Hostname: page-component-7c8c6479df-8mjnm Total loading time: 0 Render date: 2024-03-29T01:45:01.768Z Has data issue: false hasContentIssue false

What is the real meaning of increased serum plant sterol concentrations?

Published online by Cambridge University Press:  12 June 2012

Jogchum Plat
Affiliation:
Department of Human Biology, Maastricht University Medical Center, NUTRIM School for Nutrition, Toxicology and Metabolism, PO Box 616, 6200MDMaastricht, The Netherlands; j.plat@hb.unimaas.nl; j.plat@maastrichtuniversity.nl
Dieter Lutjohann
Affiliation:
Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
Ronald P. Mensink
Affiliation:
Department of Human Biology, Maastricht University Medical Center, NUTRIM School for Nutrition, Toxicology and Metabolism, PO Box 616, 6200MDMaastricht, The Netherlands
Rights & Permissions [Opens in a new window]

Abstract

Type
Letter to the editor
Copyright
Copyright © The Authors 2012

There is an ongoing discussion as to whether elevated serum plant sterol concentrations increase cardiovascular risk or not. Inherent to this question is whether the suggested beneficial effects of lowering serum LDL-cholesterol concentrations after consumption of plant sterol-enriched products are counteracted by increased serum concentrations of ‘potentially’ atherogenic plant sterols (sitosterol and campesterol). Indeed, a number of prospective cohort and case–control studies have suggested a positive association between circulating serum plant sterol concentrations and cardiovascular risk. Results, however, are not conclusive and other studies have shown no relationships at all or have even suggested a decreased risk for CVD at higher serum plant sterol concentrations. A systematic review and meta-analysis did not reveal any evidence for an association between mean serum concentrations of plant sterols and the risk of CVD(Reference Baumgartner, Mensink and Plat1, Reference Genser, Silbernagel and De Backer2). This analysis was restricted to epidemiological studies where subjects did not consume functional foods enriched with plant sterols. It is noteworthy that the discussion about potential atherogenicity centres entirely around elevated serum plant sterols and not on serum plant stanols, the hydrogenated derivatives of plant sterols. LDL-cholesterol-lowering plant stanol-enriched products are also on the market. In comparison with serum plant sterols, serum plant stanol concentrations are very low, due to very low levels of plant stanols in regular diets and lower absorption rates when compared with those of plant sterols.

It needs to be said, however, that there is a need to carry out longer-term, well-controlled human studies evaluating the effects of these functional foods on vascular function and other physiological outcomes to examine the effects beyond those on LDL-cholesterol. Recently, we have published a part of our longer-term, placebo-controlled dietary intervention study in statin-treated subjects that lasted 85 weeks, and examined the effects of daily consumption of margarines enriched with either plant sterol or plant stanol esters on various parameters related to vascular function(Reference Kelly, Plat and Mensink3). We reported a non-significant increase in retinal venular diameter in the group consuming plant sterol esters. Changes in venular diameter, however, correlated positively with changes in cholesterol-standardised serum campesterol concentrations. The correlation with cholesterol-standardised serum sitosterol concentrations nearly reached statistical significance. No relationships were observed with the arteriolar diameter or the arteriolar:venular diameter ratio(Reference Kelly, Plat and Mensink3). To our knowledge, this was the first study evaluating the effects of a dietary or pharma-type of intervention on changes in retinal vasculature. Cross-sectional studies have shown that increased retinal venular diameters are observed in patients with the metabolic syndrome, while correlations with several established CVD risk factors have been found, and positive associations between the venular diameter with the carotid plaque score have been reported(Reference Ikram, de Jong and Vingerling4Reference Kawasaki, Tielsch and Wang6). Our findings, however, must be extended and confirmed in future intervention trials before any conclusions on their external validity and clinical relevance can be made. In the same study, no effects were observed on parameters related to carotid artery compliance. In fact, Peterson's elastic modulus and the stiffness index β were improved in subjects with elevated baseline matrix metallopeptidase 9 ( ≥ 52·4 ng/ml) concentrations(Reference Jong, Plat, Hoeks and Mensink7). In general, these outcomes agree with those reported by others in studies of shorter durations and in other populations(Reference Raitakari, Salo and Gylling8Reference Jakulj, Vissers and Rodenburg10). A controlled intervention study comparing the effects of plant sterol or stanol esters v. placebo margarines in hypercholesterolaemic subjects also showed that flow-mediated dilation was unchanged, whereas the brachial artery diameter was significantly reduced after the sterol ester period when compared with the plant stanol ester period(Reference Hallikainen, Lyyra-Laitinen and Laitinen11). The reproducibility as well as the clinical relevance of these observations remain unclear and demand further study.

The question now arises: what is the actual meaning of increased serum plant sterol concentrations in the circulation? In contrast to cholesterol, which originates from endogenous synthesis and from intestinal absorption, plant sterols are by definition derived from the diet. Plant sterols and cholesterol share the same mechanisms of intestinal absorption, and plant sterols are validated markers for fractional intestinal cholesterol absorption(Reference Tilvis and Miettinen12). This is an invaluable tool for mechanistic studies, but at the same time a potential disadvantage. Because of the shared absorption machinery, it must be realised that the potential association between serum plant sterol concentrations and increased CVD risk may be an epiphenomenon. As plant sterol concentrations reflect fractional cholesterol absorption(Reference Tilvis and Miettinen12), it is also possible that an increased absorption of cholesterol, or a feature related to it, associates with CVD risk. This assumption is supported by the fact that within the same study, associations between serum plant sterols and CHD were also observed for cholestanol, a cholesterol derivative that also reflects cholesterol absorption, but is not of plant origin(Reference Matthan, Pencina and LaRocque13, Reference Silbernagel, Fauler and Hoffmann14). Thus, increased cholesterol-standardised serum plant sterol concentrations may be a flag for another characteristic: increased fractional cholesterol absorption. In fact, evidence is accumulating that cholesterol absorption relates positively to cardiovascular risk(Reference Matthan, Pencina and LaRocque13, Reference Silbernagel, Fauler and Renner15, Reference Weingärtner, Lütjohann and Vanmierlo16).

Miettinen et al. (Reference Miettinen, Gylling and Strandberg17) already suggested the potential importance of serum cholestanol concentrations for cardiovascular risk management in the late 1990s. In the Finnish subgroup of the Scandinavian Simvastatin Survival Study (4S), the serum cholestanol:cholesterol ratio at baseline was negatively related to the risk of recurrence of major coronary events. This indicated that patients classified as cholesterol absorbers may not optimally benefit from treatments aimed to lower endogenous cholesterol synthesis. This suggestion is further supported by recent findings in patients suffering from chronic kidney disease. Although statin treatment failed to show a reduced CVD mortality in chronic kidney disease patients(Reference Fellström, Jardine and Schmieder18), the recent Study of Heart and Renal Protection (SHARP) suggested that the combined treatment of statin plus ezetimibe reduced cardiovascular events in chronic kidney disease patients(Reference Baigent, Landray and Reith19). This is supported by findings that haemodialysis patients are cholesterol absorbers – indicated by increased serum cholestanol concentrations – rather than cholesterol synthesisers(Reference Rogacev, Pinsdorf and Weingartner20). Also, the efficacy of plant sterol and stanol ester-enriched products seems to be related to the characteristics of cholesterol metabolism(Reference Thuluva, Igel and Giesa21Reference Carr, Krogstrand and Schlegel24). Such findings may be used to develop personalised cardiovascular risk management strategies.

In conclusion, the possible associations found between circulating plant sterols and CVD risk might be related to the fact that serum plant sterols are a marker for intestinal cholesterol absorption and not per se to the potential atherogenic effects of plant sterols. Notwithstanding, the question of whether consumption of products enriched with plant sterol esters translates into a changed vascular function has not been answered so far. More studies are needed to answer the question whether the increase in serum plant sterol concentrations interferes with the postulated beneficial effects of lowering LDL-cholesterol.

References

1Baumgartner, S, Mensink, RP & Plat, J (2011) Plant sterols and stanols in the treatment of dyslipidemia; new insights into targets and mechanisms related to cardiovascular risk. Curr Pharm Des 17, 922932.Google Scholar
2Genser, B, Silbernagel, G, De Backer, G, et al. (2012) Plant sterols and cardiovascular disease: a systemic review and meta-analysis. Eur Heart J 33, 444451.Google Scholar
3Kelly, ER, Plat, J, Mensink, RP, et al. (2011) Effects of long term plant-sterol and -stanol consumption on the retinal vasculature: a randomized controlled trial in statin users. Atherosclerosis 214, 225230.Google Scholar
4Ikram, MK, de Jong, FJ, Vingerling, JR, et al. (2004) Are retinal arteriolar or venular diameters associated with markers for cardiovascular disorders? The Rotterdam Study. Invest Ophthalmol Vis Sci 45, 21292134.Google Scholar
5McGeechan, K, Liew, G, Macaskill, P, et al. (2009) Meta-analysis: retinal vessel caliber and risk for coronary heart disease. Ann Intern Med 151, 404413.Google Scholar
6Kawasaki, R, Tielsch, JM, Wang, JJ, et al. (2008) The metabolic syndrome and retinal microvascular signs in a Japanese population: The Funagata Study. Br J Ophthalmol 92, 161166.CrossRefGoogle Scholar
7Jong, NA, Plat, J, Hoeks, A & Mensink, RP (2007) Effects of long-term consumption of plant sterol or plant stanol esters on endothelial function and arterial stiffness in patients on stable statin treatment. Atherosclerosis 8, 1.Google Scholar
8Raitakari, OT, Salo, P, Gylling, H, et al. (2008) Plant stanol ester consumption and arterial elasticity and endothelial function. Br J Nutr 100, 603608.CrossRefGoogle ScholarPubMed
9de Jongh, S, Vissers, MN, Rol, P, et al. (2003) Plant sterols lower LDL cholesterol without improving endothelial function in prepubertal children with familial hypercholesterolaemia. J Inherit Metab Dis 26, 343351.Google Scholar
10Jakulj, L, Vissers, MN, Rodenburg, J, et al. (2006) Plant stanols do not restore endothelial function in pre-pubertal children with familial hypercholesterolemia despite reduction of low-density lipoprotein cholesterol levels. J Pediatr 148, 495500.Google Scholar
11Hallikainen, M, Lyyra-Laitinen, T, Laitinen, T, et al. (2006) Endothelial function in hypercholesterolemic subjects: effects of plant stanol and sterol esters. Atherosclerosis 188, 425432.Google Scholar
12Tilvis, RS & Miettinen, TA (1986) Serum plant sterols and their relation to cholesterol absorption. Am J Clin Nutr 43, 9297.CrossRefGoogle ScholarPubMed
13Matthan, NR, Pencina, M, LaRocque, JM, et al. (2009) Alterations in cholesterol absorption/synthesis markers characterize Framingham offspring study participants with CHD. J Lipid Res 50, 19271935.CrossRefGoogle Scholar
14Silbernagel, G, Fauler, G, Hoffmann, MM, et al. (2010) The associations of cholesterol metabolism and plasma plant sterols with all-cause and cardiovascular mortality. J Lipid Res 51, 23842393.Google Scholar
15Silbernagel, G, Fauler, G, Renner, W, et al. (2009) The relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease. J Lipid Res 50, 334341.Google Scholar
16Weingärtner, O, Lütjohann, D, Vanmierlo, T, et al. (2011) Markers of enhanced cholesterol absorption are a strong predictor for cardiovascular diseases in patients without diabetes mellitus. Chem Phys Lip 164, 451456.Google Scholar
17Miettinen, TA, Gylling, H, Strandberg, T, et al. (1998) Baseline serum cholestanol as predictor of recurrent coronary events in subgroup of Scandinavian simvastatin survival study. Finnish 4S Investigators. BMJ 316, 11271130.Google Scholar
18Fellström, BC, Jardine, AG, Schmieder, RE, et al. (2009) Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 360, 13951407.Google Scholar
19Baigent, C, Landray, MJ, Reith, C, et al. (2011) The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 377, 21812192.Google Scholar
20Rogacev, KS, Pinsdorf, T, Weingartner, O, et al. (2012) Cholesterol synthesis, cholesterol absorption, and mortality in hemodialysis patients. Clin J Am Soc Nephrol (Epublication ahead of print 29 March 2012).Google Scholar
21Thuluva, SC, Igel, M, Giesa, U, et al. (2005) Ratio of lathosterol to campesterol in serum predicts the cholesterol-lowering effect of sitostanol-supplemented margarine. Int J Clin Pharmacol Ther 43, 305310.Google Scholar
22Casas-Agustench, P, Serra, M, Pérez-Heras, A, et al. (2011) Effects of plant sterol esters in skimmed milk and vegetable-fat-enriched milk on serum lipids and non-cholesterol sterols in hypercholesterolaemic subjects: a randomised, placebo-controlled, crossover study. Br J Nutr 107, 17661775.Google Scholar
23Fuentes, F, Lopez-Miranda, J, Garcia, A, et al. (2008) Basal plasma concentrations of plant sterols can predict LDL-C response to sitosterol in patients with familial hypercholesterolemia. Eur J Clin Nutr 62, 495501.Google Scholar
24Carr, TP, Krogstrand, KL, Schlegel, VL, et al. (2009) Stearate-enriched plant sterol esters lower serum LDL cholesterol concentration in normo- and hypercholesterolemic adults. J Nutr 139, 14451450.CrossRefGoogle ScholarPubMed