Myocardial DNA Damage Predicts Heart Failure Outcome in Various Underlying Diseases

Zhehao Dai; Toshiyuki Ko; Kanna Fujita; Seitaro Nomura; Yukari Uemura; Kenji Onoue; Momoko Hamano; Manami Katoh; Shintaro Yamada; Mikako Katagiri; Bo Zhang; Satoshi Hatsuse; Takanobu Yamada; Shunsuke Inoue; Masayuki Kubota; Kosuke Sawami; Tuolisi Heryed; Masamichi Ito; Eisuke Amiya; Masaru Hatano; Norifumi Takeda; Hiroyuki Morita; Yoshihiro Yamanishi; Yoshihiko Saito; Issei Komuro

doi:10.1016/j.jchf.2023.09.027

Myocardial DNA Damage Predicts Heart Failure Outcome in Various Underlying Diseases

JACC Heart Fail. 2024 Apr;12(4):648-661. doi: 10.1016/j.jchf.2023.09.027. Epub 2023 Nov 6.

Authors

Zhehao Dai¹, Toshiyuki Ko², Kanna Fujita³, Seitaro Nomura⁴, Yukari Uemura⁵, Kenji Onoue⁶, Momoko Hamano⁷, Manami Katoh³, Shintaro Yamada³, Mikako Katagiri³, Bo Zhang³, Satoshi Hatsuse³, Takanobu Yamada³, Shunsuke Inoue³, Masayuki Kubota³, Kosuke Sawami³, Tuolisi Heryed³, Masamichi Ito³, Eisuke Amiya², Masaru Hatano⁸, Norifumi Takeda³, Hiroyuki Morita³, Yoshihiro Yamanishi⁹, Yoshihiko Saito¹⁰, Issei Komuro¹¹

Affiliations

¹ Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Electronic address: https://twitter.com/ZhehaoDai_Cards.
² Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Department of Therapeutic Strategy for Heart Failure, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
³ Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
⁴ Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Department of Frontier Cardiovascular Science, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Electronic address: senomura-cib@umin.ac.jp.
⁵ Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan.
⁶ Department of Cardiovascular Medicine, Nara Medical University, Kashihara, Japan.
⁷ Department of Bioscience and Bioinformatics, Faculty of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka, Japan.
⁸ Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Advanced Medical Center for Heart Failure, University of Tokyo Hospital, Tokyo, Japan.
⁹ Department of Bioscience and Bioinformatics, Faculty of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka, Japan; Department of Complex Systems Science, Graduate School of Informatics, Nagoya University, Nagoya, Japan.
¹⁰ Department of Cardiovascular Medicine, Nara Medical University, Kashihara, Japan; Nara Prefectural Seiwa Medical Center, Nara Prefectural Hospital Organization, Nara, Japan.
¹¹ Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Department of Frontier Cardiovascular Science, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; International University of Health and Welfare, Tokyo, Japan. Electronic address: komuro-tky@umin.ac.jp.

PMID: 37930291
DOI: 10.1016/j.jchf.2023.09.027

Abstract

Background: Reliable predictors of treatment efficacy in heart failure have been long awaited. DNA damage has been implicated as a cause of heart failure.

Objectives: The purpose of this study was to investigate the association of DNA damage in myocardial tissue with treatment response and prognosis of heart failure.

Methods: The authors performed immunostaining of DNA damage markers poly(ADP-ribose) (PAR) and γ-H2A.X in endomyocardial biopsy specimens from 175 patients with heart failure with reduced ejection fraction (HFrEF) of various underlying etiologies. They calculated the percentage of nuclei positive for each DNA damage marker (%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 cardiovascular death, heart transplantation, and ventricular assist device implantation.

Results: Patients who did not achieve LVRR after the optimization of medical therapies presented with significantly higher %PAR and %γ-H2A.X. The ROC analysis demonstrated good performance of both %PAR and %γ-H2A.X for predicting LVRR (AUCs: 0.867 and 0.855, respectively). There was a negative correlation between the mean proportion of DNA damage marker-positive nuclei and the probability of LVRR across different underlying diseases. In addition, patients with higher %PAR or %γ-H2A.X had more long-term clinical events (PAR HR: 1.63 [95% CI: 1.31-2.01]; P < 0.001; γ-H2A.X HR: 1.48 [95% CI: 1.27-1.72]; P < 0.001).

Conclusions: DNA damage determines the consequences of human heart failure. Assessment of DNA damage is useful to predict treatment efficacy and prognosis of heart failure patients with various underlying etiologies.

Keywords: DNA damage; heart failure; poly(ADP-ribose); reverse remodeling; γ-H2A.X.

MeSH terms

Genetic Markers
Heart Failure*
Humans
Myocardium
Prognosis
Stroke Volume / physiology
Treatment Outcome
Ventricular Function, Left / physiology
Ventricular Remodeling / physiology

Substances

Genetic Markers