The role of dietary phenolic compounds in cardiovascular diseases

High intake of vegetables decreases the risk of chronic diseases such as cardiovascular diseases (CVD) and cancer. It has been suggested that the protection is partly mediated by dietary antioxidants such as ß-carotene, vitamin C and E. In addition to these, flavonoids and other phenolic compounds are also potential protective antioxidants. Phenolic compounds are widely distributed in vegetables, fruits and beverages such as coffee, tea, beer and wine and are consumed daily by most people. Currently more than 4000 flavonoids and total amount of 8000 phenolic compounds have been identified. The estimated daily intake varies from few milligrams to as high as grams.

Mechanisms Antioxidant compounds may protect from CVD in several mechanisms, but antioxidant theory is the most commonly stated. According to the current knowledge, oxidative modification of low-density lipoproteins (LDL) plays an important role in atherogenesis. It has been suggested that antioxidative agents which would prevent oxidation of LDL in the arterial wall could also attenuate the development of atherosclerosis. Among the most potent diet-derived antioxidants are polyphenolic compounds such as flavonoids and other phenolic compounds. The role of phenolic compounds in CVD has been studied using different in vitro, animal, human and epidemiological studies.

The results of in vitro and animal studies concerning the antioxidant effects of polyphenolic compounds are promising. Several flavonoids and other phenolic compounds have shown to possess high antioxidant capacity in vitro. Additionally, evidence from animal studies suggests that ingestion of flavonoids inhibits lipid peroxidation and may retard the progression of atherosclerosis. However, in humans controlled long-term flavonoid supplementation studies have resulted in inconsistent findings on the oxidation resistance of LDL.

The use of different methods in assessing the oxidizability of LDL ex vivo could partly explain the inconsistency of the results. New, 'state of the art' in vivo methodology, such as F2-isoprostanes, has been seldom used in flavonoid studies, even though that is one of the most advanced tools to measure lipid peroxidation. One possibility also is that people with increased oxidative stress, such as smokers, patients with diabetes or CVD would respond differently to antioxidative compounds and that theory should be tested in the future studies. It is also possible that the protective effect of flavonoids is mediated partly by other mechanism than decreased lipid peroxidation. The effects of phenolic compounds on haemostatic factors and the function of endothelial cells should be studied.

Epidemiological evidence Evidence from epidemiological studies is also inconsistent. The results of some, but not all studies suggests that high intake of flavonoids may decrease the risk of coronary heart disease (CHD). However, at the moment it is too early to make final conclusions about the cardiovascular effects of flavonoids, as currently nutritional databases used to evaluate the dietary intake of flavonoids are inconclusive. In previous epidemiological studies usually only five to seven flavonoids, out of total of 5000 known, have been used to estimate the total amount of flavonoid ingested.

The aims of our flavonoid studies:

1. Augment flavonoid databases and study the role of dietary flavonoids in CVD in The Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study and Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) studies conducted at the Research Institute of Public Health.

To address the effects of phenolic compounds on lipid peroxidation we have conducted five supplementation studies. In these studies we have used phloem, chocolate, coffee, herbs and mixture of green tea, onion and apple as a source of phenolic compounds. The effects on lipid peroxidation have been evaluated by measuring the oxidation susceptibility of whole serum to oxidation, oxidation susceptibility of LDL to oxidation, antioxidant capacity, the formation of baseline conjugated dienes in vivo, formation of hydroxy fatty acids in vivo, formation of F2-isoprostanes in vivo. In addition we have measured the activity of antioxidant enzymes (paraoxonase, glutathione peroxidase). The results of these studies will be published in the near future.

We have also studied the role of flavonoids in CVD in epidemiological setting. The study population consisted of total of 2682 men aged 42-60 years and free of prior CHD or stroke at the KIHD Study baseline. In this study we used four-day food recording at the baseline to assess dietary intakes of nutrients. Nutrients were also adjusted for energy intake using the residual method. These preliminary results were presented at the 43rd Annual Conference on Cardiovascular Disease and Prevention, Miami, Florida, March 5-8, 2003. In this study we found that men in the highest quarter of quercetin intake had 37% decreased risk of stroke when compared with men in the lower quarters. We adjusted the results for age, examination years, systolic blood pressure, serum LDL and HDL cholesterol, triglycerides, smoking, BMI, diabetes and energy adjusted intake of saturated fat, folate, fiber, beta-carotene, vitamin E and C.

Currently we are augmenting the databases of phenolic compounds in order to study the role of these compounds in CVD, cancer, depression and other diseases. In addition we are studying the role of the foodstuffs rich in phenolic compounds such as tea and coffee in these diseases. We are also developing methods to analyze the phenolic compounds and their metabolites present in human blood and urine. This would enable us to study the metabolism of phenolic compounds as well as the role of phenolic compounds in CVD and other diseases.

More information
jaakko.mursu@uku.fi (health effects), tarja.nurmi@uku.fi (Analyses of phenolic compounds)

Our publications

Jaakko Mursu et al: Flavonoid intake and the risk of ischaemic stroke and CVD mortality in middle-aged Finnish men: the Kuopio Ischaemic Heart Disease Risk Factor Study. Brit J Nutr 2008;1:1-6.

Jaakko Mursu et al: Intake of flavonoids and risk of cancer in Finnish men: The Kuopio Ischaemic Heart Disease Risk Factor Study. Int J Cancer 2008 Mar 13. [Epub ahead of print]

Sari Voutilainen et al. Coffee intake and the incidence of hypertension. Am J Clin Nutr 2007;86:1248;author reply 1249. PDF

Jaakko Mursu et al. The intake of flavonoids and carotid atherosclerosis: the Kuopio Ischaemic Heart Disease Risk Factor Study. Brit J Nutr 2007;98:814-18. Epub 2007 Apr 30.

Results of the Eurolive Study was published in the Annals of Internal Medicine; Maribel Covas et al. The effect of polyphenols in olive oil on heart disease risk factors: a randomized trial. Ann Intern Med 2006 Sep 5;145(5):333-41. PDF

Anna Nurmi et al. Consumption of Juice Fortified with Oregano Extract Markedly Increases Excretion of Phenolic Acids but Lacks Short- and Long-Term Effects on Lipid Peroxidation in Healthy Nonsmoking Men.
J Agric Food Chem 2006;54:5790-96. PDF

Anna Nurmi et al. Ingestion of Oregano Extract Increases Excretion of Urinary Phenolic Metabolites in Humans. J Agric Food Chem 2006;54:6916-23. PDF

Jaakko Mursu et al. Polyphenol-rich phloem enhances the resistance of total serum lipids to oxidation in men. J Agric Food Chem 2005 20;53:3017-22. PDF

Happonen P, Voutilainen S, Salonen JT. Coffee drinking is dose-dependently related to the risk of acute coronary events in middle-aged men. J Nutr 2004;134:2381-86. PDF

Mursu J, Voutilainen S, Nurmi T, Alfthan G, Virtanen JK, Rissanen TH, Happonen P, Nyyssonen K, Kaikkonen J, Salonen R, Salonen JT. The effects of coffee consumption on lipid peroxidation and plasma total homocysteine concentrations: a clinical trial. Free Radic Biol Med. 2005;38(4):527-34. PDF

Mursu J, Voutilainen S, Nurmi T, Rissanen TH, Virtanen JK, Kaikkonen J, Nyyssonen K, Salonen JT. Dark chocolate consumption increases HDL cholesterol concentration and chocolate fatty acids may inhibit lipid peroxidation in healthy humans. Free Radic Biol Med. 2004;37(9):1351-9. PDF

References

Epidemiological studies

1. Hertog, M.; Feskens, E.; Hollman, P.; Katan, M.; Kromhout, D. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet. 342, 1007-1011. 1993.

2. Keli, S.O.; Hertog, M.G.; Feskens, E.J.; Kromhout, D. Dietary flavonoids, antioxidant vitamins, and incidence of stroke: the Zutphen study. Arch. Intern. Med. 156: 637-642; 1996.

3. Yochum, L.; Kushi, L.H.; Meyer, K.; Folsom, A. Dietary flavonoid intake and risk of cardiovascular disease in postmenopausal women. Am. J. Epidem. 1999;149:943-949.

4. Rimm, E.; Katan, M.; Ascherio, A.; Stampfer, M.J.; Willett, W.C. Relation between intake of flavonoids and risk for coronary heart disease in male health professional. Ann. Intern. Med. 125:384-389; 1996.

5. Knekt, P.; Isotupa, S.; Rissanen, H.; Heliövaara, M.; Järvinen, R.; Häkkinen, S.; Aromaa, A.; Reunanen, A. Quercetin intake and the incidence of cerbrovascular disease. Eur. J. Clin. Nutr. 54:415-417; 2002

Reviews

6. Scalbert, A; Williamson, G. Dietary intake and bioavailability of polyphenols. J Nutr 2000;130:2073-2085.

7. Fuhrman, B.; Aviram, M. Flavonoids protect LDL from oxidation and attenuate atherosclerosis. Curr. Opin. Lipidol. 12:41-48; 2001.

8. Bravo, L. Polyphenols: Chemistry, dietary sources, metabolism, and nutritional significance. Nutr. Rev. 56:317-333; 1998.

In vitro, animal and human supplementation studies

9. Lotito, S.B.; Fraga, C.G. (+)-Catechin prevents human plasma oxidation. Free. Radic. Biol. Med. 24:435-441; 1998.

10. Yamakoshi, J.; Kataoka, S.; Koga, T.; Ariga, T. Proanthocyanidin-rich extract from grape seeds attenuates the development of aortic atherosclerosis in cholesterol-fed rabbits. Atherosclerosis 142:139-149; 1999.

11. de Rijke, Y.B.; Demacker, P.N.; Assen, N.A.; Sloots, L.M.; Katan, M.B.; Stalenhoef, A.F. Red wine consumption does not affect oxidizability of low-density lipoproteins in volunteers. Am. J. Clin. Nutr. 63:329-334; 1996.

12. Nigdikar, S.V.; Williams, N.R.; Griffin, B.A.; Howard, A.N. Consumption of red wine polyphenols reduces the susceptibility of low-density lipoproteins to oxidation in vivo. Am. J. Clin. Nutr. 68:258-265; 1998.

13. van het Hof, K.H.; de Boer, H.S. M.; Wiseman, S.A.; Lien, N.; Weststrate, J.A.; Tijburg, L.B.M. Consumption of green or black tea does not increase resistance of low-density lipoprotein to oxidation in humans. Am. J. Clin. Nutr. 66:1125-1132; 1997.

14. Hodgson, J.M.; Puddey, I.B.; Croft, K.D.; Burke, V.; Mori, T.A.; Caccetta, R.A.A.; Beilin, L.J. Acute effects of ingestion of black tea and green tea on lipoprotein oxidation. Am. J. Clin. Nutr. 71:1103-1107; 2000.

For further information, please contact Sari Voutilainen (sari.voutilainen@uku.fi)