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The association of accelerated epigenetic age with all-cause mortality in cardiac catheterization patients as mediated by vascular and cardiometabolic outcomes.

Publication ,  Journal Article
Jiang, R; Hauser, ER; Kwee, LC; Shah, SH; Regan, JA; Huebner, JL; Kraus, VB; Kraus, WE; Ward-Caviness, CK
Published in: Clin Epigenetics
December 3, 2022

BACKGROUND: Epigenetic age is a DNA methylation-based biomarker of aging that is accurate across the lifespan and a range of cell types. The difference between epigenetic age and chronological age, termed age acceleration (AA), is a strong predictor of lifespan and healthspan. The predictive capabilities of AA for all-cause mortality have been evaluated in the general population; however, its utility is less well evaluated in those with chronic conditions. Additionally, the pathophysiologic pathways whereby AA predicts mortality are unclear. We hypothesized that AA predicts mortality in individuals with underlying cardiovascular disease; and the association between AA and mortality is mediated, in part, by vascular and cardiometabolic measures. METHODS: We evaluated 562 participants in an urban, three-county area of central North Carolina from the CATHGEN cohort, all of whom received a cardiac catheterization procedure. We analyzed three AA biomarkers, Horvath epigenetic age acceleration (HAA), phenotypic age acceleration (PhenoAA), and Grim age acceleration (GrimAA), by Cox regression models, to assess whether AAs were associated with all-cause mortality. We also evaluated if these associations were mediated by vascular and cardiometabolic outcomes, including left ventricular ejection fraction (LVEF), blood cholesterol concentrations, angiopoietin-2 (ANG2) protein concentration, peripheral artery disease, coronary artery disease, diabetes, and hypertension. The total effect, direct effect, indirect effect, and percentage mediated were estimated using pathway mediation tests with a regression adjustment approach. RESULTS: PhenoAA (HR = 1.05, P < 0.0001), GrimAA (HR = 1.10, P < 0.0001) and HAA (HR = 1.03, P = 0.01) were all associated with all-cause mortality. The association of mortality and PhenoAA was partially mediated by ANG2, a marker of vascular function (19.8%, P = 0.016), and by diabetes (8.2%, P = 0.043). The GrimAA-mortality association was mediated by ANG2 (12.3%, P = 0.014), and showed weaker evidence for mediation by LVEF (5.3%, P = 0.065). CONCLUSIONS: Epigenetic age acceleration remains strongly predictive of mortality even in individuals already burdened with cardiovascular disease. Mortality associations were mediated by ANG2, which regulates endothelial permeability and angiogenic functions, suggesting that specific vascular pathophysiology may link accelerated epigenetic aging with increased mortality risks.

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Published In

Clin Epigenetics

DOI

EISSN

1868-7083

Publication Date

December 3, 2022

Volume

14

Issue

1

Start / End Page

165

Location

Germany

Related Subject Headings

  • Ventricular Function, Left
  • Stroke Volume
  • Humans
  • Epigenesis, Genetic
  • DNA Methylation
  • Cardiovascular Diseases
  • Cardiac Catheterization
  • 3105 Genetics
  • 1114 Paediatrics and Reproductive Medicine
  • 1103 Clinical Sciences
 

Citation

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Jiang, R., Hauser, E. R., Kwee, L. C., Shah, S. H., Regan, J. A., Huebner, J. L., … Ward-Caviness, C. K. (2022). The association of accelerated epigenetic age with all-cause mortality in cardiac catheterization patients as mediated by vascular and cardiometabolic outcomes. Clin Epigenetics, 14(1), 165. https://doi.org/10.1186/s13148-022-01380-x
Jiang, Rong, Elizabeth R. Hauser, Lydia Coulter Kwee, Svati H. Shah, Jessica A. Regan, Janet L. Huebner, Virginia B. Kraus, William E. Kraus, and Cavin K. Ward-Caviness. “The association of accelerated epigenetic age with all-cause mortality in cardiac catheterization patients as mediated by vascular and cardiometabolic outcomes.Clin Epigenetics 14, no. 1 (December 3, 2022): 165. https://doi.org/10.1186/s13148-022-01380-x.
Jiang R, Hauser ER, Kwee LC, Shah SH, Regan JA, Huebner JL, et al. The association of accelerated epigenetic age with all-cause mortality in cardiac catheterization patients as mediated by vascular and cardiometabolic outcomes. Clin Epigenetics. 2022 Dec 3;14(1):165.
Jiang, Rong, et al. “The association of accelerated epigenetic age with all-cause mortality in cardiac catheterization patients as mediated by vascular and cardiometabolic outcomes.Clin Epigenetics, vol. 14, no. 1, Dec. 2022, p. 165. Pubmed, doi:10.1186/s13148-022-01380-x.
Jiang R, Hauser ER, Kwee LC, Shah SH, Regan JA, Huebner JL, Kraus VB, Kraus WE, Ward-Caviness CK. The association of accelerated epigenetic age with all-cause mortality in cardiac catheterization patients as mediated by vascular and cardiometabolic outcomes. Clin Epigenetics. 2022 Dec 3;14(1):165.
Journal cover image

Published In

Clin Epigenetics

DOI

EISSN

1868-7083

Publication Date

December 3, 2022

Volume

14

Issue

1

Start / End Page

165

Location

Germany

Related Subject Headings

  • Ventricular Function, Left
  • Stroke Volume
  • Humans
  • Epigenesis, Genetic
  • DNA Methylation
  • Cardiovascular Diseases
  • Cardiac Catheterization
  • 3105 Genetics
  • 1114 Paediatrics and Reproductive Medicine
  • 1103 Clinical Sciences