|Year : 2004 | Volume
| Issue : 11 | Page : 465-471
Association of serum antioxidants and risk of coronary heart disease in South Indian population
D Rajasekhar, P VLN Srinivasa Rao, S AA Latheef, K SS Saibaba, G Subramanyam
Departments of Cardiology, Sri VenkateswaraInstitute of Medical Sciences, Tirupati - 517507, Andhra Pradesh, India
Department of Cardiology, Sri Venkateswara Institute of Medical Sciences, Tirupati - 517507, Andhra Pradesh, India
BACKGROUND AND AIM: Higher prevalence of coronary heart disease (CHD) has been reported in south Indian population, which cannot be accounted for by the traditional risk factors like hyperlipidemia. Identification of new risk factors may help in treatment and prevention of CHD in this part of the world. In an attempt to investigate the causes of increased incidence of CHD in this part of the world, we intended to look for oxidative stress in our patients as a possible risk factor. As an initial step in this perspective, a case- control study was conducted to find out the serum antioxidant levels and their association with CHD in south Indian population. SETTINGS AND DESIGN: A tertiary care hospital; Case - control study. MATERIALS AND METHODS: One hundred thirty nine angiographically proven CHD patients (aged 29-75 years) were studied against 59 population based healthy controls (aged 29-72 years) free of CHD. Fasting serum cholesterol, triglycerides, HDL cholesterol, erythrocyte and plasma glutathione peroxidase and superoxide dismutase were estimated on automated clinical chemistry analyzer. LDL cholesterol and VLDL cholesterol were calculated. Vitamins A and E were estimated using high performance liquid chromatography (HPLC). STATISTICAL ANALYSIS: Unpaired t test was used to compare means. Binary logistic regression was done to find out the association between dependent and independent variables. RESULTS: Significantly higher levels of Total Cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratio and lower HDL cholesterol levels were observed in patients when compared to controls. No significant difference of plasma and erythrocyte glutathione peroxidase and superoxide dismutase activity was observed between patients and controls. Significantly lower levels of vitamin E in patients than in controls was observed (P<0.001). Serum vitamin E was inversely associated with coronary heart disease even after controlling for age and other coronary risk factors (Odds ratio 0.898, 95% CI 0.826-0.976 P=0.01). CONCLUSIONS: The results of present study suggest that deficiency of vitamin E may be an independent risk factor of CHD. This study brings out the need for long- term monitoring of vitamin E supplementation as a preventive measure for CHD in the population studied.
|How to cite this article:|
Rajasekhar D, Srinivasa Rao P V, Latheef S A, Saibaba K S, Subramanyam G. Association of serum antioxidants and risk of coronary heart disease in South Indian population. Indian J Med Sci 2004;58:465-71
|How to cite this URL:|
Rajasekhar D, Srinivasa Rao P V, Latheef S A, Saibaba K S, Subramanyam G. Association of serum antioxidants and risk of coronary heart disease in South Indian population. Indian J Med Sci [serial online] 2004 [cited 2015 Apr 18];58:465-71. Available from: http://www.indianjmedsci.org/text.asp?2004/58/11/465/13494
| ¤ Introduction|| |
Coronary heart disease (CHD) is a leading cause of morbidity and mortality in developed countries and is emerging as an epidemic in developing countries. It is predicted that there will be an increase of 111% in cardiovascular deaths in India by the year 2020 when compared to the year 1990. This is much higher than that predicted to any other region both in Asia as well as outside Asia. In India, the prevalence of CHD is much higher in south when compared to north India., This high prevalence warrants probing into the presence of various risk factors and their association with CHD. Traditional risk factors like serum cholesterol, blood pressure and smoking account for not more than 50% difference in mortality of CHD. This led to studies on newer risk factors like fibrinogen, Lp(a), plasminogen activator, antioxidants etc. Harman first suggested oxidation of biopolymers as etiology in aging. Oxidative modification hypothesis of atherosclerosis originated with the observation of Goldstein et al. Oxidized LDL has been identified in atherosclerotic lesions. This has prompted the study of antioxidants in the prevention of the initiation and progression of cardiovascular disease. Descriptive, case-control and prospective cohort studies have found inverse associations between the frequency of coronary heart disease and dietary intake of antioxidant vitamins. Case-control studies,, have shown low levels of serum antioxidants in CHD patients when compared to controls and suggested the role of Vitamin E in prevention of CHD.
In India Dube et al (Jaipur), Nand et al (Haryana) and Singh et al (Moradabad) have reported deficiency of serum vitamin E levels in CHD patients. In one study efficacy of antioxidant vitamins was tested on serum lipid profile and lipid peroxide levels in a clinical trial which lasted for 30 days. Decreased lipid peroxide levels were observed in supplemented group as compared to placebo group.
But the results of the prospective studies have been equivocal. As a result some considered this as a set back for antioxidant therapy as well as oxidative hypothesis of atherosclerosis. However, a closer examination of these reports reveal many lacunae like improper design of trial, inadequate dosage of antioxidant vitamins, improper selection of patients., Hence, we studied the serum antioxidant levels and their relation to coronary heart disease in south Indian population as there are no reports from this part of world.
| ¤ Materials and methods|| |
One hundred thirty nine consecutive patients attending cardiology clinic from November, 2000 to November, 2002 and willing to get enrolled in the study formed the patient group. Coronary heart disease status was confirmed by angiographic evidence. The patient group included 79 smokers, 66 diabetics and 51 hypertensives. Fifty patients had a family history of CHD. Age of the patients ranged from 29-75 years. Patients with pancreatic insufficiency, cystic fibrosis, betalipoproteinemia or small intestinal resection were excluded. Fifty nine population-based controls free of clinical CHD (substantiated by 12 lead rest ECG and history) were included in the study. Their age ranged from 29-72 years. An ethics committee of our Institute cleared the protocol for execution of the study. Informed consent of the subjects was taken for participation in the study.
Fasting blood samples were drawn from subjects who were on 12 hour fasting. Triglycerides, total cholesterol (total-C) and high density lipoprotein cholesterol (HDL-C) were estimated using commercial kits on the synchron cx4 analyzer from Beckman Instruments Inc., California, USA. Erythrocyte and plasma glutathione peroxidase and superoxide dismutase activities were measured using Ransel and Ransod kits (Randox Laboratories Limited Crumlin, UK) on the same analyzer. Low density cholesterol (LDL-C) and very low density lipoprotein cholesterol (VLDL-C) were calculated using Friedewald's formula. Total-C/HDL-C and LDL-C/HDL-C ratios were calculated. Serum Vitamin A and E were measured simultaneously by high performance liquid chromatography. Hemoglobin was estimated by the cyanomethemoglobin method using commercial kits.
ll continuous variables except superoxide ismutase, plasma glutathione peroxidase showed skewness and hence a non-parametric test, Mann-Whitney U test, was used to compare means. Logistic regression analysis was done to find out the association of dependent variable (CHD) and independent variables using the forward stepwise likelihood ratio method. All statistical analysis were done using windows based SPSS version 11.5.
| ¤ Results|| |
Mean ± S.D values of demographic, lipid and lipoprotein parameters factors are presented in [Table - 1]; serum antioxidant levels in patients and controls are shown in [Table - 2].
Total-C/HDL-C and LDL-C/HDL-C ratio (P<0.001) were significantly higher and HDL-C (P<0.002) levels were lower in patients when compared to controls.
Significantly lower levels of vitamin E in patients than in controls (P<0.001) were observed. No significant difference of serum and erythrocyte glutathione peroxidase activity and superoxide dismutase activity and serum levels of vitamin A were observed between patients and controls.
The association of vitamin E with CHD remained inversely significant even after controlling for age and other coronary risk factors (sex, smoking, diabetes, family history, total cholesterol, triglycerides, HDL cholesterol and VLDL cholesterol).
| ¤ Discussion|| |
An important implication of oxidative modification hypothesis of atherosclerosis is that antioxidants may inhibit atherogenesis, through mechanisms like protection of LDL against oxidative modification. Antioxidant enzymes are present in small amounts only in plasma and other external fluids. Besides these, antioxidants like Vitamin E are of major importance.
Increased prevalence of coronary heart disease necessitated the intervention that can reduce the risk of CHD. Hence, correspondingly greater attention is being focused on prevention of CHD. In this area antioxidants may serve an important role.
Activity of glutathione peroxidase was shown to be increased in blood and decreased in erythrocyte, whereas decreased or no change in super oxide dismutase was reported in patients than in controls in earlier studies.,, Our study did not reveal any change in the antioxidant enzymes of blood in patients with CHD when compared to the control group. Also, administration of antioxidant enzymes to improve the antioxidant defense has its own practical implications. Hence the attention logically gets diverted towards the antioxidant vitamins. Decrease or no change in concentration of vitamin A was observed in earlier studies., In the present study also no significant changes in vitamin A levels were observed in patients when compared to controls. However, there was a significant decrease in the plasma vitamin E levels in patients with CHD when compared to healthy controls (P<0.001). This is in agreement with other reports.,,, Vitamin E is a lipid soluble peroxyl radical scavenger in human cells. Vitamin E interrupts lipid peroxidation by scavenging peroxyl radical intermediates.
Vitamin E may inhibit cell mediated LDL oxidation by reducing cellular production and release of reactive oxygen species. Beneficial effects of vitamin E includes inhibition of smooth muscle cell proliferation, preservation of endothelial function, inhibition of monocyte-endothelial adhesion, inhibition of monocyte reactive oxygen species and cytokine release, inhibition of platelet adhesion and aggregation, protection of LDL against oxidation, increased resistance of LDL to oxidation as well as, lowering of cytotoxicity of oxidized LDL towards endothelial cells.,,,
Because of this multiple beneficial action, emphasis with respect to the study of antioxidant status as well as its improvement revolves round vitamin E. Also the ease of administration and lack of side effects add to the concept.
Patients with pancreatic insufficiency, cystic fibrosis, betalipoproteinemia or small intestinal resection are at increased risk of vitamin E deficiency. Our study did not include any patient with above mentioned disorders. Decreased serum vitamin E levels may be due to the reduced intake or smoking. Reduced levels of vitamin E may also be due to the increased requirement of vitamin E in pro-oxidant milieu with enhanced free radical status, leading to the increased lipid peroxidation, a resultant depletion of free radical scavenger and antioxidant reserves of the body. Esterbauer et al have reported that endogenous antioxidants, mainly tocopherol, contained in LDL particles are rapidly consumed after induced oxidation and propagation of the oxidative process doesn't begin until antioxidant molecules are largely exhausted. Low levels of vitamin E was associated with increased risk of CHD.
Significant inverse association of vitamin E and CHD was observed in studies conducted in India and abroad., In our study also we have observed significant inverse relation of serum vitamin E with CHD after adjustment for age, sex, smoking, diabetes, hypertension, family history of CHD, lipids and lipoproteins (Odds ratio 0.898, 95 CI% 0.826-0.976 P<0.01).
Diabetes, hypertension and smoking, which are known to produce oxidative stress are present in the patients studied and might have contributed to the low levels of vitamin E observed in our study. However, the significant association observed between vitamin E levels and CHD even after correcting for these factors points towards a greater attention to this and treat this as an independent risk factor.
Further efforts are on to identify the local causes of low vitamin E levels and the effects of vitamin supplementation on the CHD incidence.
| ¤ References|| |
|1.||Yusoff K. Vitamin E in cardiovascular disease: Has the diet been cast? Asia Pac J Clin Nutr 2002;11:S443-7. [PUBMED] |
|2.||Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global burden of disease study. Lancet 1997;349:1269-76. [PUBMED] [FULLTEXT]|
|3.||Mohan V, Deepa R, Rani SS, Premalatha G. Prevalence of coronary artery disease and its relationship to lipids in a selected population in south India. J Am Coll Cardiol 2001;38:682-7. |
|4.||Gupta R, Gupta VP, Sarna M, Bhatnagar S, Thanvi J, Sharma V, et al. Prevalence of coronary heart disease and risk factors in an urban population: Jaipur Heart Watch-2. Indian Heart J 2002;54:59-66. [PUBMED] |
|5.||Gey KF, Puska J, Jordon P, Moser UK. Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Am J Clin Nutr 1991;53:S326-34. |
|6.||Harman D. Atherosclerosis: A hypothesis concerning the initiating steps in pathogenesis. J Gerontol 1957;12:199-202. [PUBMED] |
|7.||Goldstein JL, Ho YK, Basu SK, Borown MS. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acd Sci USA 1979;76:333-7. |
|8.||Steinberg D, Parthasarathy C, Carew TE, Khoo JC, Witzum JL. Beyond cholesterol:modifications of low density lipoprotein in atherogenecity. N Engl J Med 1989;320:915-24. |
|9.||Fong LG, Steiberg D. Oxidatively modified low density lipoproteins: A potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci USA 1987;84:2995-8. |
|10.||Diaz MN, Frei B, Vita JA, Keaney JF. Antioxidants and Atherosclerotic heart disease. New Engl J Med 2001;7:408-16. |
|11.||Riemersma RA, Wood DA, Macintyre CC, Elton R, Gey KF, Oliver MF. Low plasma vitamin E and C: Increased risk of angina in Scottish men. Ann NY Acad Sci 1989;570:291-5. [PUBMED] |
|12.||Feki M, Souissi M, Mokhtar EH, Sairi M, Kaabachi N, Antebi H, et al. Vitamin E and coronary heart disease in Tunisians. Clin Chem 2000;46:1401-5. |
|13.||Bakalova RA, Hadzhimitova V, Ribarov S. Relationships between serum levels of autoantibodies against oxidized low LDL, lipid soluble antioxidants and apolipoprotein B in patients with coronary heart disease. Gen Physiol Biophys 2000;19:103-13. [PUBMED] |
|14.||Dube A, Khalsa A, Gupta SK, Singh U, Sharma P. Serum tocopherol and lipids in patients with coronary artery disease. Ind Heart J 1998;50:292-4. [PUBMED] |
|15.||Nand N, Budhirajan N, Singh GP, Sharma M, Aggarwal HK. Lipid peroxidation and vitamin E in ischemic heart disease. J Assoc Physician India 1997;45:839-42. |
|16.||Singh RB, Niaz MA, Bishnoi I, Sharma JP, Gupta S, Rastogi SS. Diet, antioxidant vitamins, oxidative stress and risk of coronary artery disease: The Peerzada prospective study. Acta Cardiol 1994;49:453-67. |
|17.||Singhal S, Gupta R, Goyle A. Comparison of antioxidant efficacy of vitamin E, vitamin C, vitamin A and fruits in coronary heart disease: A controlled trial. J Assoc Physician India 2000;49:327-31. |
|18.||Srinivas Rao PV. Antioxidant vitamins to counter atheroclerosis-where do we stand now? In: Current Advances in atherosclerosis research. (Ed) D Rajasekhar, Department of cardiology, SVIMS, Tirupati. 2003;215-24. |
|19.||Parthasarthy S, Khan-Merchant N, Penumetcha M, Khan BV, Santanam N. Did the antioxidant trials fail to validate the oxidation hypothesis? Curr Atheroscler Rep 2001;3:392-8. |
|20.||Freidewald WT, Levy RJ, Fredrickson DS. Estimation of concentration of LDL-C in plasma without use of the preparative ultracentrifuge. Clin Chem 1972;8:499. |
|21.||Catignani GL, Bieri JG. Simultaneous determination of retinal and atocopherol in serum or plasma by liquid chromatography. Clin Chem 1983;29:708-12. [PUBMED] |
|22.||Weinbrenner T, Cladellas M, Isabelcovas M, Fito M, Tonas M, Senti M, et al. Higher oxidative stress in patients with stable coronary heart disease. Athersclorosis 2003;168:99-106. |
|23.||Akkus I, Suglam NI, Caglayan O, Vural H, Kalak S, Saglam M. Investigations of erythrocyte membrane lipid peroxidation and antioxidant defense systems of patients with coronary artery disease documented by angiography. Clin Chim Acta 1996;53:33-9. |
|24.||Kesavulu MM, Rao BK, Giri R, Vijaya J, Subramanyam G, Apparao C. Lipid peroxidation and antioxidant enzyme status in type 2 diabetes with coronary heart disease. Diabetic Res Clin Pract 2001;53:33-9. [PUBMED] [FULLTEXT]|
|25.||Nojiri S, Daida H, Mouno H, Iwama Y, Mae K, Ushino F, et al. Association of serum antioxidant capacity with coronary artery disease in middle aged men. Jpn Heart J 2001;42:677-90. |
|26.||Devraj S, Jialal I. The effect of alpha-tocopherol in atherogenesis. Curr Opin Lipidol 1998;9:11-5. |
|27.||Pryor WA. Vitamin E and heart disease: Basic science to clinical intervention Trials. Free Radic Bio Med 2000;28:141-64. |
|28.||Wei W, Kim Y, Boudreau N. Association of smoking with serum and dietary levels of antioxidants in adults: NHANES III, 1998-1994. Am J Public Health 2001;91:258-64. [PUBMED] [FULLTEXT]|
|29.||Sklodowska M, Wasowicz W, Growmadzinska J, Miroslaw W, Strzeleyk M, Malczyk J, et al. Selenium and vitamin E concentrations in plasma and erythrocytes of angina pectoris patients. Trace Elem Med 1991;8:113-7. |
|30.||Randall A, Swain, Machlis BK, Pharma D. Therapeutic uses of vitamin E in prevention of atherosclerosis. Altern Med Rev 1999;4:414-23. |
|31.||Esterbauer H, Jurgens G, Quehenberger O, Koller E. Autoxidation of human low density lipoproteins: loss of polyunsaturated fatty acids and vitamin E and generation of aldehydes. J Lipid Res 1987;28:495-509. [PUBMED] [FULLTEXT]|