Epigenetic age acceleration is not strongly associated with cardiorespiratory fitness in heart failure: a pilot study

Background In heart failure (HF), standard measures such as left ventricular ejection fraction and cardiopulmonary exercise testing incompletely capture interindividual differences in disease status or prognosis. DNA methylation (DNAm) epigenetic clocks, which estimate biological age and epigenetic age acceleration (EAA), may provide complementary insight into cardiorespiratory fitness and systemic aging in HF.Research design and methods We analyzed peripheral blood DNAm from fourteen patients enrolled in REDHART2, a clinical trial of interleukin-1 blockade following hospitalization for acute systolic HF. Genome-wide DNAm was assayed using Illumina EPIC arrays and several clocks were applied to these data. Associations between biological age or EAA and cardiorespiratory fitness measures, inflammatory markers, and clinical parameters were evaluated.Results All epigenetic clocks demonstrated moderate to strong correlations with chronological age. Biological age was consistently associated with measures of cardiorespiratory fitness, particularly oxygen consumption normalized to fat free mass (VO2_FFM). However, chronological age showed similar associations, and biological age did not significantly improve prediction of VO2 parameters beyond chronological age alone. EAA was not significantly associated with cardiorespiratory fitness for any clock.Conclusions In this pilot study, neither biological age nor EAA provided significant predictive value beyond chronological age for cardiorespiratory fitness in patients with HF.Clinical trial registration number NCT03797001