J Am Coll Cardiol, 2005; 45:1794-1801, doi:10.1016/j.jacc.2005.02.063

Miettinen et al., Plant Sterols in Serum and in Atherosclerotic
Plaques of Patients Undergoing Carotid Endarterectomy

OBJECTIVES: The purpose of this research was to determine whether
serum plant sterol levels are associated with those in atheromatous
plaque.

BACKGROUND: Cholesterol of low-density lipoprotein (LDL) particles
contributes to atheromatous plaque formation; LDL also contains most
serum non-cholesterol sterols, including plant sterols. The role of
plant sterols in atheromatous plaque formation is open.

METHODS: Free, ester, and total cholesterol and the respective non-
cholesterol sterols were measured by gas-liquid chromatography in
serum and arterial tissue of 25 consecutive patients undergoing
carotid endarterectomy. The population was ranked to triads according
to tissue cholesterol concentration.

RESULTS: Cholesterol concentration increased markedly in tissues but
not in serum with triads. The ester percentage was lower in the third
than in the first triad (47% vs. 56%; p < 0.01) and lower than in
serum triads (70%; p < 0.001). Ratios to cholesterol of non-
cholesterol sterols decreased in increasing tissue triads, but were
unchanged in serum. A major new observation was that the higher the
ratio to cholesterol of the surrogate absorption sterols (cholestanol,
campesterol, sitosterol, and avenasterol) in serum, the higher was
their ratio also in the carotid artery wall (e.g., r = 0.683 for
campesterol). Despite undetectable differences in serum and tissue
cholesterol concentrations off and on statins, an additional important
novel finding was that statin treatment was associated with increased
ratios of the absorption sterols in serum and also in the arterial
plaque.

CONCLUSIONS: The higher the absorption of cholesterol, the higher are
the plant sterol contents in serum resulting also in their higher
contents in atherosclerotic plaque. However, the role of dietary plant
sterols in the development of atherosclerotic plaque is not known.

* * *
I don't think this study proves anything but it seems somewhat
concerning.
* * *
J Am Coll Cardiol, 2006; 47:1496-1497, doi:10.1016/j.jacc.2006.01.031
(Published online 14 March 2006).

CORRESPONDENCE: LETTER TO THE EDITOR

Serum Plant Sterols and Atherosclerosis: Is There a Place for Statin-
Ezetimibe Combination?
Régis P. Radermecker, MD* and André J. Scheen, MD, PhD

We read with interest the paper by Miettinen et al. (1) demonstrating
that the higher the absorption of cholesterol, the higher the plant
sterol contents are in serum resulting in their higher contents in
atherosclerotic plaque. The prospective Cardiovascular Münster
(PROCAM) study found that people in the upper quartile of sitosterol
levels had a 1.8-fold increased risk of major coronary events compared
with those in the lower three quartiles (2). Statin treatment
decreases cholesterol synthesis but increases absorption of plant
sterols (3). In the Scandinavian Simvastatin Survival Study (4S), no
reduction was observed in recurrence of coronary heart disease with
the use of simvastatin in patients with high baseline plant sterol
contents and with marked increase of serum plant sterols during the
five-year treatment period (4). Additional treatment with inhibition
of sterol absorption (e.g., with plant stanol esters) was suggested
for this particular group of patients (3,4). To this respect, we were
surprised that Miettinen et al. (1) did not consider the potential of
combining ezetimibe with statin. Indeed, in addition to inhibiting
intestinal cholesterol absorption, a well-known effect, ezetimibe also
reduces plasma concentrations of the non-cholesterol sterols
sitosterol and campesterol, suggesting an effect on the absorption of
these compounds as well (5). It has been demonstrated recently that
the Niemann-Pick C1-like 1 (NPC1L1) transporter is most likely
responsible for the transport of cholesterol and plant sterols from
the brush border membrane into the intestinal mucosa (6). The
intestinal absorption of plant sterols differs markedly from that of
cholesterol and their biliary excretion as well. The presence of two
specific ABCG5/ABCG8 transporters in the intestinal wall is
responsible for rapid resecretion of plant sterols into the intestine
lumen and thus rather low intestinal absorption of campesterol and
sitosterol, and their presence in the liver explains why plant sterols
are excreted much faster in the bile than cholesterol (7,8). Ezetimibe
interferes with NPC1L1, reducing the intestinal uptake of cholesterol
and plant sterols (6-8). Interestingly, the reduction of plant sterol
serum levels with ezetimibe was significantly more pronounced than the
reduction of serum cholesterol (7,8). Clinical data on ezetimibe could
demonstrate that the concept of inhibiting intestinal absorption of
neutral sterols is beneficial in both patients with
hypercholesterolemia as well in patients with hypersitosterolemia, an
inherited disease with identified mutations in ABCG5/ABCG8
transporters that leads to a high prevalence of cardiovascular disease
(9). Recent observations, such as those by Miettinen et al. (1), that
elevated serum plant sterols pose an increased cardiovascular risk
suggest that increases of serum plant sterol levels should be avoided,
especially in atherosclerosis-prone individuals (1). Therefore,
subjects with high cholesterol absorption and low synthesis may need a
therapy combining statin and ezetimibe to lower more effectively their
serum cholesterol levels and prevent an increase in the levels of
plant sterols (3). The question remains, however, as to whether
lowering serum levels of plant sterols (especially in high-absorber
patients on statin therapy) with a drug such as ezetimibe will
decrease the incidence of coronary artery disease.

* * *
I think that last sentence is key.

* * *
J Am Coll Cardiol, 2006; 47:1497-1498, doi:10.1016/j.jacc.2006.01.030
(Published online 14 March 2006).

Reply
Tatu A. Miettinen, MD, PhD*, Mikael Railo, MD, PhD, Mauri Lepäntalo,
MD, PhD and Helena Gylling, MD, PhD

In the letter by Drs. Radermecker and Scheen, it was noted that we
have not commented the potential of combining ezetimibe to statins
(1). The additional low-density lipoprotein (LDL) lowering of
combining cholesterol absorption inhibitors to statins is relatively
small, usually approximately 15%, for instance, for ezetimibe or plant
stanols. No clinical studies have been published defining their
additional reduction of coronary events during these treatments, which
seems to be true also for their monotherapy, even though they are
suitable for treatment of modestly increased LDL cholesterol, and
stanol ester management also provides the heart-healthy fatty acids.
Relatively low LDL cholesterol lowering either in mono- or in
combination with statin treatment certainly requires randomized large-
enough study populations treated for relatively long periods of time
to record changes in heart events. In addition to LDL cholesterol
lowering, cholesterol absorption inhibitors lower also plant sterol
levels off or on statin treatment. Thus, they also normalize statin-
induced increase of plant sterols. The endarterectomized patients
treated with statin in our study had increased serum plant sterol
ratios to cholesterol, which appeared also to be reflected in
atheromatous plaques of carotid arteries (1). This finding certainly
rises a question as to whether the lowering of serum plant sterols
with cholesterol absorption inhibitors, e.g., ezetimibe or plant
stanols, also could reduce plant sterol contents in the plaques.
However, it also raises the question of whether an increase of serum
plant sterols, e.g., during the consumption of plant sterol-enriched
functional foods, also could enhance their concentrations in
atheromatous plaques. Several studies have shown that increased serum
plant sterols, even their ratios to cholesterol, are associated with
enhanced coronary artery disease in crossover or follow-up
investigations (2). However, in the Scandinavian Simvastatin Survival
Study, no association was found in the control group between the five-
year coronary events and baseline plant sterol concentrations or
ratios to cholesterol (2). In the respective simvastatin treatment
group, coronary events were reduced significantly in the low absorber
but unchanged in the high absorbers, suggesting that additional
lowering of LDL cholesterol is needed in the latter type of patients,
e.g., by combination with cholesterol malabsorption. Statin treatment
seems to improve endothelial function of carotid arteries despite
increasing serum plant sterols (3); however, vascular function was
unaffected with phytosterol-enriched food when LDL cholesterol was
lowered and serum plant sterols were increased (4,5). Drs. Radermecker
and Scheen concluded that "elevated serum plant sterols pose an
increased cardiovascular risk," but clinical heart event reduction
with their pharmacological lowering is still open.

* * *
There are obviously some unanswered questions here.  I, for one, am
not clear on why food manufacturers are allowed to promote plant
sterols as "heart healthy" when that really is unclear.  It is quite
possible that the opposite is true.

Marilyn