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

Background Thymosin beta‐4 ( TB 4) is an X‐linked gene product with cardioprotective properties. Little is known about plasma concentration of TB 4 in heart failure ( HF ), and its relationship with other cardiovascular biomarkers. We sought to evaluate circulating TB 4 in HF patients with preserved ( HF p EF ) or reduced ( HF r EF ) ejection fraction compared to non‐ HF controls. Methods and Results TB 4 was measured using a liquid chromatography and mass spectrometry assay in age‐ and sex‐matched HF p EF (n=219), HF r EF (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 TB 4 was elevated in HF p EF (985 [421–1723] ng/mL versus 1401 [720–2379] ng/mL, P <0.001), but not in HF r EF (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 TB 4 in the setting of HF p EF . 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 TB 4 (1.668, P =0.036), but not in men (0.791, P =0.456) with HF . TB 4 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. Conclusions We show that plasma TB 4 is elevated in women with HF p EF and has prognostic information. Because TB 4 can preserve EF in animal studies of cardiac injury, the relation of endogenous, circulating TB 4 to X chromosome biology and differential outcomes in female heart disease warrants further study.