Abstract 12721: Myocardial DNA Damage Predicts Heart Failure Outcome in Various Underlying Diseases
Zhehao Dai, Toshiyuki Ko, Seitaro Nomura, Kanna Fujita, Shunsuke Inoue, Kenji Onoue, Eisuke Amiya, Masaru Hatano, Norifumi Takeda, Hiroyuki Morita, Yoshihiko Saito, Issei Komuro- Physiology (medical)
- Cardiology and Cardiovascular Medicine
Background: Responses to treatment for heart failure vary widely, and a reliable predictor has been long awaited.
Aims: To investigate the relationship between DNA damage in myocardial tissue and treatment response and prognosis of heart failure.
Methods: In this multicenter cohort study including patients with heart failure with reduced ejection fraction (HFrEF) of various underlying etiologies, we performed immunostaining of DNA damage markers, poly(ADP-ribose) (PAR) and γ-H2A.X on endomyocardial biopsy specimens. We calculated the percentage of nuclei positive for each DNA damage marker as %PAR and %γ-H2A.X. The primary outcome was left ventricular reverse remodeling (LVRR) at 1 year, and the secondary outcome was a composite of cardiac death, heart transplantation, and ventricular assist device implant. Inverse probability weighted method was used to restore the balance of baseline variables.
Results: Of the 175 included patients with a mean age at 56 years and a median follow-up of 1213 days, 72% were male, and 55% achieved LVRR. A lower DNA damage marker positivity was associated with a higher probability of achieving LVRR [OR per 10 increase in %PAR 0.07 (95%CI 0.03–0.17); OR per 10 increase in % γ-H2A.X 0.40 (95%CI 0.29–0.55)]. There was a negative correlation between the average degree of DNA damage and the probability of LVRR, across different underlying diseases. Patients with higher %PAR or %γ-H2A.X had more long-term clinical events [HR per 10 increase in %PAR 1.63 (95%CI 1.31-2.01); HR per 10 increase in %γ-H2A.X, 1.48 (1.27-1.72)]. Of the 41 patients who consented on whole exome sequencing, those with non-sarcomere gene mutations (LMNA, etc; 10 patients) had a higher degree of DNA damage than those with sarcomere gene mutations (TTN, etc; 4 patients).
Conclusions: DNA damage determines the consequences of heart failure. Assessment of DNA damage is useful to predict treatment efficacy and prognosis of patients with HFrEF of various underlying etiologies.