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

Subclinical hypothyroidism (SCH) and atherosclerotic cardiovascular disease are associated independent of traditional risk factors. Although it has been shown that SCH is likely to up-regulate inflammation and impair endothelial function, the role of SCH in the evolution of atherosclerotic plaques has yet to be determined. This paper begins to address this with the hypothesis that SCH may enhance the inflammatory potential of atherosclerotic plaques, favouring instability.

Subjects with asymptomatic carotid artery stenosis enlisted to undergo carotid endarterectomy for extracranial high-grade internal carotid artery stenosis were enrolled in this study. Three patient groups were used: 30 controls without SCH, 23 patients with SCH on l-thyroxine (LTR) replacement therapy and 34 patients with SCH not treated with LTR. Plaques were analysed for macrophage infiltration, proinflammatory cytokines, localization of nitrotyrosine and concentration of matrix metalloproteinase-9 (MMP-9).

Untreated SCH patients had a significantly greater proportion of plaque area occupied by macrophages, greater concentrations of MMP-9 and higher concentrations of nitrotyrosine than treated SCH patients. These features were observed to be higher in all SCH patients compared with those in the control group (P < 0.01 for all). The plaques of the SCH patients were more inflamed than the control group with more nuclear factor-κB (NF-κB) activation (P < 0.01) and lower inhibitory-κBβ concentrations (P < 0.001). The markers indicate that there was significantly more inflammation in the plaques of the untreated SCH patients than the treated patients (P < 0.001). Higher concentrations of nitrotyrosine (P < 0.001) and activated NF-κB in the plaques of SCH patients demonstrated a higher burden of oxidative stress.

The evidence presented in this paper correlates with prospective studies showing that LTR can negatively modulate most cardiovascular risk factors and improve endothelial function in SCH patients. Further work would be needed to determine the pathophysiology of LTR-dependent plaque stabilization, but these results may suggest that LTR can mediate inflammatory activity by reducing oxidative stress.