Abstract
BackgroundCardiac re-expression of fetal genes in patients with heart failure (HF) suggests the presence of low cardiac tissue thyroid hormone (TH) function. However, serum concentrations of T3 and T4 are often normal or subclinically low, necessitating an alternative serum biomarker for low cardiac TH function to guide treatment of these patients. The clinical literature suggests that serum Brain Natriuretic Peptide (BNP) levels are inversely associated with serum triiodo-L-thyronine (T3) levels. The objective of this study was to investigate BNP as a potential serum biomarker for TH function in the heart.MethodsTwo animal models of thyroid hormone deficiency: (1) 8-weeks of propyl thiouracil-induced hypothyroidism (Hypo) in adult female rats were subsequently treated with oral T3 (10 μg/kg/d) for 3, 6, or 14 days; (2) HF induced by coronary artery ligation (myocardial infarction, MI) in adult female rats was treated daily with low dose oral T3 (5 μg/kg/d) for 8 or 16 wks.ResultsSix days of T3 treatment of Hypo rats normalized most cardiac functional parameters. Serum levels of BNP increased 5-fold in Hypo rats, while T3 treatment normalized BNP by day 14, showing a significant inverse relationship between serum BNP and free or total T3 concentrations. Myocardial BNP mRNA was increased 2.5-fold in Hypo rats and its expression was decreased to normal values by 14 days of T3 treatment. Measurements of hemodynamic function showed significant dysfunction in MI rats after 16 weeks, with serum BNP increased by 4.5-fold and serum free and total T3 decreased significantly. Treatment with T3 decreased serum BNP while increasing total T3 indicating an inverse correlation between these two biologic factors (r2 = 0.676, p < 0.001). Myocardial BNP mRNA was increased 5-fold in MI rats which was significantly decreased by T3 over 8 to 16 week treatment periods.ConclusionsResults from the two models of TH dysfunction confirmed an inverse relationship between tissue and serum T3 and BNP, such that the reduction in serum BNP could potentially be utilized to monitor efficacy and dosing of T3 treatment. Thus, serum BNP may serve as a reliable biomarker for cardiac TH function.
Highlights
Echocardiography Data Cardiac function declined after PTU treatment with ejection fraction (EF) values significantly decreased compared to euthyroid controls (EU) (EF, 70 ± 5 vs 82 ± 1%; Supplementary Table)
These changes were normalized within the 3–14 day period of T3 treatment
Echocardiography showed significant changes in measures of wall thickness and left ventricular (LV) chamber diameters in both diastole and systole (Supplementary Table). All these parameters were significantly improved by the third day of T3 treatment, demonstrating restoration of normal cardiac dimensions and function
Summary
MATERIALS AND METHODSIn recent years, numerous clinical studies have shown a significant association between low thyroid hormone (TH) function and worsening cardiac function, and increased mortality in heart failure (HF; Tseng et al, 2012; Mitchell et al, 2013; Chuang et al, 2014; Wang et al, 2015; Brozaitiene et al, 2016; Gil-Cayuela et al, 2017, 2018; She et al, 2018; Sato et al, 2019). Low TH function in patients with heart disease typically goes untreated largely due to many unanswered questions related to treatment optimization, fear of inducing arrhythmias, and identification of the patient cohort that may obtain the greatest benefit from treatment In response to these concerns, a serum biomarker reflecting cardiac tissue TH function is needed. Holmager et al (2015) found that when BNP levels were unchanged in HF patients treated with T3, no improvement in cardiac function was recorded, suggesting inadequate dosing These examples indicate the potential value of a serum biomarker that is already in widespread use and would directly correlate with TH function in the heart tissue itself. The objective of this study was to investigate BNP as a potential serum biomarker for TH function in the heart
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