EDITORIAL COMMENT
Vascular Effects of Diets, Especially Plant Sterol Ester Consumption*
Tatu A. Miettinen, MD, PhD ,* and
Helena Gylling, MD, PhD
Department of Medicine, Division of Internal Medicine, University of Helsinki, Helsinki, Finland
Department of Clinical Nutrition, University of Kuopio, and the Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
* Reprint requests and correspondence: Dr. Tatu A. Miettinen, Biomedicum Helsinki, Room C4 22, P.O. Box 700, FIN-00029 HUS, Finland. (Email: tatu.a.miettinen{at}helsinki.fi).
Long-term occurrence of coronary risk factors, especially increased serum total and low-density lipoprotein cholesterol concentration, results in impaired endothelial function through a slow accumulation of lipids, mainly of cholesterol, to arterial endothelium (1) developing finally over decades to atheroma formation. That the increased serum cholesterol concentration is one of the most important risk factors of atherosclerosis is indicated by several clinical prevention trials showing that effective reduction of serum cholesterol by statins prevents subsequent clinical manifestations and can even regress coronary atheromatosis (2). Diet contains normally small amounts, about 300 mg/day, of plant sterols, mainly sitosterol and campesterol, of which less than 5% are absorbed. In addition, diet contains even smaller amounts of plant stanols, about 20 mg/day, which are the saturated forms of plant sterols, and their absorption is less than 0.5%. Accordingly, human sera contains normally small amounts of plant sterols and almost undetectable amounts of plant stanols derived from diet (3). Dietary plant sterols and stanols can be enriched in food such as fatty acid esters. The commercially available phytosterol ester-enriched spreads contain enough plant sterols and stanols so that it is possible to get the recommended daily intake of plant stanols and sterols, which is 2 g/day. The consumption of this amount is known to prevent cholesterol absorption and subsequently lower serum cholesterol concentration (3), and they have widely been recommended as a population strategy for treatment of hypercholesterolemia. The difference between the consumption of enriched amounts of plant stanol or sterol esters is that plant stanols decrease not only the serum level of cholesterol but also that of plant sterols, whereas the consumption of plant sterols doubles their serum levels. No scientific data are available to determine whether the use of diet-enriched plant stanol or sterol esters in humans could prevent the development of coronary artery disease or atherosclerosis in general. However, recent studies have shown signs of improved endothelial function with plant sterol and stanol ester consumption (4,5). In this issue of the Journal, a mixture of mice and human studies shows that increased consumption of plant sterol esters could alter arterial function in mice and increase plant sterol concentration in human aortic valves (6).
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Plant sterol ester consumption in mice
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Plant sterol ester supplementation to wild-type mice increased their plant sterol but not cholesterol levels in plasma; endothelial function was impaired and experimental cerebral lesion size was increased. These findings can be interpreted to indicate the harmfulness of the increased plasma plant sterol concentrations. It should be kept in mind that high serum plant sterol concentrations in humans with familial phytosterolemia are known to cause severe premature atherosclerosis. In addition, in home-dwelling 75-year-old elders, recurrences of major cardiovascular events were increased in those with highest versus lowest serum sitosterol ratios to cholesterol during a 3- to 4-year follow-up (7). In fact, several clinical studies have actually shown some association between serum plant sterols and coronary artery disease in nonphytosterolemic subjects (3), but in recent epidemiological studies the association is questioned (8–10).
Additional studies were performed by the investigators with apolipoprotein E–/– mice on Western-type diet with plant sterol esters and ezetimibe (6). The latter drug, too, inhibits cholesterol absorption and lowers plasma cholesterol and plant sterol levels. The diet resulted in a marked atheroma formation in aortic root, which was reduced by the addition of either plant sterol esters or ezetimibe. However, the size of the plaques was larger on diet + plant sterol esters than on diet + ezetimibe (20.4 ± 2.1% vs. 10.0 ± 1.5%). Because plasma cholesterol concentrations were similar, the finding was interpreted to result from the higher plasma plant sterol concentrations. Similar results were obtained in mice on normal chow with low dietary cholesterol. The most pronounced reduction of lesion size was obtained during ezetimibe treatment as compared with plant sterol esters with comparable plasma cholesterol levels. The investigators could not show any correlation of plasma cholesterol concentration with plaque size, but plasma plant sterol levels were positively related to the lesion size. Thus, the major observation of the present study was that for different test conditions the increased plasma plant sterol concentrations were associated with enhanced atheroma size, which could not be explained with plasma cholesterol concentration. A question now arises: what will happen if plant sterols consumed were not absorbed, and their serum levels were not increased but even reduced? In fact, supplementation of plant sterols and stanols, known to cause respective increase and decrease in plasma plant sterols, to human subjects, or apolipoprotein-E-deficient mice suggested that the decrease of cholesterol reduces atherosclerosis despite some increase in blood plant sterol contents (4,11).
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Human studies
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The investigators evaluated whether increased plant sterol consumption in humans resulted in tissue accumulation of plant sterols (6). For the tissue of interest, they selected aortic valves washed from both ventricular and aortic sides by bloodstream lipoproteins. In a recent study, nonrheumatic aortic valve stenosis resembled atherosclerosis of arterial wall including inflammatory cells, lipoproteins, and calcified nodules (12). Accordingly, the risk factors of aortic stenosis include those of atherosclerosis. The investigators studied sterol composition (cholesterol, lathosterol, and plant sterols campesterol and sitosterol) of plasma and aortic valve cusps from 82 patients undergoing selective aortic valve replacement. Almost 40% of the subjects were on statins. Only 6 of the patients had consumed plant sterol ester supplementation regularly and 4 irregularly. No direct measurement of dietary plant sterol intake was performed, but the consumption was categorized according to patient questionnaires as none, irregular, or regular. The concentrations and ratios to cholesterol of plant sterols were related in plasma to those of aortic cusps in the whole study population. The high correlation (p < 0.0001) was mainly determined by individuals not using plant sterol supplementation (n = 72). However, despite the small number of plant sterol consumers (only 10%) and the wide variation of their plasma and aortic cusp plant sterol levels, the correlation was higher in regular consumers than in nonconsumers, and the irregular consumer values fell to the nonconsumer area. The results indicate that the increase in plasma plant sterols by increased dietary consumption increases proportionately the plant sterol levels in cusps. Even though no actual attempts were made for dietary plant sterol measurement, historical estimation of the intake suggested that the higher the intake was, the higher the serum level of plant sterols was, and the higher the plant sterol content was in tissues including aortic valve cusps. This type of conclusion has been made in an earlier study (13) that analyzed plant sterols in human sera and in surgically removed carotid artery plaques. Because the stenotic aortic valve cusps are frequently filled by atheromatous plaques, and even calcifications, which increases their cholesterol concentration (12), it is difficult to conclude what is the additional effect, if any, of increased minor amounts of plant sterols.
As pointed out by the investigators, the study is limited by retrospective design and small number of subjects on plant sterol esters. In addition, further information could have been obtained if, in addition to plant sterols, plant stanol esters had been used, because by decreasing serum plant sterols they could have had a similar action on aortic cusp sterols. Diets enriched with plant stanols lower serum cholesterol and plant sterols and slightly increase serum plant stanols, yet they may improve arterial function (4,5,14). The investigators performed microscopic studies in animal experiments, but no histology was given for human aortic cusps. Accordingly, the pathogenic contribution of plant sterols to aortic valve stenosis remains open. A recent study has revealed that in stenotic aortic valves novel mechanisms of inflammation, fibrosis, and elastin fiber degradation can be detected (12), suggesting that they may be pathogenetic factors of the stenosis and may offer a new target for medical therapy.
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Conclusions
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Several experimental studies in normal and apolipoprotein-E-deficient mice in the study by Weingärtner et al. (6) indicated that the increase in serum plant sterol contents with diet-enriched plant sterol ester consumption worsens arterial function. Humans consuming a diet enriched with plant sterol esters had increased contents of plant sterols in serum and in atherosclerotic aortic valves. However, it remains open whether high plant sterol levels in aortic valves cause atherosclerosis. Even though excessively increased serum plant sterols in serum of sitosterolemic patients with mutated plant sterol metabolism can result in early atheromatosis, no consistent association is available with serum plant sterols and atheromatosis under normal conditions.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness Arterioscler Thromb Vasc Biol 2005;25:932-943.[Abstract/Free Full Text]2. Nissen SE, Nicolls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis. The ASTEROID trial. JAMA 2006;295:1556-1565.[Abstract/Free Full Text] 3. Miettinen TA, Gylling H. Plant stanol and sterol esters in prevention of cardiovascular diseases: a review Int J Clin Pharmacol Ther 2006;44:247-250.[Web of Science][Medline] 4. de Jong A, Plat J, Hoeks AP, Mensink RP. Effects of long-term plant sterol or stanol ester consumption on endothelial function and arterial stiffness in patients on statin treatment(abstr) Atherosclerosis 2007;8:1. 5. Raitakari OT, Salo P, Gylling H, Miettinen TA. Plant stanol ester consumption and arterial elasticity and endothelial function Br J Nutr 2008Feb 18;[E-pub ahead of print]. 6. Weingärtner O, Lütjohann D, Ji S, et al. Vascular effects of diet supplementation with plant sterols J Am Coll Cardiol 2008;51:1553-1561.[Abstract/Free Full Text] 7. Strandberg TE, Tilvis RS, Pitkälä KH, Miettinen TA. Cholesterol and glucose metabolism and recurrent cardiovascular events among the elderly J Am Coll Cardiol 2006;49:708-714. 8. Wilund KR, Yu L, Xu F, et al. No association between plasma levels of plant sterols and atherosclerosis in mice and men Arterioscler Thromb Vasc Biol 2004;24:2326-2332.[Abstract/Free Full Text] 9. Fassbender K, Lütjohann D, Dik MG, et al. Moderately elevated plant sterol levels are associated with reduced cardiovascular risk—the LASA study Atherosclerosis 2008;196:283-288.[CrossRef][Web of Science][Medline] 10. Pinedo S, Vissers MN, von Bergmann K, et al. Plasma levels of plant sterols and the risk of coronary artery disease: the prospective EPIC-Norfolk Population Study J Lipid Res 2007;48:139-144.[Abstract/Free Full Text] 11. John S, Sorokin AV, Thompson PD. Phytosterols and vascular disease Curr Opin Lipidol 2007;18:35-40.[Web of Science][Medline] 12. Helske S, Syväranta S, Kupari M, et al. Possible role for mast cell-derived cathepsin G in the adverse remodelling of stenotic aortic valves Eur Heart J 2006;27:1495-1504.[Abstract/Free Full Text] 13. Miettinen TA, Railo M, Lepäntalo M, Gylling H. Plant sterols in serum and in atherosclerotic plaques of patients undergoing endarterectomy J Am Coll Cardiol 2005;45:1794-1801.[Abstract/Free Full Text] 14. Hallikainen M, Lyyra-Laitinen T, Laitinen T, et al. Endothelial function in hypercholesterolemic subjects: effects of plant stanol and sterol esters Atherosclerosis 2006;188:425-432.[Medline]
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