@article {1214, title = {Change in circulating adiponectin in advanced old age: determinants and impact on physical function and mortality. The Cardiovascular Health Study All Stars Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {65}, year = {2010}, month = {2010 Nov}, pages = {1208-14}, abstract = {

BACKGROUND: Cross-sectional studies show that adiponectin is higher in older than in younger adults but long-term change in adiponectin, its determinants, and its relationship to functional decline or survival in the elderly population have not been evaluated.

METHODS: We investigated predictors of longitudinal change in adiponectin, and the association of this adipokine or its antecedent change with physical deterioration and all-cause mortality in 988 participants in a population-based study who completed examinations in 1996-1997 and 2005-2006, had serial adiponectin measurements and underwent follow-up through June 2009.

RESULTS: Adiponectin level rose significantly during follow-up, but the increase was smaller in blacks, was associated with declining weight or fasting glucose and, in men, lower albumin, and was affected by medications. Adiponectin was independently associated with greater physical decline, but the relationship for adiponectin change was driven by concomitant weight decrease. Both adiponectin and its change independently predicted mortality, even after adjustment for weight change. The association for adiponectin and mortality was observed in whites but not in blacks and only for levels in the upper range (hazard ratio = 1.85, 95\% confidence interval = 1.36-2.52 per SD >= 20 mg/L), whereas that for adiponectin change was linear throughout in both racial groups (hazard ratio = 1.30, 95\% confidence interval = 1.10-1.52 per SD).

CONCLUSIONS: Adiponectin levels increase over time in long-lived adults and are associated with greater physical disability and mortality. Such increases may occur in response to age-related homeostatic dysregulation. Additional investigation is required to define the underlying mechanisms and whether this represents a marker or causal factor for mortality in this age group.

}, keywords = {Adiponectin, Age Factors, Aged, Aging, Analysis of Variance, Cardiovascular Diseases, Cause of Death, Chi-Square Distribution, Cohort Studies, Cross-Sectional Studies, Female, Health Status, Humans, Linear Models, Male, Physical Fitness, Proportional Hazards Models, Risk Factors, Sex Factors, Time Factors, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glq122}, author = {Kizer, Jorge R and Arnold, Alice M and Strotmeyer, Elsa S and Ives, Diane G and Cushman, Mary and Ding, Jingzhong and Kritchevsky, Stephen B and Chaves, Paulo H M and Hirsch, Calvin H and Newman, Anne B} } @article {6062, title = {Circulating 25-hydroxyvitamin D is associated with insulin resistance cross-sectionally but not longitudinally in older adults: The Cardiovascular Health Study.}, journal = {Metabolism}, volume = {62}, year = {2013}, month = {2013 Dec}, pages = {1788-94}, abstract = {

BACKGROUND: Despite extensive study, the role of vitamin D in insulin resistance and secretion remains unclear.

OBJECTIVE: To examine the cross-sectional and longitudinal relationships between 25-hydroxyvitamin D (25(OH)D) concentrations and indices of insulin resistance and secretion in older adults.

METHODS AND RESULTS: Among 2134 participants of the Cardiovascular Health Study who were free from cardiovascular disease, we measured serum 25(OH)D concentrations in samples collected in 1992-1993. We examined insulin resistance and secretion using Homeostasis Model Assessment (HOMA) estimates cross-sectionally and among 1469 participants who had repeated HOMA measures four years later (1996-1997). In cross-sectional analysis, each 10 ng/mL increment in 25(OH)D concentration was associated with a 0.09 lower adjusted HOMA-IR [95\% CI (-0.17, -0.02), p=0.01]. However, baseline 25(OH)D concentrations were not associated with change in HOMA-IR over 4 years of follow up (p=0.48). 25(OH)D concentrations were not associated with insulin secretion, as determined by HOMA-β, in either cross-sectional or longitudinal analysis.

CONCLUSIONS: Circulating 25(OH)D concentrations are associated with lower insulin resistance in cross-sectional but not longitudinal analyses. Whether this reflects residual confounding in cross-sectional analyses or the short-term nature of the relationship between vitamin D and insulin sensitivity will require trials with repeated measures of these factors.

}, keywords = {Adiposity, Aged, Anthropometry, Cardiovascular Diseases, Cross-Sectional Studies, Exercise, Female, Humans, Hydroxycholecalciferols, Inflammation, Insulin, Insulin Resistance, Longitudinal Studies, Male, Middle Aged, Obesity, Risk Factors, Surveys and Questionnaires}, issn = {1532-8600}, doi = {10.1016/j.metabol.2013.07.008}, author = {Danziger, John and Biggs, Mary L and Niemi, Matt and Ix, Joachim H and Kizer, Jorge R and Djouss{\'e}, Luc and de Boer, Ian H and Siscovick, David S and Kestenbaum, Bryan and Mukamal, Kenneth J} } @article {6080, title = {Common FABP4 genetic variants and plasma levels of fatty acid binding protein 4 in older adults.}, journal = {Lipids}, volume = {48}, year = {2013}, month = {2013 Nov}, pages = {1169-75}, abstract = {

We examined common variants in the fatty acid binding protein 4 gene (FABP4) and plasma levels of FABP4 in adults aged 65 and older from the Cardiovascular Health Study. We genotyped rs16909187, rs1054135, rs16909192, rs10808846, rs7018409, rs2290201, and rs6992708 and measured circulating FABP4 levels among 3190 European Americans and 660 African Americans. Among European Americans, the minor alleles of six single nucleotide polymorphisms (SNP) were associated with lower FABP4 levels (all p~<=~0.01). Among African Americans, the SNP with the lowest minor allele frequency was associated with lower FABP4 levels (p~=~0.015). The C-A haplotype of rs16909192 and rs2290201 was associated with lower FABP4 levels in both European Americans (frequency~=~16~\%; p~=~0.001) and African Americans (frequency~=~8~\%; p~=~0.04). The haplotype combined a SNP in the first intron with one in the 3{\textquoteright}untranslated region. However, the alleles associated with lower FABP4 levels were associated with higher fasting glucose in meta-analyses from the MAGIC consortium. These results demonstrate associations of common SNP and haplotypes in the FABP4 gene with lower plasma FABP4 but higher fasting glucose levels.

}, keywords = {African Americans, Aged, Aged, 80 and over, Blood Glucose, Body Mass Index, Cohort Studies, European Continental Ancestry Group, Fatty Acid-Binding Proteins, Female, Gene Frequency, Genetic Association Studies, Haplotypes, Humans, Insulin, Linkage Disequilibrium, Male, Polymorphism, Single Nucleotide}, issn = {1558-9307}, doi = {10.1007/s11745-013-3838-7}, author = {Mukamal, Kenneth J and Wilk, Jemma B and Biggs, Mary L and Jensen, Majken K and Ix, Joachim H and Kizer, Jorge R and Tracy, Russell P and Zieman, Susan J and Mozaffarian, Dariush and Psaty, Bruce M and Siscovick, David S and Djouss{\'e}, Luc} } @article {6337, title = {Circulating fibrosis biomarkers and risk of atrial fibrillation: The Cardiovascular Health Study (CHS).}, journal = {Am Heart J}, volume = {167}, year = {2014}, month = {2014 May}, pages = {723-8.e2}, abstract = {

BACKGROUND: Cardiac fibrosis is thought to play a central role in the pathogenesis of atrial fibrillation (AF). Retrospective studies have suggested that circulating fibrosis biomarkers are associated with AF, but prospective studies are limited.

METHODS: We measured circulating levels of 2 fibrosis biomarkers, procollagen type III, N-terminal propeptide (PIIINP) and transforming growth factor β1 among participants of the CHS, a population-based study of older Americans. We used Cox proportional hazards and competing risks models to examine adjusted risk of incident AF over a median follow-up of 8.8 years.

RESULTS: Levels of PIIINP were assessed in 2,935 participants, of whom 767 developed AF. Compared with the median PIIINP level (4.45 μg/L), adjusted hazard ratios (95\% CIs) were 0.85 (0.72-1.00) at the 10th percentile, 0.93 (0.88-0.99) at the 25th percentile, 1.04 (0.95-1.04) at the 75th percentile, and 1.07 (0.90-1.26) at the 90th. Transforming growth factor β1 levels, assessed in 1,538 participants with 408 cases of incident AF, were not associated with AF risk.

CONCLUSION: In older adults, PIIINP levels were associated with risk of incident AF in a complex manner, with an association that appeared to be positive up to median levels but with little relationship beyond that. Further studies are required to confirm and possibly delineate the mechanism for this relationship.

}, keywords = {Aged, Atrial Fibrillation, Biomarkers, Cardiomyopathies, Electrocardiography, Enzyme-Linked Immunosorbent Assay, Female, Fibrosis, Follow-Up Studies, Humans, Incidence, Male, Peptide Fragments, Procollagen, Prospective Studies, Risk Factors, Time Factors, Transforming Growth Factor beta1, United States}, issn = {1097-6744}, doi = {10.1016/j.ahj.2014.01.010}, author = {Rosenberg, Michael A and Maziarz, Marlena and Tan, Alex Y and Glazer, Nicole L and Zieman, Susan J and Kizer, Jorge R and Ix, Joachim H and Djouss{\'e}, Luc and Siscovick, David S and Heckbert, Susan R and Mukamal, Kenneth J} } @article {6375, title = {Circulating levels of carboxy-methyl-lysine (CML) are associated with hip fracture risk: the Cardiovascular Health Study.}, journal = {J Bone Miner Res}, volume = {29}, year = {2014}, month = {2014}, pages = {1061-6}, abstract = {

Advanced glycation end products (AGE) in bone tissue are associated with impaired biomechanical properties and increased fracture risk. Here we examine whether serum levels of the AGE carboxy-methyl-lysine (CML) are associated with risk of hip fracture.We followed 3373 participants from the Cardiovascular Health Study (age 78 years; range, 68{\textendash}102 years; 39.8\% male) for a median of 9.22 years (range, 0.01{\textendash}12.07 years). Rates of incident hip fracture were calculated by quartiles of baseline CML levels, and hazard ratios were adjusted for covariates associated with hip fracture risk. A subcohort of 1315 participants had bone mineral density (BMD)measurement. There were 348 hip fractures during follow-up, with incidence rates of hip fracture by CML quartiles of 0.94, 1.34, 1.18, and 1.69 per 100 participant-years. The unadjusted hazard ratio of hip fracture increased with each 1 SD increase (189 ng/mL) of CML level (hazard ratio, 1.27; 95\% confidence interval [CI], 1.16{\textendash}1.40]; p<0.001). Sequential adjustment for age, gender, race/ethnicity,body mass index (BMI), smoking, alcohol consumption, prevalent coronary heart disease (CHD), energy expenditure, and estimated glomerular filtration rate (based on cystatin C), moderately attenuated the hazard ratio for fracture (1.17; 95\% CI, 1.05{\textendash}1.31; p=0.006).In the cohort with BMD testing, total hip BMD was not significantly associated with CML levels. We conclude that increasing levels of CML are associated with hip fracture risk in older adults, independent of hip BMD. These results implicate AGE in the pathogenesis of hip fractures.

}, keywords = {Age Factors, Aged, Female, Follow-Up Studies, Glycation End Products, Advanced, Hip Fractures, Humans, Incidence, Lysine, Male, Prospective Studies, Retrospective Studies, Risk Factors}, issn = {1523-4681}, author = {Barzilay, Joshua I and B{\r u}zkov{\'a}, Petra and Zieman, Susan J and Kizer, Jorge R and Djouss{\'e}, Luc and Ix, Joachim H and Tracy, Russell P and Siscovick, David S and Cauley, Jane A and Mukamal, Kenneth J} } @article {6737, title = {Changes in insulin-like growth factor-I and its binding proteins are associated with diabetes mellitus in older adults.}, journal = {J Am Geriatr Soc}, volume = {63}, year = {2015}, month = {2015 May}, pages = {902-9}, abstract = {

OBJECTIVES: To determine whether changes in insulin-like growth factor (IGF) protein levels are greater in participants with type 2 diabetes mellitus or worsening glycemia than in normoglycemic individuals over a 9-year follow-up period.

DESIGN: Retrospective analysis of a cohort study.

SETTING: Participants were recruited from North Carolina, California, Maryland, and Pennsylvania.

PARTICIPANTS: Cardiovascular Health Study All Stars participants, a cohort study of community-dwelling adults aged 65 and older (N=897).

MEASUREMENTS: Plasma IGF-I, IGF binding protein (IGFBP)-1, and IGFBP-3 levels were assessed and American Diabetes Association cut-points for impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and diabetes mellitus were used to classify participants at baseline (1996-97) and follow-up (2005-06).

RESULTS: At baseline, mean age was 76.3{\textpm}3.6, and 18.5\% had diabetes mellitus. Participants with IFG alone and IGT plus IFG had higher IGF-I levels and lower IGFBP-1 levels than those with normoglycemia or diabetes mellitus. The greatest percentage change in IGF levels occurred in those who had diabetes mellitus at baseline (9-year changes: -9.3\% for IGF-I, 59.7\% for IGFBP-1, -13.4\% for IGFBP-3), the smallest in individuals who remained normoglycemic at follow-up (9-year changes: -3.7\% for IGF-I, 25.6\% for IGFBP-1, -6.4\% for IGFBP-3), and intermediate in those who were normoglycemic but developed IFG at follow-up.

CONCLUSION: Degrees of glycemic impairment are associated with varying degrees of change in IGF protein levels. The changes observed in the diabetes mellitus group have been previously shown to be associated with heart failure, cancer, and noncancer mortality.

}, keywords = {Aged, Blood Glucose, Cohort Studies, Diabetes Mellitus, Type 2, Female, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Male, Retrospective Studies}, issn = {1532-5415}, doi = {10.1111/jgs.13390}, author = {Aneke-Nash, Chino S and Parrinello, Christina M and Rajpathak, Swapnil N and Rohan, Thomas E and Strotmeyer, Elsa S and Kritchevsky, Stephen B and Psaty, Bruce M and B{\r u}zkov{\'a}, Petra and Kizer, Jorge R and Newman, Anne B and Strickler, Howard D and Kaplan, Robert C} } @article {8486, title = {Characterization of cardiac mechanics and incident atrial fibrillation in participants of the Cardiovascular Health Study.}, journal = {JCI Insight}, volume = {5}, year = {2020}, month = {2020 Oct 02}, abstract = {

BACKGROUND: Left atrial (LA) and left ventricular (LV) remodeling are associated with atrial fibrillation (AF). The prospective associations of impairment in cardiac mechanical function, as assessed by speckle-tracking echocardiography, with incident AF are less clear.

METHODS: In the Cardiovascular Health Study, a community-based cohort of older adults, participants free of AF with echocardiograms of adequate quality for speckle tracking were included. We evaluated the associations of indices of cardiac mechanics (LA reservoir strain, LV longitudinal strain, and LV early diastolic strain rate) with incident AF.

RESULTS: Of 4341 participants with strain imaging, participants with lower LA reservoir strain were older, had more cardiometabolic risk factors, and had lower renal function at baseline. Over a median follow-up of 10 years, 497 (11.4\%) participants developed AF. Compared with the highest quartile of LA reservoir strain, the lowest quartile of LA reservoir strain was associated with higher risk of AF after covariate adjustment, including LA volume and LV longitudinal strain (heart rate [HR], 1.80; 95\% CI, 1.31-2.45; P < 0.001). The association of LA reservoir strain and AF was stronger in subgroups with higher blood pressure, NT-proBNP, and LA volumes. There were no associations of LV longitudinal strain and LV early diastolic strain rate with incident AF after adjustment for LA reservoir strain.

CONCLUSION: Lower LA reservoir strain was associated with incident AF, independent of LV mechanics, and with stronger associations in high-risk subgroups. These findings suggest that LA mechanical dysfunction precedes the development of AF. Therapies targeting LA mechanical dysfunction may prevent progression to AF.

FUNDING: This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grants KL2TR001424, R01HL107577, U01HL080295, and U01HL130114 from the NIH{\textquoteright}s National Center for Advancing Translational Sciences, and 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 National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org.

}, issn = {2379-3708}, doi = {10.1172/jci.insight.141656}, author = {Patel, Ravi B and Delaney, Joseph A and Hu, Mo and Patel, Harnish and Cheng, Jeanette and Gottdiener, John and Kizer, Jorge R and Marcus, Gregory M and Turakhia, Mintu P and Deo, Rajat and Heckbert, Susan R and Psaty, Bruce M and Shah, Sanjiv J} } @article {8787, title = {Cumulative burden of clinically significant aortic stenosis in community-dwelling older adults.}, journal = {Heart}, year = {2021}, month = {2021 Jun 02}, abstract = {

OBJECTIVES: Current estimates of aortic stenosis (AS) frequency have mostly relied on cross-sectional echocardiographic or longitudinal administrative data, making understanding of AS burden incomplete. We performed case adjudications to evaluate the frequency of AS and assess differences by age, sex and race in an older cohort with long-term follow-up.

METHODS: We developed case-capture methods using study echocardiograms, procedure and diagnosis codes, heart failure events and deaths for targeted review of medical records in the Cardiovascular Health Study to identify moderate or severe AS and related procedures or hospitalisations. The primary outcome was clinically significant AS (severe AS or procedure). Assessment of incident AS burden was based on subdistribution survival methods, while associations with age, sex and race relied on cause-specific survival methods.

RESULTS: The cohort comprised 5795 participants (age 73{\textpm}6, 42.2\% male, 14.3\% Black). Cumulative frequency of clinically significant AS at maximal 25-year follow-up was 3.69\% (probable/definite) to 4.67\% (possible/probable/definite), while the corresponding 20-year cumulative incidence was 2.88\% to 3.71\%. Of incident cases, about 85\% had a hospitalisation for severe AS, but roughly half did not undergo valve intervention. The adjusted incidence of clinically significant AS was higher in men (HR 1.62 [95\% CI 1.21 to 2.17]) and increased with age (HR 1.08 [95\% CI 1.04 to 1.11]), but was lower in Blacks (HR 0.43 [95\% CI 0.23 to 0.81]).

CONCLUSIONS: In this community-based study, we identified a higher burden of clinically significant AS than reported previously, with differences by age, sex and race. These findings have important implications for public health resource planning, although the lower burden in Blacks merits further study.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2021-319025}, author = {Owens, David S and Bartz, Traci M and B{\r u}zkov{\'a}, Petra and Massera, Daniele and Biggs, Mary L and Carlson, Selma D and Psaty, Bruce M and Sotoodehnia, Nona and Gottdiener, John S and Kizer, Jorge R} } @article {9256, title = {Circulating Androgen Concentrations and Risk of Incident Heart Failure in Older Men: The Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {11}, year = {2022}, month = {2022 Nov}, pages = {e026953}, abstract = {

Background Circulating androgen concentrations in men decline with age and have been linked to diabetes and atherosclerotic cardiovascular disease (ASCVD). A similar relationship has been reported for low total testosterone and incident heart failure (HF) but remains unstudied for free testosterone or the more potent androgen dihydrotestosterone (DHT). We hypothesized that total/free testosterone are inversely related, sex hormone-binding globulin is positively related, and total/free DHT bear a U-shaped relationship with incident HF. Methods and Results In a sample of men from the CHS (Cardiovascular Health Study) without atherosclerotic cardiovascular disease or HF, serum testosterone and DHT concentrations were measured by liquid chromatography-tandem mass spectrometry, and sex hormone-binding globulin by immunoassay. Free testosterone or DHT was calculated from total testosterone or total DHT, sex hormone-binding globulin, and albumin. We used Cox regression to estimate relative risks of HF after adjustment for potential confounders. In 1061 men (aged 76{\textpm}5 years) followed for a median of 9.6 years, there were 368 HF events. After adjustment, lower calculated free testosterone was significantly associated with higher risk of HF (hazard ratio [HR], 1.14 [95\% CI, 1.01-1.28]). Risk estimates for total testosterone (HR, 1.12 [95\% CI, 0.99-1.26]), total DHT (HR, 1.10 [95\% CI, 0.97-1.24]), calculated free dihydrotestosterone (HR, 1.09 [95\% CI, 0.97-1.23]), and sex hormone-binding globulin (HR, 1.07 [95\% CI, 0.95-1.21]) were directionally similar but not statistically significant. Conclusions Calculated free testosterone was inversely associated with incident HF, suggesting a contribution of testosterone deficiency to HF incidence among older men. Additional research is necessary to determine whether testosterone replacement therapy might be an effective strategy to lower HF risk in older men.

}, keywords = {Aged, Androgens, Cardiovascular Diseases, Dihydrotestosterone, Estradiol, Heart Failure, Humans, Male, Sex Hormone-Binding Globulin, Testosterone}, issn = {2047-9980}, doi = {10.1161/JAHA.122.026953}, author = {Njoroge, Joyce N and Tressel, William and Biggs, Mary L and Matsumoto, Alvin M and Smith, Nicholas L and Rosenberg, Emily and Hirsch, Calvin H and Gottdiener, John S and Mukamal, Kenneth J and Kizer, Jorge R} } @article {9320, title = {Cardiac Mechanics and Kidney Function Decline in the Cardiovascular Health Study.}, journal = {Kidney360}, year = {2023}, month = {2023 Mar 08}, abstract = {

BACKGROUND: Clinical heart failure frequently coexists with chronic kidney disease (CKD) and may precipitate kidney function decline. However, whether earlier-stage myocardial dysfunction assessable by speckle tracking echocardiography is a contributor to kidney function decline remains unknown.

METHODS: We studied 2135 Cardiovascular Health Study (CHS) participants who were free of clinical heart failure and had Year 2-baseline 2D speckle tracking echocardiography and two measurements of estimated glomerular filtration rate (eGFR) (Year 2 and Year 9). "Archival" speckle tracking of digitized echocardiogram videotapes was utilized to measure left ventricular longitudinal strain (LVLS), LV early diastolic strain rate (EDSR), left atrial reservoir strain (LARS), right ventricular free wall strain (RVFWS), and mitral annular velocity (e{\textquoteright}). Multivariable Poisson regression models that adjusted for demographics and cardiovascular risk factors were used to investigate the independent associations of cardiac mechanics indices and decline in kidney function defined as a 30\% decline in eGFR over 7 years.

RESULTS: In risk factor (RF) models LVLS, EDSR, RVFWS, and e{\textquoteright} were all significantly associated with the prevalence of kidney disease. After multivariable adjustment, left atrial dysfunction (RR 1.18 [95\% CI 1.01, 1.38] per SD lower LARS] and left ventricular diastolic dysfunction (RR 1.21 [95\% CI 1.04, 1.41] per SD lower EDSR) were each significantly associated with 30\% decline in eGFR.

CONCLUSIONS: Subclinical myocardial dysfunction suggesting abnormal diastolic function detected by 2D speckle-tracking echocardiography was independently associated with decline in kidney function over time. Further studies are needed to understand the mechanisms of these associations and to test whether interventions that may improve subclinical myocardial dysfunction can prevent decline of kidney function.

}, issn = {2641-7650}, doi = {10.34067/KID.0000000000000100}, author = {Mehta, Rupal and B{\r u}zkov{\'a}, Petra and Patel, Harnish and Cheng, Jeanette and Kizer, Jorge R and Gottdiener, John S and Psaty, Bruce and Khan, Sadiya S and Ix, Joachim H and Isakova, Tamara and Shlipak, Michael G and Bansal, Nisha and Shah, Sanjiv J} } @article {9481, title = {Circulating Growth Differentiation Factors 11 and 8, Their Antagonists Follistatin and Follistatin-like-3, and Risk of Heart Failure in Elders.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2023}, month = {2023 Aug 25}, 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 follistatin-like (FSTL)-3 by immunoassay, in two longitudinal cohorts of older adults.

RESULTS: In 2,599 participants (age 75.2{\textpm}4.3) followed for 10.8{\textpm}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.

}, issn = {1758-535X}, doi = {10.1093/gerona/glad206}, author = {Kizer, Jorge R and Patel, Sheena and Ganz, Peter and Newman, Anne B and Bhasin, Shalender and Lee, Se-Jin and Cawthon, Peggy M and LeBrasseur, Nathan and Shah, Sanjiv J and Psaty, Bruce M and Tracy, Russell P and Cummings, Steven R} } @article {9913, title = {Circulating non-esterified fatty acids, risk of dementia and cognitive decline: The cardiovascular health study and multi-ethnic study of atherosclerosis.}, journal = {Neurobiol Aging}, volume = {148}, year = {2025}, month = {2025 Apr}, pages = {71-79}, abstract = {

Circulating non-esterified fatty acids (NEFAs) have toxic effects on a variety of organs central to cardiometabolic disease and can cross the blood-brain barrier. Whether NEFAs associate with cognitive decline or dementia remains unknown. Circulating total NEFA levels were measured in 3242 participants without dementia among older adults of the Cardiovascular Health Study (CHS) and related to adjudicated dementia over 6 years (n = 456 cases) and annually assessed cognitive decline. For confirmation, we related circulating NEFAs to cognition assessed 10 years later among 4361 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). In CHS participants, each SD higher NEFA levels were associated with a hazard ratio (HR) for all-cause dementia of 1.11 (95 \% CI: 1.01; 1.22). Baseline NEFA levels were also associated with more rapid decline in cognition over 6 years of follow-up. In MESA, circulating NEFA measurements were associated with lower cognitive scores measured 10 years later.{\textquoteright}

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Cognition, Cognitive Dysfunction, Cohort Studies, Dementia, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Male, Middle Aged, Risk, Risk Factors}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2025.01.009}, author = {Moseholm, Kristine F and Jensen, Majken K and B{\r u}zkov{\'a}, Petra and Aroner, Sarah A and Fitzpatrick, Annette L and Longstreth, W T and Lopez, Oscar and Siscovick, David S and Kizer, Jorge R and Ix, Joachim H and Hughes, Timothy M and Hayden, Kathleen M and Nomura, Sarah and Tsai, Michael Y and McClelland, Robyn and Djouss{\'e}, Luc and Mukamal, Kenneth J} }