Cardiovascular disease (CVD) is the number one cause of mortality in the US. According to American heart association statistics, nearly one million men and women succumb to various complications from CVD. In the US, CVD claims more lives than cancer and AIDS combined (CDC, 2012). It is also one of the leading causes of deaths worldwide (WHO). The economic cost of CVD in 2008 was estimated to be $448.9 billion, which was double the cost estimated for the year 2007, $219 billion.
There are a number of factors to the incidence of CVD. These include non modifiable factors such as age, sex, heredity etc. Among the factors that are identified as modifiable, lifestyle, physical activity and diet have been demonstrated to play a key role in the progression of CVD. There are some key changes that can be made to diet to improve the heart health, including consumption of more fruits and vegetable, removal of trans-fats from the diet, consumption of fish and food rich in unsaturated fatty acids etc. Mediterranean diet or the Mediterranean-style diet generally describes the diet traditionally consumed by people living in countries bordering the Mediterranean Sea. The prototype of the Mediterranean diet has been described in the traditional healthy Mediterranean diet pyramid (oldwaysptw.org). The Mediterranean diet is primarily a diet derived from plant based sources. It includes whole grains, legumes, fruits, vegetables and nuts. The primary source of fat is olive oil that is used with salads and in cooking. Fish and poultry are eaten once or twice a week. The diet recommends moderate consumption of dairy including cheese and yoghurt daily, on the other hand red meat is placed on the top of the Mediterranean diet pyramid and is consumed once or twice a month. The MD allows for consumption of wine in moderation, usually with food. Another key component of a traditional MD is intake of small portions.
The various dietary components of the MD have known dietary benefits associated with them. Monounsaturated fatty acids, including the omega -9, oleic acid are derived from olive oil, canola oil, sunflower oil, nuts including pistachios, peanuts, almonds etc. Oleic acid has been shown to lower the LDL levels. It also reduces the triglyceride level and improves the amount of HDL. In addition to being a good source of oleic acid, olive oil has been demonstrated to contain a number of biologically active phenolic compounds that have shown to function as anti-oxidant and lower the plasma lipoprotein levels, reduce oxidative damage and inflammatory markers in the plasma. It is believed that these phenolic compounds, such as Oleocanthal are responsible for the heart healthy effects of olive oil (Cicerale, Conlan, Sinclair & Keast, 2009). Nuts such as walnuts are a great source of omega-3 fatty acids.
Medline (National library of Medicine, Bethesda MD) was searched for Mediterranean diet (MD) and Cardiovascular disease for studies published post 2004. Published studies were selected as primary references that covered broad range of research correlating MD and CVD.
The first study selected was published in 2013 in the New England journal of medicine. It reports the largest randomized control trial completed which looked at the effect of Mediterranean diet on prevention of cardiovascular disease in high risk subjects. The name of the study was PREDIMED trial (Prevención con Dieta Mediterránea).The study recruited 7447 participants, between the ages of 55 and 80 years. 57% of the participants of the study were women. In order to qualify for the study, the participants had to have type 2 diabetes, or three of the following listed risk factors: elevated LDL, smoking, high BP, obesity, low HDL levels, family history of premature coronary heart disease (CHD); however the participants were not to have CVD. Participants were divided into three groups of equal numbers. The first two groups were assigned Mediterranean diet with group 1 MD being supplemented with olive oil and group 2 diet was supplemented with nuts, participants of the third group were asked to follow their usual diet. It has been demonstrated from observations of cohort studies that eating MD has preventive effect on cardiovascular disease development risk (Sofi,Abbate, Gensini, &Casini, 2010) . It has also been validated that people traditionally consuming Mediterranean based diet have lower incidence of coronary heart diseases. This study is possibly the largest randomized clinical study that utilizes diet based evidence for prevention of primary CVD. The participants of the intervention group had to eat a diet based on Mediterranean diet. A dietician offered individual and group training sessions at the beginning of study and after every three months thereafter to modify their dietary habits to increase their intake of fruits, vegetables, whole grains, nuts and virgin olive oil. The primary outcome of the study was combination of stroke, myocardial infarction and death from CVD. The secondary endpoint was MI, stroke, death from CVD and other causes. At the end of the study participants in the intervention groups adhered to the diet and consumed the required amount of various dietary components. It was observed that at the end of the study 8.1, 8 and 11.2 primary outcome events per 1000 person years occurred for groups 1, 2 and 3 respectively. The unadjusted hazard ratio was 0.7 each with CI of 95% for both (olive oil and nut supplemented) intervention groups when compared to the control for CVD events. The key observations of this RCT were that an almost 30% relative risk reduction of cardiovascular events was observed in subjects consuming MD, who were at high risk but free of any previous CVD. When the authors carried out adjusted analyses of the data they found that significant beneficial effects were observed against stroke and combined cardiovascular end points in subjects consuming the two MD; however, the number of MI did not differ significantly between intervention and control groups. 32 and 49 occurrences of stroke were observed in intervention group compared to 59 for control group. A reduction on deaths associated with CVD was observed in intervention groups with the group whose diet was supplemented with olive oil had a significantly better reduction (hazard ratio of 0.69 with 90% CI). The reduction in stroke is probably related to reduction in the blood pressure level associated with the MD. The overall reduction in combined CVD endpoint could stem from the fact that the components of MD exert synergistic effects in the biochemical pathways associated with metabolic and cardiovascular system. The effect on serum lipids, oxidative stress reductions, inhibition of inflammation and effect on vasoreactivity could have a combined beneficial preventive effect on risk of CVD. This elegant yet simple study very clearly demonstrates the benefits of consuming MD diet as a modification to lifestyle in reducing the risk for CVD, especially in high risk population. Modification to diet is a very economic way of lowering risk for CVD. It should be noted that the components of MD diet are generally more expensive than energy rich diet components, however, when looking at the total cost associated with morbidity and mortality associated with CVD, this increased cost for food seems minimal. (Estruch,et. al, 2013)
The next study investigated the effect of consumption of MD, which is rich in virgin olive oil could mediate its beneficial effects on CVD by changing the expression of atherosclerosis associated genes. This is an example of a RCT and was published in the journal FASEB in 2009.
A number of reports have suggested that olive oil which is the primary source of fat in MD is responsible for beneficial effect of MD. However, other studies suggest that the sum total of components including high fiber content is responsible for heart healthy effects. The monounsaturated fat and polyphenolic compounds in the olive oil contribute to the cardio-preventive effect. It has been demonstrated that MD has an effect on peripheral blood mononuclear cells (PBMC) (Khymenets,et. al, 2009). In this study 90, generally healthy men and women were recruited and randomly assigned to three groups. Groups 1 and 2 had to eat a Mediterranean based diet, while group 3 were asked to continue with their habitual diet. The key difference between groups 1 and 2 was that the key source of fat in group 1 was virgin olive oil (VOO) while group 2 was provided washed virgin olive oil (WVOO). WVOO has half of the polyphenolic compounds of the VOO. At the end of the three month trial period the various markers of oxidative damage and inflammation were measured. The levels of TC, HDL,LDL, blood glucose level, IFN-, monocyte chemoattract protein (MCP-1), soluble P selectin (s,P-selectin)and soluble CD40L were measured. It was observed that reduction in expression of inflammation, oxidative stress and DNA damage associated genes in MD supplemented with VOO. The expression of IFN-, ARHGAP-15(Rho GTPase-activating protein15), IL-7R (markers of inflammation), ADRB2(adrenergic -2 receptor) (marker of oxidative stress) and POLK(polymerase DNA directed ) (marker of DNA damage) genes was down-regulated. The authors cite previous work demonstrating the anti-inflammatory activity of MD. MD is known to inhibit the increase in expression of COX-2and LDL-receptor related protein (LRP-1) gene expression and reduce the expression of MCP-1. These genes are associated with inflammatory response. IFN- mediates the induction of pro-inflammatory IL-6, which controls the synthesis of C-reactive protein (CRP) in liver. The gene ARHGAP-15 codes for Rho GTPase activating proteins that are known mediators of cardiac hypertrophy. IL-7R gene codes for the receptor protein for IL-7 which is known to induce chemokines expression. The gene POLK is associated with DNA damage repair. The gene ADRB2 induces the synthesis of macrophage cytokine and its inhibition has been shown to improve survival following traumatic injury. This study demonstrated that ingestion of MD+VOO resulted in down-regulation of genes associated with atherosclerosis. Additionally reduction in markers of oxidative damage and inflammatory response was also observed. This study is the first systematic investigation looking at the nutrigenomic effect of polyphenol, such as oleocanthal present in olive oil in reduction of genomic markers of atherosclerosis. This study describes the molecular mechanism behind cardio protective effects of MD, which is modulated by certain genes. (Konstantinidou et. al, 2009)
A study published in 2004 the journal of American medical association looked at the effect of a Mediterranean diet on markers of vascular inflammation, blood pressure, platelet aggregation potential and measurement of lipid parameters in patients with metabolic syndrome. Metabolic syndrome is described by a number of symptoms that increase the risk or CVD, diabetes and stroke. The presence of only one of the symptoms does not suggest that the subject has metabolic syndrome, however presentation of one or more of the symptoms increase the risk for chronic diseases. The pathophysiology of metabolic syndrome is not completely understood, however it involves interaction of environmental, genetic and metabolic factors. It has been demonstrated that metabolic syndrome is usually associated with low grade inflammation. The study was carried out for a period of three years between 2001 and 2004. The study group comprised of 180 participants with 99 men and 81 women. The participants recruited for the study had 3 or more of the symptoms of metabolic syndrome such as elevated TG level, low HDL level, elevated fasting glucose level, high BP, etc listed in the study design. People who were already diagnosed with CVD were excluded from the study. Participants were randomly divided into 2 groups with 90 subjects in each group. The participants of the intervention group had to eat a diet based on Mediterranean diet rich in fruits, vegetables, whole grains, nuts and virgin olive oil. The control group ate their regular diet and was not offered any counseling sessions. A follow up was performed after two years of consuming Mediterranean diet. At the 2 year follow up it was observed that participants from the intervention group lost more weight than control group (4 kg vs. 1.2 kg), had lower serum LDL, triglycerides, waist circumference, blood pressure and glucose level than control group. Level of cytokines such as IL-6, 7and 8 and hs-CRP (high sensitivity C reactive protein), which are markers of inflammation of vascular system, went down in the intervention group as opposed to control group that saw no changes. The endothelial cell function which was measured by evaluating the response of vascular endothelial cells to L arginine, was improved in the intervention group and unchanged in control. It was observed that 60 of the 90 patients in intervention group experienced reduction in symptoms associated with metabolic syndrome and only 40 participants of the initial 90 could be classified as having metabolic syndrome. In the control group 78 participants still qualified for metabolic syndrome category. In this study it was demonstrated that consumption of Mediterranean diet could be used as a treatment strategy for people diagnosed with metabolic syndrome. A reduction in symptoms associated with metabolic syndrome could lower the risk for CVD. The authors hypothesize that a reduction in inflammation and improvement in the functioning of endothelial cells lead to improvement in metabolic syndrome symptoms. The increase fiber intake might result in lowering of pro-inflammatory symptoms and oxidative stress. The authors suggest that hCRP might be useful as a marker of endothelial dysfunction in metabolic syndrome. This study offered further insight in the biochemical mechanism of cardio-protective effects of MD (Esposito, et al. 2004)
A study published in the journal Nutrition research in 2009 examined the effect of consuming a Greek-Mediterranean based diet in healthy non- obese women. A total of 69 non obese healthy women (ages 25-59) were recruited in the study. These women were all college educated and came from well to do economic backgrounds. The women in the MD intervention diet were provided with specific information to incorporate elements of MD and were provided specific goals regarding consumption of 7-9 servings of fruits and vegetables and importantly the fat intake had to be maintained at a level of PUFA/saturated FA/MUFA in ratio 1:2:5. The women were provided with a exchange list to provide a variety of permitted foods. Women who were part of the MD group were given 3L of EVOO at the start of study and after 3 months. The duration of study was 6 months. Dietician consulted with the subjects in person and by telephonic sessions. The consumption of MD has been associated with increase in the level of carotenoids and plasma monounsaturated fatty acids which are associated with breast cancer preventive and insulin resistance decreasing activity. The authors cite previous work done in the field of epidemiological research and consumption of a nutritionally complete diet as opposed to intake of dietary supplements. Following the completion of study duration the levels of plasma triglyceride, HDL, LDL and total cholesterol, blood insulin, blood glucose, IGF-1, insulin-like growth factor 1; IGF-bp3, insulin-like growth factor binding protein 3 and C-reactive protein were measured. There was no effect on the blood lipid level, insulin, glucose or C reactive protein levels. However, the levels of plasma carotenoids and monounsaturated fatty acid content of blood were increased as compared to baseline levels and the participants of control. This study demonstrated an important observation regarding the lack of heart health improving effect of Mediterranean diet on healthy subjects. As opposed to other studies where the participants had a higher risk for CVD, the women in this study were highly educated with little to no health problems. This study provided one scenario in which MD did not demonstrate any significant beneficial effects (Djuric, Ren, Blythe, VanLoon & Sen, 2009).
The next report was an observational study published in the journal Preventive medicine in 2005. This study observed the effect of adherence to MD in Jewish population in Israel and its association with prevention of CVD and associated mortality. The study was carried out by recruiting 520 men and 639 women from a town in Israel. The participants were surveyed based on the consumption of their diet. Trained interviewers surveyed the participants in their homes based on a 24 question survey. The food consumed by the participants was scored in the range of 0-8. The foods described by subjects were categorized and points assigned based on adherence to components of MD, such as olive oil, legumes, fruits, vegetables etc. Persons who had a score of 5 or more were defined as high MD consumers while a score of 4 or less was classified into low MD consumers. The authors had hypothesized that the higher the score received by the subjects, the greater the cardiovascular benefits of MD would be seen. Based on the answers from questionnaire it was seen that only 19% men and 17% women could be defined as belonging to the high MD consumers. The subjects were also surveyed for incidence of MI, CABG (coronary artery bypass grafting), coronary angioplasty (CA) and some other CVD markers. The authors found an inverse correlation between the occurrence of CVD as reported by the subjects and consumption of MD. This effect was much more pronounced in men as opposed to women who had lower incidence of CVD. The diet score demonstrated an association with the occurrence of MI, CAB, PTCA etc in men (Bilenko, Fraser, Vardi, Shai, &Shahar, 2005). A similar study was published in British Medical Journal in 1995 by Trichoupaulo et al. They demonstrated that an improvement of one unit in their diet score resulted in 17% drop in rate of mortality, while 2 point improvement resulted in 33% reduction in mortality associated with CVD.
A number of other studies have been published based on assigning scores to the participants’ diet and evaluating the relation between the diet score and occurrence of CVD. A large cohort study was published in 2009 in Am. J. Epidem. It recruited 41,078 participants between ages of 25-69. The diet consumed by the participants was rated on an 18 point score. It was observed that subjects who were rated to have higher score had significantly lower risk of CHD (hazard ratio = 0.60, CI 95%). It was also observed that an improvement in the diet score by 1 point lowered the risk of CHD by 8%(95% CI). (Buckland et al., 2009)
The Mediterranean diet is diet that is consumed by people living in countries surrounding the Mediterranean Sea. The diet itself varies from place to place; however, the essential components are the same including consumption of large amount of fruits and vegetables, use of olive oil as the only source of fat, moderate consumption of nuts, dairy and fish. A number of epidemiological studies have demonstrated that people living in southern European countries experienced lower rate of CVD and mortality associated with it. The cardio-protective effects of MD can be attributed to various nutritional components that target many biochemical pathways and genes. Olive oil and nuts are source of omega-3, -6 and -9 fatty acids which exhibit vaso-protective effect. The MD diet consumption has been demonstrated to lower the level of inflammatory cytokines such as IL-6, 7and 8 and hs-CRP (high sensitivity C reactive protein), and improve the endothelial cell function. Additionally specific genes that are associated with atherosclerosis such as of IFN-, ARHGAP-15, IL-7R, ADRB2 etc were demonstrated to be down-regulated following supplementation of MD with olive oil. Fruits and vegetables are an excellent source of compounds, such as catechin with anti-oxidant, anti-aggregant and anti-inflammatory properties.
Randomized clinical trials have demonstrated the effect of MD on lowering the risk for CVD, especially in participants who are at a high risk. Incorporation of MD improved the symptoms of participants with metabolic syndrome(MS) and in almost half the subjects’ diagnosis of MS was lost following MD intervention. The RCT published in NEJM in 2013 is the largest performed till date that clearly demonstrates the beneficial effect of MD against CVD. While there are fewer published RCT demonstrating the cardio-protective activity of MD; a much larger number of observational studies are present that clearly demonstrate the evidence for MD intervention as strategy to lower risk for CVD.
The one area where the effectiveness of MD has not been clearly established is in healthy subjects. Two studies were identified in which incorporation of MD as an intervention showed little to no improvements in CVD risk factors. It might be possible that incorporation of MD has more clear beneficial effects on subjects who are at higher risk for CVD.
Cardiovascular disease (CVD) is the number one cause of mortality in the US and a major cause of death worldwide. Incorporation of Mediterranean diet as a lifestyle with ability to lower the incidence of CVD could have major beneficial effects on cardiovascular health and wellness.
References
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Buckland, G., González, C.A., Agudo, A, Vilardell, M., Berenguer, A., Amiano, P., Ardanaz, E., Arriola, L., Barricarte, A., & Basterretxea, M.(2009). Adherence to the Mediterranean diet and risk of coronary heart disease in the Spanish EPIC cohort study. Am J Epidemiol, 170: 1518–29
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Djuric, Z., Ren, J., Blythe, J, VanLoon G, Sen A (2009).A Mediterranean dietary intervention in healthy American women changes plasma carotenoids and fatty acids in distinct clusters. Nutrition Research, 29,156–163
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