Controversial Role of Plant Sterol Esters in the Management of Hypercholesterolaemia

Oliver Weingärtner; Michael Böhm; Ulrich Laufs

Disclosures

Eur Heart J. 2009;30(4):404-409. 

In This Article

Phytosterols and Cardiovascular Risk

Meta-analyses of more than 40 clinical studies indicate that phytosterols taken as dietary supplements can induce a reduction of LDL-cholesterol up to 15%[23,24] (Figure 2). However, ingestion of more than 3 g/day does not lead to any further lowering of cholesterol levels. Of note, a diet supplementation with plant stanol esters reduces not only serum cholesterol levels, but also serum plant sterol concentrations.[25] The effectiveness of cholesterol-lowering products does not only depend on the amount of dietary phytosterols, but also on genetically determined differences in sterol metabolism. Thus, for example, Apo E-4 (apolipoprotein E-4) homozygote patients on a diet supplementation with phytosterols show a more significant reduction in LDL-cholesterol due to their increased cholesterol absorption capacity.[26] However, with this genotype lowered cholesterol levels are associated with markedly increased plant sterol serum concentrations. The significance of increased plant sterol levels, however, is not clear.

Figure 2.

Plant sterols reduce serum cholesterol levels. Total cholesterol and LDL-cholesterol dependent on diet (modified from ref.[23]).

Speculations that plant sterols may represent a cardiovascular risk factor were first brought up after the understanding of the autosomal-recessively inherited disease of sitosterolaemia.[27] Elevated plant sterol concentrations, xanthomatosis, and premature, frequently lethal atherosclerosis in young subjects are the most striking features regarding patients with homozygous sitosterolaemia. Additional findings are thrombocytopenia, abnormally deformed erythrocytes with membranous incorporation of phytosterols, extending to haemolytic crisis, arthralgias, and increased liver enzyme levels. The reason for this are mutations of the gene locus of the ABCG5 and ABCG8 co-transporters, resulting in increased absorption and reduced biliary elimination of all sterols.[28] In contrast to healthy subjects who have a plant sterol plasma concentration lower than 1 mg/dL, patients who suffer from this rare autosomal-recessive, inherited disease, have plasma concentrations of between 12 and 50 mg/dL. On the other hand, cholesterol does not need to be excessively high. The fact that patients with this disease present with an aggressive vascular disease process despite nearly normal cholesterol levels brought up the question whether phytosterols have a particularly atherogenous potential. As sterol analyses of xanthomas of such patients indicate that phytosterols only contain a small portion of sterols and that the major portion consists of free and esterified cholesterol, it is currently suggested that plant sterols can promote the incorporation of cholesterol in tissue.[27] [29] This speculation is in agreement with the findings of a recently published study in which the NPC1L1 inhibitor ezetimibe led to a regression in xanthomatosis in parallel to lowering of both cholesterol and plant sterol levels.[30]

Even though many different clinical trials have clearly demonstrated that phytosterols reduce LDL-cholesterol, it is unclear whether phytosterols have a positive effect on cardiovascular disease.[24] Until now, there are no data on the effect of phytosterol consumption on the development of cardiovascular diseases available.[32] In fact, there is evidence that elevated levels of plant sterols are associated with an increased cardiovascular risk. Glueck et al.[33] were the first to report that elevated plant sterols might be a risk factor for coronary heart disease. In a study with 595 hypercholesterolaemic patients, they found that slightly elevated plasma levels of plant sterols were a heritable marker for an increased cardiovascular risk. Salen et al.[31] reported that in homozygotes of sitosterolaemia cholesterol accounted for over 80% of plasma, tissue, and atheroma sterol. In seven subjects in a Glueck study, serum cholesterol was 7.09 mmol/L, whereas the concentration of campesterol, stigmasterol, and sitosterol combined was only 43.86 μmol/L.[34] Therefore, it can be speculated that a slight excess of serum plant sterol levels may increase sterol deposition in cardiovascular tissue. This hypothesis is supported by the study of Rajaratnam et al.[35] who found that in postmenopausal women, plant sterols were independently associated with coronary heart disease in a multivariate analysis. These findings were confirmed by Sutherland and his team in a study involving both sexes over all age groups.[36] Sudhop et al.[37] analysed the relation of a positive family history of coronary heart disease to serum plant sterol concentrations in CAD patients without lipid-modifying medications. There were no differences in levels of serum cholesterol, cholesterol precursors, and lipoproteins. The serum campesterol level in the control group was 0.38 mg/dL compared to 0.50 mg/dL in those patients with a positive family history. Given that the level of plant sterols was small compared with cholesterol (0.16 vs. 0.21%), the effect inducing a negative cardiovascular outcome in this study is indeed very potent. Similar findings have been reported for patients on statin treatment. The Scandinavian Simvastatin Survey Study (4S study) also identified a subpopulation of coronary artery disease patients with low endogenous synthesis of cholesterol and high absorption of cholesterol and plant sterols. The subjects of this subpopulation had the highest levels of plant sterols and the highest risk of recurrent coronary events despite lower levels of serum cholesterol due to simvastatin ingestion.[38] Larger epidemiological studies reported similar data. Results of the PROCAM-study showed that patients afflicted with myocardial infarction or sudden cardiac death had increased plant sterol concentrations.[39] Upper normal levels of plant sterols were associated with a three-fold increase of risk for coronary events among men in the highest tertile of coronary risk according to the PROCAM-algorithm (Figure 3). Similar data are available for the plant sterol campesterol from the MONICA/KORA-study. In this prospective study, campesterol correlated directly with the incidence of acute myocardial infarction.[40] Current experimental findings from our own research group show that a diet supplementation with plant sterol esters that is equivalent to a commercially available spread induces endothelial dysfunction and leads to an increase of ischaemic stroke size in wild-type mice.[29] In atherosclerotic-prone apoE–/– mice, we compared the effects of a diet supplementation with plant sterol esters with equal cholesterol lowering by a second intervention in relation to atherosclerotic lesion formation. Ezetimibe was chosen as a comparator, because similar to plant sterols, this two-azetidione is an inhibitor of intestinal cholesterol absorption and lowers plasma cholesterol levels. As expected, the substantial lipid-lowering by both treatment principles reduced atherosclerotic lesion formation. However, despite equal plasma cholesterol levels, plant sterol ester supplementation was associated with twice the amount of plaque formation compared with ezetimibe. Thus, we found a positive correlation between sterol concentrations and the extent of atherosclerotic lesions.[29] Moreover, in a clinical study, we demonstrated that patients who were consuming plant sterol ester enriched margarine had increased concentrations of plant sterols in cardiovascular tissue.[29] Further mechanistic data suggest that vascular deposits of sterols, when compared with cholesterol, result in increased oxidation and release of oxygen radicals.[41] On the other hand, previous animal and in vitro experiments have shown that plant sterols have positive effects that directly inhibit tumour growth, including the slowing of cell cycle progression, the induction of apoptosis, and the inhibition of tumour metastasis, suggesting that these compounds have anticancer properties.[42] However, the induction of apoptosis is not limited to tumour cells, but extends also to vascular cells. Recent in vitro experiments demonstrated that the plant sterol sitosterol exerts a strong cytotoxic propensity inducing apoptosis in human endothelial cells, revealing detrimental effects on the vasculature.[43] In fact, the first experimental study reporting negative cardiovascular effects dates back to the year 2000. Ratnayake et al.[44] reported that increased serum levels of plant sterols increase rigidity of erythrocytes and shorten the life span of stroke-prone spontaneously hypertensive (SHRSP) rats. These findings were the reason for Health Canada, the federal department responsible for helping Canadians maintain and improve their health, to raise significant safety issues and not to allow functional foods enriched with plant sterol esters to be sold in Canada.[45]

Figure 3.

Plant sterols increase cardiac risk. PROCAM-score for the 10 year risk to develop coronary heart disease (n = 477) according to subgroups with increasing risk (PROCAM-score <10, 10–20, >20). Slightly elevated sitosterol levels are associated with increased cardiac risk. *P < 0.05 low sitosterol (<0.21 mg/dL) vs. elevated sitosterol (>0.21 mg/dL) (modified from ref.[39]).

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