Phytosterols and blood lipid risk factors for cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Lifestyle improvements including dietary changes are important for CVD prevention. This thesis aimed to advance insights in the role of phytosterols, lipid-like compounds present in foods or plant origin, in the management of blood lipid risk factors for CVD. Phytosterols include plant sterols and their saturated form, plant stanols. These compounds resemble cholesterol in both structure and function, but cannot be produced by the human body. The intake of phytosterols occurs through plant-based foods and/or enriched foods like margarine. Elevated blood low-density lipoprotein cholesterol (LDL-C) is a major risk factor for CVD, especially for coronary heart disease (CHD) resulting from atherosclerosis. We studied the dose-response relationship between dietary phytosterols and blood LDL-C in two meta-analyses (Chapters 2 and 3). A meta-analysis of 81 randomized controlled trials (Chapter 2) demonstrated a non-linear, continuous dose-response relationship for the LDL-C-lowering effect of phytosterols. Based on this dose-response curve, it may be predicted that phytosterols at a dose of 2 g/d lower LDL-C by 0.35 mmol/L or 9%. The dose-response curve reached a plateau at phytosterol doses of ~3 g/d, above which there is limited additional LDL-C-lowering effect. In another meta-analysis of 124 randomized controlled trials (Chapter 3), we showed that plant sterols and plant stanols up to ~3 g/d are equally effective in lowering LDL-C by a maximum of 12%. No conclusions could be drawn for phytosterol doses exceeding 4 g/d because of the limited number of studies. Elevated blood triglycerides (TGs) may also be involved in the onset of CVD, although its role is less established than for LDL-C. The effect of plant sterols on blood TG concentrations was assessed in a meta-analysis of individual subject data from 12 randomized controlled trials (Chapter 4). We showed that plant sterols, at a dose of ~2 g/d, modestly reduce TG concentrations by on average 0.12 mmol/L or 6%. The TG-lowering effect of plant sterols was larger in subjects with higher initial TG concentrations. Our double-blind, placebo-controlled, randomized trial with 332 subjects (Chapter 5) showed more pronounced TG-lowering effects of 9-16% when plant sterols (2.5 g/d) were combined with low doses of omega-3 fish fatty acids (0.9 to 1.8 g/d). Dietary phytosterols are, after initial absorption by intestinal cells, actively excreted back into the intestinal lumen. Nevertheless, small amounts reach the circulation. We assessed the effect of plant sterol intake on blood plant sterol concentrations in a meta-analysis of 41 randomized controlled trials (Chapter 6). The intake of plant sterols, at a dose of ~1.6 g/d, increased blood sitosterol concentrations by on average 2 μmol/L (31%) and campesterol concentrations by 5 μmol/L (37%). At the same time, total cholesterol and LDL-C concentrations were reduced by on average 0.36 mmol/L (6%) and 0.33 mmol/L (9%), respectively. After supplemental intake, plant sterol concentrations remained below 1% of total sterols circulating in the blood. Whether phytosterols, due to their LDL-C-lowering properties, affect the risk of CVD events is at present unknown. The relation between phytosterol intake from natural sources (e.g. vegetables, cereals, nuts) and CVD risk in the population was examined in a large prospective cohort of 35,597 Dutch men and women with 12 years of follow-up (Chapter 7). The intake of phytosterols from natural sources (~300 mg/d) was not related to risk of CVD (total of 3,047 events) with a relative risk ranging from 0.90 to 0.99 across quintiles of phytosterol intake. Also, no association with incident CHD and myocardial infarction were found. In a cross-sectional analysis using baseline data of this cohort, phytosterol intake was associated with lower blood LDL-C in men (-0.18 mmol/L per 50 mg/d; 95% CI: -0.29; -0.08) but not in women (-0.03 mmol/L; 95% CI: -0.08; 0.03). Most randomized trials with enriched foods have tested phytosterol doses between 1.5 and 2.4 g/d. In practice, however, users of such foods consume much lower amounts (~1 g/d), which is about 3 times higher than obtained from a regular Western diet. Individuals who consume diets with emphasis on plant-based foods (e.g. vegetarians) may reach phytosterol intakes between 0.5 and 1 g/d. Health authorities recommend various types of diets for CVD prevention, almost all rich in plant-based foods and, consequently, relatively rich in phytosterols. In conclusion, a high intake of phytosterols with enriched foods was shown to lower LDL-C in a dose-dependent manner. Furthermore, a high intake of plant sterols with enriched foods modestly lowered TG concentrations and increased plasma plant sterol concentrations. A low intake of naturally occurring phytosterols in the general population did not show a clear association with CVD risk. Based on these findings, the intake of phytosterols may be considered in the management of hypercholesterolemia. Whether a high intake of phytosterols can play a role in CVD prevention in the population at large remains to be established.