Clinical and genetic determinants of anthracycline-induced cardiac iron accumulation
Clinical and genetic determinants of anthracycline-induced cardiac iron accumulation
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DOI：
10.1016/j.ijcard.2010.09.046
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发表时间：
2012-02-09
影响因子：
3.5
通讯作者：
Ayala de la Pena, Francisco
中科院分区：
文献类型：
--
作者：
Cascales, Almudena;Sanchez-Vega, Beatriz;Ayala de la Pena, Francisco
背景资料：铁参与蒽环类药物心脏毒性得到了广泛的实验数据和铁螯合剂右雷佐生的预防效果的支持。然而，没有蒽环类药物诱导的心脏铁蓄积的临床证据是可用的，以前的铁过载或遗传因素在人类引起的心脏病的影响在很大程度上是未知的。我们的目的是检验这一假设，即蒽环类药物增加铁心脏浓度和HFE基因型调节这种铁存款.Methods：我们回顾性评估了心脏事件，心脏铁和HFE基因型在97个连续尸检的固体和血液肿瘤患者。心脏和肝脏铁浓度测定原子吸收光谱法。通过荧光共振能量转移（FRET）基因分型分析与遗传性血色素沉着症相关的HFE基因突变（C282 Y和H63 D）。结果：在累积阿霉素剂量大于200 mg/m2（490 vs 240 μ g/g; p = 0.01）的病例中，心脏铁浓度增加，与肝脏铁负荷或输血史无关。HFE突变单倍型282 C/63 D（p = 0.049）和282 Y/63 H（p = 0.027）与较高的心脏铁沉积相关。单倍型C282 Y-Y/H63 D-H与蒽环类药物相互作用，增加心脏铁负荷。在多元线性回归分析中，HFE基因型和蒽环类药物都有助于心脏铁浓度（R-2 = 0.284）。结论：我们的数据支持HFE调制的心脏铁积累的发生与蒽环类药物治疗的个体，独立于全身铁负荷。如果得到前瞻性证实，铁相关参数可能是有用的蒽环类药物心脏毒性的预测因素。(C)2010爱思唯尔爱尔兰有限公司版权所有。
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 200 mg/m(2) (490 vs 240 mu g/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. (C) 2010 Elsevier Ireland Ltd. All rights reserved.