Dataset Information

Proteomic architecture of frailty across the spectrum of cardiovascular disease.

ABSTRACT: While frailty is a prominent risk factor in an aging population, the underlying biology of frailty is incompletely described. Here, we integrate 979 circulating proteins across a wide range of physiologies with 12 measures of frailty in a prospective discovery cohort of 809 individuals with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation. Our aim was to characterize the proteomic architecture of frailty in a highly susceptible population and study its relation to clinical outcome and systems-wide phenotypes to define potential novel, clinically relevant frailty biology. Proteomic signatures (specifically of physical function) were related to post-intervention outcome in AS, specifying pathways of innate immunity, cell growth/senescence, fibrosis/metabolism, and a host of proteins not widely described in human aging. In published cohorts, the "frailty proteome" displayed heterogeneous trajectories across age (20-100 years, age only explaining a small fraction of variance) and were associated with cardiac and non-cardiac phenotypes and outcomes across two broad validation cohorts (N > 35,000) over ≈2-3 decades. These findings suggest the importance of precision biomarkers of underlying multi-organ health status in age-related morbidity and frailty.

SUBMITTER: Perry AS

PROVIDER: S-EPMC10652351 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Proteomic architecture of frailty across the spectrum of cardiovascular disease.

Perry Andrew S AS Zhao Shilin S Gajjar Priya P Murthy Venkatesh L VL Lehallier Benoit B Miller Patricia P Nair Sangeeta S Neill Colin C Carr J Jeffrey JJ Fearon William W Kapadia Samir S Kumbhani Dharam D Gillam Linda L Lindenfeld JoAnn J Farrell Laurie L Marron Megan M MM Tian Qu Q Newman Anne B AB Murabito Joanne J Gerszten Robert E RE Nayor Matthew M Elmariah Sammy S Lindman Brian R BR Shah Ravi R

Aging cell 20230920 11

While frailty is a prominent risk factor in an aging population, the underlying biology of frailty is incompletely described. Here, we integrate 979 circulating proteins across a wide range of physiologies with 12 measures of frailty in a prospective discovery cohort of 809 individuals with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation. Our aim was to characterize the proteomic architecture of frailty in a highly susceptible population and study its relation to c ...[more]

PMID: 37731195

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Project description:BackgroundProspective cohort studies suggest that frailty is associated with an increased risk of incident cardiovascular disease (CVD) morbidity and mortality, but their mechanistic and developmental relations are not fully understood. We investigated whether frailty predicted an increased risk of incident nonfatal and fatal CVD among community-dwelling older adults.MethodsA population cohort of 5015 participants aged 55 years and above free of CVD at baseline was followed for up to 10 years. Pre-frailty and frailty were defined as the presence of 1-2 and 3-5 modified Fried criteria (unintentional weight loss, weakness, slow gait speed, exhaustion, and low physical activity), incident CVD events as newly diagnosed registered cases of myocardial infarction (MI), stroke, and CVD-related mortality (ICD 9: 390 to 459 or ICD-10: I00 to I99). Covariate measures included traditional cardio-metabolic and vascular risk factors, medication therapies, Geriatric Depression Scale (GDS), Mini-Mental State Exam (MMSE), and blood biomarkers (haemoglobin, albumin, white blood cell counts and creatinine).ResultsPre-frailty and frailty were significantly associated with elevated HR = 1.26 (95%CI: 1.02-1.56) and HR = 1.54 (95%CI:1.00-2.35) of overall CVD, adjusted for cardio-metabolic and vascular risk factors and medication therapies, but not after adjustment for GDS depression and MMSE cognitive impairment. The HR of association between frailty status and both CVD mortality and overall mortality, however, remained significantly elevated after full adjustment for depression, cognitive and blood biomarkers.ConclusionFrailty was associated with increased risk of CVD morbidity and especially mortality, mediated in parts by traditional cardio-metabolic and vascular risk factors, and co-morbid depression and associated cognitive impairment and chronic inflammation. Given that pre-frailty and frailty are reversible by multi-domain lifestyle and health interventions, there is potential benefits in reducing cardiovascular diseases burden and mortality from interventions targeting pre-frailty and early frailty population.

Project description:BackgroundInsulin resistance and diabetes are associated with an increased risk of frailty, and frailty is associated with cardiovascular disease and premature mortality. We aim to investigate the impact of long-term insulin resistance trajectories on future frailty and cardiovascular risk among young adults.MethodsIn total, 3168 participants with a 30-year follow-up period. The baseline period covered the first 15 years as the exposure period. Insulin resistance was determined using the homeostasis model assessment for insulin resistance (HOMA-IR), and three trajectories (low, moderate, and high) were constructed. The subsequent 15 years constituted the event accrual period. Frailty was assessed using a deficit accumulation mode, and cardiovascular outcomes were obtained from the 15-year event accrual period.ResultsThe mean age of all 3168 participants was 41.0 (37.0-43.0) years, with 1750 (55.2%) being women. Participants in the high level of insulin resistance trajectory had an increased prevalence of frailty (OR: 1.55, 95% CI: 1.05-2.30, P = 0.028). Although no statistically significant associations were observed after full adjustment, single-factor analysis indicated association between the moderate and high trajectories and frailty progression. Additionally, participants with high level of insulin resistance trajectory were associated with an increased risk of cardiovascular disease, coronary heart disease, and stroke. A notable correlation between HOMA-IR trajectory and cardiovascular diseases was still discernible within the subgroup where the frailty index ≥0.12 (HR: 2.12, 95% CI: 1.17-3.83, P = 0.013) (P for interaction >0.05).ConclusionsLong-term high level of insulin resistance is associated with high prevalence of frailty, and an increased risk of cardiovascular events. Emphasizing the importance of early prevention and intervention for abnormal glucose metabolism in young adults to prevent frailty and cardiovascular disease.

Dataset Information

Proteomic architecture of frailty across the spectrum of cardiovascular disease.

Publications

Proteomic architecture of frailty across the spectrum of cardiovascular disease.

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