Antioxidants, Oxidative Stress, and Cardiovascular Diseases

136 Pages·2008·0.79 MB·English

Antioxidants, Oxidative Stress, and
Cardiovascular Diseases

Cross-Cultural Comparisons and
Prospective Cohort Studies

Brian Buijsse
Promotoren: Prof. dr. ir. D .Kromhout
Hoogleraar Volksgezondheidsonderzoek
Wageningen Universiteit

Prof. dr. ir. F.J. Kok
Hoogleraar Voeding en Gezondheid
Wageningen Universiteit

Co-promotor: Prof. dr. ir. E.J.M. Feskens
Persoonlijk hoogleraar bij de afdeling Humane Voeding
Wageningen Universiteit

Promotiecommissie: Prof. dr. F.X.R. van Leeuwen
Wageningen Universiteit, Wageningen

Dr. ir. P.C.H. Hollman
Instituut voor Voedselveiligheid RIKILT, Wageningen

Prof. dr. A. Bast
Universiteit Maastricht, Maastricht

Prof. dr. H. Boeing
German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke,
Germany

Het onderzoek beschreven in dit proefschrift is uitgevoerd binnen de onderzoeksschool VLAG.
Antioxidants, Oxidative Stress, and
Cardiovascular Diseases

Cross-Cultural Comparisons and
Prospective Cohort Studies

Ir. G.M. Buysse

Proefschrift
Ter verkrijging van de graad van doctor
op gezag van de rector magnificus
van Wageningen Universiteit,
Prof. dr. M.J. Kropff,
in het openbaar te verdedigen
op woensdag 11 juni 2008
des namiddags te half twee in de Aula
Brian Buijsse

Antioxidants, Oxidative Stress, and Cardiovascular Diseases; Cross-Cultural Comparisons and
Prospective Cohort Studies

Thesis Wageningen University, Wageningen, The Netherlands, 2008
With abstract – with references – with summaries in English and Dutch

ISBN: 978-90-8504-960-9
Abstract
Abstract
Background: Antioxidants in plant foods have been proposed to reduce the risk of cardiovascular
diseases (CVD) by reducing oxidative stress. The objective was to confirm prospective studies on
CVD and traditional antioxidants (beta-carotene, alpha-tocopherol), and to investigate emerging
antioxidants (alpha-carotene, gamma-tocopherol, cocoa flavanols), and oxidative stress (enzyme
activity of glutathione peroxidase-3) with CVD risk.
Methods: In cross-cultural studies, the Cretan (Greece) and Zutphen (The Netherlands) cohorts of
Seven Countries Study were compared with respect to long-term mortality of coronary heart disease
(CHD), diet, and indicators of oxidative stress. In prospective cohort studies, data were used from
the Zutphen Elderly Study (~500 men aged 65-84 y), the ‘Survey in Europe on Nutrition and the
Elderly: a Concerted Action’ (SENECA, 1168 men and women aged 70-75 y), and the Minnesota
Heart Survey (270 men and women aged 26-85 y).
Results: The comparison between the Cretan and Zutphen cohorts revealed a 3-fold lower 40-year
CHD mortality rate in Crete. This lower mortality in Crete was paralleled by a higher consumption
of fruit, tomatoes, and olive oil, amongst others, and by a lower consumption of meat, poultry, and
dairy. Consequently, the Cretan men had higher intakes of carotenoids, alpha-tocopherol, vitamin C,
and dietary fiber, and lower intakes of trans and saturated fatty acids. This was confirmed at the age
of ≥80 years, when the Cretan men had higher plasma concentrations of major dietary antioxidants
(major carotenoids and alpha-tocopherol), a lower iron status, and a lower level of oxidative stress.
In the Zutphen Elderly Study, the relative risk (RR) of 15-y CVD mortality for 1 standard deviation
(SD) increase in dietary intake was 0.81 [95% confidence interval (CI): 0.66-0.99] for alpha-
carotene and 0.80 (95% CI: 0.66-0.97) for beta-carotene. The intake of tocopherols was not related
to CVD death. In SENECA, plasma concentrations of carotene (sum of alpha- and beta-carotene)
were inversely related to CVD mortality (RR for 1 SD increase: 0.83; 95% CI: 0.70-1.00), but
plasma concentrations of alpha-tocopherol were not. The daily use of 4 grams of cocoa, a rich source
of flavanols, was related to a 3.7 mm Hg lower systolic (95% CI: –7.1 to –0.3) and a 2.1 mm Hg
lower (95% CI: –4.0 to –0.2) diastolic blood pressure. The same amount of cocoa was also related to
a 50% lower risk of 15-year CVD mortality (RR: 0.50; 95% CI: 0.32-0.78). Finally, in the
Minnesota Heart Survey, the odds ratio of CVD mortality for the highest vs. the lowest quartile of
glutathione peroxidase-3 activity was 0.42 (95% CI: 0.21-0.86). This inverse relation was confined
to those with low concentrations of HDL cholesterol (odds ratio highest vs. lowest quartile: 0.17;
95% CI: 0.06-0.47).
Conclusion: The Cretan Mediterranean diet is rich in antioxidants, which may partly contribute to
the low observed CHD mortality. The findings on beta-carotene support previous observational
studies suggesting that this carotenoid relates to a lower CVD risk. We showed that alpha-carotene is
correlated with beta-carotene in the diet, and alpha-carotene was also related to a lower CVD
mortality. The results on alpha-tocopherol are in line with the outcomes of clinical trials and do not
indicate a role for this vitamin in lowering CVD mortality in elderly populations.
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Contents
Contents
Introduction
1. Plant foods, antioxidants, and cardiovascular diseases 9
Cross-cultural studies
2. Oxidative stress, and iron and antioxidant status in elderly men: differences between
the Mediterranean south (Crete) and northern Europe (Zutphen) (Eur J Cardiovasc
Prev Rehabil. 2007;14:495-500) 21
3. Diet, biomarkers, major risk factors, and 40-year coronary mortality in the Cretan and
Zutphen cohort of the Seven Countries Study (Submitted for publication) 33
Prospective cohort studies
4. Both alpha- and beta-carotene, but not tocopherols and vitamin C, are inversely related
to 15-year cardiovascular mortality in Dutch elderly men (J Nutr. 2008;138:344-350) 49
5. Plasma carotene and alpha-tocopherol in relation to 10-y all-cause and cause-specific
mortality in European elderly: the Survey in Europe on Nutrition and the Elderly, a
Concerted Action (SENECA) (Am J Clin Nutr. 2005;82:879-886) 63
6. Cocoa intake, blood pressure, and cardiovascular mortality: the Zutphen Elderly Study
(Arch Intern Med. 2006;166:411-417) 77
7. Serum glutathione peroxidase 3 activity in relation to cardiovascular mortality: the
Minnesota Heart Survey (Submitted for publication) 91
General discussion
8. The antioxidant paradox, oxidative stress, and cardiovascular diseases 103
Summary 117
Samenvatting 121
Dankwoord – Acknowledgement – Danksagung 125
About the author 129
Publications 131
Educational programme 133

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Plant foods, antioxidants, and cardiovascular diseases

Plant Foods, Antioxidants, and
Cardiovascular Diseases

Plant foods, in particular fruit and vegetables, are known to contain large amounts of
antioxidants. In the early 1980s, antioxidants became promising compounds in preventing or, at
least, lowering the risk of cardiovascular diseases. Vitamin E, beta-carotene, and to a lesser
extent vitamin C were extensively studied. Later, other carotenoids than beta-carotene and also
polyphenolic antioxidants became a topic of scientific interest. This thesis comprises cross-
cultural and prospective cohort studies on plant foods, antioxidants, and oxidative stress in
relation to cardiovascular diseases. This introductory chapter describes what kinds of
antioxidants are found in plant foods, how they are proposed to protect against cardiovascular
diseases, the results of observational and intervention studies on antioxidants, and, finally, the
rationale for the research in this thesis.
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Plant foods, antioxidants, and cardiovascular diseases
Plant foods and antioxidants
Plant foods, such as fruit and vegetables, whole grains, nuts and seeds, and olive oil as the
principle source of fat, form key components of traditional Mediterranean diets. Diets rich in
plant foods may prevent a variety of chronic diseases, including cardiovascular diseases (CVD)
(1,2). Compounds that are considered to contribute to the cardiovascular beneficial effects of
plant foods include dietary fiber, unsaturated fatty acids, folate, potassium, and also
antioxidants.
Antioxidants are widely distributed in plant foods, in particular fruit and vegetables.
Well-known antioxidants are vitamin C, vitamin E, carotenoids including beta-carotene, and
polyphenols such as flavonoids. Their functions in plants are inherent to their immobility. Plants
frequently have to cope with stressful environmental changes, such as drought, extreme
temperatures, high levels of sunlight (radiation), and attacks by insects and pathogens (3). By
synthesizing an impressive array of antioxidants, plants are able to protect themselves from
these environmental threats. In general, antioxidants tend to concentrate in those parts of the
plant that are most prone for oxidative damage (4). Vitamin C, for example, is in fairly high
concentrations present in chloroplasts to protect the plant from reactive oxygen species that are
developed during photosynthesis (4,5). Vitamin E is thought to protect plants against excess
exposure to sunlight (6). Apart from absorbing light and transferring its energy to chlorophyll,
carotenoids also protect plant tissues from photo-oxidative damage by losing excess of thermal
energy and scavenging harmful oxygen species like triplet chlorophyll and singlet oxygen (6).
Finally, phenolics, to which the flavonoids belong, possess antibacterial and antiviral effects (7).
By consuming plant foods, humans ingest antioxidants. The amount of antioxidants in
the diet depends on the consumed amount and the antioxidant content of the particular plant
foods. A typical diet of adults in The Netherlands provides daily roughly 80 mg of vitamin C, 13
mg of vitamin E, and about 1.3 mg of beta-carotene (8,9). There is no precise estimate of the
average intake of flavonoids in The Netherlands, but it is likely to be about 180 mg per day
(reference 10 and personal communication M. Bekkers).
It is thought that a mild to moderate deficiency of certain antioxidants, although in the
case of the vitamins not severely enough to cause classical deficiency diseases, may increase the
risk of developing CVD (11). Therefore, high intakes of antioxidants may reduce CVD risk in
humans. The mode of action is proposed to be similar as in plants: by preventing oxidative
damage. More specifically, antioxidants are hypothesized to inhibit the main underlying process
that leads to CVD, atherosclerosis.
The oxidative modification hypothesis and its implications
Atherosclerosis is a chronic inflammatory disease of the arterial wall in which lipid
accumulation is accompanied by thickening and hardening of the vessel wall (12). One of the
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