Myocardial DNA Damage Predicts Heart Failure Outcome in Various Underlying Diseases

BACKGROUNDReliable predictors of treatment efficacy in heart failure have been long awaited. DNA damage has beenimplicated as a cause of heart failure.OBJECTIVESThe purpose of this study was to investigate the association of DNA damage in myocardial tissue withtreatment response and prognosis of heart failure.METHODSThe authors performed immunostaining of DNA damage markers poly(ADP-ribose) (PAR) andg-H2A.X inendomyocardial biopsy specimens from 175 patients with heart failure with reduced ejection fraction (HFrEF) of variousunderlying etiologies. They calculated the percentage of nuclei positive for each DNA damage marker (%PAR and %g-H2A.X). The primary outcome was left ventricular reverse remodeling (LVRR) at 1 year, and the secondary outcome wasa composite of cardiovascular death, heart transplantation, and ventricular assist device implantation.RESULTSPatients who did not achieve LVRR after the optimization of medical therapies presented with significantlyhigher %PAR and %g-H2A.X. The ROC analysis demonstrated good performance of both %PAR and %g-H2A.X forpredicting LVRR (AUCs: 0.867 and 0.855, respectively). There was a negative correlation between the mean proportionof DNA damage marker-positive nuclei and the probability of LVRR across different underlying diseases. In addition,patients with higher %PAR or %g-H2A.X had more long-term clinical events (PAR HR: 1.63 [95% CI: 1.31-2.01];P<0.001;g-H2A.X HR: 1.48 [95% CI: 1.27-1.72];P<0.001).CONCLUSIONSDNA damage determines the consequences of human heart failure. Assessment of DNA damage isuseful to predict treatment efficacy and prognosis of heart failure patients with various underlying etiologies.(J Am Coll Cardiol HF 2024;12:648-661) (c) 2024 The Authors. Published by Elsevier on behalf of the American College ofCardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).ISSN 2213-1779https://doi.org/10.1016/j.jchf.2023.09.027From theaDepartment of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan;bDepartmentof Therapeutic Strategy for Heart Failure, Graduate School of Medicine, University of Tokyo, Tokyo, Japan;cDepartment ofFrontier Cardiovascular Science, Graduate School of Medicine, University of Tokyo, Tokyo, Japan;dCenter for Clinical Sciences,National Center for Global Health and Medicine, Tokyo, Japan;eDepartment of Cardiovascular Medicine, Nara Medical University,Kashihara, Japan;fDepartment of Bioscience and Bioinformatics, Faculty of Computer Science and Systems Engineering, KyushuInstitute of Technology, Iizuka, Japan;gAdvanced Medical Center for Heart Failure, University of Tokyo Hospital, Tokyo, Japan;hDepartment of Complex Systems Science, Graduate School of Informatics, Nagoya University, Nagoya, Japan;iNara PrefecturalSeiwa Medical Center, Nara Prefectural Hospital Organization, Nara, Japan; and thejInternational University of Health andWelfare, Tokyo, Japan. *Drs Dai and Ko contributed equally to this work.The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors'institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,visit theAuthor Center.Manuscript received June 22, 2023; revised manuscript received September 27, 2023, accepted September 28, 2023.JACC: HEART FAILUREVOL. 12, NO. 4, 20242024 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICANCOLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDERTHE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).