Innate Immune Activity in Plaque of Patients with Untreated and L-Thyroxine-Treated Subclinical Hypothyroidism

Context: A strong association between subclinical hypothyroidism (SCH) and atherosclerotic diseases, independent of the traditional risk factors, was noted. Objective: The objective of the study was to evaluate the association between SCH and the inflammatory potential of atherosclerotic plaques as well as the role of L-T-4 replacement therapy (LTR) on regulation of plaque inflammation. Experimental Design and Main Outcome Measures: We examined the differences in macrophage content, proinflammatory cytokine infiltration, and oxidative stress between asymptomatic carotid plaques of patients with and without SCH and LTR. Setting and Participants: Plaques were obtained from 23 SCH patients with LTR (treated), 34 untreated SCH patients, and 30 control patients without SCH enlisted to undergo carotid endarterectomy for extracranial high-grade (>70%) internal carotid artery stenosis. Plaques were analyzed for macrophages, T lymphocytes, human leukocyte antigen (HLA)-DR+ cells, nuclear factor-kappa B (NF-kappa B), inhibitory-kappa B beta (I kappa B beta), TNF-alpha, nitrotyrosine, matrix metalloproteinase-9 (MMP-9), and collagen content (immunohistochemistry and ELISA). Results: Compared with control plaques, SCH plaques had more macrophages, T lymphocytes, and HLA-DR+ cells, TNF-alpha, NF-kappa B, markers of oxidative stress (nitrotyrosine and O2- production), and MMP-9(P < 0.01, for all), along with a lesser collagen content and I kappa B beta levels (P < 0.001). Compared with plaques from treated patients, plaques from untreated patients had more macrophages, T lymphocytes, HLA-DR+ cells, TNF-alpha, NF-kappa B (P < 0.001), nitrotyrosine, O2- production, and MMP-9 (P < 0.01, for all), along with a lesser collagen content and I kappa B beta levels (P < 0.001). Conclusions: These data suggest a potential interplay between SCH and inflammatory activity in atherosclerotic plaque progression toward instability. Moreover, LTR might contribute to plaque stabilization by inhibiting the innate immunity-dependent plaque rupture in patients with SCH. (J Clin Endocrinol Metab 96: 1015-1020, 2011)