A few studies on circulating plant sterols and cardiovascular disease were published after April 2010 and, therefore, were not included in the meta-analysis. One prospective study in a cohort of 623 people, who were older than 75 years, showed an association of low circulating sitosterol with increased mortality . Similarly, campesterol and the campesterol and sitosterol to cholesterol ratios showed weak negative associations with carotid intima-media thickness measured by ultrasound in 583 people aged 25–60 years without prevalent cardiovascular disease . On the contrary, a study comprising 177 patients without diabetes who were referred for coronary angiography reported increased campesterol-to-cholesterol ratio in the subgroup with coronary artery disease . Significant associations between circulating plant sterols and cardiovascular disease were absent in a cohort of 127 people on and off hemodialysis .
In interpreting the associations between circulating plant sterols and cardiovascular disease, it should again be considered that plant sterols reflect intestinal cholesterol absorption [25▪]. In fact, we think that the repeatedly observed positive correlation between circulating plant sterols and cardiovascular disease is accounted for by the atherogenic effects of high cholesterol absorption . This view is supported by the finding that circulating cholestanol was increased in people with cardiovascular disease and also predictive of future cardiovascular events [30,39–42]. Thus, a raised phytosterol concentration may be a marker of disturbed cholesterol metabolism and not itself causally related to atherosclerosis. However, the positive associations of high cholesterol absorption and consequently high circulating plant sterols with cardiovascular risk may be blunted or even reversed by several factors. For example, cholesterol absorption and thus circulating plant sterols are decreased in disorders characterized by increased cholesterol synthesis such as the metabolic syndrome, type 2 diabetes, and fatty liver [25▪]. Another relevant confounder is the positive correlation of circulating plant sterols with high vegetable and fruit intake .
In short, there is currently no evidence that moderately increased circulating plant sterols seen in the general population are associated with increased cardiovascular risk.
There is solid evidence that the use of plant-sterol-enriched functional foods will reduce LDL cholesterol . Two recent dietary intervention studies deserve closer attention. Jenkins et al.  report on a very accurate randomized trial comparing the effects of a dietary portfolio including plant sterols, soy protein, viscous fibers, and nuts with a low-saturated fat diet in 351 hyperlipidemic people over a period of 6 months. Notably, a substantial decrease in LDL cholesterol of −26 mg/dl was achieved for the dietary portfolio, whereas only a decrease of −8 mg/dl was achieved for the low-fat diet . A considerable portion of the LDL cholesterol reduction was attributed to the plant sterol supplementation . Lin et al.  performed a crossover study in 22 individuals who received three different treatments lasting 3 weeks each, namely ezetimibe placebo plus phytosterol placebo, ezetimibe 10 mg/day plus phytosterol placebo, and ezetimibe 10 mg/day plus phytosterol supplement 1.9 g/2000 kcal. They found that ezetimibe plus phytosterol treatment was superior to ezetimibe alone in terms of lowering LDL cholesterol. Although both studies were able to confirm beneficial effects of dietary plant sterols on LDL cholesterol, they raised some skepticism because the ultimate proof that plant sterols will reduce cardiovascular risk is currently not available [46,47]. A prospective, randomized, and controlled dietary intervention study would be needed to conclusively demonstrate a reduction in cardiovascular endpoints by plant sterol supplementation. However, because of feasibility problems such a study is not planned so far.
The potentially vasculoprotective role of plant sterol supplementation has been supported by a randomized placebo-controlled trial comprising 108 patients with the metabolic syndrome. This study revealed that phytosterol supplementation decreases plasma small and dense LDL levels .
It has widely been speculated that persons heterozygous for mutations causing sitosterolemia were particularly vulnerable against plant sterols. A very important clarification of this concern has been achieved by Myrie et al. [49▪▪]. They were able to show that heterozygous mutation carriers are not specifically predisposed to excessive increases in circulating phytosterols following plant sterol supplementation.
Another approach to study the impact of dietary plant sterols on lipids and atherogenesis is the evaluation of food frequency questionnaires . A previous report in 37 150 male and 40 502 female participants of the Västerbotten Intervention Program, who were aged 29–61 years, demonstrated high dietary intake of plant sterols to be associated with lower circulating LDL cholesterol . The results of the Swedish study were lately confirmed by a Chinese community-based cross-sectional study comprising 1160 men and 2780 women aged 31–75 years. Of interest, the authors also observed a trend toward an inverse relationship between plant sterol intake and ultrasound measurements of the carotid intima-media thickness .
Briefly, dietary plant sterol supplementation is effective in the treatment of hypercholesterolemia. However, an association of high plant sterol intake with a reduction in cardiovascular risk has not been demonstrated. As long as a controlled intervention trial is not available, large, prospective cohort studies with detailed and periodic dietary assessments may help to improve the level of evidence on the relationship between plant sterol supplementation and cardiovascular disease .
A few interesting novel studies in experimental animals may help us to better understand the role of plant sterols in vascular disease. Weingärtner et al.  reported that plant sterol supplementation was effective in reducing serum cholesterol and in retarding atherosclerotic lesion formation in apoE-knockout mice on a Western-type diet. However, plant sterol administration at the same time impaired endothelial vasodilation. This finding may have been explained by an increase in a harmful monocyte subpopulation in response to plant sterol administration. Another investigation showed that phytosterol supplementation is associated with a decrease in lipoprotein oxidizability in mice on a high-fat diet . Likewise, plant sterol supplementation had beneficial effects on plasma lipids and, in contrast to the study by Weingärtner et al., also improved vascular function in hamsters . Finally, we want to highlight a relatively new mouse model which may serve as a resource for studying sitosterolemia .
All in all, animal data tend to support vasculoprotective effects of dietary plant sterol supplementation.
Regular intake of plant sterols is associated with a decrease in LDL cholesterol of about 13 mg/dl and an increase in circulating plant sterols of about 0.5 mg/dl [10,13]. Hence, consumption of plant sterols should reduce cardiovascular risk if circulating plant sterols are not about 26 times more atherogenic than LDL cholesterol. Current evidence argues against such a strong relationship between circulating plant sterols and cardiovascular disease. Thus, we share the view of the American Heart Association that the additive use of plant sterols should be considered for lowering LDL cholesterol [1,2]. Nevertheless, speculation about a potentially atherogenic role of plant sterols will probably continue unless proven otherwise.
Papers of particular interest, published within the annual period of review, have been highlighted as:
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 88).
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