Mediterranean diet and endothelial function in patients with coronary heart disease: An analysis of the CORDIOPREV randomized controlled trial

Autoři: Elena M. Yubero-Serrano aff001;  Carolina Fernandez-Gandara aff001;  Antonio Garcia-Rios aff001;  Oriol A. Rangel-Zuñiga aff001;  Francisco M. Gutierrez-Mariscal aff001;  Jose D. Torres-Peña aff001;  Carmen Marin aff001;  Javier Lopez-Moreno aff001;  Justo P. Castaño aff002;  Javier Delgado-Lista aff001;  José M. Ordovás aff004;  Pablo Perez-Martinez aff001;  Jose Lopez-Miranda aff001
Působiště autorů: Unidad de Gestión Clinica de Medicina Interna, Lipids and Atherosclerosis Unit, Maimonides Institute for Biomedical Research in Córdoba, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain aff001;  CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, Madrid, Spain aff002;  Department of Cell Biology, Physiology and Immunology, University of Córdoba, IMIBIC/Reina Sofia University; Campus de Excelencia Internacional Agroalimentario (ceiA3), Córdoba, Spain aff003;  Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University School of Medicine, Boston, Massachusetts, United States of America aff004
Vyšlo v časopise: Mediterranean diet and endothelial function in patients with coronary heart disease: An analysis of the CORDIOPREV randomized controlled trial. PLoS Med 17(9): e32767. doi:10.1371/journal.pmed.1003282
Kategorie: Research Article



Endothelial dysfunction is a crucial step in atherosclerosis development, and its severity is determinant for the risk of cardiovascular recurrence. Diet may be an effective strategy to protect the endothelium, although there is no consensus about the best dietary model. The CORonary Diet Intervention with Olive oil and cardiovascular PREVention (CORDIOPREV) study is an ongoing prospective, randomized, single-blind, controlled trial in 1,002 coronary heart disease (CHD) patients, whose primary objective is to compare the effect of 2 healthy dietary patterns (low-fat versus Mediterranean diet) on the incidence of cardiovascular events. Here, we report the results of one secondary outcome of the CORDIOPREV study: to evaluate the effect of these diets on endothelial function, assessed by flow-mediated dilation (FMD) of the brachial artery.

Methods and findings

From the total participants taking part in the CORDIOPREV study, 805 completed endothelial function study at baseline and were randomized to follow a Mediterranean diet (35% fat, 22% monounsaturated fatty acids [MUFAs], and <50% carbohydrates) or a low-fat diet (28% fat, 12% MUFAs, and >55% carbohydrates), with endothelial function measurement repeated after 1 year. As secondary objectives and to explore different underlying mechanisms in the modulation of endothelial function, we quantified endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) and evaluated, in 24 preselected patients, in vitro cellular processes related to endothelial damage (reactive oxygen species, apoptosis, and senescence) and endothelial repair (cell proliferation and angiogenesis), as well as other modulators (micro-RNAs [miRNAs] and proteins). Patients who followed the Mediterranean diet had higher FMD (3.83%; 95% confidence interval [CI]: 2.91–4.23) compared with those in the low-fat diet (1.16%; 95% CI: 0.80 to 1.98) with a difference between diets of 2.63% (95% CI: 1.89–3.40, p = 0.011), even in those patients with severe endothelial dysfunction. We observed higher EPC levels (group difference: 1.64%; 95% CI: 0.79–2.13, p = 0.028) and lower EMPs (group difference: −755 EMPs/μl; 95% CI: −1,010 to −567, p = 0.015) after the Mediterranean diet compared with the low-fat diet in all patients. We also observed lower intracellular reactive oxygen species (ROS) production (group difference: 11.1; 95% CI: 2.5 to 19.6, p = 0.010), cellular apoptosis (group difference: −20.2; 95% CI: −26.7 to −5.11, p = 0.013) and senescence (18.0; 95% CI: 3.57 to 25.1, p = 0.031), and higher cellular proliferation (group difference: 11.3; 95% CI: 4.51 to 13.5, p = 0.011) and angiogenesis (total master segments length, group difference: 549; 95% CI: 110 to 670, p = 0.022) after the Mediterranean diet than the low-fat diet. Each dietary intervention was associated with distinct changes in the epigenetic and proteomic factors that modulate biological process associated with endothelial dysfunction. The evaluation of endothelial function is a substudy of the CORDIOPREV study. As in any substudy, these results should be treated with caution, such as the potential for false positives because of the exploratory nature of the analyses.


Our results suggest that the Mediterranean diet better modulates endothelial function compared with a low-fat diet and is associated with a better balance of vascular homeostasis in CHD patients, even in those with severe endothelial dysfunction.

Clinical trial registration

URL, number NCT00924937.

Klíčová slova:

Analysis of variance – C-reactive proteins – Coronary heart disease – Diet – Diet and type 2 diabetes – Endothelial cells – Homeostasis – MicroRNAs


1. Brown JR, O'Connor GT. Coronary heart disease and prevention in the United States. N Engl J Med. 2010;362(23):2150–3. doi: 10.1056/NEJMp1003880 20558365.

2. WHO. World Health Report 2013: Research for universal health coverage. Geneva: WHO; 2013.

3. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002;106(6):653–8. doi: 10.1161/01.cir.0000025404.78001.d8 12163423.

4. Bertoluci MC, Ce GV, da Silva AM, Wainstein MV, Boff W, Punales M. Endothelial dysfunction as a predictor of cardiovascular disease in type 1 diabetes. World J Diabetes. 2015;6(5):679–92. doi: 10.4239/wjd.v6.i5.679 26069717; PubMed Central PMCID: PMC4458497.

5. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340(8828):1111–5. doi: 10.1016/0140-6736(92)93147-f 1359209.

6. Gori T, Muxel S, Damaske A, Radmacher MC, Fasola F, Schaefer S, et al. Endothelial function assessment: flow-mediated dilation and constriction provide different and complementary information on the presence of coronary artery disease. Eur Heart J. 2012;33(3):363–71. Epub 2011 Sept 14. doi: 10.1093/eurheartj/ehr361 21920964.

7. Spiro JR, Digby JE, Ghimire G, Mason M, Mitchell AG, Ilsley C, et al. Brachial artery low-flow-mediated constriction is increased early after coronary intervention and reduces during recovery after acute coronary syndrome: characterization of a recently described index of vascular function. Eur Heart J. 2011;32(7):856–66. Epub 2010 Oct 9. doi: 10.1093/eurheartj/ehq401 21037253; PubMed Central PMCID: PMC3069386.

8. Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation. 2005;111(3):363–8. doi: 10.1161/01.CIR.0000153339.27064.14 15668353.

9. Xu Y, Arora RC, Hiebert BM, Lerner B, Szwajcer A, McDonald K, et al. Non-invasive endothelial function testing and the risk of adverse outcomes: a systematic review and meta-analysis. Eur Heart J Cardiovasc Imaging. 2014;15(7):736–46. doi: 10.1093/ehjci/jet256 24399339.

10. Matsuzawa Y, Sugiyama S, Sumida H, Sugamura K, Nozaki T, Ohba K, et al. Peripheral endothelial function and cardiovascular events in high-risk patients. J Am Heart Assoc. 2013;2(6):e000426. doi: 10.1161/JAHA.113.000426 24275629; PubMed Central PMCID: PMC3886751.

11. Schnabel RB, Schulz A, Wild PS, Sinning CR, Wilde S, Eleftheriadis M, et al. Noninvasive vascular function measurement in the community: cross-sectional relations and comparison of methods. Circ Cardiovasc Imaging. 2011;4(4):371–80. doi: 10.1161/CIRCIMAGING.110.961557 21551420.

12. Fathi R, Haluska B, Isbel N, Short L, Marwick TH. The relative importance of vascular structure and function in predicting cardiovascular events. J Am Coll Cardiol. 2004;43(4):616–23. doi: 10.1016/j.jacc.2003.09.042 14975472.

13. Enderle MD, Schroeder S, Ossen R, Meisner C, Baumbach A, Haering HU, et al. Comparison of peripheral endothelial dysfunction and intimal media thickness in patients with suspected coronary artery disease. Heart. 1998;80(4):349–54. doi: 10.1136/hrt.80.4.349 9875110; PubMed Central PMCID: PMC1728800.

14. Berezin A, Zulli A, Kerrigan S, Petrovic D, Kruzliak P. Predictive role of circulating endothelial-derived microparticles in cardiovascular diseases. Clin Biochem. 2015;48(9):562–8. doi: 10.1016/j.clinbiochem.2015.02.003 25697107.

15. Lee PS, Poh KK. Endothelial progenitor cells in cardiovascular diseases. World J Stem Cells. 2014;6(3):355–66. doi: 10.4252/wjsc.v6.i3.355 25126384; PubMed Central PMCID: PMC4131276.

16. Aragona CO, Imbalzano E, Mamone F, Cairo V, Lo Gullo A, D'Ascola A, et al. Endothelial Progenitor Cells for Diagnosis and Prognosis in Cardiovascular Disease. Stem Cells Int. 2016;2016:8043792. doi: 10.1155/2016/8043792 26839569; PubMed Central PMCID: PMC4709789.

17. Burger D, Touyz RM. Cellular biomarkers of endothelial health: microparticles, endothelial progenitor cells, and circulating endothelial cells. J Am Soc Hypertens. 2012;6(2):85–99. doi: 10.1016/j.jash.2011.11.003 22321962.

18. Berezin AE, Kremzer AA, Samura TA, Martovitskaya YV, Malinovskiy YV, Oleshko SV, et al. Predictive value of apoptotic microparticles to mononuclear progenitor cells ratio in advanced chronic heart failure patients. J Cardiol. 2015;65(5):403–11. doi: 10.1016/j.jjcc.2014.06.014 25123603.

19. Weech M, Altowaijri H, Mayneris-Perxachs J, Vafeiadou K, Madden J, Todd S, et al. Replacement of dietary saturated fat with unsaturated fats increases numbers of circulating endothelial progenitor cells and decreases numbers of microparticles: findings from the randomized, controlled Dietary Intervention and VAScular function (DIVAS) study. Am J Clin Nutr. 2018;107(6):876–82. doi: 10.1093/ajcn/nqy018 29741564.

20. Davis CR, Hodgson JM, Woodman R, Bryan J, Wilson C, Murphy KJ. A Mediterranean diet lowers blood pressure and improves endothelial function: results from the MedLey randomized intervention trial. Am J Clin Nutr. 2017;105(6):1305–13. doi: 10.3945/ajcn.116.146803 28424187.

21. Singh N, Graves J, Taylor PD, MacAllister RJ, Singer DR. Effects of a 'healthy' diet and of acute and long-term vitamin C on vascular function in healthy older subjects. Cardiovasc Res. 2002;56(1):118–25. doi: 10.1016/s0008-6363(02)00514-x 12237172.

22. Fuentes F, Lopez-Miranda J, Sanchez E, Sanchez F, Paez J, Paz-Rojas E, et al. Mediterranean and low-fat diets improve endothelial function in hypercholesterolemic men. Ann Intern Med. 2001;134(12):1115–9. doi: 10.7326/0003-4819-134-12-200106190-00011 11412051.

23. Perez-Martinez P, Mikhailidis DP, Athyros VG, Bullo M, Couture P, Covas MI, et al. Lifestyle recommendations for the prevention and management of metabolic syndrome: an international panel recommendation. Nutr Rev. 2017;75(5):307–26. doi: 10.1093/nutrit/nux014 28521334; PubMed Central PMCID: PMC5914407.

24. Buscemi S, Verga S, Tranchina MR, Cottone S, Cerasola G. Effects of hypocaloric very-low-carbohydrate diet vs. Mediterranean diet on endothelial function in obese women*. Eur J Clin Invest. 2009;39(5):339–47. doi: 10.1111/j.1365-2362.2009.02091.x 19302563.

25. Noad RL, Rooney C, McCall D, Young IS, McCance D, McKinley MC, et al. Beneficial effect of a polyphenol-rich diet on cardiovascular risk: a randomised control trial. Heart. 2016;102(17):1371–9. doi: 10.1136/heartjnl-2015-309218 27164919.

26. Rallidis LS, Lekakis J, Kolomvotsou A, Zampelas A, Vamvakou G, Efstathiou S, et al. Close adherence to a Mediterranean diet improves endothelial function in subjects with abdominal obesity. Am J Clin Nutr. 2009;90(2):263–8. doi: 10.3945/ajcn.2008.27290 19515732.

27. Schwingshackl L, Hoffmann G. Mediterranean dietary pattern, inflammation and endothelial function: a systematic review and meta-analysis of intervention trials. Nutr Metab Cardiovasc Dis. 2014;24(9):929–39. doi: 10.1016/j.numecd.2014.03.003 24787907.

28. Delgado-Lista J, Perez-Martinez P, Garcia-Rios A, Alcala-Diaz JF, Perez-Caballero AI, Gomez-Delgado F, et al. CORonary Diet Intervention with Olive oil and cardiovascular PREVention study (the CORDIOPREV study): Rationale, methods, and baseline characteristics: A clinical trial comparing the efficacy of a Mediterranean diet rich in olive oil versus a low-fat diet on cardiovascular disease in coronary patients. Am Heart J. 2016;177:42–50. doi: 10.1016/j.ahj.2016.04.011 27297848; PubMed Central PMCID: PMC4910622.

29. Quintana-Navarro GM, Alcala-Diaz JF, Lopez-Moreno J, Perez-Corral I, Leon-Acuna A, Torres-Pena JD, et al. Long-term dietary adherence and changes in dietary intake in coronary patients after intervention with a Mediterranean diet or a low-fat diet: the CORDIOPREV randomized trial. Eur J Nutr. 2020;59(5): 2099–2110. Epub 2019 Jul 24. doi: 10.1007/s00394-019-02059-5 31342228.

30. Torres-Pena JD, Garcia-Rios A, Delgado-Casado N, Gomez-Luna P, Alcala-Diaz JF, Yubero-Serrano EM, et al. Mediterranean diet improves endothelial function in patients with diabetes and prediabetes: A report from the CORDIOPREV study. Atherosclerosis. 2018;269: 50–6. doi: 10.1016/j.atherosclerosis.2017.12.012 29274507.

31. Eriksson L, Erdogdu O, Nystrom T, Zhang Q, Sjoholm A. Effects of some anti-diabetic and cardioprotective agents on proliferation and apoptosis of human coronary artery endothelial cells. Cardiovasc Diabetol. 2012;11: 27. doi: 10.1186/1475-2840-11-27 22436702; PubMed Central PMCID: PMC3353852.

32. Srimahachota S, Wunsuwan R, Siritantikorn A, Boonla C, Chaiwongkarjohn S, Tosukhowong P. Effects of lifestyle modification on oxidized LDL, reactive oxygen species production and endothelial cell viability in patients with coronary artery disease. Clin Biochem. 2010;43(10–11):858–62. doi: 10.1016/j.clinbiochem.2010.04.056 20416290.

33. Suomi T, Seyednasrollah F, Jaakkola MK, Faux T, Elo LL. ROTS: An R package for reproducibility-optimized statistical testing. PLoS Comput Biol. 2017;13(5):e1005562. doi: 10.1371/journal.pcbi.1005562 28542205; PubMed Central PMCID: PMC5470739.

34. Shen X, Li Y, Sun G, Guo D, Bai X. miR-181c-3p and -5p promotes high-glucose-induced dysfunction in human umbilical vein endothelial cells by regulating leukemia inhibitory factor. Int J Biol Macromol. 2018;115:509–17. doi: 10.1016/j.ijbiomac.2018.03.173 29605252.

35. Lin Z, Ge J, Wang Z, Ren J, Wang X, Xiong H, et al. Let-7e modulates the inflammatory response in vascular endothelial cells through ceRNA crosstalk. Sci Rep. 2017;7:42498. doi: 10.1038/srep42498 28195197; PubMed Central PMCID: PMC5307339.

36. Hou S, Fang M, Zhu Q, Liu Y, Liu L, Li X. MicroRNA-939 governs vascular integrity and angiogenesis through targeting gamma-catenin in endothelial cells. Biochem Biophys Res Commun. 2017;484(1):27–33. doi: 10.1016/j.bbrc.2017.01.085 28115160.

37. Mao YY, Wang JQ, Guo XX, Bi Y, Wang CX. Circ-SATB2 upregulates STIM1 expression and regulates vascular smooth muscle cell proliferation and differentiation through miR-939. Biochem Biophys Res Commun. 2018;505(1):119–25. doi: 10.1016/j.bbrc.2018.09.069 30241943.

38. Bai B, Liang Y, Xu C, Lee MY, Xu A, Wu D, et al. Cyclin-dependent kinase 5-mediated hyperphosphorylation of sirtuin-1 contributes to the development of endothelial senescence and atherosclerosis. Circulation. 2012;126(6):729–40. doi: 10.1161/CIRCULATIONAHA.112.118778 22753194.

39. Yao Y, Sun W, Sun Q, Jing B, Liu S, Liu X, et al. Platelet-Derived Exosomal MicroRNA-25-3p Inhibits Coronary Vascular Endothelial Cell Inflammation Through Adam10 via the NF-kappaB Signaling Pathway in ApoE(-/-) Mice. Front Immunol. 2019;10:2205. doi: 10.3389/fimmu.2019.02205 31632389; PubMed Central PMCID: PMC6783608.

40. Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F, Giugliano G, et al. Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA. 2004;292(12):1440–6. doi: 10.1001/jama.292.12.1440 15383514.

41. Ros E, Nunez I, Perez-Heras A, Serra M, Gilabert R, Casals E, et al. A walnut diet improves endothelial function in hypercholesterolemic subjects: a randomized crossover trial. Circulation. 2004;109(13): 1609–14. doi: 10.1161/01.CIR.0000124477.91474.FF 15037535.

42. Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, et al. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts. N Engl J Med. 2018;378(25):e34. doi: 10.1056/NEJMoa1800389 29897866.

43. Renaud S, de Lorgeril M, Delaye J, Guidollet J, Jacquard F, Mamelle N, et al. Cretan Mediterranean diet for prevention of coronary heart disease. Am J Clin Nutr. 1995;61(6 Suppl):1360S–7S. doi: 10.1093/ajcn/61.6.1360S 7754988.

44. Ajala O, English P, Pinkney J. Systematic review and meta-analysis of different dietary approaches to the management of type 2 diabetes. Am J Clin Nutr. 2013;97(3):505–16. doi: 10.3945/ajcn.112.042457 23364002.

45. Huo R, Du T, Xu Y, Xu W, Chen X, Sun K, et al. Effects of Mediterranean-style diet on glycemic control, weight loss and cardiovascular risk factors among type 2 diabetes individuals: a meta-analysis. Eur J Clin Nutr. 2015;69(11):1200–8. Epub 2014 Nov 5. doi: 10.1038/ejcn.2014.243 25369829.

46. Shai I, Schwarzfuchs D, Henkin Y, Shahar DR, Witkow S, Greenberg I, et al. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med. 2008;359(3):229–41. doi: 10.1056/NEJMoa0708681 18635428.

47. Jovanovski E, Zurbau A, Vuksan V. Carbohydrates and endothelial function: is a low-carbohydrate diet or a low-glycemic index diet favourable for vascular health? Clin Nutr Res. 2015;4(2):69–75. doi: 10.7762/cnr.2015.4.2.69 25954727; PubMed Central PMCID: PMC4418418.

48. Lopez-Moreno J, Quintana-Navarro GM, Camargo A, Jimenez-Lucena R, Delgado-Lista J, Marin C, et al. Dietary fat quantity and quality modifies advanced glycation end products metabolism in patients with metabolic syndrome. Mol Nutr Food Res. 2017;61(8): 1601029. doi: 10.1002/mnfr.201601029 28233454.

49. Lopez-Moreno J, Quintana-Navarro GM, Delgado-Lista J, Garcia-Rios A, Delgado-Casado N, Camargo A, et al. Mediterranean Diet Reduces Serum Advanced Glycation End Products and Increases Antioxidant Defenses in Elderly Adults: A Randomized Controlled Trial. J Am Geriatr Soc. 2016;64(4):901–4. doi: 10.1111/jgs.14062 27100598.

50. Stirban A, Gawlowski T, Roden M. Vascular effects of advanced glycation endproducts: Clinical effects and molecular mechanisms. Mol Metab. 2014;3(2):94–108. doi: 10.1016/j.molmet.2013.11.006 24634815; PubMed Central PMCID: PMC3953708.

51. Marin C, Ramirez R, Delgado-Lista J, Yubero-Serrano EM, Perez-Martinez P, Carracedo J, et al. Mediterranean diet reduces endothelial damage and improves the regenerative capacity of endothelium. Am J Clin Nutr. 2011;93(2):267–74. doi: 10.3945/ajcn.110.006866 21123460.

52. Benndorf RA, Schwedhelm E, Gnann A, Taheri R, Kom G, Didie M, et al. Isoprostanes inhibit vascular endothelial growth factor-induced endothelial cell migration, tube formation, and cardiac vessel sprouting in vitro, as well as angiogenesis in vivo via activation of the thromboxane A(2) receptor: a potential link between oxidative stress and impaired angiogenesis. Circ Res. 2008;103(9):1037–46. doi: 10.1161/CIRCRESAHA.108.184036 18802021.

53. Kim YW, Byzova TV. Oxidative stress in angiogenesis and vascular disease. Blood. 2014;123(5):625–31. doi: 10.1182/blood-2013-09-512749 24300855; PubMed Central PMCID: PMC3907751.

54. Benjamin EJ, Larson MG, Keyes MJ, Mitchell GF, Vasan RS, Keaney JF Jr., et al. Clinical correlates and heritability of flow-mediated dilation in the community: the Framingham Heart Study. Circulation. 2004;109(5):613–9. doi: 10.1161/01.CIR.0000112565.60887.1E 14769683.

Článek vyšel v časopise

PLOS Medicine

2020 Číslo 9
Nejčtenější tento týden
Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Důležitost adherence při depresivním onemocnění
nový kurz
Autoři: MUDr. Eliška Bartečková, Ph.D.

Koncepce osteologické péče pro gynekology a praktické lékaře
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková, Ph.D.

Hypertenze a hypercholesterolémie – synergický efekt léčby
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Všechny kurzy
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se