New Coronary Heart Disease Risk Factors: The Dark Side of the Moon

We appreciate your Commentary “New Coronary Heart Disease Risk Factors.”1Alpert JS New coronary heart disease risk factors.Am J Med. 2023; 136: 331-332Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar In accordance with your observation that systemic inflammation and related various diseases represent a new risk factor, we are pleased to underline our experience in this field. Previous observations documented that CD11b/CD18 is a well-known surface receptor to mediate cellular inflammatory responses on neutrophils and monocytes/macrophages. CD11b/CD18 may promote the adhesion of neutrophils and monocytes/macrophages to the endothelium, as the inflammasome. Like all integrins, CD11B/CD18 integrin is an adhesion molecule in which a common β2 subunit is noncovalently associated with an α L subunit. The metal-ion–dependent adhesion site, a short amino-acid motif within the I domain, is most likely where the CD11B/CD18 integrin interacts with intercellular adhesion molecule (ICAM)-1. The proinflammatory cytokine interleukin (IL)6 promotes the adhesion of inflammatory monocytes to endothelium mediated by ICAM, and interaction between platelets, to favor thrombosis.2Mazzone A Ricevuti G Leukocyte CD11/CD18 integrins: biological and clinical relevance.Haematologica. 1995; 80: 161-175Google Scholar,3Zizzo G Tamburello A Castelnovo L et al.Immunotherapy of COVID-19: inside and beyond IL-6 signalling.Front Immunol. 2022; 13795315Crossref PubMed Scopus (27) Google Scholar Thirty years ago, I underlined the role of increased expression of adhesion molecules of neutrophils and monocytes in unstable angina.4Mazzone A De Servi S Ricevuti G et al.Increased expression of neutrophil and monocyte adhesion molecules in unstable coronary artery disease.Circulation. 1993; 88: 358-363Crossref Scopus (314) Google Scholar In an editorial in the same issue of Circulation, Entman and Ballantyne5Entman ML Ballantyne CM Inflammation in acute coronary syndromes.Circulation. 1993; 88: 800-803Crossref Scopus (83) Google Scholar supported my hypothesis of the role of inflammation in atherosclerosis and cardiovascular diseases. Inflammation and thrombotic events are frequently observed, as reported in the Commentary,1Alpert JS New coronary heart disease risk factors.Am J Med. 2023; 136: 331-332Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar in patients affected by gout, inflammatory bowel disease, autoimmune collagen vascular disease, and psoriatic arthritis. Neutrophils and monocytes/macrophages are an active part of these diseases to induce thrombosis and hemostasis cascade, but their role has not yet been sufficiently explored in the pathologies with systemic inflammation. Previous observations documented that inflammation mediated by phagocytes in rat lungs is blocked by preincubation with anti-Mo1 monoclonal antibodies (heterodimeric glycoproteins expressed on the plasma membrane of neutrophils, monocytes, macrophages, and a subset of large granular lymphoid cells), thus preventing pulmonary injury.6Ismail G Morganroth ML Todd III, RF Boxer LA Prevention of pulmonary injury in isolated perfused rat lungs by activated human neutrophils preincubated with anti-Mo1 monoclonal antibody.Blood. 1987; 69: 1167-1174Google Scholar These antibodies react with CD11b/CD18 integrin complex, which represents a major adhesion molecular structure on neutrophils and monocytes/macrophages to link ICAM on the endothelium. Moreover, IL6 promotes the adhesion of inflammatory monocytes to the endothelium through the interaction with ICAM, also acting on platelets, to favor thrombosis.3Zizzo G Tamburello A Castelnovo L et al.Immunotherapy of COVID-19: inside and beyond IL-6 signalling.Front Immunol. 2022; 13795315Crossref PubMed Scopus (27) Google Scholar,7Falanga A Marchetti M Barbui T Smith CW Pathogenesis of thrombosis in essential thrombocythemia and polycythemia vera: the role of neutrophils.Semin Hematol. 2005; 42: 239-247Crossref PubMed Scopus (76) Google Scholar Activated monocytes release IL1, which induces biosynthesis and cell surface expression of procoagulant factors and enhances platelet aggregation and activation. Platelet activation seems, in turn, to help neutrophil accumulation within inflammatory sites; the CD11B/CD18 interacts with platelets, fibrinogen, and factor X.7Falanga A Marchetti M Barbui T Smith CW Pathogenesis of thrombosis in essential thrombocythemia and polycythemia vera: the role of neutrophils.Semin Hematol. 2005; 42: 239-247Crossref PubMed Scopus (76) Google Scholar,8Mazzone A De Servi S Mazzucchelli I et al.Increased expression of CD11b/CD18 on phagocytes in ischaemic disease: a bridge between inflammation and coagulation.Eur J Clin Invest. 1997; 27: 648-652Crossref Scopus (51) Google Scholar Therefore, as has also been reported in ischemic diseases and unstable angina,3Zizzo G Tamburello A Castelnovo L et al.Immunotherapy of COVID-19: inside and beyond IL-6 signalling.Front Immunol. 2022; 13795315Crossref PubMed Scopus (27) Google Scholar activated leukocytes and platelets potentiate each other's effects, favoring the occurrence of thrombosis. In addition, Altieri and Edgington9Altieri DC Edgington TS The saturable high affinity association of factor X to ADP-stimulated monocytes defines a novel function of the Mac-1 receptor.J Biol Chem. 1988; 263: 7007-7015Abstract Full Text PDF PubMed Google Scholar described the binding of soluble clotting factor X to CD11b/CD18. Fibrinogen and factor X effectively compete with each other and with C3bI for binding to CD11b/CD18, suggesting spatial proximity or identity in the binding sites involved. The physiological significance of factor X and fibrinogen binding with activated CD11b/CD18 in vivo is one of the possible bridges between inflammation and thrombosis. The demonstration that CD11B/CD18 interaction with endothelial ICAM is responsible for inflammation and thrombosis and plays a key role in cardiovascular disease, is supported by data on the use of iloprost analog of prostacyclin.10Grant SM Goa KL Iloprost. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in peripheral vascular disease, myocardial ischaemia and extracorporeal circulation procedures.Drugs. 1992; 43: 889-924Crossref PubMed Scopus (272) Google Scholar In vivo, this drug modifies the expression of the CD11B/CD18 of phagocytes11Mazzone A Mazzucchelli I Fossati G et al.Iloprost effects on phagocytes in patients suffering from ischaemic diseases: in vivo evidence for down-regulation of alpha M beta 2 integrin.Eur J Clin Invest. 1996; 26: 860-866Crossref Scopus (40) Google Scholar,12Mazzone A Faggioli P Cusa C Stefanin C Rondena M Morelli B Effects of iloprost on adhesion molecules and F1 + 2 in peripheral ischemia.Eur J Clin Invest. 2002; 32: 882-888Crossref Scopus (35) Google Scholar that have a key role in leukocyte-endothelium interactions in cases of inflammation and thrombosis. In fact, in clinical use to prevent cardiovascular events in patients with connective diseases, scleroderma patients who received this flexible IV iloprost regimen achieved clinical improvement, and reduced cardiovascular diseases and renal crisis.13Constans T Diot E Lasfargues G Iloprost for scleroderma.Ann Intern Med. 1991; 114: 606Crossref Scopus (6) Google Scholar,14Martins P Dourado E Fonseca JE Romão V Resende C The safety and persistence of intravenous iloprost in systemic sclerosis.ARP Rheumatol. 2022; 1: 122-128Google Scholar In patients with lower limb ischemia such as claudication or acute critical ischemia, iloprost as an adjuvant to surgery significantly reduced mortality and overall major event rate.15de Donato G Gussoni G de Donato G et al.The ILAILL study: iloprost as adjuvant to surgery for acute ischemia of lower limbs: a randomized, placebo-controlled, double-blind study by the italian society for vascular and endovascular surgery.Ann Surg. 2006; 244: 185-193Crossref Scopus (39) Google Scholar,16Mazzone A Di Salvo M Mazzuca S et al.FADOI 2bPILOT Study Group Effects of iloprost on pain-free walking distance and clinical outcome in patients with severe stage IIb peripheral arterial disease: the FADOI 2bPILOT Study.Eur J Clin Invest. 2013; 43: 1163-1170Google Scholar Neutrophils and monocytes of atherosclerosis and scleroderma patients showed a significant decrease in the expression of the CD11B/CD18 adhesion receptor after 6 hours of iloprost infusion.11Mazzone A Mazzucchelli I Fossati G et al.Iloprost effects on phagocytes in patients suffering from ischaemic diseases: in vivo evidence for down-regulation of alpha M beta 2 integrin.Eur J Clin Invest. 1996; 26: 860-866Crossref Scopus (40) Google Scholar Neutrophils and monocytes released a lower amount of anion superoxide (O2−) after 6 hours of iloprost treatment. These data confirm other clinical observations that inflammation endothelial dysfunction and thrombosis are linked by the interaction of CD11B/CD18, with ICAM, fibrinogen, factor X, and platelets. Finally, statins, a very important drug in this field, inhibited CD11B/CD18 integrin.17Frenette PS Locking a leukocyte integrin with statins.N Engl J Med. 2001; 345: 1419-1421Crossref Scopus (66) Google Scholar This inhibition by statins was specific, and in part explains the anti-inflammatory action of these molecules that block the interaction between monocytes to endothelium via ICAM.18McCarey DW McInnes IB Sattar N The antiinflammatory effects of statins.N Engl J Med. 2001; 345 (; author reply 1210-1211): 1209-1210Crossref Scopus (9) Google Scholar These mechanisms in diseases with systemic inflammation, and the use of biological drugs to modify these aspects, need new research to explain new coronary risk factors and clinical impact on the outcome.