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(Circulation. 1996;94:14-18.)
© 1996 American Heart Association, Inc.

Articles

Vitamin E Deficiency in Variant Angina

Kunihisa Miwa, MD; Yuko Miyagi, MD; Akihiko Igawa, MD; Keiko Nakagawa, MD; Hiroshi Inoue, MD

the 2nd Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama 930-01, Japan.

Correspondence to Kunihisa Miwa, MD, 2nd Department of Internal Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-01, Japan.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Oxidative modification of LDL has been suggested to increase coronary vasoreactivity to agonists. A deficiency of vitamin E, a major antioxidant, may be related to the occurrence of coronary artery spasm.

Methods and Results Vitamin E levels were determined with the use of high-performance liquid chromatography in normolipidemic subjects, including 29 patients with active variant angina (group 1), 13 patients with inactive stage of variant angina without anginal attacks during the past 6 months (group 2), 32 patients with a significant (>75%) organic coronary stenosis and stable effort angina (group 3), and 30 patients without coronary artery disease (group 4). Total lipid levels in blood were calculated as total cholesterol plus triglyceride levels. The plasma -tocopherol levels as well as -tocopherol/lipids were significantly lower in group 1 than in groups 2 through 4. Also, the plasma -tocopherol levels were significantly lower in group 1 than in groups 2 through 4. The vitamin E levels were not significantly different between group 1 patients with and those without a significant organic stenosis. In group 1, both - and -tocopherol levels were significantly elevated after a 6-month angina-free period. The -tocopherol levels in the LDL fraction were significantly lower in group 1 than in group 4. Plasma -tocopherol levels were significantly correlated with those in the LDL fractions. In 6 patients of group 1 still having anginal attacks while receiving calcium channel blockers, the addition of vitamin E acetate (300 mg/d) significantly elevated plasma -tocopherol levels and inhibited the occurrence of angina.

Conclusions Plasma vitamin E levels were significantly lower in patients with active variant angina than in subjects without coronary spasm, suggesting an association between vitamin E deficiency and coronary artery spasm.

Key Words: antioxidants • angina • coronary disease • lipoproteins • vasospasm

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Coronary artery spasm has been established as an important cause of a wide spectrum of ischemic heart disease, although the precise mechanisms by which coronary artery spasm is triggered remain to be elucidated.^{1 2 3 4} Recent, rapidly accumulating evidence suggests that oxidation of LDL plays an important role in the development of atherosclerosis.^{5 6 7 8} Oxidized LDL has been identified in atherosclerotic lesions^{6 7} and may be involved in the pathogenesis of coronary artery spasm or increased coronary vasoreactivity to agonists, as in vitro studies have indicated that the formation of oxidized LDL enhanced agonist-induced coronary vascular contractions and reduced endothelium-dependent vasorelaxations.^{9 10 11 12 13}

Vitamin E is potent and is the most readily available naturally occurring, lipid-soluble antioxidant carried in LDL.¹⁴ It increased the resistance of LDL to oxidation when added to plasma.¹⁵ Vitamin E has other beneficial actions on vascular reactivity, such as antiplatelet properties¹⁶ and inhibition of vascular smooth muscle cell proliferation.¹⁷ When the relation between risk of angina pectoris and plasma concentrations of vitamins A, C, and E and carotene was examined in a population case-control study, vitamin E was found to be independently and inversely related to the risk of angina after adjustment for age, smoking habit, blood pressure, lipids, and relative weight.¹⁸ In the present study, we tested the hypothesis that the plasma concentration of vitamin E may be related to the presence of coronary artery spasm in patients with variant angina by determining the plasma vitamin E levels (- and -tocopherol) in patients with active variant angina compared with control subjects or patients with stable effort angina as well as patients with the inactive stage of variant angina.

	Methods

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We studied 29 patients with active variant angina who had had spontaneous angina with ST-segment elevation at least twice a week before the study (group 1); 13 patients with inactive variant angina who had had no anginal attacks during the preceding 6 months while receiving medical treatment with calcium channel blockers as well as during a 3-day observation period without medication,¹⁹ when Holter monitoring revealed no objective evidence of a myocardial ischemic episode (group 2); 32 patients with stable effort angina pectoris without rest angina who had significant (>75%) organic coronary stenoses (group 3); and 30 patients without coronary artery disease (group 4). These four groups of patients were age and sex matched. Stable effort angina pectoris was defined as chest pain occurring during exercise and lasting <10 minutes in patients with objective evidence of coronary angiographic or ECG changes indicating ischemia during episodes of chest pain. Patients were excluded from the study if their serum cholesterol levels were >240 mg/dL or they were taking any drugs known to interfere with serum lipid levels. Patients receiving any drugs containing vitamin E were also excluded.

Venous blood samples were obtained by venipuncture with the use of Vacutainer tubes after the patients underwent a 12-hour fast. Total cholesterol was measured directly in the serum, and HDL cholesterol (HDL-C) was measured after precipitation of VLDL cholesterol and LDL cholesterol (LDL-C) with dextran sulfate/magnesium chloride according to an enzymatic method. The concentration of triglycerides in serum was determined by measuring glycerol after enzymatic hydrolysis with lipase/esterase. The LDL-C concentration was calculated according to the following formula: total cholesterol minus HDL-C minus (triglycerides/5). An additional blood sample was drawn into Vacutainer tubes containing EDTA. Plasma was immediately separated through centrifugation. Plasma LDL fraction was prepared with the use of sequential ultracentrifugation at preselected densities (1.019 through 1.063) as previously described.²⁰ The protein concentration of LDL was then determined according to the method of Lowry et al²¹ with bovine serum albumin as the standard. Vitamin E (- and -tocopherol) content in plasma and LDL fraction was estimated according to the high-performance liquid chromatography method of Thompson and Hatina²² with vitamin E acetate as the internal standard added before lipid extraction. To better identify the plasma status of vitamin E, the ratio of -tocopherol to lipids (in µmol/g) was determined as the ratio of -tocopherol to total cholesterol plus triglycerides.

Group 1 patients were followed up with medication, including a sufficient dosage of calcium channel blockers (diltiazem [120 to 240 mg/d] and/or nifedipine [40 to 80 mg/d]) to prevent the occurrence of anginal attacks. Blood samples were obtained again in nine of the group 1 patients who had had no angina during the 3-day observation period without medication after a 6-month period without angina.

In six patients of group 1 who still had anginal attacks while receiving calcium channel blockers for 1 to 2 months, vitamin E acetate (300 mg/d) was added to their medication, and the number of anginal attacks was determined before and 2 weeks after the addition of vitamin E acetate.

Statistical Analysis
All data are reported as mean±SEM. Intergroup comparisons concerning serum lipid levels and plasma tocopherol levels were made with a Bonferroni multiple comparisons test after analysis with one-way ANOVA. Student's paired t test was used to compare the tocopherol levels before and after follow-up in the same subject. Wilcoxon's rank sum test was used to compare the frequency of anginal attacks before and after the administration of vitamin E acetate. To compare the smoking prevalence between the groups, ² test was performed, with Yates' correction if one of the frequency tables was smaller than 5. Differences were considered statistically significant at P<.05.

	Results

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Table 1 shows clinical data and plasma lipid profiles in the study groups. Smoking was significantly more prevalent in group 1 than in group 2 (P<.01) or group 4 (P<.05) and significantly (P<.05) more prevalent in group 3 than in group 2. HDL-C levels were significantly lower in group 1 (P<.05) and group 3 (P<.05) than in group 4.

View this table: [in this window] [in a new window]   Table 1. Clinical Data and Lipid Profiles in Study Patients

Plasma -tocopherol, -tocopherol:lipids, and -tocopherol levels in each group are shown in Table 2. Other tocopherols, ß- and -tocopherol, were below the detectable limit or detected in a very low concentration. Plasma -tocopherol levels were significantly lower in group 1 than in group 2 (P<.05), group 3 (P<.01), or group 4 (P<.01). Plasma -tocopherol:lipids levels were also significantly lower in group 1 than in group 2 (P<.05), group 3 (P<.05), or group 4 (P<.01). Also, -tocopherol levels were significantly lower in group 1 than in group 2 (P<.01), group 3 (P<.05), or group 4 (P<.01) (Table 2). The -tocopherol levels were significantly (P<.05) lower in group 3 than in group 4. However, these parameters were not significantly different between group 1 patients with and those without a significant organic coronary stenosis (Table 3). Comparisons were also made between smokers and nonsmokers in groups 1 and 4 (Table 4). Plasma -tocopherol, -tocopherol:lipids, and -tocopherol levels were significantly higher in current nonsmokers than in current smokers of group 4. These differences between smokers and nonsmokers were not significant in group 1. However, among the current nonsmoking patients, plasma -tocopherol, -tocopherol:lipids, and -tocopherol levels were significantly (P<.01 for each) lower in group 1 than in group 4.

View this table: [in this window] [in a new window]   Table 2. Plasma Vitamin E Content

View this table: [in this window] [in a new window]   Table 3. Plasma Vitamin E Level in Patients With Variant Angina With and Without Organic Stenosis

View this table: [in this window] [in a new window]   Table 4. Plasma Vitamin E Level in Smokers and Nonsmokers

Group 1 patients were followed up, and blood samples were obtained in nine of them after a 6-month angina-free period while receiving medication consisting of calcium channel blockers. Plasma -tocopherol (P<.05), -tocopherol:lipids (P<.05), and -tocopherol (P<.01) levels were significantly elevated after follow-up in these patients (Table 5). In six patients of group 1 who had anginal attacks while receiving medication consisting of calcium entry blockers, the additional medication of vitamin E acetate (300 mg/d) for 2 weeks significantly inhibited the occurrence of angina (frequency of attacks/last week, from 1.8±0.3 to 0.3±0.2 times, P<.05). The plasma -tocopherol level was significantly (P<.01) elevated after the administration of vitamin E acetate (from 15.2±2.3 to 33.9±3.2 µmol/L).

View this table: [in this window] [in a new window]   Table 5. Follow-up Data of Plasma Vitamin E Level in Patients With Variant Angina

The - and -tocopherol levels were also determined in LDL fractions. As shown in Table 6, the -tocopherol levels were significantly (P<.05) lower in group 1 than in group 4. However, -tocopherol levels were not significantly different between the groups. The correlation was examined of the -tocopherol level between plasma and LDL fraction and found to be significantly correlated between plasma and LDL fraction (r=.50, P<.01).

View this table: [in this window] [in a new window]   Table 6. Vitamin E Content in LDL Fractions

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Oxygen free radicals seriously damage arteries in animal models as soon as the physiological radical scavengers, such as the vitamins E and C, glutathione, and ubiquinol 10, are exhausted.^{23 24} Vitamin E is the most important endogenous lipid-soluble antioxidant, and the resistance of LDL to oxidation has been shown to be increased by oral intake of vitamin E.¹⁵ Although lipid peroxidation can occur in LDL at a slower rate before the depletion of lipid-soluble antioxidants, rapid and substantial oxidative modification of LDL is achieved only after complete consumption of endogenous -tocopherol.²⁵

Vitamin E Deficiency in Patients WithVariant Angina
In the present study, significantly lower levels of vitamin E (both - and -tocopherol) were demonstrated in plasma of patients with active variant angina compared with subjects without coronary spasm. This was true even after the vitamin E levels were corrected for blood lipid concentrations. In contrast, patients without anginal attacks during the past 6 months had a level of vitamin E comparable with that of the control patients. As the significant correlation of the -tocopherol level between plasma and LDL fraction was confirmed in the present study, a low plasma level of vitamin E indicated vitamin E deficiency in the LDL fraction. Recently, we demonstrated that plasma LDL in patients with active variant angina is vitamin E deficient and highly susceptible to oxidative modification.¹⁹

-Tocopherol Deficiency in Patients With Organic Coronary Artery Disease
Plasma -tocopherol levels are usually 5- to 10-fold higher than -tocopherol levels, despite the fact that most diets are richer in -tocopherol by many fold.²⁶ The biological activity of -tocopherol has been reported to be much higher than that of -tocopherol.²⁷ In addition, the turnover of -tocopherol in tissues is known to be more rapid than that of -tocopherol.²⁴ Although both - and -tocopherol are absorbed to the same extent, -tocopherol is eliminated from the tissues at a much more rapid rate.²⁸ According to a nutrition assay, the biological activity of -tocopherol relative to -tocopherol was 10%.²⁸ In the present study, both plasma - and -tocopherol levels determined with the use of high-performance liquid chromatography were significantly lower in the patients with active variant angina than in the control subjects and the patients with a significant organic coronary artery stenosis but without spasm. Compared with the control subjects, in the patients with organic coronary artery disease, plasma -tocopherol levels were slightly lower but not significantly different, whereas -tocopherol levels were significantly lower. The increased turnover rate of -tocopherol compared with that of -tocopherol may have resulted in the apparent discrepancy of plasma - and -tocopherol levels in these patients. Another explanation may be mobilization of the conversion of -tocopherol to biologically more active tocopherol, -tocopherol, as a possible compensatory mechanism for vitamin E deficiency, as it has been suggested that -tocopherol could be the precursor of -tocopherol in some plant tissues.²⁹ However, the conversion of -tocopherol to -tocopherol has not been confirmed in animals.

Vitamin E and Coronary Spasm
The precise mechanisms for low plasma level of vitamin E in patients with active variant angina and the relation between vitamin E level and coronary artery spasm remain to be elucidated. Low levels of vitamin E may be the result of exhaustion of this antioxidant by increased lipid oxidation stress, such as free radical production induced by frequently repeated alteration between severe transient regional myocardial ischemia and reperfusion. On the other hand, it is also possible that oxidizability of lipids, especially LDL, could be directly related to the pathogenesis of coronary artery spasm. Oxidized LDL has potentially cytotoxic and atherogenic properties.⁵ In addition, oxidized LDL has been shown to cause impairment of endothelium-dependent vasoregulation⁹ and to potentiate agonist-induced vasoconstriction through direct action on vascular smooth muscle.¹⁰ The preservation of endothelium-dependent vessel relaxation by vitamin E has been shown in a rabbit model³⁰ and subsequently confirmed.^{31 32} Although the conversion from native LDL to its oxidized form takes place in the subendothelium, this process may be regulated by the propensity for LDL to undergo lipid oxidation. The reduced content of the antioxidant vitamin E in LDL may promote oxidizability, resulting in the formation of oxidized LDL in the subendothelial space, although LDL or plasma -tocopherol levels do not always correlate with the resistance to oxidation, as reported previously.^{33 34} Plasma vitamin E deficiency as demonstrated in the present study may cause an imbalance between pro-oxidants and antioxidants, and this process may be crucial in predisposing the occurrence of coronary artery spasm.

Vitamin E, other than its antioxidant property, has actions that may be relevant to the vascular reactivity. Vitamin E, or -tocopherol, is an effective in vitro inhibitor of the platelet-release reaction.¹⁶ The sharp rise in lipid peroxide levels normally associated with platelet aggregation has been shown to be markedly reduced by -tocopherol.¹⁶ Therefore, platelet-dependent processes³⁵ such as serotonin release, which may cause exaggerated coronary vasoconstriction, may be inhibited by this vitamin. Vitamin E has also been shown to inhibit smooth muscle cell proliferation¹⁷ and inhibit protein kinase C stimulation,^{17 36} which has been implicated in endothelial dysfunction due to diabetes³⁷ and oxidized LDL.³⁸ Further investigations will be required to clarify the possible relation between vitamin E deficiency and the genesis of coronary artery spasm.

Effects of Smoking on Vitamin E Level
Smoking status significantly influences plasma vitamin E level, as shown in the control patients. As smoking is prevalent in the patients with active variant angina but not in the treated patients with inactive variant angina, this may be one of the causes of the low vitamin E levels in the patients with active variant angina. However, smoking prevalence cannot fully explain the low vitamin E levels in patients with active variant angina because nonsmoking patients had significantly lower levels of vitamin E than did nonsmoking control subjects. Also, plasma - and -tocopherol levels in patients with stable effort angina were significantly higher than in the patients with active variant angina despite the comparably high smoking prevalence.

In our study population, significant differences were seen in HDL-C levels as well as in smoking prevalence between patients with active variant angina and control subjects. As HDL has been shown to exert a protective effect against LDL oxidation and to reverse the oxidized LDL–induced impairment of endothelium-dependent relaxation by removing lysophosphatidylcholine from oxidized LDL and preventing lysophosphatidylcholine from acting on the endothelium,³⁹ it is possible that the HDL-C level may significantly influence the vitamin E level.

Clinical Implications
In the present study, vitamin E supplementation to calcium channel blocker therapy raised plasma vitamin E levels and appeared to be effective in the prevention of anginal attacks in a small number of the patients with variant angina in whom conventional therapy with calcium channel blockers failed to completely inhibit angina. Antioxidant therapy with vitamin E supplementation can be effective treatment for coronary spasm in patients with variant angina. However, further studies with a larger population of patients are needed to clarify the possible beneficial effects of vitamin E supplementation on coronary spasm.

In conclusion, a low plasma level of antioxidant vitamin E was demonstrated in patients with active variant angina but not in patients with the inactive stage of variant angina, suggesting that the plasma status of vitamin E is linked to the activity of coronary artery spasm.

	Acknowledgments

 
This study was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science and Culture of Japan. We are greatly indebted to Eisai Co, Ltd, Japan, for technical guidance in the assay of vitamin E.

Received October 11, 1995; revision received January 3, 1996; accepted January 4, 1996.

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