Circulating Growth Differentiation Factors 11 and 8, Their Antagonists Follistatin and Follistatin-Like-3, and Risk of Heart Failure in Elders.
Document Type
Article
Publication Date
1-1-2024
Original Citation
Kizer J,
Patel S,
Ganz P,
Newman A,
Bhasin S,
Lee S,
Cawthon P,
LeBrasseur N,
Shah S,
Psaty B,
Tracy R,
Cummings S.
Circulating Growth Differentiation Factors 11 and 8, Their Antagonists Follistatin and Follistatin-Like-3, and Risk of Heart Failure in Elders. J Gerontol A Biol Sci Med Sci. 2024;79(1).
Keywords
JGM, Aged, Humans, Male, Biomarkers, Follistatin, Growth Differentiation Factor 15, Heart Failure, Myostatin, Bone Morphogenetic Proteins, Growth Differentiation Factors
JAX Source
J Gerontol A Biol Sci Med Sci. 2024;79(1).
ISSN
1758-535X
PMID
37624693
DOI
https://doi.org/10.1093/gerona/glad206
Grant
The present research was supported by R01 AG052964 from the National Institute on Aging (NIA) to J.R.K., P.G., A.B.N., R.P.T., and S.R.C. The Cardiovascular Health Study (C.H.S.) was supported by R01 AG053325 from the NIA; and by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006, and grants U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the NIA. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. Health ABC was supported by NIA Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6- 2106; NIA grant R01-AG028050, and National Institute of Nursing Research grant R01-NR012459. The research was funded in part by the Intramural Research Program of the NIH, NIA.
Abstract
BACKGROUND: Heterochronic parabiosis has identified growth differentiation factor (GDF)-11 as a potential means of cardiac rejuvenation, but findings have been inconsistent. A major barrier has been lack of assay specificity for GDF-11 and its homolog GDF-8.
METHODS: We tested the hypothesis that GDF-11 and GDF-8, and their major antagonists follistatin and follistatin-like (FSTL)-3, are associated with incident heart failure (HF) and its subtypes in elders. Based on validation experiments, we used liquid chromatography-tandem mass spectrometry to measure total serum GDF-11 and GDF-8, along with follistatin and FSTL-3 by immunoassay, in 2 longitudinal cohorts of older adults.
RESULTS: In 2 599 participants (age 75.2 ± 4.3) followed for 10.8 ± 5.6 years, 721 HF events occurred. After adjustment, neither GDF-11 (HR per doubling: 0.93 [0.67, 1.30]) nor GDF-8 (HR: 1.02 per doubling [0.83, 1.27]) was associated with incident HF or its subtypes. Positive associations with HF were detected for follistatin (HR: 1.15 [1.00, 1.32]) and FLST-3 (HR: 1.38 [1.03, 1.85]), and with HF with preserved ejection fraction for FSTL-3 (HR: 1.77 [1.03, 3.02]). (All HRs per doubling of biomarker.) FSTL-3 associations with HF appeared stronger at higher follistatin levels and vice versa, and also for men, Blacks, and lower kidney function.
CONCLUSIONS: Among older adults, serum follistatin and FSTL-3, but not GDF-11 or GDF-8, were associated with incident HF. These findings do not support the concept that low serum levels of total GDF-11 or GDF-8 contribute to HF late in life, but do implicate transforming growth factor-β superfamily pathways as potential therapeutic targets.