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CLINICAL RESEARCH: ACUTE CORONARY SYNDROME

Enhanced T-Helper-1 Lymphocyte Activation Patterns in Acute Coronary Syndromes

Heiko Methe, MD^_*,,_*, Stefan Brunner^_*, Daniela Wiegand^_*, Michael Nabauer, MD^_*, Joerg Koglin, MD^_* and Elazer R. Edelman, MD, PhD

^_* Department of Cardiology, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, and the Cardiovascular Division, Department of Internal Medicine, Brigham and Women’s Hospital, Boston, Massachusetts

Manuscript received November 12, 2004; revised manuscript received March 2, 2005, accepted March 10, 2005.

^_* Reprint requests and correspondence: Dr. Heiko Methe, Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 56-322, Cambridge, Massachusetts 02139. (Email: hmethe{at}mit.edu).

OBJECTIVES: We sought to determine whether different stages of coronary artery disease (CAD) are associated with distinct differentiation patterns of activated T cells.

BACKGROUND: Atherosclerosis is an inflammatory disease. However, little is known about specific inflammatory cell activation in atherosclerosis, for example, the T-helper (Th)1/Th2-balance.

METHODS: We studied 18 patients with stable angina (SA), 28 patients with acute coronary syndrome (ACS) (16 with unstable angina pectoris and 12 with ST-segment elevation myocardial infarction), 19 patients with unheralded myocardial infarction (UH), and 16 control patients. Cytokine patterns and transcription factor signaling pathways of circulating T cells were characterized using reverse transcription polymerase chain reaction and flow cytometry.

RESULTS: Although interferon (IFN)-⁺/CD3⁺ T cells were 2-fold greater in patients with SA or UH than in control subjects, there was a massive expansion of Th1 cells in patients with ACS (p < 0.001). This increase was paralleled by significantly increased mRNA transcript levels for signal-transducer-and-activator-4 (ACS 1.17 ± 0.14 relative units [RU]; control patients 0.44 ± 0.09 RU; SA 0.67 ± 0.12 RU; UH 0.61 ± 0.17 RU), interleukin-2 (ACS 1.55 ± 0.51 RU; control patients 0.21 ± 0.09 RU; SA 0.54 ± 0.18 RU; UH 0.45 ± 0.16 RU), and IFN- in ACS (1.27 ± 0.39 RU; control patients 0.35 ± 0.09 RU; SA 0.58 ± 0.11 RU; UH 0.53 ± 0.24 RU; p < 0.002). Th2 and Th0 cells were not different across patient subsets. The burden of CAD was identical between SA (1.4 ± 0.2 diseased vessels, 68 ± 13% diameter stenosis) and ACS (1.4 ± 0.2 diseased vessels, 64 ± 17% diameter stenosis) but significantly greater in patients with UH (2.5 ± 0.5 diseased vessels, 95 ± 7% diameter stenosis; p < 0.05).

CONCLUSIONS: Patients with UH have a greater burden of obstructive CAD than SA but no greater T-cell activation. Patients with ACS have the same extent of CAD than SA but significantly greater activation of Th1 cells that may contribute to the increasing instability. Differences in circulating Th1 cells might indicate different pathogenic components, leading to ACS and UH.

Abbreviations and Acronyms   ACS = acute coronary syndrome   CAD = coronary artery disease   CK = creatine kinase   CRP = C-reactive protein   FACS = fluorescence-activated cell sorter   IFN = interferon   IL = interleukin   PBS = phosphate-buffered saline   SA = stable angina pectoris   STAT = signal transducer and activator of transcription   STEMI = ST-segment elevation myocardial infarction   Th = T-helper   UA = unstable angina pectoris   UH = unheralded myocardial infarction

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