Innate immune activity in plaque of patients with untreated and L-thyroxine-treated subclinical hypothyroidism.

Abstract

A strong association between subclinical hypothyroidism (SCH) and atherosclerotic diseases, independent of the traditional risk factors, was noted. 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. 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-κB (NF-κB), inhibitory-κBβ (IκBβ), TNF-α, nitrotyrosine, matrix metalloproteinase-9 (MMP-9), and collagen content (immunohistochemistry and ELISA). Compared with control plaques, SCH plaques had more macrophages, T lymphocytes, and HLA-DR(+) cells, TNF-α, NF-κB, markers of oxidative stress (nitrotyrosine and O(2-) production), and MMP-9 (P < 0.01, for all), along with a lesser collagen content and IκBβ levels (P < 0.001). Compared with plaques from treated patients, plaques from untreated patients had more macrophages, T lymphocytes, HLA-DR(+) cells, TNF-α, NF-κB (P < 0.001), nitrotyrosine, O(2-) production, and MMP-9 (P < 0.01, for all), along with a lesser collagen content and IκBβ levels (P<0.001). 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.