Role of Immune Responses After Acute Myocardial Infarction (BATTLE-AMI)

Role of Innate and Adaptive Immunity After Acute Myocardial Infarction BATTLE-AMI Study (B And T Types of Lymphocytes Evaluation in Acute Myocardial Infarction)

The fascinating role of lymphocyte subtypes in the development of coronary artery disease may be a new strategic target for understanding and therapy of acute myocardial infarction. The determinants of cell viability are unknown, postulating that they arise from factors not only related to microcirculation or energy expenditure, but also to inflammatory and immune responses. Furthermore, the intense mobilization of progenitor cells secondary to myocardial infarction triggers large lymphocyte proliferation that colonizes plaques in development, contributing to recurrent ischemic outcomes. This project aims to evaluate the immune and metabolic mechanisms involved in the recovery of the ischemic myocardium and coronary disease progression.

Specifically, the investigators will study the innate and adaptive immunity, with emphasis on lymphocytes subtypes involved in the early and late surrogate outcomes of patients with acute myocardial infarction, their characterization (B1, B2 and T lymphocytes) in cell culture and by flow-cytometry, and immune responses (IgM and IgG for oxLDL and specific epitopes of apoB). In addition, the project will evaluate new biomarkers identified by studies of metabolomics, as well as the corresponding signaling pathways. Therapeutic pharmacological strategies and changes on intestinal microbiota will be evaluated since the acute phase of myocardial infarction up to 6 months. In the study, the investigators will compared four arms of combined therapy: clopidogrel with rosuvastatin; or clopidogrel with simvastatin; or ticagrelor with rosuvastatin; or ticagrelor with simvastatin. The investigator's hypothesis is that the improvement of microcirculation with rosuvastatin and ticagrelor (synergic pleiotropic effects) may decrease the infarcted mass area, resulting in better left ventricular ejection fraction when compared to the other combined therapies. The monitoring and genotype of microbiota will be examined together the metabolomics and cardiac MRIs obtained at the acute phase of MI and after 1-mo and 6-mo FU.

To compare the effects of the four combined therapies on the percentage of subjects with left ventricular ejection fraction < 40% after STEMI

To compare the effects of the four combined therapies on the percentage of subjects with left ventricular ejection fraction < 40% after STEMI

To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with left ventricular ejection fraction after STEMI

To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with left ventricular ejection fraction after STEMI

To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with left ventricular ejection fraction after STEMI

To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with infarcted mass area after STEMI

To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with infarcted mass area after STEMI

To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with infarcted mass area after STEMI

To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with left ventricular ejection fraction <40% after STEMI

To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with left ventricular ejection fraction <40% after STEMI

To quantify the percentage and absolute number of B1, B2, TCD4, and TCD8 subtypes of lymphocytes and their correlation with left ventricular ejection fraction <40% after STEMI

Intestinal microbiota will be genotyped and diabetes status (non-diabetic, pre-diabetic or diabetic) according to HbA1c levels.

Intestinal microbiota will be genotyped and diabetes status (non-diabetic, pre-diabetic or diabetic) according to HbA1c levels.

Intestinal microbiota will be genotyped and diabetes status (non-diabetic, pre-diabetic or diabetic) according to HbA1c levels.

Comparison between the four arm of combined therapies on microparticles and endothelial progenitor cells

Endothelial, platelet, and monocyte-derived microparticles as well as endothelial progenitor cells will be quantified by flow-cytometry

Comparison between the four arm of combined therapies on microparticles and endothelial progenitor cells

Endothelial, platelet, and monocyte-derived microparticles as well as endothelial progenitor cells will be quantified by flow-cytometry

Comparison between the four arm of combined therapies on microparticles and endothelial progenitor cells

Endothelial, platelet, and monocyte-derived microparticles as well as endothelial progenitor cells will be quantified by flow-cytometry

Correlation between the severity of coronary disease with antibodies against oxidized LDL and peptide D of apolipoprotein B of LDL

Antibodies IgG and IgM against oxidized LDL as well as against peptide D of LDL will be quantified by ELISA. Coronary disease severity will be quantified by the Gensini Score

TIMI flow grade and blush grade will be determined based on coronary angiogram obtained at baseline by two independent and blinded certified invasive cardiologists

Inclusion Criteria: 1. Stable patients with ST elevation myocardial infarction (STEMI) treated with thrombolytics in the first 6h or the initial of symptoms of MI. Exclusion Criteria: Contraindication or known intolerance to the study drug protocol Those with comorbidities such as neoplasm, renal insufficiency (stage 4 or higher) Patients should be randomized in the first 24 hours of AMI and treated by one of the four combined therapies at least 2h prior to coronary angiogram followed by percutaneous intervention when necessary.

Fonseca FA, Izar MC, Fuster V, Gallo R, Padurean A, Fallon JT, Schachter EN, Chesebro JH, Badimon JJ. Chronic endothelial dysfunction after oversized coronary balloon angioplasty in pigs: a 12-week follow-up of coronary vasoreactivity in vivo and in vitro. Atherosclerosis. 2001 Jan;154(1):61-9. doi: 10.1016/s0021-9150(00)00458-5.

Silva EP, Fonseca FA, Ihara SS, Izar MC, Lopes IL, Pinto LE, Badimon JJ, Tuffik S, Paiva TB, Kasinski N, de Paola AV, Carvalho AC. Early benefits of pravastatin to experimentally induced atherosclerosis. J Cardiovasc Pharmacol. 2002 Mar;39(3):389-95. doi: 10.1097/00005344-200203000-00010.

Fonseca FA, Paiva TB, Silva EG, Ihara SS, Kasinski N, Martinez TL, Filho EE. Dietary magnesium improves endothelial dependent relaxation of balloon injured arteries in rats. Atherosclerosis. 1998 Aug;139(2):237-42. doi: 10.1016/s0021-9150(98)00069-0.

Fonseca FA, Ihara SS, Izar MC, Silva EP, Kasinski N, Lopes IE, Pinto LE, Paiva TB, Tufik S, de Paola AA, Carvalho AC. Hydrochlorothiazide abolishes the anti-atherosclerotic effect of quinapril. Clin Exp Pharmacol Physiol. 2003 Oct;30(10):779-85. doi: 10.1046/j.1440-1681.2003.03911.x.

Ferreira WP, Bertolami MC, Santos SN, Barros MR, de Matos Barretto RB, Pontes SC Jr, Fonseca FH, Carvalho AC. One-month therapy with simvastatin restores endothelial function in hypercholesterolemic children and adolescents. Pediatr Cardiol. 2007 Jan-Feb;28(1):8-13. doi: 10.1007/s00246-005-1304-x. Epub 2007 Jan 25.

Monteiro CM, Pinheiro LF, Izar MC, Barros SW, Vasco MB, Fischer SM, Povoa RM, Brandao SA, Santos AO, Oliveira L, Carvalho AC, Fonseca FA. Highly sensitive C-reactive protein and male gender are independently related to the severity of coronary disease in patients with metabolic syndrome and an acute coronary event. Braz J Med Biol Res. 2010 Mar;43(3):297-302. doi: 10.1590/s0100-879x2010005000008. Epub 2010 Mar 5.

da Silva EF, Fonseca FA, Franca CN, Ferreira PR, Izar MC, Salomao R, Camargo LM, Tenore SB, Lewi DS. Imbalance between endothelial progenitors cells and microparticles in HIV-infected patients naive for antiretroviral therapy. AIDS. 2011 Aug 24;25(13):1595-601. doi: 10.1097/QAD.0b013e32834980f4.

Franca CN, Pinheiro LF, Izar MC, Brunialti MK, Salomao R, Bianco HT, Kasmas SH, Barbosa SP, de Nucci G, Fonseca FA. Endothelial progenitor cell mobilization and platelet microparticle release are influenced by clopidogrel plasma levels in stable coronary artery disease. Circ J. 2012;76(3):729-36. doi: 10.1253/circj.cj-11-1145. Epub 2011 Dec 28.

Pomaro DR, Ihara SS, Pinto LE, Ueda I, Casarini DE, Ebihara F, Santos AO, Izar MC, Fonseca FA. High glucose levels abolish antiatherosclerotic benefits of ACE inhibition in alloxan-induced diabetes in rabbits. J Cardiovasc Pharmacol. 2005 Apr;45(4):295-300. doi: 10.1097/01.fjc.0000155384.64350.45.

Relvas WG, Izar MC, Segreto HR, Giordani AJ, Ihara SS, Mariano M, Lopes JD, Popi AF, Helfenstein T, Pomaro D, Povoa RM, Carvalho AC, Fonseca FA. Resident peritoneal inflammatory cells are pivotal in the development of experimental atherosclerosis. J Atheroscler Thromb. 2010 Apr 30;17(4):378-85. doi: 10.5551/jat.3418. Epub 2010 Mar 9.

Helfenstein T, Fonseca FA, Ihara SS, Bottos JM, Moreira FT, Pott H Jr, Farah ME, Martins MC, Izar MC. Impaired glucose tolerance plus hyperlipidaemia induced by diet promotes retina microaneurysms in New Zealand rabbits. Int J Exp Pathol. 2011 Feb;92(1):40-9. doi: 10.1111/j.1365-2613.2010.00753.x.

Feio CA, Izar MC, Ihara SS, Kasmas SH, Martins CM, Feio MN, Maues LA, Borges NC, Moreno RA, Povoa RM, Fonseca FA. Euterpe oleracea (acai) modifies sterol metabolism and attenuates experimentally-induced atherosclerosis. J Atheroscler Thromb. 2012;19(3):237-45. doi: 10.5551/jat.11205. Epub 2011 Dec 3.

Albert MA, Glynn RJ, Fonseca FA, Lorenzatti AJ, Ferdinand KC, MacFadyen JG, Ridker PM. Race, ethnicity, and the efficacy of rosuvastatin in primary prevention: the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. Am Heart J. 2011 Jul;162(1):106-14.e2. doi: 10.1016/j.ahj.2011.03.032. Epub 2011 Jun 12.

de Lima Sanches P, de Mello MT, Elias N, Fonseca FA, de Piano A, Carnier J, Oyama LM, Tock L, Tufik S, Damaso AR. Improvement in HOMA-IR is an independent predictor of reduced carotid intima-media thickness in obese adolescents participating in an interdisciplinary weight-loss program. Hypertens Res. 2011 Feb;34(2):232-8. doi: 10.1038/hr.2010.225. Epub 2010 Dec 2.

Fonseca FA, Franca CN, Povoa RM, Izar MC. [Statins and stroke: potential mechanisms for neurovascular protection]. Rev Neurol. 2010 Nov 1;51(9):551-60. Spanish.

Ridker PM, MacFadyen JG, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Study Group. Number needed to treat with rosuvastatin to prevent first cardiovascular events and death among men and women with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin (JUPITER). Circ Cardiovasc Qual Outcomes. 2009 Nov;2(6):616-23. doi: 10.1161/CIRCOUTCOMES.109.848473. Epub 2009 Sep 22.

Brandao SA, Izar MC, Fischer SM, Santos AO, Monteiro CM, Povoa RM, Helfenstein T, Carvalho AC, Monteiro AM, Ramos E, Gidlund M, Figueiredo Neto AM, Fonseca FA. Early increase in autoantibodies against human oxidized low-density lipoprotein in hypertensive patients after blood pressure control. Am J Hypertens. 2010 Feb;23(2):208-14. doi: 10.1038/ajh.2009.214. Epub 2009 Nov 12.

Fonseca FA, Izar MC. Primary prevention of vascular events in patients with high levels of C-reactive protein: the JUPITER study. Expert Rev Cardiovasc Ther. 2009 Sep;7(9):1041-56. doi: 10.1586/erc.09.93.

Santos AO, Fonseca FA, Fischer SM, Monteiro CM, Brandao SA, Povoa RM, Bombig MT, Carvalho AC, Monteiro AM, Ramos E, Gidlund M, Figueiredo Neto AM, Izar MC. High circulating autoantibodies against human oxidized low-density lipoprotein are related to stable and lower titers to unstable clinical situation. Clin Chim Acta. 2009 Aug;406(1-2):113-8. doi: 10.1016/j.cca.2009.06.005. Epub 2009 Jun 10.

Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Ridker PM. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med. 2009 Apr 30;360(18):1851-61. doi: 10.1056/NEJMoa0900241. Epub 2009 Mar 29.

Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, Macfadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Trial Study Group. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009 Apr 4;373(9670):1175-82. doi: 10.1016/S0140-6736(09)60447-5. Epub 2009 Mar 28.

Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008 Nov 20;359(21):2195-207. doi: 10.1056/NEJMoa0807646. Epub 2008 Nov 9.

Ridker PM, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, Khurmi NS, Koenig W, Libby P, Lorenzatti AJ, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Trial Study Group. Baseline characteristics of participants in the JUPITER trial, a randomized placebo-controlled primary prevention trial of statin therapy among individuals with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein. Am J Cardiol. 2007 Dec 1;100(11):1659-64. doi: 10.1016/j.amjcard.2007.09.072. Epub 2007 Oct 24.

Ramos SC, Fonseca FA, Kasmas SH, Moreira FT, Helfenstein T, Borges NC, Moreno RA, Rezende VM, Silva FC, Izar MC. The role of soluble fiber intake in patients under highly effective lipid-lowering therapy. Nutr J. 2011 Aug 2;10:80. doi: 10.1186/1475-2891-10-80.

Izar MC, Tegani DM, Kasmas SH, Fonseca FA. Phytosterols and phytosterolemia: gene-diet interactions. Genes Nutr. 2011 Feb;6(1):17-26. doi: 10.1007/s12263-010-0182-x. Epub 2010 Aug 28.

Fonseca HA, Izar MC, Bianco HT, Fonseca FA. Ezetimibe, oxidized low density lipoprotein, Lp (a), and dyslipidemia. J Atheroscler Thromb. 2010 Aug 31;17(8):888. doi: 10.5551/jat.5918. Epub 2010 Aug 10. No abstract available.

Kasmas SH, Izar MC, Franca CN, Ramos SC, Moreira FT, Helfenstein T, Moreno RA, Borges NC, Figueiredo-Neto AM, Fonseca FA. Differences in synthesis and absorption of cholesterol of two effective lipid-lowering therapies. Braz J Med Biol Res. 2012 Nov;45(11):1095-101. doi: 10.1590/s0100-879x2012007500118. Epub 2012 Jul 19.

da Fonseca HA, Fonseca FA, Monteiro AM, Farias NC Jr, Bianco HT, Brandao SA, Povoa RM, Gidlund M, Izar MC. Inflammatory environment and immune responses to oxidized LDL are linked to systolic and diastolic blood pressure levels in hypertensive subjects. Int J Cardiol. 2012 May 17;157(1):131-3. doi: 10.1016/j.ijcard.2012.03.041. Epub 2012 Mar 28. No abstract available.

Izar MC, Fonseca HA, Pinheiro LF, Monteiro CM, Povoa RM, Monteiro AM, Figueiredo-Neto AM, Gidlund MA, Fonseca FA. Adaptive immunity is related to coronary artery disease severity after acute coronary syndrome in subjects with metabolic syndrome. Diab Vasc Dis Res. 2013 Jan;10(1):32-9. doi: 10.1177/1479164112443374. Epub 2012 Apr 23.

Colossimo AP, Costa Fde A, Riera AR, Bombig MT, Lima VC, Fonseca FA, Izar MC, L Filho B, Souza D, Povoa RM. Electrocardiogram sensitivity in left ventricular hypertrophy according to gender and cardiac mass. Arq Bras Cardiol. 2011 Sep;97(3):225-31. doi: 10.1590/s0066-782x2011005000085. Epub 2011 Aug 12. English, Portuguese.

Costa Fde A, Bombig MT, de Lima VC, de Souza D, Luna Filho B, Fonseca FH, Izar MC, da Costa W, Riera AR, Povoa R. Geometric patterns of left ventricular hypertrophy and electrocardiography. Int J Cardiol. 2011 Sep 15;151(3):374-5. doi: 10.1016/j.ijcard.2011.06.103. Epub 2011 Jul 18. No abstract available.

Marui FR, Bombig MT, Francisco YA, Thalenberg JM, Fonseca FA, Souza Dd, Costa Fde A, Izar MC, Carvalho AC, Povoa R. [Assessment of resistant hypertension with home blood pressure monitoring]. Arq Bras Cardiol. 2010 Oct;95(4):536-40. doi: 10.1590/s0066-782x2010005000120. Epub 2010 Sep 8. Multiple languages.

Santos MA, Costa Fde A, Travessa AF, Bombig MT, Fonseca FH, Luna Filho B, Mussi A, Souza Dd, Oliveira Ad, Povoa R. [Duchenne muscular dystrophy: electrocardiographic analysis of 131 patients]. Arq Bras Cardiol. 2010 May;94(5):620-4. doi: 10.1590/s0066-782x2010005000024. Epub 2010 Apr 2. Portuguese.

Schwartz GG, Olsson AG, Ballantyne CM, Barter PJ, Holme IM, Kallend D, Leiter LA, Leitersdorf E, McMurray JJ, Shah PK, Tardif JC, Chaitman BR, Duttlinger-Maddux R, Mathieson J; dal-OUTCOMES Committees and Investigators. Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J. 2009 Dec;158(6):896-901.e3. doi: 10.1016/j.ahj.2009.09.017.

Brollo L, Bombig MT, Mazzaro Cdo L, Francisco YA, Fonseca FA, Carvalho AC, Harima H, Hirai A, Povoa R. Relationship between electrocardiogram with diabetes mellitus and metabolic syndrome in Japanese-Brazilians. Arq Bras Cardiol. 2009 May;92(5):351-5, 381-6. doi: 10.1590/s0066-782x2009000500008. English, Multiple languages.

Monteiro CM, Oliveira L, Izar MC, Helfenstein T, Santos AO, Fischer SM, Barros SW, Pinheiro LF, Carvalho AC, Fonseca FA. Early glucometabolic profile in patients with acute coronary syndromes and metabolic syndrome. Arq Bras Cardiol. 2009 Feb;92(2):89-99. doi: 10.1590/s0066-782x2009000200004. English, Portuguese, Spanish.

da Costa W, Riera AR, Costa Fde A, Bombig MT, de Paola AA, Carvalho AC, Fonseca FH, Luna Filho B, Povoa R. Correlation of electrocardiographic left ventricular hypertrophy criteria with left ventricular mass by echocardiogram in obese hypertensive patients. J Electrocardiol. 2008 Nov-Dec;41(6):724-9. doi: 10.1016/j.jelectrocard.2008.05.010.

Izar MC, Helfenstein T, Ihara SS, Relvas WG, Santos AO, Fischer SC, Pinto LE, Lopes IE, Pomaro DR, Fonseca MI, Bodanese LC, Moriguchi EH, Saraiva JF, Introcaso L, Souza AD, Scartezini M, Torres KP, Zagury L, Jardim PC, Costa EA, Tacito LH, Forti A, Magalhaes ME, Chacra AR, Bertolami MC, Loures-Vale AA, Barros MA, Xavier HT, Lyra R, Argamanijan D, Guimaraes A, Novazzi JP, Kasinski N, Afiune A, Martinez TL, Santos RD, Nicolau JC, Cesar LA, Povoa RM, Carvalho AC, Han SW, Fonseca FA; GOLD Investigators. Association of lipoprotein lipase D9N polymorphism with myocardial infarction in type 2 diabetes: the genetics, outcomes, and lipids in type 2 diabetes (GOLD) study. Atherosclerosis. 2009 May;204(1):165-70. doi: 10.1016/j.atherosclerosis.2008.08.006. Epub 2008 Aug 14.

Middleton A, Binbrek AS, Fonseca FA, Wilpshaar W, Watkins C, Strandberg TE. Achieving 2003 European lipid goals with rosuvastatin and comparator statins in 6743 patients in real-life clinical practice: DISCOVERY meta-analysis. Curr Med Res Opin. 2006 Jun;22(6):1181-91. doi: 10.1185/030079906X100177.

Helfenstein T, Fonseca FA, Relvas WG, Santos AO, Dabela ML, Matheus SC, D'Almeida V, Tufik S, Souza FG, Rodrigues PR, Taglieri R, Sousa EF, Izar MC. Prevalence of myocardial infarction is related to hyperhomocysteinemia but not influenced by C677T methylenetetrahydrofolate reductase and A2756G methionine synthase polymorphisms in diabetic and non-diabetic subjects. Clin Chim Acta. 2005 May;355(1-2):165-72. doi: 10.1016/j.cccn.2004.12.002.

Relvas WG, Izar MC, Helfenstein T, Fonseca MI, Colovati M, Oliveira A, Ihara SS, Han SW, Las Casas AA Jr, Fonseca FA. Relationship between gene polymorphisms and prevalence of myocardial infarction among diabetic and non-diabetic subjects. Atherosclerosis. 2005 Jan;178(1):101-5. doi: 10.1016/j.atherosclerosis.2004.05.025.

Pinheiro LF, Franca CN, Izar MC, Barbosa SP, Bianco HT, Kasmas SH, Mendes GD, Povoa RM, Fonseca FA. Pharmacokinetic interactions between clopidogrel and rosuvastatin: effects on vascular protection in subjects with coronary heart disease. Int J Cardiol. 2012 Jun 28;158(1):125-9. doi: 10.1016/j.ijcard.2012.04.051. Epub 2012 May 7. No abstract available.

Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011 Apr 29;145(3):341-55. doi: 10.1016/j.cell.2011.04.005.

Weber C, Meiler S, Doring Y, Koch M, Drechsler M, Megens RT, Rowinska Z, Bidzhekov K, Fecher C, Ribechini E, van Zandvoort MA, Binder CJ, Jelinek I, Hristov M, Boon L, Jung S, Korn T, Lutz MB, Forster I, Zenke M, Hieronymus T, Junt T, Zernecke A. CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice. J Clin Invest. 2011 Jul;121(7):2898-910. doi: 10.1172/JCI44925.

Vitale G, Mion F, Pucillo C. Regulatory B cells: evidence, developmental origin and population diversity. Mol Immunol. 2010 Nov-Dec;48(1-3):1-8. doi: 10.1016/j.molimm.2010.09.010. Epub 2010 Oct 14.

Miller YI, Choi SH, Wiesner P, Fang L, Harkewicz R, Hartvigsen K, Boullier A, Gonen A, Diehl CJ, Que X, Montano E, Shaw PX, Tsimikas S, Binder CJ, Witztum JL. Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ Res. 2011 Jan 21;108(2):235-48. doi: 10.1161/CIRCRESAHA.110.223875.

Galkina E, Kadl A, Sanders J, Varughese D, Sarembock IJ, Ley K. Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is partially L-selectin dependent. J Exp Med. 2006 May 15;203(5):1273-82. doi: 10.1084/jem.20052205. Epub 2006 May 8.

Ponnuswamy P, Van Vre EA, Mallat Z, Tedgui A. Humoral and cellular immune responses in atherosclerosis: spotlight on B- and T-cells. Vascul Pharmacol. 2012 May-Jun;56(5-6):193-203. doi: 10.1016/j.vph.2012.01.009. Epub 2012 Feb 8.

van Gils JM, Derby MC, Fernandes LR, Ramkhelawon B, Ray TD, Rayner KJ, Parathath S, Distel E, Feig JL, Alvarez-Leite JI, Rayner AJ, McDonald TO, O'Brien KD, Stuart LM, Fisher EA, Lacy-Hulbert A, Moore KJ. The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nat Immunol. 2012 Jan 8;13(2):136-43. doi: 10.1038/ni.2205.

Campbell KA, Lipinski MJ, Doran AC, Skaflen MD, Fuster V, McNamara CA. Lymphocytes and the adventitial immune response in atherosclerosis. Circ Res. 2012 Mar 16;110(6):889-900. doi: 10.1161/CIRCRESAHA.111.263186.

Gerszten RE, Tager AM. The monocyte in atherosclerosis--should I stay or should I go now? N Engl J Med. 2012 May 3;366(18):1734-6. doi: 10.1056/NEJMcibr1200164. No abstract available.

Goodchild TT, Robinson KA, Pang W, Tondato F, Cui J, Arrington J, Godwin L, Ungs M, Carlesso N, Weich N, Poznansky MC, Chronos NA. Bone marrow-derived B cells preserve ventricular function after acute myocardial infarction. JACC Cardiovasc Interv. 2009 Oct;2(10):1005-16. doi: 10.1016/j.jcin.2009.08.010.

Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, Iwamoto Y, Thompson B, Carlson AL, Heidt T, Majmudar MD, Lasitschka F, Etzrodt M, Waterman P, Waring MT, Chicoine AT, van der Laan AM, Niessen HW, Piek JJ, Rubin BB, Butany J, Stone JR, Katus HA, Murphy SA, Morrow DA, Sabatine MS, Vinegoni C, Moskowitz MA, Pittet MJ, Libby P, Lin CP, Swirski FK, Weissleder R, Nahrendorf M. Myocardial infarction accelerates atherosclerosis. Nature. 2012 Jul 19;487(7407):325-9. doi: 10.1038/nature11260.

Moreira FT, Ramos SC, Monteiro AM, Helfenstein T, Gidlund M, Damasceno NR, Neto AM, Izar MC, Fonseca FA. Effects of two lipid lowering therapies on immune responses in hyperlipidemic subjects. Life Sci. 2014 Mar 11;98(2):83-7. doi: 10.1016/j.lfs.2014.01.001. Epub 2014 Jan 18.

Hilgendorf I, Theurl I, Gerhardt LM, Robbins CS, Weber GF, Gonen A, Iwamoto Y, Degousee N, Holderried TA, Winter C, Zirlik A, Lin HY, Sukhova GK, Butany J, Rubin BB, Witztum JL, Libby P, Nahrendorf M, Weissleder R, Swirski FK. Innate response activator B cells aggravate atherosclerosis by stimulating T helper-1 adaptive immunity. Circulation. 2014 Apr 22;129(16):1677-87. doi: 10.1161/CIRCULATIONAHA.113.006381. Epub 2014 Jan 31.

Kyaw T, Tay C, Krishnamurthi S, Kanellakis P, Agrotis A, Tipping P, Bobik A, Toh BH. B1a B lymphocytes are atheroprotective by secreting natural IgM that increases IgM deposits and reduces necrotic cores in atherosclerotic lesions. Circ Res. 2011 Sep 30;109(8):830-40. doi: 10.1161/CIRCRESAHA.111.248542. Epub 2011 Aug 25.

Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T; Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001 Apr 4;285(13):1711-8. doi: 10.1001/jama.285.13.1711.

Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004 Apr 8;350(15):1495-504. doi: 10.1056/NEJMoa040583. Epub 2004 Mar 8. Erratum In: N Engl J Med. 2006 Feb 16;354(7):778.

Spencer FA, Fonarow GC, Frederick PD, Wright RS, Every N, Goldberg RJ, Gore JM, Dong W, Becker RC, French W; National Registry of Myocardial Infarction. Early withdrawal of statin therapy in patients with non-ST-segment elevation myocardial infarction: national registry of myocardial infarction. Arch Intern Med. 2004 Oct 25;164(19):2162-8. doi: 10.1001/archinte.164.19.2162.

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