Olive oil in the primary prevention of cardiovascular disease

Olive oil in the primary prevention of cardiovascular disease Miguel Ruiz-Canela , Miguel A. Martínez-González a Department of Biomedical Humanities, Medical School, University of Navarra, Pamplona, Spainb Department of Preventive Medicine and Public Health, Medical School, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, Navarra, Spain Ischemic heart disease is the leading cause of mortality worldwide. Many mechanistic reasons sup- port that a high consumption of olive oil may provide a protection against myocardial infarction, the hallmark of ischemic heart disease. International comparisons are also consistent with this hypothesis.
Surprisingly, there is not much evidence coming from analytical epidemiological studies about this issue.
A case-control study conducted at the University of Navarra (Spain) found a strong inverse association between olive oil consumption and the risk of a first non-fatal myocardial infarction. Subsequently a large cohort in Italy and another case-control study conducted in Greece also found inverse associations. How- ever, no complete consistency exists and further prospective studies and trials are being implemented in order to obtain more complete evidence.
2010 Elsevier Ireland Ltd. All rights reserved.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 Olive oil components and its biological mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 Olive oil and primary prevention of cardiovascular diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 Available epidemiological evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 The case-control study in the University of Navarra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 Limitations and inconsistencies in case-control studies: the need for further evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 Olive oil and cardiovascular health promotion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 1. Introduction
developed countries. Acute myocardial infarction (AMI) constitutesa catastrophic manifestation of IHD and coronary atherosclerosis.
Globally, noncommunicable diseases will cause over three quar- Unacceptable high absolute rates of mortality from AMI still ters of all deaths in 2030. The major noncommunicable conditions exist in many developed countries. However, a surprisingly low are cardiovascular diseases. Worldwide deaths from cardiovascu- incidence is found in several Southern European countries such as lar diseases are projected to rise from 17.1 million in 2004 to 23.4 France, Spain, Greece, Italy or Portugal, as compared with Northern million in 2030 heart disease (IHD) was ranked as the European countries or the US. This contrast partially contributes first global cause of death in 2004 and it is unfortunately broad- to explain the higher life expectancy in Mediterranean areas. The casted to remain the first cause of death in 2030 As well as Mediterranean diet (Med-Diet) has been proposed as the major remaining the major cause of death in industrialized countries, the protective factor responsible for this advantage incidence and mortality from IHD are also rapidly growing in less some inconsistencies still persist classical Med-Diet is iden-tified as the traditional dietary pattern found in olive-growing areassuch as Crete, Greece, and Southern Italy in the late 1950s and early 1960s of the most important characteristics of the Med- Corresponding author. Tel.: +34 948 425 600; fax: +34 948 425 649.
Diet is the abundant presence of olive oil, which is the characteristic 0378-5122/$ – see front matter 2010 Elsevier Ireland Ltd. All rights reserved.
M. Ruiz-Canela, M.A. Martínez-González / Maturitas 68 (2011) 245–250 Cumulative evidence suggests that olive oil may have a pro- fat. In a randomized trial a MUFA-rich Med-Diet improved the found influence on health ore specifically, recent reviews endothelium-dependent vasodilatadory response suggesting that have summarised the effects of olive oil on cardiovascular risk fac- a Med-Diet rich in olive oil may be able to avoid the postprandial tors reviews have emphasized the effects of some deterioration of endothelial function Another trial showed components of olive oil other than oleic acid, and are thus chal- the antithrombotic and anti-inflammatory effect of extra virgin lenging the reasoning that olive oil is healthy only because it is a olive oil anti-inflammatory activity had been previously good source of monounsaturated fatty acids (MUFA) supported by the discovery of oleocanthal, an olive oil phenolic ing to its biological effects, a strong protection by olive oil against compound, which inhibits COX-1 and COX-2 AMI is expected to be found in analytical epidemiological studies It is well known that the metabolic syndrome increases the assessing this relationship. Surprisingly, there is not much evi- risk of AMI. In a Spanish cohort of university graduates including dence coming from analytical epidemiological studies and research initially healthy participants, a higher adherence to the classical results with primary end points for cardiovascular disease are still Me-Diet was found to be associated with a lower risk of developing the metabolic syndrome after 74-month follow-up n a ran- In this paper we review the available evidence on biological domized clinical trial, participants receiving a Med-Diet education mechanisms of olive oil as well as the epidemiological evidence showed a reduction in the overall prevalence of the metabolic syn- to support a beneficial effect on cardiovascular risk factors. After- drome compared to participants who had been advised to follow a wards, we summarise the state of the art concerning the role that low-fat diet protective outcome may be better explained olive oil may have in the primary prevention of cardiovascular dis- by the overall effect of the Mediterranean dietary pattern than by the effect of a single component. In diabetic patients, olive oilimproved the lipid profile and glycaemic control two recent large cohort studies and a clinical trial have reported a 2. Olive oil components and its biological mechanisms
strong protection of Med-Diets, rich in olive oil, against type-2 dia-betes trial found that a Med-Diet delayed the need The major components of olive oil represent the glyceride frac- tion, and oleic acid makes up 68–81.5% of the fatty acids The minor components are present in about 2% of oil weight andinclude more than 230 chemical compounds A group to be 3. Olive oil and primary prevention of cardiovascular
highlighted among these minor components are the phenolic com- diseases
pounds which can also be found in different fruits and vegetables.
The most abundant lipohilic phenolic compound is ␣-tocopherol and there are also several hydrophilic phenolic compounds such asoleuropein and hydroxytirosol.
No primary prevention trial has ever assessed the association Different processing methods produce virgin, refined, and ordi- between adherence to an olive-oil-rich Med-Diet and the incidence nary olive oil This classification is important to understand (and not only mortality) of a first IHD event. The pioneering results the variable composition of olive oil and consequently its poten- of the Seven Countries Study showed that coronary heart disease tial health benefits. Virgin olive oil is obtained only by mechanical death rates were low in countries where olive oil was the main fat means that do not lead to alterations in the oil. When the acidity of A very important cohort study found that a Mediterranean virgin olive oil exceeds 3.0 degrees, this oil is refined with the use food pattern was protective against mortality from IHD of chemical and physical filters. During this process the hydrophilic ever, they included only fatal IHD cases (54 coronary deaths) as the phenolic compounds are lost; therefore, these compounds are outcome. Subsequently other studies confirmed the protection of peculiar to virgin olive oil. Numerous studies are centred exclu- Mediterranean-type diets against overall mortality n any sively in virgin olive oil with the belief that these minor components case, mortality from IHD is not only related to its incidence but also have a cardiovascular protective effect n ordinary olive oil is to the quality and timeliness of medical care. If the quality of medi- obtained by mixing refined and virgin olive oil.
cal care is associated with the adherence to a Med-Diet pattern, the In comparison to saturated fatty acids, olive oil reduces use of mortality as outcome would lead to confounding low-density lipoprotein (LDL) cholesterol, and compared with car- A randomized secondary prevention trial conducted in France bohydrates, it maintains or even increases the levels of high-density an impressive protection provided by an experimen- lipoprotein (HDL) cholesterol. In addition, it is relatively resistant tal Mediterranean diet on the risk of death and re-infarction among to oxidation and contains a large amount of antioxidants relative survivors of a first acute myocardial infarction (AMI). Neverthe- to its polyunsaturated fat content. Some polyphenol constituents less, as the major element of the assigned diet was an experimental of virgin olive oil (hydroxytirosol and oleuropein) are potent scav- canola-oil based margarine and the diet simultaneously included engers of superoxide radicals and inhibit LDL oxidation a high intake of alpha-linolenic acid, fruit and vegetables, it was Moreover, the phenolic compounds can modify the composition of not possible to attribute its benefit to a single factor. In addition, very low-density lipoprotein oil has induced a regression no special consideration was given to olive oil, which is the major of atherosclerosis in animal models and may slow the development source of MUFA in Mediterranean countries. The fat composition of coronary atherosclerosis, being associated with a reduced DNA of the experimental group in the Lyon Diet Heart Study was 30.5% synthesis in human coronary smooth muscle cells oil also of energy intake as total fat (12.9% MUFA). These values are far favourably affects postprandial factor VII activity, avoiding a pro- from the characteristic 35–40% total fat and 15–20% MUFA content longed thrombotic response to a high-fat diet. A beneficial effect of present in the traditional Med-Diet. Some methodological caveats MUFA on von Willebrand factor, as well as other benefits of olive been raised on the Lyon Diet Heart Study, including the oil on the haemostatic system have also been suggested small number of observed primary events in the experimental and The preservation of the endothelial function is a key mechanism for the prevention of atherosclerosis. The available information A few studies have assessed the specific role of olive oil on the about the effects of olive oil on the endothelial function also risk of clinical coronary events. A protective role for olive oil on suggests a benefit. The vascular endothelium plays a key role in mortality among patients with a previous AMI has been reported local vascular tone regulation and can be modulated by dietary by the investigators of the large cohort of patients who partici- M. Ruiz-Canela, M.A. Martínez-González / Maturitas 68 (2011) 245–250 pated in a previous trial. This study included 11,246 survivors of a myocardial infarction. Through a brief, non-validated question- Non-nutritional characteristics of case and control participants.
naire, the authors assessed the consumption of five food items, at baseline, and after 6, 18 and 42 months of follow-up. After 6.5-year follow-up the mortality odds ratio (OR) for the categories of olive oil consumption “often” and “regularly” compared with the “never or sometimes” category were 0.77 (95% CI 0.62–0.94) and 0.71 (95% In a recent case-control study (748 cases and 1048 controls) conducted in Greece, a protection was also found for the exclu- sive use of olive oil (Odds Ratio = 0.53 (95% CI: 0.34–0.71) against acute coronary syndromes the authors grouped the participants in three categories (no use; exclusive use; olive plus other oils or fats), and they apparently did not further quantify the amount of olive oil nor they adjusted for total energy intake.
Nevertheless, conflicting results have been also reported. A Greek case-control study reported no significant association of monounsaturated fatty acid intake with the risk of coronary disease for olive oil, a small randomized trial of corn oil and olive oil carried out more than 40 years ago found no benefit for olive oil and even an adverse significant effect for corn oil in 80 coro- nary patients after 2 years of follow-up oreover, two Italian case-control studies did not find any association between olive oil consumption and non-fatal AMI. The first one, a case-control study in Italian women (287 cases/649 controls), reported no significant benefit for oil consumption The second case-control study (507 cases/478 controls) provided additional data showing no trend in risk with the consumption of olive oil Age and gender were matching variables.
3.2. The case-control study in the University of Navarra Both crude (non-adjusted for total energy intake) and energy- In order to assess the potential role of olive oil for the pri- adjusted quintiles of olive oil were used as exposure. No distinction mary prevention of CHD and to quantify the reduction in the risk between virgin olive oil and ordinary olive oil was done. The selec- of a first AMI that can be provided by a high olive oil intake, tion of dietary and non-dietary confounders was done by taking a hospital-based case-control study was conducted at the Uni- into account previously published literature about coronary risk versity of Navarra, Spain The case series was comprised by factors. When the quintiles of olive oil intake without energy- 171 patients (81% males, age <80 years) who suffered their first adjustment were used as the exposure variable (the acute myocardial infarction. The control series included 171 age-, point-estimates for the OR were lower than 1 for the three upper gender- and hospital-matched controls with a wide variety of con- quintiles (vs. the lowest quintile) of olive oil intake. Exposure to the ditions believed to be unrelated to diet. A previously validated upper quintile of olive oil was associated with a relative risk reduc- semi-quantitative food frequency questionnaire (136 items) was tion of 64% (OR = 0.36, 95% CI: 0.12–1.08) with respect to the first used to appraise long-term dietary exposures. The same physi- quintile (median intake: 7 g/day). In the fully adjusted model, the cian conducted the face-to-face interview for each case patient and linear trend test was statistically significant (p = 0.02) and the OR his/her matched control. Conditional logistic regression modelling was 0.26 (0.08–0.85) for the upper vs. the lowest quintile was used to take into account potential dietary and non-dietary Conditional logistic regression models were also fitted using confounders. The description of cases and controls is shown in quintiles of energy-adjusted intake of olive oil as the exposure variable The risk reduction was then more apparent.
Quintiles of olive oil intake defined according to the distribution Point-estimates lower than 1 for the OR were found in the four among controls were compared regarding several potential nutri- upper quintiles of energy-adjusted olive oil intake and a significant tional and non-nutritional confounding variables linear trend test either when non-dietary confounders (P = 0.03) Table 2
Distribution of potential non-nutritional confounding variables across quintiles of energy-adjusted olive oil intake among control subjects (n = 171).
Quintiles of energy-adjusted olive oil intake Leisure-time physical activity (METSmean) M. Ruiz-Canela, M.A. Martínez-González / Maturitas 68 (2011) 245–250 Table 3
Distribution of potential nutritional confounding variables across quintiles of energy-adjusted olive oil intake among control subjects (n = 171).
Quintiles of energy-adjusted olive oil intake a Monounsaturated fatty acids/saturated fatty acids.
Table 4
Odds ratio (OR) (95% CI) of a first myocardial infarction according to olive oil intake (unadjusted for total energy intake).
b Conditional logistic regression (age-, hospital- and gender-matched pairs), adjusted for smoking, body mass index, high blood pressure, high blood cholesterol, diabetes, leisure time physical activity (METS-hours/week), marital status, occupation and study level.
c Additionally adjusted for saturated fat, trans fat and total fibre intake.
or also some relevant nutrients (p = 0.03) were adjusted for. The would introduce a selection bias in the case series. This could be a OR of a first myocardial infarction for the upper quintile was plausible explanation of the discordant findings between the case- OR = 0.22 (0.07–0.67) after adjusting for non-dietary confounders control study conducted in Navarra other two case-control and OR = 0.18 (0.05–0.63) after adjustment for dietary and non- studies conducted in Italy hich did not find any significant Recall bias is a potential concern when the case-control design 3.3. Limitations and inconsistencies in case-control studies: the is used. But differential over-reporting would be more probable to exist among cases than among controls because cases are morelikely to be aware of the role of nutrition as a determinant of IHD.
The results found in the case-control study conducted in Navarra Therefore, recall bias does not seem to be a likely alternative expla- suggest that olive oil consumption may substantially reduce the nation of the findings of the Navarra case-control study. Moreover, risk of coronary disease. Interestingly, a previous diagnosis of when the assessment of exposure was done through different items angina pectoris, a previous history of IHD or other prior diagno- in a comprehensive questionnaire, it would be more difficult that sis of major cardiovascular disease were exclusion criteria in this patients might consistently underestimate their exposure to olive case-control study. This is important because an inverse association oil. Although the in-hospital selection of controls facilitates a higher between olive oil and IHD has long been suggested. This belief is participation, it also imposes some caution in the interpretation of also held by the general public in Mediterranean countries. There- findings because the exposure may be related to the diseases caus- fore, it is likely that subjects who perceive themselves at higher ing the hospital admission of controls. However, olive oil has not risk of IHD may think that they should increase their consumption been found to induce the most frequent diseases usually present in of olive oil in order to obtain a better protection. This possibility the control series: any trauma or genitourinary disease or any com- Table 5
Odds ratio (OR) (95% CI) of a first myocardial infarction according to energy-adjusted olive oil intake.
Quintiles of energy adjusted olive oil intake b Conditional logistic regression (age-, hospital- and gender-matched pairs), adjusted for smoking, body mass index, high blood pressure, high blood cholesterol, diabetes, leisure time physical activity (METS-hours/week), marital status, occupation and study level.
c Additionally adjusted for % energy derived from saturated fat, % energy derived from trans fat, total fibre consumption, folic acid intake, vitamin C intake, glycaemic load and ethanol intake (adding a quadratic term to account for non-linearity).
M. Ruiz-Canela, M.A. Martínez-González / Maturitas 68 (2011) 245–250 mon disease needing minor surgery. Thus, a control selection bias an individual’s overall food pattern oreover, a prospective does not seem very likely. Another limitation is the lack of distinc- cohort study found that the intake of olive oil is associated with tion between virgin and ordinary olive oil consumption. A higher other healthy aspects of the diets as well as with higher educational protective effect could be expected when virgin olive oil was used Olive oil availability has experimented a significant increase Subsequent studies have confirmed the findings of the Span- during the last 40 years not only in Mediterranean regions but ish case-control study regarding clinical coronary events also in several non-Mediterranean countries, especially in Northern Europe t the same time, an undesirable departure from the tality further prospective studies are required traditional Med-Diet has been reported to have occurred in South- to obtain better evidence of the protective effect that olive oil may ern European countries We hope that the expected results have on the incidence in cardiovascular disease. Prospective cohort from prospective studies will reinforce the cardiovascular healthy studies are less susceptible to bias and provide the opportunity to consequences that an increased use of olive oil and Med-Diet pat- obtain repeated measures of diet over time. Experimental studies tern may have at the population level.
reduce the potentially distorting effects of variables distributionwhen they are randomly distributed between the treatment and Contributors
The on-going SUN study is a dynamic prospective cohort currently including more than 20,000 healthy university graduates Miguel A. Martínez-González; Financial support: Miguel A.
followed-up every two years. The recruitment is permanently open Martínez-González; Data analysis and interpretation: Miguel and the first participants were included in 1999. However most A. Martínez-González; Manuscript writing: Miguel Ruiz-Canela participants have been admitted to the cohort during the period and Miguel A. Martínez-González; Final approval of manuscript: 2003–2007 and some additional follow-up time (1–2 years more) Miguel Ruiz-Canela and Miguel A. Martínez-González.
will be needed before being able to prospectively ascertain the asso-ciation between the consumption of olive oil and the incidence of Competing interest
new clinical events of IHD. The PREDIMED study a primarycardiovascular prevention trial that has already randomized more There is no conflict of interest. There is no financial arrange- than 7000 older high-risk participants. They have been randomly ment with any food company. All funding has been provided by the allocated to three different food patterns, one of them being a Med- Spanish Ministry of Health and the Navarra Regional Government.
Diet rich in virgin olive oil recruitment started in 2003 andthe final results regarding clinical events are expected in 2012 Provenance and peer review
The results of the SUN cohort and the PREDIMED trial will providethe best evidence on this topic in the next few years.
Commissioned and externally peer reviewed.
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4. Olive oil and cardiovascular health promotion
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