Abstract 650 Epigenetic aging and global and regional DNA methylation in the development and progression of heart failure

Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w
Epigenetic aging and global and regional DNA methylation in the development and progression of heart failure
M. Krolevets¹, V. ten Cate¹, J. Prochaska², A. Schulz¹, S. Rapp¹, S. Horvath³, C. Niehrs⁴, P. S. Wild¹
¹Präventive Kardiologie und Medizinische Prävention, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; ²Zentrum für Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; ³Altos labs, San Diego, US; ⁴DNA Demethylation, DNA Repair and Reprogramming, Institute of Molecular Biology (IMB), Mainz;
Introduction: Heart failure (HF) is a disease with severe morbidity and poor prognosis. The role of DNA methylation (DNAm) in the progression of heart failure is unclear. We investigated the importance of global and regional DNAm and epigenetic aging in the development and progression of HF. Methods: Individuals with symptomatic HF (stage C/D) of the MyoVasc cohort (N=3,289; NCT04064450) and individuals without cardiovascular disease (CVD) from a population-based cohort (Gutenberg Health Study, N=15,010) were investigated. DNA was extracted from peripheral blood and stored in -80°C. DNAm was measured using the Infinium EPIC 850k methylation array (San Diego, USA). Data were preprocessed using the CHAMP pipeline. Batch effects were removed using the ComBat method. Epigenetic age was modeled with established clocks GrimAge and Hannum. Multivariable regression models were used to assess the relationship between DNAm and presence and severity of HF, premature aging (residual epigenetic aging clock-predicted age after adjusting for calendar age) and clinical outcome, adjusting for traditional cardiovascular risk factors. Depending on the dependent variable, Poisson regression with robust covariance estimators, linear regression or Cox regression were used. Differences between chromosomes were investigated using coefficient of variation (CV). Interaction analysis was performed using individual regression models. Results: Data from 1,002 individuals with symptomatic HF and 702 CVD-free individuals were analyzed. Global demethylation was observed in HF (Prevalence Ratio, PR=1.51 [1.29-1.75], p=1.2×10-7), which was consistent across HF phenotypes. Compared to CVD-free individuals, HF patients were 20 [95% bootstrap CI: 13-26] years ‘older’ in terms of global methylation (methylation-predicted age). Premature aging derived from GrimAge is significantly associated with all cause death (HR=1.66 [1.42-1.95], p=3.79×10-10;) and worsening of heart failure (HR=1.56 [1.33-1.83], p=3.804×10-8); Residual epigenetic age (GrimAge) was higher with greater NT-proBNP levels, i.e. severity of HF (estimate: 0.29, p=0.038). Global DNAm was inversely related to all-cause death (HR=1.28 [1.12-1.47], p=0.0003). Chromosome 19 had the lowest coefficient of variation (0.075) and chr 21 the highest (0.092). Chr 19 showed higher difference in CV with chromosomes 1, 2, 3 and 9, while other chromosomes showed virtually no difference to each other. Region-specifically, differences in methylation were most discriminatory for HF in shore regions (i.e., those adjacent to CpG islands, PR=1.09 [1.06-1.13], p=4.6×10−8), and least in CpG islands (PR=1.03, [1.00-1.06], p=0.03). Among gene regions, methylation in TSS1500 (OR=0.6, [0.51-0.71], p=9.5×10-8) and 5’UTR (OR=0.61, [0.52-0.72], p=5×5-7) was most discriminative for HF while methylation in the 1st Exon (PR=1.04, [1.01-1.07], p=0.004) was least discriminative. Methylation in CpG islands significantly interacted with all 3 other regions (all p<0.003), positively contributing to the probability of HF, while these regions did not interact with each other. Conclusion: Global demethylation and accelerated aging are related to the severity and clinical outcome of individuals with HF across phenotypes. Marked differences of DNAm in HF by gene region and localization were detected, which should be investigated in future studies, particularly with regard to relevance to disease development and progression. Results: Data from 1,002 individuals with symptomatic HF and 702 CVD-free individuals were analyzed. Global demethylation was observed in HF (Prevalence Ratio, PR=1.51 [1.29-1.75], p=1.2×10-7), which was consistent across HF phenotypes. Compared to CVD-free individuals, HF patients were 20 [95% bootstrap CI: 13-26] years ‘older’ in terms of global methylation (methylation-predicted age). Premature aging derived from GrimAge is significantly associated with all cause death (HR=1.66 [1.42-1.95], p=3.79×10-10;) and worsening of heart failure (HR=1.56 [1.33-1.83], p=3.804×10-8); Residual epigenetic age (GrimAge) was higher with greater NT-proBNP levels, i.e. severity of HF (estimate: 0.29, p=0.038). Global DNAm was inversely related to all-cause death (HR=1.28 [1.12-1.47], p=0.0003). Chromosome 19 had the lowest coefficient of variation (0.075) and chr 21 the highest (0.092). Chr 19 showed higher difference in CV with chromosomes 1, 2, 3 and 9, while other chromosomes showed virtually no difference to each other. Region-specifically, differences in methylation were most discriminatory for HF in shore regions (i.e., those adjacent to CpG islands, PR=1.09 [1.06-1.13], p=4.6×10−8), and least in CpG islands (PR=1.03, [1.00-1.06], p=0.03). Among gene regions, methylation in TSS1500 (OR=0.6, [0.51-0.71], p=9.5×10-8) and 5’UTR (OR=0.61, [0.52-0.72], p=5×5-7) was most discriminative for HF while methylation in the 1st Exon (PR=1.04, [1.01-1.07], p=0.004) was least discriminative. Methylation in CpG islands significantly interacted with all 3 other regions (all p<0.003), positively contributing to the probability of HF, while these regions did not interact with each other. Conclusion: Global demethylation and accelerated aging are related to the severity and clinical outcome of individuals with HF across phenotypes. Marked differences of DNAm in HF by gene region and localization
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