Epigenetic signatures of biological vulnerability and residual risk in heart failure
- 1Cardiology Department, University Hospital Basel
Abstract
BackgroundDNA methylation (DNAm) signatures capture cumulative lifestyle exposures and biological aging. This prospective study evaluated whether DNAm-based scores and epigenetic aging clocks are associated with clinical outcomes and mortality in a multinational cohort of patients with heart failure (HF).
MethodsWe studied 2,594 patients with HF from 40 countries in the Global Congestive Heart Failure (G-CHF) registry with whole-blood DNAm data. Fifteen published DNAm-based scores and epigenetic aging clocks reflecting lifestyle, environmental and physiological exposures, inflammation, frailty, mortality risk, and biological aging were derived. Associations with HF hospitalization, cardiovascular death, and all-cause death were assessed using multivariable Cox regression adjusted for age, sex, ancestry, the MAGGIC risk score, and NT-proBNP. Incremental prognostic value was compared to MAGGIC score and NT-proBNP. Extreme DNAm profiles were defined as scores or clocks exceeding {+/-}1.5 standard deviations (s.d.) from the population mean.
ResultsMean age was 62.7{+/-}14.0 years, 66.2% were male, and mean left ventricular ejection fraction was 40.1{+/-}14.1%. During a median follow-up of 3.0 years, 338 patients were hospitalized for HF, 349 died from cardiovascular causes, and 565 died from any cause. Higher epigenetic age and DNAm scores for CRP, frailty, and mortality were associated with increased risk, whereas higher diet-related DNAm scores were inversely associated. For all-cause death, adjusted hazard ratios per 1-s.d. were 1.36 (95% CI, 1.24-1.50) for GrimAge, 1.27 (95% CI, 1.17-1.38) for the DNAm score for CRP, 1.44 (95% CI, 1.28-1.63) for the DNAm score for frailty, and 1.48 (95% CI, 1.32-1.65) for the DNAm score for mortality, compared with 0.81 (95% CI, 0.75-0.88) and 0.86 (95% CI, 0.79-0.94) for the DNAm scores for Alternative Healthy Eating Index and Mediterranean Diet Score. These patterns were directionally consistent for cardiovascular death and weaker for HF hospitalization and were more pronounced among patients with lower clinical risk (MAGGIC<17, Pinteraction<0.05), particularly for all-cause death. Patients with 4-5 extreme-high DNAm scores or clocks had more than twice the risk of death (HR, 2.27; 95% CI, 1.65-3.13).
ConclusionsDNAm-based scores and epigenetic aging clocks reflect multiple dimensions of biological vulnerability in HF and are associated with clinical outcomes and mortality beyond clinical risk factors.
Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIIn 2,594 patients with heart failure (HF) from 40 countries, blood-based DNA methylation (DNAm) scores for inflammation, frailty, and mortality, as well as epigenetic aging measures, were associated with mortality and other clinical outcomes after adjustment for established risk factors and NT-proBNP. C_LIO_LIThese associations were stronger among patients with lower clinical risk, suggesting that epigenetic signatures may capture biological vulnerability not fully reflected by conventional risk assessment. C_LIO_LIA greater accumulation of adverse epigenetic signatures was associated with progressively higher mortality risk; each additional extreme-high DNAm score or aging clock was associated with an 18% higher risk of death. C_LI
What are the clinical implications?O_LIDNA methylation may complement conventional clinical risk assessment by identifying biological vulnerability beyond established clinical risk factors. C_LIO_LIMultidimensional epigenetic profiling may provide a framework for molecular phenotyping of HF and for identifying patients with residual biological risk who may warrant further investigation. C_LI
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BibTeX
@misc{meyre2026epigenetic,
title = {{Epigenetic signatures of biological vulnerability and residual risk in heart failure}},
author = {P. B. Meyre and M. Chong and E. Shemesh and S. Mao and S. Narula and A. Roy and K. M. Karaye and G. Ertl and L. M. Mielniczuk and S. K. Sharma and B. Mohan and F. Lanas and T. Wittlinger and A. Celik and J. Abdullakutty and J. Nunez and O. S. Ogah and N. Jathappa and A. Budaj and A. P. Maggioni and J. Rouleau and K. Balasubramanian and T. McCready and A. Grinvalds and D. Leong and P. Joseph and S. Yusuf and G. Pare},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.01.26361996},
url = {https://www.medrxiv.org/content/10.64898/2026.09.01.26361996v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Epigenetic signatures of biological vulnerability and residual risk in heart failure
AU - P. B. Meyre
AU - M. Chong
AU - E. Shemesh
AU - S. Mao
AU - S. Narula
AU - A. Roy
AU - K. M. Karaye
AU - G. Ertl
AU - L. M. Mielniczuk
AU - S. K. Sharma
AU - B. Mohan
AU - F. Lanas
AU - T. Wittlinger
AU - A. Celik
AU - J. Abdullakutty
AU - J. Nunez
AU - O. S. Ogah
AU - N. Jathappa
AU - A. Budaj
AU - A. P. Maggioni
AU - J. Rouleau
AU - K. Balasubramanian
AU - T. McCready
AU - A. Grinvalds
AU - D. Leong
AU - P. Joseph
AU - S. Yusuf
AU - G. Pare
PY - 2026
DA - 2026/09/01
PB - medRxiv
DO - 10.64898/2026.09.01.26361996
UR - https://www.medrxiv.org/content/10.64898/2026.09.01.26361996v1
AB - BackgroundDNA methylation (DNAm) signatures capture cumulative lifestyle exposures and biological aging. This prospective study evaluated whether DNAm-based scores and epigenetic aging clocks are associated with clinical outcomes and mortality in a multinational cohort of patients with heart failure (HF). MethodsWe studied 2,594 patients with HF from 40 countries in the Global Congestive Heart Failure (G-CHF) registry with whole-blood DNAm data. Fifteen published DNAm-based scores and epigenetic aging clocks reflecting lifestyle, environmental and physiological exposures, inflammation, frailty, mortality risk, and biological aging were derived. Associations with HF hospitalization, cardiovascular death, and all-cause death were assessed using multivariable Cox regression adjusted for age, sex, ancestry, the MAGGIC risk score, and NT-proBNP. Incremental prognostic value was compared to MAGGIC score and NT-proBNP. Extreme DNAm profiles were defined as scores or clocks exceeding {+/-}1.5 standard deviations (s.d.) from the population mean. ResultsMean age was 62.7{+/-}14.0 years, 66.2% were male, and mean left ventricular ejection fraction was 40.1{+/-}14.1%. During a median follow-up of 3.0 years, 338 patients were hospitalized for HF, 349 died from cardiovascular causes, and 565 died from any cause. Higher epigenetic age and DNAm scores for CRP, frailty, and mortality were associated with increased risk, whereas higher diet-related DNAm scores were inversely associated. For all-cause death, adjusted hazard ratios per 1-s.d. were 1.36 (95% CI, 1.24-1.50) for GrimAge, 1.27 (95% CI, 1.17-1.38) for the DNAm score for CRP, 1.44 (95% CI, 1.28-1.63) for the DNAm score for frailty, and 1.48 (95% CI, 1.32-1.65) for the DNAm score for mortality, compared with 0.81 (95% CI, 0.75-0.88) and 0.86 (95% CI, 0.79-0.94) for the DNAm scores for Alternative Healthy Eating Index and Mediterranean Diet Score. These patterns were directionally consistent for cardiovascular death and weaker for HF hospitalization and were more pronounced among patients with lower clinical risk (MAGGIC<17, Pinteraction<0.05), particularly for all-cause death. Patients with 4-5 extreme-high DNAm scores or clocks had more than twice the risk of death (HR, 2.27; 95% CI, 1.65-3.13). ConclusionsDNAm-based scores and epigenetic aging clocks reflect multiple dimensions of biological vulnerability in HF and are associated with clinical outcomes and mortality beyond clinical risk factors. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIIn 2,594 patients with heart failure (HF) from 40 countries, blood-based DNA methylation (DNAm) scores for inflammation, frailty, and mortality, as well as epigenetic aging measures, were associated with mortality and other clinical outcomes after adjustment for established risk factors and NT-proBNP. C_LIO_LIThese associations were stronger among patients with lower clinical risk, suggesting that epigenetic signatures may capture biological vulnerability not fully reflected by conventional risk assessment. C_LIO_LIA greater accumulation of adverse epigenetic signatures was associated with progressively higher mortality risk; each additional extreme-high DNAm score or aging clock was associated with an 18% higher risk of death. C_LI What are the clinical implications?O_LIDNA methylation may complement conventional clinical risk assessment by identifying biological vulnerability beyond established clinical risk factors. C_LIO_LIMultidimensional epigenetic profiling may provide a framework for molecular phenotyping of HF and for identifying patients with residual biological risk who may warrant further investigation. C_LI
ER -