Abstract 11521: Circulating Thymosin Beta-4 is Elevated in Women With Heart Failure

Background: Heart failure with preserved ejection (HFpEF) predominates in females, is often difficult to diagnose, has no specific circulating biomarkers, and no proven therapeutic options. Thymosin beta-4 (TB4) is an endogenously produced peptide with cardioprotective properties. In animal models, exogenously delivered TB4 was reported to reduce apoptosis, attenuate inflammation, minimize fibrosis, activate stem cells, preserve ejection fraction, and promote angiogenesis. Measurements of circulating TB4 in humans are limited, and its levels in heart failure (HF) relative to controls is not known. Hypothesis: We hypothesized that TB4 is upregulated in HF as a compensatory mechanism, and may be a plasma marker of HF with either preserved ejection fraction (HFpEF) or reduced ejection fraction (HFrEF). Because TB4 is an X-linked gene, sex-specific regulation is suspected. Methods: To measure plasma levels of TB4, we developed a quantitative and targeted liquid chromatography mass spectroscopy (LCMS) assay. The assay was applied to age- and sex- matched HFpEF (n=219), HFrEF (n=219) and controls (n=219) from a prospective nationwide study. Results: Compared to controls, plasma TB4 was elevated in HFpEF [985(421-1723) ng/mL vs. 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 vs. 942(386-1891) ng/mL, p<0.001], but not men [1238.5(586-1967) ng/mL vs 1004(451-1538) ng/mL, p=1.0], had elevated TB4 in the setting of HFpEF. Over 2 years, there were 60 deaths among patients with HF. TB4 predicted time to all-cause mortality in women (p=0.046) but not men (p=0.454) with HF, independent of clinical risk factors and N-terminal pro-B-type natriuretic peptide (adjusted hazards ratio for LnTB4=1.64; 95% CI, 1.01-2.67). Conclusion: Circulating TB4 is a novel marker of HFpEF in women. The independent prognostic impact of plasma TB4 in women with HFpEF suggests the presence of sex-specific mechanisms in HFpEF.