Mediterranean Diet Reduces Atherosclerosis Progression in Coronary Heart Disease

An Analysis of the CORDIOPREV Randomized Controlled Trial

Jose Jimenez-Torres, MD; Juan F. Alcalá-Diaz, MD, PhD; Jose D. Torres-Peña, MD, PhD; Francisco M. Gutierrez-Mariscal, PhD; Ana Leon-Acuña, MD, PhD; Purificación Gómez-Luna, PhD; Carolina Fernández-Gandara, BS; Gracia M. Quintana-Navarro, BS; Jose C. Fernandez-Garcia, MD, PhD; Pablo Perez-Martinez, MD, PhD; Jose M. Ordovas, PhD; Javier Delgado-Lista MD, PhD; Elena M. Yubero-Serrano, PhD; Jose Lopez-Miranda, MD, PhD

Disclosures

Stroke. 2021;52(11):3440-3449.

Abstract and Introduction

Abstract

Background and Purpose: Lifestyle and diet affect cardiovascular risk, although there is currently no consensus about the best dietary model for the secondary prevention of cardiovascular disease. The CORDIOPREV study (Coronary Diet Intervention With Olive Oil and Cardiovascular Prevention) is an ongoing prospective, randomized, single-blind, controlled trial in 1002 coronary heart disease patients, whose primary objective is to compare the effect of 2 healthy dietary patterns (low-fat rich in complex carbohydrates versus Mediterranean diet rich in extra virgin olive oil) on the incidence of cardiovascular events. Here, we report the results of one secondary outcome of the CORDIOPREV study. Thus, to evaluate the efficacy of these diets in reducing cardiovascular disease risk. Intima-media thickness of both common carotid arteries (IMT-CC) was ultrasonically assessed bilaterally. IMT-CC is a validated surrogate for the status and future cardiovascular disease risk.

Methods: From the total participants, 939 completed IMT-CC evaluation at baseline and were randomized to follow a Mediterranean diet (35% fat, 22% monounsaturated fatty acids, <50% carbohydrates) or a low-fat diet (28% fat, 12% monounsaturated fatty acids, >55% carbohydrates) with IMT-CC measurements at 5 and 7 years. We also analyzed the carotid plaque number and height.

Results: The Mediterranean diet decreased IMT-CC at 5 years (−0.027±0.008 mm; P<0.001), maintained at 7 years (−0.031±0.008 mm; P<0.001), compared to baseline. The low-fat diet did not modify IMT-CC. IMT-CC and carotid plaque_max height were higher decreased after the Mediterranean diet, compared to the low-fat diet, throughout follow-up. Baseline IMT-CC had the strongest association with the changes in IMT-CC after the dietary intervention.

Conclusions: Long-term consumption of a Mediterranean diet rich in extravirgin olive oil, 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.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00924937.

Graphic Abstract: An online graphic abstract is available for this article.

Introduction

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 al^[13] 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.

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Table 1. Baseline Clinical and Metabolic Characteristics, Lipid Profiles and Treatment Regimens of the Total CHD Patients, Who Completed Baseline Carotid Ultrasonography, by Randomized Groups
	Total population (n=939)	Low-fat diet (n=459)	Mediterranean diet (n=480)	P value*
Age, y	59.6±0.3	59.5±0.4	59.7±0.4	0.735
Men, %	82.4	82.4	82.4	0.919
Weight, kg 85.0±0.4 85.2±0.6 84.9±0.6 0.684
BMI, kg/m2†	31.1±0.1	31.1±0.2	31.0±0.2	0.684
Waist circumference, mm	105.0±0.3	105.2±0.5	104.9±0.5	0.649
Diastolic blood pressure, mm Hg	77.2±0.3	77.2±0.5	77.2±0.4	0.992
Systolic blood pressure, mm Hg	138.8±0.6	139.0±6.0	138.5±4.1	0.693
LDL-cholesterol, mg/dL	88.5±0.8	88.0±1.1	88.9±1.2	0.594
HDL-cholesterol, mg/dL	42.2±0.3	42.1±0.5	42.3±0.4	0.804
Total cholesterol, mg/dL	159.0±1.0	158.9±1.3	159.1±1.5	0.950
Triglycerides, mg/dL	135.4±2.2	136.2±3.2	134.6±3.1	0.731
hsCRP, mg/mL	3.10±0.11	3.30±0.53	2.90±0.30	0.272
Fasting glucose, mg/dL	113.6±1.2	112.6±1.6	114.5±1.8	0.432
Fasting insulin, mU/L	10.9±0.3	10.8±0.5	11.1±0.5	0.627
HbA1c, %	6.64±0.03	6.67±0.06	6.62±0.05	0.604
T2DM, %‡	53.8	56.8	50.9	0.338
Hypertension, %§	68.5	69.0	67.3	0.590
Smoking, %	10.0	11.3	8.80	0.810
Carotid ultrasonography
IMT-CC, mm	0.74±0.01	0.75±0.01	0.74±0.01	0.167
Carotid plaque presence, %	82.3	82.3	82.4	0.811
Carotid plaque number, n	1.56±0.05	1.56±0.07	1.57±0.07	0.890
Carotid plaque height, mm	1.91±0.04	1.89±0.06	1.93±0.06	0.559
Use of antihypertensive drugs, %
ACE inhibitors or ARB	82.7	83.4	82.3	0.765
Calcium channel blockers	19.0	18.4	17.3	0.568
Beta-blockers	62.4	64.4	60.5	0.213
Nitrates	10.0	9.8	10.1	0.891
Diuretics	37.8	41.0	34.5	0.199
Use of lipid-lowering drugs (%)
Statins	85.7	86.7	84.8	0.812
Fibrates	3.6	3.6	3.7	0.901
Use of oral antidiabetics, %	34.8	35.8	33.9	0.734

Values are represented as the mean±SE or percentage of participants unless otherwise stated. We used unpaired t tests for quantitative variables and χ2 tests for categorical variables. ACE indicates angiotensin-converting enzyme; ARB, angiotensin-receptor blockers; BMI, body mass index; CHD, cardiovascular heart disease; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; hsCRP, high sensitive C-reactive protein; IMT-CC, intima-media thickness of both common
carotid arteries; LDL, low-density lipoprotein; and T2DM, type 2 diabetes mellitus.
*Low-fat diet vs Mediterranean diet, P<0.05
†BMI was calculated as weight in kg divided by the square of height in m (kg/m²).
‡Diabetes was defined as being diagnosed as diabetic before the start of the study (350, 34.9%) and those diagnosed by a fasting blood glucose level ≥ 126 mg/dL on two occasions, or a 2-h plasma glucose level ≥ 200 mg/dL during a 75-g oral glucose tolerance test, during the first procedures of the study.
§Hypertension was defined as a systolic blood pressure ≥140 mm Hg, a diastolic blood pressure ≥90 mm Hg, or the use of antihypertensive therapy.

Table 2. Changes in Carotid Plaque Height and Number By Dietary Intervention Groups*
	Change between baseline and after 5 y			Change between baseline and after 7 years
	Low-fat diet	Mediterranean diet	P value†	Low-fat diet	Mediterranean diet	P value†
Carotid plaquemax height, mm‡	0.13±0.07	-0.09±0.05	0.031	0.10±0.05	-0.10±0.07	0.028
Carotid plaque number (n)	0.21±0.12	-0.01±0.09	0.191	0.19±0.07	0.03±0.06	0.235

Carotid plaque data at 5 y (n=291 after low-fat diet and n=307 after Mediterranean diet). Carotid plaque data at 7 y (n=249 after low-fat diet and n=265 after Mediterranean diet).
*Data are presented as changes produced between postintervention and preintervention±SE.
†P<0.05, differences in changes at 5 and 7 y between both diets by univariate ANOVA.
‡Carotid plaque_max height: maximum carotid plaque height.

Table 3. Statistically Significant Multiple Linear Regression Coefficients to Predict Changes in IMT-CC
Independent variables	Unstandardized coefficients		Standardized coefficients	P value
Independent variables	B	SE		P value
Age, y	0.002	4.5×10⁻⁵	0.154	7.0×10⁻⁶
Allocation into Mediterranean diet (vs low-fat diet)†	−0.027	0.007	−0.117	2.7×10-4
BMI at baseline, kg/m²	0.002	0.001	0.076	0.020
Energy intake at baseline, kcal/d	1.5×10⁻⁵	7.0×10⁻⁷	0.073	0.024
T2DM at baseline, yes	0.017	0.008	0.074	0.029
IMT-CC at baseline, mm	−0.521	0.027	−0.678	3.1×10⁻⁶⁶
Carotid plaque number at baseline, n	0.008	0.003	0.085	0.010

(Constant)=0.166; (R)=0.642. Predictive variables tested by stepwise method: sex, age, ever smoking, BMI, presence of T2DM, dietary group allocation (Mediterranean diet vs low-fat diet), energy intake and pharmacological treatments (use of lipid-lowering drugs, use of antidiabetic drugs, and use of antihypertensive drugs), IMT-CC and carotid plaque number at baseline, and parameters related to changes (postintervention minus baseline) due to dietary intervention after 5 y of follow-up (changes in energy and nutrient intake –MUFA, PUFA, SFA, total carbohydrates, total protein, and fiber), assuming that all predictor variables were quantitative or categorical (with 2 categories), and the outcome variable was quantitative, continuous and unbounded. BMI indicates body mass index; IMT-CC, intima-media thickness of both common carotid arteries; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids; and T2DM, type 2 diabetes mellitus.

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Mediterranean Diet Reduces Atherosclerosis Progression in Coronary Heart Disease

An Analysis of the CORDIOPREV Randomized Controlled Trial

Abstract and Introduction

Abstract

Introduction

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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