Patients With Acute Coronary Syndrome Show Oligoclonal T-Cell Recruitment Within Unstable Plaque Evidence for a Local, Intracoronary Immunologic Mechanism Raffaele De Palma, MD, PhD; Francesco Del Galdo, MD; Gianfranco Abbate, MD; Massimo Chiariello, MD; Raffaele Calabró, MD; Lavinia Forte, MD; Giovanni Cimmino, MD; Maria Francesca Papa, BSc; Maria Giovanna Russo, MD; Giuseppe Ambrosio, MD, PhD; Claudio Giombolini, MD; Isabella Tritto, MD; Salvatore Notaristefano, MD; Liberato Berrino, MD; Francesco Rossi, MD; Paolo Golino, MD, PhD Background—Recent studies indicate that T-cell activation may play an important role in the pathophysiology of acute coronary syndromes (ACS). However, although those studies detected T-cell expansion in peripheral blood cells, demonstration of specific T-cell expansion within the plaque of patients with ACS is lacking. The present study aims to address whether a specific, immune-driven T-lymphocyte recruitment occurs within the unstable plaque of patients with ACS. Methods and Results—We simultaneously examined the T-cell repertoire using CDR3 size analysis both in coronary plaques (obtained by directional atherectomy) and in peripheral blood of patients with either ACS (n=11) or chronic stable angina (n=10). Unstable plaques showed a 10-fold increase in T-cell content by quantitative PCR. Using spectratyping analysis, we found several specific T-cell clonotype expansions only in unstable plaque from each patient with ACS, indicating a specific, antigen-driven recruitment of T cells within unstable lesions. Conclusions—For the first time, T-cell repertoire was investigated directly into coronary plaques; using this approach, we demonstrate that coronary plaque instability in the setting of ACS is associated with immune-driven T-cell recruitment, specifically within the plaque. (Circulation. 2006;113:640-646.) Key Words: immune system  inflammation  lymphocytes  plaque C oncepts on the pathophysiology of acute coronary syn- dromes (ACS) have recently undergone considerable evo- lution, focusing our attention on plaque biology rather than on hemodynamic factors. Indeed, it currently is believed that plaque rupture/erosion, with the consequent superimposed thrombosis, represents a key event causing the sudden conversion of coro- nary syndromes from chronic to acute. 1 In this respect, recent data suggest that immunocompetent, cell-derived inflammation may play an important role in the pathophysiology of plaque rupture. 2–4 Thus, to date, the prevailing hypothesis considers inflammation a key event in the pathophysiology of plaque rupture, with macrophages possibly being major effector cells in this process, through the release of matrix-degrading enzymes such as matrix metalloproteinases. Because T cells, through cell-to-cell contact and production and release of cytokines, are the most powerful regulators of macrophage activity, 5 T-cell activation has been proposed to represent an important mecha- nism in the pathophysiology of plaque complication. 3 Indeed, it has been reported that lymphocytes from peripheral blood of patients with ACS are characterized by clonal expansions of T cells 6–8 ; these expansions have been attributed to an ongoing antigenic stimulus possibly related to chronic infection. 6–8 Indi- rect evidence of this theory is the finding of a T-cell response against pathogens such as Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus in patients with ACS. 9,10 Clinical Perspective p 646 However, the dynamics of T-cell response within the plaque are still poorly understood. In particular, it is unclear whether the inflammation observed in the culprit lesion of patients with ACS is invariably the consequence of a wide- spread systemic inflammatory status or whether the T-cell Received January 21, 2005; revision received September 28, 2005; accepted November 22, 2005. From the Department of Clinical and Experimental Medicine (R.D.P., F.D.G., G.A., M.F.P.), Department of Experimental Medicine, Section of Pharmacology (L.B., F.R.), and Department of Cardiothoracic and Respiratory Sciences, Section of Cardiology (R.C., L.F., G.C., M.G.R., P.G.), Second University of Naples, Naples; Department of Internal Medicine and Cardiovascular Sciences (M.C.), Division of Cardiology, University of Naples “Federico II”, Naples; and the Division of Cardiology (G.A., C.G., I.T., S.N.), University of Perugia, Perugia, Italy. Presented in part at the 2003 Scientific Sessions of the American Heart Association, Orlando, Fla, November 9 –12, 2003, and published in abstract form (Circulation. 2003;108[suppl IV]:IV-469). Correspondence to Paolo Golino, MD, PhD, Division of Cardiology, Second University of Naples, Ospedale Monaldi, Via Leonardo Bianchi, 80131 Naples, Italy. E-mail paolo.golino@unina2.it © 2006 American Heart Association, Inc. Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.105.537712 640 Coronary Heart Disease by guest on December 31, 2015 http://circ.ahajournals.org/ Downloaded from