02821nas a2200289 4500008004100000022001400041245010000055210006900155260001600224520195600240100001602196700002202212700002502234700001802259700002002277700002302297700001802320700002302338700001702361700002002378700002102398700001802419700001802437700001802455700002202473856003602495 2023 eng d a1474-972600aLate-life plasma proteins associated with prevalent and incident frailty: A proteomic analysis.0 aLatelife plasma proteins associated with prevalent and incident  c2023 Sep 113 a

Proteomic approaches have unique advantages in the identification of biological pathways that influence physical frailty, a multifactorial geriatric syndrome predictive of adverse health outcomes in older adults. To date, proteomic studies of frailty are scarce, and few evaluated prefrailty as a separate state or examined predictors of incident frailty. Using plasma proteins measured by 4955 SOMAmers in the Atherosclerosis Risk in Community study, we identified 134 and 179 proteins cross-sectionally associated with prefrailty and frailty, respectively, after Bonferroni correction (p < 1 × 10 ) among 3838 older adults aged ≥65 years, adjusting for demographic and physiologic factors and chronic diseases. Among them, 23 (17%) and 82 (46%) were replicated in the Cardiovascular Health Study using the same models (FDR p < 0.05). Notably, higher odds of prefrailty and frailty were observed with higher levels of growth differentiation factor 15 (GDF15; p  = 1 × 10 , p  = 2 × 10 ), transgelin (TAGLN; p  = 2 × 10 , p  = 6 × 10 ), and insulin-like growth factor-binding protein 2 (IGFBP2; p  = 5 × 10 , p  = 1 × 10 ) and with a lower level of growth hormone receptor (GHR, p  = 3 × 10 , p  = 2 × 10 ). Longitudinally, we identified 4 proteins associated with incident frailty (p < 1 × 10 ). Higher levels of triggering receptor expressed on myeloid cells 1 (TREM1), TAGLN, and heart and adipocyte fatty-acid binding proteins predicted incident frailty. Differentially regulated proteins were enriched in pathways and upstream regulators related to lipid metabolism, angiogenesis, inflammation, and cell senescence. Our findings provide a set of plasma proteins and biological mechanisms that were dysregulated in both the prodromal and the clinical stage of frailty, offering new insights into frailty etiology and targets for intervention.

1 aLiu, Fangyu1 aAustin, Thomas, R1 aSchrack, Jennifer, A1 aChen, Jingsha1 aWalston, Jeremy1 aMathias, Rasika, A1 aGrams, Morgan1 aOdden, Michelle, C1 aNewman, Anne1 aPsaty, Bruce, M1 aRamonfaur, Diego1 aShah, Amil, M1 aWindham, Gwen1 aCoresh, Josef1 aWalker, Keenan, A uhttps://chs-nhlbi.org/node/948304295nas a2200529 4500008004100000022001400041245009000055210006900145260001600214300001200230490000600242520289400248653000903142653001503151653001103166653001203177653001803189653001103207653001403218653000903232653001603241653001503257653001703272100002103289700002003310700002103330700001603351700002303367700002303390700002203413700001903435700002303454700002003477700003103497700001903528700002003547700002003567700002003587700002203607700001603629700001803645700001703663700001803680700001303698700001803711856003603729 2024 eng d a2380-659100aHigh Throughput Plasma Proteomics and Risk of Heart Failure and Frailty in Late Life.0 aHigh Throughput Plasma Proteomics and Risk of Heart Failure and  c2024 Jul 01 a649-6580 v93 a

IMPORTANCE: Heart failure (HF) and frailty frequently coexist and may share a common pathobiology, although the underlying mechanisms remain unclear. Understanding these mechanisms may provide guidance for preventing and treating both conditions.

OBJECTIVE: To identify shared pathways between incident HF and frailty in late life using large-scale proteomics.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, 4877 aptamers (Somascan v4) were measured among participants in the community-based longitudinal Atherosclerosis Risk In Communities (ARIC) cohort study at visit 3 (V3; 1993-1995; n = 10 638) and at visit 5 (V5; 2011-2013; n = 3908). Analyses were externally replicated among 3189 participants in the Cardiovascular Health Study (CHS). Data analysis was conducted from February 2022 to June 2023.

EXPOSURES: Protein aptamers, measured at study V3 and V5.

MAIN OUTCOMES AND MEASURES: Outcomes assessed included incident HF hospitalization after V3 and after V5, prevalent frailty at V5, and incident frailty between V5 and visit 6 (V6; 2016-2017; n = 4131). Frailty was assessed using the Fried criteria. Analyses were adjusted for age, gender, race, field center, hypertension, diabetes, smoking status, body mass index, estimated glomerular filtration rate, prevalent coronary heart disease, prevalent atrial fibrillation, and history of myocardial infarction. Mendelian randomization (MR) analysis was performed to assess potential causal effects of candidate proteins on HF and frailty.

RESULTS: A total of 4877 protein aptamers were measured among 10 638 participants at V3 (mean [SD] age, 60 [6] years; 4886 [46%] men). Overall, 286 proteins were associated with incident HF after V3 (822 events; P < 1.0 × 10-5), 83 of which were also associated with incident after V5 (336 events; P < 1.7 × 10-4). Among HF-free participants at V5 (n = 3908; mean [SD] age, 75 [5] years; 1861 [42%] men), 48 of 83 HF-associated proteins were associated with prevalent frailty (223 cases; P < 6.0 × 10-4), 18 of which were also associated with incident frailty at V6 (152 cases; P < 1.0 × 10-3). These proteins enriched fibrosis and inflammation pathways and demonstrated stronger associations with incident HF with preserved ejection fraction (HFpEF) than HF with reduced ejection fraction. All 18 proteins were associated with both prevalent frailty and incident HF in CHS. MR identified potential causal effects of several proteins on frailty and HF.

CONCLUSIONS AND RELEVANCE: In this study, the proteins associated with risk of HF and frailty enrich for pathways related to inflammation and fibrosis as well as risk of HFpEF. Several of these proteins could potentially contribute to the shared pathophysiology of frailty and HF.

10aAged10aBiomarkers10aFemale10aFrailty10aHeart Failure10aHumans10aIncidence10aMale10aMiddle Aged10aProteomics10aRisk Factors1 aRamonfaur, Diego1 aBuckley, Leo, F1 aArthur, Victoria1 aYang, Yimin1 aClaggett, Brian, L1 aNdumele, Chiadi, E1 aWalker, Keenan, A1 aAustin, Thomas1 aOdden, Michelle, C1 aFloyd, James, S1 avan Wijk, Sandra, Sanders-1 aNjoroge, Joyce1 aKizer, Jorge, R1 aKitzman, Dalane1 aKonety, Suma, H1 aSchrack, Jennifer1 aLiu, Fangyu1 aWindham, Gwen1 aPalta, Priya1 aCoresh, Josef1 aYu, Bing1 aShah, Amil, M uhttps://chs-nhlbi.org/node/9705