Clinical and genetic determinants of anthracycline-induced cardiac iron accumulation.
BACKGROUND
The involvement of iron in anthracycline cardiotoxicity is supported by extensive experimental data, and by the preventive efficacy of dexrazoxane, an iron chelator. However, no clinical evidence of anthracycline-induced cardiac iron accumulation is available and the influence of previous iron overload or of genetic factors in human-induced heart disease is largely unknown. Our aim was to test the hypothesis that anthracyclines increase iron heart concentration and that HFE genotype modulates this iron deposit.


METHODS
We retrospectively evaluated cardiac events, cardiac iron and HFE genotype in 97 consecutive necropsies from patients with solid and hematological neoplasms. Heart and liver iron concentration was determined by atomic absorption spectroscopy. HFE gene mutations (C282Y and H63D) linked to hereditary hemochromatosis were analyzed by Fluorescence Resonance Energy Transfer (FRET) genotyping.


RESULTS
Heart iron concentration was increased in cases treated with a cumulative doxorubicin dose greater than 200mg/m(2) (490 vs 240 μg/g; p=0.01), independently of liver iron load or transfusion history. HFE mutated haplotypes 282C/63D (p=0.049) and 282Y/63H (p=0.027) were associated to higher cardiac iron deposits. The haplotype C282Y-Y/H63D-H interacted with anthracyclines for increasing cardiac iron load. In a multivariate linear regression analysis both HFE genotypes and anthracyclines contributed to heart iron concentration (R(2)=0.284).


CONCLUSIONS
Our data support the occurrence of an HFE-modulated heart iron accumulation in individuals treated with anthracyclines, independently of systemic iron load. If prospectively confirmed, iron-related parameters might be useful as predictive factors for anthracycline cardiotoxicity.
Centro Regional de Hemodonación. Ronda de Garay, s/n. 30003, Murcia, Spain.
Almudena
A
Cascales
Beatriz
B
Sánchez-Vega
Noelia
N
Navarro
Francisco
F
Pastor-Quirante
Javier
J
Corral
Vicente
V
Vicente
Francisco Ayala
FA
de la Peña
D000328:Adult; D018943:Anthracyclines / Q000009:adverse effects*; D002102:Cadaver; D005260:Female; D005838:Genotype; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D012189:Retrospective Studies
D018943:Anthracyclines; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D007501:Iron