title: Association of anthracycline-related cardiac histological lesions with NADPH oxidase functional polymorphisms.
abstract: OBJECTIVE
  Treatment with anthracyclines may cause cardiac dysfunction, but the sequence of anthracycline-induced heart lesions has been incompletely characterized. NADPH oxidase, a key mediator of oxidative cardiac damage and remodeling, modulates anthracycline clinical cardiotoxicity. Our aim was to determine which cardiac histological lesions are specifically induced by anthracycline treatment and to investigate the role of NADPH functional genetic polymorphisms in their development.
  
  
  METHODS
  Using a retrospective case-control design, we evaluated cardiac histological lesions and NADPH genotype (polymorphisms rs1883112, rs4673, and rs13058338) in 97 consecutive decedents with a cancer diagnosis (48 treated with anthracyclines).
  
  
  RESULTS
  Myocytolysis (60%), patched myocardial necrosis (19%), and myocardial fibrosis (diffuse and patched; 62% and 23%, respectively) were associated with anthracycline treatment. In patients receiving anthracyclines, NADPH oxidase polymorphism rs4673 protected against focal myocardial necrosis (odds ratio [OR], 0.11; 95% confidence interval [CI], 0.20-0.63) whereas rs1883112 was strongly associated with cardiac fibrosis (OR, 5.11; 95% CI, 1.59-16.43), which was present in all homozygotes.
  
  
  CONCLUSIONS
  Anthracyclines induce a cardiac remodeling pattern characterized by interstitial or patched fibrosis. The contribution of the functionally relevant NADPH polymorphisms rs1883112 and rs4673 to anthracycline-related heart lesions provides a plausible explanation for their modulation of cardiotoxicity. If confirmed, these findings may lead to better individualized strategies for early detection and prevention of anthracycline cardiotoxicity.
authors.affiliation: Centro Regional de Hemodonación, Murcia, Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Cascales
authors.forename: Francisco
authors.initials: F
authors.lastname: Pastor-Quirante
authors.forename: Beatriz
authors.initials: B
authors.lastname: Sánchez-Vega
authors.forename: Ginés
authors.initials: G
authors.lastname: Luengo-Gil
authors.forename: Javier
authors.initials: J
authors.lastname: Corral
authors.forename: Guzmán
authors.initials: G
authors.lastname: Ortuño-Pacheco
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
authors.forename: Francisco Ayala
authors.initials: FA
authors.lastname: de la Peña
mesh_terms: D000328:Adult; D018943:Anthracyclines / Q000008:administration & dosage* / Q000009:adverse effects; D001344:Autopsy; D016022:Case-Control Studies; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology*; D019255:NADPH Oxidases / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D018384:Oxidative Stress; D011110:Polymorphism, Genetic; D012189:Retrospective Studies
chemical_list: D018943:Anthracyclines; D019255:NADPH Oxidases; C086986:CYBA protein, human; C113333:NCF4 protein, human