An Intense and Short-Lasting Burst of Neutrophil Activation Differentiates Early Acute Myocardial Infarction from Systemic Inflammatory Syndromes

Background Neutrophils are involved in thrombus formation. We investigated whether specific features of neutrophil activation characterize patients with acute coronary syndromes (ACS) compared to stable angina and to systemic inflammatory diseases. Methods and Findings The myeloperoxidase (MPO) content of circulating neutrophils was determined by flow cytometry in 330 subjects: 69 consecutive patients with acute coronary syndromes (ACS), 69 with chronic stable angina (CSA), 50 with inflammation due to either non-infectious (acute bone fracture), infectious (sepsis) or autoimmune diseases (small and large vessel systemic vasculitis, rheumatoid arthritis). Four patients have also been studied before and after sterile acute injury of the myocardium (septal alcoholization). One hundred thirty-eight healthy donors were studied in parallel. Neutrophils with normal MPO content were 96% in controls, >92% in patients undergoing septal alcoholization, 91% in CSA patients, but only 35 and 30% in unstable angina and AMI (STEMI and NSTEMI) patients, compared to 80%, 75% and 2% of patients with giant cell arteritis, acute bone fracture and severe sepsis. In addition, in 32/33 STEMI and 9/21 NSTEMI patients respectively, 20% and 12% of neutrophils had complete MPO depletion during the first 4 hours after the onset of symptoms, a feature not observed in any other group of patients. MPO depletion was associated with platelet activation, indicated by P-selectin expression, activation and transactivation of leukocyte β2-integrins and formation of platelet neutrophil and -monocyte aggregates. The injection of activated platelets in mice produced transient, P-selectin dependent, complete MPO depletion in about 50% of neutrophils. Conclusions ACS are characterized by intense neutrophil activation, like other systemic inflammatory syndromes. In the very early phase of acute myocardial infarction only a subpopulation of neutrophils is massively activated, possibly via platelet-P selectin interactions. This paroxysmal activation could contribute to occlusive thrombosis.

[1]  A. Mantovani,et al.  Selective up-regulation of the soluble pattern-recognition receptor pentraxin 3 and of vascular endothelial growth factor in giant cell arteritis: relevance for recent optic nerve ischemia. , 2012, Arthritis and rheumatism.

[2]  N. Maugeri,et al.  Platelet-leukocyte deregulated interactions foster sterile inflammation and tissue damage in immune-mediated vessel diseases. , 2012, Thrombosis research.

[3]  F. Ciceri,et al.  Clearance of circulating activated platelets in polycythemia vera and essential thrombocythemia. , 2011, Blood.

[4]  Alberto Mantovani,et al.  Neutrophils in the activation and regulation of innate and adaptive immunity , 2011, Nature Reviews Immunology.

[5]  C. Garlanda,et al.  Early and Transient Release of Leukocyte Pentraxin 3 during Acute Myocardial Infarction , 2011, The Journal of Immunology.

[6]  Yuji Hamazaki,et al.  Activated inflammatory cells participate in thrombus size through tissue factor and plasminogen activator inhibitor-1 in acute coronary syndrome: Immunohistochemical analysis. , 2011, Thrombosis research.

[7]  F. Apple,et al.  Myeloperoxidase improves risk stratification in patients with ischemia and normal cardiac troponin I concentrations. , 2011, Clinical chemistry.

[8]  A. Domínguez-Rodríguez,et al.  Current role of myeloperoxidase in routine clinical practice , 2011, Expert review of cardiovascular therapy.

[9]  M. Sperandio,et al.  Myeloperoxidase attracts neutrophils by physical forces. , 2011, Blood.

[10]  R. Virmani,et al.  Response to Letter Regarding Article, “High Levels of Systemic Myeloperoxidase Are Associated With Coronary Plaque Erosion in Patients With Acute Coronary Syndromes: A Clinicopathological Study” , 2011 .

[11]  LiciaTotani,et al.  Platelet–Leukocyte Interactions in Cardiovascular Disease and Beyond , 2010 .

[12]  V. Evangelista,et al.  Platelet-leukocyte interactions in cardiovascular disease and beyond. , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[13]  P. Kubes,et al.  Intravascular Danger Signals Guide Neutrophils to Sites of Sterile Inflammation , 2010, Science.

[14]  P. Rovere-Querini,et al.  The mitochondrion--a Trojan horse that kicks off inflammation? , 2010, The New England journal of medicine.

[15]  N. Maugeri,et al.  Dangerous connections: neutrophils and the phagocytic clearance of activated platelets , 2010, Current opinion in hematology.

[16]  W. Junger,et al.  Circulating Mitochondrial DAMPs Cause Inflammatory Responses to Injury , 2009, Nature.

[17]  O. Wagner,et al.  Local complement activation triggers neutrophil recruitment to the site of thrombus formation in acute myocardial infarction , 2009, Thrombosis and Haemostasis.

[18]  A. Maseri,et al.  Anti-inflammatory action of apoptotic cells in patients with acute coronary syndromes. , 2009, Atherosclerosis.

[19]  D. Atar,et al.  Cardiac Troponin I Degradation in Serum of Patients with Hypertrophic Obstructive Cardiomyopathy Undergoing Percutaneous Septal Ablation , 2009, Cardiology.

[20]  T. Meinertz,et al.  Neutrophil activation precedes myocardial injury in patients with acute myocardial infarction. , 2009, Free radical biology & medicine.

[21]  N. Maugeri,et al.  Translational Mini‐Review Series on Immunology of Vascular Disease: Mechanisms of vascular inflammation and remodelling in systemic vasculitis , 2009, Clinical and experimental immunology.

[22]  A. Maseri,et al.  Neutrophils phagocytose activated platelets in vivo: a phosphatidylserine, P-selectin, and {beta}2 integrin-dependent cell clearance program. , 2009, Blood.

[23]  B. Psaty,et al.  Usefulness of myeloperoxidase levels in healthy elderly subjects to predict risk of developing heart failure. , 2009, The American journal of cardiology.

[24]  P. Frenette,et al.  HETEROTYPIC INTERACTIONS ENABLED BY POLARIZED NEUTROPHIL MICRODOMAINS MEDIATE THROMBO-INFLAMMATORY INJURY , 2009, Nature Medicine.

[25]  A. Maseri,et al.  Leukocyte and platelet activation in patients with giant cell arteritis and polymyalgia rheumatica: A clue to thromboembolic risks? , 2009, Autoimmunity.

[26]  P. Libby,et al.  The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models , 2008, Nature Reviews Immunology.

[27]  B. Furie,et al.  Mechanisms of thrombus formation. , 2008, The New England journal of medicine.

[28]  P. Lavie,et al.  Delayed neutrophil apoptosis in patients with sleep apnea. , 2008, American journal of respiratory and critical care medicine.

[29]  F. Apple,et al.  Multiple biomarker use for detection of adverse events in patients presenting with symptoms suggestive of acute coronary syndrome. , 2007, Clinical chemistry.

[30]  M. Rojas,et al.  Src family kinases mediate neutrophil adhesion to adherent platelets. , 2007, Blood.

[31]  G. Maurer,et al.  Active endothelin is an important vasoconstrictor in acute coronary thrombi , 2007, Thrombosis and Haemostasis.

[32]  C. Cerletti,et al.  Prevention of platelet-polymorphonuclear leukocyte interactions: new clues to the antithrombotic properties of parnaparin, a low molecular weight heparin. , 2005, Haematologica.

[33]  W. G. Daniel,et al.  Delay of neutrophil apoptosis in acute coronary syndromes , 2004, Journal of leukocyte biology.

[34]  F. Crea,et al.  Widespread coronary inflammation in unstable angina. , 2003, The New England journal of medicine.

[35]  D. Staunton,et al.  CD18 Activation Epitopes Induced by Leukocyte Activation , 2001, The Journal of Immunology.

[36]  R. Goldberg,et al.  Circulating monocyte-platelet aggregates are an early marker of acute myocardial infarction. , 2001, Journal of the American College of Cardiology.

[37]  M. Furman,et al.  Circulating Monocyte-Platelet Aggregates Are a More Sensitive Marker of In Vivo Platelet Activation Than Platelet Surface P-Selectin: Studies in Baboons, Human Coronary Intervention, and Human Acute Myocardial Infarction , 2001, Circulation.

[38]  A. Michelson,et al.  Regulation of P-selectin binding to the neutrophil P-selectin counter-receptor P-selectin glycoprotein ligand-1 by neutrophil elastase and cathepsin G. , 2001, Blood.

[39]  C. Di Mario,et al.  Progressive decrease of outflow gradient and septum thickness after percutaneous alcoholization of the interventricular septum in hypertrophic obstructive cardiomyopathy. , 2000, Italian heart journal : official journal of the Italian Federation of Cardiology.

[40]  N. Hogg,et al.  Neutrophil apoptosis is associated with a reduction in CD16 (Fc gamma RIII) expression. , 1994, Journal of immunology.

[41]  C. Benjamin,et al.  Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets , 1992, Nature.

[42]  F. Arnett.  Revised criteria for the classification of rheumatoid arthritis. , 1990, Orthopedic nursing.

[43]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[44]  L. T. Swaim.  American Rheumatism Association , 1950 .