Subclinical Thyrotoxicosis and Cardiovascular Risk: Assessment of Circulating Endothelial Progenitor Cells, Proangiogenic Cells, and Endothelial Function


Cardiovascular disease develops mostly as a result of endothelial dysfunction. Endothelial regeneration may benefit greatly from the presence of circulating endothelial progenitor cells (cEPCs). Low or undetectable thyroid stimulating hormones and normal thyroid hormones are the hallmarks of subclinical thyrotoxicosis (SCT). Despite being linked to increased cardiovascular risk (CVR) and death, the course of treatment for SCT is unknown. Circulating angiogenic cells (CACs) and endothelial progenitor cells (cEPCs) have been found to be diminished in CVR-positive circumstances.

Significant knowledge gaps exist concerning the precise molecular and biochemical mechanisms governing the effects of abnormalities in thyroid function in patients and risk of cardiovascular disease. In a new study published in Frontiers in Endocrinology, Newcastle University researchers Jason Phowira, Dr. Anuradha Doddaballapur and led by Dr. Jolanta Weaver together with Sherin Bakhashab at King Abdulaziz University investigated wether SCT was linked to abnormally high levels of cEPCs or CACs that would contribute to endothelial dysfunction and ultimately elevated CVR. The authors cultured CACs from peripheral blood mononuclear cells of SCT patients and cEPCs were quantified by flow cytometry and results was compared with controls with matched ages and sex volunteers. Moreover, the research team looked in depth at the molecular mechanisms involved by assessing CAC apoptosis and eNOS expression in response to high T3 concentrations, endothelial function, plasma asymmetric dimethylarginine levels, the in-vitro paracrine function of CACs, and plasma asymmetric dimethylarginine levels.

According to the authors, SCT is linked to a decreased cEPC count and less FMD. Due to the prevalence of SCT in this group of participants, they evaluated SCT subjects in the context of cardiovascular risk factors. It was not possible to grow pro-angiogenic cells (PACs) in-vitro from the patients they studied since they used middle-aged senior participants with CVD risk factors. In order to explore the paradigm of subclinical thyrotoxicosis, PAC cultures were established from healthy persons, while researchers solely looked at CACs and cEPCs from those patients. The authors found that compared to controls, CD34+ cells were dramatically decreased in SCT. After accounting for CVD risk, the SCT state uniquely predicted the decline in cEPCs, demonstrating that the SCT state can be categorised as having an elevated CVD risk. In comparison to controls, the number of CD34+VEGFR+2 cells was considerably lower in SCT group.

Jolanta Weaver and her colleagues for the first time demonstrated the expression of thyroid hormone receptors in PACs, indicating an important function for thyroid hormones in PACs. To simulate in vivo model of SCT, they used an in vitro model of T3 high concentration. They found that eNOS expression was decreased in PACs at higher T3 levels, indicating that greater tissue T3 levels have an impact on eNOS expression in PACs. Moreover, an increase in T3 concentration promoted PAC apoptosis, which may help to explain how cEPC levels are decreased. Their, in-vitro SCT model has also demonstrated that NO may as a role in both the mobilization of cEPC from the bone marrow and endothelial dysfunction. After accounting for age differences, their study found that FMD was considerably lower in SCT individuals (9 subjects in each group) than controls.

In conclusion, decreased cEPC count and FMD are linked to SCT, supporting higher CVR in SCT. Future trials on outcomes are necessary to see whether treating subclinical hyperactive state enhances cardiovascular outcomes. Furthermore, poor vascular health is evident in patients with SCT which is consistent with an elevated risk of cardiovascular disease. Randomized controlled interventional trials are recommended to determine whether the high risk can be reduced.


Phowira J, Bakhashab S, Doddaballapur A, Weaver JU. Subclinical Thyrotoxicosis and Cardiovascular Risk: Assessment of Circulating Endothelial Progenitor Cells, Proangiogenic Cells, and Endothelial Function. Frontiers in Endocrinology. 2022;13.

Go To Frontiers in Endocrinology.