The relationship between history of thyroid diseases and risk of in-hospital cardiovascular outcomes in patients with atrial fibrillation: Findings From the CCC-AF (Improving Care for Cardiovascular Disease in China-Atrial Fibrillation) Project.

BACKGROUND: Atrial fibrillation (AF) has the close relation to thyroid dysfunction and these two diseases lead to poor cardiovascular outcomes. But the prognostic value of thyroid diseases in AF remains unclear. We aimed to determine whether history of thyroid diseases is associated with risk of in-hospital cardiovascular outcomes in AF. METHODS: Based on the data from the CCC-AF (Improving Care for Cardiovascular Diseases in China-Atrial Fibrillation) project, 31,486 inpatients with a definitive diagnosis of AF and record of history of thyroid diseases were included. Logistic regression analysis was performed to investigate the relationship between history of thyroid diseases and risk of in-hospital major adverse cardiovascular events (MACE) in AF. RESULTS: Among AF patients, 503 (1.6%) had a history of hypothyroidism, 642 (2.0%) had a history of hyperthyroidism and 30,341 (96.4%) had no thyroid dysfunction. During this hospitalization, 5146 (16.3%) AF patients suffered from MACE. The incidence was 13.1% in hypothyroidism, 16.3% in euthyroidism and 19.0% in hyperthyroidism, in which there was a significant difference among three groups (p=0.028). Multivariable logistic regression analysis revealed that history of hypothyroidism decreased but history of hyperthyroidism increased the risk of in-hospital MACE in AF patients (adjusted odds ratio [OR]=0.603; 95% confidence interval [CI], 0.449-0.811; p=0.001 versus adjusted OR=1.327; 95% CI, 1.060-1.661; p=0.013). CONCLUSION: History of hypothyroidism was an independent protective factor, whereas history of hyperthyroidism was an independent risk factor for in-hospital cardiovascular outcomes in AF. Our study indicated that hyperthyroidism should be treated aggressively in order to improve the prognosis of AF.

Angiotensin II deteriorates advanced atherosclerosis by promoting MerTK cleavage and impairing efferocytosis through the AT1R/ROS/p38 MAPK/ADAM17 pathway.

Vulnerable plaques in advanced atherosclerosis have defective efferocytosis. The role of ANG II in the progression of atherosclerosis is not fully understood. Herein, we investigated the effects and the underlying mechanisms of ANG II on macrophage efferocytosis in advanced atherosclerosis. ANG II decreased the surface expression of Mer tyrosine kinase (MerTK) in macrophages through a disintegrin and metalloproteinase17 (ADAM17)-mediated shedding of the soluble form of MerTK (sMer) in the medium, which led to efferocytosis suppression. ANG II-activated ADAM17 required reactive oxygen species (ROS) and p38 MAPK phosphorylation. Selective angiotensin II type 1 receptor (AT1R) blocker losartan suppressed ROS production, and ROS scavenger N-acetyl-l-cysteine (NAC) prevented p38 MAPK phosphorylation. In addition, mutant MERTKΔ483-488 was resistant to ANG II-induced MerTK shedding and efferocytosis suppression. The advanced atherosclerosis model that is characterized by larger necrotic cores, and less collagen content was established by feeding apolipoprotein E knockout (ApoE-/-) mice with a high-fat diet for 16 wk. NAC and losartan oral administration prevented atherosclerotic lesion progression. Meanwhile, the inefficient efferocytosis represented by decreased macrophage-associated apoptotic cells and decreased MerTK+CD68+double-positive macrophages in advanced atherosclerosis were prevented by losartan and NAC. Additionally, the serum levels of sMer were increased and positively correlated with the upregulated levels of ANG II in acute coronary syndrome (ACS) patients. In conclusion, ANG II promotes MerTK shedding via AT1R/ROS/p38 MAPK/ADAM17 pathway in macrophages, which led to defective efferocytosis and atherosclerosis progression. Defining the molecular mechanisms of defective efferocytosis may provide a promising prognosis and therapy for ACS patients.