Mediterranean Diet Reduces Atherosclerosis Progression in Coronary Heart Disease: An Analysis of the CORDIOPREV Randomized Controlled Trial

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in developed countries and imposes a significant economic burden on both the health-care system and society.^1,2 Lifestyle and dietary habits have been demonstrated to affect cardiovascular risk.³ Evidence supports that certain individual nutrients and foods exert cardiovascular benefits. However, the study of overall dietary patterns may provide a more powerful tool for assessing dietary habits by the evaluation of the synergistic and cumulative effects of specific nutrients on cardiovascular health.

The Mediterranean diet is an increasingly popular dietary pattern, recognized for its health benefits such as CVD prevention.^4,5 The effectiveness of the Mediterranean diet in reducing cardiovascular risk has been seen in primary prevention. In this context, the PREDIMED study (Prevención con Dieta Mediterránea) has shown that the Mediterranean diet would provide long-term high benefits on CVD compared with a reduced-fat diet.⁶ However, no scientific evidence is currently available to indicate which dietary pattern is more effective in secondary cardiovascular prevention. The CORDIOPREV study (Coronary Diet Intervention With Olive Oil and Cardiovascular Prevention), an ongoing dietary intervention trial, compares the rate of cardiovascular events of 2 healthy dietary patterns for secondary cardiovascular prevention.⁷ One of these diets is low in fat and rich in complex carbohydrates, as recommended by the National Cholesterol Education Program for these type of patients.⁸ The other diet in this study is a Mediterranean diet, rich in extravirgin olive oil (EVOO), fruit and vegetables, whole grains, fish, and nuts, and low in saturated fats.⁹

Evaluation of the intima-media thickness of both common carotid arteries (IMT-CC) using B mode ultrasound is a noninvasive, well-validated clinical method. IMT-CC is considered a surrogate marker of subclinical atherosclerosis and a strong predictor of new myocardial infarction and stroke.^10,11 A large body of evidence supports the beneficial effect of dietary strategies in decreasing IMT-CC. In a 15-year prospective cohort study in older women, the consumption of a range of vegetables was inversely associated with IMT-CC.¹² Similarly, in a cross-sectional analysis, Maugeri et al¹³ found an inverse relationship between the intake of dietary antioxidants and IMT-CC in adults. The PREDIMED study did not show changes in IMT-CC but found a decrease in internal carotid-IMT and plaque height after consumption of a Mediterranean diet supplemented with nuts (but not with EVOO), compared to a reduced-fat diet.¹⁴

Based on these previous evidence, in this secondary prevention study, we evaluated the efficacy of 2 healthy dietary patterns (a Mediterranean diet rich in EVOO compared to a low-fat diet and rich in complex carbohydrates) in decreasing IMT-CC in patients with coronary heart disease (CHD). The secondary objective was to investigate the effect of these dietary patterns on other parameters related to atherosclerosis progression, as carotid plaque number and height.

Methods

Data Availability

Data are available to researchers on request for purpose of reproducing the results or replicating the procedure by directly contacting the corresponding author.

Design and Study Population

The current work was conducted within the framework of the CORDIOPREV study. Full details of the design and methods have been reported previously.⁷ Briefly, the CORDIOPREV study is an ongoing prospective, randomized, single-blind, controlled trial including 1002 CHD patients, who had their last coronary event >6 months before enrollment. The updated guidelines for the reporting of parallel-group randomized trials (CONSORT 2020 Statement) have been followed for this report¹⁵ (please see Data Supplement). The main objective of the CORDIOPREV study is to evaluate the efficacy of a Mediterranean diet, rich in monounsaturated fatty acids (MUFA) from EVOO, as compared to a low-fat diet and rich in complex carbohydrates to prevent clinical events and mortality in patients with previous CHD, in a long-term follow-up study. The present study aims to evaluate a secondary end point of the CORDIOPREV study, the effectiveness of both healthy dietary patterns in reducing CVD risk, assessed by quantification of intima-media thickness of both common carotid arteries (IMT-CC).

Patients were recruited from November 2009 to February 2012, mostly at Reina Sofia University Hospital, Cordoba, Spain, and other hospitals in Cordoba and Jaen. Details of the rationale, study methods, inclusion and exclusion criteria, cardiovascular risk factors, and baseline characteristics of the patients have been recently described.⁷ To summarize, patients were eligible if they were aged 20 to 75 years, with established CHD but without clinical events in the last 6 months, were willing to follow a long-term monitoring study, and had no other serious illnesses and a life expectancy of at least 5 years. Established CHD was defined as history of acute myocardial infarction, admission to hospital for unstable angina, or chronic high-risk ischemic heart disease (in the last two cases, a combination of clinic and lab, electrocardiography, or angiographic criteria were needed. More in detail information has been published elsewhere).⁷ All the patients gave their written informed consent to participate in the study. Following institutional and Good Clinical Practice guidelines, the study protocol was approved by the Human Investigation Review Committee at Reina Sofia University Hospital.

Randomization and Dietary Intervention

Randomization was performed by the Andalusian School of Public Health, as previously described (Figure 1).⁷ The study dietitians were the only members of the intervention team to know about each participant’s dietary group. Briefly, the randomization was based on the following variables: sex (male, female), age (<60 and ≥60 years old), and previous myocardial infarction (yes, no). Each patient was randomly stratified, in addition to the conventional treatment for CHD, to 1 of 2 potentially healthy diets: (1) the Mediterranean diet, with a minimum of 35% of total calories from fat (22% MUFA, 6% polyunsaturated fatty acids [PUFA], and <10% saturated fatty acids [SFA]), 15% proteins, and a maximum of 50% carbohydrates and (2) a low-fat, high complex carbohydrate diet, as recommended by the National Cholesterol Education Program, with <30% of total calories from fat (12%–14% MUFAs, 6%–8% PUFAs,<10% SFAs), ≥55% from carbohydrates and 15% from protein. In both diets, the cholesterol content was adjusted to <300 mg/day. Both study diets included foods from all major food groups, but no total calorie restriction was set. Full details on dietary assessment and follow-up visits are published elsewhere.^7,16 No intervention to increase physical activity or lose weight was included. The present study was performed over a follow-up period of 5 and 7 years. Details of the specific recommended diets are summarized in the Data Supplement.

• Download figure
• Download PowerPoint

In our study, although both dietary models share common characteristics in some of the major components (ie, high intake of vegetables, fruit, legumes, and whole grains), patients consuming the Mediterranean diet also had a high intake of oily fish, nuts, and extra virgin olive oil, together with a low intake of harmful foods such as red/processed meats and pastries/commercial bakery products.¹⁶

Laboratory Tests

The measurement of the anthropometric and biochemical parameters has been previously described.⁷ As biomarkers of the long-term adherence of the patients to both dietary models, the quantification of plasma fatty acid (FA) levels was performed by fast gas chromatography with previous derivatization to their corresponding FA methyl esters.¹⁷ The results were expressed as relative percentages of the total FA. The average of 2 measurements was used to analyze the variables at baseline and after 3 years of dietary intervention.

Carotid Ultrasonography

Out of the 1002 patients, a total of 939 completed the carotid ultrasound study at baseline (n=459, low-fat diet and n=480, Mediterranean diet; 63 patients did not complete the ultrasonography study). Of these patients, 809 completed the 5-year follow-up carotid ultrasound study (n=377, low-fat diet and n=432, Mediterranean diet; 130 patients did not complete the ultrasonography study) and 731 patients completed the 7-year follow-up carotid ultrasound study (n=335, low-fat diet and n=396, Mediterranean diet; 78 patients did not complete the ultrasonography study). To sum up, data were missing for 271 patients, mainly because they did not complete the ultrasonography study (at baseline or during follow-up) due to problems related to disapproval of the technique, refusal to participate, death, or withdrawal for other reasons (Figure 1). The estimation of the appropriate sample size used in the study is provided in the Data Supplement. Baseline characteristics of those patients with complete the ultrasonography study (during follow-up) did not differ from patients who did not complete it (Table I in the Data Supplement).

The carotid study was ultrasonically assessed bilaterally by quantification of IMT-CC and carotid plaques (number and height), at the beginning of the study and after 5 and 7 years of dietary intervention, as previously described.¹⁸ Briefly, carotid arteries were examined using a Doppler ultrasound high-resolution B-mode (Envisor C Ultrasound System, Philips, Eindhoven, the Netherlands), following the recommendations of the American Society of Echocardiography Carotid Intima-Media Thickness Task Force.¹⁹ All images were analyzed offline using dedicated analysis tools (QLAB Advance Ultrasound Quantification Software, v5.0, Phillips). Analysis was performed by technicians blinded to clinical information and previous imaging. A full description of the methodology is described in the Data Supplement.^18,20

Statistical Analysis

Normal distribution was tested for all the measured variables, and log10 transformation was used to normalize skewed variables. In all cases, the dataset was deemed suitable for performing the statistical parametric test. The patients’ baseline characteristics, dietary intake and adherence, and carotid ultrasound variables (IMT-CC and carotid plaque height and number) were presented as mean±SEM (SE) for the continuous variables and as proportions for the categorical variables. Within- and between-group changes were assessed with a paired t test and unpaired t test, respectively. To evaluate the data variation according to diet and time (baseline to 5 and 7 years), repeated-measures ANOVA analyses were used, as well as post hoc multiple comparisons analysis using the Bonferroni correction.

Age, sex, body mass index, ever smoking, presence of type 2 diabetes mellitus, energy intake, and pharmacological treatments (use of lipid-lowering drugs, use of antidiabetic drugs, and use of antihypertensive drugs) at baseline were tested as covariates in all tests/assays. Differences were considered to be significant when P<0.05.

To investigate whether changes in IMT-CC during the follow-up period were predicted by carotid morphology at baseline (IMT-CC and carotid plaque number and height) or due dietary intervention and composition (allocation into the Mediterranean or the low-fat diet at baseline and changes in energy and nutrient intake—MUFA, PUFA, SFA, total carbohydrates, total protein and fiber, and adherence to Mediterranean diet score), we performed a stepwise multiple linear regression analysis adjusting for sex, age, ever smoking, body mass index, presence of type 2 diabetes mellitus, energy intake, and pharmacological treatments (use of lipid-lowering drugs, use of antidiabetic drugs and use of antihypertensive drugs) at baseline, assuming that all predictor variables were quantitative or categorical (with 2 categories) and the outcome variable was quantitative, continuous, and unbounded. All the statistical analyses were performed using the SPSS (Statistical Package for the Social Sciences) version 18.0 for Windows (SPSS, Inc, Chicago, IL).

Results

Baseline Characteristics of the Study Population

The baseline clinical and metabolic characteristics, lipid profiles, and treatment regimens of all the CHD patients who underwent the baseline ultrasound measurements of IMT-CC and carotid plaques (n=939) and were assigned to randomized dietary groups are presented in Table 1. No significant differences were observed between randomized dietary groups or between refusers and compliers in terms of baseline characteristics, lipid profiles, and treatments (data not shown).

Baseline Intake of Energy and Nutrients and Changes by Intervention Group

As shown in Table II in the Data Supplement, the patients were balanced for baseline intake of energy and nutrients and adherence to the Mediterranean diet (14-item Mediterranean Diet Adherence Screener)¹⁶ in the 2 randomized groups. The habitual diet of the study patients was high in total fat (>35%), mainly consisting of MUFAs, with 41% of the energy from carbohydrates and 18.5% from proteins.

During follow-up, both dietary interventions (the Mediterranean and the low-fat diet) reduced total energy intake after 5 and 7 years (all P<0.001). In the Mediterranean diet group, patients increased their intake of fiber and total fat due to increased MUFAs and PUFAs but reduced their consumption of SFAs, total carbohydrates, and cholesterol (all P<0.05). Moreover, these patients also showed a significant increase of 2.5±0.1 and 2.3±0.1 points after 5 and 7 years, respectively, in consumption of the Mediterranean diet from baseline Mediterranean Diet Adherence Screener (P<0.001). In the low-fat diet group, the participants increased their intake of total carbohydrates and fiber and decreased cholesterol and total fat (decreasing MUFAs and SFAs but increasing PUFAs; all P<0.05). In this dietary group, the patients showed a significant reduction of −1.1±0.1 and −0.9±0.1 points after 5 and 7 years, respectively, from baseline Mediterranean Diet Adherence Screener (P<0.001).

Effect of Dietary Intervention on IMT-CC and Carotid Plaques

Our results showed that the Mediterranean diet significantly decreased IMT-CC after both 5 years (−0.027±0.008 mm; P<0.001) and 7 years (−0.031±0.008 mm; P<0.001) compared to baseline. The low-fat diet did not exert any change on IMT-CC after 5 or 7 years (Figure 2). The Mediterranean diet produced a higher decrease in IMT-CC and carotid plaque_max height, compared with the low-fat diet throughout follow-up (Figure 2 and Table 2). We did not observe any differences in carotid plaque numbers after both dietary interventions (Table 2).

• Download figure
• Download PowerPoint

Changes in Plasma FA Levels and Profile as Biomarkers of Dietary Adherence

Baseline and changes, according to the intervention group, of plasma FA levels and plasma FA profile, respectively, evaluated by fast gas chromatography are showed in the Table III in the Data Supplement. No significant differences were found in either plasma FA levels or the FA profile between the 2 groups at baseline.

After the consumption of both diets, patients reduced plasma SFA levels compared with baseline (all P<0.001), without significant differences between the 2 diets. Although both the low-fat diet and the Mediterranean diet increased total plasma MUFA levels compared to baseline (all P<0.001), the Mediterranean diet produced a higher increase in MUFAs, at the expense of oleic acid (C18:1n-9), in comparison to the low-fat diet (P=0.008). Similarly, both dietary models significantly increased the total plasma PUFA levels compared to baseline (all P<0.001). However, the low-fat diet produced a higher increase in total PUFAs, compared with the Mediterranean diet, increasing linoleic acid levels (C18:2n-6c; P<0.001). The Mediterranean diet significantly increased γlinolenic acid (C18:3n-6c) compared with the low-fat diet (P=0.008).

Independent Determinants of Changes in IMT-CC by Multiple Regression Analysis

In a stepwise multiple linear regression analysis using changes in IMT-CC after 5 years of dietary intervention as the dependent variable, IMT-CC at baseline (B=−0.521, P=3.1×10^-66) appears as the most important predictor of changes in IMT-CC. Age (B=0.002, P=7.0×10^-6), allocation to the Mediterranean diet (versus low-fat diet; B=−0.027, P=2.7×10^-4), body mass index at baseline (B=0.002, P=0.020), energy intake at baseline (B=1.5×10^-5, P=0.024), presence of type 2 diabetes mellitus at baseline (B=0.017, P=0.029), and carotid plaque number at baseline (B=0.008, P=0.010) were also significant contributors to changes in IMT-CC (Table 3).

Discussion

In this randomized, secondary prevention and controlled clinical trial, conducted in patients with CHD, we found that the long-term consumption of 2 healthy dietary patterns exerted different effects on IMT-CC and carotid plaque height, but not on carotid plaque number. In this sense, 5-year consumption of the Mediterranean diet decreased IMT-CC, which was maintained over time until 7 years. The Mediterranean diet produced a higher decrease in carotid plaque height, compared to the low-fat diet, throughout follow-up. However, the Mediterranean diet did not exert any effect on the number of carotid plaques. The low-fat diet did not modify either IMT-CC or carotid plaque number and height after 5 and 7 years of follow-up.

Structural or morphological changes in the common carotid artery play a major role in the cause of stroke and CVD. IMT-CC and carotid plaque are the most commonly studied parameters when evaluating subclinical atherosclerosis and have been associated with prevalent atherosclerotic disease.¹¹ Different clinical studies have evaluated the influence of the Mediterranean diet on markers related to atherosclerosis progression, mainly in primary prevention. In this context, in a large, cross-sectional, observational population-based epidemiological study, greater adherence to the Mediterranean diet was associated with a decreased burden of carotid atherosclerotic plaque in 1374 healthy participants. A slight decrease in IMT-CC was found per 1 SD increase in the Mediterranean score, although it was not statistically significant.²¹ A recent report from the PREDIMED study is in line with these findings in a population of 164 subjects without CVD. In this sense, this study shows that consumption of a Mediterranean diet, supplemented with nuts, decreased internal carotid-IMT, and carotid plaque height, but not IMT-CC, compared with a control diet, during a mean period of 2.4 years.¹⁴ Although internal carotid-IMT and plaque height were increased after the control diet, the authors did not find no changes in any of these atherosclerotic markers after the Mediterranean diet supplemented with EVOO. However, in our study, we found that, in patients with established CHD, a more prolonged dietary intervention (7 years of follow-up) with a Mediterranean diet rich in EVOO decreased IMT-CC and carotid plaque height, compared with a low-fat diet. We must point out that the low-fat diet used in our study is a dietary pattern recommended by the National Cholesterol Education Program for secondary cardiovascular prevention.⁸ The inconsistency in the results from both studies may have also arisen because patients following the control diet (a reduced-fat diet) used in the PREDIMED study were not as comprehensively intervened as the Mediterranean diet groups. Moreover, because the control diet from the PREDIMED study reached 37% of fat at the end of the trial,⁶ this diet is not comparable with the low-fat diet from our study (<30% of total calories from fat as objective, 31% at 5 years of intervention).¹⁶ However, our results are in line with an earlier report from the PREDIMED study, in a subsample of patients (n=187) from one of the recruitment centers, PREDIMED-Navarra. This substudy showed that the consumption of a Mediterranean diet, supplemented with either EVOO or nuts, only decreased IMT-CC²² in patients without CHD but at highest CVD risk (patients with carotid atherosclerosis, IMT-CC ≥0.9 mm, at baseline).

Moreover, our results also indicated that baseline IMT-CC had the strongest association with the changes in IMT-CC after the dietary intervention (the higher the IMT-CC at baseline, the greater the reduction in this parameter by the dietary intervention), in this case, after a Mediterranean diet. These data would confirm that those patients with a high atherosclerotic burden might be the ones who benefit more from the dietary intervention. Accordingly, the current study is, to our knowledge, the first to establish an effective dietary strategy for secondary cardiovascular prevention, reinforcing the fact that the Mediterranean diet rich in EVOO could prevent the progression of atherosclerosis.

The Mediterranean diet has been extensively analyzed by both cross-sectional and prospective studies and has been established as the most beneficial dietary pattern for cardiovascular health.^23,24 The atheroprotective effect of the Mediterranean diet on cardiovascular risk factors could be attributed to its richness in beneficial foods such as vegetables, fruit, cereals, and legumes, and EVOO, which provide a specific FA profile and the presence of certain minor components, mostly phenolic compounds, which have anti-inflammatory and antioxidant properties. As we observed in our results, although both dietary patterns increased plasma MUFA levels, the Mediterranean diet produced a higher increase in MUFAs, at the expense of oleic acid, in comparison to the low-fat diet.

The reduction in the atherosclerosis progression found in our study, determined by a decrease in IMT-CC and carotid plaque, after consumption of the Mediterranean diet, could be due to the influence of this diet in most of the different stages of the atherosclerotic process. Indeed, the effect of MUFA-rich diets, such as the Mediterranean diet, has been established as improving flow-mediated dilatation in different populations.^25–27 Recently, we have shown that 1-year of consumption of the Mediterranean diet, compared with the low-fat diet, improved endothelial function in patients with CHD, even with T2DM,²⁸ which was associated with a better balance of vascular homeostasis.²⁹ Because endothelial dysfunction occurs early in atherosclerosis development and contributes to the formation and progression of atherosclerotic plaque,³⁰ the effect of the Mediterranean diet on endothelial function could contribute to delaying atherosclerosis development.

Another critical point in the atherosclerosis process is the vascular obstruction from the arterial wall’s lipid deposits, resulting in reduced blood flow. High LDL (low-density lipoprotein)-cholesterol levels are closely related to atherosclerosis, whereas HDLs (high-density lipoprotein) improves endothelial dysfunction and seem to play a key role in reversing cholesterol transport exhibiting their antiatherogenic, antioxidant, and anti-inflammatory properties.^30,31 Our findings could also be explained by the effect of the Mediterranean diet in modulating the lipid profile, particularly by increasing HDL-cholesterol levels,^32,33 as we have demonstrated previously in the same studied population.²⁹ It is also described the effect of a Mediterranean diet-style in the improvement of HDL functionality.^34,35

The fundamental role of inflammation in mediating all the stages of atherosclerosis, from initiation through progression, is well known. The anti-inflammatory capacity of the Mediterranean diet could be another factor that contributes to reducing the progression of atherosclerosis, as observed in our results, by decreasing NF-κB (nuclear transcription factor kappaB) activation and the gene expression related to inflammation (MCP [monocyte chemoattractant protein]-1, TNF [tumor necrosis factor]-α and IL [interleukin]-6).^36–39 Endothelial injury (increased levels of endothelial microparticles) produced during atherosclerosis progression⁴⁰ also diminishes after the consumption of a Mediterranean diet.⁴¹ This diet not only improves the regenerative capacity of the endothelium (increased endothelial progenitor cell levels) but also reduces oxidative stress, prevents cellular senescence, reduces cellular apoptosis, and produces an increase of angiogenesis and proliferation processes in different models of human endothelial cells, ameliorating atherosclerotic process and its stability.^29,41,42

Our study has various important strengths. It is well known that patients with CHD are at high risk of the recurrence of cardiovascular events. Therefore, our results provide a dietary strategy as a clinical and therapeutic tool that could reduce the high cardiovascular recurrence of these patients through the consumption of a Mediterranean diet, but not a low-fat diet. Second, the study presents a randomized design that involves two different dietary patterns involving a large number of patients. Moreover, this is a comprehensive dietary intervention with both healthy diets equally. Although dietary compliance during such an extended period could be a factor, in this case, adherence to the recommended dietary patterns was excellent, as shown by the rigorous dietary assessment measurements,^7,16 including the quantification of objective biomarkers.

Nevertheless, the study also has its limitations. The evaluation of CVD risk (assessed by quantification of IMT-CC) is a secondary end point of the CORDIOPREV study. As in any substudy, the results of this study should be treated with caution. In addition, our study is confined to CHD patients and may not be suitable for extrapolating the results for the general population. However, these patients are one of the populations in which dietary changes have been shown to have a significant impact on health.

Conclusions

Long-term consumption of a Mediterranean diet rich in EVOO, if compared to a low-fat diet, was associated with decreased atherosclerosis progression, as shown by reduced IMT-CC and carotid plaque height. These findings reinforce the clinical benefits of the Mediterranean diet in the context of secondary cardiovascular prevention.

Acknowledgments

We would like to thank the Escuela Andaluza de Salud Publica (EASP), Granada (Spain), for carrying out the randomization process in this study. The CIBER Physiopathology of Obesity and Nutrition (CIBEROBN) is an initiative of the Instituto de Salud Carlos III, Madrid, Spain.

Supplemental Materials

Expanded Materials and Methods

Online Tables I–III

References 14, 18, 19 and 22

Footnotes