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Address correspondence to Graziano Riccioni, M.D., PhD., Via G. De Rogatis 12, CP 188, San Severo (FG) 71016, Italy; tel 39 333 636 6661; fax 39 088 222 7022; e-mail griccioni{at}hotmail.com.
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Keywords: vitamins A, C, E, acute coronary syndrome, acute myocardial infarction, angina pectoris, cardiac ischemia, antioxidant dietary supplements
Observational studies have demonstrated that acute coronary syndromes (ACS), in particular unstable angina (UA) and acute myocardial infarction (AMI), share a common anatomical foundation. These various clinical manifestations derive from a basic pathophysiologic mechanism that consists of the erosion or breach of an atherosclerotic plaque; moreover, many thrombotic phenomena are associated with this event [1–3]. ACS are the consequence of acute or sub-acute primary oxygen deficit to the myocardium, which can result from erosion of a atherosclerotic plaque, inflammatory phenomena, thrombosis, vasoconstriction, or micro-embolization. The Euro Heart Study, conducted from September 2000 to May 2001 in 103 medical centers in 25 European countries, reported 12% mortality within 6 mo for patients with ACS who did not show an elevation of the ST segment [4]. This study suggested that long-term results might be improved in selected patients by a clinical strategy that includes careful stratification of the risks, administration of innovative drugs, and revascularization procedures.
The principal cardiovascular diseases (CVD) include cardiac ischemic disease (CHD) with its clinical manifestations (AMI, angina pectoris, and sudden death), cerebrovascular diseases (stroke and transitory ischemic attack), and peripheral vasculopathies. Intensive efforts of researchers during the past 50 years have been concentrated on CHD, which represents 30–50% of the total prevalence of CVD [5]. In the last 30 years, mortality from CHD has been reduced by 50% [10,11], although CHD remains the main cause of unexpected death in the United States (approximately 500,000 deaths/yr) and Europe (approximately 400,000 deaths/yr). Mortality associated with CHD is attributed to AMI (60%), chronic coronary insufficiency (22%), and unexpected death (18%). A meta-analysis of world-wide mortality showed that the main causes were cerebrovascular disease, respiratory infections, neonatal diarrhea, chronic obstructive pulmonary disease, tuberculosis, varicella, accidents, and respiratory tract tumors [6].
People at risk for primary and secondary CVD appear less likely to use dietary supplements, despite the possible benefits shown in clinical trials [7]. Therefore, guidelines are needed for the general public and health professionals regarding the uncontrolled use of dietary supplements [7]. The current evidence does not support indiscriminate use of vitamins A, C, E, or ß-carotene to prevent or reduce CVD. In fact, some studies of oral antioxidant supplementation have noted harmful effect in some people [8–10]. The aim of this paper is to review published works with results that support, confirm, or contradict the postulated protective role of antioxidant vitamins in CVD.
Nutrition and atherosclerosis. Proper nutrition could be considered as non-pharmacological prevention and therapy of ischemic disease. Nutrition is important in both primary and secondary prevention, as many cardiovascular, hepatic, and renal diseases are secondary to qualitatively and quantitatively inappropriate diet and life-style [11]. Dietary practices influence the pathogenesis of atherosclerotic plaques through direct influence on the determinants of atherosclerotic processes, such as plasma lipid accumulation (triglycerides, HDL- and LDL-cholesterol, phospholipids), structural integrity of circulating lipids (oxidized-LDL), levels of plasma antioxidants, production of free radicals, homocysteinemia, hyperglycemia, blood pressure, platelet aggregation, and lipid peroxidation [8,9].
Antioxidant vitamins. Numerous in-vivo and in-vitro studies indicate that the atherosclerotic processes (including endothelial damage and proliferation, and the production of foam cells) depend in part on the peroxidative state of LDL. Antioxidant vitamins are one of the main defense mechanisms of the body’s non-enzymatic anti-oxidant systems. Ascorbic acid (vitamin C), alpha-tocopherol (the principal constitutent of vitamin E), and beta-carotene (pro-vitamin A) are the most studied natural antioxidants. Large-scale clinical trials have been conducted to determine whether vitamin supplements with antioxidant action decrease the risk of cardiovascular diseases. Some experimental and epidemiological studies seem to indicate beneficial effects of antioxidant vitamin supplementation on the development and progression of atherosclerotic plaques, resulting in reduction of cardiovascular events. However, a recently published study with well-defined primary and secondary prevention endpoints does not support this hypothesis [12].
Vitamin A. Vitamin A, the first fat-soluble vitamin to be identified, has 3 active forms: retinol, retinal, and retinoic acid; collectively called retinoids. The most important of these is beta-carotene, which has a high antioxidant effect [13,14]. The carotenoids have an important antioxidant role in quenching free radical reactions, particularly those involving singlet oxygen. This prevents damaging chain reactions that cause lipid peroxidation and damage to DNA, both of which are postulated precursors of atherosclerotic processes [15,16]. Vitamin A and carotenoids may have effects in various human diseases such as diarrhea, acute respiratory infections, ischemic heart disease, immunological disorders, and bronchial asthma [17]. Many trials have considered the effects of vitamin A dietary supplements on cardiovascular events and have yielded contradictory results. The Nurses Health Study (NHS), an epidemiological study conducted in the USA on 34,486 women, evaluated through a questionnaire the effect of the addition of vitamin A to regular diets. No association was seen between dietary supplements of vitamin A and the risk for coronary disease [18].
Several randomized controlled studies reported similar results. In the Physicians Health Study (PHS), a randomized, prospective, double-blind, placebo-controlled study of 22,071 physicians, the oral supplementation of beta-carotene (50 mg on alternating days; 12 yr follow-up), did not show a significant difference between the treated and control groups in respect to cardiovascular mortality [19]. In another study, 5 major carotenoids (alpha- and beta-carotene, beta-cryptoxanthin, lutein, and lycopene) did not show protective effects against AMI [20]. The Beta Carotene and Retinol Efficacy Trial (CARET), a prospective, randomized, placebo-controlled 4-yr study of 18,314 smokers, was interrupted at 21 mo before its planned termination because patients treated with a combination of beta-carotene and vitamin A showed increased relative risk for lung cancer and cardiovascular mortality [21]. The Alpha Tocopherol Beta Carotene Cancer Prevention (ATBC) study, which evaluated beta-carotene (20 mg/day) supplementation in 1,862 male smokers with a previous MI, did not show any significant effect on cardiac-related mortality [22].
Vitamin C. Vitamin C, an important water-soluble substance, has 2 biologically active forms: ascorbic acid and dehydroascorbic acid. Dietary vitamin C is mostly supplied by fruits and vegetables. Its biological role is related to its reducing capability; ascorbate is readily oxidized to dehydroascorbate. Vitamin C acts as a hydrogen donor to reverse oxidation and hence is termed an antioxidant, which can inactivate free radicals before they damage proteins or lipids [16]. The First National Health and Nutrition Examination Survey (NHANES) epidemiological follow-up study in 11,348 subjects, age 25 – 74 yr, reported that individuals who received a high dose of vitamin C (>50 mg/day) had lower overall total mortality rate after 10 yr, and in particular lower mortality from cardiovascular disease [23]. The Health Professionals Follow-up Study reported that a relationship between vitamin C intake and major coronary events did not exist, although subjects whose vitamin C intake exceeded 50 mg/day had a lower rate of death from all cardiovascular diseases [24]. Vitamin C’s antioxidant action, which is more effective than that of vitamin E or beta-carotene, was considered as a possible mechanism of vascular protection.
Joshipura et al [25] conducted a prospective cohort study in a population of 54,251 women and 42,148 men who were followed for 8 yr and were free of cardiovascular disease, cancer, and diabetes. The authors found that the consumption of fruits and vegetables, particularly green leafy vegetables and vitamin C-rich fruits and vegetables, appeared to have a protective effect against coronary heart disease (ie, nonfatal AMI or fatal coronary heart disease). However, subsequent reviews and meta-analyses of the relationship between antioxidants and atherosclerotic cardiac disease did not confirm these findings. An analysis of 2 studies, the Nurses Health Study (NHS) and Health Professional’s Follow-up Study, showed unclear reduction of prevalence and mortality from cardiovascular disease [26]. Increased production of free radicals derived from exposures to tobacco smoke, radiation, stress, insufficient physical activity, hypocaloric diets, drugs, and toxic substances evidently increases the need for vitamin C intake [27,28].
Two studies provide evidence contrary to the protective effects of vitamin C. Kushi et al [18] in the NHS epidemiogical study found no relationship between vitamin C intake and major coronary events. Kinlays et al [29] conducted a double-blind, randomized, placebo-controlled trial of vitamin C (1 g/day) supplement for 6 mo in 30 subjects with coronary artery disease. They found that such long-term oral vitamin C supplements did not improve key mechanisms of atherosclerosis or endothelial dysfunction, nor reduce LDL oxidation in vivo.
Vitamin E. Vitamin E is an important antioxidant vitamin, playing an essential protective role against free radical damage [30,31]. Vitamin E comprises a group of substances belonging to 2 closely related families: tocopherols and tocotrienols, each existing in a number of isomeric forms: alpha, beta, gamma, and delta. The form that accounts for 90% of the vitamin activity in tissues is alpha-tocopherol [32,33]. The chemical structure of tocopherols and tocotrienols (which have an -OH group on the ring structure) makes them effective hydrogen donors. In donating hydrogen, vitamin E becomes oxidized, preventing the oxidation of metabolically more important substances, for example polyunsaturated fatty acids (PUFA) in cell membranes. This is important when free radicals are present, as these highly reactive substances can attack double bonds, initiating chain reactions that generate more free radicals. When fatty acids are damaged, lipid peroxides are produced that can alter the function of the cell membrane and cause irreversible damage to metabolic pathways [34–37].
The nutritional requirement for vitamin E (10 mg/day) varies with the dietary intake of PUFA. Vitamin E is the most fat-soluble vitamin and is the major vitamin component in cell membranes and circulating lipoproteins. For this reason, vitamin E is the main antagonist of lipid peroxidation. Its protection of membranes is important for proper functioning of the vascular endothelial barrier, for reduction of proliferation stimuli for myocytes of the tunica media, and for decrease in chemotactic factors for monocytes [38]. The protective role of vitamin E for the endothelium is supported by a stimulatory action on the synthesis of PGI2, a vasodilator and platelet anti-aggregating agent [39]. Due to its fat solubility, vitamin E persists in membrane lipoproteins for long periods and, therefore, its dietary supplementation may not require daily dosing [40].
The Physicians Health Study (PHS) reported a prospective nested case-control study of 531 male physicians diagnosed with AMI, without prior history of cardiovascular disease, paired with control subjects and matched for age, smoking habit, and plasma levels of alpha- and gamma-tocopherol [20]. The results indicated that the men with higher plasma levels of gamma-tocopherol tended to have increased risk of AMI. In the Nurses Health Study (NHS), Kushi et al [18] found that vitamin E supplements of 100–250 UI/day reduced by 35 – 40% the incidence of major coronary events (nonfatal myocardial infarction and death from cardiac causes) among subjects in the highest quintile of vitamin E intake, over a follow-up period of 4 – 8 yr, compared to those in the lowest quintile. The benefit was greatest in subjects taking 100 to 250 UI of supplemental vitamin E per day, with little further benefit at higher doses [18].
In the Cambridge Heart Antioxidant Study (CHAOS), a randomized. controlled study of 2,002 patients with coronary artery disease (CAD), vitamin E supplements (400–800 UI/day) reduced the incidence of death from cardiovascular diseases and AMI [38]. In the Alpha–Tocopherol Beta Carotene Cancer Prevention (ATBC) trial, the group of patients treated with alpha-tocopherol supplement (50 mg/day) showed a lower number of non-fatal AMI, but no reduction of the primary study end-points (that is, cardiovascular death and AMI) [22]. In the Secondary Prevention using Antioxidants of Cardiovascular Disease in End-stage renal disease (SPACE) trial, 196 patients with pre-existing cardiovascular disease and undergoing chronic haemodialysis were enrolled in a double-blind randomized controlled study (97 patients received vitamin E supplement (800 UI/day) and 99 patients received a placebo) [41]. There was significant reduction of the primary end-points (fatal and non-fatal AMI, ischemic stroke, peripheral vascular disease, and unstable angina (UA) in subjects receiving the high dose vitamin E supplement [41].
The Prevention Study of the Italian Group for the Study of Survival in Myocardial Infarction (GISSI) reported that vitamin E supplements (300 mg/day) were associated with a non-significant reduction of total mortality (relative risk 0.86; p = 0.081) [42]. The Heart Outcomes Prevention Evaluation Study (HOPE) did not demonstrate the benefits reported by SPACE in the use of vitamin E at a dose of 400 UI/day [43].
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A discrepancy exists between the results derived from observational studies and randomized trials with vitamin supplements. In observational studies with coronary end-points, subjects with elevated plasma levels of antioxidants were protected from clinical complications of coronary disease (AMI and angina), whereas subjects treated with antioxidants in the interventional studies did not show protection against coronary disease [44].
In studies with vitamin A supplements, there is no evidence for a protective effect against AMI. In a study of beta-carotene, a higher incidence of coronary events was observed in the group that received supplements compared to a control group. The mechanisms whereby fruits and vegetables protect against CVD are likely to be multiple. The postulated beneficial components of fruits and vegetables include antioxidant vitamins, particularly vitamin C, folate, fiber, minerals, and potassium. These dietary constituents can significantly increase the antioxidant capacity of serum and protect against in vivo lipoperoxidation.
Several large-scale, double-blind, placebo-controlled trials have clearly shown that vitamin E, alone or in combination with other antioxidant vitamins, reduces the risk of fatal or nonfatal AMI in populations with CHD. Two end-point trials of vitamin E, though with much smaller patient populations, reported positive results (the SPACE and CHAOS studies).
Descriptive, case-control, and prospective cohort studies have shown inverse associations between the frequency of CAD and dietary intake of antioxidant vitamins. In contrast, randomized therapeutic trials have thus far shown a lack of benefit with beta-carotene and a possible benefit with vitamin E.
As oxidative stress is involved in the pathogenesis of atherosclerosis, during the past few years a variety of substances with antioxidant actions have been evaluated in clinical studies for primary and secondary prevention of CVD. The initial promising reports on beneficial effects with antioxidant therapies against atherosclerosis, derived from observational studies, were followed by generally negative results reported from large randomized controlled trials. For this reason, at the moment, treatment with antioxidant vitamins (A, C, and E) is not recommended for the prevention or treatment of CAD. Thus, the United States Preventive Services Task Force (USPSTF) concluded that the evidence currently available is insufficient to recommend the routine use of these supplements [45].
Although scientific rationale and observational studies are convincing, randomised primary and secondary intervention trials have failed to show any consistent benefit from the use of antioxidant supplements on CVD, and some trials suggested possible harmful effects in certain subgroups of patients.
Trials that investigate the effect of a balanced combination of antioxidants at levels achievable by diet are clearly needed [46]. New strategies are needed to clarify the exact role that antioxidants may have on the prevention of atherosclerosis [47]. There is evidence that angiotensin converting enzyme (ACE) inhibitors and angiotensin II type I (AT1) receptor blockers may have beneficial effects on oxidative stress, in addition to their antihypertensive properties. Statins, in addition to improving lipid profiles, may also lower oxidative stress [47,48]. Future antioxidant therapies need to be more specific in targeting the site of action, be devoid of deleterious effects on other signalling pathways, and be targeted to a specific reactive oxygen species (ROS) or cellular compartment [49–51].
Factors responsible for the disappointing and discrepant results from observational and clinical studies on the relationship between antioxidant vitamins and CVD may include differences in the patients’ gender, age, body weight, duration of treatment, vitamin supplement dosages. and dietary habits. It may be important to re-evaluate the selection of foods rich in antioxidant compounds rather than the selection of supplements of these substances [52–54].
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–tocopherol and ß-carotene supplements on incidence of major coronary events in men with previous MI. Lancet 1997;349:1715–1720.[Medline]
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