantage over the estimation of lipid profile. Our normolipidemic CVD group revealed that lipid profile could not competently distinguish it from the subjects of non-CVD group. This is also supported by Stringer et al. [
In our population of normolipidemic and hyperlipidemic menopausal women TC showed no correlation with atherogenic index of plasma. Atherogenic index of plasma (AIP) defined as
Malondialdehyde (MDA) which is one of the products of lipid peroxidation has been the most extensively studied marker. Its increased level marks the index of assessing oxidative stress. Accordingly, we observed an increase in the levels of MDA in both hyperlipidemic and normolipidemic menopausal women which indicated the degree of oxidation in heart disease (Figures
But appraisal of lipid oxidation may not always be informative for CAD risk assessment. Therefore, we also attempted to study LDL oxidation in terms of its protein content. Unlike lipid oxidation, protein oxidation does not have the features of chain reactions. Enhanced levels of carbonyl derivatives are formed when proteins become more susceptible to proteolytic degradation on exposure to oxygen radicals. Protein carbonyl content is actually the broadest indicator and by far the most commonly used marker of protein oxidation. In the light of this fact we estimated carbonyl content of LDL as an index of protein oxidation. Significant increase in the levels of LDL carbonyl content was observed in both normolipidemic and hyperlipidemic menopausal women. Interestingly, levels of carbonyl content were found to be more in normolipidemic ones as compared to hyperlipidemic menopausal women with CVD. It means that some oxidative events initiate even when LDL levels are normal.
Extracellular SOD (EC-SOD) is a secretary glycoprotein whose levels are found high in blood vessels so as to suppress oxidative stress under normal conditions. Our findings corroborate this theory as we observed low levels of SOD in both normolipidemic and hyperlipidemic CVD menopausal women indicating free radical generation and simultaneously decreased antioxidant production.
A new aspect gained from the present investigations indicated increased value of AIP in normolipidemic CVD menopausal women as compared to non-CVD ones. Moreover strong correlation of LDL oxidation (MDA and carbonyl content) with AIP in normolipidemic CVD menopausal women is in line with the fact that oxidation is due to the presence of small dense LDL particles and that oxidative processes seem to start earlier, even when LDL and TC levels are normal. This is also in concordance with another study [
In conclusion, strong correlation observed between atherogenic index of plasma (AIP) and oxidative stress in normolipidemics demonstrates that oxidative events initiate even when lipid levels are normal and moreover normolipidemic menopausal women are also equally susceptible to heart risk irrespective of the lipid status. It also visualizes that redox-status imbalance can be considered as an effective prognostic tool for an early detection of cardiovascular risk.
It is declared that there are no competing interests for the authors. The research work is entirely for academic purpose and no competing financial interests exist.
The cooperation of the patients involved in the study design is highly acknowledged. The authors are thankful to Professor Malkinder Singh of English Department of Khalsa College, Amritsar, for vetting the paper with respect to grammatical mistakes.