CD142⁺/CD61⁺, CD146⁺ and CD45⁺ microparticles predict cardiovascular events in high risk patients following a Mediterranean diet supplemented with nuts

Summary

Circulating microparticles (cMPs) are small phospholipid-rich microvesicles shed by activated cells that play a pivotal role in cell signalling related to the pathogenesis of atherothrombosis. We aimed to investigate the prognostic value of cMPs released from different vascular cells for cardiovascular event (CVE) presentation in asymptomatic patients at high cardiovascular risk factors under nutritional and pharmacologic treatment. This is a nested case-control study of 50 patients from the five-year follow-up prospective PREDIMED trial enrolled in the nuts arm of the Mediterranean diet (Med Diet-nuts). We randomly selected 25 patients who had suffered a CVE during follow-up and pair-matched them for sex, age, and classical CV risk factors to 25 patients who remained asymptomatic (no-CVE). Total Annexin V-(AV)⁺ cMPs and cMPs from cells of the vascular compartment were quantified by flow cytometry at baseline and after one year follow-up. MedDiet-nuts and pharmacological treatment neither modified levels nor source of MP shedding in CVE patients. However, no-CVE patients showed 40–86 % decreased total AV⁺, PAC-1⁺/AV⁺, CD61⁺/AV⁺, CD142⁺/CD61⁺/AV⁺, CD62P⁺/AV⁺, CD146⁺/AV⁺, CD63⁺/AV⁺ and CD11a⁺/AV⁺ cMPs at one year follow-up (p ≤ 0.046, all). CD142⁺/CD61⁺/AV⁺, CD146⁺/AV⁺ and CD45⁺/AV⁺ cMPs were decreased in no-CVE patients compared to CVE patients. A ROCcurve clustered model for CD142⁺/CD61⁺/AV⁺, CD45⁺/AV⁺ and CD146⁺/AV⁺ cMPs predicted a future CVE [p<0.0001, AUC=0.805 (0.672 to 0.938)]. In patients at high CV risk profile treated with a controlled MedDiet supplemented with nuts and receiving up-to-date CV drug treatment, reduced cMPs derived from activated platelets, leukocytes and endothelial cells are predictive of protection against CVE within the next four years.

Keywords

Circulating microparticles - platelets - tissue factor - cardiovascular event - leukocytes

• References

• 1 Morel O, Jesel L, Freyssinet JM. et al. Cellular mechanisms underlying the formation of circulating microparticles. Arterioscl Thromb Vasc Biol 2011; 31: 15-26.
• 2 Cherian P, Hankey GJ, Eikelboom JW. et al. Endothelial and platelet activation in acute ischemic stroke and its etiological subtypes. Stroke 2003; 34: 2132-2137.
• 3 Preston RA, Jy W, Jimenez JJ. et al. Effects of severe hypertension on endothelial and platelet microparticles. Hypertension 2003; 41: 211-217.
• 4 Suades R, Padro T, Alonso R. et al. High levels of TSP1⁺/CD142⁺ platelet-derived microparticles characterise young patients with high cardiovascular risk and subclinical atherosclerosis. Thromb Haemost 2015; 114: 1310-1321.
• 5 Suades R, Padro T, Vilahur G. et al. Circulating and platelet-derived microparticles in human blood enhance thrombosis on atherosclerotic plaques. Thromb Haemost 2012; 108: 1208-1219.
• 6 Amabile N, Guerin AP, Leroyer A. et al. Circulating endothelial microparticles are associated with vascular dysfunction in patients with end-stage renal failure. J Am Soc Nephrol 2005; 16: 3381-3388.
• 7 Suades R, Padro T, Alonso R. et al. Circulating CD45⁺/CD3⁺ lymphocyte-derived microparticles map lipid-rich atherosclerotic plaques in familial hypercholesterolaemia patients. Thromb Haemost 2014; 111: 111-121.
• 8 Nieuwland R, Berckmans RJ, McGregor S. et al. Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood 2000; 95: 930-935.
• 9 Estruch R, Ros E, Salas-Salvado J. et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013; 368: 1279-1290.
• 10 Llorente-Cortes V, Estruch R, Mena MP. et al. Effect of Mediterranean diet on the expression of pro-atherogenic genes in a population at high cardiovascular risk. Atherosclerosis 2010; 208: 442-450.
• 11 Mena MP, Sacanella E, Vazquez-Agell M. et al. Inhibition of circulating immune cell activation: a molecular antiinflammatory effect of the Mediterranean diet. Am J Clin Nutr 2009; 89: 248-256.
• 12 Estruch R, Martinez-Gonzalez MA, Corella D. et al. Effects of a Mediterraneanstyle diet on cardiovascular risk factors: a randomized trial. Ann Intern Med 2006; 145: 1-11.
• 13 Organization. WHOWHFWS. Global Atlas on cardiovascular disease prevention and control.. 2011
• 14 Martinez-Gonzalez MA, Corella D, Salas-Salvado J. et al. Cohort profile: design and methods of the PREDIMED study. Int J Epidemiol 2012; 41: 377-385.
• 15 Martinez-Gonzalez MA, Garcia-Arellano A, Toledo E. et al. A 14-item Mediterranean diet assessment tool and obesity indexes among high-risk subjects: the PREDIMED trial. PLoS One 2012; 07: e43134.
• 16 National Cholesterol Education Program Expert Panel on Detection E, Treatment of High Blood Cholesterol in A. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002 106. 3143-3421.
• 17 Chiva-Blanch G, Suades R, Crespo J. et al. CD3/CD45 and SMA-alpha circulating microparticles are increased in individuals at high cardiovascular risk who will develop a major cardiovascular event. Int J Cardiol 2016; 208: 147-149.
• 18 Chiva-Blanch G, Suades R, Crespo J. et al. Microparticle Shedding from Neural Progenitor Cells and Vascular Compartment Cells Is Increased in Ischemic Stroke. PLoS One 2016; 11: e0148176.
• 19 Zhang X, McGeoch SC, Megson IL. et al. Oat-enriched diet reduces inflammatory status assessed by circulating cell-derived microparticle concentrations in type 2 diabetes. Mol Nutr Food Res 2014; 58: 1322-1332.
• 20 Wu SY, Mayneris-Perxachs J, Lovegrove JA. et al. Fish-oil supplementation alters numbers of circulating endothelial progenitor cells and microparticles independently of eNOS genotype. Am J Clin Nutr 2014; 100: 1232-1243.
• 21 Del Turco S, Basta G, Lazzerini G. et al. Effect of the administration of n-3 polyunsaturated fatty acids on circulating levels of microparticles in patients with a previous myocardial infarction. Haematologica 2008; 93: 892-899.
• 22 Marin C, Ramirez R, Delgado-Lista J. et al. Mediterranean diet reduces endothelial damage and improves the regenerative capacity of endothelium. Am J Clin Nutr 2011; 93: 267-274.
• 23 Diamant M, Nieuwland R, Pablo RF. et al. Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus. Circulation 2002; 106: 2442-2447.
• 24 Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol 2011; 12: 204-212.
• 25 Nomura S, Inami N, Iwasaka T. et al. Platelet activation markers, microparticles and soluble adhesion molecules are elevated in patients with arteriosclerosis obliterans: therapeutic effects by cilostazol and potentiation by dipyridamole. Platelets 2004; 15: 167-172.
• 26 Lukasik M, Rozalski M, Luzak B. et al. Enhanced platelet-derived microparticle formation is associated with carotid atherosclerosis in convalescent stroke patients. Platelets 2013; 24: 63-70.
• 27 Hu SS, Zhang HG, Zhang QJ. et al. Circulating CD62P small microparticles levels are increased in hypertension. Int J Clin Exp Pathol 2014; 07: 5324-5326.
• 28 Matsumoto N, Nomura S, Kamihata H. et al. Association of platelet-derived microparticles with C-C chemokines on vascular complication in patients with acute myocardial infarction. Clin Appl Thromb Hemost 2002; 08: 279-286.
• 29 McEver RP. Selectins: initiators of leucocyte adhesion and signalling at the vascular wall. Cardiovasc Res 2015; 107: 331-339.
• 30 Suades R, Padro T, Alonso R. et al. Lipid-lowering therapy with statins reduces microparticle shedding from endothelium, platelets and inflammatory cells. Thromb Haemost 2013; 110: 366-377.