| |
Mediterranean Diet Improves LDL-Cholesterol
|
| |
| |
Effect of a Traditional Mediterranean Diet on Lipoprotein Oxidation
A Randomized Controlled Trial
Montserrat Fito, MD, PhD; Monica Guxens, MD; Dolores Corella, DPharm, PhD; Guillermo Saez, MD, PhD; Ramon Estruch, MD, PhD; Rafael de la Torre, DPharm, PhD; Francesc Frances, MD; Carmen Cabezas, MD; Maria del Carmen Lopez-Sabater, DPharm, PhD; Jaume Marrugat, MD, PhD; Ana Garcia-Arellano, PhD; Fernando Aros, MD, PhD; Valentina Ruiz-Gutierrez, PhD; Emilio Ros, MD, PhD; Jordi Salas-Salvado, MD, PhD; Miquel Fiol, MD, PhD; Rosa Sola, MD, PhD; Maria-Isabel Covas, DPharm, PhD; for the PREDIMED Study Investigators
Arch Intern Med. June 11, 2007;167:1195-1203.
"....The present study is, to our knowledge, the first randomized controlled clinical trial focused on the effect of a Mediterranean type diet on in vivo LDL oxidation. Individuals at high risk of CHD who improved their diet toward a TMD pattern had significant reductions in their in vivo LDL oxidation compared with individuals assigned to a low-fat diet...."
ABSTRACT
Background Despite the richness in antioxidants of the Mediterranean diet, to our knowledge, no randomized controlled trials have assessed its effect on in vivo lipoprotein oxidation.
Methods A total of 372 subjects at high cardiovascular risk (210 women and 162 men; age range, 55-80 years), who were recruited into a large, multicenter, randomized, controlled, parallel-group clinical trial (the Prevencion con Dieta Mediterranea [PREDIMED] Study) directed at testing the efficacy of the traditional Mediterranean diet (TMD) on the primary prevention of coronary heart disease, were assigned to a low-fat diet (n = 121) or one of 2 TMDs (TMD + virgin olive oil or TMD + nuts). The TMD participants received nutritional education and either free virgin olive oil for all the family (1 L/wk) or free nuts (30 g/d). Diets were ad libitum. Changes in oxidative stress markers were evaluated at 3 months.
Results
After the 3-month interventions, mean (95% confidence intervals) oxidized low-density lipoprotein (LDL) levels decreased in the TMD + virgin olive oil (-10.6 U/L [-14.2 to -6.1]) and TMD + nuts (-7.3 U/L [-11.2 to -3.3]) groups, without changes in the low-fat diet group (-2.9 U/L [-7.3 to 1.5]). Change in oxidized LDL levels in the TMD + virgin olive oil group reached significance vs that of the low-fat group (P = .02). Malondialdehyde changes in mononuclear cells paralleled those of oxidized LDL. No changes in serum glutathione peroxidase activity were observed.
Conclusions Individuals at high cardiovascular risk who improved their diet toward a TMD pattern showed significant reductions in cellular lipid levels and LDL oxidation. Results provide further evidence to recommend the TMD as a useful tool against risk factors for CHD.
INTRODUCTION
Adherence to the traditional Mediterranean diet (TMD) has been associated with a reduction in coronary heart disease (CHD), cancer, and overall mortality.1-3 This protective effect has been attributed, at least in part, to the richness of this diet in antioxidants.1, 3 Current evidence indicates oxidative damage as a promoter of pathophysiological changes occurring in oxidative stress-associated diseases, such as CHD, cancer, and neurodegenerative disorders and also in aging.4 Oxidized low-density lipoprotein (oxLDL) level may play a major role in atherosclerosis and cardiovascular disease and is a commonly used marker for oxidative damage.5-6 An oxLDL predictive value for the onset of mobility disability has also been recently reported.7 Adherence to a Mediterranean type diet has been shown to be associated with lower plasma oxLDL level in a cross-sectional study8 and in a linear intervention study in healthy women.9 However, to our knowledge, no randomized controlled intervention studies have assessed the efficacy of the Mediterranean diet on in vivo LDL oxidation.
Olive oil is the main fat component of the Mediterranean diet.1 Among olive oils, virgin olive oil (VOO) has the highest antioxidant phenolic content compared with other olive oils such as ordinary or pomace olive oil.10 Nuts, which are also typical Mediterranean foods, are a rich source of nutrients and antioxidant phytochemicals.11 We designed a large-scale feeding trial in a population at high risk for CHD to assess the effects on cardiovascular outcomes of 2 Mediterranean diets, one supplemented with VOO and the other with mixed nuts, compared with a low-fat diet (the Prevencion con Dieta Mediterranea [PREDIMED] Study). We report herein the results of a 3-month intervention on markers of lipid oxidative damage and endogenous antioxidant status in 372 participants recruited into the trial.
RESULTS
STUDY POPULATION
Of the 930 eligible participants, 772 met the eligibility criteria and were randomized. The effect of the 3 interventions on oxLDL and the antioxidant enzyme GSH-Px was assessed in a subpopulation of 372 individuals selected at random and with similar characteristics to those of the whole group (Table 1). Figure 1 shows the flow of participants through the study. Differences between the sexes are given in Table 1 and among intervention groups in Table 2. The lipid cardiovascular risk profile worsened from the low to the high oxLDL tertile (P<.01). Glucose, daily energy expenditure in leisure-time physical activity, LDL-HDL cholesterol ratio, and percentage of diabetic participants increased across GSH-Px tertiles (P<.05). Systolic blood pressure was lower in participants in the upper GSH-Px tertile (P = .003) and tended to be higher in the upper oxLDL tertile (P = .06) but not significantly so.
ENERGY BALANCE AND DIETARY ADHERENCE
Adherence to supplemental foods was good. a-Linolenic acid levels increased from baseline in the TDM + nuts group (P = .04) and tyrosol and hydroxytyrosol levels increased in the TMD + VOO group (P<.001) (Figure 2). Physical activity did not change during the intervention periods in any group. A reduction in energy intake was observed in the TMD + VOO and low-fat diet groups (Table 3). Participants in the TMD + nuts group increased their intake of total, monounsaturated, and polyunsaturated fat and reduced their saturated fat and carbohydrate intake. In the TMD + VOO group, a decrease in total and saturated fat was observed. Monounsaturated fat intake did not change in this group after the intervention. This fact, together with the lack of change in total olive oil consumption (Table 3) and the increase of tyrosol and hydroxytyrosol levels in urine (Figure 2B and C), indicated that participants in the TMD + VOO group replaced the ordinary olive oil they used to consume by the VOO provided to them in the frame of the PREDIMED study. Consumption of legumes increased in both TMD groups. Participants in the TMD + nuts group increased their intake of vegetables, fruits, and fish. Consumption of dairy products diminished in all groups and that of meat in both TMD groups. The global dietary pattern of adherence to the Mediterranean diet increased in the TMD groups after the intervention, as was reflected in the changes in the 14-item score.
OXIDATIVE STATUS
Oxidized LDL decreased significantly in both TMD groups (Table 4). In the unadjusted model, the decrease in oxLDL level reached significance (P = .04) in the TMD + VOO group vs that of the low-fat diet group and was not significant in the TMD + nuts group (P = .09). Models adjusted by possible confounder variables confirmed the aforementioned results. No changes were observed in GSH-Px values after the interventions (Table 4). In a subsample of 71 individuals, malondialdehyde levels in mononuclear cells decreased in both TMD groups. The mean (95% confidence interval) decreases were -0.20 (-0.31 to -0.77) nmol/mg of protein and -0.24 (-0.30 to -0.17) nmol/mg of protein for TMD + VOO and TMD + nuts groups, respectively (P<.01). No changes were observed in the low-fat diet group (0.02 [-0.09 to 0.13] nmol/mg of protein). Changes in malondialdehyde level in TMD groups vs that of the low-fat diet group reached significance (P = .004). No sex differences were observed.
CLASSIC CARDIOVASCULAR RISK FACTORS
Body mass index and waist circumference did not change in the 3 interventions. Systolic (P = .008) and diastolic (P = .03) blood pressures decreased in both TMD groups. In the TMD + nuts group, a reduction in triglyceride level (P = .04) and an increase in HDL cholesterol level (P = .03) were observed. Total cholesterol level and total-HDL and LDL/HDL cholesterol ratios decreased in the TMD groups more than that in the low-fat diet group (P<.05).
COMMENT
The present study is, to our knowledge, the first randomized controlled clinical trial focused on the effect of a Mediterranean type diet on in vivo LDL oxidation. Individuals at high risk of CHD who improved their diet toward a TMD pattern had significant reductions in their in vivo LDL oxidation compared with individuals assigned to a low-fat diet.
Oxidation of the lipids and apoproteins present in LDL leads to a change in the lipoprotein conformation by which LDL is better able to enter the monocyte-macrophage system of the arterial wall and promote the atherosclerotic process.18 However, although the role of lipid oxidation in atherosclerotic cardiovascular disease has long been recognized,19 the clinical relevance of lipoprotein oxidation is under debate. The role of the oxidant-antioxidant imbalance in atherogenesis has been questioned because, in spite of the consistent results from cohort studies showing an inverse association between customary intakes of dietary antioxidants and CHD development, large intervention trials with antioxidant vitamin supplements have shown no benefit.20 Recent results from the INTERHEART study, a large intercountry case-control study, support the protective role of dietary antioxidants on CHD risk.21 A likely explanation for this paradox is that lifetime consumption of the complex mixture of antioxidants in foods is more effective than large doses of a single antioxidant given for a finite period. The latter might deplete the endogenous antioxidant pool, thus turning an antioxidant effect into prooxidant in vivo.22
Another subject under debate is the pathophysiological and clinical relevance of the different types of oxLDL biomarkers, their added value in front of classic lipid risk factors, and their response to therapies.23 There is, however, accumulating evidence showing that circulating oxLDL levels were predictors for acute CHD, both in patients with CHD and in the general population,5-6 and were a prognostic marker for subclinical atherosclerosis.24 When lipoprotein oxidation was measured with antibodies directed against oxidized phospholipids (OxPLs), which predominantly bind to lipoprotein(a), plasma OxPL level decreased, but the OxPL-apolipoprotein B ratio increased after a lipid-lowering diet and atherosclerosis regression.19 This phenomenon was also observed after statin treatments.19 These facts support the hypothesis that lipoprotein(a) binding of OxPL is an innate immune mechanism to clear proinflammatory OxPL from atherosclerotic sites.19 Antibodies directed against malondialdehyde-lysine epitopes on LDL, such as those used in the present study, do not bind lipoprotein(a). With the use of this method, it has been found that oxLDL level decreased after a lipid-lowering diet, such as the Mediterranean diet.8-9 Oxidized LDL level, as measured by these antibodies, correlates directly with LDL cholesterol level and inversely with HDL cholesterol level.25 Given that our results were adjusted by these lipoproteins, we can assume an independent effect of the TMD intervention on circulating oxLDL level. In our study, the mean decrease in oxLDL level was -10.6 U/L and -7.3 U/L after TMD + VOO and TMD + nuts, respectively. In a recent study,6 the mean difference in circulating oxLDL values between patients with CHD and healthy controls, measured by the same antibody and method used in the present study, was 17 U/L. However, the current state-of-the-art knowledge does not allow an estimation of the attributable CHD risk associated with a 1-U/L change in oxLDL level, and further rigorous prospective studies are needed. Longer follow-up of the whole PREDIMED trial will eventually provide the information.
Recent results from the EUROLIVE study showed that olive oil rich in polyphenols, such as VOO, reduces the oxidative lipid damage more than other types of olive oils.26 Besides olive oil, the high content of vegetables, fresh fruits, and nuts in the TMD, together with a moderate consumption of wine, guarantees a high intake of antioxidant vitamins and polyphenols. In agreement with previous results,3, 27 following the TMD improved the classic cardiovascular risk lipid profile and blood pressure levels. A synergistic relationship exists between oxidative damage and inflammation, and both of these are related to endothelial dysfunction. The decrease in oxLDL level promoted by the TMD concurs with the reductions in inflammatory markers previously reported in the PREDIMED study12 as well as in diabetic patients.27 Also, a major cause for endothelial dysfunction in essential hypertension is a decreased availability of nitric oxide. Oxidative stress, through superoxide anion production, decreases nitric oxide availability, and an inhibition of the nitric oxide synthase expression by oxLDL has been reported.28 Thus, the reduction in the degree of LDL oxidation may contribute, at least in part, to the decrease in blood pressure observed in this study.
Our trial has several strengths, like its design, which is able to provide first-level scientific evidence29 and work in real-life conditions, such as with home-prepared foods. Our study also has limitations. The first was to ensure participants' compliance by means of dietary instructions. Adherence to the supplemental foods, however, was good, as observed in the changes of the compliance biomarkers. Another limitation was that participants assigned to the low-fat diet group did not receive a personalized behavioral intervention to follow the intended low-fat diet. Fat intake was only slightly reduced in this group. Thus, an important part of the differences in outcomes observed might be attributed to the supplemental foods (VOO and nuts). Also, a 3-month period provides no information about the sustainability or long-term effects of the diets on cardiovascular risk factors. However, 2 weeks is the common time frame established for fat-rich diets to reach equilibrium in the plasma lipid profile; longer intervention periods do not modify the lipid concentration.30
In summary, a TMD pattern promoted benefits on classic and novel risk factors for CHD. Our findings suggest a decrease in the oxidative damage to LDL to be one of the protective mechanisms by which the Mediterranean diet could exert protective effects on CHD development. Data from this study provide further evidence to recommend the TMD as a useful tool against atherosclerosis development, particularly in individuals at high risk for developing CHD.
|
|
| |
| |
|
|
|
