Ramon Estruch, MD, PhD; Miguel Ángel Martínez-González, MD, PhD; Dolores Corella, PhD; Jordi Salas-Salvadó, MD, PhD; Valentina Ruiz-Gutiérrez, PhD; María Isabel Covas, PhD; Miguel Fiol, MD, PhD; Enrique Gómez-Gracia, MD, PhD; Mari Carmen López-Sabater, PhD; Ernest Vinyoles, MD, PhD; Fernando Arós, MD, PhD; Manuel Conde, MD, PhD; Carlos Lahoz, MD, PhD; José Lapetra, MD, PhD; Guillermo Sáez, MD, PhD; Emilio Ros, MD, PhD; PREDIMED Study Investigators*
International Standard Randomized Controlled Trial Number (ISRCTN): 35739639.
Acknowledgments: The authors thank the Fundación Patrimonio Comunal Olivarero and Hojiblanca SA, California Walnut Commission, Borges SA, and Morella Nuts SA for donating the olive oil, walnuts, almonds, and hazelnuts, respectively, used in the study. They also thank the participants for their enthusiastic collaboration, the PREDIMED personnel for excellent assistance with all aspects of the trial, and Emili Corbella for providing expert assistance with statistical analyses.
Grant Support: By the Spanish Ministry of Health (Fondo de Investigación Sanitaria, Red G03/140).
Potential Financial Conflicts of Interest: Consultancies: E. Ros (California Walnut Commission); Honoraria: E. Ros (California Walnut Commission); Grants received: E. Ros (California Walnut Commission); Grants pending: E. Ros (California Walnut Commission).
Requests for Single Reprints: Ramon Estruch, MD, PhD, Department of Internal Medicine, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Estruch: Department of Internal Medicine, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain.
Dr. Martínez-González: Department of Preventive Medicine and Public Health, School of Medicine–Clínica Universitaria de Navarra, University of Navarra, Irunlarrea 1, 31080 Pamplona, Navarra, Spain.
Dr. Corella: Department of Preventive Medicine, School of Medicine, University of Valencia, Avda. Blasco Ibáñez 15, 46010 Valencia, Spain.
Dr. Salas-Salvadó: Human Nutrition Department, School of Medicine, University Rovira i Virgili, San Llorenç 21, 43201 Reus (Tarragona), Spain.
Dr. Ruiz-Gutiérrez: Instituto de la Grasa, Consejo Superior de Investigaciones Cientificas, Avda. Padre García Tejero 4, 41012 Sevilla, Spain.
Dr. Covas: Cardiovascular Epidemiology Unit, Municipal Institut for Medical Research (IMIM), Barcelona, Dr. Aiguader 80, 08003 Barcelona, Spain.
Dr. Fiol: Department of Cardiology, Hospital Universitario Son Dureta, Andrea Doria 55, 07014 Palma de Mallorca, Spain.
Dr. Gómez-Gracia: Department of Epidemiology, School of Medicine, University of Malaga, Capus de Teatinos s/n, 29071 Málaga, Spain.
Dr. López-Sabater: Department of Nutrition and Bromatology, School of Pharmacy, Avda. Joan XXIII s/n, Barcelona, Spain.
Dr. Vinyoles: Primary Care Division, Catalan Institute of Health, Gran Via 587, 08007 Barcelona, Spain.
Dr. Arós: Department of Cardiology, Hospital Txangorritxu, José Achotegui s/n, 01009 Vitoria, Alava, Spain.
Dr. Conde: Department of Epidemiology and Public Health, Hospitales Universitarios Vírgen del Rocío, Manuel Siurot s/n, 41013 Sevilla, Spain.
Dr. Lahoz: Arteriosclerosis Unit, Hospital Carlos III, Sinesio Delgado 10, 28029 Madrid, Spain.
Dr. Lapetra: San Pablo Health Center, Damasco s/n, 41007 Sevilla, Spain.
Dr. Sáez: Department of Biochemistry, School of Medicine, University of Valencia, Avda. Blasco Ibáñez 15, 46010 Valencia, Spain.
Dr. Ros: Lipid Clinic, Endocrinology and Nutrition Service, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain.
Author Contributions: Conception and design: R. Estruch, M.. Martínez-González, D. Corella, J. Salas-Salvadó, V. Ruiz-Gutiérrez, M.I. Covas, M. Fiol, E. Gómez-Gracia, M. Conde, C. Lahoz, J. Lapetra, G. Sáez, E. Ros.
Analysis and interpretation of the data: R. Estruch, M.. Martínez-González, D. Corella, J. Salas-Salvadó, V. Ruiz-Gutiérrez, M.I. Covas, E. Gómez-Gracia, M.C. López-Sabater, J. Lapetra, G. Sáez, E. Ros.
Drafting of the article: R. Estruch, M.. Martínez-González, D. Corella, J. Salas-Salvadó, V. Ruiz-Gutiérrez, M.I. Covas, F. Arós, C. Lahoz, G. Sáez, E. Ros.
Critical revision of the article for important intellectual content: R. Estruch, M.. Martínez-González, D. Corella, J. Salas-Salvadó, V. Ruiz-Gutiérrez, M.I. Covas, M. Fiol, E. Gómez-Gracia, M.C. López-Sabater, M. Conde, J. Lapetra, G. Sáez, E. Ros.
Final approval of the article: R. Estruch, M.. Martínez-González, D. Corella, J. Salas-Salvadó, V. Ruiz-Gutiérrez, M.I. Covas, M. Fiol, E. Gómez-Gracia, E. Vinyoles, M. Conde, J. Lapetra, G. Sáez, E. Ros.
Provision of study materials or patients: R. Estruch, M.. Martínez-González, D. Corella, J. Salas-Salvadó, V. Ruiz-Gutiérrez, M.I. Covas, M. Fiol, E. Gómez-Gracia, E. Vinyoles, M. Conde, C. Lahoz, J. Lapetra, G. Sáez, E. Ros.
Statistical expertise: R. Estruch, M.. Martínez-González, D. Corella, J. Salas-Salvadó, M.I. Covas, G. Sáez, E. Ros.
Obtaining of funding: R. Estruch, M.. Martínez-González, D. Corella, J. Salas-Salvadó, V. Ruiz-Gutiérrez, M.I. Covas, M. Fiol, E. Gómez-Gracia, M. Conde, J. Lapetra, G. Sáez, E. Ros.
Administrative, technical, or logistic support: R. Estruch, M.. Martínez-González, D. Corella, J. Salas-Salvadó, V. Ruiz-Gutiérrez, M.I. Covas, E. Gómez-Gracia, E. Vinyoles, F. Arós, M. Conde, J. Lapetra, G. Sáez, E. Ros.
Collection and assembly of data: R. Estruch, M.. Martínez-González, D. Corella, J. Salas-Salvadó, M.I. Covas, E. Gómez-Gracia, F. Arós, J. Lapetra, G. Sáez, E. Ros.
Estruch R., Martínez-González M., Corella D., Salas-Salvadó J., Ruiz-Gutiérrez V., Covas M., Fiol M., Gómez-Gracia E., López-Sabater M., Vinyoles E., Arós F., Conde M., Lahoz C., Lapetra J., Sáez G., Ros E., ; Effects of a Mediterranean-Style Diet on Cardiovascular Risk Factors: A Randomized Trial. Ann Intern Med. 2006;145:1-11. doi: 10.7326/0003-4819-145-1-200607040-00004
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Published: Ann Intern Med. 2006;145(1):1-11.
Cardiovascular disease is the main cause of death in industrialized countries, but incidence rates have marked geographic differences. The low incidence of coronary heart disease (CHD) in Mediterranean countries has been partly ascribed to dietary habits (1-3). Recent findings from large European cohort studies (4-6) suggest that a high degree of adherence to the Mediterranean diet is associated with a reduction in mortality. In small clinical studies, the Mediterranean diet or some of its components have reduced blood pressure (7) and have improved lipid profiles (8-9) and endothelial function (10). Moreover, a recent cross-sectional study (11) and a 2-year feeding trial (12) have shown that adherence to the Mediterranean diet is associated with reduced markers of vascular inflammation. These beneficial effects on surrogate markers of cardiovascular risk add biological plausibility to the epidemiologic evidence that supports a protective effect of the Mediterranean diet.
Department of Internal Medicine, University of TÃ¼bingen, Germany
July 10, 2006
Mediterranean Diets and Nonalcoholic Fatty Liver Disease
To the editor: Dr. Estruch and colleagues (1) reported interesting findings on the beneficial effect of Mediterranean diets compared to a low -fat diet on cardiovascular risk factors such as high-density cholesterol (HDL-C) levels and insulin sensitivity. They hypothesized that the beneficial effects, brought on by the Mediterranean diets, were largely mediated by an increased intake of mono- and polyunsaturated fatty acids.
Following up on this we propose a mechanism supporting this hypothesis and an additional clinical implication of these results. Increased intake of mono- and polyunsaturated fatty acids was found to be associated with less storage of fat in the liver (2). Nonalcoholic fatty liver disease (NAFLD), the syndrome that comprises more that 5 % of fat accumulation in the liver without a history of excess of alcohol intake, is associated with insulin resistance (3) and is a predictor of cardiovascular events (4). Thus, increased intake of mono- and polyunsaturated fatty acids may well have decreased fat storage in the liver in the subjects on the Mediterranean diets. Measurements of serum transaminases, that most probable were elevated in many of the obese subjects and in participants with type 2 diabetes in the study by Estruch and colleagues (1), can help to verify this hypothesis. Moreover, if the Mediterranean diets decrease fat accumulation in the liver, then the results of this study may become important for the treatment of NAFLD. Besides its role in the pathophysiology of atherosclerosis and type 2 diabetes, NAFLD is the major cause of chronic liver disease (5). While pharmacological interventions were not found to be very effective in the treatment of NAFLD, nutritional counselling and physical activity are considered to be more efficient (5). However, no controlled intervention trials exist so far that may help to address this issue. The study by Estruch and colleagues (1) can potentially add important new findings to this field of research.
1) Estruch R, Martinez-Gonzalez MA, Corella D, Salas-Salvado J, Ruiz- Gutierrez V, Covas MI et al. PREDIMED Study Investigators. Effects of a Mediterranean-style diet on cardiovascu-lar risk factors: a randomized trial. Ann Intern Med. 2006 145: 1-11.
2) Tiikkainen M, Bergholm R, Vehkavaara S, Rissanen A, Hakkinen AM, Tamminen M et al. Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content. Diabetes. 2003 52: 701-707.
3) Stefan N, Schafer S, Machicao F, Machann J, Schick F, Claussen CD et al. Liver fat and in-sulin resistance are independently associated with the -514C>T polymorphism of the hepatic lipase gene. J Clin Endocrinol Metab. 2005 90: 4238-4243.
4) Targher G, Bertolini L, Poli F, Rodella S, Scala L, Tessari R et al. Nonalcoholic Fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes. 2005 54: 3541-3546
5) Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002 346: 1221-1231.
University of Pennsylvania
July 31, 2006
Bias in study of Mediterranean Diet?
In the recently published study by the PREDIMED investigators, it was concluded that "Compared with a low-fat diet, Mediterranean diets supplemented with olive oil or nuts have beneficial effects on cardiovascular risk factors". The investigators of this study deserve credit for successfully carrying out this large multicenter study, for including persons at high cardiovascular risk (e.g. diabetes), and for achieving a high completion rate. However, there are two points that merit clarification, in order to avoid bias in the paper toward a Mediterranean diet: 1) Is it really fair to make any comparison of the Mediterranean diets to the "low fat" diet when the intervention for the low fat group was minimal, and clearly less intensive than the Mediterranean diets? In fact, the "low fat" group made very few changes at all in their diet. This is briefly mentioned in the limitations section, but the more favorable response of the Mediterranean diets compared to the low fat diet remains the core conclusion of the paper. It would have been less misleading to call this a control diet group. It would have been less biased to actually provide interventions of similar intensity to all three groups. 2) There are no baseline values provided for glycemic indices, HOMA-IR, or lipids. It is therefore very difficult to put the changes in these risk factors into the context of their clinical relevance. Regardless, it appears these changes were of marginal clinical significance (based on estimated baseline values, all <5.0% changes with the exception of HOMA-IR). This should have been discussed in the paper.
Dr. Rajesh Chauhan
MH Baroda (309/9 A.V. Colony, Sikandra, Agra). INDIA.
August 6, 2006
Better Hearts: Can it be something more for Mediterraneans than just the Mediterranean-Style Diet
To continue attributing reduced cardiovascular risks with a Mediterranean-style diet, needs to be reconsidered. Diets may help to certain extent. The interplay of other socio-cultural and psychological factors must not be overlooked in the haste to ascribe definite benefit to a particular diet itself. How about the comparative stress factors and lifestyles, work culture and behavioral patterns, levels of happiness/satisfaction and harmony at work and home. The interplay of the outlook, interactions, expectations, attitudes, and support of the family, society, community along with the societal values, role and interplay of religion and faith, the stress levels per say, and comparable stress bearing threshold levels, etc, must also be looked into.
Doubts about the efficacy of a particular diet shall continue to prevail. Probably by comparing what happens to a cohort of Mediterranean people who develop/switch over to a Type A personality or start conforming their lives to match the big American dreams, a better perspective can be provided. The cohort should be subjected to similar stress levels with switchover to American rather than Mediterranean type beliefs, attitudes, family and community support, expectations and interactions, work culture, and other factors which apparently may have any bearing on the heart, whether direct or indirect.
Maybe a Mediterranean-lifestyle is the key to a better heart rather than their diet alone. Therefore, in order to develop a comprehensive guideline for reduced cardiovascular risks, the socio-cultural factors and lifestyles must not be omitted or overlooked.
Ram B Singh
Halberg Hospital and Research Institute
September 14, 2006
Mediterranean Diet and the Columbus Foods
Sir, We enjoyed very much the most interesting study by Estruch and co-workers on the role of Mediterranean diet on cardiovascular disease(CVD) risk factors(1). We agree on the beneficial effects of olive oil and nuts in conjunction with Mediterranean foods; on total cholesterol/ high density lipoprotein cholesterol ratio (T-C/HDL-C),systolic blood pressure and blood glucose, compared to low fat diet for which nutritional education was less intense than for other two groups on Mediterranean diets. It is not clear what opposite recommendations were made to low fat "“diet group, compared to participants in the 2 Mediterranean diet group(Methods,para 7,last 5 lines).In Mediterranean countries, olive oil and nuts are traditional foods which are well known for their beneficial effects on health and disease(1 see ref). We would appreciate the authors for providing justification for such advice, especially when American Heart Association(AHA), is so incoherent about their dietary advice for prevention of CVD(2).It would be interesting to know the effects of 3 diets on endothelial dysfunction,which appears to be a better predictor of CVD risk than cholesterol as such(3,4).
The Diet and Lifestyle Recommendations 2006 of the AHA Nutrition Committee(3), continue to be under influence of food industry. The committee recommends the use of all the vegetable oils without pointing out any adverse effects of w-6 fatty acids rich sunflower oil, corn oil and soyabean oils. This means that the sale of these oils now would increase, which was reduced, after publication of the Lyon Heart Study using olive oil + rapeseed oil causing marked reduction in cardiovascular deaths(5). However these fats appear to act in presence of Mediterranean or Indo- Mediterranean diet(5,6) which have been called columbus foods by the columbus Paradigm Institute (www.columbus-concept.com). The importance and the effects of an overall diet and lifestyle are only partially known. Multiple diet and lifestyle factors influence CVD risk and not all do so via changes in the risk factors known to the experts.
Recent studies indicate the role of diet in pro- inflammatory diseases such as acute myocardial infarctions (AMI) and diabetes(3,4). While foods and beverages with added sugars and refined starches as well as excess of w-6,total and saturated fat and trans fatty acids,may be proinflammatory, increased intake of w-3 fatty acid and MUFA may be protective against surge of TNF-alpha,IL-6,IL-18 and adhesion molecules like VCAM-1(vascular cell adhsion molecule-1)and IVAM-1 caused by high glycemic, rapidly absorbed proinflammatory foods(3,7).These foods are known to initiate a proinflammatory milieu in the body which is similar to that of AMI,causing further increase in complications,among these patients. A low w-6/w-3 ratio and polyunsaturated/saturated fatty acid ratio in the diet of 1:1 has been proposed by the columbus Paradigm Institute for prevention of dyslipidemia and CAD.Columbus foods are natural foods,rich in phytochemicals which are slowly absorbed without causing any abnormal increase in blood glucose,insulin, proinflammatory cytokines and free fatty acids(7,8).The ColumbusÂ® Concept stands for a return of alpha-linolenic acid (ALA, C18:3Ã¹3) - herein referred to as wild - or game-type land-based fatty acid - into the feed ration of land-based bred animals to such an extent that their fat depots (white adipose tissue) exhibit a balanced ratio of essential fatty acids, i.e. Ã¹6:Ã¹3 = 1:1, characteristic of fat depots in wild animals or game.This return to the wild standard translates into a substantial reduction in long chain omega-6 fatty acids and a moderate species-specific increase in long chain omega-3 fatty acids in organs and peripheral tissues of these domesticated animals or livestock. The Ã¹6:Ã¹3 = 1:1 ratio is also taken as reference for the design of composite plant-derived table oils and fats as these represent other primary sources of energy in the modern human diet(8). Provided particular attention is drawn to the phytochemical content of such foods, the twofold end results are a return to animal and plant food supplies in better compliance with human genetic heritage and a possible rehabilitation of dietary cholesterol and saturated fats (former CSI, C: Cholesterol, S: Saturated fats, I: Index).Taken within a larger context, the ColumbusÂ® Concept stands for the return of a specific healthy cholesterol into men's food supply and blood stream, the so-called wild or game cholesterol that is associated with a dietary balanced essential fatty acid ratio (Ã¹6:Ã¹3 = 1:1).As observed from the overall distribution of fats in a natural untamed environment, nature recommends the consumption of a balanced ratio of saturated and polyunsaturated fatty acids as part of a dietary lipid pattern rich in monounsaturated fatty acids (P:M:S = 1:6:1).The value of such diet has also been proven in long term clinical trials(5,6).We would gratefully appreciate the opinion of the authors of above study,on our submission. Correspondence: Dr R B Singh Halberg Hospital and Research Institute, Civil Lines,Moradabad-10(UP)244001,India. Email,email@example.com,firstname.lastname@example.org
1.Estruch R and PREDIMED Investigators.Effects of a Mediterranean-style diet on cardiovascular risk factors.Ann Intern Med 2006;145:1-11.
2.American Heart Association Nutrition Committee.Diet and Lifestyle Recommendations Revision 2006.A Scientific Statement from the American Heart Association Nutrition Committee.Circulation, online,June 23,2006,http://circ.ahajournals.org
3.Esposito K,Glugliano D.Diet and inflammation:a link to metabolic and cardiovascular diseases.Euro Heart J,2006,27:15-20.
4.Singh RB,Pella D,DeMeester F.What to eat and chew in acute myocardial infarction. Eur Heart J 2006,27:1628-29.
5.De Lorgeril M, Salen P, Martin JL,Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors and the rate of cardiovascular complications after myocardial infarction .Final report of the Lyon Diet Heart Study. Circulation 1999;99:779-785.
6.Singh RB,Dubnov G,Niaz MA,Ghosh S,Singh R,Rastogi SS,Manor O,Pella D,Berry EM.Effect of an Indo-Mediterranean diet on progression of coronary disease in high risk patients:a randomized single blind trial.Lancet 2002,360:1455-1461.
7..Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano G, D'Armiento M, D'Andrea F, Giugliano D. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome : a randomized trial. JAMA 2004;292:1440-1446.
8. Jiang Z,Sim JS.Consumption of omega-3 polyunsaturated fatty acids enriched eggs and changes in plasma lipids of human subjects.Nutrition 1993,9:513-518.
Dr Fabien DeMeester is the President of Columbus Paradigm Institute which designs the foods for marketing.
Miguel Angel Martinez-GonzÃ¡lez
Department of Preventive Medicine and Public Health, School of Medicine, University of Navarra, Pamp
November 6, 2006
Re: Bias in study of Mediterranean Diet?
IN RESPONSE: We thank Dr. Samaha for his comments (1) and appreciate the point raised about our recent report(2) regarding the fairness of comparisons between the Mediterranean diets and a less intensively promoted low-fat diet. We think that it is fair to compare interventions with different grades of intensity as far as their context can be appropriately conceptualized. Our intervention was not designed as a tightly controlled feeding trial. Instead, the PREDIMED study is a demonstration project conducted among free-living individuals in a context similar to that of health-promoting lifestyle recommendations at the Primary Care setting(3). We conceptualized our intervention as the combination of enabling factors, such as providing healthy foods, and education plus counseling to achieve behavior change. The comparison group was given written instructions to follow a low-fat diet, as is common in Primary Care. However, having realized that the intervention in participants ascribed to the low fat-diet was indeed less intensive, as the study is ongoing we have now designed group sessions with provision of written instructions in a similar way to what is done in the Mediterranean diet groups.
With respect to baseline levels of the main outcome variables, they were similar among the three groups. Mean levels for systolic blood pressure ranged from 152 to 153 mm Hg; for glucose in participants with diabetes, 7.9 to 8.8 mmol/L (142 to 159 mg/dL); for HOMA indices in non- diabetic participants, 4.1 to 4.2; for LDL cholesterol, 4.1 to 4.3 mmol/L (141 to 147 mg/dL); for HDL cholesterol, 1.3 to 1.4 mmol/L (45 to 47 mg/dL); and for triglycerides, 1.6 to 1.7 mg/dL (138 to 149 mg/dL). We acknowledge that the absolute magnitude of changes in individual risk factors associated with the Mediterranean diets was small. However, taken together, these changes represented a significant reduction in coronary heart disease (CHD) risk. Thus, compared to the low-fat diet group, the changes in percent 10-year absolute risk for CHD, estimated with the Framingham charts(4), were -1.7 (-3.2 to -0.2) and -1.8 (-3.3 to -0.2) in the Mediterranean diet with olive oil and the Mediterranean diet with nuts groups, respectively. In summary, a single behavioral intervention to improve a Mediterranean-style diet plus provision of healthy foods is able to induce changes in several risk markers in the short term, which represents a sizeable effect on overall cardiovascular risk. Hopefully, longer follow-up of the PREDIMED cohorts will magnify between-group differences in both food intake and risk factor changes that will eventually translate into diverse clinical outcomes.
1.Frederick Samaha, Frederick F. Samaha. Bias in study of Mediterranean Diet?. www.annals.org - Electronic letters 31 jul 2006
2.Estruch R, MartÃnez-GonzÃ¡lez MA, Corella D, Salas-SalvadÃ³ J, Ruiz- GutiÃ©rrez V, Covas MI, et al. Effects of a Mediterranean-style diet on cardiovascular risk factors. A randomized trial. Ann Intern Med. 2006;145:1-11.
3.Krauss RM, Eckel RH, Howard B, Appel LJ, Daniels SR, Deckelbaum RJ, et al. AHA dietary guidelines. Revision 2000: A statement for health professionals from the Nutrition Committee of the American Heart Association. Circulation 2000;102:2284-99.
4.D'Agostino RB Sr, Grundy S, Sullivan LM, Wilson P; CHD Risk Prediction Group. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA 2001;286:180-7.
E. Ros (California Walnut Commission): Honoraria and Grants received.
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