Background: Blood cholesterol levels are regulated by competing mechanisms of cholesterol synthesis, absorption and excretion. Plant sterols which are natural constituents of plants, are not synthesized in humans and serve as markers for cholesterol absorption. Various studies suggest that plant sterols are “per se” atherogenic. Ezetimibe lowers the intestinal absorption of dietary cholesterol and plant sterols, whereas statins inhibit endogenous cholesterol synthesis and increase intestinal cholesterol absorption. Therapeutic effects of these lipid-lowering drugs show individual variation.

Objectives: The aim of the present study was to assess whether differences in cholesterol metabolism and in particular increased cholesterol and plant sterol absorption (e.g. campesterol and sitosterol) affect the occurrence of in-stent proliferation and in-stent restenosis (ISR) in stable coronary artery disease.

Methods: In this post-hoc analysis of a clinical, monocentric trial, we analyzed a subset of data: 59 patients (74.6 % males, 67.2 ± 9.6 years) with stable CAD underwent elective stent implantation of de novo stenosis and were further investigated regarding their individual cholesterol metabolism profile. Cholesterol and non-cholesterol sterols were quantified in serum samples by gas chromatography or mass spectrometry. All patients underwent invasive follow-up including intracoronary imaging of the stented lesion by OCT after 6 months. ISR was assessed by optical coherence tomography (OCT) and quantitative angiography (QCA) and its association to cholesterol and non-cholesterol sterol blood levels, specifically to markers of cholesterol absorption (e.g., sitosterol, campesterol, cholestanol) and to lathosterol as synthesis marker were investigated.

Results: Markers for cholesterol absorption (e.g. campesterol-to-cholesterol ratio) were positively associated with ISR measured by QCA (%diameter stenosis, late lumen loss) and OCT (proliferation volume, %area stenosis), whereas markers for cholesterol synthesis (e.g. lathosterol-to-cholesterol) were negatively associated with ISR (%area stenosis: r=-0.271, p=0.043) (Fig.1). No associations were found for the conventionally measured lipid profile (total cholesterol, LDL-C, HDL-C, triglycerides) (Fig.3). Patients on additional ezetimibe treatment were characterized by significantly reduced markers for dietary cholesterol and plant sterol absorption (e.g. campesterol-to-cholesterol) compared to patients on a statin only (1.29 ± 0.69 vs. 2.22 ± 1.23; p=0.007). Moreover, combined lipid-lowering with ezetimibe plus statin reduced ISR at 6-month invasive f/u compared to statin only (13.7 ± 10.4 vs. 22.5 ± 12.1 %diameter stenosis, p=0.015) (Fig.2).

Conclusions: In this hypothesis-generating study, differences in cholesterol metabolism, more specifically increased dietary cholesterol and plant sterol absorption, are associated with ISR. These findings underline the need for individualized dietary advice and personalized lipid-lowering therapy.