Fast Track — ArticlesDietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial
Introduction
The protective effects of foods rich in n-3 polyunsaturated fatty acids (PUFA) derived from marine vertebrates, vitamin E (α-tocopherol), and their pharmacological equivalents on cardiovascular risk has been of interest for the past 20 years.1, 2, 3, 4 Since a low rate of coronary heart disease was reported in the Eskimo population exposed to a diet rich in fish oil,5 several studies have explored and supported antiatherogenic, antithrombotic, and antiarrhythmic effects of n-3 PUFA.2, 3, 4 Although no consensus existed on the underlying mechanism of action, focus was placed on the ability of triglycerides to lower high-dose n-3 PUFA (registration approval was given for this indication), and to modify membrane composition.2, 3, 4 A protective role in the secondary prevention of coronary heart disease was seen for fatty fish in the Diet And Reinfarction Trial (DART).6
By contrast, large observational cohort studies7, 8, 9, 10 support the role of vitamin E as an antioxidant against the proatherogenic and prothrombotic effects of LDL oxidation.11, 12, 13 However, controlled trials testing this hypothesis in populations with different background cardiovascular risk produced controversial results. No decrease in cardiovascular events was seen with low-dose (50 mg daily) vitamin E supplementation in smokers;14 a significant decrease in non-fatal myocardial infarction and an increase in fatal cardiovascular events was reported with a daily regimen of 400–800 mg vitamin E in patients with angiographically proven coronary atherosclerosis.15
A possible complementary role for these two dietary components has been purported: vitamin E could improve the role of n-3 PUFA through protection from lipid peroxidation, by acting independently on the same or closely related atherogenic and thrombotic mechanisms, or both.4, 16
We investigated in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI)-Prevenzione trial the independent and combined effects of n-3 PUFA and vitamin E on morbidity and mortality after myocardial infarction.17
Section snippets
Patients
We enrolled patients with recent (≤3 months) myocardial infarction. Eligible patients had no contraindications to the dietary supplements (ie, known allergy to n-3 PUFA or α-tocopherol, or known congenital defects of coagulation), were able to provide informed written consent, and had no unfavourable short-term outlook (eg, overt congestive heart failure, cancers, &c). We did not define age limits.
Study design
We used a multicentre, open-label design, in which patients were randomly allocated to four
Results
Between October, 1993, and September, 1995, 11 324 patients were recruited (figure 1) by 172 participating centres (130 cardiological departments and 42 rehabilitation centres) across Italy. Information on vital status at the end of the study was 99·9% complete for a total person-time of 38 053 years. Median time from the index myocardial infarction to randomisation was 16 days. Baseline demographic and clinical characteristics were well balanced across the groups (table 1) and define a
Discussion
Treatment with n-3 PUFA significantly decreased, over 3·5 years, the rate of death, non-fatal myocardial infarction, and stroke. No effect was seen for vitamin E. When data were analysed by four-way analysis, the size of the beneficial effect of n-3 PUFA became more evident and more clearly significant; the absence of a significant effect was confirmed for vitamin E.
The degree of the effects on rates of death deserves to be specifically highlighted and is suggestive of hypotheses that could
References (60)
Omega-3 fatty acids in health and disease and growth and development
Am J Clin Nutr
(1991)- et al.
Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART)
Lancet
(1989) - et al.
Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS)
Lancet
(1996) - et al.
Effect of long-term fish oil supplementation on vitamin E status and lipid peroxidation in women
J Nutr
(1991) - et al.
A computerized network system for the management of a large-scale multicentre clinical trial: the GISSI-3 trial
Control Clin Trials
(1993) - et al.
GISSI-2 mortality plus extensive left ventricular damage as “end-points”
Lancet
(1990) Relative effects of dietary saturated, monounsaturated, and polyunsaturated fatty acids on cardiac arrhythmias in rats
Am J Clin Nutr
(1993)- et al.
Dietary lipid modulation of ventricular fibrillation threshold in the marmoset monkey
Am Heart J
(1992) - et al.
Effects of dietary fish oil on ventricular premature complexes
Am J Cardiol
(1995) - et al.
N-3 fatty acids and ventricular extra systoles in patients with ventricular tachyarrhythmias
Nutr Res
(1995)
Fish consumption, ω-3 fatty acids in cell membranes, and heart rate variability in survivors of myocardial infarction with left ventricular dysfunction
Am J Cardiol
Prevention and termination of the β-adrenergic agonist-induced arrhythmias by free polyunsaturated fatty acids in neonatal rat cardiac myocytes
Biochem Biophys Res Commun
Mortality in the CHAOS trial
Lancet
Mortality in the CHAOS trial
Lancet
Randomised trial of alphatocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infraction
Lancet
Blood pressure, stroke, and coronary heart disease, part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias
Lancet
Blood pressure, stroke, and coronary heart disease, part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context
Lancet
Vitamin E and human health: rationale for determining recommended intake levels
Nutrition
A randomized, single-blind, placebo-controlled trial of the effects of 200 mg α-tocopherol on the oxidation resistance of atherogenic lipoproteins
Am J Clin Nutr
Vitamin E supplementation in elderly lowers the oxidation rate of linoleic acid in LDL
Atherosclerosis
What accounts for the association of vegetables and fruit with lower incidence of cancers and coronary heart disease?
Ann Epidemiol
The antioxidant vitamins and cardiovascular disease: a critical review of epidemiological and clinical trial data
Ann Intern Med
ω-3 fatty acids in the prevention-management of cardiovascular disease
Can J Physiol Pharmacol
Per i Ricercatori GISSI-Prevenzione. Il quadro di riferimento biochimico, farmacologico, epidemiologico del GISSI-Prevenzione
G Ital Cardiol
The composition of food consumed by Greenland Eskimos
Acta Med Scand
Vitamin E consumption and the risk of coronary heart disease in men
N Engl J Med
Vitamin E consumption and the risk of coronary disease in women
N Engl J Med
Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women
N Engl J Med
Antioxidants in the prevention of human atherosclerosis
Circulation
Cited by (3815)
Effects of ocean warming on the fatty acid and epigenetic profile of Acartia tonsa: A multigenerational approach
2024, Marine Pollution BulletinA review on machine learning approaches for microalgae cultivation systems
2024, Computers in Biology and MedicineEffect of omega-3 fatty acids supplementation on the prognosis of coronary artery disease: A meta-analysis of randomized controlled trials
2024, Nutrition, Metabolism and Cardiovascular DiseasesAssociation of seafood consumption with cardiovascular disease among adults in Qingdao, China
2024, Nutrition, Metabolism and Cardiovascular DiseasesA historical, evidence-based, and narrative review on commonly used dietary supplements in lipid-lowering
2024, Journal of Lipid ResearchEffects of vitamin D, omega-3 and a simple strength exercise programme in cardiovascular disease prevention: The DO-HEALTH randomized controlled trial
2024, Journal of Nutrition, Health and Aging
Investigators listed at end of paper