Thymosin Beta‐4 Is Elevated in Women With Heart Failure With Preserved Ejection Fraction

Abstract

BackgroundThymosin beta‐4 (TB4) is an X‐linked gene product with cardioprotective properties. Little is known about plasma concentration of TB4 in heart failure (HF), and its relationship with other cardiovascular biomarkers. We sought to evaluate circulating TB4 in HF patients with preserved (HFpEF) or reduced (HFrEF) ejection fraction compared to non‐HF controls.Methods and Results TB4 was measured using a liquid chromatography and mass spectrometry assay in age‐ and sex‐matched HFpEF (n=219), HFrEF (n=219) patients, and controls (n=219) from a prospective nationwide study. Additionally, a 92‐marker multiplex proximity extension assay was measured to identify biomarker covariates. Compared with controls, plasma TB4 was elevated in HFpEF (985 [421–1723] ng/mL versus 1401 [720–2379] ng/mL, P<0.001), but not in HFrEF (1106 [556–1955] ng/mL, P=0.642). Stratifying by sex, only women (1623 [1040–2625] ng/mL versus 942 [386–1891] ng/mL, P<0.001), but not men (1238.5 [586–1967] ng/mL versus 1004 [451–1538] ng/mL, P=1.0), had significantly elevated TB4 in the setting of HFpEF. Adjusted for New York Heart Association class, N‐terminal pro B‐type natriuretic peptide, age, and myocardial infarction, hazard ratio to all‐cause mortality is significantly higher in women with elevated TB4 (1.668, P=0.036), but not in men (0.791, P=0.456) with HF. TB4 is strongly correlated with a cluster of 7 markers from the proximity extension assay panel, which are either X‐linked, regulated by sex hormones, or involved with NF‐κB signaling.ConclusionsWe show that plasma TB4 is elevated in women with HFpEF and has prognostic information. Because TB4 can preserve EF in animal studies of cardiac injury, the relation of endogenous, circulating TB4 to X chromosome biology and differential outcomes in female heart disease warrants further study.

Identification of novel pheno-groups in heart failure with preserved ejection fraction using machine learning

“…Nine of the 15 proteins with differential levels across phenogroups have previously been associated with HF and comorbidities in independent data sets using the same proximity eThese trials have relied only on signsxtension assay proteomics chip (online supplementary table S7), and an additional two proteins in previous work on partly the same patients with HFpEF as in this study,18 lending support to the importance of these proteins in HF disease processes. Of these FGF-23, PlGF, NEMO, sST2, TRAIL-R2, U-PAR have previously been associated with HF incidence and HFpEF,28 29 and all, except NEMO and sST2, have also been associated with CKD or kidney dysfunction 30. FGF-23 and U-PAR have also been associated with incident AF 31.…”

Detection and quantification of the metabolite Ac‐Tβ1–14 in in vitro experiments and urine of rats treated with Ac‐Tβ4: A potential biomarker of Ac‐Tβ4 for doping tests

“…Drum et al have reported the detection of endogenous Ac‐Tβ4 in the plasma of healthy human volunteers, but the urine samples were not tested for detecting the endogenous Ac‐Tβ4 29 . On the contrary, by the study of Mora et al, the basal levels of endogenous Ac‐Tβ4 in serum, urine, or other organs of mice were not detected, but after administration of synthetic Ac‐Tβ4, they reported the detection of Ac‐Tβ4 in serum, urine, or other organs 30 .…”

“…The extent of acetylation of lysine residues may not be high compared with endogenous Ac‐Tβ4 in the intracellular environments. In case of trauma and wound conditions, intracellular Ac‐Tβ4 was released into the blood 29 . We assumed that the intracellular Ac‐Tβ4 form can be metabolized to the form with acetylated lysine residues that is distinguishable from the synthetic Ac‐Tβ4.…”

“…In case of trauma and wound conditions, intracellular Ac-Tβ4 was released into the blood. 29 We assumed that the intracellular Ac-Tβ4 form can be metabolized to the form with acetylated lysine residues that is distinguishable from the synthetic Ac-Tβ4. This assumption remained to be further investigated.…”

“…Therapeutic drugs like Ac-Tβ4 are highly vulnerable to being abused by athletes during international sports events. Because of the presence of endogenous Ac-Tβ4 in the plasma of humans ($1 μg/ mL), 29 it is difficult to distinguish the endogenous form from the exogenous form. This disadvantage of the detection can be solved by monitoring its metabolite as a biomarker for doping tests.…”