NAD(P)H oxidase genetic polymorphisms and anthracyclines-induced cardiac lesions in patients with cancer.

Abstract

2596 Background: Anthracyclines (ANT)-induced cardiotoxicity is a growing problem in cancer survivors. Polymorphisms of NAD(P)H oxidase, involved in cardiac oxidative stress and remodeling, have been associated to cardiac dysfunction in ANT-treated individuals. Although no clear correlation has been found between pathologic findings and clinical events related to ANT, both cardiac fibrosis and myocytolisis are observed in these patients. So far, no reports are available that address the influence of inter-individual genetic variations on heart lesions related to ANT. Methods: Cardiac lesions were evaluated in a series of 97 consecutive autopsies from patients with solid and hematologic tumors. An unmatched comparison was performed between 48 decedents treated with ANT and 49 without ANT. H-E and Masson trichrome staining of random samples from the ventricular wall of all cases were examined. DNA was extracted from FFPE tissue and we genotyped single nucleotide polymorphisms (SNP) of NAD(P)H oxidase (212A-G of NCF4 subunit: rs1883112; C242T of p22phox subunit: rs4673; 7508T-A of RAC2 subunit: rs13058338) using Taqman probes. Association of SNPs with cardiac histological lesions, clinical events and cardiovascular risk factors was evaluated in the two groups. Results: Cardiac interstitial fibrosis (diffuse or patched) (p=0.019 and p=0.045), myocytolisis (p<0.001) and patched myocardial necrosis (0.001) were associated to ANT treatment. In the ANT group, cardiac interstitial fibrosis was strongly associated to rs1883112 (OR: 5.11; p=0.006), and was observed in all A/A homozygotes (n=7). Patched myocardial necrosis was also associated to rs4673 (OR: 4.01; p=0.036). No association was found for rs13058338. In this group, the presence of these lesions was not related to dose, previous cardiac disease nor cardiovascular risk factors, and we only observed a trend for association of patched fibrosis to heart failure (p=0.08). In the group without ANT, no relationship of cardiac lesions nor clinical events with any of the NAD(P)H SNPs was found. Conclusions: Our results support the modulation of anthracyclines-induced myocardial damage and heart fibrosis by genetic variability on NAD(H)P oxidase.