02430nas a2200241 4500008004100000022001400041245012600055210006900181260001600250520166100266100001401927700001801941700002401959700002201983700002002005700002002025700001902045700002302064700002202087700002302109700002002132856003602152 2022 eng d a1532-541500aSex- and race-specific associations of bone mineral density with incident heart failure and its subtypes in older adults.0 aSex and racespecific associations of bone mineral density with i c2022 Nov 053 a

BACKGROUND: Previous studies have suggested an association between bone mineral density (BMD) and heart failure (HF) risk that may be race-dependent.

METHODS: We evaluated the relationship between BMD and incident HF in a cohort of older adults, the Health, Aging, and Body Composition (Health ABC) study (n = 2835), and next performed a pooled analysis involving a second older cohort, the Cardiovascular Health Study (n = 1268). Hip BMD was measured by dual-energy X-ray absorptiometry in both cohorts and spine BMD by computed tomography in a subset from Health ABC.

RESULTS: In Health ABC, lower BMD at the total hip was associated with higher incident HF in Black women after multivariable adjustment. Similar associations were found for BMD at the femoral neck and spine. In both cohorts, pooled analysis again revealed an association between lower total hip BMD and increased risk of HF in Black women (HR = 1.41 per 0.1-g/cm decrement [95% CI = 1.23-1.62]), and showed the same to be true for White men (HR = 1.12 [1.03-1.21]). There was a decreased risk of HF in Black men (HR 0.80 [0.70-0.91]), but no relationship in White women. The associations were numerically stronger with HFpEF for Black women and White men, and with HFrEF for Black men. Findings were similar for femoral neck BMD. Sensitivity analyses delaying HF follow-up by 2 years eliminated the association in Black men.

CONCLUSIONS: Lower BMD was associated with higher risk of HF and especially HFpEF in older Black women and White men, highlighting the need for additional investigation into underlying mechanisms.

1 aGao, Hans1 aPatel, Sheena1 aFohtung, Raymond, B1 aCawthon, Peggy, M1 aNewman, Anne, B1 aCauley, Jane, A1 aCarbone, Laura1 aChaves, Paulo, H M1 aStein, Phyllis, K1 aCivitelli, Roberto1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/924802575nas a2200253 4500008004100000022001400041245014800055210006900203260001600272520175400288100002002042700001802062700001602080700002002096700002202116700001602138700002202154700002302176700002002199700002002219700002202239700002402261856003602285 2023 eng d a1758-535X00aCirculating Growth Differentiation Factors 11 and 8, Their Antagonists Follistatin and Follistatin-like-3, and Risk of Heart Failure in Elders.0 aCirculating Growth Differentiation Factors 11 and 8 Their Antago c2023 Aug 253 a

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 follistatin-like (FSTL)-3 by immunoassay, in two 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-βsuperfamily pathways as potential therapeutic targets.

1 aKizer, Jorge, R1 aPatel, Sheena1 aGanz, Peter1 aNewman, Anne, B1 aBhasin, Shalender1 aLee, Se-Jin1 aCawthon, Peggy, M1 aLeBrasseur, Nathan1 aShah, Sanjiv, J1 aPsaty, Bruce, M1 aTracy, Russell, P1 aCummings, Steven, R uhttps://chs-nhlbi.org/node/948102580nas a2200229 4500008004100000022001400041245019900055210006900254260001600323520178300339100002002122700001802142700001702160700001602177700002202193700001902215700002302234700002102257700001602278700002002294856003602314 2023 eng d a1758-535X00aEvaluation of Associations of Growth Differentiation Factor-11, Growth Differentiation Factor-8 and their Binding Proteins Follistatin and Follistatin-like protein-3 with Dementia and Cognition.0 aEvaluation of Associations of Growth Differentiation Factor11 Gr c2023 Jan 203 a

BACKGROUND: Studies using heterochronic parabiosis discovered that circulating factors mediate brain aging in animal models.

METHODS: We assessed Growth Differentiation Factor (GDF)-11 and GDF-8 using mass spectrometry and inhibitors follistatin and follistatin-like protein-3 (FSTL-3) with ELISA in in the Cardiovascular Health Study (N=1506) and the Health ABC study (N=1237). CLL-11 and Beta 2 microglobulin (B2M) were measured with ELISA in a subset of 400 individuals in Health ABC. Associations were assessed with cognitive function, brain magnetic resonance imaging (MRI) findings (CHS only) and incident dementia using correlations, linear regression and Cox proportional hazards models.

RESULTS: In CHS, levels of GDF-11, GDF-8 and follistatin were not correlated cross sectionally with the 3MSE or DSST, brain MRI findings of white matter hyperintensity, atrophy or small infarcts, nor were they associated with incident dementia. FSTL-3 was modestly correlated with poorer cognitive function, greater white matter hyperintensities and atrophy on MRI as well as with incident dementia with an adjusted HR of 1.72 (95% CI=1.13, 2.61) per doubling of FSTL-3. FSTL-3 was not associated with cognition or dementia in Health ABC, but GDF-8 was associated with both. The adjusted HR for incident dementia was 1.50 (95%CI 1.07, 2.10) per doubling of GDF-8.

CONCLUSIONS: Total GDF-11 level was not related to cognition or dementia in older adults. Associations of GDF-8 with cognitive outcomes in Health ABC were not expected, but consistent with animal models. Associations of FSTL-3 with cognition, brain abnormalities, and incident dementia in CHS implicates TGF-B superfamily inhibition in the pathogenesis of dementia.

1 aNewman, Anne, B1 aPatel, Sheena1 aKizer, Jorge1 aLee, Se-Jin1 aBhasin, Shalinder1 aCawthon, Peggy1 aLeBrasseur, Nathan1 aTracy, Russel, P1 aGanz, Peter1 aCummings, Steve uhttps://chs-nhlbi.org/node/929002440nas a2200181 4500008004100000245015400041210006900195260001600264520180100280100001802081700001802099700002002117700002102137700002002158700002002178700002402198856003602222 2024 eng d00aAssociations of Serum GDF-15 Levels with Physical Performance, Mobility Disability, Cognition, Cardiovascular Disease, and Mortality in Older Adults.0 aAssociations of Serum GDF15 Levels with Physical Performance Mob c2024 Aug 083 a

BACKGROUND: Growth differentiation factor 15 (GDF-15) is a member of the TGFβ superfamily secreted by many cell types and found at higher blood concentrations as chronological age increases (1). Given the emergence of GDF-15 as a key protein associated with aging, it is important to understand the multitude of conditions with which circulating GDF-15 is associated.

METHODS: We pooled data from 1,174 randomly selected Health ABC Study (Health ABC) participants and 1,503 Cardiovascular Health Study (CHS) participants to evaluate the risk of various conditions and age-related outcomes across levels of GDF-15. The primary outcomes were (1) risk of mobility disability and falls; (2) impaired cognitive function; (3) and increased risk of cardiovascular disease and total mortality.

RESULTS: The pooled study cohort had a mean age of 75.4 +/-4.4 years. Using a Bonferroni-corrected threshold, our analyses show that high levels of GDF-15 were associated with a higher risk of severe mobility disability (HR: 2.13 [1.64, 2.77]), coronary heart disease (HR: 1.47 [1.17, 1.83]), atherosclerotic cardiovascular disease (HR: 1.56 [1.22, 1.98]), heart failure (HR: 2.09 [1.66, 2.64]), and mortality (HR: 1.81 [1.53, 2.15]) when comparing the highest and lowest quartiles. For CHS participants, analysis of extreme quartiles in fully adjusted models revealed a 3.5-fold higher risk of dementia (HR: 3.50 [1.97, 6.22]).

CONCLUSIONS: GDF-15 is associated with several age-related outcomes and diseases, including mobility disability, impaired physical and cognitive performance, dementia, cardiovascular disease, and mortality. Each of these findings demonstrates the importance of GDF-15 as a potential biomarker for many aging-related conditions.

1 aWebber, Katey1 aPatel, Sheena1 aKizer, Jorge, R1 aEastell, Richard1 aPsaty, Bruce, M1 aNewman, Anne, B1 aCummings, Steven, R uhttps://chs-nhlbi.org/node/9748