Remote Ischemic Conditioning for Anthracycline Cardiotoxicity The Need to Protect the Most Vulnerable

• Type of Material: Article
• Authors: Purnima Singh, University of Alabama, Birmingham; David K Crossman, University of Alabama, Birmingham; Liting Zhou, University of Alabama, Birmingham; Xuexia Wang, University of Alabama, Birmingham; Noha Sharafeldin, University of Alabama, Birmingham; Lindsey Hageman, University of Alabama, Birmingham; Javier G Blanco, State University of New York at Buffalo; Paul W Burridge, Northwestern University; Saro H Armenian, Northwestern University; Frank M Balis, City Hope Natl Med Ctr; Douglas S Hawkins, Children’s Hospital of Philadelphia, Philadelphia; Frank Keller, Emory University; Melissa M Hudson, Emory University; Joseph P Neglia, University of Minnesota, Minneapolis; Kim A Ritchey, University of Pittsburgh Medical Center; Jill P Ginsberg, Children’s Hospital of Philadelphia; Wendy Landier, University of Alabama Birmingham; Smita Bhatia, University of Alabama Birmingham
• Language: English
• Date: 2023-06-01
• Publisher: ELSEVIER
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jaccao.2022.09.009
• Title of Journal or Parent Work: JACC: CARDIOONCOLOGY
• Volume: 5
• Issue: 3
• Start Page: 392
• End Page: 401
• Keywords: ferroptosis; Science & Technology; anthracycline-related cardiomyopathy; allele-specific expression; DISTENSIBILITY; gene expression; Cardiac & Cardiovascular Systems; childhood cancer survivors; Cardiovascular System & Cardiology; iron overload; Life Sciences & Biomedicine; Oncology; haptoglobin
• Research Categories: Health Sciences, Pharmacology

Abstract

Background: Anthracycline-related cardiomyopathy is a leading cause of premature death in childhood cancer survivors. The high interindividual variability in risk suggests the need to understand the underlying pathogenesis. Objectives: The authors interrogated differentially expressed genes (DEGs) to identify genetic variants serving regulatory functions or genetic variants not easily identified when using genomewide array platforms. Using leads from DEGs, candidate copy number variants (CNVs) and single-nucleotide variants (SNVs) were genotyped. Methods: Messenger RNA sequencing was performed on total RNA from peripheral blood of 40 survivors with cardiomyopathy (cases) and 64 matched survivors without cardiomyopathy (control subjects). Conditional logistic regression analysis adjusting for sex, age at cancer diagnosis, anthracycline dose, and chest radiation was used to assess the associations between gene expression and cardiomyopathy and between CNVs and SNVs and cardiomyopathy. Results: Haptoglobin (HP) was identified as the top DEG. Participants with higher HP gene expression had 6-fold greater odds of developing cardiomyopathy (OR: 6.4; 95% CI: 1.4-28.6). The HP2-specific allele among the HP genotypes (HP1-1, HP1-2, and HP2-2) had higher transcript levels, as did the G allele among SNVs previously reported to be associated with HP gene expression (rs35283911 and rs2000999). The HP1-2 and HP2-2 genotypes combined with the G/G genotype for rs35283911 and/or rs2000999 placed the survivors at 4-fold greater risk (OR: 3.9; 95% CI: 1.0-14.5) for developing cardiomyopathy. Conclusions: These findings provide evidence of a novel association between HP2 allele and cardiomyopathy. HP binds to free hemoglobin to form an HP-hemoglobin complex, thereby preventing oxidative damage from free heme iron, thus providing biological plausibility to the mechanistic basis of the present observation.