Peer-reviewed scientific article

Cardiovascular Health Benefits of the Mediterranean diet

Targeting oxidized LdL
Joseph L. Evans

JoSEPH L. EVANS Stratum Nutrition, 20 Research Park drive, Saint Charles, Mo 63304, USA KEYWoRdS: Cardiovascular, chitin-glucan, hydroxytyrosol, intervention, Mediterranean diet, nutrition, olive extract, oxLdL, oxidized LdL, polyphenolics. ABSTRACT: There is a worldwide pandemic of chronic cardiovascular disease. The purpose of this article is to highlight some promising nutrients present in the Mediterranean diet that have been shown in clinical trials to reduce oxidized low-density lipoprotein (oxLdL), a pro-atherogenic mediator and biomarker for cardiovascular disease. INTRODUCTION TO CARDIOVASCULAR DISEASE AND SCOPE OF PROBLEM There is a worldwide pandemic of chronic cardiovascular disease mediated, to a significant degree, by global increases in the prevalence of obesity, type 2 diabetes, and the metabolic syndrome. In Europe and the US, more than 1 in 3 adults currently live with one or more types of cardiovascular disease, corresponding to 220 million and 81 million adults, respectively. Cardiovascular disease, especially atherosclerotic coronary heart disease and stroke, are the leading causes of death throughout the world. Cardiovascular disease causes over 4.3 million deaths in Europe and over 2 million deaths in the European Union (EU); these figures represent 48 and 42 percent, respectively, of the total deaths. In the US, cardiovascular disease accounts for one in three deaths. There are approximately 2200 deaths every day attributed to cardiovascular disease, averaging 1 death every 40 seconds. Throughout the world, an estimated 22 million people died from cardiovascular disease in 2008, representing ~30 percent of all global deaths. The economic impact is staggering: cardiovascular disease cost the health care systems in the EU approximately 100 billion in 2006. This represents a cost per capita of 223 per annum and approximately 10 percent of the total health care expenditures across the EU. The total direct and indirect cost of cardiovascular disease in the US in 2010 is estimated be $316 billion. Irrespective of ones genetic make-up, which certainly influences ones overall risk for developing cardiovascular disease, appropriate lifestyle choices which include dietary modification, clearly result in a significant risk reduction for contracting this dreaded disease. The purpose of this article is to highlight some promising nutrients that have been shown in a clinical setting to have a beneficial effect on lowering oxidized low-density lipoprotein (oxLdL), a pro-atherogenic mediator and biomarker for cardiovascular disease. (HdL)-cholesterol levels. However, it is quite apparent that many subjects who suffer from cardiovascular disease have laboratory values for traditional risk factors that fall within the normal range. Thus, it is likely that other risk factors exist and await identification and validation. In this regard, a major candidate is oxLdL (Figure 1). As is true for all major chronic diseases, cardiovascular disease is a disease associated with oxidative stress and inflammation. Since it was first proposed by Steinberg (1), the role of oxidatively modified LdL in atherosclerotic plaque formation and the progression of atherosclerosis has garnered extensive biochemical, cellular, animal, and clinical support. There are several major lines of evidence that support the proatherogenic role of oxLdL. It is highly atherogenic in vitro and in vivo. OxLDL is a plaque-specific protein; it is not detected in normal arteries. oxidized LdL stimulates the differentiation of macrophage cells into lipid-laden foam cells. oxLdL induces apoptosis of vascular endothelial cells, and stimulates the production of many pro-inflammatory molecules, including monocyte chemotactic protein-1, high sensitivity C-reactive protein, interleukin-6, and tumour necrosis factor- (2). In clinical trials, oxLdL is reported to be a more sensitive predictor of risk for developing cardiovascular disease compared to total cholesterol and LdL-cholesterol, which are more widely accepted risk factors (3). Thus, nutritional interventions designed to reduce oxLdL offer a scientifically sound approach for improving cardiovascular health, and perhaps delaying the development of atherogenesis.

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NUTRIENTS THAT REDUCE OXIDIZED LDL A comprehensive review of every nutritional intervention that has been reported to lower oxLdL is beyond the scope of this article. However, an excellent review on this topic is available, and will provide the reader with a more extensive evaluation of this subject than can be accomplished here (4). The focus of this section will be to highlight the Mediterranean diet, along with some of its important nutritional components. A more comprehensive list of nutrients that have been reported to reduce oxLdL is provided in Table 2. Mediterranean Diet The most widely recognized diet with health promoting benefits is the Mediterranean diet (Table 1). Around 50 years ago, it was

OXIDIZED LDL AS A PROATHEROGENIC MEDIATOR AND BIOMARKER FOR CARDIOVASCULAR DISEASE Important risk factors for developing cardiovascular disease include elevated serum levels of total cholesterol, low-density lipoprotein (LdL)-cholesterol and triglycerides, and low high-density lipoprotein

Figure 1. oxidized LdL is both a mediator of atherogenesis and a biomarker.

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recognized by Keys and associates that a very low incidence of cardiovascular disease in the areas around Naples, Italy, was associated with Table 1. Key nutritional components of the Mediterranean diet. a diet now known as the Mediterranean Diet. Since that time, numerous studies have confirmed the beneficial effects of the Mediterranean diet on cardiovascular health (5-7), and related metabolic disorders. Since the initial identification of a positive correlation of the Mediterranean diet with a reduced risk for developing cardiovascular disease, consumption of this diet has now been associated with a significant overall improvement in health status, as seen by a significant reduction in overall mortality (9 percent), mortality from cardiovascular diseases (9 percent), incidence of or mortality from cancer (6 percent), and incidence of Parkinsons disease and Alzheimers disease (13 percent) (5). Several clinical studies have shown an association between the adherence to a Mediterranean Diet and a significant reduction in OxLDL (8, 9). Direct evidence for the ability of the Mediterranean diet to reduce oxLdL was obtained in a randomized, controlled study (7). In this study, a total of 372 subjects at high cardiovascular risk were recruited into a large, multicentre, randomized, controlled, parallel-group clinical trial (the Prevencion con dieta Mediterranea (PREdIMEd) Study). Subjects were assigned to a low-fat diet (n = 121), or one of 2 traditional Mediterranean diets (TMd; TMd + virgin olive oil, or TMd + nuts); diets were ad libitum. After the 3-month intervention, mean oxLdL levels decreased in the TMd + virgin olive oil (-10.6 mU/ml) and TMd + nuts (-7.3 mU/ml) groups, without changes in the low-fat diet group (-2.9 mU/ ml). The change in oxLdL level in the TMd + virgin olive oil group reached significance vs. that of the low-fat group (P = 0.02). Thus, individuals at high cardiovascular risk who improved their diet toward a TMd pattern showed significant reductions in LDL oxidation. Olive Extract/Hydroxytyrosol There is a large body of evidence indicating that olive oil provides many of the beneficial effects on health that are associated with the Mediterranean diet (10). olive oil contains a range of phenolic compounds which likely account for many of its health benefits (11). The total phenolic content of olive oil has been reported to be in the range of 196-500 mg/kg (12). Although the reported levels of phenolic compounds in olive oil vary widely, one consistent conclusion is that extra virgin olive oil has a higher phenolic content than refined virgin olive oil (12). Olive oil phenols can be divided into three categories: simple phenols, secoiridoids, and lignans, all of which inhibit autooxidation (11). Major phenols include hydroxytyrosol, tyrosol, oleuropein, and ligstroside. Hydroxytyrosol and tyrosol are simple phenols and oleuropein is a secoiridoid (Figure 2). Numerous studies performed in vitro and in vivo have concluded that polyphenolic compounds present in extra virgin olive oil play an important role in the prevention of atherosclerotic damage through their inhibition of low density lipoprotein (LdL) oxidation (13, 14). Tyrosol and hydroxytyrosol show dose-dependent activity and are considered potent antioxidants, demonstrating activity in the micro-molar range. Hydroxytyrosol, however, has biological activity beyond its antioxidant capacity, as it can affect a range of enzymes, including cyclooxygenase and NAd(P)H oxidase, reduce platelet Figure 2. Major phenolic compounds in olive oil. (a)Tyrosol; (b) Hydroxytyrosol; (c) aggregation, and increase oleuropein. mitochondrial biogenesis (15).

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Lycopene Another key ingredient of the Mediterranean diet is tomatoes. Lycopene is the most abundant carotenoid found in tomatoes, in Western diets, and in human plasma. Epidemiological evidence indicates an association with lycopene intake and reduced risk for cardiovascular disease, but intervention studies that support this finding are scarce (16). Two, relatively small dietary intervention studies evaluating lycopene in food have indicated a reduction in oxLdL in healthy humans (17, 18), but there are no data reporting the direct effect of purified lycopene intervention on oxLdL in either healthy subjects, or in those at risk for developing cardiovascular disease. Chitin-Glucan Mushrooms are frequently included as a component of the Mediterranean diet, and their consumption has been associated with cardioprotective benefits. Chitin-glucan is a natural component of the cell wall of many mushrooms and other fungi and can be regarded, nutritionally, as an insoluble dietary fibre. Chitin-glucan, extracted from the mycelium of Aspergillus niger fungus, was examined in a pilot clinical study in which twenty healthy, normocholesterolemic young males consumed 4.5 g chitin-glucan per day (as capsules, 1.5 g before each main meal) for four weeks (19). Compared to the placebo group, oxLdL was decreased by approximately 26 percent in the group that consumed chitin-glucan (19). In addition, a decrease (~20 percent) in oxidized glutathione and an increase in the ratio of reduced to oxidized glutathione (~9 percent) were also reported. These results are consistent with an increase in anti-oxidant enzyme activity as observed in atherogenic hamsters, in which chitin-glucan feeding completely prevented the development of aortic fatty streaks (20). Green tea Although green tea is not typically included in the Mediterranean diet, its consumption is associated with a reduced risk for cardiovascular disease. There is evidence from multiple clinical intervention studies, although limited in subject number and duration of intervention, that consumption of green tea in moderate amounts has a significant effect at reducing OxLDL, biomarkers of inflammation, and other measures of cardiovascular health (21-23).
Table 2. Nutrients that reduce oxidized LdL.

our risk for cardiovascular disease seems clear: stop smoking, increase physical activity, and increase our consumption of foods typically associated with the Mediterranean diet. The consumption of foods and beverages high in polyphenolic compounds clearly offers the best protection for staving off this dreaded cluster of diseases. REFERENCES AND NOTES
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-/+, equivocal evidence; +, limited evidence from 1 study; ++, moderate evidence from two studies; +++, strong evidence from multiple studies.

CONCLUSIONS While there is no avoiding the fact that our genes play a significant role in determining overall risk for developing cardiovascular disease and ultimately determining longevity, lifestyle choices including the food we eat are profoundly influential and account for 80 percent of cardiovascular disease. The recipe for reducing

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