Angiopoietin-like proteins 3, 4 and 8 are linked to cardiovascular function in naïve sub-clinical and overt hypothyroid patients receiving levothyroxine therapy

Endocr Connect. 2021 Nov 29;10(12):1570-1583. doi: 10.1530/EC-21-0398.


Objective: Angiopoietin-like proteins (ANGPTL) 3, 4 and 8 are upcoming cardiovascular biomarkers. Experimental studies showed that thyroid hormones altered their levels. We assessed ANGPTL3, 4 and 8 as predictors of cardiovascular functions among naïve subclinical and naïve overt hypothyroidism (SCH and OH) and altered ANGPTL levels with levothyroxine replacement (LT4) and their association with improved cardiovascular risk factors and cardiovascular function.

Design and methods: The study was a prospective follow-up study that assessed ANGPTL3, 4 and 8 levels, vascular status (flow-mediated dilation% of brachial artery (FMD%), carotid intima-media thickness (CIMT), aortic stiffness index (ASI)), left ventricle (LV) parameters (ejection fraction (EF), myocardial performance index (MPI), and LV mass), well-known cardiovascular risk factors and homeostatic model for the assessment of insulin resistance, at two time points, that is, among naïve SCH, naïve OH, and healthy subjects groups; and at 6 months after achieving the euthyroid state with LT4 by calculating their increased or decreased delta changes (∆↑ or ∆↓) in longitudinal arm among LT4-hypothyroid groups.

Results: Significantly elevated levels of ANGPTL3, 4 and 8 among hypothyroid groups than the healthy subjects were reduced with LT4. Multivariate analysis revealed ANGPTLs as independent predictors of cardiovascular functions and the contributors for ANGPTL level included ANGPTL3 and 4 for impaired FMD%, and ANGPTL8 for LV mass among naïve SCH; ANGPTL3 for EF% and ANGPTL8 for CIMT in naïve OH; ∆↓ANGPTL3 for ∆↓ASI meanwhile ∆↑freeT4 for ∆↓ANGPTL3, ∆↓fasting glucose, ∆↓triglyceride, and ∆↓thyroid peroxidase antibody for ∆↓ANGPTL4 among LT4-SCH. ∆↓ANGPTL4 for ∆↓MPI and ∆↓LV mass, meanwhile ∆↓TSH and ∆↓triglyceride for ∆↓ANGPTL3, ∆↑free T3 and ∆↓HOMA-IR for ∆↓ANGPTL4, and systolic blood pressure and waist circumference for ∆↓ANGPTL8 among LT4-OH.

Conclusion: Elevated ANGPTL3, 4 and 8 levels are differentially independent predictors of endothelial and cardiac function and are reduced with LT4 in SCH and OH.

Keywords: ANGPTL3; ANGPTL4; ANGPTL8; endothelial and cardiac function; subclinical and overt hypothyroidism.