Association of Anthracycline-Related Cardiac Histological Lesions With NADPH Oxidase Functional Polymorphisms
Association of Anthracycline-Related Cardiac Histological Lesions With NADPH Oxidase Functional Polymorphisms
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DOI：
10.1634/theoncologist.2012-0239
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发表时间：
2013-04-01
期刊：
影响因子：
5.8
通讯作者：
Ayala de la Pena, Francisco
中科院分区：
文献类型：
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作者：
Cascales, Almudena;Pastor-Quirante, Francisco;Ayala de la Pena, Francisco
目标。用蒽环类药物治疗可能会导致心功能不全，但由蒽环类药物引起的心脏损害的顺序尚不完全清楚。NADPH氧化酶是氧化性心脏损伤和重塑的关键介质，调节蒽环类药物的临床心脏毒性。我们的目的是确定哪些心脏组织学损害是由蒽环类药物治疗引起的，并调查NADPH功能基因多态性在其发生发展中的作用。采用回溯性病例对照设计，我们评估了97例确诊为癌症的患者(48例接受蒽环类药物治疗)的心脏组织学损害和NADPH基因(rs1883112、rs4673和rs13058338)的多态。与蒽环类药物治疗相关的有肌细胞溶解(60%)、补片心肌坏死(19%)和心肌纤维化(弥漫性和补片分别为62%和23%)。在接受蒽环类药物治疗的患者中，NADPH氧化酶多态rs4673对局灶性心肌坏死有保护作用(优势比[OR]，0.11；95%可信区间[CI]，0.20~0.63)，而rs1883112与心肌纤维化密切相关(OR，5.11；95%CI，1.59~16.43)，这在所有纯合子中都存在。蒽环类药物诱导以间质或补片状纤维化为特征的心脏重塑模式。功能性相关的NADPH多态基因rs1883112和rs4673在蒽环类药物相关心脏损害中的作用为它们对心脏毒性的调节提供了一个合理的解释。如果得到证实，这些发现可能会导致更好的个体化策略，以早期发现和预防蒽环类药物的心脏毒性。肿瘤学家2013；18：446-453
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.Patients and 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.Conclusion. 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. The Oncologist 2013;18:446-453