Plasma sitosterol elevations are associated with an increased incidence of coronary events in men: Results of a nested case-control analysis of the Prospective Cardiovascular Münster (PROCAM) study

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Summary

Background and aim

Sitosterolemia, a rare genetic disorder characterized by profoundly elevated plasma sitosterol concentrations, is associated with premature atherosclerosis in some individuals. This study was conducted to evaluate if the modest sitosterol elevations seen in the general population are also associated with the occurrence of coronary events.

Methods and results

A nested case-control study using stored samples from male participants in the Prospective Cardiovascular Münster (PROCAM) study was performed. Each of 159 men who suffered a myocardial infarction or sudden coronary death (major coronary event) within 10 years of follow-up in PROCAM was matched with 2 controls (N = 318) by age, smoking status, and date of investigation. Analysis was performed using conditional logistic regression. Plasma sitosterol concentrations were elevated in cases compared with controls (4.94 ± 3.44 μmol/L versus 4.27 ± 2.38 μmol/L; P = 0.028). The upper quartile of sitosterol (>5.25 μmol/L) was associated with a 1.8-fold increase in risk (P < 0.05) compared with the lower three quartiles. Among men with an absolute coronary risk ≥20% in 10 years as calculated using the PROCAM algorithm, high sitosterol concentrations were associated with an additional 3-fold increase in the incidence of coronary events (P = 0.032); a similar, significant relationship was observed between a high sitosterol/cholesterol ratio and coronary risk (P = 0.030).

Conclusions

Elevations in sitosterol concentrations and the sitosterol/cholesterol ratio appear to be associated with an increased occurrence of major coronary events in men at high global risk of coronary heart disease. Further evaluations are warranted to confirm these preliminary findings.

Introduction

Elevated cholesterol, the most common sterol of animal origin, is known to be associated with coronary heart disease (CHD). Sterols of plant origin (phytosterols) including sitosterol and campesterol are structurally similar to cholesterol but exhibit about a 10-fold lower net absorption from the small intestine and markedly lower circulating concentrations than cholesterol [1], [2].

In normolipidemic individuals, circulating sitosterol concentrations vary over a 5–10 fold range [3], and this variation is highly heritable [4]. Mutations in ATP-binding cassette (ABC) half-transporter genes cause sitosterolemia; a rare autosomal recessive disorder characterized by profoundly elevated absorption and reduced biliary excretion of sitosterol [5], [6], [7]. Patients with sitosterolemia may experience up to 50-fold elevations in circulating sitosterol concentrations, tendon and tuberous xanthomas at an early age, and premature atherosclerosis despite normal cholesterol levels [3], [6], [7].

The potential significance of more modest sitosterol elevations in the general population is less clear. The prevalence of angiographically documented CHD was independently and positively associated with the ratio of sitosterol to cholesterol in postmenopausal women [8]. Elevated sitosterol and other phytosterols and/or their ratios to cholesterol have also been associated with a family history of premature CHD in hypercholesterolemic patients, including candidates for elective coronary artery bypass [9], [10]. In a cross-sectional case-control study involving mildly hypercholesterolemic patients with type II diabetes mellitus, elevated cholesterol absorption was the single metabolic parameter that significantly differentiated patients with CHD from those without in multiple logistic regression analyses [11].

A possible link between plant sterols and coronary risk was also detected in the Scandinavian Simvastatin Survival Study (4S). By measuring markers of cholesterol synthesis (cholestenol, desmosterol, lathosterol) and of cholesterol absorption (cholestanol, sitosterol, campesterol) in the Finnish cohort of 4S, Miettinen and colleagues showed that participants with a high rate of cholesterol absorption and a low rate of cholesterol synthesis failed to benefit from statin therapy in terms of a reduction of coronary events, although the degree of low-density lipoprotein (LDL) cholesterol lowering in these patients was only slightly less than that seen in the low absorption/high synthesis participants [12], [13], [14]. This observation led Miettinen to comment that “the increased ratio of plant sterols during…simvastatin treatment in [non-responding cholesterol hyper-absorbers] raises a question about their atherogenicity” [13] and, more recently, that “simvastatin increases the ratios of cholestanol and plant sterols, phytosterolemia is strongly atherogenic, and high plant sterol concentrations may be atherogenic”[14].

Other investigators however have linked a high phytosterol content of the diet to atheroprotection. In the Asian diet, for example, soy typically makes up 20–65% of all protein, in contrast to the Western diet, in which most protein comes from animal sources. This increased content of soy, which is rich in phytosterols, has been invoked as one reason for the lower incidence of coronary heart disease in Asian populations [15].

The aim of the present nested case-control analysis of the Prospective Cardiovascular Münster (PROCAM) study was thus to evaluate the relationship between the modest sitosterol elevations seen in the general population and CHD risk in men from a large prospective population-based cohort.

Section snippets

Patients

The PROCAM study investigates a large-scale prospective employment-based cohort. Eligibility criteria have been published previously [16]. In brief, participants were aged 16–65 years at recruitment, and individuals with CHD or stroke were excluded. At the time of this study, 10 years of follow-up and event adjudication had been completed. PROCAM was conducted in accordance with the Declaration of Helsinki. Both the protocol and informed-consent document were approved by a local institutional

Selection of study samples for nested case-control analysis

Of 13,770 men initially recruited into PROCAM, 8162 were excluded based on age 16–34 years, prior myocardial infarction or stroke, or angina pectoris at recruitment. Of the remaining 5608 men free of disease at recruitment, 1758 were excluded because of freezer failure, failure to collect samples, or insufficient plasma volumes. Of the remaining 3850 eligible participants, 165 men suffered a coronary event within 10 years of follow-up, including 159 evaluable cases; 6 cases were excluded

Discussion

In this nested case-control study, elevated sitosterol was associated with an increased risk for the development of major coronary events over 10 years. Among men already at high global risk of CHD (>20% 10-year event risk), a high sitosterol concentration or sitosterol/cholesterol ratio was associated with an approximately 3-fold further increase in the risk of a coronary event (Figure 2, Figure 3). Of the 26 men with high global CHD risk and high sitosterol concentrations, 18 (69%) had

Acknowledgment

We thank Dr. Wayne Weng for help in developing the study protocol and reviewing the data.

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    Financial support: this study was supported by an unrestricted educational grant from Merck–Schering Plough Pharmaceuticals, North Wales, Pennsylvania, USA.

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